Syntheses of the tedanolides and myriaporones

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C. R. Chimie 11 (2008) 1419e1446 http://france.elsevier.com/direct/CRAS2C/

Account / Revue

Syntheses of the tedanolides and myriaporones Nina Schu¨bel, Myriam Roy, Markus Kalesse* Leibniz Universita¨t Hannover, Institute of Organic Chemistry, Schneiderberg 1B, 30167 Hannover, Germany Received 12 March 2008; accepted after revision 6 May 2008 Available online 22 August 2008

Abstract This review covers the synthetic contributions leading to the syntheses of the polyketides tedanolide, 13-deoxytedanolide and the structurally related myriaporones. Fragment syntheses that lead to valuable insight into the subtle synthetic problems of the tedanolides are also presented. To cite this article: N. Schu¨bel et al., C. R. Chimie 11 (2008). Ó 2008 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved. Keywords: Tedanolide; Myriaporone; Candidaspongiolide; Total synthesis

1. Introduction In 1984, Schmitz isolated a novel compound, tedanolide (1) from the Caribbean sponge Tedania ignis [1]. The crystalline nature of the compound enabled determination of the structure by X-ray crystallography. Five other related natural products forming the tedanolide family have been isolated from various organisms, namely tedanolide (1), 13-deoxytedanolide (2), tedanolide C (3) and candidaspongiolides (4, 5) (Fig. 1). The tedanolides’ complex architecture, in addition to their high cytotoxicity, attracted considerable interest within the synthetic community. Initial biological evaluation showed an arrest of P338 tumor cell growth in S-phase [1]. Seven years after, Fusetani et al. reported the isolation of a deoxygenated analogue, 13-deoxytedanolide (2), from the sponge Mycale adhaerens [2]. The amount isolated was * Corresponding author. E-mail address: [email protected] (M. Kalesse).

sufficient for only limited studies on the biological profile in the course of which a unique binding to the 60S ribosome subunit [3b,4] was demonstrated. As a result of this binding, peptide elongation in eukaryotic cells was efficiently inhibited. While several compounds exhibiting specificity for prokaryotes were identified, it is noteworthy that 13-deoxytedanolide (2) is the first known macrolide to be selective for eukaryotes [3]. This selectivity for eukaryotes and archaea was rationalized by Moore et al. who successfully co-crystallized 13-deoxytedanolide (2) with the 50S ribosome subunit of Haloarcula marismortui [4]. The binding location was identified as the E site of the ribosome. More recently, Ireland isolated tedanolide C (3) from the marine sponge Ircinia sp. [5] in 2005 and McKee et al. isolated the group of candidaspongiolides (4, 5) from the sponge of the genus Candidaspongia in 2007 [6]. Degradation studies were also performed on 13-deoxytedanolide by Fusetani to probe the structureeactivity relationships [3]. The first functionality targeted was the epoxide. Unfortunately, attempts to remove it only resulted in a skeleton rearrangement

1631-0748/$ - see front matter Ó 2008 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.crci.2008.05.013

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1420

OH

24

25 5

O

O

OH

O

OMe O

O

OH

HO 17 O

OH

13 O

R

11 O

O

OH

O

OH

O

13

11

OH

OH

(+)-tedanolide C (3)

R = OH (+)-tedanolide (1) R = H (+)-13-deoxytedanolide (2) OH

OAc

O O

O

OY

O

O

candidaspongiolides

O Y=

OH

OMe O OH OH

R = C13H27; C14H29; C15H31; C16H33; C17H35; C17H33 (4)

R

Y = H (5)

Fig. 1. The family of tedanolides.

and the formation of a furan (Scheme 1), and thus, left open the question of its significance for the biological activity. One striking feature of this family resides in their structure, raising some questions on their biosynthesis. Indeed, to the best of our knowledge, a macrolactone

with a primary linkage was unprecedented. Thus, the hypothesis of a different lactone as the direct PKS product was envisioned. On the synthesis perspective, tedanolide is prone to retro-aldol degradations due to the numerous b-hydroxyketone moieties. In addition, the epoxide containing side chain is acid sensitive. OH

OH O

OH O

OH

O

O O

CDCl3

OMe O

HO

O

H

H O O

OH

O

H2O H

O

O

O

O

MeO OH O

OH O

O

OMe O

O

O

O O

O

Scheme 1. Fragmentation of 13-deoxytedanolide under acidic conditions.

OH OH

O

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

Since the initial isolation report, tremendous efforts were devoted to the synthesis of tedanolide. These efforts culminated with the first total synthesis of 13deoxytedanolide (2) by Smith et al. [7] in 2004, followed three years later by the synthesis of tedanolide (1). Their strategy was designed to give access to both compounds in a unified approach. In 2005, a second synthesis of 13-deoxytedanolide was reported by the Roush group [8]. The first total synthesis of tedanolide was achieved by the Kalesse group [9a] in 2006. Fragment syntheses that lead to valuable insight into the subtle synthetic problems of this class of compounds will be covered as well.

