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2.7 Chiral Pool Synthesis: Starting from Terpenes
2.7 Chiral Pool Synthesis: Starting from Terpenes T Gaich, Leibniz University Hannover, Hannover, Germany J Mulzer, Universita¨t Wien, Vienna, Austria r 2012 Elsevier Ltd. All rights reserved.
2.7.1 2.7.2 2.7.2.1 2.7.2.2 2.7.2.3 2.7.3 2.7.3.1 2.7.3.1.1 2.7.3.1.2 2.7.3.1.3 2.7.3.2 2.7.3.3 2.7.3.3.1 2.7.3.3.2 2.7.3.3.3 2.7.3.4 2.7.3.5 2.7.3.6 2.7.4 2.7.4.1 2.7.4.2 References
Introduction Acyclic Monoterpenes: Citronellol, Citronellal, and Citronellene Citronellol (I) Citronellal (II) (S)-Citronellene (III) Cyclic Monoterpenes Carvone Annulations Ring contraction Ring cleavage Dihydrocarvone (VI) Pulegone (VII) Ring contraction Ring cleavage and recyclization Degradation of the pulegone isopropenyl sidechain. Formation and application of enantiomerically enriched 5-methyl-2-cyclohexanone (27.4) Perillaldehyde (IX) a-Phellandrene (X) ()-Menthone (XI) Bi- and Tricyclic Terpenes: Nepetalactone and Santonin Nepetalactone (XII) Santonin (XIII)
Glossary Chiral pool The whole entity of chiral natural products. Chiral pool synthesis Asymmetric synthesis making use of chiral natural products by incorporating part of them into the target structure. Ring annulations Formation of new rings which are attached to preexisting ones.
2.7.1
163 163 164 166 170 171 171 171 176 178 179 179 181 181 181 189 190 192 193 193 193 205
Terpenes Members of the chiral pool; constituents of natural flavors. Contain isoprenoid (five carbon) units. Monoterpenes have two and sesquiterpenes three isoprenoid units. In general, they have at least one stereogenic center. Chiral monoterpenes can be acyclic (e.g., citronellol) or cyclic (e.g., carvone).
Introduction
Terpenes, in particular monoterpenes of known absolute and relative configuration, have been used in the chiral pool synthesis of targeted and natural compounds for many years. As this topic was extensively reviewed in 1992,1 this chapter was focused on the application of selected terpenes (Chart 1) in natural product syntheses from about 1998 onward. As representative examples, our literature search unearthed the terpenes shown in Chart 1. They fall into three categories: (1) acyclic monoterpenes such as I–III; (2) monocyclic monoterpenes such as IV–IX; and (3) biand tricyclic terpenes such as X, XI. Categories 1 and 2 have been most widely used, for XI and XII only a few cases have been reported. The advantages of all these terpenes lie in their low cost and the functional versatility. Most monoterpenes are commercially available in both forms of enantiomers, the optical purity being approximately 85–95% enantiomeric excess (ee).
2.7.2
Acyclic Monoterpenes: Citronellol, Citronellal, and Citronellene
Citronellol and citronellal are natural products. (R)-(þ)-Citronellol, which is found in citronella oils, is the more common enantiomer. (S)-()-Citronellol (I) is found in the oils of rose (18–55%) and Pelargonium geraniums. It is used in perfumes and insect repellents, as a mite attractant, and for the production of rose oxide. The compound is nontoxic, but it may cause allergies. Citronellal (II) gives citronella oil its characteristic lemon scent. It is distilled from the plants Cymbopogon, lemon-scented gum, and lemon-scented teatree. Citronellal has insect-repellent properties, especially against mosquitoes, and also strong antifungal
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164
Chiral Pool Synthesis: Starting from Terpenes
Me
Me
Me
Me
Me
OH
III (S)-Citronellene
O
Me
Me
Me
Me
Me
Me
O II (R)-(+)-Citronellal
I (S)-(−)-Citronellol
Me
Me
Me
O
O
O
O Me IV (R)-(−)-Carvone
V (S)-(+)-Carvone
VI (−)-Dihydro-carvone
Me
CHO
VII (S)-(+)-Pulegone
Me Me
H
O O
IX (−)-Perillaldehyde Chart 1
Me
Me
X -Phellandrene
Me
Me
XI (−)-Menthone
VIII (R)-(−)-Pulegone
O
O Me
Me
Me
Me
Me
Me
Me
H O
H
Me
XII Nepetalactone
O XIII Santonin
Terpenes used for chiral pool synthesis.
qualities. (S)-Citronellene (III) is manufactured from (a)-pinene via catalytic hydrogenation followed by pyrolysis. III can be converted into I via hydroalumination/oxidation. From I, aldehyde II is readily available by the usual oxidation protocols.
2.7.2.1
Citronellol (I)
Apart from trivial chain extensions and endgroup modifications, the more spectacular applications of I in natural product synthesis imply cyclizations to form complex polycyclic structures. The intramolecular Diels–Alder (IMDA) reaction along with its transannular modification (transannular Diels–Alder – TADA) (see Chapter 2.17) has proven its value in the three examples depicted in Schemes 1–3. Thus, the synthesis of the antibiotic alkaloid (þ)-apiosporamide (Scheme 1, 1.10)2 features the combination of two advanced intermediates from the chiral carbon pool: amino acid 1.5 which is derived from quinic acid, and trans-decalin 1.8 which stems from citronellol (I). In the first sequence, cyclohexenone 1.1 was prepared from quinic acid as described previously3 (see Chapter 2.11) and deoxygenated to give 1.2. Addition of deprotonated b-lactam 1.3 led to adduct 1.4 (dr ¼ 1.6:1) which was separated from the mixture and converted into epoxide 1.5 stereoselectively. The lactam was opened with allyl alcohol to furnish the required amino acid derivative 1.6. In a parallel sequence, citronellol I was elaborated into alkyne 1.7 which was used for a Negishi-type chain elongation to provide the Diels–Alder precursor 1.8. IMDA reaction was accomplished with high endo-selectivity to provide the trans-decalin ketone which was carboxylated to give acid 1.9. Coupling with 1.6 was followed by removal of the allyl-protecting group and carbonyl activation. Dieckmann ring closure led to keto lactam 1.10 which was deprotected and aromatized to furnish 1.11. In a related example, (S)-()-citronellol was used in the total synthesis of the marine alkaloid (þ)-neosymbioimine (2.12, Scheme 2).4 The crucial octalene structure 2.8 was accessed by an endo-IMDA (cf. see Chapter 2.17) of triene 2.7, which was prepared from I by a strategy related to the one described in Scheme 1. Thus, I was converted into aldehyde 2.1 which was a-hydroxylated and olefinated to give enoate 2.2. Two additional olefination steps led to triene 2.7 which underwent a thermal IMDA reaction to give decalin 2.8 with 495% stereoselectivity. Chain elongation to the nitrile and stereoselective methylation provided 2.9. Routine functional group manipulation delivered ketal 2.10 which was cyclized to imine 2.11. Demethylation of the aryl OMe ethers was followed by di-sulfonation, and selective mono-hydrolysis of one sulfonate ester furnished 2.12. It is a short step from the IMDA to the TADA reaction. In fact, this is the key transformation in the synthesis of the marine diterpene (þ)-chatancin (3.8, Scheme 3).5
Chiral Pool Synthesis: Starting from Terpenes
165
O
O Quinic acid
O
5
NOPMB (1.3) TBSO KHMDS, THF, 97%, (dr 1.6:1)
(i) H2, Pd(OH)2 /C, 97%; (ii) DBU,TBSCl, TBSO heat, 72%;
O OH
steps O
NOPMB
O 1.4
1.2
1.1 H (i) TBAF, THF (98%) (ii) mCPBA, CH2Cl2, NaHCO3(54%)
TBSO
H O
TBSO
allyl alcohol, nBuLi
H
O H CO2Allyl
O TBSO
(iii) TBSCl, imidazole, CH2Cl2,100%
TBSO
80% NOPMB
NHOPMB 1.6
1.5
(i) Catalyst TEMPO, PhI(OAc)2, CH2Cl2, 70%; (ii) Ohira-Bestmann reagent, K2CO3, MeOH, r.t., 82%; (iii) Catalyst OsO4, K3Fe(CN)6, K2CO3, tBuOH/H2O, 94%;
(i) [Cp2Zr(H)Cl], CH2Cl2, r.t.; then I2, 77%; (ii) [Pd(PPh3)4] (5 mol%), (E)-BrZnCH=CHCH3, THF/Et2O/pentane (4:4:1), 74%;
O
OH 1.7
(−)-Citronellol (I)
(i) EtAlCl2, toluene, −78 °C to r.t., 72% (>97:3 dr); (ii) LiHMDS, THF, then HMPA at −78 °C; then MeOC(O)CN, 62%;
O
O
H
(iii) KOH, aq. MeOH, 0 °C, 81%; 1.8
TBSO
(i) BOP, Et3N, MeCN, 1.6, 99%; (ii) [Pd(PPh3)4], pyrrolidine, CH2Cl2, 85%;
H H
HO2C
H
(iii) Dess−Martin periodinane, py, CH2Cl2, 90%;
(iv) NaIO4, aq. THF (1:1); (v) H3CC(O)CH2P(O)(OMe)2, K2CO3, 91% (13:1 E/Z)
(iii) BOP, CH2Cl2, DBU, 20 °C, 56%;
1.9
H O
H
O
O
TBSO
H
H
(i) SmI2, THF, 98%; (ii) BrCCl3, TMG, 65%; (iii) HF·pyr, THF, 75%.
HO
H N O OPMB 1.10
O
H
OH
O
H
H H
OH N H
O
1.11 (+)-Apiosporamide
Scheme 1 Synthesis of decalin substructure 1.9 via IMDA reaction starting from (S)-()-citronellol.
The synthesis started with the conversion of citronellol I into bromide 3.1 which was added to the anion of sulfone 3.2. Desulfonation was followed by oxidation to aldehyde 3.3 which elaborated into a keto sulfone at one end and into an alkynoic ester at the other. Lindlar hydrogenation and oxidation furnished a strong Michael acceptor, which was used for macrocyclization to form the TADA precursor 3.6. Heating in the presence of water furnished the Diels–Alder substrate 3.7 which cyclized in situ to chatancin. An organocatalytic intramolecular Michael addition was used for the synthesis of the polycyclic neurotrophic iridoid ()-litteralisone (Scheme 4).6 Citronellol I was converted into ester aldehyde 4.1 which was subjected to an organocatalytic
166
Chiral Pool Synthesis: Starting from Terpenes
(i) TBSCI, imidazole DMF, 95%; (ii) O3, CH2Cl2/MeOH (1:1), then Me2S, 93%
(i) nitrosobenzene, D-proline, DMSO,
O
(ii) triethylphosphono acetate, DBU, LiCl, (iii) MeOH, NH4Cl, Cu(OAc)2, 24 h;
(iv)TBSCl, imidazole, DMAP, CH2Cl2, 88%
OH
OTBS
(−)-S-Citronellol (I)
2.1
CO2Et
CO2Et
(i) CSA, MeOH, 87%; (ii) Dess−Martin periodinane, CH2Cl2, 96%
OTBS
CO2Et
toluene, 100 °C, 30 h, 88%;
OTBS
OTBS CHO
CHO
O
OTBS 2.2
2.3
Ph3P
2.5
(2.4)
OMe (O)P(EtO)2
(2.6)
OMe
CO2Et Ar
TBSO
CHCl3, 60 °C, 2 h 86%;
OTBS CO2Et H Ar
KOtBu, THF, −78 to 0 °C
H 2.8
2.7
NC TBSO H
(i) DIBAL-H, CH2Cl2, 24 h, 88%; (ii) MsCl, Et3N, CH2Cl2, 94%; (iii) NaCN, DMSO, 98%; (iv) LDA, THF, MeI, 87%;
Ar
(i) TBAF, THF, 99%; (ii) Dess−Martin periodinane, CH2Cl2, 96%; (iii) (CH2OH)2, CSA, C6H6, 94%
NC O
O Ar H
H
H
2.9
2.10 OSO3−
N (i) LiAlH4, Et2O, (ii) 3 M HCl, THF, 90%;
H
Ar
(i) BBr3, CH2Cl2, 84%; (ii) SO3, Py, pyridine, (iii) H2O/MeOH (1:2), 79% brsm.
H
N
OH
H 2.11
H
H 2.12 (+)-Neosymbioimine
Scheme 2 (S)-()-Citronellol as starting material for an IMDA cyclization to provide (þ)-neosymbioimine.
a-hydroxylation to furnish hydroxy enoate 4.2 after Keck–Masamune olefination. 4.2 was elaborated into di-aldehyde 4.3 which was the substrate of the proline-catalyzed Michael addition to generate glycoside 4.4 after acetylation. Vilsmeyer formylation and Pinnick oxidation led to the formation of lactone 4.5 which was used for glycosidation with 1-O-TMS-b-D-glucose tetraacetate (4.6). Anomerically pure diene 4.7 was obtained and was subjected to photocycloaddition, which gave the cyclobutane ring. Hydrogenolysis furnished ()-litteralisone 4.8.
2.7.2.2
Citronellal (II)
Similar to citronellol, the chiral pool applications of citronellal are characterized by the utilization of the differentiable end groups in various ring-forming operations.
Chiral Pool Synthesis: Starting from Terpenes (i) PivCl, pyr. (ii) SeO2, t BuOOH (iii) MsCl, NEt3, LiBr
167
Br OPiv
OH
36%
3.1
(S)-Citronellol (I) (i) nBuLi, THF (ii) + 3.1 (iii) Na/Hg, NaH2PO4, (iv) HCl, iPrOH (v) TPAP, NMO
PhO2S
OMOM
OPiv O
45%
(i) LDA, MeSOPh, (ii) Dess−Martin Ox. (iii) HCCCOOMe, LDA 70%
3.3
3.2
O
(i) H2, Lindlar (ii) Dess− Martin Ox. (iii) I2, Et2O
HO
SOPh 3.4
O
O
O
70%
3.5
64% CO2Me
OH
DMSO/H2O 1:1, 110 °C
O
89%
3.6
O
SOPh
CO2Me
CO2Me
(i) Cs2CO3, acetone (ii) PhMe 110 °C
OH O
CO2Me
CO2Me 3.7
3.8 (+)-Chatancin
Scheme 3 TADA-approach to (þ)-chatancin.
So, it is no big surprise that II has been used for IMDA reactions, for instance, in the synthesis of the fungal metabolite hirsutellone B (Scheme 5).7 Thus, (R)-citronellal II was converted into epoxy vinyl iodide 5.2 which was used in a Stille cross coupling with stannane 5.3 to give polyene 5.4. Under the influence of Et2AlCl, the stannane undergoes a Sakurai-type cyclization with the epoxide to generate cyclohexane derivative 5.5 to which two additional rings are annulated in a tandem IMDA reaction. The tricyclic intermediate 5.6 was thus obtained stereoselectively. The next subgoal was the conversion of 5.6 into sulfone 5.10. Mukaiyama etherification and reduction of the ester led to aldehyde 5.7 which was used for the extension of the sidechain to deliver ketone 5.8 after functionalization of the aryl methyl group. Introduction of a thioaetate- and a primary iodide led to intermediate 5.9 which was cyclized to the thioether under basic conditions. Oxidation furnished sulfone 5.10. Ramberg– Ba¨cklund ring contraction led to (Z)-cycloolefin which was carboxylated to the b-keto ester. Sharpless asymmetric dihydroxylation (AD) of the olefin and regioselective Barton–McCombie deoxygenation of the diol afforded alcohol 5.11 stereoselectively. Oxidation of the alcohol to the ketone was followed by heating with NH3 to obtain 5.12 via an amidation – C-17 – epimerization cyclization cascade. A similarly sophisticated polycyclization, this time under the catalysis of Au(I), has been employed in the synthesis of ()-englerin A (Scheme 6).8 The sequence started with the differentiation of the end groups in citronellal II to procure the alkynoic enal 6.1. Asymmetric aldol addition (see Chapter 2.13) led to hydroxyl ketone 6.2 which was cyclized with AuCl to give the polycyclic intermediate 6.5 stereoselectively, presumably via intermediates 6.3 and 6.4. The construction of the strained trans-fused ring of englerin was achieved via epoxidation and shift of the double bond to give allylic alcohol 6.6. Inversion of the OH-function and hydrogenation furnished diol 6.7, whose more accessible OH-group was protected as the ketone. The remaining alcohol was esterified and then the ketone was reduced to give 6.8. The remaining task was the introduction of a second ester group, which was achieved via SN2-reaction of an intermediate sulfone with the anion of 2-hydroxyacetic acid. Citronellal has also been used for the synthesis of alkaloids. The required nitrogen was introduced via the end group functionality. Thus, in the synthesis of the lycopodium alkaloid ()-cernuine (Scheme 7),9 citronellal II was used for the final construction of no less than four annulated six-membered rings. Thus, II was first converted into the monoprotected aldehyde 7.1 which was used for an organocatalytic electrophilic a-amination with di-carbobenzoxy-diimide and prolinol catalyst 7.2 to
168
Chiral Pool Synthesis: Starting from Terpenes
(i) Mesityl-Cl, DMAP, pyridine, CH2Cl2; (ii) O3, MeOH, CH2Cl2,
O
OH 95%
CO2Me
56%
O
(S)-(−)-Citronellol (I)
HO
(i) PhNO, D-proline (40 mol%), DMSO; (ii) (EtO)2P(O)CH2CO2Me, LiCl, DBU; NH4Cl, MeOH.
O
4.1
(i) TBDPSCl, imidazole, DMF. (ii) DIBAL,Et2O, (iii) DMP, CH2Cl2
OMes
(i) L-proline (30 mol%), DMSO, (ii) Ac2O, DMAP, pyridine
TBDPSO CHO O
92%
83%
H
4.2
4.3 OBn
(i) POCl3, DMF, (ii) NaClO2, NaH2PO4, t BuOH. (iii) HF‚ pyridine, THF. (iv) DCC, CH2Cl2
TBDPSO H O H
OAc 4.4
56%
O O TMSO
H
O OAc
4.5
4.6 TMSOTf (0.4 equivalent), CH3CN 74%
OH O
(i) 350 nm, (ii) H2 Pd/C 84%.
O
84%
H
O O O
O
O
OBn OBn OBn
OBn OBn OBn
O
OBn
O
H
O
H
O H
O
4.7
O OH
O H
O
O
O
OH OH
4.8 (−)-Littoralisone
Scheme 4 Organocatalytic key steps in the synthesis of ()-litteralisone.
urethane 7.3, after reduction. Deprotection led to the cyclic aminal 7.5 which underwent a Sakurai-type allylation to give 7.6. Hydrolysis of the urethane and amide formation with acryloylchloride paved the way for ring-closing metathesis (RCM), which led to the bicyclic intermediate 7.8 after some functional group modifications. The aldehyde function was used for a 2-aza-Cope rearrangement with optically active amine 7.9 to generate amine 7.10 with 94% de under auxiliary control. Acid-catalyzed formation of amidine 7.11 was followed by reduction to the aminal, amidation with acryloylchloride, and RCM to close the fourth ring. Hydrogenation completed the synthesis of 7.12. In the total synthesis of the anti-HIV drug biyouyanagin A (Scheme 8),10 the aldehyde end group of II is used for ring closure whereas the trisubstituted olefin part is transferred into the target molecule unchanged. The strategy involves a biomimetic [2 þ 2]photocycloaddition of the components 8.3 (ent-zingberene, from citronellal) and 8.6 (hyperolactone C, from malic acid in seven steps (see Chapter 2.10). The synthesis of 8.3 commenced with a Robinson annulation of methyl vinyl ketone under the asymmetric catalysis of prolinol 8.1. Cyclohexenone 8.2 was formed with 86% de and converted into cyclohexadiene 8.3. To prepare compound 8.6, L-malic acid was converted into lactone 8.4 which was elaborated into alkyne 8.5. Palladium-catalyzed addition of a benzoyl group followed by spirolactonization furnished 8.6 after formation of the vinyl sidechain. The envisaged photoaddition indeed furnished 8.7 as postulated.
Chiral Pool Synthesis: Starting from Terpenes (i) Ph3PCH2I2, KHMDS, THF, (ii) O3, CH2Cl2; then Me2S, 80% for 2 steps; (iii) Ph3P=CHCHO, CHCl3,
Bu3Sn
O CO2Me
CuTC, NMP, 25 °C, 6 h, 70%
(iv) Catalyst 5.1, H2O2 CH2Cl2; (v) Ph3P = CHCO2Me, 58%;
CHO
I
Ph Ph
(R)-(+)-Citronellal (II)
(5.1) N H
5.2
OTMS
CO2Me
OAlEt 2
H Et2AlCl, CH2Cl2, 50%;
O
CO2Me
TMS
H 5.5
5.4
OH H
H
TMS 5.3
(i) pTol4BiF, Cy2NMe, Cu(OAc)2, PhMe, (ii) LiAlH4, Et2O,
CO2Me
H
(iii) TEMPO, PhI(OAc)2 CH2Cl2, 78% for 3 steps
HH
O
H
CHO
HH
5.6
5.7 SAc HO OH
(i) BrMg(CH2)3OTBS, THF, (ii) DMP, CH2Cl2, 91% for 2 steps;
O
H
H (iii) CAN, MeCN/H2O (20:1), (iv) NaBH(OAc)3, PhH, 81% for 2 steps;
O
HH
(i) NaOMe, MeOH/THF (1:1, 1.0 m M); (ii) H2O2, 35%, Na2WO4, THF/MeOH (1:1), 79% for 2 steps;
O S O
O H
O
HH
H
O
O H
17
CO2Me
5.9 (i) CF2Br2, KOH/Al2O3, CH2Cl2 /tBuOH (1:1), (ii) LHMDS, NCCO2Me, THF, 61% for 2 steps; (iii) AD-mix-⇓, MeSO2NH2, tBuOH/H2O (1:1), 90%; (iv) S=CCl2, 4-DMAP, CH2Cl2, (v) AIBN, nBu3SnH, PhMe, 65% for two steps
5.10 OH (i) DMP, CH2Cl2, 92%; (ii) NH3, MeOH/H2O (4:1), 50%
H
O
NH
O H
17
O HH
HH 5.11 Scheme 5 IMDA reaction in the synthesis of hirsutellone B.
O H
HH
H
O
H
5.8
OH
I
ZnI2, AcSH, CH2Cl2, 68%;
5.12 (hirsutellone B)
169
170
Chiral Pool Synthesis: Starting from Terpenes (i) P(OPh)3, Br2, Et3N (ii) tBuOK, 18-crown-6, petroleum ether (iii) SeO2, TBHP, salicylic acid, CH2Cl2 (iv) IBX, EtOAc
O H (S)-Citronellal
H
O (i) 3-methyl-2-butanone, (−)-Ipc2BCl, Et3N (ii) MeOH, H2O, pH 7
Me
95%
39% 6.1
(II) H OH O Me Me
AuCl 10 mol%, CH2Cl2, r.t., 20 min
Me
LAu
OH
Me
87%
(i) TPAP, NMO, CH2Cl2, MeOH (ii) NaBH4, MeOH OH (iii) Raney-Ni, H2 (90 atm), 75 °C EtOH
O
H Me
Me
6.5
O
iPr − AuCl
OH H Me 6.4
6.3
HO
H
Me
48%
OH (i) mCPBA, CH2Cl2 (ii) CSA, CH2Cl2 H
LAu
Me
6.2
O
iPr O Me
OH HO
O
H Me
65%
H Me
6.6
6.7 Ph
(i) DMP, NaHCO3, CH2Cl2 (ii) cinnamic acid, 2,4,6,trichlorobenzoyl chloride, DMAP, Et3N (iii) NaBH4, MeOH 74%
O OH Ph
O H Me
O
6.8
H Me
(i) LiHMDS, (imid)2SO2, THF (ii) HOCH2CO2Cs, 18-crown-6, PhMe, reflux, 48 h
O H
O H
66%
O
O O HO
6.9 (−)-Englerin A
Scheme 6 Gold(I)-catalyzed cyclization in the synthesis of ()-englerin.
2.7.2.3
(S)-Citronellene (III)
Citronellene is commercially available in acceptable optical purity. Alternatively, it may be prepared from citronellol via E2-elimination of citronellyl bromide (Scheme 9). The synthetic utility arises from the differentiation of the olefinic end groups. The more electron-rich trisubstituted double bond reacts selectively with meta-chloroperoxybenzoic acid (mCPBA) which allows the formation of alcohol 9.1. This is one of the key fragments in the stereocontrolled synthesis of the microtubule-stabilizing antitumor agent (MSAA) epothilone B (Scheme 8).11 Alcohol 9.1 was converted into bromide 9.2 and then into the Grignard derivative 9.3, which was added to ketone 9.4, readily available from D-mannitol. Chelate Cram-controlled addition furnished the tertiary alcohol 9.5 with high diastereoselectivity (see Chapter 2.12). Chain elongation and deprotection led to triol 9.6 whose three OH-functions were differentiated to give tesyl mesylate 9.7. Epoxide formation afforded 9.8 stereoselectively which was oxidized to aldehyde 9.9 and subjected to diastereoselective aldol addition (cf. see Chapter 2.13) with enolate 9.10. Adduct 9.11 was formed exclusively and elaborated into macrolide 9.12. Deprotection gave epothilone B (9.13). In a synthesis of the ansa-macrocyclic antibiotic kendomycin (Scheme 10),12 citronellene (II) was used to incorporate the stereogenic centers at C-18 and C-12 independently. Thus, II was converted into aldehyde 10.1 which was olefinated via the acetylide to give (E)-vinyl iodide 10.3. Negishi cross coupling with aryl bromide 10.4 furnished styrene 10.5 which was oxidized to benzofuran 10.5. Conversion of the end group gave carboxylic acid 10.6 which was esterified with alcohol 10.7, readily obtained from aldehyde 10.1 via Hiyama–Kishi addition of isopropenyl bromide. Ester 10.8 was used for a Claisen–Ireland rearrangement (see Chapter 2.21) to furnish olefin 10.8 after reduction of the carboxylic acid to the primary alcohol. Further reduction to the methyl group was followed by oxidation of the end group to aldehyde 10.10. Evans–Metternich aldolization with oxazolidinone 10.11 and reduction of the ketone (see Chapter 2.3) led to the stereoselective formation of lactone 10.12, which was opened to the methyl ester, saponified to the carboxylic acid, and cyclized to give macrolactone 10.13. Ring contraction via photo-Fries
Chiral Pool Synthesis: Starting from Terpenes (i) ethylene glycol, p-TsOH, PhH, reflux; (ii) RuCl3, NaIO4, DCM, H2O, r.t., 87% (2 steps);
OHC
O O
O (R)-(+)-Citronellal (II) O
HN O
N
(i) H2, Pd/C, THF, r.t.; (ii) H2, Raney-Ni, MeOH, 60 °C
O
O
(i) CbzN=NCbz, 6.2 (10 mol%), DCM (ii) NaBH4, MeOH; (iii) K2CO3, toluene, 94%;
7.1
Cbz
N H O
Ph Ph 7.2 OTMS
p-TsOH, MeOH, reflux
HN
O
171
O
O 7.4
7.3 OMe TiCl4, DCM, 7.5, 0 °C N
O
N
TMS
(i) aqueous NaOH, MeOH reflux; (ii) acryloylchloride, NEt3, DCM,
O
O
O
56% (6 steps);
7.6
7.5 (i) Grubbs I cat, DCM, r.t.; (ii) H2, Pd/C, EtOH, r.t., 99% (2 steps); (iii) IBX, DMSO, r.t.; (iv) Ph3CH2(OMe)Cl, KHMDS, THF, (v) 3 M HCl, THF, r.t., 62% (3 steps);
N O OH
(i) CSA, DCM, 6.9, r.t. (ii) NH2OH-AcOH, 92%, 94% de
N O
O 7.8
NH2 O
(7.9)
7.7
N H2N
TiCl4, xylene, reflux, 80%; O
7.10
N N
7.11
(i) NaBH4, AcOH, MeOH, (ii) acryloylchloride, NEt3, DCM, 62% (2 steps); (iii) Grubbs II, DCM, r.t., 78% (iv) H2, Pd/C, EtOH, r.t., 96%;
N
H N
O
7.12 Cernuine
Scheme 7 Alkaloid synthesis from citronellal.
rearrangement led to ketone 10.14 which was reduced to the alcohol and then cyclized to tetrahydropyran 10.15. Oxidation of the benzenoid system to the p-chinomethide furnished kendomycin 10.16.
2.7.3
Cyclic Monoterpenes
2.7.3.1
Carvone
(S)-(þ)-Carvone smells like caraway because it is the principal constituent (50–70%) of the oil from caraway seeds (Carum carvi),13 which is produced on a scale of approximately 10 tons per year. (R)-()-Carvone smells like spearmint and it is present at levels greater than 51% in spearmint oil, which is produced on a scale of approximately 1500 tons annually.14 Both enantiomers have been used extensively in asymmetric natural product synthesis. The strategies involved fall into three groups: (1) annulations of rings of various sizes to the original cyclohexane rings, (2) ring contraction of the cyclohexane to cyclopentane, and (3) ring fission of the cyclohexane and formation of new rings.
2.7.3.1.1
Annulations
A straightforward annulations method is Diels–Alder addition of an electron-rich diene. Thus, in the synthesis of the cell adhesion inhibitor (þ)-peribysin E (Scheme 11),15 (R)-carvone IV was treated with diene 11.1 under Lewis acid catalysis to furnish
172
Chiral Pool Synthesis: Starting from Terpenes
(i) MVK (1.5 equivalent), 8.1 (5 mol%), ethyl 3,4− dihydroxybenzoate (20 mol%), CHO (R)-(+)-Citronellal II
(ii) KOH (0.1 N aq, 1.0 equivalent), nBu4NOH (40% aq, catalyst), Et2O/THF/H2O (3:1:3), 68% yield, 86% de
H
8.2
(i) KHMDS (1.5 equivalent), THF, (ii) Comins reagent (1.5 equivalent), THF (iii) MeMgI (3.0 M in Et2O, 1.5 equivalent), CuI (2 mol%), THF
O
80% (2 steps)
H
8.3 (ent-zingberene)
Ph Ph
(8.1) N H OBn HO
O
O
OMe OBn
(i) DMP (2.0 equivalent), CH2Cl2, 92%; (ii) acetylene, nBuLi, HO THF, 79%, 3:1 dr O
O
Ph O 8.5
8.4
(i) Pd(PPh3)4] (5 mol%), PhI, CO (200 psi), CO2 (200 psi), Et3N, 77%; (ii) BBr3 (1.5 equivalent), CH2Cl2
(from malic acid)
DCM, 2′-acetonaphthone (1 equivalent), h, 46%
(iii) o-NO2PhSeCN (1.2 equivalent), P(nBu)3 (1.2 equivalent), THF, (iv) H2O2 (30% aq, excess), THF, 73% (3 steps)
H
H H
H Ph
O 8.6 (Hyperolactone C)
O
O
O
8.3 + 8.6
O
O
O
8.7
Biyouyanagin A Scheme 8 Citronellal forms the left-hand component in a biomimetic [2 þ 2]-photocycloaddition to generate biyouyanagin A.