1421

epoxide or by displacement of an iodide would generate tedanolide (1) or 13-deoxytedanolide (2), respectively (Fig. 2). The use of a dithiane anion reversed the reactivity of the aldehyde for the coupling to proceed and protected the carbonyl from possible hemiketal formation. This hemiketal was indeed detrimental as it prevented Roush from completing the synthesis of tedanolide. Two different routes were reported by Smith for the southern fragment. The first generation [6] disclosed for the synthesis of 13-deoxytedanolide (2) was linear and closely similar to the one developed by Roush for his synthesis [8]. The second generation [7c] developed for tedanolide (1) was more convergent and more efficient (Scheme 2). One of the main challenges encountered during the syntheses was the protecting group strategy. The change from DEIPS to SEM for C17 allylic alcohol between the two routes is noteworthy. The SEM was easily deprotected selectively in presence of a TIPS and TBS and was also more stable than the DEIPS.

2. Results and discussion 2.1. The common approach to the tedanolides by Smith As already stated, Smith developed a unified strategy to synthetize both tedanolide (1) and 13-deoxytedanolide (2) from a common late stage intermediate. Retrosynthetic disconnections at the macrolactone linkage and at the C11eC12 bond gave rise to the northern and the southern fragments. While the northern fragment is identical for both compounds, simple variation of the southern fragment was required. Coupling by opening an

2.2. Synthesis of the first-generation southern fragment Starting from alcohol 6 standard transformations generated acetate 8. Next the terminal double bond was OH

Yamaguchi macrolactonization

O

O

OH

OH

O

OMe O

O

R

R = OH; tedanolide (1) R = H; 13-deoxytedanolide (2)

O

dithiane coupling

13-deoxytedanolide synthesis

tedanolide synthesis Evans aldol

Roush crotylation

vinyl addition

O

O

SEMO HO

OTIPS

I DEIPSO 12

OMe O

O

SEMO

PMB 24

vinyl addition S S

Fig. 2. Common strategy for the synthesis of tedanolide and 13-deoxytedanolide.

17

O

O

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1422 OPMB

OPMB

OPMB O

1) Swern

1) DEIPSOTf, 2,6-lut.

Xc

2) Bu2BOTf, Et3N 83% 2 steps OH

O

6

DEIPSO

OH

O N

OAc

2) LiBH4, MeOH, Et2O 3) Ac2O, DMAP, Et3N 63% 3 steps

7

8

O

Bn OPMB

1) OsO4, NMO 2) NaIO4 3)

OPMB 1) K2CO3, MeOH

OAc CO2i-Pr

O

CO2i-Pr

B O

O

2) PPTS, acetone 77% 2 steps MeO

OH

DEIPSO

OMe

10

9

68% 3 steps

O

DEIPSO

OH

2) Ac2O, Et3N 3) DDQ, H2O 75% 3 steps

OAc O

DEIPSO

O

1) Dess-Martin 2) Ph3P=CHCH3

O

1) 9-BBN, THF/Et2O H2O2, NaOH

3) K2CO3, MeOH 4) (PhO)3PCH3I, DIEA 53% 4 steps

11

I DEIPSO

O

12

Scheme 2. First-generation approach of the synthesis of the southern fragment of 13-deoxytedanolide.

selectively oxidized and subjected to a Roush crotylation which proved to be more appropriate for this transformation than the Brown protocol. Indeed, the boronate was more labile and thus provided higher yields in the

hydrolytic work up. After protecting group manipulations and oxidation, the Z-alkene could be introduced via Wittig olefination. Finally, saponification and iodination provided the southern segment. OH

OPMB

PMBO

t-BuLi

I

1) SEMCl, (i-Pr)2NEt, CH2Cl2, rt

O O O

17 O

13

OTBS

OTBS

13

OH

O 14

2) DDQ, pH=8 buffer, CH2Cl2, 0 °C 70%, 2 steps

O 17

O

SEMO

13

15

OTBS

OTBS

OTBS

OTBS

1) Dess-Martin periodinane NaHCO3, CH2Cl2, rt 2) Ph3P=CHCH3, THF,-78°C to rt 74%, 2steps

O

O 1) TBAF, THF, rt 17 SEMO 16

O

OTBS

13

2) N-Trisim, NaH,THF, 0°C 82%, 2 steps

17

O

SEMO

13

17

O

OTBS

Scheme 3. Second-generation approach of the synthesis of the southern fragment of tedanolide.

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446 S

1) n-BuLi, MeOH 64%

S 1) Swern

S

OH

Br

S

2) CBr 4, PPh3 92%, 2 steps

2) t-BuLi, MeI 91%

Br

18

19

1423 1) Bu3SnH PdCl2(PPh3)2

S S

2) I2, CH2Cl2 79% 2 steps

20

SEMO

O O

S I

S

OH OMe O

t-BuLi; 64%, 4:1

PMB S

O OMe O 22

O PMB

HO

OTIPS OMe O PMB

4) SEMCl, TBAI, DIEA 5) K2CO3, MeOH 68% 4 steps

O

21

1) TIPSOTf; 89% 2) PPTS, MeOH 3) AcCl

S

S

23

S

24

Scheme 4. Synthesis of the northern fragment of tedanolide.