Diels–Alder adduct 11.2 stereoselectively under the influence of the bulky isopropenyl sidechain. The enone double bond was introduced by a Saegusa oxidation. Protection of the more reactive ketone, as the thioketal and Wittig reaction of the unprotected one, led to alcohol 11.3 after reduction of the intermediate aldehyde. Further reduction to a methyl group was followed by deprotection of the thioketal and oxidation of the isopropenyl appendage to methyl ketone 11.4. Baeyer–Villiger oxidation to the acetate and a-iodination furnished vinyl iodide 11.5 which was used in a Suzuki coupling with vinyl boronic ester 11.6 to give diene 11.7. Scheffer–Weitz epoxidation and ketone reduction proceeded with high diastereoselectivity from the less hindered a-face to give hydroxyl epoxide 11.8. Lewis acid-induced semipinacol ring contraction generated aldehyde 11.9 which was immediately trapped as the methyl acetal to give (þ)-peribysin E (11.10). A similar Diels–Alder strategy16 was used for the generation of a cis-decalin system in the synthesis of the eudesmane sesquiterpene lairdinol A (Scheme 12).17 Diene 12.1 was added to (R)-carvone (IV) to give di-one 12.2. Regioselective Rubottom a-hydroxylation gave 12.3 which was converted into enone 12.4 via four steps. Base-catalyzed isomerization to the trans-decalin was possible only after reduction of the adjacent ketone. Epoxidation with H2O2/NaOMe in methanol led to 12.5 as the main product. The OH-function was removed by a Barton–McCombie deoxygenation to give epoxy ketone 12.6, whose stereoselective hydroxylation was achieved with phenyl iodosodiacetate (PIDA). Wharton rearrangement furnished allylic alcohol 12.7 which was oxidized to ketone 12.8. Hydrogenation with Stryker’s reagent18 and ketone reduction led to lairdinol A (12.9). A sophisticated Prins-pinacol annulation was used in the synthesis of the marine diterpene briarellin F (Scheme 13).19 The synthesis started with (S)-carvone (V) which was converted into a mixture of diol diastereomers, from which 13.1 was isolated. Further manipulation led to vinyl iodide 13.3 which was lithiated and added to aldehyde 13.4. Diol 13.5 was formed as a mixture of diastereomers which was subjected to a Prins-pinacol rearrangement with aldehyde 13.6, whose mechanism is described in Scheme 14. Thus, it may be assumed that ketal 14.1 is formed first which is opened to a carboxonium species 14.2. A [3.3]-sigmatropic rearrangement generates enol 14.3 under stereocontrolled CC-bond formation trans to the neighboring sidechain. A Mukaiyama-type aldol addition leads to the ring closure under formation of aldehyde 13.7. Photolytic decarbonylation and epoxidation furnished 13.8, which was opened to form triol 13.9. Ring closure to 13.10 and introduction of a tertiary alcohol via epoxidation/ring opening was followed by a Nozaki–Kishi macrocyclization of vinyl iodo aldehyde 13.12 to generate briarellin E (13.13) which was oxidized to briarellin F (13.14).
Chiral Pool Synthesis: Starting from Terpenes (i) PPh3, CBr4, CH2Cl2 (ii) KOtBu, THF
173
(i) mCPBA, CH2Cl2, NaHCO3 (ii) LAH, Et2O
OH 68%
44%
(S)-(−)-Citronlellol I, ee c. 80%
(S)-(+)-Citronellene III (i) TsCl, pyridine (ii) LiBr, acetone
HO
Mg, THF
Br
80%
9.1
OPMB Me
OPMB HO O
78%
O
Me
Me
O
73% 9.5 dr > 96:4
9.4 S
(i) DDQ, CH2Cl2, H2O (ii) DMP, CH2Cl2 (iii) Horner−olefination (iv) 2 N HCl, EtOH
Me
O O
9.3
9.2
(i) MgBr2-OEt2, CH2Cl2 (ii) 9.3, THF
Me
BrMg
Me
HO
Me
(i) 3 equivalent TESCl, NEt3 Me (ii) MsCl, NEt3
Me
Me
N
S
Me
Me
Me
N TESO
84%
OH OH 9.6
HO OMs 9.7
O K2CO3, MeOH
Me 15
S
95%
Me
Me
(i) OsO4, NMO (ii) NaIO4, H2O, MeOH 62%
Me
N OTES 9.8
Me
O S Me
TBSO OLi (9.10)
Me 15
N
OTES
O Me
OH
N
89% dr >95:5
O
TBSO 8.11
9.9 O 6 steps
S
85%
N
OTroc O
(i) Zn/MeOH (ii) HF/pyridine
Me O TBSO
Me
TBSO
7
Me
Me
S
O
9.12
O
O S OH
N 62%
O
Me O
OH O 9.13 Epothilone B
Scheme 9 Citronellene as a key fragment in the synthesis of epothilone B.
Another possibility is the successive addition of carbon appendages which are used for ring formation later on. An example of this strategy is provided by the synthesis of the MSAA drug sarcodictyn A (15.9, Scheme 15).20 The sequence is entirely substrate controlled and starts with the Scheffer–Weitz epoxidation of (S)-carvone. The first carbon appendage is then added via aldol addition of formaldehyde to provide 15.1. Reductive epoxide opening led to allylic alcohol 15.2 which was used for a Johnson–Claisen rearrangement to furnish aldehyde 15.3 after reduction of the ester. Further manipulation of the two sidechains was achieved via intermediates 15.4 and 15.5 to generate functionality suitable for macrocyclization. This step was accomplished by deprotonating the alkyne moiety in 15.5 and adding it to the aldehyde. Ketone 15.6 was obtained after reoxidation of the intermediate alcohol. Hydrogenation to the double bond led to the formation of the dihydrofuran ring in 15.7 and the synthesis was concluded with the esterification of the secondary alcohol and the elaboration of the carbomethoxy sidechain.
174
Chiral Pool Synthesis: Starting from Terpenes
(i) mCPBA, DCM (ii) H5IO6 (iii) Li(OEt)3H
18
(i) TMSCHN2, nBuLi, THF, 83%; (ii) [Cp2ZrHCl], benzene, (iii) I2, 76%;
O
I
OTBDPS 10.2
OTBDPS 10.1
Citronellene (III) [Pd(PPh3)4], tBuLi, ZnCl2, Et2O/THF, 67%
TBDPSO
Br
(i) DMDO, acetone, 99% (dr 1.1:1); (ii) Pd(OAc)2, PBu3, tBuOH, 81% (2 steps);
OMOM
OMOM MOMO
TBDPSO O
MOMO
OMe
MOMO OMe 10.4
10.3
OMe 10.5 O
HO2C
EDCI, DMAP, 9.6, CH2Cl2, 85%;
(i) TfOH, toluene/EtOH (4:1), MS 4 A; (ii) MOMCl, NaH, DMF, 90% (2 steps) (iii) TBAF, THF, r.t., 89%;
O
(iv) IBX, DMSO, r.t., 97%; (v) NaClO2/NaH2PO4
O
OH
O
12
MOMO OMe
OTBDPS
10.6
(10.7)
MOMO
TBDPSO
10.8 OMe
OH (i) LHMDS, HMPA, TBSCl,
(i) MsCl, Et3N, CH2Cl2; (ii) LiAlH4, Et2O, 94% (2 steps); O
TBDPSO
(ii) LiAlH4, Et2O, 84% (dr 4:1, 2 steps);
O
MOMO
MOMO 10.9
OMe
(i) Sn(OTf)2, CH2Cl2, Et3N, 87% (dr 6:1); (ii) Me4NBH(OAc)3, CH3CN/AcOH (2:1), 72% (dr 20:1); (iii) LiOH, H2O2, THF/H2O (3:1), 96%
10.10
O HO
O
N
O O
(iv) EDCI, DMAP, DMAP·HCl, CHCl3, 55%;
MOMO
O
OMe
(i) 3 M HCl, dioxane; (ii) (CH3)2C(OMe)2, CSA, 85% (2 steps); (iii) LiOH, THF/MeOH/H2O (2:1:1), 84%;
O
O
O
(iii) TBAF, THF, r.t., 93%; (iv) IBX, DMSO, r.t., 93%.
OMe Bn
10.12
(10.11)
h (254 nm), cyclohexane, 50 min, 75%
OH
O
O
O
O
HO
HO O
HO OMe
10.13 Scheme 10 Citronellene in the synthesis of kendomycin.
10.14
OMe
(i) NaBH4, MeOH, r.t., then 0.5 m HCl; (ii) TsOH, toluene, 60 °C, 71% (2 steps). (iii) TESOTf, Et3N, CH2Cl2, 82%;
Chiral Pool Synthesis: Starting from Terpenes
12 18
(i) IBX, DMF, r.t., 24 h; (ii) 0.1M HF, MeCN, r.t., 30% (2 steps)
O
O
O
OH O
HO
TESO
HO
HO
O
OMe
10.15
10.16 (Kendomycin)
Scheme 10 Continued.
OTMS +
H
(i) EtACl2, PhMe (ii) Pd(OAc)2, MeCN
(i) 1,2-ethandithiol, MeOH, BF3-OEt2 (ii) PPh3=CHOMe, THF
O
(iii) 4 N HCl, MeOH, THF (iv) NaBH4, MeOH, THF (66%, 4 steps)
63% 11.1
O (R)-(−)-Carvone IV
(i) MsCl, Et3N, CH2Cl2 (ii) LiBHEt3, THF (iii) PIFA, MeOH, H2O, CH2Cl2
S S
11.3
O O
O
O Me
I
H
O
(i) mCPBA, CH2Cl2 (ii) TMSN3, I2, pyidine, CH2Cl2
Me Me 11.4
(11.6)
B
H
Me
O
(iv) OsO4, H2O2, NaIO4, 2,6-lutidine,dioxane (53%, 4 steps)
Me
O
Me 11.2
H
HO
O
O
OTBS
Pd(PhCN)2Cl2, Ag2O, Ph3As THF, H2O
(32%, 2 steps)
H
O
O
OTBS
Me Me 11.7
(89%)
11.5
(i) H2O2, NaOH, MeOH
HO
(ii) NaBH4, MeOH, THF (77%, 2 steps)
H
OH
Me Me
OTBS
(i) TESCl, imidazole, THF (ii) TiCl4, CH2Cl2
(37%, from 11.8)
HO
H H OH Me O Me OH
O
11.9
11.8
HCl, MeOH
TESO
H O Me OH OMe Me 11.10 (−)-Peribysin E
Scheme 11 Diels–Alder annulation to carvone as the key step in the synthesis of peribysin E.
175
176
Chiral Pool Synthesis: Starting from Terpenes
O Me
(i) LDA, TMSCl (ii) mCPBA, CH2Cl2
Me Me
O
(i) EtAlCl2, PhMe (ii) NaOH, MeOH 74%
(R)-(−)-Carvone IV
HO
O Me
(12.1)
TMSO
O Me
O
O
12.3
O Me Me
(iii) Tf2O, iPr2NEt (iv) Et3SiH, LiCl, Pd(PPh3)4
Me
90% 12.2
(i) Swern-oxidation (ii) SiO2, Et3N Me
Me H Me
NaOH, H2O2
O
c. 80%
MeH
OH Me
O
Me
Me H 12.5
12.4
79%
(i) NaHMDS, CS2, MeI (ii) Bu3SnH, AIBN
Me
O O
Me
MeH 12.6
85% O
Me
DMP Me 91%
HO MeH 12.8
OH Me
(i) PhI(OAc)2, NaOH, MeOH (ii) HCl (iii) NH2-NH2, HOAc
Me HO MeH
77%
12.7 (i) [CuH(PPh3)]6, PhMe2SiH, PhMe (ii) NaBH4, MeOH 91%
OH Me Me HO MeH 12.9 Lairdinol A
Scheme 12 Diels–Alder annulation to carvone in the synthesis of the eudesmane sesquiterpene lairdinol A.
A Pt(II)-catalyzed ‘Ohloff–Rautenstrauch’ annulation of a cyclopropane and a cyclopentene ring to (S)-carvone (V) was the key operation in a synthesis of the sesquiterpenes cubebene (16.10 and 16.11, Scheme 16).21 Thus, V was converted into enol triflate 16.1 which was used for a Stille coupling with vinylstannane. Hydroboration–oxidation and addition of acetylide led to propargylic alcohol 16.2. The alcohol was oxidized to the ketone which was reduced stereoselectively to the (S)-enantiomer (16.4) with Noyori’s catalyst (16.3). Acetylation led to 16.5 which was treated with PtCl2 to induce the above mentioned rearrangement. A plausible mechanism postulates the formation of an oxolanylium species 16.6 which then undergoes double bond shift to generate a Pt-carbenoid 16.7. Cyclopropanation leads to 16.8, which was deacylated to ketone 16.9, and then elaborated into the target structures 16.10/16.11.
2.7.3.1.2
Ring contraction
It was reported in 1994 that carvone undergoes a Favorskii ring contraction to the highly functionalized cyclopentane derivative (Scheme 17).22 This intermediate was first used in the total synthesis of the sesquiterpene lactone (þ)-cladantholide (Scheme 17).23 Thus, stereoselective epoxidation of IV and opening of the resulting oxirane with lithium chloride gave the chlorohydrins 17.1 after tetrahydropyranyl (THP)-protection. Treatment with methoxide induced the Favorskii rearrangement to 17.2 as the sole product. Reduction to the aldehyde followed by Felkin Anh selective addition of vinyl magnesium bromide (see Chapters 2.4 and 2.12) gave 17.3 which was alkylated with 17.4 to give bromo-acetal 17.5. Free radical cyclization led to the exclusive formation of 17.6 which was converted to the ketone, and a-hydroxylated to furnish 17.7. Shapiro reaction followed by oxidation of the acetal to the lactone and a-methylation delivered 17.8. The corresponding enantiomer ent-17.2, obtained from (S)-carvone, was used for a synthesis of the more complex guaianolide thapsivillosin F (Scheme 18).24 The OTHP-protecting group was exchanged for the more robust TBDPS in 18.1 which was elaborated into 18.2 and then into di-olefin 18.3 via similar organometal carbonyl additions. RCM and dihydroxylation of the resulting enol ether furnished hydroxyl ketone 18.4. A Horner reaction was used for the annulation of lactone 18.5. Reductive opening and protection gave the diol derivative 18.6 which was dihydroxylated, oxidized, and closed to lactone 18.7. Several functional group adjustments via 18.8 and 18.9 including the introduction of three ester appendages furnished 18.11.
Chiral Pool Synthesis: Starting from Terpenes
(i) 9-BBN, H2O2, NaOH (ii) MPLC
O
Me
(i) TIPSCl, imidazole (ii) PCC, NaOAc
H
c. 40%
87% OH
OH 13.1
(S)-(+)-Carvone V Me
tBuLi, THF, add (i) LDA, Comins′ reagent (ii) (PPh3)4Pd, (Me3Sn)2 (iii) NIS
H OTIPS
O
Me
H MeO OTIPS
65%
(13.4) TMS
Me
Me
H
O TIPSO
(13.6)
OH
OTIPS
H
CHO
p-TsOH, MgClO4, CH2Cl2 then SnCl4, CH2Cl2 84%
TMS Me
H
TIPSO
H
H
TBDPSO
43%
TMS 13.7
Me
(i) Ac2O, DMAP (ii) TFA, H2O (iii) Ac2O, DMAP
H O
O
(i) h, dioxane (ii) KOH, MeOH (iii) (tBuO)3Al, tBuOOH
O
OTBDPS
HO 13.5
H
then PPTS, MeOH 62%
H H
O
O
I
13.3
13.2 Me
177
H
TIPSO
H
HO
86%
H H
(i) mCPBA (ii) TBAF, THF (iii) Tf2O, 2,6-lutidine
O
45%
AcO
Me
(i) H2SO4, THF, H2O (ii) MsCl, Et3N (iii) LAH, Et2O
O
H H
H
O H
AcO 13.10 Me OH H
H H
O O R
H
O
O
O R
CrCl2, NiCl2 DMSO-Me2S
R 13.12
O
49% 13.11
Me OH H
H H H
O
(i) Bu3SnAlEt2, CuCN (ii) I2 (iii) (tBu)2OHSnCl, MeOH (iv) DMP
O
O
I H
H
AcO
Me
79% O
Me OH H
H H
(iv) Bu8Sn2Cl4O2, iPrOAc (v) n-C7H15COCl =RCOCl 61%
AcO
Me
Me
O
O
13.9
AcO
13.8
HO
O
OH
O 13.13 (briarellin E)
Me
Me OH H
H H
DMP
O
79%
H
O R
O
O
O 13.14 (briarellin F)
Scheme 13 Prins-pinacol annulation to carvone in the synthesis of briarellins E and F.
A related application of cyclopentane 17.2 has been reported for the synthesis of the guaianolide 8-epi-grosheimin (19.7, Scheme 19).25 In this case, the ‘methoxymethyl (MOM)’ group was selected for the protection of the secondary alcohol so that aldehyde 19.1 was the chiral starting material. Mukaiyama aldol addition of butyrolactone-TMS-enol ether to 19.1 furnished adduct 19.2 with moderate stereoselectivity. Refunctionalization furnished lactone 19.3 which was reduced to alcohol 19.4. Swern oxidation to the aldehyde was followed by an ene cyclization to generate 19.5 stereoselectively. Eschenmoser methylenation led to 19.6 which was oxidized to 19.7. The synthesis of a steroid D-ring fragment from 17.2 has also been reported.26 Recently, an application of 17.2 in the synthesis of the monoterpene alkaloid incavilline was described (Scheme 20).27
178
Chiral Pool Synthesis: Starting from Terpenes
Me
H
Me
H OH
OTIPS
R
O
H
H
HO
13.5 TMS
SnCl4, CH2Cl2
TIPSO
(13.6)
R
p-TsOH, MgClO4, CH2Cl2
O O
14.1 TMS
Me
H
Me OSnCl3
OTIPS R
Me
H
TIPSO TIPSO
H H
OSnCl3 R
O
CHO O
O
TBDPSO 14.2
TMS
14.3
TMS
TMS 13.7
Scheme 14 Mechanism of the Prins-pinacol annulation from 13.5 to 13.7.
Stereoselective hydroboration of 17.2 led to alcohol ester 20.1,22 which was reduced to the diol and then di-mesylated to give 20.2. Cyclization with methylamine and deprotection furnished 20.3.
2.7.3.1.3
Ring cleavage
A third option in the use of carvone is cleavage of the original ring to an acyclic fragment whose end groups are modified and used for a new cyclization reaction. This strategy has been pursued in the syntheses of guanacastepenes, retigeranic acid, and platensimycin. In the synthesis of guanacatepene E (Scheme 21),28 (S)-carvone (V) was selectively hydrogenated to provide an isopropyl sidechain and then methylated to give 21.1. Ozonolytic cleavage of the endocyclic double bond followed by hydrocyanantion of the aldhehyde furnished 21.2 which was lactonized to 21.2. Anionic ring contraction led to cyclopentene 21.4. Conversion to the nonaflate and Wulff–Stille coupling furnished stannane 21.5 which was connected via allyl-Stille coupling with allyl acetate 21.6 to give tri-olefin 21.7. Photolytic [2.2]-cycloaddition led to cyclobutane 21.8. Reductive ring cleavage and selenation of the resulting enolate gave 21.9. Oxidative elimination of the selenium led to diene 21.10. Hydroxylation and O-acetylation followed by oxa-Michael cyclization furnished 21.12. Another ring cleavage of carvone has been utilized in the synthesis of ()-retigeranic acid (Scheme 22).29 The synthesis entails the addition of the dianion of carboxylic acid 22.2 to aldehyde 22.7 to form triene 22.8 after decarboxylative dehydration of the intermediate b-hydroxy acid. Acid 22.2 was prepared from (R)-carvone via selective hydrogenation of the exocyclic double bond, followed by the formation of the epoxide 22.1 via the bromo-acetate. Fragmentation led to the d-keto acid which gave olefin 22.2 after Wittig methylenation. Aldehyde 22.7 was prepared from 3-methyl glutarate 22.3 which was elaborated into enantiomerically pure arene olefin 22.5 via ketone 22.4. Arene olefin meta-photo-cycloaddition gave tetracyclic intermediate 22.6 (mixture of isomers). Free radical addition of the formamide radical followed by N-dimethylation and oxidation of the allylic methyl group led to aldehyde 22.7, which was connected to acid 22.2 via aldol addition and decarboxylative dehydration. Electrocyclization led to 22.9 as a mixture of isomers, which was converted to diene 22.10 via the epoxide. Mono-hydrogenation to 22.11/22.12 followed by conversion of the amide to the acid gave 22.13. A Baeyer–Villiger oxidative cleavage of the original ring and the de-novo formation of a cyclopentane ring are the characteristics of the synthesis of the antibiotic platensimycin (23.15) from (S)-carvone (Scheme 23).30 The key step of the synthesis is the IMDA addition of triene 23.10 (see Chapter 2.17) to generate the characteristic polycyclic core 23.11 of platensimycin. First the exocyclic double bond of (S)-carvone was converted into the bromohydrin which was then used in a free radical addition to the endocyclic double bond to give the bicyclic hydroxyl ketone 23.1. Baeyer–Villiger oxidation and relactonization led to lactone 23.2, the hydroxymethyl appendage of which was removed by a second Baeyer–Villiger oxidation to give OTBS-alcohol 23.3. Tebbe olefination followed by stereoselective hydroboration generated alcohol 23.4, which was converted into ketone 23.5. Asymmetric Horner olefinierung with phosphonate 23.6 gave olefin 23.7 with good (E)-selectivity. After protection, a second Horner olefination was used to generate enoate 23.9 via alcohol 23.8. Next, the diene system was installed to form enol ether 23.10 as a mixture of E/Z-isomers. On thermolysis, only the (E)-isomer underwent the
Chiral Pool Synthesis: Starting from Terpenes
O
(i) H2O2, NaOH (ii) H2, PtO, EtOH
O
O
(iii) LDA, CH2O, THF (iv) TBSCl, Et3N, CH2Cl2 46%
HO
(iv) Na-naph, THF OTBS
OTBS
79%
15.1
(S)-(+)-Carvone V
(i) CH3C(OEt)3 iPrCO2H (catalyst) (ii) DIBAL, CH2Cl2
(i) L-selectride, THF (ii) MsCl, Et3N, THF
CHO
15.2
OH
(i) CH2=CHOEt tBuLi, THF (ii) H2SO4, Et2O
72% OTBS
179
(i) TESOTf, Et3N, CH2Cl2 (ii) PPTS, MeOH, CH2Cl2
HO
(iii) HCCMgBr, THF (iv) TBAF, THF 32%
15.3
(iii) TPAP, NMO, CH2Cl2 (iv) NCCH2CO2Et, -alanine, EtOH 91%
OH 15.4
OH OTES TESO CO2Et NC
OH
(iv) DMP, NaHCO3, CH2Cl2 (v) HF-NEt3, THF 58%
OTIPS 15.6
N (ii) TBAF, THF
O
O
(i) NEt3, DMAP O MeN
80%
O
15.5
OH
(i) H2, [Rh(nbd)(dppb)]BF4, acetone (ii) MeOH, PPTS
(i) DIBAL, hexanes (ii) TIPSOTf, iPr2NEt, CH2Cl2 (iii) LiHMDS, THF
O O
tBu
Me N
O
(15.8)
N O
OMe OTIPS 15.7
(iii) DMP, NaHCO3, CH2Cl2 (iv) NaClO2, NaH2PO4, 2-methyl-2-butene, THF, tBuOH (v) CH2N2, Et2O (vi) CSA, CH2Cl2, H2O 58%
OH CO2Me 15.9 Sarcodictyn A
Scheme 15 Addition of vic. carbon appendages to carvone for ring formation to 15.6.
IMDA cyclization to furnish 23.11 stereoselectively in 44% yield. Chain elongation of the ester led to 23.12 after hydrogenation of the endocyclic double bond. Conversion of the methyl ether to the ketone followed by re-introduction of the endocyclic double bond and ester hydrolysis provided platensic acid 23.13 which was amidated with amine 23.14 to give platensimycin (23.15).
2.7.3.2
Dihydrocarvone (VI)
Both enantiomers of dihydrocarvone are commercially available. For an application of trans-()-dihydrocarvone (VI) in natural product synthesis, colombiasin A (Scheme 24) is discussed here.31 The cyclohexane ring of VI is maintained until the end of the synthesis, whose key step is a Moore annulation of squarate 24.7 to form quinone 24.11 which has been shown to undergo thermal IMDA reaction to 24.12. The sequence was started with an unselective hydroboration of VI to furnish alcohol 24.2 which was chain elongated to aldehyde 24.3 and converted to diene 24.5 via Julia–Lythgoe–Kocienski olefation with sulfone 24.4. Oxidation to ketone 24.6 was followed by Shapiro reaction and the resulting vinyl carbanion was trapped with 24.7 to give adduct 24.8. Thermolysis led to electrocyclic formation of trienyl ketene 24.9 which underwent electrocyclization to 24.10. Oxidation with air furnished quinone 24.11. The IMDA product 24.12 was demethylated to afford colombiasin A (24.13).
2.7.3.3
Pulegone (VII)
Pulegone is obtained from the essential oils of a variety of plants such as Nepeta cataria (catnip), Mentha piperita, and pennyroyal.32 Pulegone is clear, colorless, and has a pleasant odor similar to pennyroyal, peppermint, and camphor. It is used in
180
Chiral Pool Synthesis: Starting from Terpenes
(i) [(PPh3)3RhCl], H2 (ii) Pd/C, H2
O
(i) CH2=CHSnBu3, [Pd(PPh3)4], LiCl, THF (ii) 9-BBN, THF (iii) H2O2, H2O
TfO
(iii) NaOMe/MeOH (iv) LTMP, THF Comins′ reagent (77% overall)
(S)-(+)-Carvone V
16.1 (i) DMP, CH2Cl2 (ii) (S,S)-16.3, iPrOH(88%)
HO
(iv) DMP, CH2Cl2 (v) TMSCCH, BuLi, CeCl3, THF 35%
HO
Ts N Ru Ph N H (S,S)-16.3 Ph
TMS 16.2
PtCl2, PhMe, 80 °C
AcO
(i) TBAF, THF
TMS 16.4
Me
O O
(ii) Ac2O,DMAP, Et3N CH2Cl2 (82%)
(92%) Cl2Pt 16.5 16.6
Me
O
−PtCl2
O AcO H Cl2Pt
16.8
16.7
Ph3P=CH2 DMSO (99%)
K2CO3, MeOH (76%)
H
H H
O H
H 16.9
16.10 (−)--Cubebene (i) LDA, THF, Comins′ reagent (ii) MeMgBr, [Fe(acac)3] THF, NMP (82%, 2 steps)
H H 16.11 (−)--Cubebene
Scheme 16 Pt(II)-catalyzed Ohloff–Rautenstrauch annulation to carvone leads to the cubebenes.
flavoring agents, in perfumery, and in aromatherapy.33 Interestingly, (R)-(þ)-pulegone is much cheaper (c. 3h g1) than the (S)-enantiomer (c. 200h g1). In the exemplary natural product syntheses given below (Sections 2.7.3.1 to 2.7.3.3), pulegone has been used not as such. Instead, it has been modified by ring contraction to a cyclopentane, or by ring cleavage and recyclization or by degradation of the exo-methylene moiety.
Chiral Pool Synthesis: Starting from Terpenes (i) H2O2, NaOH (ii) LiCl, TFA (iii) PPTS, DHP
H
73%
O (R)-Carvone (IV)
(i) DIBAL, THF (ii) vinylMgBr, THF
Cl
H
H
H
(iii) LDA, THF, TMSCl (iv) DMDO, CH2Cl2 63%
O
HO
H
17.6
H
Br
O
99%
17.5
Me (i) TsNHNH2, MeOH (ii) MeLi, THF
O H O
OEt
Bu3SnH, AIBN, benzene, reflux
THPO
OEt
98%
Me
THPO
Br (17.4)
Et3N, DMAP, CH2Cl2
17.3
(i) p-TsOH, MeOH (ii) PCC,
CO2Me H 17.2
Br
OH
THPO
O 17.1
OEt H
H
NaOMe, MeOH 95%
THPO
77%
H
H
THPO
181
OEt 17.7
(iii) CrO3, H2SO4, acetone (iv) LDA, THF, MeI 18%
O
H
Me
H
Me
H Me
O O
17.8 (+)-Cladantholide Scheme 17 Favorskii-ring contraction of carvone in the synthesis of guaianolides.
2.7.3.3.1
Ring contraction
In the synthesis of the alga diterpene (þ)-epoxydictymene (Scheme 25),34 pulegone was converted into cyclopentyl-carboxylic acid 25.1 via a Favorskii ring contraction.35 Acid-catalyzed hydration and LiAlH4-reduction gave diol 25.2. Acylation and dehydration led to olefin 25.3 which was saponified, metallated with BuLi, and trapped with TMSCl to give allyl silane 25.4. Alkynylation of the triflate with 25.5 generated 25.6 which was subjected to a Nicholas reaction.36 Ring closure to cobalt complex 25.7 was followed by a Pauson–Khand cyclization37 to furnish cyclopentenone 25.8. As the configuration at C-12 is wrong, the cyclopentane ring was cleaved to give keto aldehyde 25.9 with correct stereochemistry at C-12 after base-catalyzed equilibration. Twofold olefination afforded di-olefin 25.10 which was reduced to alcohol 25.11. Transformation into the iodide, lithiation, and Michael addition closed the missing cyclopentane ring. Reductive decyanation delivered the angular methyl group to complete the synthesis of 25.12.
2.7.3.3.2
Ring cleavage and recyclization
In the synthesis of the phospholipase inhibitor pinnaic acid (26.15, Scheme 26),38 the main challenge was to obtain an easy access to the crucial 6-aza-spiro-[4.5]decane core 26.11 in enantiomerically enriched form. The solution presented here implied the oxidative ring cleavage of pulegone to di-ester 26.1 with subsequent Dieckmann cyclization/alkylation to provide cyclopentanone 26.2. Decarboxylation and Saegusa oxidation led to cyclopentenone 26.3. Trost annulation of 26.4 gave diquinane 26.5 stereoselectively and Beckmann rearrangement led to lactam 26.6. Removal of the exo-double bond via the tosylhydrazone furnished 26.7. Reduction of the lactam and deprotection produced alcohol 26.8 which was oxidized to the aldehyde and olefinated to give enone 26.10. Reductive amination induced ring closure, and the allylic double bond was introduced via the Grieco protocol39 to give 26.11. Grubbs’-cross metathesis (CM) with ester 26.12 delivered enoate 26.13 which was elaborated into 26.15 via a second CM with diene 26.14.
2.7.3.3.3
Degradation of the pulegone isopropenyl sidechain. Formation and application of enantiomerically enriched 5-methyl-2-cyclohexanone (27.4)
A number of natural product syntheses is based on key intermediate 27.4 which is readily available from pulegone via oxidative degradation of the sidechain (Scheme 27).40 Thus (S)-pulegone was converted into epoxides 27.1 which were treated with thiophenoxide to give sulfides 27.2. Oxidation to the sulfoxides 27.3 and thermal elimination furnished (R)-5-methyl-2-cyclohexanone (27.4). Analogously, (R)-pulegone was converted into ent-27.4.
182
Chiral Pool Synthesis: Starting from Terpenes
(i) PPTS, MeOH H (ii) TBDPSCl, imidazole TBDPSO CO2Me 82% H
THPO
(i) LAH (ii) NaH, PMBCl (iii) OsO4, NaIO4 (iv) AllylMgBr (v) MOMCl, DIPEA
H
CO2Me
ent-17.2
H
OMOM
H
H
(i) Grubbs II (ii) OsO4
TBDPSO
OMOM
TBDPSO
OTES
H
OTES
H
H OTES
H
OMOM
18.7
OH
H
HO H
77%
O
O O
(i) TMSCl (ii) DMDO (iii)TMSCl (iv) PhSeBr O
O
OAc
H O
HO
OH
senecioic acid anhydride, DMAP 73%
TMSO
74%
O O
O O 18.9
O
OAc O
H
HO
O O
O OH
OH
O 18.10
OTMS
H
O 18.8
O
(i) NaBH4 (dr 4:1) (ii) angelic acid, 2,4,6-trichlorobenzoyl chloride (iii)TBAF, (iv) iso-propenyl acetate, PPTS (v) HCl, H2O 35%
(i) Amberlyst-15, acetone (ii) TBAF O (iii) TPAP/NMO
OH
O
62%
OAc
18.6
OMOM HO
(i) OsO4 (ii) K2CO3 (iii) TPAP/NMO
OMOM
18.5
H
OMOM
TBDPSO
80%
O
79%
O
18.4 (dr 16:1)
(i) LiBH4 (ii) Ac2O (iii) MOMCl
O
(i) EDCI HO2CCH(Me)P(O)(OEt)2 (ii) NaH, THF
OH H
18.3 H
OMOM
83%
H OEt OTES
76%
OPMB
18.2 3.5:1 (major isomer shown)
18.1
(i) DDQ (ii) TPAP, NMO (iii) tBuLi CH2CHOEt TBDPSO (iv)TES-Cl
TBDPSO
TBDPSO
64%
H
OMOM
H
O
O 18.11 Thapsivillosin F
Scheme 18 Synthesis of a complex guaianolide lactone from (S)-carvone via intermediate 17.2.
The application of ent-27.4 in the synthesis of the lycopodium alkaloid nankurine A and B is shown in Scheme 28.41 Diels–Alder reaction with diene 28.1 gave cis-decalin 28.2 stereoselectively. Condensation with benzoic hydrazide and reduction led to hydrazide 28.3. On heating with para-formaldehyde, azomethinimine 28.4 was formed (see Chapter 2.18), which underwent stereoselective intramolecular 1,3-dipolar cycloaddition to furnish pyrazolidine 28.5. Reductive cleavage of the NNbond and selective in situ methylation gave 28.6, which was cyclized via the O-mesylate to 28.7 and converted into 28.8 and 28.9, respectively. A similar Diels–Alder strategy was applied in the synthesis of the cytotoxid lycopodium alkaloid (þ)-lyconadine A (Scheme 29).42 Thus, ent-27.4 was treated with isoprene in the presence of TMSOTf which acted as a Lewis acid and as a dehydrating agent for ketal formation so that adduct 29.1 was formed. After deketalization, the resulting ketone was subjected to reductive amination to give 29.2 stereoselectively. An aza-Prins reaction with formalin led to a shift of the double bond, which was cyclopropanated to give tetracyclic intermediate 29.3. Electrocyclic ring opening generated the carbenium ion 29.4 which was
Chiral Pool Synthesis: Starting from Terpenes
183
OTMS Me
Me
(i) KOH, H2O, THF (ii) CH2N2 (iii) TEMPO, CH2Cl2, NCS
O MOMO
MOMO
O Me
BF3-OEt2, CH2Cl2
H
92%, dr = 3:1
19.1
Me MOMO
CO2Me Me
77%
H
HO
O
19.2
(i) NaOH, H2O, THF (ii) oxalyl chloride, DMF (iii) NaBH4, DMF, THF
Me MOMO
O
85% O 19.4 O
OH
MOMO
(i) Swern-oxidation (ii) (iPrO)2TiCl2, CH2Cl2
CH2OH Me
64%
O
19.3
Me
O Me
(i) LDA, THF (ii) Me2N=CH2I
Me
(iii) mCPBA
O
OH
O
91%
O
O 19.7 8-Epi-grosheimin
19.6
19.5
8 Me
O
72%
O
(i) iPrOH, O p-TsOH (ii) IBX, DMSO
OH
MOMO
Scheme 19 Synthesis of 8-epi-grosheimin from cyclopentane 19.1.
H
Me (i) disiamylborane, THF (ii) H2O2, NaOH, H2O
THPO Me
H
CO2Me
Me
(i) LiAlH4, THF (ii) MsCl, DMAP, Et3N, CH2Cl2
OH
THPO
62%
17.2
Me
H
H
CO2Me
20.1
Me
H
OMs
(i) MeNH2, DMF (ii) PPTS, MeOH
H
Me
HO
THPO
NMe OMs Me
H 20.2
63% from 20.1
Me
H
20.3 Incarvilline
Scheme 20 Annulation of a piperidine ring to 17.2.
trapped by a transannular attack of the nitrogen to give 29.5 under removal of the ‘tertiary butoxy carbonyl (Boc)’-protecting group. The vinyl bromide was metallated and added to isoamyl nitrite to give a nitroso intermediate which was rearranged to the oxime. This was hydrolyzed to ketone 29.6. Michael addition of deprotonated sulfide 29.7 and treatment with HCl resulted in cyclization and desulfination to furnish the pyridone ring of 29.8. In the synthesis of the lycopodium alkaloid complanadine A (Scheme 30),43 ent-27.4 was converted into ketal 30.1. However, enamide 30.2 was hydrolyzed to give 30.3. In situ condensation of the enol of 30.3 with 30.1 gave 30.4 which underwent a Mannich cyclization to 30.5. Boc-protection led to 30.6. Oxidation to pyridine 30.7 was followed by removal of the OTf-group and regioselective C–H-activation to furnish boronate 30.8. Suzuki coupling of 30.8 and 30.7 led to 30.9 after removal of the Boc-group. A Grubbs enynene RCM strategy was used in the synthesis of the lycopodium alkaloid (þ)-lycoflexine (Scheme 31).44 The key intermediate 31.5 was prepared from ent-27.4 via a tandem Sakurai/aldol sequence to give alcohol 31.1 which was oxidized to the diketone and alkylated with 31.2 to give compound 31.3. Introduction of the triple bond was achieved via the triflate 31.4 to give 31.5 on elimination with pyridine. Tandem catalysis with Grubbs II catalyst accomplished ring closure and selective
184
Chiral Pool Synthesis: Starting from Terpenes (i) O3, EtOAc (ii) H2, Pd/C, (iii) NaCN, pTsOH, THF, H2O
(i) PtO2, H2, (ii) LDA, MeI, THF O
O
96%
OH NC
O OH
(48%, 3 steps)
Me
(S)-(+)-Carvone V
Me 21.2
21.1 (dr = 5.5:1)
CN EDCI, CH2Cl2
O
79%
O
(i) LiHMDS (3 equivalent), THF (ii) 1 M HCl O
OH
(59% 2 steps)
54% 21.4
21.3 O
O O
PMP O
O
O OAc
SnMe3
O
(21.6)
O
PMP
O
Pd(PPh3)4 LiCl, CuCl, DMSO
21.5
(i) NfF, NEt3, CH2Cl2 (ii) Pd(dppf)Cl2 (Me3Sn)2, NMP
21.7 O
h, iPr2NEt, Et2O
(i) SmI2, HMPA, THF (ii) PhSeBr
PMP
O
(50%)
(64% 2 steps) 21.8 PMP
O
O
O
PMP
O
O
SePh
(i) TESOTf, NEt3, CH2Cl2 (ii) mCPBA, CH2Cl2
O
mCPBA, CH2Cl2
(iii) Ac2O, DMAP, pyridine (45% 3 steps)
86% 21.10
21.9
O
AcO
O
PMP
O
O
H (i) PPTS, MeOH (ii) SiO2, CH2Cl2
AcO
O OH
(69%, 2 steps) 21.11
21.12 (+)-Guanacastepene E
Scheme 21 Synthesis of guanacastepene E from (S)-carvone.
hydrogenation to furnish tricycle 31.6 which was hydroborated and oxidized to diketone 31.7. Transannular Mannich cyclization delivered 31.8. An intramolecular Mannich reaction was also the key step in the synthesis of the lycopodium alkaloid (þ)-fastigatine (32.13) which was prepared from ent-27.4 by maintaining the endocyclic double bond over quite a number of steps (Scheme 32).45 Following an earlier protocol,46 27.4 was iodinated to give ketal 32.1 which was converted into cuprate 32.2 and added to cyclopropane 32.3 (prepared from (S)-epichlorohydrin)47 to give 32.4 in 93% yield. Alkylation to form azide 32.5 and exchange
Chiral Pool Synthesis: Starting from Terpenes
O (i) (Ph3P)3RhCl, H2, PhH (ii) Br2, AcOH (iii) KOH
O
O
(i) KOH (ii) Ph3P+CH3Br −, nBuLi THF CO2H
74%
46%
(R)-(−)-Carvone IV
22.2
22.1 (i) liver esterease (ii) dipyridyl disulfide, PPh3, CH2Cl2 (iii) p-xylyl bromide, Li, Et2O, CuI
Me CO2Me
MeO2C
185
O
(i) LiAlH4, Et2O (ii) H2, Pd/C, EtOH, HClO4 (iii) nBu3P, 2-NO2-Ph-SeCN, H2O2
Me CO2Me
78%
86%
22.3
22.4 (i) h, HCONH2, acetone, tBuOH (ii) KOH, MeI, DMSO
h cyclohexane
H
H
72% 22.5
30%
(i) LDA, THF, 50 °C (ii) + 22.7
H
22.7
250 °C, PhCH3
H
22.2
64%
(iii) HOAc, HC(OMe)2NMe2 65%
H
O Me2NOC
(iii) SeO2, tBuOOH 1,2-dichloroethane
22.6
CONMe2 22.8
(i) mCPBA, NaOAc, CH2Cl2 (ii) tBuOK, DMSO 100 °C
H
H
H
CONMe2
10% Pd/C, H2 (400 psi)
H
95%
CONMe2 22.10
22.9
H H
H + H
CONMe2 22.11
H
CONMe2
H
(i) LAH, THF (ii) PDC, CH2Cl2 (iii) Pinnick Ox.
22.12
H
H
CO2H
22.13 (−)-Retigeranic acid
Scheme 22 Ring cleavage of carvone to acid 22.2 and application in the synthesis of ()-retigeranic acid.
of the N-protecting group for nosylate 32.6 was followed by the addition of enolate 32.7 to give the keto ester first which was cyclized to enanimide 32.8 by a Staudinger reaction. On treatment with HCl, the ketal was hydrolyzed to form enone 32.9 which underwent a tandem Michael aldol reaction to form pentacycle 32.10. N-Methylation and deprotection gave amine 32.13 which underwent a Mannich cyclization to provide 32.12. Decarboxylation and N-acetylation led to 32.13. The cyclohexane ring of ent-27.4 was used as a chiral template for an intramolecular Diels–Alder reaction in the synthesis of the marine alkaloid norzanthamine (Scheme 33).48 Conjugate addition of cuprate 33.1 to cycloxenone ent-27.4 provided enol ether 33.2 which was added to aldehyde 33.3 via Mukaiyama conditions to provide aldol adduct 33.4. Dehydration to the enone
186
Chiral Pool Synthesis: Starting from Terpenes
O
H
mCPBA CH2Cl2
(i) NBS, THF/H2O (ii) Bu3SnH, AIBN
O
H
O
77% (S)-Carvone
Me 23.2
Me
HO
Me
O
90%
OH
23.1 (dr = 1:1)
(i) Swern-oxidation (ii) CF3CO3H, CH2Cl2
H
H
O
H
81%, dr = 2:1
OH
Me 23.3
Ph
O
TBDPSO
THPO
H
OH
Me
O TBDPSO
Me 23.7 (E):(Z) = 4:1 HO
H H O EtO2C
91%
23.8
HO
H
H
(23.6)
(i) Swern-oxidation (ii) Wittigolefination (iii) CSA, EtOH
H O
99%
OMe OMe
nBuLi, −50 °C then DIBALH 68%
Me 23.5
(i) DHP, PPTS (ii) TBAF, THF
OTBS Me
O
O
H H O
87%
H
23.4 O
(i) TBDPSCl, imidazole (ii) DDQ, THF/H2O (iii) Swern-oxidation
H O
OTBS
O
(iii) K2CO3, MeOH (iv) TBSCl, imidazole 83%
(i) Cp2TiMe2, PhMe (ii) 9-BBN, THF
Me
Me 23.9
OMe H
(i) DMP (ii) PPh3=CHOMe
H
PhCl, BHT, 270 °C
EtO2C
OMe
Me
(+ starting material)
O
82% EtO2C
(i) LAH (ii) DMP (iii) KHMDS, Horner-olefination (iv) Pd(OH)2, H2, EtOH
Me
Me
44%
Me 23.11
23.10 (E):(Z) = 1:1.5
M
EtO2C
OMe
(i) RuCl3, NaIO4, CCl4, MeCN, H2O (ii) PhSeCl, HCl (iii) NaIO4, THF, H2O (iv) NaOH, EtOH
O
82%
TMSEO2C
O Me 23.13 (platensic acid) OH
(23.14)
O
OH NH2
HO2C OH
HATU, Et3N, DMF, then TASF, DMF 49%
Me O
HO2C
43%
Me 23.12
HO
O
Me O
N H
O 23.15 (−)-Platensimycin
Me
Scheme 23 Synthesis of the antibiotic platensimycin from (S )-carvone via Baeyer–Villiger ring cleavage.
was followed by hydrosilylation to give cyclohexanone 33.5 after base-induced equilibration. Functional manipulation generated enone 33.6. Photooxidation of the furan moiety led to 33.7 which was converted to enol ether 33.8. Thermal IMDA reaction via an exo-transition state furnished cyclization product 33.9 as a mixture of isomers which was desilylated to the ketone from which the major isomer 33.10 was isolated by crystallization. An additional 28 steps were required to elaborate 33.10 into 33.11. A slightly modified procedure was used for the degradation of (R)-pulegone to dimethyl cyclohexenone 34.1 in the synthesis of the diterpene phomactin,49 which is a potent platelet aggregation factor antagonist. The quaternary center was installed via an
Chiral Pool Synthesis: Starting from Terpenes Me
Me
O
(i) LAH (ii) (−)-Ipc2BH (iii) H2O2, NaOH
Me
86%
Me OH
OH
H
H
+ OH
Me
(−)-Dihydro-carvone (VI)
24.1
OH
Me 24.2
2:5
Me
(i) TsCl (ii) NaCN, DMF (iii) DIBALH
Me S
OH H Me
OH
SO2 Me (24.4)
N
H
40%
H H
NaHMDS 79%
O 24.3
24.5 (E):(Z) = 1:3 O
H H
92%
Me
Me
Me (i) Swern-oxid (ii) I2
187
Me
(i) trisylhydrazine, THF, r.t. (ii) nBuLi (4 equivalent), −78−20 °C (iii) + 24.7 tBuO
Me
OtBu
OH O
H
O
24.6 purely (E)
H
(24.7) Me
Me
Me
Me
Me
O
24.8 36% from 24.6 Me
THF, -wave, 110 °C
Me
OH
OH
OtBu H
OtBu H
Me
O
Me
H Me O
Me
Me
O OtBu
150 °C, toluene
H Me
Me 24.10
24.9
Me O
H 24.12
Me
O OtBu
OH
Me
61% from 24.8
Me
air, r.t.
24.11
Me
BF3-OEt2 (2 equivalent), 0 °C 78 °C
O OH
H Me
Me O
Me
H 24.13 (Colombiasin A)
Scheme 24 Dihydrocarvone VI as chiral starting material for the synthesis of the sesquiterpene colombiasin A.
aldol addition with phenylselenoacetaldehyde and subsequent treatment with MsCl/Et3N to give the vinyl appendage in 34.2 stereoselectively. A 1,3-enone transposition led to 34.3 which was reduced to the allylic alcohol and epoxidized to give 34.4. Oxidation to the ketone and regioselective epoxide opening with magnesium bromide provided bromohydrin 34.5 which eliminated water to give vinyl bromide 34.6 after exchange of the MOM for the more labile ‘3,4-dimethoxybenzyl (DMB)’protecting group. The ketone was reduced and the alcohol was inverted and silylated to give 34.7. Lithiation and addition of aldehyde 34.8 (prepared from geraniol in 11 steps) delivered ketone 34.9 after oxidation. Removal of the tertiary-butyldimethylsilyl-group led to the formation of dihydro-pyranone 34.10. Protection with TESCl was followed by removal of the DMB group whereon the hemiacetal was formed and silylated to give 34.11. Intramolecular Suzuki coupling closed the macrocyclic ring to furnish 34.12 after deprotection (Scheme 34). In the synthesis of the lycopodium alkaloid (þ)-fawcettidine (Scheme 35),50 the degradation of (R)-pulegone was stopped at the stage of sulfoxide ent-27.2, which allowed the introduction of the two sidechains in 35.2 by alkylation/elimination to form 35.1 and subsequent conjugate addition. Condensation with amine 35.3 led to enamide 35.4 which gave tricycle 35.5 after
188
Chiral Pool Synthesis: Starting from Terpenes HO
HO (i) 1 N HCl, reflux (ii) LAH
O (i) Br2 (ii) NaOMe, H2O
O
OH
(42% 4 steps)
(R)-(+)-Pulegone (VII)
25.1
25.2
(i) K2CO3 (ii) nBuLi, KOtBu Me3SiCl
AcO (i) Ac2O (ii) Ac2O, reflux
H
HO
(i) Tf2O, 2,6-lut (ii) 25.5, nBuLi (74% 2 steps)
TMS
25.3
(25.5)
OEt
(iii) K2CO3, MeOH (50% 3 steps)
(71% 2 steps)
O
25.4
H
(i) Co2(CO)8 (ii) Me3SiOTf
O
OEt TMS
(CO)3 Co Co(CO)3
H
(82% 2 steps)
25.6
CH3CN reflux
O
H
85%
25.7 O H
(i) Li, NH3 (ii) KHMDS, Davis oxaziridine
H
O H
CHO (i) PPh3=CHOMe (ii) NaH, (EtO)2P(O)CH2CN (71% 2 steps)
H (iii) NaHB(OAc)3 (iv) Pb(OAc)4 (v) DBU (31% 5 steps)
O
H
O
H 25.9
25.8 OMe
NC H
(i) HCl, THF (ii) NaBH4
H H
OH
NC
O
H H
(92%, 2 steps)
O H
25.10
(i) PPh3, I2, imid (ii) tBuLi, Et2O
25.11
(iii) K, 18-crown-6 (3 steps 49%)
H H H
O
25.12 (+)-Epoxydictymene
Scheme 25 Ring contraction of pulegone provides the chiral starting material in the synthesis of epoxydictymene.
platinum-catalyzed annulations and allylic oxidation with selenium dioxide. Deprotection of the sulfur was followed by transannular 10-endo-trig- thia-Michael addition to give sulfide 35.6 which was ketalized, oxidized to the sulfone, and converted to the olefin via a Ramberg–Ba¨cklund reaction. Hydrogenation and reduction of the amide gave 35.7 after deketalization. In a formal synthesis of fawcettimine (Scheme 36),51 ent-27.4 was converted into iodide 36.1 and used for a free radical addition to acrylonitrile followed by a conjugate addition/iodination to prepare 36.2. Free radical annulations provided 36.3 which was converted into enone 36.4 via allylic oxidation with selenium oxide. Conjugate addition of ketene acetal 36.5 led to compound 36.6 which may be converted into fawcettimine along the route by Heathcock.52 A regioisomer of 27.4, namely 37.2, has been used in a synthesis of the sesquiterpene valerenic acid (Scheme 37), which is a constituent of valerian root and has been found to be an allosteric modulator of the GABAA receptor. The synthesis started with the conversion of (R)-pulegone into ketal alcohol 37.1 which was dehydrated and deprotected to give 37.2.53 Substrate-directed 1,4-addition of the cuprate prepared from bromide 37.3 gave the TMS enol ether which was oxidized via Saegusa reaction to give enone 37.4. Hydrolysis of the ketal generated the diketone 37.5 which was hydrogenated with Stryker’s reagent and then cyclized to 37.6 via Robinson annulation. Wittig methylenation followed by stereoselective hydroboration gave the alcohol which was oxidized to aldehyde 37.7. A second Wittig olefination provided the enoate which was saponified to valerenic acid (37.8).54
Chiral Pool Synthesis: Starting from Terpenes Me
Me
O
(i) K, allyl-OH, PhMe (ii) I-(CH2)2OPMP
CO2Allyl
(i) O3, AcOH, EtOAc, H2O, 0 °C (ii) allyl-OH, H2SO4, reflux
189
CO2Allyl
89%
26.1
(S)-Pulegone (VIII) O
OPMP
(i) 1 M HCl (ii) Pd(OAc)2 (2 mol%), MeCN, reflux
OPMP
O
49% from 26.1
26.2 O
OPMP
Me O
mesityl-SO2-ONH2, Ms 4 A, Al2O3, CH2Cl2 43%
Me
26.3
(26.4)
H N
80% (i) O3, MeOH, Me2S (ii) TsNHNH2, MeOH (iii) NaBH3CN, TsOH, THF
OPMP
Me
49% 26.6
26.5
HO
OPMP H N
(i) NaH, CbzCl, THF (ii) NaBH4, LiBr, THF
Me 26.7
(iii) TBDPSCl, DMAP, Et3N, CH2Cl2 (iv) CAN, MeCN/H2O 66%
O
OAc
Pd(OAc)2, (iPrO)3P, THF
CO2Allyl
Me
O OTHP TBDPSO
TMS
TBDPSO O Me 26.8
THPO
Me
(iii) PPTS, EtOH TBDPSO (iv) o-NO2PhSeCN, Bu3P, THF, then mCPBA
TFA
EtO2C
Me
TFA
N
Me
TBDPSO
26.13
(iv) HF, pyridine (v) NaBH4, EtOH (vi) NaOH, EtOH, H2O TBDPSO
34% Cl OTBS
74% 26.11
(i) HF, pyridine (ii) o-NO2PhSeCN, Bu3P, THf (iii) Grubbs II-CM with 26.14
Me
(26.12)
CO2Et GrubbsHoveyda CM
N
71%
26.10
P(O)(OMe)2 (26.9)
(i) H2, Pd(OH)2/C, HOAc, EtOH (ii) TFAA, iPr2NEt, DCE
CbzHN
Me
(i) SO3-py, DMSO, Et3N (ii) Et3N, LiCl, THF
CbzHN
NaO2C Me OH Cl
OH
HN
Me (26.14)
26.15 Pinnaic acid sodium salt
Scheme 26 Construction of a 6-aza-spiro-[4.5]decane core from pulegone.
2.7.3.4
Perillaldehyde (IX)
Perillaldehyde, or perilla aldehyde, is found most abundantly in the annual herb perilla, but also in a wide variety of other plants and essential oils. It is used as a food additive for flavoring and in perfumery to add spiciness. Perillaldehyde (IX) is commercially available in both forms of enantiomers with c. 90% ee. ()-IX has been used in the synthesis of the novel antibiotic platencin (38.6, Schemes 38 and 39). The first one55 of two rather similar approaches started with the Diels–Alder reaction of commercially available Rawal’s diene (38.1) to ()-IX to give adduct 38.2 stereoselectively, due to the induction by the isopropylidene sidechain. Wittig methylenation and Grubbs’ RCM led to 38.3. To shift the endocyclic double
190
Chiral Pool Synthesis: Starting from Terpenes O
O
O NaOH, H2O2
O
SPh Me
Me
89%
Me
(i) NaH, PhSH (ii) NH4Cl, H2O
27.2
27.1 (S)-Pulegone O
mCPBA CH2Cl2
O
CaCO3, CCl4 heat
Ph S O
49% from
Me
Me 27.4
27.3 Scheme 27 Degradation of the pulegone sidechain to provide key compound 27.4.
(28.1) O
(CH2)4OBn
O
BzHN H
(i) NH2NHBz (ii) NaCNBH3
(i) (TMSOCH2)2 10% TMSOTf (ii) FeCl3 /SiO2 64%
ent-27.4
CH2O
BzN N
(CH2)4OBn
H
(i) Pd(OH)2, H2 (ii) AIH3 NHBz (CH2)4OBn
[3+2]
(CH2)4OBn
N
BzN
(i) SmI2 (ii) CH2O, NaCNBH3
BnO(H2C)4
80% 28.5
Pd/C
N Bn N
(iii) MsCl, NEt3 71%
28.6
H 28.3
28.4
N
80%
28.2
85%
BnO(H2C)4
NH H
28.7
96%
N R N
28.8 R = H, ((+)-nankakurine A) 28.9 R = Me, ((+)-nankakurine B)
NaCNBH3, CH2O 80%
Scheme 28 Synthesis of the Nankakurines from ent-27.4.
bond into the exocyclic position, 38.3 was brominated to bromonium ion 38.4 which was reduced in situ with chromium(II)chloride to furnish exo-olefin 38.5. This was an intermediate in an earlier synthesis of 38.6.56 The second approach to 38.657 (Scheme 39) also started with a Diels–Alder reaction. Danishefsky’s diene 39.1 was added to ()-IX under forced conditions to provide adduct 39.2. Conversion into di-carbonyl intermediate 39.3 was followed by pinacol cyclization to give diol enone 39.4 after ketal hydrolysis. Selective acetylation of the secondary OH-group was followed by elimination of water to give exocyclic olefin 39.5 which was deacetylated to furnish 38.6.
2.7.3.5
a-Phellandrene (X)
a-Phellandrene was named after Eucalyptus phellandra, from which it was isolated. The phellandrenes are used in fragrances because of their pleasing aromas. a-Phellandrene can form hazardous peroxides with air at elevated temperature.
Chiral Pool Synthesis: Starting from Terpenes
H
isoprene TMSOTf, glycol CH2Cl2 (71%)
(i) FeCl3/SiO2 acetone (ii) BnNH2, NaBH(OAc)3 1,2-dichloroethane
H O
191
H H
(96% 2 steps)
O
NHBn
O ent -27.4
29.2
29.1
Br (i) HCHO, AcOH (ii) H2, Pd(OH)2, Boc2O
H
(iii) CHBr3, NaOH, BnNEt3CI (46% 3 steps)
H
H
(i) TFA, DCM (ii) pyr, reflux
Br
H
(96% 2 steps)
H
Br
HN
BocN
H
29.4
29.3 O H
Br
H N
H
(i) tBuLi, isoamyl nitrite (ii) HCl, acetone
H
O
NaH, THF; HCl, MeOH
H
(33% 2 steps) N
H
Ph
O S
29.6
N
H
H
O
29.7 29.5
H
HN
87%
NH3
29.8 (+)-Lyconadin A
Scheme 29 Diels–Alder reaction with ent-27.4 in the synthesis of (þ)-lyconadin A.
The diene moiety in X can be used for diastereoselective cycloaddition trans to the isopropyl appendage. [2 þ 2]-Additions of ketenes to the more accessible, secondary olefin have been proven extremely valuable in natural product synthesis. Thus, the synthesis of the MSAA drug ()-eleutherobin (Scheme 40)58 was initiated by the addition of dichloroketene to ()-X which gave adduct 40.1 after dechlorination. Condensation with N,N-dimethyl-formamide di-t-butyl acetal furnished 40.2 which was hydrolyzed to the keto aldehyde and fragmented to give an ester aldehyde. In situ addition of 5-bromo-1-lithiofuran provided adduct 40.3 after protection with dr 3:1. Chain elongation gave aldehyde 40.4 which was cyclized to 40.5 via Nozaki–Kishi reaction. Achmatowicz-reaction (see Chapter 2.18) and addition of methyl lithium to the ketone afforded dihydropyran 40.6. Ring contraction and oxidation to ketone 40.7 was achieved over six steps. The ketone was converted into the enol triflate which was used for attaching the sugar sidechain via Stille coupling to provide 40.9. Deprotection and esterification with acid 40.10 gave 40.11 after removal of the acetonide-protecting group. A related [2 þ 2]-ketene olefin cycloaddition was employed in the synthesis of the eunicellin diterpene deacetoxyalcyonin acetate (Scheme 41).59 Adduct 41.1 was obtained stereoselectively and photochemically rearranged to di-acetal 41.2. Under treatment with TiCl4, oxonium ion 41.2 was formed which was trapped by Brassard’s diene 41.4 to give the [3 þ 3]-annulation product 41.5. Methylation and decarboxylation led to ketone 41.6 which was equilibrated and converted into enone 41.7. Conjugate addition of the cuprate formed from bromide 41.8 and trapping of the resulting enolate led to enol triflate 41.9 which was used for a Nozaki–Kishi cyclization to furnish tetracycle 41.10. Acetylation gave 41.11. The less substituted olefin was protected via the epoxide, then the tetrasubstituted double bond was cleaved by ozonolysis to give diketone 41.12 after de-epoxidation with low-valent tungsten. The two keto functions were differentiated by formation of the silyl enol ether to allow a selective Wittig methylenation of the ‘upper’ ketone. Deprotection and stereoselective addition of methyl lithium led to 41.13. The diene system in X has also been used in a stereoselective Friedel–Crafts alkylation (Scheme 42).60 Thus methoxydi-hydroxy acetophenone 42.1 was added to X, under protonation, to give 42.2 regio- and stereoselectively. Acetylation gave 42.3 which was epoxidized to give epoxides 42.4 and 42.5 which were separated. 42.4 was deacetylated, cyclized, and subjected to an aldol addition with benzaldehyde to give linderol (42.6).