2.3. Synthesis of the second-generation southern fragment The second-generation synthesis disconnected the southern fragment at the C17eC18 bond. The coupling proceeded accordingly to Yonemitsu’s study of this transformation. Starting from the protected Roche aldehyde, an alkyne was generated via the CoreyeFuchs protocol. Regioselective E-vinyl iodide formation was achieved by stannyl cupration to provide 13. Several conditions were investigated in order to obtain only the desired isomer (Schemes 3 and 4). The C12eC17 aldehyde synthesis featured a Brown crotylation and an Evans aldol condensation. The subsequent coupling directed by the inherent properties of the aldehyde yielded 14 in a 6:1 diastereoselectivity. The southern fragment 17 was then completed by a Z-selective Wittig olefination and a Fraser-Reid epoxide formation.

dianion of the northern fragment 24 (dithiane and free primary alcohol) was used for the key coupling which proved to be high yielding (80% BORSM). As previously stated, the dithiane was seen as a protecting group of the carbonyl to prevent hemiketalization. The downside of this strategy was the dithiane sensitivity to common oxidation methods. This issue was addressed by the development of Tishchenko oxidation. This specific oxidation promoted by samariumII relied on an internaloxidationereduction in the presence of a bhydroxyketone (26). The resulting ester 27 was hydrolyzed and subsequent macrolactonization of the triol (C15, C17 and C29) selectively closed on the less hindered primary alcohol to provide 28. Diastereoselective epoxidation of 30 directed by the C17 allylic alcohol (Henbest effect) and global deprotection finalized the synthesis. The longer linear sequence was of 31 steps with an overall yield of 0.31% (Scheme 7).

2.4. Synthesis of the northern fragment

2.6. The Roush synthesis of 13-deoxytedanolide

In a similar fashion to the southern fragment, the northern fragment 24 [7] was assembled by the addition of a vinyl iodide to an aldehyde. The vinyl iodide 21 was generated as previously from an alkyne and a hydrostannylation. Iterative Evans aldol reactions provided the C1eC7 aldehyde intermediate 22.

Roush envisioned a disconnection between C12 and C13 (Fig. 3). This approach should allow access to both tedanolide and 13-deoxytedanolide from the same precursor [8]. The configuration at C15 was chosen to be anti with respect to the configuration at C14 in order to maximize the Felkin enhancing effect of both stereocenters. Additionally, they decided to carry the functionality at C5 as the ketone through the synthesis. Having recognized that mild deprotection conditions were needed for the ester moiety, they employed an allyl group and the Alloc protecting group for the C29 primary alcohol. Thus, both could be removed simultaneously (Fig. 4).

2.5. Coupling of the northern and southern segments for the tedanolides The endgame strategy for 13-deoxytedanolide (Scheme 5) and tedanolide (Scheme 6) are closely related and only one will be described herein. The

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1424

OSEM

OSEM OH

t-BuLi (2.05 eq.) THF, 10% HMPA; 75%

OTIPS

OH

OTIPS O

OMe OPMB

OMe OPMB

O

24

DEIPSO

S S

S

O

S

I DEIPSO

25

O 12 OSEM

1) SO3•pyr, DMSO

RO2C

2) SmI2 (35 mol %) O

OTIPS O

OH

26

DEIPSO

OMe OPMB

S

O

1) PPTS, MeOH 85%, BORSM 2) LiOH, THF/H2O, 74% BORSM 3a) 2,4,6-Trichlorobenzoyl choride, DIEA, THF 3b) DMAP, Toluene

S

75%, 2 steps 27

OSEM

OSEM O

OTIPS OMe OPMB

O

OH

O

1) TESCl, DMF 2) DDQ, pH 7 buffer

S

OH

O

3) PhI(O2CCF3)22,6-di-t-Butyl-4methylpyridine 4) Dess-Martin

S

OTIPS

TESO

O

46%, 4 steps

28

OMe O

O 29

OH O

OTIPS

1) HF•pyr, pyr

OMe O

O

2) MgBr2, MeNO2/ Et2O

1) m-CPBA, NaHCO3; 48% 2) TBAF, DMPU; 38%

84%, 2 steps HO

O

O 30

OH O

OH O

OMe O

O

OH

O R= HO

O

O

13-deoxytedanolide (2)

Scheme 5. Endgame of the Smith’s 13-deoxytedanolide synthesis.

2.7. Synthesis of the C1eC12 segment The Roush synthesis of the C1eC12 segment began with a Noyori reduction of keto ester 38 and subsequent methylation. A sequence of reduction, acetylation and

regioselective reductive acetal opening provided after oxidation compound 42. Allyl stannylation, methylation and oxidative cleavage of the double bond provided aldehyde 44 which was transformed to allyl ester 45 through Pinnack oxidation, Mitsunobu esterification and oxidation of C11 to

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1425 SEM

OSEM 7

O

t-BuLi 10% HMPA/THF, -78°C, 3 min

OTIPS

HO

OTIPS OSEM

OH

OMe S

24

OPMB

O

23

11

17

O

S

SEMO

13

17

(1.1 equiv)