192
Chiral Pool Synthesis: Starting from Terpenes (i) I2, pyr (ii) acrylnitrile, AIBN, SnBu3H
O
O NH2
(iii) (OHCH2)2, CSA (iv) LAH (no yields provided)
ent-27.4
H N
O
O
70% HClO4
30.1
O
+ 30.1
NH2 O
dioxane 30.3
30.2
O
Boc2O, Et3N, THF
NH2 H O
O
H O N
N 65% 2 steps
N H
N H
N Boc 30.6
30.4
30.5
(i) Pb(OAc)4, CH2Cl2 (ii) Tf2O, pyridine
N
(i) Catalyst Pd (OAc)2, dppf NH4CO2H, Et3N (54% 3 steps)
OTf
(ii) [Ir(COD)(OMe)]2 [B(pin)]2, THF
N Boc 30.7
N (i) PdCl2, 30.7 dppf, K3PO4, (ii) 6 N HCl
N N Boc
30.8
B O O
N H
H N
N H
(32% 3 steps) H 30.9. ((+)-Complanadine A)
Scheme 30 Mannich cyclization in the synthesis of complanadine A from ent-27.4.
2.7.3.6
()-Menthone (XI)
Menthone is a constituent of many essential oils, though as a minor compound. It is cheaply available as a mixture of isomers; when enantiopure, it costs approximately 1h g1. In the laboratory, ()-menthone has only seldom been used as a starting material in the synthesis of complex natural products. The synthesis of ent-nanolobalolide61 in Scheme 43 is an exception. In the event, the authors converted XI into the thermodynamically favored enol ether 43.1 which was cyclopropanated to give 43.2. Ring enlargement with FeCl3 led to cycloheptanone 43 which was dehydrohalogenated to give enone 43.4. Formation of the enol triflate allowed the introduction of the vinyl ketone appendage in 43.5 which was used in a Nazarov cyclization62 to furnish cyclopentanone 43.6. Conversion to diene 43.7 paved the way for a Diels–Alder addition of ethyl acrylate and delivered the polycyclic compound 43.8 stereoselectively. To convert the ester into acid, a reduction–oxidation sequence was performed. Luckily, in the Pinnick oxidation of the intermediate aldehyde to the acid, an epoxide 43.9 was formed which underwent lactonization to give 43.10.
Chiral Pool Synthesis: Starting from Terpenes
193
H H
(i) IBX, EtOAc (ii) Cs2CO3, 31.2, DMF
(i) TiCl4, allyl-TMS DCM (ii) acetaldehyde
N Boc (31.2) (68%, 2 steps)
I
ent-27.4
O
(70%)
OH 31.1
H
Cl N
pyridine 60 °C
(85%)
O
O
BocN 31.3
H
NTf2
KHMDS, THF
O
O
(99%)
OTf
BocN 31.4
BocN 31.5 O
O
O
H
(i) BH3 THF (ii) IBX, EtOAc
HCHO, H2O, HCl EtOH, reflux
(i) Grubbs II catalyst (20 mol%), 1,2dichloroethane, reflux (ii) H2, 10 atm, 70 °C 52%
O
H O
H
(64% from) NBoc 31.6
N
NBoc 31.7
31.8 (+)-Lycoflexine
Scheme 31 Tandem–Grubbs catalysis and transannular Mannich cyclization in the synthesis of lycoflexine from ent-27.4.
2.7.4 2.7.4.1
Bi- and Tricyclic Terpenes: Nepetalactone and Santonin Nepetalactone (XII)
Nepetalactone was first isolated in 1941 from the plant catnip, Nepeta cataria, which acts as a cat attractant. Nepetalactone is a bicyclic monoterpene, with two fused rings, a cyclopentane, and a lactone. Depending on the Nepeta species, the active ingredient nepetalactone consists of a mixture of four diastereomers which can be obtained in pure form. In the first synthesis of englerin A (cf. the synthesis from citronellal, Scheme 6) trans,cis-nepetalactone XII was used as the chiral starting material (Scheme 43).63 The oxidation of XII to 44.1 with mCPBA installed the desired configuration at C-10. Treatment with sodium methoxide led to ring contraction of the epoxylactone ring to generate formyl lactone 44.2. Allylation of the aldehyde with bromide 44.3 under Barbier conditions and subsequent reduction with LiAlH4 led to diastereomer 44.5 stereoselectively. Acetalization of the vic. OH-groups was followed by oxidation to the aldehyde, epimerization, and Wittig methylenation to give di-olefin 44.6. Grubbs’ RCM and removal of the acetonide furnished cycloolefin 44.7. Esterification of the more accessible hydroxyl function and epoxidation of the double bond afforded 44.8 with moderate stereoselectivity. Transannular opening of the epoxide gave 44.9 which was esterified with cinnamic acid and desilylated to furnish englerin A (Scheme 44).
2.7.4.2
Santonin (XIII)
Santonin is derived from the flower-heads of Artemisia maritima var. stechmanniana and was widely used in the past as an anthelminthic. In the synthesis of the anthelminthic (þ)-absinthin (Scheme 45),64 the known65 photochemical rearrangement of santonin to O-acetylisophotosantonic lactone (45.1) has been used as the key operation. To prepare the cyclopentadiene moiety, the ketone was reduced to alcohol 45.2 which was converted to selenide 45.3. Oxidative elimination furnished cyclopentadiene 45.4 which underwent stereoselective Diels–Alder dimerization to 45.5 at room temperature. To invert the configuration of the tertiary alcohol, it was transformed into ketone 45.6 which added methyl lithium from the less hindered side to give 45.7.
194
Chiral Pool Synthesis: Starting from Terpenes (i) I2 (0.6 equivalent), PhI(OCOCF3)2 (0.6 equivalent), pyridine, (1.2 equivalent), CH2Cl2; r.t. (ii) 1,2-ethane-diol, CSA
ent-27.4
O
O
3,3,-dimethyl1-butyne, BuLi, CuI
I
Me tBu O
Me
O
32.1
Cu Li-LiI
32.2
O
O
TMSEO2C
NBoc
Me
TMSEO2C
(32.3) O
THF, 93%
(i) Cs2CO3, I(CH2)2Cl, DMF (ii) NaN3, NaI, DMF, 65 °C (iii) TBAF, DBU, THF
NBoc
89%
O 32.4
N3
O
Me
NBoc
O
(i) Mg(ClO4)2, MeCN, 60 °C (ii) LiHMDS, NsCl, THF
N3
(i) Me
O
78% from
Me
CO2tBu H N
HCl, THF/H2O
Me NHNs O
O
Me HN
(32.7) THF, −78 °C
32.6
32.5
O
OLi
NNs
(ii) PPh3, PhH, 50 °C
O
tBuO
OtBu
O
CO2tBu H N
92%
O
(i) K2CO3, MeI, DMF (ii) PhSH (iii) CF3CH2OH, 80 °C
HO
O
74%
NHNs NHNs
32.8
Me
Me
Me
CO2tBu H N
CO2tBu H N
(i) p-TsOH, H2O, PhH, 80 °C (ii) Ac2O, Et3N
Ac N Me
O
Me
N
NHMe 32.11
32.10
32.9
N
81%
32.12
Scheme 32 Intramolecular Mannich cyclization in the synthesis of (þ)-fastigatine from ent-27.4.
32.13 (+)-Fastigiatine
Chiral Pool Synthesis: Starting from Terpenes Me LiCu
2 (33.1)
(i) BuLi, ZnBr2 THF (ii) + 33.3
OTMS
OTIPS
ent-27.4
Me
Me
TMSCl, THF
Me H
OTIPS 33.2
Me O
OH TBS
O Me
Me
(i) Im2C=S, toluene (ii) Et3SiH, ClRh(PPh3)3 THF, 50 °C (iii) K2CO3, MeOH
Me O
Me OTIPS
33.4 (84% from 27.4)
33.5
Me
(i) LiBEt3H, THF (ii) Ac2O, pyridine, DMAP CH2Cl2 (iii) TBAF, THF (iv) MnO2, CH2Cl2 (v) MeLi, Et2O (vi) TPAP, NMO, CH2Cl2
OAc
(i) h, O2, rose bengal CH2Cl2 TBS (ii) TBAF, MeI, THF
O
Me
33.6
Me
O
240 °C, 1,2,4-trichlorobenzene, 1,5 h
CO2Me
28 steps
O Me
H
H
Me
H
H Me
Me
H
O H
Me
N
O
O
33.10 Me 33.11 Norzoanthamine Scheme 33 IMDA reaction in the synthesis of the alkaloid norzoanthamine.
CO2Me
Me
CO2Me
O
H
Me
OTBS 33.9 (exo:endo 3:1) O
OAc H
O Me
Me
O
Me Me
OAc H
33.8(exo-TS)
Me
O
33.7
Me AcO H
TBSOTf, Me2NEt CH2Cl2
HF, pyridine, THF
O Me
Me
97%
Me
TBSO
CO2Me
OAc
Me
Me
89%
51% from 33.7
TBS
O Me
79%
OTIPS
TBS O (33.3)
O
O
195
196
Chiral Pool Synthesis: Starting from Terpenes O
(i) LDA, LiCl, MeI (ii) KOH reflux
(R)-Pulegone (IX)
O
(iii) LDA, TMSCl, Br2 (vi) Li2CO3, DMF (38% 4 steps)
O
(i) nBuLi, Bu3SnCH2OMOM
(ii) MsCl, NEt3 (63% over 2 steps)
34.1
(ii) PCC (66% 2 steps)
34.2
OMOM
OMOM
OMOM
O
(i) NaBH4, CeCl3 (ii) mCPBA
O
(i) LDA, Ph-selenoacetaldehyde
(81% 2 steps)
OH Br
(i) DMP (ii) MgBr2*OEt2
OH
34.3
O
(71% 2 steps)
34.4
34.5
ODMB (i) TFAA, pyr. (ii) MgBr2*OEt2, BuSH (iii) CSA, DMBONPy (73% 3 steps)
ODMB
(i) NaBH4, CeCl3 (ii) PPh3, DEAD, pNO2− benzoic acid, NaOMe
Br O
Br
(iii) TBSCl (74% 3 steps)
OTBS
34.6
34.7
DMBO
O
O
I
OHC (34.8)
DMBO O
OTBS I
(i) tBuLi (ii) DMP (45% 2 steps)
(i) TESCl (ii) DDQ
O
(iii) TMSOTf, pyr (58% 3 steps)
OH
(59% 2 steps)
O 34.10 I
34.9
O OTMS OTES
O
(i) TBAF (ii) 1% HCl t-amylOH
O OH (i) 9-BBN (ii) Pd(dppf)Cl2, AsPh3, Tl2CO3
OH O
(iii) TBAF (29% 3 steps)
I 34.11 Scheme 34 Pulegone and geraniol in the synthesis of the diterpene (þ)-phomactin.
34.12 (+)-Phomactin
Chiral Pool Synthesis: Starting from Terpenes
O
O
(i) H2O2, LiOH (ii) NaH, PhSH
(R)-(+)-Pulegone (IX)
O SPh
DBU, DMF, Me-acrylate 40 °C 72%
(iii) NaBO3, AcOH (88% over 3 steps) ent-27.2 O BrMg(CH2)2CCSiMe3 CuBr*DMS, THF
O CO2Me
H
CO2Me
83% TMS
35.2 35.1 EtHN S(CH2)2NH3+ TFA−
EtHN
S
O
O
N
(i) PtCl2, PhMe, 90 °C (ii) SeO2, 1,4-dioxane, 85 °C
(35.3) O AcOH, 110 °C
47%
70% TMS
35.4
EtHN
O S
(i) (OHCH2)2 PPTS, PhH (ii) mCPBA, CH2Cl2 (iii) CBr2F2, KOH*alumina tBuOH, CH2Cl2
O O
1 M NaOH
S N
76%
N
H H
H O
O
(iv) H2, Pd/C, EtOH, THF (v) LAH, THF (vi) 3 M HCl, THF (10% over 6 steps)
35.6 35.5 Scheme 35 Transannular Ramberg–Ba¨cklund olefination in the synthesis of (þ)-fawcettidine.
N H H
H
O 35.7 (+)-Fawcettidine
197
198
Chiral Pool Synthesis: Starting from Terpenes
O
(i) acrylonitrile, AIBN, Bu3SnH, PhH (ii) 1-chloro-4-TMS-3-butyne Mg, CuI, TMSCl, HMPA, THF
O I2, pyr, CH2Cl2
Me
I Me
95%
O
I
CN
Me TMS
(iii) NaI, mCPBA, THF
36.1
ent-27.4
36.2
52% O
AIBN, Bu3SnH, PhH, 60 °C 64%
CN
CN TMS
(i) TFA, CH2Cl2 (ii) SeO2, tBuOOH, CH2Cl2 (iii) Jones oxidation
Me
36.4 CO2Me
CN (36.5)
O Me
41%
36.3 OTBS
O
O
HO
OMe
N O
O
LiClO4, Et2O AcOH, THF, H2O 40%
Me
Me 36.6
36.7 Fawcettimine
Scheme 36 Free radical annulation in a formal synthesis of fawcettimine.
O (i) NaBH4, MeOH (ii) O3, Me2S
O
O
(i) Tf2O, pyr. (ii) DBU, 50 °C
O OH
(iii) THF, aq. H2SO4 (71% over 6 steps)
(iii) (HOCH2)2, CSA
(R)-(+)-Pulegone (VIII)
37.2
37.1
O (37.3)
O
O Br
O
Mg, CuBr*SMe2 TMSCl
then 10 mol% Pd(OAc)2, O2, DMSO
O
2 N HCl, DMSO (43% over 3 steps)
37.4 O
O O
(i) MePPh3Br, NaNH2 (ii) 9-BBN
(i) [PPh3CuH]6, PhH (ii) NaOtBu, tBuOH
(iii) DMP (61% over 3 steps) (58% over 2 steps)
H 37.6
37.5
CO2H O (i) Ph3P=C(Me)CO2Me (ii) LiOH, iPrOH, 40 °C (60% over 2 steps) H 37.7 Scheme 37 Synthesis of valerenic acid from (R)-pulegone.
H 37.8 Valerenic acid
Chiral Pool Synthesis: Starting from Terpenes
199
O (i) toluene, reflux, 4.5 h, (ii) HCl (1.2 M), THF, r.t., 16 h, 68% (dr 20:1);
OTBS
CHO
H
+
CHO NMe2
(−)-Perillaldehyde (IX)
38.1 (Rawal's diene)
(i) Ph3PMeBr, tBuOK, THF, 80%; (ii) Grubbs (II), CH2Cl2, reflux, 95%
38.2
O
O H
H NBS, tBuOH, r.t.;
Br
38.3
38.4
CrCl3, LiAlH4, THF, DMF, 2-propanol, r.t., 48% from 38.3
OH O
O Me O
H
HO2C OH
38.5
N H
H
38.6 Platencin
Scheme 38 Diels–Alder RCM-sequence with perillaldehyde in the synthesis of platencin.
MeCN, 15 kbar, r.t. to 50 °C, 16 h; then Yb(OTf)3 (0.03 equivalent), MeOTMS (0.10 equivalent), toluene, 0 °C, 6 h, 81%; H
OTBS
(−)-IX
(i) Ph3PMeBr (1.30 equivalent), KOtBu (1.10 equivalent), THF, 86%; (ii) ethylene glycol (10.0 equivalent), PPTS (0.25 equivalent), benzene, reflux, 16 h;
O
+
(iii) O3, pyridine (4.0 equivalent), CH2Cl2/ MeOH (1:1), Ph3P (3.0 equivalent), 91% (over 2 steps);
CHO
OMe 39.1 39.2
O
(i) SmI2 (0.1 M in THF, 5.0 equivalent), MeOH (5.2 equivalent), THF, r.t., 10 min; (ii) TsOH, wet CH2Cl2, r.t., 30 min, 85% (over 2 steps)
O
H
O
(i) Ac2O (5.0 equivalent), DMAP, CH2Cl2/pyr. (20:1), 0 °C to r.t., 1.5 h, quant.; (ii) Burgess reagent (2.0 equivalent), toluene, 70 °C, 15 min, 48%
H
CHO Me
OH
HO O
39.4
39.3
O H
O Pd2(dba)3] (0.1 equivalent), PBu3 (0.2 equivalent), Et3N (6.0 equivalent), HCO2H (6.0 equivalent), THF, reflux, 18 h, 60%.
OAc 39.5
Scheme 39 Diels–Alder pinacol cyclization in the synthesis of platencin.
H
38.6
200
Chiral Pool Synthesis: Starting from Terpenes (i) trichloroacetyl chloride, Zn, Et2O, sonication, 0 °C, 65%; (ii) Zn, MeOH, NH4Cl, 87%;
H
O
H (−)-−Phellandrene (X)
H
40.1 OTBDPS
O CO Me 2 H
(iv) TBDPSCl, imidazole, DMAP, 0 °C 97%;
OTBDPS
O
(iv) DIBAL-toluene, −78 to 0 °C, 84%;
40.3 (major isomer)
OH
(i) DMDO/acetone, DCM, −78 °C, 94%; (ii) MeLi, THF, −78 °C, 42%;
H O
Br
O
(i) DIBAL-toluene, CH2Cl2, −78 °C, >95%; (ii) MsCl, pyridine, DMAP, 0 °C, 95%; (iii) KCN, 18-c-6 ether, CH3CN, 80 °C, 96%;
Br
(i) CrCl2, NiCl2, DMF, 74%; (ii) PivCl, DMAP, DCM, NEt3, 91%; (iii) TBAF, THF, 95%;
H
O
40.2
H
(i) p-TsOH‚ H2O, MeOH, 60 °C (ii) p-TsOH‚ H2O, acetone, 60%; (iii) 2,5-dibromofuran, n-BuLi, THF, −78 °C, 57%;
H
Me2N H
(tBuO)2CHNMe2, 60 °C, 75%;
H OPiv
40.4
H
40.5 (i) Ac2O, DMAP, DCM, 73%; (ii) Ag2O, MeI, CH3CN, r.t., 90%; (iii) KCN, EtOH, reflux, 2 h, 95%; (iv) TBSOTf, DCM, 2,6-lut. 0 °C, 83%;
HO H O OH
H
H O OMe
H
(v) DIBAL-H, DCM, −78 °C, 88%; (vi) TPAP, NMO, DCM, 87%
OPiv
(i) LHMDS, Comins reagent, 71−80%; (ii) 40.8, Pd(PPh3)4, LiCl, PMBOCH2SnBu3, THF, 130 °C, 55%
OTBS
O
O O
O
40.7
OAc
40.6
(Bu)3Sn
(i) TBAF, THF, r.t., 67%; (ii) 40.10, DCC, DMAP, CH3Cl, 50 °C, 80%; (iii) PPTS, MeOH, 70%.
OTBS H O OMe
H O
O
O
Me N
HO O
AcO
40.9
(40.10) O
N
O
(40.8) Me N
O H
N O
H O
OMe O
AcO OH 40.11 (−)-Eleutherobin
Scheme 40 Synthesis of eleutherobin from a-phellandrene.
O
OH
Chiral Pool Synthesis: Starting from Terpenes
methoxyacetylchloide, Et3N
H
25%
H
H OMe
OMe AcOH, h
-Phellandrene
86%
O
H
41.1
(X)
TiCl4, −80 °C
O OAc
41.2
OMe
H OMe O
OTES TESO
H
O
(41.4)
(i) BuLi, LiCl, (ii) MeI (iii) LiCl, H2O, DMSO, 130 °C
tBuLi, CuBr.DMS then Comins′ reagent, then 1 M HCl, THF 71%
41.7
H 41.9
H O
H OH
O H
Ac2O, DMAP, pyridine quant
O OAc O
H O 41.12
Scheme 41 Synthesis of a complex diterpene from phellandrene.
OAc
O H 41.11
41.10
H
OTf
O
O
H
88%
Me
H
OEt (41.8)
H
40%
H 41.6
Br O
O
O
50%
H
CrCl2, NiCl2 (catalyst), DMF/THF
(i) mCPBA (ii) O3, DMS (iii) WCl6, nBuLi
H
41.5
41.3
(iii) PhSeCl (iv) mCPBA 71%
OH
H
43−80%
(i) NaOMe, MeOH, reflux (ii) TBSCl, KH
CO2Me
H
(i) KHMDS, TBSOTf (ii) Ph3P=CH2, THF (iii) 1 M HCl (iv) MeLi, Yb(OTF)3 40%
H O
OAc
H HO Me 41.13 Deacetoxyalcyonine acetate
201
202
Chiral Pool Synthesis: Starting from Terpenes
OMe OMe
HO
Ac2O, py, 70 °C, 91%
p-TsOH, toluene, r.t.
+ OH O
Me
(−)-−Phellandrene (X)
76%
HO
OH O
42.2
Me
42.1
OMe
OMe
OMe
m-CPBA, r.t., DCM 94%. AcO
AcO
OAc O
+
O
O
Me
O
OAc
AcO 2:1
Me
OAc O
42.4
42.3
OMe
H
(i) NaOH (2%), MeOH-H2O, r.t.
42.4
HO (ii) NaOH, PhCHO, MeOH, 80 °C 66%.
Scheme 42 Friedel–Crafts alkylation of phellandrene in the synthesis of linderol.
Me 42.5
O O
H Ph
42.6 Linderol
OH
Chiral Pool Synthesis: Starting from Terpenes (i) iPr2NH, MeMgBr, Et2O, 25 °C,12 h (ii) TMSCl, Et3N, 25 °C, 8 h
Me
O Me
Me
Me CH2I2, Et2Zn, hexanes OTMS
Me
Me
(−)-Menthone (XI)
Me 43.1
Me
Me FeCl3, DMF
Me
NaOAc, MeOH
Cl Me
56%
O
Me
O
Me
Me 43.2
(i) LHMDS, PhNTf2, THF (ii) tetravinyltin, Pd(PPh3)4, CO, DMF
Me
43.3
60%
43.4
Me
Me Sc(OTf)3, CH2Cl2
Me Me
(i) MeLi, Et2O, THF (ii) BF3-OEt2,
Me Me
75%
O
43.6
43.5
O
Me CO2Et
Me ethyl acrylate toluene, −20 to 0 °C
Me
34%
Me
43.8
43.7 Me CO2H
Me
Me
43.9
Me
Me
O
48% from O
Me O
(i) DIBALH, toluene (ii) Dess−Martinperiodinane, NaHCO3
Me Me
Me
Me
OTMS
72%
Me HO
Me
ent-Nanolobalolide (43.10)
Scheme 43 ()-Menthone as starting material in the synthesis of ent-nanolobalolide.
(iii) NaClO2, 2-methyl2-butene, tBuOH, pH 7 buffer
203
204
Chiral Pool Synthesis: Starting from Terpenes
H
O O
m-CPBA, CH2Cl2, (dr 1.5:1) 55% (for major stereoisomer);
H
O
H O
H
trans,cis-Nepetalactone (XII)
O
44.1 (major)
H
OH OH
Br OH
O
O
(i) Grubbs−(II) 20 mol%, CH2Cl2, reflux, 99%; (ii) aq. HCl, MeOH, 88%
CHO
H 44.3
(i) Me2C(OMe)2, catalyst pTsOH, CH2Cl2, 95%; (ii) IBX, DMSO, 96%;
H
(iii) DBU, toluene, 70% (dr 3:1); (iv) MePPh3Br, nBuLi, THF, 95%
H
O O 44.6
44.5
(ii) LiAlH4, THF, 98%;
O
H
NaOMe, 93%
44.2 (minor)
H
(44.4)
O +
H
(i) Zn, 44.4, sonication, aq. NH4Cl, THF 93% (dr 5:1);
O
H
H
(i) ClCOCH2OTBS, pyr, CH2Cl2, 91%;
H
H
(ii) mCPBA, DCM, 90% (dr 2.3:1);
O
O
OH
OH
OH
O TBSO
44.8
44.7 Ph reflux in CHCl3,
HO H
O
2,4,6 −
(i) cinnamic acid, trichlorobenzoylchloride, NEt3, DMAP, toluene, 60%
O
O H O
O
99% H 44.9
O
(ii) TBAF, THF, 91%.
O H
TBSO
HO 6.9 (+)-Englerin A
Scheme 44 Trans,cis-Nepetalactone as starting material in the synthesis of englerin A.
O
Chiral Pool Synthesis: Starting from Terpenes
O H
OAc H
AcOH, h, 17 °C,
O
NaBH4, MeOH, r.t.,
O H
38%
99% O
O Santonin (XIII)
45.1
O OAc H
OAc H OH
SeAr
ArSeCN, PBu3, THF, r.t.,
NaIO4, MeOH, r.t., H
H
68%
O
72%
O
O 45.3
O
45.2
OAc OAc H
OAc H H
neat, r.t., 10 d 72%
H
HH O H
O O
(iii) OsO4.NMO (iv) NaIO4, acetone 62%
O
O
O
(i) KOH, MeOH, 30 °C (ii) SOCl2, Et3N
H
H
45.5
45.4 AcO
O O
H H
H
H
H H
AcO
H O
O
O O
H
H HH O
89%
HH O H
MeLi, THF, −78 °C
45.6
O
O
45.7 (+)-Absinthin
Scheme 45 Diels–Alder dimerization in the synthesis of absinthin from santonin.
References 1. Ho, T.-L. Enantioselective Synthesis. Natural Products from Chiral Terpenes; Wiley: New York, 1992. 2. Williams, D. R.; Kammler, D. C.; Donnell, A. F.; Goundry, W. R. F. Angew. Chem. Int. Ed. 2005, 44, 6715–6718. 3. Audia, J. E.; Biosvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738–3740; See also: Trost, B. M.; Romero, A. G. J. Org. Chem. 1986, 56, 2332–2342; Evarts, J. B.; Fuchs, P. L. Tetrahedron Lett. 2001, 42, 3673–3675. 4. Varseev, G. N.; Maier, M. E. Org. Lett. 2007, 9, 1461–1464. 5. Soucy, P.; L’Heureux, A.; Toro, A.; Deslongchamps, P. J. Org. Chem. 2003, 68, 9983–9987. 6. Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696–3697. 7. Nicolaou, K. C.; Sarlah, D.; Wu, T. R.; Zhan, W. Angew. Chem. Int. Ed. 2009, 48, 6870–6874. 8. Zhou, Q.; Chen, X.; Ma, D. Angew. Chem. Int. Ed. 2010, 49, 3513–3516. 9. Nishikawa, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10, 1987–1990. 10. Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem. Int. Ed. 2007, 46, 4708–4711. 11. Martin, H. J.; Pojarliev, P.; Ka¨hlig, H.; Mulzer, J. Chem. Eur. J. 2001, 7, 2261–2271. 12. Martin, H. J.; Magauer, T.; Mulzer, J. Angew. Chem. Int. Ed. 2010, 49, 5614–5626; Magauer, T.; Martin, H. J.; Mulzer, J. Chem. Eur. J. 2010, 16, 507–519. 13. De Carvalho, C. C. C. R.; Da Fonseca, M. M. R. Food Chem. 2006, 95, 413–422. 14. Leitereg, T. J.; Guadagni, D. G.; Harris, J.; Mon, T. R.; Teranishi, R. J. Agric. Food Chem. 1971, 19, 785. 15. Angeles, A. R.; Waters, S. P.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13765–13770. 16. Haaksma, A. A.; Jansen, B. J. M.; de Groot, A. Tetrahedron 1992, 48, 3121–3130.
205
206
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.
Chiral Pool Synthesis: Starting from Terpenes
Pardeshi, S. G.; Ward, D. E. J. Org. Chem. 2008, 73, 1071–1076. (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110, 291–293. (b) Lee, D. W.; Yun, J. Tetrahedron Lett. 2005, 46, 2037–2039. Corminboeuf, O.; Overman, L. E.; Pennington, L. D. J. Org. Chem. 2009, 74, 5458–5470. Nicolaou, K. C.; Xu, J. Y.; Kim, S.; et al. J. Am. Chem. Soc. 1998, 120, 8661–8673. Fuerstner, A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006–3019. Lee, E.; Lim, J. W.; Yoon, Ch. J. Chem. Soc. Chem. Commun. 1994, 479. Lee, E.; Lim, J. W.; Yoon, Ch. H.; Sung, Y.-S.; Kim, Y. K. J. Am. Chem. Soc. 1997, 119, 8391–8392. (a) Oliver, S. F.; Ho¨genauer, K.; Simic, O.; et al. Angew. Chem. Int. Ed. 2003, 42, 5996–6000. (b) Andrews, S. P.; Ball, M.; Wierschem, F.; et al. Chem. Eur. J. 2007, 13, 5688–5712. Yang, H.; Qiao, X.; Li, F.; et al. Tetrahedron Lett. 2009, 50, 1110–1112. Pogrebnoi, S.; Saraber, F. C. E.; Jansen, B. J. M.; Groot, A. Tetrahedron 2006, 62, 1743–1748. Zhang, F.; Jia, Y. Tetrahedron 2009, 65, 6840–6843. Shipe, W. D.; Sorensen, E. J. J. Am. Chem. Soc. 2006, 128, 7025–7035. Wender, P. A.; Singh, S. K. Tetrahedron Lett. 1990, 31, 2517–2520. Ghosh, A. K.; Xi, K. J. Org. Chem. 2009, 74, 1163–1170. Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne, H. O. Angew. Chem. Int. Ed. 2005, 46, 1221–1222. Literature review of pulegone: Grundschober, F. Perfum. Flavorist 1979, 4, 15–17. Sullivan, J. B.; Rumack, B. H.; Thomas, H.; Peterson, R. G.; Brysch, P. J. Am. Med. Assoc. 1979, 242, 2873–2874. Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1994, 116, 5505–5506. Wolinsky, J.; Gibson, T.; Chan, D.; Wolf, H. Tetrahedron 1965, 21, 1247–1261. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214. (a) Pauson, P. L.; Khand, I. U. Ann. N.Y. Acad. Sci. 1977, 295. (b) Magnus, P. Tetrahedron Lett. 1985, 26, 4851–4854. Xu, S.; Arimoto, H.; Uemura, D. Angew. Chem. Int. Ed. 2007, 46, 5746–5749. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485–1486. Caine, D.; Procter, K.; Cassell, R. A. J. Org. Chem. 1984, 49, 2647–2648. Nilsson, B. L.; Overman, L. E.; Read de Alaniz, J.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 11297–11299; cf. Cheng, X.; Waters, S. P. Org. Lett. 2010, 12, 205–207. Nishimura, T.; Unni, A. K.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2011, 133, 418–419. Fischer, D. F.; Sarpong, R. J. Am. Chem. Soc. 2010, 132, 5926–5927. Ramharter, J.; Weinstabl, H.; Mulzer, J. J. Am. Chem. Soc. 2010, 132, 14338–14339. Liau, B. B.; Shair, M. D. J. Am. Chem. Soc. 2010, 132, 9594–9595. Benhida, R.; Blanchard, P.; Fourrey, J.-L. Tetrahedron Lett. 1998, 39, 6849–6852. Medda, A. K.; Lee, H. S. Synlett 2009, 921–924. Myashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science 2004, 305, 495–499. Mohr, P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003, 125, 1712–1713. Kozak, J. A.; Dake, G. R. Angew. Chem. Int. Ed. 2008, 47, 4221–4223. Liu, K.-M.; Chau, C.-M.; Sha, C.-K. Chem. Commun. 2008, 91–93. Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J. Org. Chem. 1989, 54, 1548–1562. Lee, H. W.; Ji, S. K.; Lee, I.-Y. C.; Lee, J. H. J. Org. Chem. 1996, 61, 2542–2543. Kopp, S.; Schweizer, W. B.; Altmann, K.-H. Synlett 2009, 1769–1772. Tiefenbacher, K.; Mulzer, J. J. Org. Chem. 2009, 74, 2937–2941. Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J. Angew. Chem. Int. Ed. 2008, 47, 1780–1783. Waalboer, D. C. J.; Schaapman, M. C.; van Delft, F. L.; Rutjes, F. P. J. T. Angew. Chem. Int. Ed. 2008, 47, 6576–6578. Chen, X.-T.; Bhattacharya, S. K.; Zhou, B.; et al. J. Am. Chem. Soc. 1999, 121, 6563–6579. Molander, G. A.; St. Jean, D. J., Jr.; Haas, J. J. Am. Chem. Soc. 2004, 126, 1642–1643. Delaye, P.-O.; Lameiras, P.; Kervarec, N.; Mirand, C.; Berber, H. J. Org. Chem. 2010, 75, 2501–2509. Cheng, H. M.; Tian, W.; Peixoto, P. A.; Dhudshia, B.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2011, 50, 4165–4168. Review: Habermas, K. I.; Denmark, S. E. Org. React. 1994, 45, 1–158. Willot, M.; Radtke, L.; Konning, D.; et al. Angew. Chem. Int. Ed. 2009, 48, 9105–9108. Zhang, W.; Luo, S.; Fang, F.; et al. J. Am. Chem. Soc. 2005, 127, 18–19. (a) Barton, D. H. R.; De Mayo, P.; Shafiq, M. J. Chem. Soc. 1957, 929. (b) Blay, G.; Cardona, L.; Garcia, B.; Lahoz, L.; Pedro, J. R. J. Org. Chem. 2001, 66, 7700–7705 and references therein.
2.7.1 2.7.2 2.7.2.1 2.7.2.2 2.7.2.3 2.7.3 2.7.3.1 2.7.3.1.1 2.7.3.1.2 2.7.3.1.3 2.7.3.2 2.7.3.3 2.7.3.3.1 2.7.3.3.2 2.7.3.3.3 2.7.3.4 2.7.3.5 2.7.3.6 2.7.4 2.7.4.1 2.7.4.2 References
Introduction Acyclic Monoterpenes: Citronellol, Citronellal, and Citronellene Citronellol (I) Citronellal (II) (S)-Citronellene (III) Cyclic Monoterpenes Carvone Annulations Ring contraction Ring cleavage Dihydrocarvone (VI) Pulegone (VII) Ring contraction Ring cleavage and recyclization Degradation of the pulegone isopropenyl sidechain. Formation and application of enantiomerically enriched 5-methyl-2-cyclohexanone (27.4) Perillaldehyde (IX) a-Phellandrene (X) ()-Menthone (XI) Bi- and Tricyclic Terpenes: Nepetalactone and Santonin Nepetalactone (XII) Santonin (XIII)
Glossary Chiral pool The whole entity of chiral natural products. Chiral pool synthesis Asymmetric synthesis making use of chiral natural products by incorporating part of them into the target structure. Ring annulations Formation of new rings which are attached to preexisting ones.
2.7.1
163 163 164 166 170 171 171 171 176 178 179 179 181 181 181 189 190 192 193 193 193 205
Terpenes Members of the chiral pool; constituents of natural flavors. Contain isoprenoid (five carbon) units. Monoterpenes have two and sesquiterpenes three isoprenoid units. In general, they have at least one stereogenic center. Chiral monoterpenes can be acyclic (e.g., citronellol) or cyclic (e.g., carvone).
Introduction
Terpenes, in particular monoterpenes of known absolute and relative configuration, have been used in the chiral pool synthesis of targeted and natural compounds for many years. As this topic was extensively reviewed in 1992,1 this chapter was focused on the application of selected terpenes (Chart 1) in natural product syntheses from about 1998 onward. As representative examples, our literature search unearthed the terpenes shown in Chart 1. They fall into three categories: (1) acyclic monoterpenes such as I–III; (2) monocyclic monoterpenes such as IV–IX; and (3) biand tricyclic terpenes such as X, XI. Categories 1 and 2 have been most widely used, for XI and XII only a few cases have been reported. The advantages of all these terpenes lie in their low cost and the functional versatility. Most monoterpenes are commercially available in both forms of enantiomers, the optical purity being approximately 85–95% enantiomeric excess (ee).
2.7.2
Acyclic Monoterpenes: Citronellol, Citronellal, and Citronellene
Citronellol and citronellal are natural products. (R)-(þ)-Citronellol, which is found in citronella oils, is the more common enantiomer. (S)-()-Citronellol (I) is found in the oils of rose (18–55%) and Pelargonium geraniums. It is used in perfumes and insect repellents, as a mite attractant, and for the production of rose oxide. The compound is nontoxic, but it may cause allergies. Citronellal (II) gives citronella oil its characteristic lemon scent. It is distilled from the plants Cymbopogon, lemon-scented gum, and lemon-scented teatree. Citronellal has insect-repellent properties, especially against mosquitoes, and also strong antifungal
Comprehensive Chirality, Volume 2
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163
164
Chiral Pool Synthesis: Starting from Terpenes
Me
Me
Me
Me
Me
OH
III (S)-Citronellene
O
Me
Me
Me
Me
Me
Me
O II (R)-(+)-Citronellal
I (S)-(−)-Citronellol
Me
Me
Me
O
O
O
O Me IV (R)-(−)-Carvone
V (S)-(+)-Carvone
VI (−)-Dihydro-carvone
Me
CHO
VII (S)-(+)-Pulegone
Me Me
H
O O
IX (−)-Perillaldehyde Chart 1
Me
Me
X -Phellandrene
Me
Me
XI (−)-Menthone
VIII (R)-(−)-Pulegone
O
O Me
Me
Me
Me
Me
Me
Me
H O
H
Me
XII Nepetalactone
O XIII Santonin
Terpenes used for chiral pool synthesis.
qualities. (S)-Citronellene (III) is manufactured from (a)-pinene via catalytic hydrogenation followed by pyrolysis. III can be converted into I via hydroalumination/oxidation. From I, aldehyde II is readily available by the usual oxidation protocols.
2.7.2.1
Citronellol (I)
Apart from trivial chain extensions and endgroup modifications, the more spectacular applications of I in natural product synthesis imply cyclizations to form complex polycyclic structures. The intramolecular Diels–Alder (IMDA) reaction along with its transannular modification (transannular Diels–Alder – TADA) (see Chapter 2.17) has proven its value in the three examples depicted in Schemes 1–3. Thus, the synthesis of the antibiotic alkaloid (þ)-apiosporamide (Scheme 1, 1.10)2 features the combination of two advanced intermediates from the chiral carbon pool: amino acid 1.5 which is derived from quinic acid, and trans-decalin 1.8 which stems from citronellol (I). In the first sequence, cyclohexenone 1.1 was prepared from quinic acid as described previously3 (see Chapter 2.11) and deoxygenated to give 1.2. Addition of deprotonated b-lactam 1.3 led to adduct 1.4 (dr ¼ 1.6:1) which was separated from the mixture and converted into epoxide 1.5 stereoselectively. The lactam was opened with allyl alcohol to furnish the required amino acid derivative 1.6. In a parallel sequence, citronellol I was elaborated into alkyne 1.7 which was used for a Negishi-type chain elongation to provide the Diels–Alder precursor 1.8. IMDA reaction was accomplished with high endo-selectivity to provide the trans-decalin ketone which was carboxylated to give acid 1.9. Coupling with 1.6 was followed by removal of the allyl-protecting group and carbonyl activation. Dieckmann ring closure led to keto lactam 1.10 which was deprotected and aromatized to furnish 1.11. In a related example, (S)-()-citronellol was used in the total synthesis of the marine alkaloid (þ)-neosymbioimine (2.12, Scheme 2).4 The crucial octalene structure 2.8 was accessed by an endo-IMDA (cf. see Chapter 2.17) of triene 2.7, which was prepared from I by a strategy related to the one described in Scheme 1. Thus, I was converted into aldehyde 2.1 which was a-hydroxylated and olefinated to give enoate 2.2. Two additional olefination steps led to triene 2.7 which underwent a thermal IMDA reaction to give decalin 2.8 with 495% stereoselectivity. Chain elongation to the nitrile and stereoselective methylation provided 2.9. Routine functional group manipulation delivered ketal 2.10 which was cyclized to imine 2.11. Demethylation of the aryl OMe ethers was followed by di-sulfonation, and selective mono-hydrolysis of one sulfonate ester furnished 2.12. It is a short step from the IMDA to the TADA reaction. In fact, this is the key transformation in the synthesis of the marine diterpene (þ)-chatancin (3.8, Scheme 3).5
Chiral Pool Synthesis: Starting from Terpenes
165
O
O Quinic acid
O
5
NOPMB (1.3) TBSO KHMDS, THF, 97%, (dr 1.6:1)
(i) H2, Pd(OH)2 /C, 97%; (ii) DBU,TBSCl, TBSO heat, 72%;
O OH
steps O
NOPMB
O 1.4
1.2
1.1 H (i) TBAF, THF (98%) (ii) mCPBA, CH2Cl2, NaHCO3(54%)
TBSO
H O
TBSO
allyl alcohol, nBuLi
H
O H CO2Allyl
O TBSO
(iii) TBSCl, imidazole, CH2Cl2,100%
TBSO
80% NOPMB
NHOPMB 1.6
1.5
(i) Catalyst TEMPO, PhI(OAc)2, CH2Cl2, 70%; (ii) Ohira-Bestmann reagent, K2CO3, MeOH, r.t., 82%; (iii) Catalyst OsO4, K3Fe(CN)6, K2CO3, tBuOH/H2O, 94%;
(i) [Cp2Zr(H)Cl], CH2Cl2, r.t.; then I2, 77%; (ii) [Pd(PPh3)4] (5 mol%), (E)-BrZnCH=CHCH3, THF/Et2O/pentane (4:4:1), 74%;
O
OH 1.7
(−)-Citronellol (I)
(i) EtAlCl2, toluene, −78 °C to r.t., 72% (>97:3 dr); (ii) LiHMDS, THF, then HMPA at −78 °C; then MeOC(O)CN, 62%;
O
O
H
(iii) KOH, aq. MeOH, 0 °C, 81%; 1.8
TBSO
(i) BOP, Et3N, MeCN, 1.6, 99%; (ii) [Pd(PPh3)4], pyrrolidine, CH2Cl2, 85%;
H H
HO2C
H
(iii) Dess−Martin periodinane, py, CH2Cl2, 90%;
(iv) NaIO4, aq. THF (1:1); (v) H3CC(O)CH2P(O)(OMe)2, K2CO3, 91% (13:1 E/Z)
(iii) BOP, CH2Cl2, DBU, 20 °C, 56%;
1.9
H O
H
O
O
TBSO
H
H
(i) SmI2, THF, 98%; (ii) BrCCl3, TMG, 65%; (iii) HF·pyr, THF, 75%.
HO
H N O OPMB 1.10
O
H
OH
O
H
H H
OH N H
O
1.11 (+)-Apiosporamide
Scheme 1 Synthesis of decalin substructure 1.9 via IMDA reaction starting from (S)-()-citronellol.
The synthesis started with the conversion of citronellol I into bromide 3.1 which was added to the anion of sulfone 3.2. Desulfonation was followed by oxidation to aldehyde 3.3 which elaborated into a keto sulfone at one end and into an alkynoic ester at the other. Lindlar hydrogenation and oxidation furnished a strong Michael acceptor, which was used for macrocyclization to form the TADA precursor 3.6. Heating in the presence of water furnished the Diels–Alder substrate 3.7 which cyclized in situ to chatancin. An organocatalytic intramolecular Michael addition was used for the synthesis of the polycyclic neurotrophic iridoid ()-litteralisone (Scheme 4).6 Citronellol I was converted into ester aldehyde 4.1 which was subjected to an organocatalytic
166
Chiral Pool Synthesis: Starting from Terpenes
(i) TBSCI, imidazole DMF, 95%; (ii) O3, CH2Cl2/MeOH (1:1), then Me2S, 93%
(i) nitrosobenzene, D-proline, DMSO,
O
(ii) triethylphosphono acetate, DBU, LiCl, (iii) MeOH, NH4Cl, Cu(OAc)2, 24 h;
(iv)TBSCl, imidazole, DMAP, CH2Cl2, 88%
OH
OTBS
(−)-S-Citronellol (I)
2.1
CO2Et
CO2Et
(i) CSA, MeOH, 87%; (ii) Dess−Martin periodinane, CH2Cl2, 96%
OTBS
CO2Et
toluene, 100 °C, 30 h, 88%;
OTBS
OTBS CHO
CHO
O
OTBS 2.2
2.3
Ph3P
2.5
(2.4)
OMe (O)P(EtO)2
(2.6)
OMe
CO2Et Ar
TBSO
CHCl3, 60 °C, 2 h 86%;
OTBS CO2Et H Ar
KOtBu, THF, −78 to 0 °C
H 2.8
2.7
NC TBSO H
(i) DIBAL-H, CH2Cl2, 24 h, 88%; (ii) MsCl, Et3N, CH2Cl2, 94%; (iii) NaCN, DMSO, 98%; (iv) LDA, THF, MeI, 87%;
Ar
(i) TBAF, THF, 99%; (ii) Dess−Martin periodinane, CH2Cl2, 96%; (iii) (CH2OH)2, CSA, C6H6, 94%
NC O
O Ar H
H
H
2.9
2.10 OSO3−
N (i) LiAlH4, Et2O, (ii) 3 M HCl, THF, 90%;
H
Ar
(i) BBr3, CH2Cl2, 84%; (ii) SO3, Py, pyridine, (iii) H2O/MeOH (1:2), 79% brsm.
H
N
OH
H 2.11
H
H 2.12 (+)-Neosymbioimine
Scheme 2 (S)-()-Citronellol as starting material for an IMDA cyclization to provide (þ)-neosymbioimine.
a-hydroxylation to furnish hydroxy enoate 4.2 after Keck–Masamune olefination. 4.2 was elaborated into di-aldehyde 4.3 which was the substrate of the proline-catalyzed Michael addition to generate glycoside 4.4 after acetylation. Vilsmeyer formylation and Pinnick oxidation led to the formation of lactone 4.5 which was used for glycosidation with 1-O-TMS-b-D-glucose tetraacetate (4.6). Anomerically pure diene 4.7 was obtained and was subjected to photocycloaddition, which gave the cyclobutane ring. Hydrogenolysis furnished ()-litteralisone 4.8.
2.7.2.2
Citronellal (II)
Similar to citronellol, the chiral pool applications of citronellal are characterized by the utilization of the differentiable end groups in various ring-forming operations.
Chiral Pool Synthesis: Starting from Terpenes (i) PivCl, pyr. (ii) SeO2, t BuOOH (iii) MsCl, NEt3, LiBr
167
Br OPiv
OH
36%
3.1
(S)-Citronellol (I) (i) nBuLi, THF (ii) + 3.1 (iii) Na/Hg, NaH2PO4, (iv) HCl, iPrOH (v) TPAP, NMO
PhO2S
OMOM
OPiv O
45%
(i) LDA, MeSOPh, (ii) Dess−Martin Ox. (iii) HCCCOOMe, LDA 70%
3.3
3.2
O
(i) H2, Lindlar (ii) Dess− Martin Ox. (iii) I2, Et2O
HO
SOPh 3.4
O
O
O
70%
3.5
64% CO2Me
OH
DMSO/H2O 1:1, 110 °C
O
89%
3.6
O
SOPh
CO2Me
CO2Me
(i) Cs2CO3, acetone (ii) PhMe 110 °C
OH O
CO2Me
CO2Me 3.7
3.8 (+)-Chatancin
Scheme 3 TADA-approach to (þ)-chatancin.
So, it is no big surprise that II has been used for IMDA reactions, for instance, in the synthesis of the fungal metabolite hirsutellone B (Scheme 5).7 Thus, (R)-citronellal II was converted into epoxy vinyl iodide 5.2 which was used in a Stille cross coupling with stannane 5.3 to give polyene 5.4. Under the influence of Et2AlCl, the stannane undergoes a Sakurai-type cyclization with the epoxide to generate cyclohexane derivative 5.5 to which two additional rings are annulated in a tandem IMDA reaction. The tricyclic intermediate 5.6 was thus obtained stereoselectively. The next subgoal was the conversion of 5.6 into sulfone 5.10. Mukaiyama etherification and reduction of the ester led to aldehyde 5.7 which was used for the extension of the sidechain to deliver ketone 5.8 after functionalization of the aryl methyl group. Introduction of a thioaetate- and a primary iodide led to intermediate 5.9 which was cyclized to the thioether under basic conditions. Oxidation furnished sulfone 5.10. Ramberg– Ba¨cklund ring contraction led to (Z)-cycloolefin which was carboxylated to the b-keto ester. Sharpless asymmetric dihydroxylation (AD) of the olefin and regioselective Barton–McCombie deoxygenation of the diol afforded alcohol 5.11 stereoselectively. Oxidation of the alcohol to the ketone was followed by heating with NH3 to obtain 5.12 via an amidation – C-17 – epimerization cyclization cascade. A similarly sophisticated polycyclization, this time under the catalysis of Au(I), has been employed in the synthesis of ()-englerin A (Scheme 6).8 The sequence started with the differentiation of the end groups in citronellal II to procure the alkynoic enal 6.1. Asymmetric aldol addition (see Chapter 2.13) led to hydroxyl ketone 6.2 which was cyclized with AuCl to give the polycyclic intermediate 6.5 stereoselectively, presumably via intermediates 6.3 and 6.4. The construction of the strained trans-fused ring of englerin was achieved via epoxidation and shift of the double bond to give allylic alcohol 6.6. Inversion of the OH-function and hydrogenation furnished diol 6.7, whose more accessible OH-group was protected as the ketone. The remaining alcohol was esterified and then the ketone was reduced to give 6.8. The remaining task was the introduction of a second ester group, which was achieved via SN2-reaction of an intermediate sulfone with the anion of 2-hydroxyacetic acid. Citronellal has also been used for the synthesis of alkaloids. The required nitrogen was introduced via the end group functionality. Thus, in the synthesis of the lycopodium alkaloid ()-cernuine (Scheme 7),9 citronellal II was used for the final construction of no less than four annulated six-membered rings. Thus, II was first converted into the monoprotected aldehyde 7.1 which was used for an organocatalytic electrophilic a-amination with di-carbobenzoxy-diimide and prolinol catalyst 7.2 to
168
Chiral Pool Synthesis: Starting from Terpenes
(i) Mesityl-Cl, DMAP, pyridine, CH2Cl2; (ii) O3, MeOH, CH2Cl2,
O
OH 95%
CO2Me
56%
O
(S)-(−)-Citronellol (I)
HO
(i) PhNO, D-proline (40 mol%), DMSO; (ii) (EtO)2P(O)CH2CO2Me, LiCl, DBU; NH4Cl, MeOH.
O
4.1
(i) TBDPSCl, imidazole, DMF. (ii) DIBAL,Et2O, (iii) DMP, CH2Cl2
OMes
(i) L-proline (30 mol%), DMSO, (ii) Ac2O, DMAP, pyridine
TBDPSO CHO O
92%
83%
H
4.2
4.3 OBn
(i) POCl3, DMF, (ii) NaClO2, NaH2PO4, t BuOH. (iii) HF‚ pyridine, THF. (iv) DCC, CH2Cl2
TBDPSO H O H
OAc 4.4
56%
O O TMSO
H
O OAc
4.5
4.6 TMSOTf (0.4 equivalent), CH3CN 74%
OH O
(i) 350 nm, (ii) H2 Pd/C 84%.
O
84%
H
O O O
O
O
OBn OBn OBn
OBn OBn OBn
O
OBn
O
H
O
H
O H
O
4.7
O OH
O H
O
O
O
OH OH
4.8 (−)-Littoralisone
Scheme 4 Organocatalytic key steps in the synthesis of ()-litteralisone.
urethane 7.3, after reduction. Deprotection led to the cyclic aminal 7.5 which underwent a Sakurai-type allylation to give 7.6. Hydrolysis of the urethane and amide formation with acryloylchloride paved the way for ring-closing metathesis (RCM), which led to the bicyclic intermediate 7.8 after some functional group modifications. The aldehyde function was used for a 2-aza-Cope rearrangement with optically active amine 7.9 to generate amine 7.10 with 94% de under auxiliary control. Acid-catalyzed formation of amidine 7.11 was followed by reduction to the aminal, amidation with acryloylchloride, and RCM to close the fourth ring. Hydrogenation completed the synthesis of 7.12. In the total synthesis of the anti-HIV drug biyouyanagin A (Scheme 8),10 the aldehyde end group of II is used for ring closure whereas the trisubstituted olefin part is transferred into the target molecule unchanged. The strategy involves a biomimetic [2 þ 2]photocycloaddition of the components 8.3 (ent-zingberene, from citronellal) and 8.6 (hyperolactone C, from malic acid in seven steps (see Chapter 2.10). The synthesis of 8.3 commenced with a Robinson annulation of methyl vinyl ketone under the asymmetric catalysis of prolinol 8.1. Cyclohexenone 8.2 was formed with 86% de and converted into cyclohexadiene 8.3. To prepare compound 8.6, L-malic acid was converted into lactone 8.4 which was elaborated into alkyne 8.5. Palladium-catalyzed addition of a benzoyl group followed by spirolactonization furnished 8.6 after formation of the vinyl sidechain. The envisaged photoaddition indeed furnished 8.7 as postulated.
Chiral Pool Synthesis: Starting from Terpenes (i) Ph3PCH2I2, KHMDS, THF, (ii) O3, CH2Cl2; then Me2S, 80% for 2 steps; (iii) Ph3P=CHCHO, CHCl3,
Bu3Sn
O CO2Me
CuTC, NMP, 25 °C, 6 h, 70%
(iv) Catalyst 5.1, H2O2 CH2Cl2; (v) Ph3P = CHCO2Me, 58%;
CHO
I
Ph Ph
(R)-(+)-Citronellal (II)
(5.1) N H
5.2
OTMS
CO2Me
OAlEt 2
H Et2AlCl, CH2Cl2, 50%;
O
CO2Me
TMS
H 5.5
5.4
OH H
H
TMS 5.3
(i) pTol4BiF, Cy2NMe, Cu(OAc)2, PhMe, (ii) LiAlH4, Et2O,
CO2Me
H
(iii) TEMPO, PhI(OAc)2 CH2Cl2, 78% for 3 steps
HH
O
H
CHO
HH
5.6
5.7 SAc HO OH
(i) BrMg(CH2)3OTBS, THF, (ii) DMP, CH2Cl2, 91% for 2 steps;
O
H
H (iii) CAN, MeCN/H2O (20:1), (iv) NaBH(OAc)3, PhH, 81% for 2 steps;
O
HH
(i) NaOMe, MeOH/THF (1:1, 1.0 m M); (ii) H2O2, 35%, Na2WO4, THF/MeOH (1:1), 79% for 2 steps;
O S O
O H
O
HH
H
O
O H
17
CO2Me
5.9 (i) CF2Br2, KOH/Al2O3, CH2Cl2 /tBuOH (1:1), (ii) LHMDS, NCCO2Me, THF, 61% for 2 steps; (iii) AD-mix-⇓, MeSO2NH2, tBuOH/H2O (1:1), 90%; (iv) S=CCl2, 4-DMAP, CH2Cl2, (v) AIBN, nBu3SnH, PhMe, 65% for two steps
5.10 OH (i) DMP, CH2Cl2, 92%; (ii) NH3, MeOH/H2O (4:1), 50%
H
O
NH
O H
17
O HH
HH 5.11 Scheme 5 IMDA reaction in the synthesis of hirsutellone B.
O H
HH
H
O
H
5.8
OH
I
ZnI2, AcSH, CH2Cl2, 68%;
5.12 (hirsutellone B)
169
170
Chiral Pool Synthesis: Starting from Terpenes (i) P(OPh)3, Br2, Et3N (ii) tBuOK, 18-crown-6, petroleum ether (iii) SeO2, TBHP, salicylic acid, CH2Cl2 (iv) IBX, EtOAc
O H (S)-Citronellal
H
O (i) 3-methyl-2-butanone, (−)-Ipc2BCl, Et3N (ii) MeOH, H2O, pH 7
Me
95%
39% 6.1
(II) H OH O Me Me
AuCl 10 mol%, CH2Cl2, r.t., 20 min
Me
LAu
OH
Me
87%
(i) TPAP, NMO, CH2Cl2, MeOH (ii) NaBH4, MeOH OH (iii) Raney-Ni, H2 (90 atm), 75 °C EtOH
O
H Me
Me
6.5
O
iPr − AuCl
OH H Me 6.4
6.3
HO
H
Me
48%
OH (i) mCPBA, CH2Cl2 (ii) CSA, CH2Cl2 H
LAu
Me
6.2
O
iPr O Me
OH HO
O
H Me
65%
H Me
6.6
6.7 Ph
(i) DMP, NaHCO3, CH2Cl2 (ii) cinnamic acid, 2,4,6,trichlorobenzoyl chloride, DMAP, Et3N (iii) NaBH4, MeOH 74%
O OH Ph
O H Me
O
6.8
H Me
(i) LiHMDS, (imid)2SO2, THF (ii) HOCH2CO2Cs, 18-crown-6, PhMe, reflux, 48 h
O H
O H
66%
O
O O HO
6.9 (−)-Englerin A
Scheme 6 Gold(I)-catalyzed cyclization in the synthesis of ()-englerin.
2.7.2.3
(S)-Citronellene (III)
Citronellene is commercially available in acceptable optical purity. Alternatively, it may be prepared from citronellol via E2-elimination of citronellyl bromide (Scheme 9). The synthetic utility arises from the differentiation of the olefinic end groups. The more electron-rich trisubstituted double bond reacts selectively with meta-chloroperoxybenzoic acid (mCPBA) which allows the formation of alcohol 9.1. This is one of the key fragments in the stereocontrolled synthesis of the microtubule-stabilizing antitumor agent (MSAA) epothilone B (Scheme 8).11 Alcohol 9.1 was converted into bromide 9.2 and then into the Grignard derivative 9.3, which was added to ketone 9.4, readily available from D-mannitol. Chelate Cram-controlled addition furnished the tertiary alcohol 9.5 with high diastereoselectivity (see Chapter 2.12). Chain elongation and deprotection led to triol 9.6 whose three OH-functions were differentiated to give tesyl mesylate 9.7. Epoxide formation afforded 9.8 stereoselectively which was oxidized to aldehyde 9.9 and subjected to diastereoselective aldol addition (cf. see Chapter 2.13) with enolate 9.10. Adduct 9.11 was formed exclusively and elaborated into macrolide 9.12. Deprotection gave epothilone B (9.13). In a synthesis of the ansa-macrocyclic antibiotic kendomycin (Scheme 10),12 citronellene (II) was used to incorporate the stereogenic centers at C-18 and C-12 independently. Thus, II was converted into aldehyde 10.1 which was olefinated via the acetylide to give (E)-vinyl iodide 10.3. Negishi cross coupling with aryl bromide 10.4 furnished styrene 10.5 which was oxidized to benzofuran 10.5. Conversion of the end group gave carboxylic acid 10.6 which was esterified with alcohol 10.7, readily obtained from aldehyde 10.1 via Hiyama–Kishi addition of isopropenyl bromide. Ester 10.8 was used for a Claisen–Ireland rearrangement (see Chapter 2.21) to furnish olefin 10.8 after reduction of the carboxylic acid to the primary alcohol. Further reduction to the methyl group was followed by oxidation of the end group to aldehyde 10.10. Evans–Metternich aldolization with oxazolidinone 10.11 and reduction of the ketone (see Chapter 2.3) led to the stereoselective formation of lactone 10.12, which was opened to the methyl ester, saponified to the carboxylic acid, and cyclized to give macrolactone 10.13. Ring contraction via photo-Fries
Chiral Pool Synthesis: Starting from Terpenes (i) ethylene glycol, p-TsOH, PhH, reflux; (ii) RuCl3, NaIO4, DCM, H2O, r.t., 87% (2 steps);
OHC
O O
O (R)-(+)-Citronellal (II) O
HN O
N
(i) H2, Pd/C, THF, r.t.; (ii) H2, Raney-Ni, MeOH, 60 °C
O
O
(i) CbzN=NCbz, 6.2 (10 mol%), DCM (ii) NaBH4, MeOH; (iii) K2CO3, toluene, 94%;
7.1
Cbz
N H O
Ph Ph 7.2 OTMS
p-TsOH, MeOH, reflux
HN
O
171
O
O 7.4
7.3 OMe TiCl4, DCM, 7.5, 0 °C N
O
N
TMS
(i) aqueous NaOH, MeOH reflux; (ii) acryloylchloride, NEt3, DCM,
O
O
O
56% (6 steps);
7.6
7.5 (i) Grubbs I cat, DCM, r.t.; (ii) H2, Pd/C, EtOH, r.t., 99% (2 steps); (iii) IBX, DMSO, r.t.; (iv) Ph3CH2(OMe)Cl, KHMDS, THF, (v) 3 M HCl, THF, r.t., 62% (3 steps);
N O OH
(i) CSA, DCM, 6.9, r.t. (ii) NH2OH-AcOH, 92%, 94% de
N O
O 7.8
NH2 O
(7.9)
7.7
N H2N
TiCl4, xylene, reflux, 80%; O
7.10
N N
7.11
(i) NaBH4, AcOH, MeOH, (ii) acryloylchloride, NEt3, DCM, 62% (2 steps); (iii) Grubbs II, DCM, r.t., 78% (iv) H2, Pd/C, EtOH, r.t., 96%;
N
H N
O
7.12 Cernuine
Scheme 7 Alkaloid synthesis from citronellal.
rearrangement led to ketone 10.14 which was reduced to the alcohol and then cyclized to tetrahydropyran 10.15. Oxidation of the benzenoid system to the p-chinomethide furnished kendomycin 10.16.