O

O

O

SEM

O

OTIPS OH

RO2C OSEM OMe O PMB

O

O

S

SmI2 75% 2 steps

S

O

O

O

TBS

SEM

OTIPS

O

1) PPTS, MeOH/THF 72% BORSM 2) LiOH•H2O

OMe O PMB

O

SEMO

OH

1) DDQ, H2O; 84% 2) PhI(CF3CO2)2, 2,6-di-t-butyl-4-methylpyridine 3) DMP; 39% 2 steps

S

TBS

SEM

OH

O

SEMO

S

O

34

OTIPS O

O 35

S

33

O

O

S TBS

32

3) 2,4,6-trichlorobenzoyl chloride, DIPEA then DMAP 46% 2 steps

SEM

OTIPS OSEM OMe O PMB

O

S

31

O

2) HF • pyr 83% 2 steps 3) SO3 • pyr

S

OH

O

O

1) TBSOTf

OMe O PMB

OMe O

O

O TBS

1) MgBr2, EtSH 2) m-CPBA 60% 2 step BORSM 3) HF•Et3N; 58%

OH

O O

OMe O

O

OH

O

OH

1

O R=

OH

O

Scheme 6. Endgame of Smith’s tedanolide synthesis.

the ketone. The key aldol coupling proceeded in high yield to provide the northern fragment 36. 2.8. Synthesis of the C13eC23 segment One of the key issues in this segment synthesis was the appropriate introduction of the protecting groups.

In particular the introduction of the Alloc group was achieved at a relative late stage since it would interfere with oxidative transformation employed in this segment synthesis. Therefore, the BEC group was exploited as a transient protecting group for the primary alcohol. Starting from the commercially available Roche ester (Scheme 8), Wittig olefination followed by Dibal-H

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1426 O

O OMe

Me

OH

(R)-Binap-Ru(II)Cl2 H2 (60 psi), MeOH

1) LDA, THF -78 °C OMe

Amberlyst 15, 100 °C 99%, >99%e.e

38

O

Me

2) MeI, HMPA

39 Ar

OH

O

O

1) DiBAl-H CH2Cl2, -78 °C 2) (COCl)2, DMSO

O

1) LAH, Et2O. 0 °C OMe Me

2) ArCHO, TsOH C6H6, reflux

Me 40

BF3 • OEt2, CH2Cl2 -78 °C 75%, > 95:5 ds

Me 42

OH

DMPMO

DMPMO

OTBS

44

THF, aq. acetone 3) Pb(OAc)4, EtOAc 55% (3 steps)

OTBS

43

O

OMe O

HO

O Me

Me

OTBS 45

DMPMO

OH

O

OMe O

Me

O

O Me

Me

Me

Me Me

Me

3) DDQ 4) TPAP, NMO 66%

1) TiCl4, i-Pr2NEt, CH2Cl2 -78 °C DMPMO

Me

1) NaClO2, KH2PO4 2) Ph3P, DEAD,

O H

Me

1) MeOTf, DBMePy CH2Cl2, 23 °C 2) OsO4, NMO

OH

OTBS 15

H

Me

41

SnBu3

O

Et3N, CH2Cl2, -78 °C 64% from 39

Me

Ar = 3,4-(MeO)2C3H5

DMPMO

Me

Me

Me

OTBS

47

Me

46 (1.8 eq.) -78°C,- ->0 °C, 73% TBSO

O 1) TBSOTf, 2,6-lutidine 2) DDQ

O

OMe O

Me

3) TPAP, NMO, 65%

O Me

Me

Me

Me

OTBS

36

Scheme 7. Synthesis of the C1eC12 segment of tedanolide.

reduction generated the allylic alcohol 6 required for the stereoselective introduction of the epoxide. An Evans aldol reaction using (S)-56 established olefin 51 which could be transformed to the double acetate aldol O

OMe O

OTBS

O

TES O OTBS O

+ 13 12

O 1 TBSO

O

36

protected intermediate 53. Introduction of the C12e C22 double bond was performed with standard conditions. Finally, the pivotal introduction of the Alloc group was achieved by treatment of 54 with allyl alcohol and MeMgBr. This simultaneously liberated diol was then transformed to the corresponding aldehyde through Pd(OAc)4 cleavage. 2.9. Endgame of the synthesis

OAlloc

23 37

Felkin enhancing

Fig. 3. Retrosynthetic disconnection of tedanolide in the Roush synthesis.

The aldol coupling was effectively achieved using LiHMDS in THF (Scheme 9). Upon deprotection of the C15 hydroxyl group, intermediate 59 spontaneously cyclized to form an undesired and stable

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446 OH

TBSO OH

O 1

23

O

29

OMe O

18 O

1427

OTBS

O

8

O

OMe O

O

O

13 OH

O

O

OH

TBSO

1

62

OMe O

O HO

TES OTBS

O

O

63

OMe O

TES OTBS

O

O 1 TBSO

TBS PMB OTBS O

13

1 TBSO

O

O TBS

29

O 12

+

OH

O

23

PMB OTBS

H 13 65

64

31

OMMTr

23

Fig. 4. Retrosynthesis of tedanolide.

hemiketal. The deoxygenation of C13 allowed the equilibrium with the acyclic ketone to exist, and thus, to be further processed. However, this prevented the synthesis of tedanolide (1). Oxidation of the open form drove the equilibrating mixture to the triketone 60. Simultaneous allyl ester and Alloc deprotection to provide the seco acid which was followed by a modified Yamaguchi macrolactonization yielded 61 in 31% over two steps. Finally, global sillyl deprotection provided (þ)-13deoxytedanolide (2). 2.10. The Kalesse synthesis of tedanolide As a consequence of the labile epoxide moiety in tedanolide (1) the Kalesse group decided to introduce this functional group at the last step of the synthesis. As in all other syntheses of the tedanolides an essential issue was the appropriate choice of orthogonal protecting groups for the C29 alcohol and the carboxylate. After substantial variations, the monomethoxytrityl group (MMTr) was identified to be an ideal choice for C29 hydroxyl since its installation and chemical stability were compatible with the operations employed. Additionally, the very mild conditions for its removal, namely treatment with hexafluoro isopropanol allowed removal even in the presence of unprotected b-hydroxyketones.

2.11. Synthesis of aldehyde 65 The originally published route had its drawbacks due to a relatively greater number of steps and occasionally uncontrolled migration of protecting groups. These disadvantages led to an improved synthesis of the C13eC23 aldehyde 65, using a more convergent aldol coupling between C16 and C17 that paralleled the fragment synthesis proposed by Loh. The synthesis commenced with trityl protected Roche aldehyde 66 and subsequent olefination to yield alkene 67. The acid catalyzed cleavage of trityl ether and subsequent Swern oxidation provided an aldehyde which was directly subjected to Wittig olefination providing the unsaturated ester 68. Dibal-H reduction and MnO2 oxidation provided aldehyde 69 (Scheme 10). Ketone 72 was synthesized in four steps according to the route described by Loh. An anti-selective aldol addition between 72 and 69 set the desired anti-relation between the C17 hydroxy and the C16 hydroxymethyl group. The diastereomeric ratio, however, was only of 2:1 in favor of the desired isomer 73. Dibal-H reduction provided exclusively syn-diol 74 (dr > 95:5). The TBS group was removed with TBAF. The three alcohol moieties were selectively protected with an MMTr group on the primary alcohol, a TBS group on the allylic alcohol and the closure of the PMP acetal on the third. Reductive opening of this acetal with Dibal-H

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1428

1) Ph3P=CMeCO2Et CH2Cl2, 23 °C

Me PMBO

CHO

PMBO O

50

CHO

2) SO3•py, Et3N DMSO 65%

6

1) 56, Bu2BOTf, Et3N CH2Cl2, -78 °C

Me

1) Ti(Oi-Pr)4, TBHP (-)-DIPT

Me OH

2) DiBAl-H, Et2O, -78 °C 83%

48

Me

Me PMBO

Me

1) Br(CH2)2OC(O)Cl, DMAP 2) OsO4, NMO 3) Pd(OAc)4

OH

Me

PMBO

2) TBSOTf, lutidine 3) LiBH4, THF, H2O 62%

O 51

4) (S,S)-57 toluene 71% OTBS

OBEC

OBEC Me

PMBO

Me

O TBS

Me

1) TESOTf, 2,6-lutidine 2) OsO4, NMO O

3) (MeO)AcCl, DMAP 83%

OH

Me

O

PMBO

TBS

OAc(OMe) O

OBEC

3) Ph3P=CHCH3 51%

OAc(OMe)

53

52

1) DDQ 2) Dess-Martin

OH

Me

Me

OAlloc

23

OAc(OMe)

Me

Me

1) allyl alcohol MeMgBr, THF O TBS

O

OH

OAc(OMe)

13

2) Pb(OAc)4, 75%

TBS

54

O

O

O N

O

O i-Pr

OH

O

37

CO2iPr

B

O

(S)-56

O

57

CO2iPr

Scheme 8. Synthesis of the C13eC23 segment.

followed by oxidation with TPAP/NMO provided the southern fragment 65 (Scheme 10). Aldol reaction. Screening of different bases for the enolization of 64 was needed for the pivotal aldol coupling with aldehyde 65. KHMDS was identified to provide the highest selectivities for obtaining the Felkin product 77 (Scheme 11). To liberate the seco acid the monomethoxytrityl group was removed with hexafluoro isopropanol and the allyl group by palladium. The Yamaguchi protocol which was previously employed in both syntheses of 13-deoxytedanolide (2) provided 10e35% of the undesired 14-membered macrolactone 79 [9e]. To avoid the undesired lactonization the secondary alcohol at C13 was protected with TBS triflate. The moderate yield of 55% in the conversion of 77e80 could be attributed to considerable retro aldol of 77.