2.7.3
Cyclic Monoterpenes
2.7.3.1
Carvone
(S)-(þ)-Carvone smells like caraway because it is the principal constituent (50–70%) of the oil from caraway seeds (Carum carvi),13 which is produced on a scale of approximately 10 tons per year. (R)-()-Carvone smells like spearmint and it is present at levels greater than 51% in spearmint oil, which is produced on a scale of approximately 1500 tons annually.14 Both enantiomers have been used extensively in asymmetric natural product synthesis. The strategies involved fall into three groups: (1) annulations of rings of various sizes to the original cyclohexane rings, (2) ring contraction of the cyclohexane to cyclopentane, and (3) ring fission of the cyclohexane and formation of new rings.
2.7.3.1.1
Annulations
A straightforward annulations method is Diels–Alder addition of an electron-rich diene. Thus, in the synthesis of the cell adhesion inhibitor (þ)-peribysin E (Scheme 11),15 (R)-carvone IV was treated with diene 11.1 under Lewis acid catalysis to furnish
172
Chiral Pool Synthesis: Starting from Terpenes
(i) MVK (1.5 equivalent), 8.1 (5 mol%), ethyl 3,4− dihydroxybenzoate (20 mol%), CHO (R)-(+)-Citronellal II
(ii) KOH (0.1 N aq, 1.0 equivalent), nBu4NOH (40% aq, catalyst), Et2O/THF/H2O (3:1:3), 68% yield, 86% de
H
8.2
(i) KHMDS (1.5 equivalent), THF, (ii) Comins reagent (1.5 equivalent), THF (iii) MeMgI (3.0 M in Et2O, 1.5 equivalent), CuI (2 mol%), THF
O
80% (2 steps)
H
8.3 (ent-zingberene)
Ph Ph
(8.1) N H OBn HO
O
O
OMe OBn
(i) DMP (2.0 equivalent), CH2Cl2, 92%; (ii) acetylene, nBuLi, HO THF, 79%, 3:1 dr O
O
Ph O 8.5
8.4
(i) Pd(PPh3)4] (5 mol%), PhI, CO (200 psi), CO2 (200 psi), Et3N, 77%; (ii) BBr3 (1.5 equivalent), CH2Cl2
(from malic acid)
DCM, 2′-acetonaphthone (1 equivalent), h, 46%
(iii) o-NO2PhSeCN (1.2 equivalent), P(nBu)3 (1.2 equivalent), THF, (iv) H2O2 (30% aq, excess), THF, 73% (3 steps)
H
H H
H Ph
O 8.6 (Hyperolactone C)
O
O
O
8.3 + 8.6
O
O
O
8.7
Biyouyanagin A Scheme 8 Citronellal forms the left-hand component in a biomimetic [2 þ 2]-photocycloaddition to generate biyouyanagin A.
Diels–Alder adduct 11.2 stereoselectively under the influence of the bulky isopropenyl sidechain. The enone double bond was introduced by a Saegusa oxidation. Protection of the more reactive ketone, as the thioketal and Wittig reaction of the unprotected one, led to alcohol 11.3 after reduction of the intermediate aldehyde. Further reduction to a methyl group was followed by deprotection of the thioketal and oxidation of the isopropenyl appendage to methyl ketone 11.4. Baeyer–Villiger oxidation to the acetate and a-iodination furnished vinyl iodide 11.5 which was used in a Suzuki coupling with vinyl boronic ester 11.6 to give diene 11.7. Scheffer–Weitz epoxidation and ketone reduction proceeded with high diastereoselectivity from the less hindered a-face to give hydroxyl epoxide 11.8. Lewis acid-induced semipinacol ring contraction generated aldehyde 11.9 which was immediately trapped as the methyl acetal to give (þ)-peribysin E (11.10). A similar Diels–Alder strategy16 was used for the generation of a cis-decalin system in the synthesis of the eudesmane sesquiterpene lairdinol A (Scheme 12).17 Diene 12.1 was added to (R)-carvone (IV) to give di-one 12.2. Regioselective Rubottom a-hydroxylation gave 12.3 which was converted into enone 12.4 via four steps. Base-catalyzed isomerization to the trans-decalin was possible only after reduction of the adjacent ketone. Epoxidation with H2O2/NaOMe in methanol led to 12.5 as the main product. The OH-function was removed by a Barton–McCombie deoxygenation to give epoxy ketone 12.6, whose stereoselective hydroxylation was achieved with phenyl iodosodiacetate (PIDA). Wharton rearrangement furnished allylic alcohol 12.7 which was oxidized to ketone 12.8. Hydrogenation with Stryker’s reagent18 and ketone reduction led to lairdinol A (12.9). A sophisticated Prins-pinacol annulation was used in the synthesis of the marine diterpene briarellin F (Scheme 13).19 The synthesis started with (S)-carvone (V) which was converted into a mixture of diol diastereomers, from which 13.1 was isolated. Further manipulation led to vinyl iodide 13.3 which was lithiated and added to aldehyde 13.4. Diol 13.5 was formed as a mixture of diastereomers which was subjected to a Prins-pinacol rearrangement with aldehyde 13.6, whose mechanism is described in Scheme 14. Thus, it may be assumed that ketal 14.1 is formed first which is opened to a carboxonium species 14.2. A [3.3]-sigmatropic rearrangement generates enol 14.3 under stereocontrolled CC-bond formation trans to the neighboring sidechain. A Mukaiyama-type aldol addition leads to the ring closure under formation of aldehyde 13.7. Photolytic decarbonylation and epoxidation furnished 13.8, which was opened to form triol 13.9. Ring closure to 13.10 and introduction of a tertiary alcohol via epoxidation/ring opening was followed by a Nozaki–Kishi macrocyclization of vinyl iodo aldehyde 13.12 to generate briarellin E (13.13) which was oxidized to briarellin F (13.14).
Chiral Pool Synthesis: Starting from Terpenes (i) PPh3, CBr4, CH2Cl2 (ii) KOtBu, THF
173
(i) mCPBA, CH2Cl2, NaHCO3 (ii) LAH, Et2O
OH 68%
44%
(S)-(−)-Citronlellol I, ee c. 80%
(S)-(+)-Citronellene III (i) TsCl, pyridine (ii) LiBr, acetone
HO
Mg, THF
Br
80%
9.1
OPMB Me
OPMB HO O
78%
O
Me
Me
O
73% 9.5 dr > 96:4
9.4 S
(i) DDQ, CH2Cl2, H2O (ii) DMP, CH2Cl2 (iii) Horner−olefination (iv) 2 N HCl, EtOH
Me
O O
9.3
9.2
(i) MgBr2-OEt2, CH2Cl2 (ii) 9.3, THF
Me
BrMg
Me
HO
Me
(i) 3 equivalent TESCl, NEt3 Me (ii) MsCl, NEt3
Me
Me
N
S
Me
Me
Me
N TESO
84%
OH OH 9.6
HO OMs 9.7
O K2CO3, MeOH
Me 15
S
95%
Me
Me
(i) OsO4, NMO (ii) NaIO4, H2O, MeOH 62%
Me
N OTES 9.8
Me
O S Me
TBSO OLi (9.10)
Me 15
N
OTES
O Me
OH
N
89% dr >95:5
O
TBSO 8.11
9.9 O 6 steps
S
85%
N
OTroc O
(i) Zn/MeOH (ii) HF/pyridine
Me O TBSO
Me
TBSO
7
Me
Me
S
O
9.12
O
O S OH
N 62%
O
Me O
OH O 9.13 Epothilone B
Scheme 9 Citronellene as a key fragment in the synthesis of epothilone B.
Another possibility is the successive addition of carbon appendages which are used for ring formation later on. An example of this strategy is provided by the synthesis of the MSAA drug sarcodictyn A (15.9, Scheme 15).20 The sequence is entirely substrate controlled and starts with the Scheffer–Weitz epoxidation of (S)-carvone. The first carbon appendage is then added via aldol addition of formaldehyde to provide 15.1. Reductive epoxide opening led to allylic alcohol 15.2 which was used for a Johnson–Claisen rearrangement to furnish aldehyde 15.3 after reduction of the ester. Further manipulation of the two sidechains was achieved via intermediates 15.4 and 15.5 to generate functionality suitable for macrocyclization. This step was accomplished by deprotonating the alkyne moiety in 15.5 and adding it to the aldehyde. Ketone 15.6 was obtained after reoxidation of the intermediate alcohol. Hydrogenation to the double bond led to the formation of the dihydrofuran ring in 15.7 and the synthesis was concluded with the esterification of the secondary alcohol and the elaboration of the carbomethoxy sidechain.
174
Chiral Pool Synthesis: Starting from Terpenes
(i) mCPBA, DCM (ii) H5IO6 (iii) Li(OEt)3H
18
(i) TMSCHN2, nBuLi, THF, 83%; (ii) [Cp2ZrHCl], benzene, (iii) I2, 76%;
O
I
OTBDPS 10.2
OTBDPS 10.1
Citronellene (III) [Pd(PPh3)4], tBuLi, ZnCl2, Et2O/THF, 67%
TBDPSO
Br
(i) DMDO, acetone, 99% (dr 1.1:1); (ii) Pd(OAc)2, PBu3, tBuOH, 81% (2 steps);
OMOM
OMOM MOMO
TBDPSO O
MOMO
OMe
MOMO OMe 10.4
10.3
OMe 10.5 O
HO2C
EDCI, DMAP, 9.6, CH2Cl2, 85%;
(i) TfOH, toluene/EtOH (4:1), MS 4 A; (ii) MOMCl, NaH, DMF, 90% (2 steps) (iii) TBAF, THF, r.t., 89%;
O
(iv) IBX, DMSO, r.t., 97%; (v) NaClO2/NaH2PO4
O
OH
O
12
MOMO OMe
OTBDPS
10.6
(10.7)
MOMO
TBDPSO
10.8 OMe
OH (i) LHMDS, HMPA, TBSCl,
(i) MsCl, Et3N, CH2Cl2; (ii) LiAlH4, Et2O, 94% (2 steps); O
TBDPSO
(ii) LiAlH4, Et2O, 84% (dr 4:1, 2 steps);
O
MOMO
MOMO 10.9
OMe
(i) Sn(OTf)2, CH2Cl2, Et3N, 87% (dr 6:1); (ii) Me4NBH(OAc)3, CH3CN/AcOH (2:1), 72% (dr 20:1); (iii) LiOH, H2O2, THF/H2O (3:1), 96%
10.10
O HO
O
N
O O
(iv) EDCI, DMAP, DMAP·HCl, CHCl3, 55%;
MOMO
O
OMe
(i) 3 M HCl, dioxane; (ii) (CH3)2C(OMe)2, CSA, 85% (2 steps); (iii) LiOH, THF/MeOH/H2O (2:1:1), 84%;
O
O
O
(iii) TBAF, THF, r.t., 93%; (iv) IBX, DMSO, r.t., 93%.
OMe Bn
10.12
(10.11)
h (254 nm), cyclohexane, 50 min, 75%
OH
O
O
O
O
HO
HO O
HO OMe
10.13 Scheme 10 Citronellene in the synthesis of kendomycin.
10.14
OMe
(i) NaBH4, MeOH, r.t., then 0.5 m HCl; (ii) TsOH, toluene, 60 °C, 71% (2 steps). (iii) TESOTf, Et3N, CH2Cl2, 82%;
Chiral Pool Synthesis: Starting from Terpenes
12 18
(i) IBX, DMF, r.t., 24 h; (ii) 0.1M HF, MeCN, r.t., 30% (2 steps)
O
O
O
OH O
HO
TESO
HO
HO
O
OMe
10.15
10.16 (Kendomycin)
Scheme 10 Continued.
OTMS +
H
(i) EtACl2, PhMe (ii) Pd(OAc)2, MeCN
(i) 1,2-ethandithiol, MeOH, BF3-OEt2 (ii) PPh3=CHOMe, THF
O
(iii) 4 N HCl, MeOH, THF (iv) NaBH4, MeOH, THF (66%, 4 steps)
63% 11.1
O (R)-(−)-Carvone IV
(i) MsCl, Et3N, CH2Cl2 (ii) LiBHEt3, THF (iii) PIFA, MeOH, H2O, CH2Cl2
S S
11.3
O O
O
O Me
I
H
O
(i) mCPBA, CH2Cl2 (ii) TMSN3, I2, pyidine, CH2Cl2
Me Me 11.4
(11.6)
B
H
Me
O
(iv) OsO4, H2O2, NaIO4, 2,6-lutidine,dioxane (53%, 4 steps)
Me
O
Me 11.2
H
HO
O
O
OTBS
Pd(PhCN)2Cl2, Ag2O, Ph3As THF, H2O
(32%, 2 steps)
H
O
O
OTBS
Me Me 11.7
(89%)
11.5
(i) H2O2, NaOH, MeOH
HO
(ii) NaBH4, MeOH, THF (77%, 2 steps)
H
OH
Me Me
OTBS
(i) TESCl, imidazole, THF (ii) TiCl4, CH2Cl2
(37%, from 11.8)
HO
H H OH Me O Me OH
O
11.9
11.8
HCl, MeOH
TESO
H O Me OH OMe Me 11.10 (−)-Peribysin E
Scheme 11 Diels–Alder annulation to carvone as the key step in the synthesis of peribysin E.
175
176
Chiral Pool Synthesis: Starting from Terpenes
O Me
(i) LDA, TMSCl (ii) mCPBA, CH2Cl2
Me Me
O
(i) EtAlCl2, PhMe (ii) NaOH, MeOH 74%
(R)-(−)-Carvone IV
HO
O Me
(12.1)
TMSO
O Me
O
O
12.3
O Me Me
(iii) Tf2O, iPr2NEt (iv) Et3SiH, LiCl, Pd(PPh3)4
Me
90% 12.2
(i) Swern-oxidation (ii) SiO2, Et3N Me
Me H Me
NaOH, H2O2
O
c. 80%
MeH
OH Me
O
Me
Me H 12.5
12.4
79%
(i) NaHMDS, CS2, MeI (ii) Bu3SnH, AIBN
Me
O O
Me
MeH 12.6
85% O
Me
DMP Me 91%
HO MeH 12.8
OH Me
(i) PhI(OAc)2, NaOH, MeOH (ii) HCl (iii) NH2-NH2, HOAc
Me HO MeH
77%
12.7 (i) [CuH(PPh3)]6, PhMe2SiH, PhMe (ii) NaBH4, MeOH 91%
OH Me Me HO MeH 12.9 Lairdinol A
Scheme 12 Diels–Alder annulation to carvone in the synthesis of the eudesmane sesquiterpene lairdinol A.
A Pt(II)-catalyzed ‘Ohloff–Rautenstrauch’ annulation of a cyclopropane and a cyclopentene ring to (S)-carvone (V) was the key operation in a synthesis of the sesquiterpenes cubebene (16.10 and 16.11, Scheme 16).21 Thus, V was converted into enol triflate 16.1 which was used for a Stille coupling with vinylstannane. Hydroboration–oxidation and addition of acetylide led to propargylic alcohol 16.2. The alcohol was oxidized to the ketone which was reduced stereoselectively to the (S)-enantiomer (16.4) with Noyori’s catalyst (16.3). Acetylation led to 16.5 which was treated with PtCl2 to induce the above mentioned rearrangement. A plausible mechanism postulates the formation of an oxolanylium species 16.6 which then undergoes double bond shift to generate a Pt-carbenoid 16.7. Cyclopropanation leads to 16.8, which was deacylated to ketone 16.9, and then elaborated into the target structures 16.10/16.11.
2.7.3.1.2
Ring contraction
It was reported in 1994 that carvone undergoes a Favorskii ring contraction to the highly functionalized cyclopentane derivative (Scheme 17).22 This intermediate was first used in the total synthesis of the sesquiterpene lactone (þ)-cladantholide (Scheme 17).23 Thus, stereoselective epoxidation of IV and opening of the resulting oxirane with lithium chloride gave the chlorohydrins 17.1 after tetrahydropyranyl (THP)-protection. Treatment with methoxide induced the Favorskii rearrangement to 17.2 as the sole product. Reduction to the aldehyde followed by Felkin Anh selective addition of vinyl magnesium bromide (see Chapters 2.4 and 2.12) gave 17.3 which was alkylated with 17.4 to give bromo-acetal 17.5. Free radical cyclization led to the exclusive formation of 17.6 which was converted to the ketone, and a-hydroxylated to furnish 17.7. Shapiro reaction followed by oxidation of the acetal to the lactone and a-methylation delivered 17.8. The corresponding enantiomer ent-17.2, obtained from (S)-carvone, was used for a synthesis of the more complex guaianolide thapsivillosin F (Scheme 18).24 The OTHP-protecting group was exchanged for the more robust TBDPS in 18.1 which was elaborated into 18.2 and then into di-olefin 18.3 via similar organometal carbonyl additions. RCM and dihydroxylation of the resulting enol ether furnished hydroxyl ketone 18.4. A Horner reaction was used for the annulation of lactone 18.5. Reductive opening and protection gave the diol derivative 18.6 which was dihydroxylated, oxidized, and closed to lactone 18.7. Several functional group adjustments via 18.8 and 18.9 including the introduction of three ester appendages furnished 18.11.
Chiral Pool Synthesis: Starting from Terpenes
(i) 9-BBN, H2O2, NaOH (ii) MPLC
O
Me
(i) TIPSCl, imidazole (ii) PCC, NaOAc
H
c. 40%
87% OH
OH 13.1
(S)-(+)-Carvone V Me
tBuLi, THF, add (i) LDA, Comins′ reagent (ii) (PPh3)4Pd, (Me3Sn)2 (iii) NIS
H OTIPS
O
Me
H MeO OTIPS
65%
(13.4) TMS
Me
Me
H
O TIPSO
(13.6)
OH
OTIPS
H
CHO
p-TsOH, MgClO4, CH2Cl2 then SnCl4, CH2Cl2 84%
TMS Me
H
TIPSO
H
H
TBDPSO
43%
TMS 13.7
Me
(i) Ac2O, DMAP (ii) TFA, H2O (iii) Ac2O, DMAP
H O
O
(i) h, dioxane (ii) KOH, MeOH (iii) (tBuO)3Al, tBuOOH
O
OTBDPS
HO 13.5
H
then PPTS, MeOH 62%
H H
O
O
I
13.3
13.2 Me
177
H
TIPSO
H
HO
86%
H H
(i) mCPBA (ii) TBAF, THF (iii) Tf2O, 2,6-lutidine
O
45%
AcO
Me
(i) H2SO4, THF, H2O (ii) MsCl, Et3N (iii) LAH, Et2O
O
H H
H
O H
AcO 13.10 Me OH H
H H
O O R
H
O
O
O R
CrCl2, NiCl2 DMSO-Me2S
R 13.12
O
49% 13.11
Me OH H
H H H
O
(i) Bu3SnAlEt2, CuCN (ii) I2 (iii) (tBu)2OHSnCl, MeOH (iv) DMP
O
O
I H
H
AcO
Me
79% O
Me OH H
H H
(iv) Bu8Sn2Cl4O2, iPrOAc (v) n-C7H15COCl =RCOCl 61%
AcO
Me
Me
O
O
13.9
AcO
13.8
HO
O
OH
O 13.13 (briarellin E)
Me
Me OH H
H H
DMP
O
79%
H
O R
O
O
O 13.14 (briarellin F)
Scheme 13 Prins-pinacol annulation to carvone in the synthesis of briarellins E and F.
A related application of cyclopentane 17.2 has been reported for the synthesis of the guaianolide 8-epi-grosheimin (19.7, Scheme 19).25 In this case, the ‘methoxymethyl (MOM)’ group was selected for the protection of the secondary alcohol so that aldehyde 19.1 was the chiral starting material. Mukaiyama aldol addition of butyrolactone-TMS-enol ether to 19.1 furnished adduct 19.2 with moderate stereoselectivity. Refunctionalization furnished lactone 19.3 which was reduced to alcohol 19.4. Swern oxidation to the aldehyde was followed by an ene cyclization to generate 19.5 stereoselectively. Eschenmoser methylenation led to 19.6 which was oxidized to 19.7. The synthesis of a steroid D-ring fragment from 17.2 has also been reported.26 Recently, an application of 17.2 in the synthesis of the monoterpene alkaloid incavilline was described (Scheme 20).27
178
Chiral Pool Synthesis: Starting from Terpenes
Me
H
Me
H OH
OTIPS
R
O
H
H
HO
13.5 TMS
SnCl4, CH2Cl2
TIPSO
(13.6)
R
p-TsOH, MgClO4, CH2Cl2
O O
14.1 TMS
Me
H
Me OSnCl3
OTIPS R
Me
H
TIPSO TIPSO
H H
OSnCl3 R
O
CHO O
O
TBDPSO 14.2
TMS
14.3
TMS
TMS 13.7
Scheme 14 Mechanism of the Prins-pinacol annulation from 13.5 to 13.7.
Stereoselective hydroboration of 17.2 led to alcohol ester 20.1,22 which was reduced to the diol and then di-mesylated to give 20.2. Cyclization with methylamine and deprotection furnished 20.3.
2.7.3.1.3
Ring cleavage
A third option in the use of carvone is cleavage of the original ring to an acyclic fragment whose end groups are modified and used for a new cyclization reaction. This strategy has been pursued in the syntheses of guanacastepenes, retigeranic acid, and platensimycin. In the synthesis of guanacatepene E (Scheme 21),28 (S)-carvone (V) was selectively hydrogenated to provide an isopropyl sidechain and then methylated to give 21.1. Ozonolytic cleavage of the endocyclic double bond followed by hydrocyanantion of the aldhehyde furnished 21.2 which was lactonized to 21.2. Anionic ring contraction led to cyclopentene 21.4. Conversion to the nonaflate and Wulff–Stille coupling furnished stannane 21.5 which was connected via allyl-Stille coupling with allyl acetate 21.6 to give tri-olefin 21.7. Photolytic [2.2]-cycloaddition led to cyclobutane 21.8. Reductive ring cleavage and selenation of the resulting enolate gave 21.9. Oxidative elimination of the selenium led to diene 21.10. Hydroxylation and O-acetylation followed by oxa-Michael cyclization furnished 21.12. Another ring cleavage of carvone has been utilized in the synthesis of ()-retigeranic acid (Scheme 22).29 The synthesis entails the addition of the dianion of carboxylic acid 22.2 to aldehyde 22.7 to form triene 22.8 after decarboxylative dehydration of the intermediate b-hydroxy acid. Acid 22.2 was prepared from (R)-carvone via selective hydrogenation of the exocyclic double bond, followed by the formation of the epoxide 22.1 via the bromo-acetate. Fragmentation led to the d-keto acid which gave olefin 22.2 after Wittig methylenation. Aldehyde 22.7 was prepared from 3-methyl glutarate 22.3 which was elaborated into enantiomerically pure arene olefin 22.5 via ketone 22.4. Arene olefin meta-photo-cycloaddition gave tetracyclic intermediate 22.6 (mixture of isomers). Free radical addition of the formamide radical followed by N-dimethylation and oxidation of the allylic methyl group led to aldehyde 22.7, which was connected to acid 22.2 via aldol addition and decarboxylative dehydration. Electrocyclization led to 22.9 as a mixture of isomers, which was converted to diene 22.10 via the epoxide. Mono-hydrogenation to 22.11/22.12 followed by conversion of the amide to the acid gave 22.13. A Baeyer–Villiger oxidative cleavage of the original ring and the de-novo formation of a cyclopentane ring are the characteristics of the synthesis of the antibiotic platensimycin (23.15) from (S)-carvone (Scheme 23).30 The key step of the synthesis is the IMDA addition of triene 23.10 (see Chapter 2.17) to generate the characteristic polycyclic core 23.11 of platensimycin. First the exocyclic double bond of (S)-carvone was converted into the bromohydrin which was then used in a free radical addition to the endocyclic double bond to give the bicyclic hydroxyl ketone 23.1. Baeyer–Villiger oxidation and relactonization led to lactone 23.2, the hydroxymethyl appendage of which was removed by a second Baeyer–Villiger oxidation to give OTBS-alcohol 23.3. Tebbe olefination followed by stereoselective hydroboration generated alcohol 23.4, which was converted into ketone 23.5. Asymmetric Horner olefinierung with phosphonate 23.6 gave olefin 23.7 with good (E)-selectivity. After protection, a second Horner olefination was used to generate enoate 23.9 via alcohol 23.8. Next, the diene system was installed to form enol ether 23.10 as a mixture of E/Z-isomers. On thermolysis, only the (E)-isomer underwent the
Chiral Pool Synthesis: Starting from Terpenes
O
(i) H2O2, NaOH (ii) H2, PtO, EtOH
O
O
(iii) LDA, CH2O, THF (iv) TBSCl, Et3N, CH2Cl2 46%
HO
(iv) Na-naph, THF OTBS
OTBS
79%
15.1
(S)-(+)-Carvone V
(i) CH3C(OEt)3 iPrCO2H (catalyst) (ii) DIBAL, CH2Cl2
(i) L-selectride, THF (ii) MsCl, Et3N, THF
CHO
15.2
OH
(i) CH2=CHOEt tBuLi, THF (ii) H2SO4, Et2O
72% OTBS
179
(i) TESOTf, Et3N, CH2Cl2 (ii) PPTS, MeOH, CH2Cl2
HO
(iii) HCCMgBr, THF (iv) TBAF, THF 32%
15.3
(iii) TPAP, NMO, CH2Cl2 (iv) NCCH2CO2Et, -alanine, EtOH 91%
OH 15.4
OH OTES TESO CO2Et NC
OH
(iv) DMP, NaHCO3, CH2Cl2 (v) HF-NEt3, THF 58%
OTIPS 15.6
N (ii) TBAF, THF
O
O
(i) NEt3, DMAP O MeN
80%
O
15.5
OH
(i) H2, [Rh(nbd)(dppb)]BF4, acetone (ii) MeOH, PPTS
(i) DIBAL, hexanes (ii) TIPSOTf, iPr2NEt, CH2Cl2 (iii) LiHMDS, THF
O O
tBu
Me N
O
(15.8)
N O
OMe OTIPS 15.7
(iii) DMP, NaHCO3, CH2Cl2 (iv) NaClO2, NaH2PO4, 2-methyl-2-butene, THF, tBuOH (v) CH2N2, Et2O (vi) CSA, CH2Cl2, H2O 58%
OH CO2Me 15.9 Sarcodictyn A
Scheme 15 Addition of vic. carbon appendages to carvone for ring formation to 15.6.
IMDA cyclization to furnish 23.11 stereoselectively in 44% yield. Chain elongation of the ester led to 23.12 after hydrogenation of the endocyclic double bond. Conversion of the methyl ether to the ketone followed by re-introduction of the endocyclic double bond and ester hydrolysis provided platensic acid 23.13 which was amidated with amine 23.14 to give platensimycin (23.15).
2.7.3.2
Dihydrocarvone (VI)
Both enantiomers of dihydrocarvone are commercially available. For an application of trans-()-dihydrocarvone (VI) in natural product synthesis, colombiasin A (Scheme 24) is discussed here.31 The cyclohexane ring of VI is maintained until the end of the synthesis, whose key step is a Moore annulation of squarate 24.7 to form quinone 24.11 which has been shown to undergo thermal IMDA reaction to 24.12. The sequence was started with an unselective hydroboration of VI to furnish alcohol 24.2 which was chain elongated to aldehyde 24.3 and converted to diene 24.5 via Julia–Lythgoe–Kocienski olefation with sulfone 24.4. Oxidation to ketone 24.6 was followed by Shapiro reaction and the resulting vinyl carbanion was trapped with 24.7 to give adduct 24.8. Thermolysis led to electrocyclic formation of trienyl ketene 24.9 which underwent electrocyclization to 24.10. Oxidation with air furnished quinone 24.11. The IMDA product 24.12 was demethylated to afford colombiasin A (24.13).