After cleavage of the allyl ester, the free carboxylic acid was subjected to different lactonization methods. The Mitsunobu protocol led to the desired macrolactone 81 in good yields (Scheme 12). The oxidation state manipulation required deprotection of the PMB and TES groups followed by oxidation. Global silyl deprotection with 3HF$Et3N provided 82 after five days (Scheme 12). The final epoxidation could be achieved with substoichiometric amounts of m-CPBA at 45  C, taking full advantage of the directing Henbest effect. 2.12. The Yonemitsu approach Early contributions by Yonemitsu were based on computational analyses of the seco acid 84 and unraveled the cyclic acetals to induce the desired conformation for the

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

O

OMe O

OTBS

O

O

1429

TES OTBS O O

LiHMDS, THF, -78 °C

OAlloc

59% plus 14% recovered 37 and 27% of 36

+

O 1 TBSO

36

37 OTBS

OTBS O AllocO

OTBS O

OR

O

OMe O

TFA, AcOH H2O, 23 °C 71%

O AllocO

OMe O

O O

O O

TBS

O

OH

O

OH

O

TBS

TES

58

stable hemiketal

59

OH

OTBS O 1) C6F5OC(S)Cl, DMAP

OTBS O

2) Et3B, n-BuSnH 50% 3) DMP 71%

OMe O

2) i-Pr2NEt, DMAP Cl3C6H2COCl 31%

OAlloc

O TBS

O

1) Pd(PPh3)4, n-Bu3SnH

O

O

60

OTBS O

OTBS O

O TBS

O

OMe O

Et3N•HF, Et3N 66%

2

O

O

61 Scheme 9. Endgame of Roush’s synthesis of 13-deoxytedanolide.

lactonization. The aldol reaction between 86 and 87 was an additional example of how subtle differences can dominate the outcome of synthetic strategies. Indeed, the aldol reaction using LiHMDS provided a 1:1.2e1:1.9 mixture of diastereoisomers in favor of the undesired isomer. Fortunately, the isomers could be separated by chromatography and macrolactonization was achieved by using the Yamaguchi protocol in 87% yield (Fig. 5). Different disconnections can be envisioned to generate 86. Initially, 86 was generated from the coupling of known vinyl iodide 89 and aldehyde 88 (Fig. 6). The coupling, however, suffered from low selectivity and irreproducibility. The synthesis of the northern fragment was then reviewed, this time highlighted by a tin triflate based synaldol pioneered by Paterson between 90 and 91. The pivotal Paterson aldol provided the adduct in 80% yield with a diastereoselectivity greater than

20:1 (Scheme 13). After protecting group manipulations and oxidation of 93, a Wittig homologation provided the carbon skeleton of the C1eC11 fragment. Subsequent dihydroxylation followed by DDQ treatment provided the first acetal unit. Finally, the methyl ketone was introduced through methyl lithium addition and oxidation. The C13eC23 fragment was further disconnected at the C17eC18 bond with the addition of vinyl lithium 97 to aldehyde 96 (Scheme 14). The synthesis of 96 began with a TiCl4-mediated addition of oxazolidinone (R)-56 to the Roche ester-derived aldehyde 98. Reduction and acetalization provided 100. Reductive opening of the acetal followed by TBSCl protection and oxidative cleavage of the double bond provided aldehyde 96. In contrast to the previously discussed syntheses Jung, Miyashita and Loh mainly focused on providing

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1430

TrO

1) EtPPh3+Br-, n-BuLi, 85%, Z/E = 92:8

O

O

HO 1) Swern Oxidation

H

2) MnO2, 90%

2) EtO2CC(CH3)=PPh3

2) p-TsOH MeOH

66

1) DiBAl-H, 87%

EtO

68

67

O H

69

PMBO

1) LDA, CH3CO2Et 88%

O H

PMBO

OH

2) LiAlH4, 95%

PMBO

1) TBSCl, imdazole; 93%

71 PMBO

OTBS

O

OH

72 DiBAl-H, 76%, dr > 95:5

PMBO

OH

73 OH

OH

OTBS

OTBS

PMBO

O

2) Swern oxidation; 97%

70 Cy2BCl, Et3N then 69; 68%, dr = 2:1

OH

74

PMP OH

1) TBAF, 95% 2) MMTrCl, Et3N, 69%

1) TBSCl, imidazole, 92%

O

O

OTBS

2) DDQ, 85% OMMTr

OMMTr

75

76

PMB O

O

OTBS

1) DiBAl-H, 81% 2) TPAP, NMO, 95%

H

65

OMMTr

Scheme 10. Synthesis of fragment 65.

segment syntheses and new approaches toward tedanolide (1). The groups of Jung and Miyashita synthesized the northern and southern fragments, respectively. Loh et al. reported the synthesis of the northern and the southern hemispheres as well as the fragment coupling via an aldol reaction to provide the corresponding seco acid 126. Additionally, the approaches of Jung and Miyashita also aimed on developing an efficient synthetic route flexible enough to provide access to 13-deoxytedanolide (2) and tedanolide (1). 2.13. The Miyashita approach Miyashita et al. published the stereoselective synthesis of the C13eC23 segment in 2005 [11a]. Their

retrosynthetic analysis (Fig. 7) paralleled the one presented by Roush and Lane [8], Hassfeld and Kalesse [9] and Yonemitsu et al. [10]. The first retrosynthetic disconnection was also made at the macrolactone linkage. Further disconnection divided the seco acid into the C13eC23 fragment 102, already containing the labile epoxide functionality, and the C1eC12 segment 103. Both segments were envisioned to be assembled by an aldol under FelkineAnh control [11a]. Miyashita et al. designed a synthetic route for the C13eC23 segment 102 starting from the chiral unsaturated ester 105 in 23 linear steps. The main drawback was the linearity of the synthesis. However, it is interesting to note that the stereoselective synthesis was achieved without the use of any aldol reaction. Instead, the strategy is highlighted by two stereoselective