2.7.3.3
Pulegone (VII)
Pulegone is obtained from the essential oils of a variety of plants such as Nepeta cataria (catnip), Mentha piperita, and pennyroyal.32 Pulegone is clear, colorless, and has a pleasant odor similar to pennyroyal, peppermint, and camphor. It is used in
180
Chiral Pool Synthesis: Starting from Terpenes
(i) [(PPh3)3RhCl], H2 (ii) Pd/C, H2
O
(i) CH2=CHSnBu3, [Pd(PPh3)4], LiCl, THF (ii) 9-BBN, THF (iii) H2O2, H2O
TfO
(iii) NaOMe/MeOH (iv) LTMP, THF Comins′ reagent (77% overall)
(S)-(+)-Carvone V
16.1 (i) DMP, CH2Cl2 (ii) (S,S)-16.3, iPrOH(88%)
HO
(iv) DMP, CH2Cl2 (v) TMSCCH, BuLi, CeCl3, THF 35%
HO
Ts N Ru Ph N H (S,S)-16.3 Ph
TMS 16.2
PtCl2, PhMe, 80 °C
AcO
(i) TBAF, THF
TMS 16.4
Me
O O
(ii) Ac2O,DMAP, Et3N CH2Cl2 (82%)
(92%) Cl2Pt 16.5 16.6
Me
O
−PtCl2
O AcO H Cl2Pt
16.8
16.7
Ph3P=CH2 DMSO (99%)
K2CO3, MeOH (76%)
H
H H
O H
H 16.9
16.10 (−)--Cubebene (i) LDA, THF, Comins′ reagent (ii) MeMgBr, [Fe(acac)3] THF, NMP (82%, 2 steps)
H H 16.11 (−)--Cubebene
Scheme 16 Pt(II)-catalyzed Ohloff–Rautenstrauch annulation to carvone leads to the cubebenes.
flavoring agents, in perfumery, and in aromatherapy.33 Interestingly, (R)-(þ)-pulegone is much cheaper (c. 3h g1) than the (S)-enantiomer (c. 200h g1). In the exemplary natural product syntheses given below (Sections 2.7.3.1 to 2.7.3.3), pulegone has been used not as such. Instead, it has been modified by ring contraction to a cyclopentane, or by ring cleavage and recyclization or by degradation of the exo-methylene moiety.
Chiral Pool Synthesis: Starting from Terpenes (i) H2O2, NaOH (ii) LiCl, TFA (iii) PPTS, DHP
H
73%
O (R)-Carvone (IV)
(i) DIBAL, THF (ii) vinylMgBr, THF
Cl
H
H
H
(iii) LDA, THF, TMSCl (iv) DMDO, CH2Cl2 63%
O
HO
H
17.6
H
Br
O
99%
17.5
Me (i) TsNHNH2, MeOH (ii) MeLi, THF
O H O
OEt
Bu3SnH, AIBN, benzene, reflux
THPO
OEt
98%
Me
THPO
Br (17.4)
Et3N, DMAP, CH2Cl2
17.3
(i) p-TsOH, MeOH (ii) PCC,
CO2Me H 17.2
Br
OH
THPO
O 17.1
OEt H
H
NaOMe, MeOH 95%
THPO
77%
H
H
THPO
181
OEt 17.7
(iii) CrO3, H2SO4, acetone (iv) LDA, THF, MeI 18%
O
H
Me
H
Me
H Me
O O
17.8 (+)-Cladantholide Scheme 17 Favorskii-ring contraction of carvone in the synthesis of guaianolides.
2.7.3.3.1
Ring contraction
In the synthesis of the alga diterpene (þ)-epoxydictymene (Scheme 25),34 pulegone was converted into cyclopentyl-carboxylic acid 25.1 via a Favorskii ring contraction.35 Acid-catalyzed hydration and LiAlH4-reduction gave diol 25.2. Acylation and dehydration led to olefin 25.3 which was saponified, metallated with BuLi, and trapped with TMSCl to give allyl silane 25.4. Alkynylation of the triflate with 25.5 generated 25.6 which was subjected to a Nicholas reaction.36 Ring closure to cobalt complex 25.7 was followed by a Pauson–Khand cyclization37 to furnish cyclopentenone 25.8. As the configuration at C-12 is wrong, the cyclopentane ring was cleaved to give keto aldehyde 25.9 with correct stereochemistry at C-12 after base-catalyzed equilibration. Twofold olefination afforded di-olefin 25.10 which was reduced to alcohol 25.11. Transformation into the iodide, lithiation, and Michael addition closed the missing cyclopentane ring. Reductive decyanation delivered the angular methyl group to complete the synthesis of 25.12.
2.7.3.3.2
Ring cleavage and recyclization
In the synthesis of the phospholipase inhibitor pinnaic acid (26.15, Scheme 26),38 the main challenge was to obtain an easy access to the crucial 6-aza-spiro-[4.5]decane core 26.11 in enantiomerically enriched form. The solution presented here implied the oxidative ring cleavage of pulegone to di-ester 26.1 with subsequent Dieckmann cyclization/alkylation to provide cyclopentanone 26.2. Decarboxylation and Saegusa oxidation led to cyclopentenone 26.3. Trost annulation of 26.4 gave diquinane 26.5 stereoselectively and Beckmann rearrangement led to lactam 26.6. Removal of the exo-double bond via the tosylhydrazone furnished 26.7. Reduction of the lactam and deprotection produced alcohol 26.8 which was oxidized to the aldehyde and olefinated to give enone 26.10. Reductive amination induced ring closure, and the allylic double bond was introduced via the Grieco protocol39 to give 26.11. Grubbs’-cross metathesis (CM) with ester 26.12 delivered enoate 26.13 which was elaborated into 26.15 via a second CM with diene 26.14.
2.7.3.3.3
Degradation of the pulegone isopropenyl sidechain. Formation and application of enantiomerically enriched 5-methyl-2-cyclohexanone (27.4)
A number of natural product syntheses is based on key intermediate 27.4 which is readily available from pulegone via oxidative degradation of the sidechain (Scheme 27).40 Thus (S)-pulegone was converted into epoxides 27.1 which were treated with thiophenoxide to give sulfides 27.2. Oxidation to the sulfoxides 27.3 and thermal elimination furnished (R)-5-methyl-2-cyclohexanone (27.4). Analogously, (R)-pulegone was converted into ent-27.4.
182
Chiral Pool Synthesis: Starting from Terpenes
(i) PPTS, MeOH H (ii) TBDPSCl, imidazole TBDPSO CO2Me 82% H
THPO
(i) LAH (ii) NaH, PMBCl (iii) OsO4, NaIO4 (iv) AllylMgBr (v) MOMCl, DIPEA
H
CO2Me
ent-17.2
H
OMOM
H
H
(i) Grubbs II (ii) OsO4
TBDPSO
OMOM
TBDPSO
OTES
H
OTES
H
H OTES
H
OMOM
18.7
OH
H
HO H
77%
O
O O
(i) TMSCl (ii) DMDO (iii)TMSCl (iv) PhSeBr O
O
OAc
H O
HO
OH
senecioic acid anhydride, DMAP 73%
TMSO
74%
O O
O O 18.9
O
OAc O
H
HO
O O
O OH
OH
O 18.10
OTMS
H
O 18.8
O
(i) NaBH4 (dr 4:1) (ii) angelic acid, 2,4,6-trichlorobenzoyl chloride (iii)TBAF, (iv) iso-propenyl acetate, PPTS (v) HCl, H2O 35%
(i) Amberlyst-15, acetone (ii) TBAF O (iii) TPAP/NMO
OH
O
62%
OAc
18.6
OMOM HO
(i) OsO4 (ii) K2CO3 (iii) TPAP/NMO
OMOM
18.5
H
OMOM
TBDPSO
80%
O
79%
O
18.4 (dr 16:1)
(i) LiBH4 (ii) Ac2O (iii) MOMCl
O
(i) EDCI HO2CCH(Me)P(O)(OEt)2 (ii) NaH, THF
OH H
18.3 H
OMOM
83%
H OEt OTES
76%
OPMB
18.2 3.5:1 (major isomer shown)
18.1
(i) DDQ (ii) TPAP, NMO (iii) tBuLi CH2CHOEt TBDPSO (iv)TES-Cl
TBDPSO
TBDPSO
64%
H
OMOM
H
O
O 18.11 Thapsivillosin F
Scheme 18 Synthesis of a complex guaianolide lactone from (S)-carvone via intermediate 17.2.
The application of ent-27.4 in the synthesis of the lycopodium alkaloid nankurine A and B is shown in Scheme 28.41 Diels–Alder reaction with diene 28.1 gave cis-decalin 28.2 stereoselectively. Condensation with benzoic hydrazide and reduction led to hydrazide 28.3. On heating with para-formaldehyde, azomethinimine 28.4 was formed (see Chapter 2.18), which underwent stereoselective intramolecular 1,3-dipolar cycloaddition to furnish pyrazolidine 28.5. Reductive cleavage of the NNbond and selective in situ methylation gave 28.6, which was cyclized via the O-mesylate to 28.7 and converted into 28.8 and 28.9, respectively. A similar Diels–Alder strategy was applied in the synthesis of the cytotoxid lycopodium alkaloid (þ)-lyconadine A (Scheme 29).42 Thus, ent-27.4 was treated with isoprene in the presence of TMSOTf which acted as a Lewis acid and as a dehydrating agent for ketal formation so that adduct 29.1 was formed. After deketalization, the resulting ketone was subjected to reductive amination to give 29.2 stereoselectively. An aza-Prins reaction with formalin led to a shift of the double bond, which was cyclopropanated to give tetracyclic intermediate 29.3. Electrocyclic ring opening generated the carbenium ion 29.4 which was
Chiral Pool Synthesis: Starting from Terpenes
183
OTMS Me
Me
(i) KOH, H2O, THF (ii) CH2N2 (iii) TEMPO, CH2Cl2, NCS
O MOMO
MOMO
O Me
BF3-OEt2, CH2Cl2
H
92%, dr = 3:1
19.1
Me MOMO
CO2Me Me
77%
H
HO
O
19.2
(i) NaOH, H2O, THF (ii) oxalyl chloride, DMF (iii) NaBH4, DMF, THF
Me MOMO
O
85% O 19.4 O
OH
MOMO
(i) Swern-oxidation (ii) (iPrO)2TiCl2, CH2Cl2
CH2OH Me
64%
O
19.3
Me
O Me
(i) LDA, THF (ii) Me2N=CH2I
Me
(iii) mCPBA
O
OH
O
91%
O
O 19.7 8-Epi-grosheimin
19.6
19.5
8 Me
O
72%
O
(i) iPrOH, O p-TsOH (ii) IBX, DMSO
OH
MOMO
Scheme 19 Synthesis of 8-epi-grosheimin from cyclopentane 19.1.
H
Me (i) disiamylborane, THF (ii) H2O2, NaOH, H2O
THPO Me
H
CO2Me
Me
(i) LiAlH4, THF (ii) MsCl, DMAP, Et3N, CH2Cl2
OH
THPO
62%
17.2
Me
H
H
CO2Me
20.1
Me
H
OMs
(i) MeNH2, DMF (ii) PPTS, MeOH
H
Me
HO
THPO
NMe OMs Me
H 20.2
63% from 20.1
Me
H
20.3 Incarvilline
Scheme 20 Annulation of a piperidine ring to 17.2.
trapped by a transannular attack of the nitrogen to give 29.5 under removal of the ‘tertiary butoxy carbonyl (Boc)’-protecting group. The vinyl bromide was metallated and added to isoamyl nitrite to give a nitroso intermediate which was rearranged to the oxime. This was hydrolyzed to ketone 29.6. Michael addition of deprotonated sulfide 29.7 and treatment with HCl resulted in cyclization and desulfination to furnish the pyridone ring of 29.8. In the synthesis of the lycopodium alkaloid complanadine A (Scheme 30),43 ent-27.4 was converted into ketal 30.1. However, enamide 30.2 was hydrolyzed to give 30.3. In situ condensation of the enol of 30.3 with 30.1 gave 30.4 which underwent a Mannich cyclization to 30.5. Boc-protection led to 30.6. Oxidation to pyridine 30.7 was followed by removal of the OTf-group and regioselective C–H-activation to furnish boronate 30.8. Suzuki coupling of 30.8 and 30.7 led to 30.9 after removal of the Boc-group. A Grubbs enynene RCM strategy was used in the synthesis of the lycopodium alkaloid (þ)-lycoflexine (Scheme 31).44 The key intermediate 31.5 was prepared from ent-27.4 via a tandem Sakurai/aldol sequence to give alcohol 31.1 which was oxidized to the diketone and alkylated with 31.2 to give compound 31.3. Introduction of the triple bond was achieved via the triflate 31.4 to give 31.5 on elimination with pyridine. Tandem catalysis with Grubbs II catalyst accomplished ring closure and selective
184
Chiral Pool Synthesis: Starting from Terpenes (i) O3, EtOAc (ii) H2, Pd/C, (iii) NaCN, pTsOH, THF, H2O
(i) PtO2, H2, (ii) LDA, MeI, THF O
O
96%
OH NC
O OH
(48%, 3 steps)
Me
(S)-(+)-Carvone V
Me 21.2
21.1 (dr = 5.5:1)
CN EDCI, CH2Cl2
O
79%
O
(i) LiHMDS (3 equivalent), THF (ii) 1 M HCl O
OH
(59% 2 steps)
54% 21.4
21.3 O
O O
PMP O
O
O OAc
SnMe3
O
(21.6)
O
PMP
O
Pd(PPh3)4 LiCl, CuCl, DMSO
21.5
(i) NfF, NEt3, CH2Cl2 (ii) Pd(dppf)Cl2 (Me3Sn)2, NMP
21.7 O
h, iPr2NEt, Et2O
(i) SmI2, HMPA, THF (ii) PhSeBr
PMP
O
(50%)
(64% 2 steps) 21.8 PMP
O
O
O
PMP
O
O
SePh
(i) TESOTf, NEt3, CH2Cl2 (ii) mCPBA, CH2Cl2
O
mCPBA, CH2Cl2
(iii) Ac2O, DMAP, pyridine (45% 3 steps)
86% 21.10
21.9
O
AcO
O
PMP
O
O
H (i) PPTS, MeOH (ii) SiO2, CH2Cl2
AcO
O OH
(69%, 2 steps) 21.11
21.12 (+)-Guanacastepene E
Scheme 21 Synthesis of guanacastepene E from (S)-carvone.
hydrogenation to furnish tricycle 31.6 which was hydroborated and oxidized to diketone 31.7. Transannular Mannich cyclization delivered 31.8. An intramolecular Mannich reaction was also the key step in the synthesis of the lycopodium alkaloid (þ)-fastigatine (32.13) which was prepared from ent-27.4 by maintaining the endocyclic double bond over quite a number of steps (Scheme 32).45 Following an earlier protocol,46 27.4 was iodinated to give ketal 32.1 which was converted into cuprate 32.2 and added to cyclopropane 32.3 (prepared from (S)-epichlorohydrin)47 to give 32.4 in 93% yield. Alkylation to form azide 32.5 and exchange
Chiral Pool Synthesis: Starting from Terpenes
O (i) (Ph3P)3RhCl, H2, PhH (ii) Br2, AcOH (iii) KOH
O
O
(i) KOH (ii) Ph3P+CH3Br −, nBuLi THF CO2H
74%
46%
(R)-(−)-Carvone IV
22.2
22.1 (i) liver esterease (ii) dipyridyl disulfide, PPh3, CH2Cl2 (iii) p-xylyl bromide, Li, Et2O, CuI
Me CO2Me
MeO2C
185
O
(i) LiAlH4, Et2O (ii) H2, Pd/C, EtOH, HClO4 (iii) nBu3P, 2-NO2-Ph-SeCN, H2O2
Me CO2Me
78%
86%
22.3
22.4 (i) h, HCONH2, acetone, tBuOH (ii) KOH, MeI, DMSO
h cyclohexane
H
H
72% 22.5
30%
(i) LDA, THF, 50 °C (ii) + 22.7
H
22.7
250 °C, PhCH3
H
22.2
64%
(iii) HOAc, HC(OMe)2NMe2 65%
H
O Me2NOC
(iii) SeO2, tBuOOH 1,2-dichloroethane
22.6
CONMe2 22.8
(i) mCPBA, NaOAc, CH2Cl2 (ii) tBuOK, DMSO 100 °C
H
H
H
CONMe2
10% Pd/C, H2 (400 psi)
H
95%
CONMe2 22.10
22.9
H H
H + H
CONMe2 22.11
H
CONMe2
H
(i) LAH, THF (ii) PDC, CH2Cl2 (iii) Pinnick Ox.
22.12
H
H
CO2H
22.13 (−)-Retigeranic acid
Scheme 22 Ring cleavage of carvone to acid 22.2 and application in the synthesis of ()-retigeranic acid.
of the N-protecting group for nosylate 32.6 was followed by the addition of enolate 32.7 to give the keto ester first which was cyclized to enanimide 32.8 by a Staudinger reaction. On treatment with HCl, the ketal was hydrolyzed to form enone 32.9 which underwent a tandem Michael aldol reaction to form pentacycle 32.10. N-Methylation and deprotection gave amine 32.13 which underwent a Mannich cyclization to provide 32.12. Decarboxylation and N-acetylation led to 32.13. The cyclohexane ring of ent-27.4 was used as a chiral template for an intramolecular Diels–Alder reaction in the synthesis of the marine alkaloid norzanthamine (Scheme 33).48 Conjugate addition of cuprate 33.1 to cycloxenone ent-27.4 provided enol ether 33.2 which was added to aldehyde 33.3 via Mukaiyama conditions to provide aldol adduct 33.4. Dehydration to the enone
186
Chiral Pool Synthesis: Starting from Terpenes
O
H
mCPBA CH2Cl2
(i) NBS, THF/H2O (ii) Bu3SnH, AIBN
O
H
O
77% (S)-Carvone
Me 23.2
Me
HO
Me
O
90%
OH
23.1 (dr = 1:1)
(i) Swern-oxidation (ii) CF3CO3H, CH2Cl2
H
H
O
H
81%, dr = 2:1
OH
Me 23.3
Ph
O
TBDPSO
THPO
H
OH
Me
O TBDPSO
Me 23.7 (E):(Z) = 4:1 HO
H H O EtO2C
91%
23.8
HO
H
H
(23.6)
(i) Swern-oxidation (ii) Wittigolefination (iii) CSA, EtOH
H O
99%
OMe OMe
nBuLi, −50 °C then DIBALH 68%
Me 23.5
(i) DHP, PPTS (ii) TBAF, THF
OTBS Me
O
O
H H O
87%
H
23.4 O
(i) TBDPSCl, imidazole (ii) DDQ, THF/H2O (iii) Swern-oxidation
H O
OTBS
O
(iii) K2CO3, MeOH (iv) TBSCl, imidazole 83%
(i) Cp2TiMe2, PhMe (ii) 9-BBN, THF
Me
Me 23.9
OMe H
(i) DMP (ii) PPh3=CHOMe
H
PhCl, BHT, 270 °C
EtO2C
OMe
Me
(+ starting material)
O
82% EtO2C
(i) LAH (ii) DMP (iii) KHMDS, Horner-olefination (iv) Pd(OH)2, H2, EtOH
Me
Me
44%
Me 23.11
23.10 (E):(Z) = 1:1.5
M
EtO2C
OMe
(i) RuCl3, NaIO4, CCl4, MeCN, H2O (ii) PhSeCl, HCl (iii) NaIO4, THF, H2O (iv) NaOH, EtOH
O
82%
TMSEO2C
O Me 23.13 (platensic acid) OH
(23.14)
O
OH NH2
HO2C OH
HATU, Et3N, DMF, then TASF, DMF 49%
Me O
HO2C
43%
Me 23.12
HO
O
Me O
N H
O 23.15 (−)-Platensimycin
Me
Scheme 23 Synthesis of the antibiotic platensimycin from (S )-carvone via Baeyer–Villiger ring cleavage.
was followed by hydrosilylation to give cyclohexanone 33.5 after base-induced equilibration. Functional manipulation generated enone 33.6. Photooxidation of the furan moiety led to 33.7 which was converted to enol ether 33.8. Thermal IMDA reaction via an exo-transition state furnished cyclization product 33.9 as a mixture of isomers which was desilylated to the ketone from which the major isomer 33.10 was isolated by crystallization. An additional 28 steps were required to elaborate 33.10 into 33.11. A slightly modified procedure was used for the degradation of (R)-pulegone to dimethyl cyclohexenone 34.1 in the synthesis of the diterpene phomactin,49 which is a potent platelet aggregation factor antagonist. The quaternary center was installed via an
Chiral Pool Synthesis: Starting from Terpenes Me
Me
O
(i) LAH (ii) (−)-Ipc2BH (iii) H2O2, NaOH
Me
86%
Me OH
OH
H
H
+ OH
Me
(−)-Dihydro-carvone (VI)
24.1
OH
Me 24.2
2:5
Me
(i) TsCl (ii) NaCN, DMF (iii) DIBALH
Me S
OH H Me
OH
SO2 Me (24.4)
N
H
40%
H H
NaHMDS 79%
O 24.3
24.5 (E):(Z) = 1:3 O
H H
92%
Me
Me
Me (i) Swern-oxid (ii) I2
187
Me
(i) trisylhydrazine, THF, r.t. (ii) nBuLi (4 equivalent), −78−20 °C (iii) + 24.7 tBuO
Me
OtBu
OH O
H
O
24.6 purely (E)
H
(24.7) Me
Me
Me
Me
Me
O
24.8 36% from 24.6 Me
THF, -wave, 110 °C
Me
OH
OH
OtBu H
OtBu H
Me
O
Me
H Me O
Me
Me
O OtBu
150 °C, toluene
H Me
Me 24.10
24.9
Me O
H 24.12
Me
O OtBu
OH
Me
61% from 24.8
Me
air, r.t.
24.11
Me
BF3-OEt2 (2 equivalent), 0 °C 78 °C
O OH
H Me
Me O
Me
H 24.13 (Colombiasin A)
Scheme 24 Dihydrocarvone VI as chiral starting material for the synthesis of the sesquiterpene colombiasin A.
aldol addition with phenylselenoacetaldehyde and subsequent treatment with MsCl/Et3N to give the vinyl appendage in 34.2 stereoselectively. A 1,3-enone transposition led to 34.3 which was reduced to the allylic alcohol and epoxidized to give 34.4. Oxidation to the ketone and regioselective epoxide opening with magnesium bromide provided bromohydrin 34.5 which eliminated water to give vinyl bromide 34.6 after exchange of the MOM for the more labile ‘3,4-dimethoxybenzyl (DMB)’protecting group. The ketone was reduced and the alcohol was inverted and silylated to give 34.7. Lithiation and addition of aldehyde 34.8 (prepared from geraniol in 11 steps) delivered ketone 34.9 after oxidation. Removal of the tertiary-butyldimethylsilyl-group led to the formation of dihydro-pyranone 34.10. Protection with TESCl was followed by removal of the DMB group whereon the hemiacetal was formed and silylated to give 34.11. Intramolecular Suzuki coupling closed the macrocyclic ring to furnish 34.12 after deprotection (Scheme 34). In the synthesis of the lycopodium alkaloid (þ)-fawcettidine (Scheme 35),50 the degradation of (R)-pulegone was stopped at the stage of sulfoxide ent-27.2, which allowed the introduction of the two sidechains in 35.2 by alkylation/elimination to form 35.1 and subsequent conjugate addition. Condensation with amine 35.3 led to enamide 35.4 which gave tricycle 35.5 after
188
Chiral Pool Synthesis: Starting from Terpenes HO
HO (i) 1 N HCl, reflux (ii) LAH
O (i) Br2 (ii) NaOMe, H2O
O
OH
(42% 4 steps)
(R)-(+)-Pulegone (VII)
25.1
25.2
(i) K2CO3 (ii) nBuLi, KOtBu Me3SiCl
AcO (i) Ac2O (ii) Ac2O, reflux
H
HO
(i) Tf2O, 2,6-lut (ii) 25.5, nBuLi (74% 2 steps)
TMS
25.3
(25.5)
OEt
(iii) K2CO3, MeOH (50% 3 steps)
(71% 2 steps)
O
25.4
H
(i) Co2(CO)8 (ii) Me3SiOTf
O
OEt TMS
(CO)3 Co Co(CO)3
H
(82% 2 steps)
25.6
CH3CN reflux
O
H
85%
25.7 O H
(i) Li, NH3 (ii) KHMDS, Davis oxaziridine
H
O H
CHO (i) PPh3=CHOMe (ii) NaH, (EtO)2P(O)CH2CN (71% 2 steps)
H (iii) NaHB(OAc)3 (iv) Pb(OAc)4 (v) DBU (31% 5 steps)
O
H
O
H 25.9
25.8 OMe
NC H
(i) HCl, THF (ii) NaBH4
H H
OH
NC
O
H H
(92%, 2 steps)
O H
25.10
(i) PPh3, I2, imid (ii) tBuLi, Et2O
25.11
(iii) K, 18-crown-6 (3 steps 49%)
H H H
O
25.12 (+)-Epoxydictymene
Scheme 25 Ring contraction of pulegone provides the chiral starting material in the synthesis of epoxydictymene.
platinum-catalyzed annulations and allylic oxidation with selenium dioxide. Deprotection of the sulfur was followed by transannular 10-endo-trig- thia-Michael addition to give sulfide 35.6 which was ketalized, oxidized to the sulfone, and converted to the olefin via a Ramberg–Ba¨cklund reaction. Hydrogenation and reduction of the amide gave 35.7 after deketalization. In a formal synthesis of fawcettimine (Scheme 36),51 ent-27.4 was converted into iodide 36.1 and used for a free radical addition to acrylonitrile followed by a conjugate addition/iodination to prepare 36.2. Free radical annulations provided 36.3 which was converted into enone 36.4 via allylic oxidation with selenium oxide. Conjugate addition of ketene acetal 36.5 led to compound 36.6 which may be converted into fawcettimine along the route by Heathcock.52 A regioisomer of 27.4, namely 37.2, has been used in a synthesis of the sesquiterpene valerenic acid (Scheme 37), which is a constituent of valerian root and has been found to be an allosteric modulator of the GABAA receptor. The synthesis started with the conversion of (R)-pulegone into ketal alcohol 37.1 which was dehydrated and deprotected to give 37.2.53 Substrate-directed 1,4-addition of the cuprate prepared from bromide 37.3 gave the TMS enol ether which was oxidized via Saegusa reaction to give enone 37.4. Hydrolysis of the ketal generated the diketone 37.5 which was hydrogenated with Stryker’s reagent and then cyclized to 37.6 via Robinson annulation. Wittig methylenation followed by stereoselective hydroboration gave the alcohol which was oxidized to aldehyde 37.7. A second Wittig olefination provided the enoate which was saponified to valerenic acid (37.8).54
Chiral Pool Synthesis: Starting from Terpenes Me
Me
O
(i) K, allyl-OH, PhMe (ii) I-(CH2)2OPMP
CO2Allyl
(i) O3, AcOH, EtOAc, H2O, 0 °C (ii) allyl-OH, H2SO4, reflux
189
CO2Allyl
89%
26.1
(S)-Pulegone (VIII) O
OPMP
(i) 1 M HCl (ii) Pd(OAc)2 (2 mol%), MeCN, reflux
OPMP
O
49% from 26.1
26.2 O
OPMP
Me O
mesityl-SO2-ONH2, Ms 4 A, Al2O3, CH2Cl2 43%
Me
26.3
(26.4)
H N
80% (i) O3, MeOH, Me2S (ii) TsNHNH2, MeOH (iii) NaBH3CN, TsOH, THF
OPMP
Me
49% 26.6
26.5
HO
OPMP H N
(i) NaH, CbzCl, THF (ii) NaBH4, LiBr, THF
Me 26.7
(iii) TBDPSCl, DMAP, Et3N, CH2Cl2 (iv) CAN, MeCN/H2O 66%
O
OAc
Pd(OAc)2, (iPrO)3P, THF
CO2Allyl
Me
O OTHP TBDPSO
TMS
TBDPSO O Me 26.8
THPO
Me
(iii) PPTS, EtOH TBDPSO (iv) o-NO2PhSeCN, Bu3P, THF, then mCPBA
TFA
EtO2C
Me
TFA
N
Me
TBDPSO
26.13
(iv) HF, pyridine (v) NaBH4, EtOH (vi) NaOH, EtOH, H2O TBDPSO
34% Cl OTBS
74% 26.11
(i) HF, pyridine (ii) o-NO2PhSeCN, Bu3P, THf (iii) Grubbs II-CM with 26.14
Me
(26.12)
CO2Et GrubbsHoveyda CM
N
71%
26.10
P(O)(OMe)2 (26.9)
(i) H2, Pd(OH)2/C, HOAc, EtOH (ii) TFAA, iPr2NEt, DCE
CbzHN
Me
(i) SO3-py, DMSO, Et3N (ii) Et3N, LiCl, THF
CbzHN
NaO2C Me OH Cl
OH
HN
Me (26.14)
26.15 Pinnaic acid sodium salt
Scheme 26 Construction of a 6-aza-spiro-[4.5]decane core from pulegone.
2.7.3.4
Perillaldehyde (IX)
Perillaldehyde, or perilla aldehyde, is found most abundantly in the annual herb perilla, but also in a wide variety of other plants and essential oils. It is used as a food additive for flavoring and in perfumery to add spiciness. Perillaldehyde (IX) is commercially available in both forms of enantiomers with c. 90% ee. ()-IX has been used in the synthesis of the novel antibiotic platencin (38.6, Schemes 38 and 39). The first one55 of two rather similar approaches started with the Diels–Alder reaction of commercially available Rawal’s diene (38.1) to ()-IX to give adduct 38.2 stereoselectively, due to the induction by the isopropylidene sidechain. Wittig methylenation and Grubbs’ RCM led to 38.3. To shift the endocyclic double
190
Chiral Pool Synthesis: Starting from Terpenes O
O
O NaOH, H2O2
O
SPh Me
Me
89%
Me
(i) NaH, PhSH (ii) NH4Cl, H2O
27.2
27.1 (S)-Pulegone O
mCPBA CH2Cl2
O
CaCO3, CCl4 heat
Ph S O
49% from
Me
Me 27.4
27.3 Scheme 27 Degradation of the pulegone sidechain to provide key compound 27.4.
(28.1) O
(CH2)4OBn
O
BzHN H
(i) NH2NHBz (ii) NaCNBH3
(i) (TMSOCH2)2 10% TMSOTf (ii) FeCl3 /SiO2 64%
ent-27.4
CH2O
BzN N
(CH2)4OBn
H
(i) Pd(OH)2, H2 (ii) AIH3 NHBz (CH2)4OBn
[3+2]
(CH2)4OBn
N
BzN
(i) SmI2 (ii) CH2O, NaCNBH3
BnO(H2C)4
80% 28.5
Pd/C
N Bn N
(iii) MsCl, NEt3 71%
28.6
H 28.3
28.4
N
80%
28.2
85%
BnO(H2C)4
NH H
28.7
96%
N R N
28.8 R = H, ((+)-nankakurine A) 28.9 R = Me, ((+)-nankakurine B)
NaCNBH3, CH2O 80%
Scheme 28 Synthesis of the Nankakurines from ent-27.4.
bond into the exocyclic position, 38.3 was brominated to bromonium ion 38.4 which was reduced in situ with chromium(II)chloride to furnish exo-olefin 38.5. This was an intermediate in an earlier synthesis of 38.6.56 The second approach to 38.657 (Scheme 39) also started with a Diels–Alder reaction. Danishefsky’s diene 39.1 was added to ()-IX under forced conditions to provide adduct 39.2. Conversion into di-carbonyl intermediate 39.3 was followed by pinacol cyclization to give diol enone 39.4 after ketal hydrolysis. Selective acetylation of the secondary OH-group was followed by elimination of water to give exocyclic olefin 39.5 which was deacetylated to furnish 38.6.