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

O 64

OMe O

TES OTBS

O

1431

OH

O

PMB OTBS

KHMDS, then 65 , 59% O 1 TBSO

13 29

O

TES OTBS

OMe O

23

OMMTr

77

O

OH

O

PMB OTBS

1) (CF3)2CHOH, MeOH, 85% HO

2) Pd(PPh3)2Cl2, Bu3SnH

TBSO

OH

78 TBSO O 2,4,6-Cl3C6H2COCl DMAP, i-Pr2NEt

TBSO

OTES

OPMB O 13

OMe OTBS

(35%, 2 steps) 29

OH

O

79

Scheme 11. Aldol coupling and lactonization.

epoxidation reactions of trisubstituted olefins (epoxidation/epoxide opening) and a stereospecific SN20 methylation reaction of a trans-g,d-epoxy-cis-a,bunsaturated ester 104 (Scheme 15). The C13eC21 portion was constructed from the chiral unsaturated ester 105 via Sharpless asymmetric epoxidation followed by epoxide opening using

O 77

vinylmagnesium chloride and copper(I)bromide dimethyl sulphide complex. The E-configured double bond of the C18eC19 moiety was installed via Wittig reaction. To introduce an a-secondary methyl group at the C20 position stereoselectively, the use of the stereospecific SN20 methylation reaction developed by Miyashita et al. was applied [11b]. For this purpose,

OMe O

TES OTBS

O

O

TBS PMB O OTBS

TBSOTf, lutidine, 55% O TBSO

80

OMMTr

TBSO O 1) (CF3)2CHOH, MeOH, 85%

OTBS O

OMe O TES

2) Pd(PPh3)2Cl2, n-Bu3SnH 3) PPh3, DEAD 66%, 2 steps

TBSO

O

4) Dess-Martin 90% 5) 3HF•Et3N, CH3CN/Et3N, 32%.

O O PMB TBS

81

OH O

OH O

OH O

OMe O

O

OH

m-CPBA, -45 °C, 3 d, 28%.

O

82

OH OMe O

O

O OH

1) DDQ, 68% 2) Dess-Martin 65% 3) PPTS, MeOH, 67%

OH

O

OH 1

Scheme 12. Cyclization of hydroxy acid 80.

O

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1432 MOMO

DMP

DMP

O

OMOM

MOMO

15

13

O

O

O

O

O

O

O

O

OMOM

O

HO

DMP

O

15

13

MOMO

OMOM

O

84

OH

O 83

DMP DMP O

OMOM

O

OH

O

TESO

O

DMPM OMOM

15

MOMO

85

15

OTBS

Felkin

OH

O +

anti-Felkin 1:1.2 to 1:1.9

DMP O

OMOM

O

O

+

TESO

O

12

O

DMPM OMOM

15

MOMO

23

OTBS 86

87

Fig. 5. Lactonization by Yonemitsu.

the requisite ester 104 was synthesized via the HornereWadswortheEmmons reaction with the Ando reagent (Scheme 15). This reaction not only installed the methyl group at the C20 but also opened the epoxide at the same time to obtain the C17 hydroxyl stereoselectively. To obtain the southern fragment 102, the C13eC21 polypropionate chain was extended via a Z-selective Wittig reaction. After several protecting group manipulations and stereoselective epoxidation of the C18eC19 alkene with m-CPBA, a protectioneoxidation sequence yielded 102.

2.14. The Loh approach Loh and Feng [12] reported on the synthesis of the northern hemisphere 114 and the southern hemisphere 113 of tedanolide (1) as well as the fragment coupling via aldol reaction to complete the carbon backbone. However, the successful total synthesis of tedanolide (1) has not been reported yet. The retrosynthetic analysis of tedanolide (1) is outlined in Fig. 8. Disconnection at the C29 lactone and the C12, C13 aldol units created the two subunits 113 C13eC23 and 114 C1eC12.

PMP TESO

O

PMP

O

OMOM

O

O

12 MOMO

O

O

OMOM

O

MeO MOMO 87

86

20:1

3.6:1 PMP PivO

O

O

O

OTBS +

PMBO

O

O

OTBS

+

I

MOMO 88

89

90

Fig. 6. Retrosynthetic disconnection of tedanolide according to Yonemitsu.

91

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446 PMBO

O

PMBO

OH

OH

OTBS 1) DDQ 2) MOMCl

1) Sn(OTf)2, i-Pr2EtN O

OTBS

90

1433

OH

PMP O

PMB O OMOM

OH

1) DDQ 2) MOMCl

OTBS

O

OH

O

O

OMOM

MeO

3) TBAF 56% 3 steps

MeO

O MOM

94

95

PMP O

1) Dess-Martin 2) MeLI

O

O

OMOM

O

MeO 3) Dess-Martin 38% 3 steps

O MOM

86

Scheme 13. Synthesis of the C1eC12 segment.