2.7.3.5
a-Phellandrene (X)
a-Phellandrene was named after Eucalyptus phellandra, from which it was isolated. The phellandrenes are used in fragrances because of their pleasing aromas. a-Phellandrene can form hazardous peroxides with air at elevated temperature.
Chiral Pool Synthesis: Starting from Terpenes
H
isoprene TMSOTf, glycol CH2Cl2 (71%)
(i) FeCl3/SiO2 acetone (ii) BnNH2, NaBH(OAc)3 1,2-dichloroethane
H O
191
H H
(96% 2 steps)
O
NHBn
O ent -27.4
29.2
29.1
Br (i) HCHO, AcOH (ii) H2, Pd(OH)2, Boc2O
H
(iii) CHBr3, NaOH, BnNEt3CI (46% 3 steps)
H
H
(i) TFA, DCM (ii) pyr, reflux
Br
H
(96% 2 steps)
H
Br
HN
BocN
H
29.4
29.3 O H
Br
H N
H
(i) tBuLi, isoamyl nitrite (ii) HCl, acetone
H
O
NaH, THF; HCl, MeOH
H
(33% 2 steps) N
H
Ph
O S
29.6
N
H
H
O
29.7 29.5
H
HN
87%
NH3
29.8 (+)-Lyconadin A
Scheme 29 Diels–Alder reaction with ent-27.4 in the synthesis of (þ)-lyconadin A.
The diene moiety in X can be used for diastereoselective cycloaddition trans to the isopropyl appendage. [2 þ 2]-Additions of ketenes to the more accessible, secondary olefin have been proven extremely valuable in natural product synthesis. Thus, the synthesis of the MSAA drug ()-eleutherobin (Scheme 40)58 was initiated by the addition of dichloroketene to ()-X which gave adduct 40.1 after dechlorination. Condensation with N,N-dimethyl-formamide di-t-butyl acetal furnished 40.2 which was hydrolyzed to the keto aldehyde and fragmented to give an ester aldehyde. In situ addition of 5-bromo-1-lithiofuran provided adduct 40.3 after protection with dr 3:1. Chain elongation gave aldehyde 40.4 which was cyclized to 40.5 via Nozaki–Kishi reaction. Achmatowicz-reaction (see Chapter 2.18) and addition of methyl lithium to the ketone afforded dihydropyran 40.6. Ring contraction and oxidation to ketone 40.7 was achieved over six steps. The ketone was converted into the enol triflate which was used for attaching the sugar sidechain via Stille coupling to provide 40.9. Deprotection and esterification with acid 40.10 gave 40.11 after removal of the acetonide-protecting group. A related [2 þ 2]-ketene olefin cycloaddition was employed in the synthesis of the eunicellin diterpene deacetoxyalcyonin acetate (Scheme 41).59 Adduct 41.1 was obtained stereoselectively and photochemically rearranged to di-acetal 41.2. Under treatment with TiCl4, oxonium ion 41.2 was formed which was trapped by Brassard’s diene 41.4 to give the [3 þ 3]-annulation product 41.5. Methylation and decarboxylation led to ketone 41.6 which was equilibrated and converted into enone 41.7. Conjugate addition of the cuprate formed from bromide 41.8 and trapping of the resulting enolate led to enol triflate 41.9 which was used for a Nozaki–Kishi cyclization to furnish tetracycle 41.10. Acetylation gave 41.11. The less substituted olefin was protected via the epoxide, then the tetrasubstituted double bond was cleaved by ozonolysis to give diketone 41.12 after de-epoxidation with low-valent tungsten. The two keto functions were differentiated by formation of the silyl enol ether to allow a selective Wittig methylenation of the ‘upper’ ketone. Deprotection and stereoselective addition of methyl lithium led to 41.13. The diene system in X has also been used in a stereoselective Friedel–Crafts alkylation (Scheme 42).60 Thus methoxydi-hydroxy acetophenone 42.1 was added to X, under protonation, to give 42.2 regio- and stereoselectively. Acetylation gave 42.3 which was epoxidized to give epoxides 42.4 and 42.5 which were separated. 42.4 was deacetylated, cyclized, and subjected to an aldol addition with benzaldehyde to give linderol (42.6).
192
Chiral Pool Synthesis: Starting from Terpenes (i) I2, pyr (ii) acrylnitrile, AIBN, SnBu3H
O
O NH2
(iii) (OHCH2)2, CSA (iv) LAH (no yields provided)
ent-27.4
H N
O
O
70% HClO4
30.1
O
+ 30.1
NH2 O
dioxane 30.3
30.2
O
Boc2O, Et3N, THF
NH2 H O
O
H O N
N 65% 2 steps
N H
N H
N Boc 30.6
30.4
30.5
(i) Pb(OAc)4, CH2Cl2 (ii) Tf2O, pyridine
N
(i) Catalyst Pd (OAc)2, dppf NH4CO2H, Et3N (54% 3 steps)
OTf
(ii) [Ir(COD)(OMe)]2 [B(pin)]2, THF
N Boc 30.7
N (i) PdCl2, 30.7 dppf, K3PO4, (ii) 6 N HCl
N N Boc
30.8
B O O
N H
H N
N H
(32% 3 steps) H 30.9. ((+)-Complanadine A)
Scheme 30 Mannich cyclization in the synthesis of complanadine A from ent-27.4.
2.7.3.6
()-Menthone (XI)
Menthone is a constituent of many essential oils, though as a minor compound. It is cheaply available as a mixture of isomers; when enantiopure, it costs approximately 1h g1. In the laboratory, ()-menthone has only seldom been used as a starting material in the synthesis of complex natural products. The synthesis of ent-nanolobalolide61 in Scheme 43 is an exception. In the event, the authors converted XI into the thermodynamically favored enol ether 43.1 which was cyclopropanated to give 43.2. Ring enlargement with FeCl3 led to cycloheptanone 43 which was dehydrohalogenated to give enone 43.4. Formation of the enol triflate allowed the introduction of the vinyl ketone appendage in 43.5 which was used in a Nazarov cyclization62 to furnish cyclopentanone 43.6. Conversion to diene 43.7 paved the way for a Diels–Alder addition of ethyl acrylate and delivered the polycyclic compound 43.8 stereoselectively. To convert the ester into acid, a reduction–oxidation sequence was performed. Luckily, in the Pinnick oxidation of the intermediate aldehyde to the acid, an epoxide 43.9 was formed which underwent lactonization to give 43.10.
Chiral Pool Synthesis: Starting from Terpenes
193
H H
(i) IBX, EtOAc (ii) Cs2CO3, 31.2, DMF
(i) TiCl4, allyl-TMS DCM (ii) acetaldehyde
N Boc (31.2) (68%, 2 steps)
I
ent-27.4
O
(70%)
OH 31.1
H
Cl N
pyridine 60 °C
(85%)
O
O
BocN 31.3
H
NTf2
KHMDS, THF
O
O
(99%)
OTf
BocN 31.4
BocN 31.5 O
O
O
H
(i) BH3 THF (ii) IBX, EtOAc
HCHO, H2O, HCl EtOH, reflux
(i) Grubbs II catalyst (20 mol%), 1,2dichloroethane, reflux (ii) H2, 10 atm, 70 °C 52%
O
H O
H
(64% from) NBoc 31.6
N
NBoc 31.7
31.8 (+)-Lycoflexine
Scheme 31 Tandem–Grubbs catalysis and transannular Mannich cyclization in the synthesis of lycoflexine from ent-27.4.
2.7.4 2.7.4.1
Bi- and Tricyclic Terpenes: Nepetalactone and Santonin Nepetalactone (XII)
Nepetalactone was first isolated in 1941 from the plant catnip, Nepeta cataria, which acts as a cat attractant. Nepetalactone is a bicyclic monoterpene, with two fused rings, a cyclopentane, and a lactone. Depending on the Nepeta species, the active ingredient nepetalactone consists of a mixture of four diastereomers which can be obtained in pure form. In the first synthesis of englerin A (cf. the synthesis from citronellal, Scheme 6) trans,cis-nepetalactone XII was used as the chiral starting material (Scheme 43).63 The oxidation of XII to 44.1 with mCPBA installed the desired configuration at C-10. Treatment with sodium methoxide led to ring contraction of the epoxylactone ring to generate formyl lactone 44.2. Allylation of the aldehyde with bromide 44.3 under Barbier conditions and subsequent reduction with LiAlH4 led to diastereomer 44.5 stereoselectively. Acetalization of the vic. OH-groups was followed by oxidation to the aldehyde, epimerization, and Wittig methylenation to give di-olefin 44.6. Grubbs’ RCM and removal of the acetonide furnished cycloolefin 44.7. Esterification of the more accessible hydroxyl function and epoxidation of the double bond afforded 44.8 with moderate stereoselectivity. Transannular opening of the epoxide gave 44.9 which was esterified with cinnamic acid and desilylated to furnish englerin A (Scheme 44).
2.7.4.2
Santonin (XIII)
Santonin is derived from the flower-heads of Artemisia maritima var. stechmanniana and was widely used in the past as an anthelminthic. In the synthesis of the anthelminthic (þ)-absinthin (Scheme 45),64 the known65 photochemical rearrangement of santonin to O-acetylisophotosantonic lactone (45.1) has been used as the key operation. To prepare the cyclopentadiene moiety, the ketone was reduced to alcohol 45.2 which was converted to selenide 45.3. Oxidative elimination furnished cyclopentadiene 45.4 which underwent stereoselective Diels–Alder dimerization to 45.5 at room temperature. To invert the configuration of the tertiary alcohol, it was transformed into ketone 45.6 which added methyl lithium from the less hindered side to give 45.7.
194
Chiral Pool Synthesis: Starting from Terpenes (i) I2 (0.6 equivalent), PhI(OCOCF3)2 (0.6 equivalent), pyridine, (1.2 equivalent), CH2Cl2; r.t. (ii) 1,2-ethane-diol, CSA
ent-27.4
O
O
3,3,-dimethyl1-butyne, BuLi, CuI
I
Me tBu O
Me
O
32.1
Cu Li-LiI
32.2
O
O
TMSEO2C
NBoc
Me
TMSEO2C
(32.3) O
THF, 93%
(i) Cs2CO3, I(CH2)2Cl, DMF (ii) NaN3, NaI, DMF, 65 °C (iii) TBAF, DBU, THF
NBoc
89%
O 32.4
N3
O
Me
NBoc
O
(i) Mg(ClO4)2, MeCN, 60 °C (ii) LiHMDS, NsCl, THF
N3
(i) Me
O
78% from
Me
CO2tBu H N
HCl, THF/H2O
Me NHNs O
O
Me HN
(32.7) THF, −78 °C
32.6
32.5
O
OLi
NNs
(ii) PPh3, PhH, 50 °C
O
tBuO
OtBu
O
CO2tBu H N
92%
O
(i) K2CO3, MeI, DMF (ii) PhSH (iii) CF3CH2OH, 80 °C
HO
O
74%
NHNs NHNs
32.8
Me
Me
Me
CO2tBu H N
CO2tBu H N
(i) p-TsOH, H2O, PhH, 80 °C (ii) Ac2O, Et3N
Ac N Me
O
Me
N
NHMe 32.11
32.10
32.9
N
81%
32.12
Scheme 32 Intramolecular Mannich cyclization in the synthesis of (þ)-fastigatine from ent-27.4.
32.13 (+)-Fastigiatine
Chiral Pool Synthesis: Starting from Terpenes Me LiCu
2 (33.1)
(i) BuLi, ZnBr2 THF (ii) + 33.3
OTMS
OTIPS
ent-27.4
Me
Me
TMSCl, THF
Me H
OTIPS 33.2
Me O
OH TBS
O Me
Me
(i) Im2C=S, toluene (ii) Et3SiH, ClRh(PPh3)3 THF, 50 °C (iii) K2CO3, MeOH
Me O
Me OTIPS
33.4 (84% from 27.4)
33.5
Me
(i) LiBEt3H, THF (ii) Ac2O, pyridine, DMAP CH2Cl2 (iii) TBAF, THF (iv) MnO2, CH2Cl2 (v) MeLi, Et2O (vi) TPAP, NMO, CH2Cl2
OAc
(i) h, O2, rose bengal CH2Cl2 TBS (ii) TBAF, MeI, THF
O
Me
33.6
Me
O
240 °C, 1,2,4-trichlorobenzene, 1,5 h
CO2Me
28 steps
O Me
H
H
Me
H
H Me
Me
H
O H
Me
N
O
O
33.10 Me 33.11 Norzoanthamine Scheme 33 IMDA reaction in the synthesis of the alkaloid norzoanthamine.
CO2Me
Me
CO2Me
O
H
Me
OTBS 33.9 (exo:endo 3:1) O
OAc H
O Me
Me
O
Me Me
OAc H
33.8(exo-TS)
Me
O
33.7
Me AcO H
TBSOTf, Me2NEt CH2Cl2
HF, pyridine, THF
O Me
Me
97%
Me
TBSO
CO2Me
OAc
Me
Me
89%
51% from 33.7
TBS
O Me
79%
OTIPS
TBS O (33.3)
O
O
195
196
Chiral Pool Synthesis: Starting from Terpenes O
(i) LDA, LiCl, MeI (ii) KOH reflux
(R)-Pulegone (IX)
O
(iii) LDA, TMSCl, Br2 (vi) Li2CO3, DMF (38% 4 steps)
O
(i) nBuLi, Bu3SnCH2OMOM
(ii) MsCl, NEt3 (63% over 2 steps)
34.1
(ii) PCC (66% 2 steps)
34.2
OMOM
OMOM
OMOM
O
(i) NaBH4, CeCl3 (ii) mCPBA
O
(i) LDA, Ph-selenoacetaldehyde
(81% 2 steps)
OH Br
(i) DMP (ii) MgBr2*OEt2
OH
34.3
O
(71% 2 steps)
34.4
34.5
ODMB (i) TFAA, pyr. (ii) MgBr2*OEt2, BuSH (iii) CSA, DMBONPy (73% 3 steps)
ODMB
(i) NaBH4, CeCl3 (ii) PPh3, DEAD, pNO2− benzoic acid, NaOMe
Br O
Br
(iii) TBSCl (74% 3 steps)
OTBS
34.6
34.7
DMBO
O
O
I
OHC (34.8)
DMBO O
OTBS I
(i) tBuLi (ii) DMP (45% 2 steps)
(i) TESCl (ii) DDQ
O
(iii) TMSOTf, pyr (58% 3 steps)
OH
(59% 2 steps)
O 34.10 I
34.9
O OTMS OTES
O
(i) TBAF (ii) 1% HCl t-amylOH
O OH (i) 9-BBN (ii) Pd(dppf)Cl2, AsPh3, Tl2CO3
OH O
(iii) TBAF (29% 3 steps)
I 34.11 Scheme 34 Pulegone and geraniol in the synthesis of the diterpene (þ)-phomactin.
34.12 (+)-Phomactin
Chiral Pool Synthesis: Starting from Terpenes
O
O
(i) H2O2, LiOH (ii) NaH, PhSH
(R)-(+)-Pulegone (IX)
O SPh
DBU, DMF, Me-acrylate 40 °C 72%
(iii) NaBO3, AcOH (88% over 3 steps) ent-27.2 O BrMg(CH2)2CCSiMe3 CuBr*DMS, THF
O CO2Me
H
CO2Me
83% TMS
35.2 35.1 EtHN S(CH2)2NH3+ TFA−
EtHN
S
O
O
N
(i) PtCl2, PhMe, 90 °C (ii) SeO2, 1,4-dioxane, 85 °C
(35.3) O AcOH, 110 °C
47%
70% TMS
35.4
EtHN
O S
(i) (OHCH2)2 PPTS, PhH (ii) mCPBA, CH2Cl2 (iii) CBr2F2, KOH*alumina tBuOH, CH2Cl2
O O
1 M NaOH
S N
76%
N
H H
H O
O
(iv) H2, Pd/C, EtOH, THF (v) LAH, THF (vi) 3 M HCl, THF (10% over 6 steps)
35.6 35.5 Scheme 35 Transannular Ramberg–Ba¨cklund olefination in the synthesis of (þ)-fawcettidine.
N H H
H
O 35.7 (+)-Fawcettidine
197
198
Chiral Pool Synthesis: Starting from Terpenes
O
(i) acrylonitrile, AIBN, Bu3SnH, PhH (ii) 1-chloro-4-TMS-3-butyne Mg, CuI, TMSCl, HMPA, THF
O I2, pyr, CH2Cl2
Me
I Me
95%
O
I
CN
Me TMS
(iii) NaI, mCPBA, THF
36.1
ent-27.4
36.2
52% O
AIBN, Bu3SnH, PhH, 60 °C 64%
CN
CN TMS
(i) TFA, CH2Cl2 (ii) SeO2, tBuOOH, CH2Cl2 (iii) Jones oxidation
Me
36.4 CO2Me
CN (36.5)
O Me
41%
36.3 OTBS
O
O
HO
OMe
N O
O
LiClO4, Et2O AcOH, THF, H2O 40%
Me
Me 36.6
36.7 Fawcettimine
Scheme 36 Free radical annulation in a formal synthesis of fawcettimine.
O (i) NaBH4, MeOH (ii) O3, Me2S
O
O
(i) Tf2O, pyr. (ii) DBU, 50 °C
O OH
(iii) THF, aq. H2SO4 (71% over 6 steps)
(iii) (HOCH2)2, CSA
(R)-(+)-Pulegone (VIII)
37.2
37.1
O (37.3)
O
O Br
O
Mg, CuBr*SMe2 TMSCl
then 10 mol% Pd(OAc)2, O2, DMSO
O
2 N HCl, DMSO (43% over 3 steps)
37.4 O
O O
(i) MePPh3Br, NaNH2 (ii) 9-BBN
(i) [PPh3CuH]6, PhH (ii) NaOtBu, tBuOH
(iii) DMP (61% over 3 steps) (58% over 2 steps)
H 37.6
37.5
CO2H O (i) Ph3P=C(Me)CO2Me (ii) LiOH, iPrOH, 40 °C (60% over 2 steps) H 37.7 Scheme 37 Synthesis of valerenic acid from (R)-pulegone.
H 37.8 Valerenic acid
Chiral Pool Synthesis: Starting from Terpenes
199
O (i) toluene, reflux, 4.5 h, (ii) HCl (1.2 M), THF, r.t., 16 h, 68% (dr 20:1);
OTBS
CHO
H
+
CHO NMe2
(−)-Perillaldehyde (IX)
38.1 (Rawal's diene)
(i) Ph3PMeBr, tBuOK, THF, 80%; (ii) Grubbs (II), CH2Cl2, reflux, 95%
38.2
O
O H
H NBS, tBuOH, r.t.;
Br
38.3
38.4
CrCl3, LiAlH4, THF, DMF, 2-propanol, r.t., 48% from 38.3
OH O
O Me O
H
HO2C OH
38.5
N H
H
38.6 Platencin
Scheme 38 Diels–Alder RCM-sequence with perillaldehyde in the synthesis of platencin.
MeCN, 15 kbar, r.t. to 50 °C, 16 h; then Yb(OTf)3 (0.03 equivalent), MeOTMS (0.10 equivalent), toluene, 0 °C, 6 h, 81%; H
OTBS
(−)-IX
(i) Ph3PMeBr (1.30 equivalent), KOtBu (1.10 equivalent), THF, 86%; (ii) ethylene glycol (10.0 equivalent), PPTS (0.25 equivalent), benzene, reflux, 16 h;
O
+
(iii) O3, pyridine (4.0 equivalent), CH2Cl2/ MeOH (1:1), Ph3P (3.0 equivalent), 91% (over 2 steps);
CHO
OMe 39.1 39.2
O
(i) SmI2 (0.1 M in THF, 5.0 equivalent), MeOH (5.2 equivalent), THF, r.t., 10 min; (ii) TsOH, wet CH2Cl2, r.t., 30 min, 85% (over 2 steps)
O
H
O
(i) Ac2O (5.0 equivalent), DMAP, CH2Cl2/pyr. (20:1), 0 °C to r.t., 1.5 h, quant.; (ii) Burgess reagent (2.0 equivalent), toluene, 70 °C, 15 min, 48%
H
CHO Me
OH
HO O
39.4
39.3
O H
O Pd2(dba)3] (0.1 equivalent), PBu3 (0.2 equivalent), Et3N (6.0 equivalent), HCO2H (6.0 equivalent), THF, reflux, 18 h, 60%.
OAc 39.5
Scheme 39 Diels–Alder pinacol cyclization in the synthesis of platencin.
H
38.6
200
Chiral Pool Synthesis: Starting from Terpenes (i) trichloroacetyl chloride, Zn, Et2O, sonication, 0 °C, 65%; (ii) Zn, MeOH, NH4Cl, 87%;
H
O
H (−)-−Phellandrene (X)
H
40.1 OTBDPS
O CO Me 2 H
(iv) TBDPSCl, imidazole, DMAP, 0 °C 97%;
OTBDPS
O
(iv) DIBAL-toluene, −78 to 0 °C, 84%;
40.3 (major isomer)
OH
(i) DMDO/acetone, DCM, −78 °C, 94%; (ii) MeLi, THF, −78 °C, 42%;
H O
Br
O
(i) DIBAL-toluene, CH2Cl2, −78 °C, >95%; (ii) MsCl, pyridine, DMAP, 0 °C, 95%; (iii) KCN, 18-c-6 ether, CH3CN, 80 °C, 96%;
Br
(i) CrCl2, NiCl2, DMF, 74%; (ii) PivCl, DMAP, DCM, NEt3, 91%; (iii) TBAF, THF, 95%;
H
O
40.2
H
(i) p-TsOH‚ H2O, MeOH, 60 °C (ii) p-TsOH‚ H2O, acetone, 60%; (iii) 2,5-dibromofuran, n-BuLi, THF, −78 °C, 57%;
H
Me2N H
(tBuO)2CHNMe2, 60 °C, 75%;
H OPiv
40.4
H
40.5 (i) Ac2O, DMAP, DCM, 73%; (ii) Ag2O, MeI, CH3CN, r.t., 90%; (iii) KCN, EtOH, reflux, 2 h, 95%; (iv) TBSOTf, DCM, 2,6-lut. 0 °C, 83%;
HO H O OH
H
H O OMe
H
(v) DIBAL-H, DCM, −78 °C, 88%; (vi) TPAP, NMO, DCM, 87%
OPiv
(i) LHMDS, Comins reagent, 71−80%; (ii) 40.8, Pd(PPh3)4, LiCl, PMBOCH2SnBu3, THF, 130 °C, 55%
OTBS
O
O O
O
40.7
OAc
40.6
(Bu)3Sn
(i) TBAF, THF, r.t., 67%; (ii) 40.10, DCC, DMAP, CH3Cl, 50 °C, 80%; (iii) PPTS, MeOH, 70%.
OTBS H O OMe
H O
O
O
Me N
HO O
AcO
40.9
(40.10) O
N
O
(40.8) Me N
O H
N O
H O
OMe O
AcO OH 40.11 (−)-Eleutherobin
Scheme 40 Synthesis of eleutherobin from a-phellandrene.
O
OH
Chiral Pool Synthesis: Starting from Terpenes
methoxyacetylchloide, Et3N
H
25%
H
H OMe
OMe AcOH, h
-Phellandrene
86%
O
H
41.1
(X)
TiCl4, −80 °C
O OAc
41.2
OMe
H OMe O
OTES TESO
H
O
(41.4)
(i) BuLi, LiCl, (ii) MeI (iii) LiCl, H2O, DMSO, 130 °C
tBuLi, CuBr.DMS then Comins′ reagent, then 1 M HCl, THF 71%
41.7
H 41.9
H O
H OH
O H
Ac2O, DMAP, pyridine quant
O OAc O
H O 41.12
Scheme 41 Synthesis of a complex diterpene from phellandrene.
OAc
O H 41.11
41.10
H
OTf
O
O
H
88%
Me
H
OEt (41.8)
H
40%
H 41.6
Br O
O
O
50%
H
CrCl2, NiCl2 (catalyst), DMF/THF
(i) mCPBA (ii) O3, DMS (iii) WCl6, nBuLi
H
41.5
41.3
(iii) PhSeCl (iv) mCPBA 71%
OH
H
43−80%
(i) NaOMe, MeOH, reflux (ii) TBSCl, KH
CO2Me
H
(i) KHMDS, TBSOTf (ii) Ph3P=CH2, THF (iii) 1 M HCl (iv) MeLi, Yb(OTF)3 40%
H O
OAc
H HO Me 41.13 Deacetoxyalcyonine acetate
201
202
Chiral Pool Synthesis: Starting from Terpenes
OMe OMe
HO
Ac2O, py, 70 °C, 91%
p-TsOH, toluene, r.t.
+ OH O
Me
(−)-−Phellandrene (X)
76%
HO
OH O
42.2
Me
42.1
OMe
OMe
OMe
m-CPBA, r.t., DCM 94%. AcO
AcO
OAc O
+
O
O
Me
O
OAc
AcO 2:1
Me
OAc O
42.4
42.3
OMe
H
(i) NaOH (2%), MeOH-H2O, r.t.
42.4
HO (ii) NaOH, PhCHO, MeOH, 80 °C 66%.
Scheme 42 Friedel–Crafts alkylation of phellandrene in the synthesis of linderol.
Me 42.5
O O
H Ph
42.6 Linderol
OH
Chiral Pool Synthesis: Starting from Terpenes (i) iPr2NH, MeMgBr, Et2O, 25 °C,12 h (ii) TMSCl, Et3N, 25 °C, 8 h
Me
O Me
Me
Me CH2I2, Et2Zn, hexanes OTMS
Me
Me
(−)-Menthone (XI)
Me 43.1
Me
Me FeCl3, DMF
Me
NaOAc, MeOH
Cl Me
56%
O
Me
O
Me
Me 43.2
(i) LHMDS, PhNTf2, THF (ii) tetravinyltin, Pd(PPh3)4, CO, DMF
Me
43.3
60%
43.4
Me
Me Sc(OTf)3, CH2Cl2
Me Me
(i) MeLi, Et2O, THF (ii) BF3-OEt2,
Me Me
75%
O
43.6
43.5
O
Me CO2Et
Me ethyl acrylate toluene, −20 to 0 °C
Me
34%
Me
43.8
43.7 Me CO2H
Me
Me
43.9
Me
Me
O
48% from O
Me O
(i) DIBALH, toluene (ii) Dess−Martinperiodinane, NaHCO3
Me Me
Me
Me
OTMS
72%
Me HO
Me
ent-Nanolobalolide (43.10)
Scheme 43 ()-Menthone as starting material in the synthesis of ent-nanolobalolide.
(iii) NaClO2, 2-methyl2-butene, tBuOH, pH 7 buffer
203
204
Chiral Pool Synthesis: Starting from Terpenes
H
O O
m-CPBA, CH2Cl2, (dr 1.5:1) 55% (for major stereoisomer);
H
O
H O
H
trans,cis-Nepetalactone (XII)
O
44.1 (major)
H
OH OH
Br OH
O
O
(i) Grubbs−(II) 20 mol%, CH2Cl2, reflux, 99%; (ii) aq. HCl, MeOH, 88%
CHO
H 44.3
(i) Me2C(OMe)2, catalyst pTsOH, CH2Cl2, 95%; (ii) IBX, DMSO, 96%;
H
(iii) DBU, toluene, 70% (dr 3:1); (iv) MePPh3Br, nBuLi, THF, 95%
H
O O 44.6
44.5
(ii) LiAlH4, THF, 98%;
O
H
NaOMe, 93%
44.2 (minor)
H
(44.4)
O +
H
(i) Zn, 44.4, sonication, aq. NH4Cl, THF 93% (dr 5:1);
O
H
H
(i) ClCOCH2OTBS, pyr, CH2Cl2, 91%;
H
H
(ii) mCPBA, DCM, 90% (dr 2.3:1);
O
O
OH
OH
OH
O TBSO
44.8
44.7 Ph reflux in CHCl3,
HO H
O
2,4,6 −
(i) cinnamic acid, trichlorobenzoylchloride, NEt3, DMAP, toluene, 60%
O
O H O
O
99% H 44.9
O
(ii) TBAF, THF, 91%.
O H
TBSO
HO 6.9 (+)-Englerin A
Scheme 44 Trans,cis-Nepetalactone as starting material in the synthesis of englerin A.
O
Chiral Pool Synthesis: Starting from Terpenes
O H
OAc H
AcOH, h, 17 °C,
O
NaBH4, MeOH, r.t.,
O H
38%
99% O
O Santonin (XIII)
45.1
O OAc H
OAc H OH
SeAr
ArSeCN, PBu3, THF, r.t.,
NaIO4, MeOH, r.t., H
H
68%
O
72%
O
O 45.3
O
45.2
OAc OAc H
OAc H H
neat, r.t., 10 d 72%
H
HH O H
O O
(iii) OsO4.NMO (iv) NaIO4, acetone 62%
O
O
O
(i) KOH, MeOH, 30 °C (ii) SOCl2, Et3N
H
H
45.5
45.4 AcO
O O
H H
H
H
H H
AcO
H O
O
O O
H
H HH O
89%
HH O H
MeLi, THF, −78 °C
45.6
O
O
45.7 (+)-Absinthin
Scheme 45 Diels–Alder dimerization in the synthesis of absinthin from santonin.
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