O

O

DMPM OMOM

H 13 23

OTBS 87

TBSO

O

DMPM O +

I

OTBDPS

H OTBS 96

N (R)-56

O

97

O

O

TBSO

O

TBSO

OH

O

O N

O

1) LiBH4 2) DMPCH(OMe)2 CSA

TiCl4, i-Pr2EtN 99

98 DMP

DMPM TBSO

O

O

1) DiBAl-H 2) TBSCl

TBSO

O

1) OsO4 2) NaIO4

TBSO

O

OTBS 100

OTBS

93

91 2) DiBAl-H 80% 2 steps

3) AD-mix 81% 3 steps

PMB OMOM

3) DiBAl-H 63% 3 steps

92

1) Dess-Martin 2) Ph3P=CHCO2Me

O

101

Scheme 14. Synthesis of the C13eC23 segment.

DMPM O

OTBS 96

OH

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1434

OH

macrolactonization O 1 23

O

OH

O

OMe O

O

R

16 OH

tedanolide (1) R = OH 13-deoxytedanolide (2) R = H

O

aldol reaction

OP

SN2´ methylation reaction

dihydroxylation

O

O

13 CHO O

OP 1 OMe OMe O

O

23

+

12

103

O

O

TES 102

O O EtO

OMPM O

O

EtO

OMPM O

104

105

Fig. 7. Retrosynthetic analysis of tedanolide by Miyashita et al.

The key step of the southern fragment 113 [12] synthesis displayed a boron-mediated aldol reaction developed by Paterson and Tillyer [13] between the a,b-unsaturated aldehyde 115 and ketone 72 in very good yield and selectivity (95% yield, major:minor ¼ 85:15). It is interesting to note that Kalesse et al. followed the same strategy using the same ketone 72 to assemble the carbon backbone of the C13eC23 fragment. However, in the case of the Kalesse synthesis, another aldehyde was used and lower yields and stereoselectivity were obtained (68%, major:minor ¼ 2:1). Ketone 72 could be easily synthesized from the commercially available Roche ester via aldol reaction with methyl acetate and several oxidation and protecting group manipulations. Aldehyde 115 was synthesized from the readily available (S)-methyl-3-hydroxy-2methylpropionate as reported by Paterson and Tillyer [13] (Scheme 16). Further elaboration of fragment C13eC23 was effectuated with a Wittig reaction to install the C21e

C22 Z-olefin. After protecting group transformations, the C18eC19 epoxide was generated with m-CPBA and 121 was obtained in 54% as a single diastereomer (Scheme 17). It is the first example of a late stage epoxidation of these substrates. Indeed, it was initially expected to give a mixture of diastereomers or even the undesired isomer [19]. Gratifyingly, the desired product was formed exclusively. The C1eC12 subunit [12] was generated from the intermediate 122 which could be obtained from the coupling of the two precursors 117 and 118 (Scheme 18). The key feature also presents a syne syn boron-mediated aldol reaction developed by Paterson and Tillyer [13]. Ketone 117 was synthesized from the Roche ester via Wittig reaction and Sharpless asymmetric dihydroxylation to incorporate the alcohol functionalities at C2 and C3. The t-butyl ester was selected due to its stability toward nucleophilic attack (Scheme 19). The coupling of the northern and southern fragments was achieved via an aldol reaction. Optimization

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

EtO

1) DiBAl-H, THF;95%

OMPM

HO

2) Ti(Oi-Pr)4, (-)-DET, TBHP

OMPM

1435

CH2=CHMgCl

HO

MS 4 Å, CH2Cl2; 96%

O

105

OH 107

106 O

1) (MeO)2CMe2 PPTS; 75%

O OMPM

2) OsO4, NMO

O

NaIO4

O

1) Ph3P=C(CH3)CO2Et toluene, 70 °C; 98% 2) DiBAl-H, THF; 99%

HO

OMPM

HO

OMPM O

O

O

O

1) Dess-Martin periodinane pyridine, H2O, CH2Cl2 2) (o-MeC6H4O)2P(O)CH2CO2Et KHMDS, THF, -78°C 81% 2 steps

110

O OMPM

EtO

O

O

O 7 steps

EtO

OMPM OH

Me2Zn, CuCN DMF, 10 °C, 74%

104

O

111

m-CPBA CH2Cl2, 0 °C

109

108 O

O

OMPM

CuBr • DMS

O

O

OMPM

112 TBSO

5 steps

O

O CHO O

OTES O

102 Scheme 15. Synthesis of the C13eC23 fragment of tedanolide by Miyashita et al.

of this pivotal transformation identified (c-hex)2BCl as a Lewis acid to provide the highest yields and diastereoselectivities. 2.15. The Jung approach Jung et al. proposed in their approach of tedanolides 1 and 2 the preparation of the C1eC12 fragment [14] via a stereoselective non-aldol aldol process, which was developed in their laboratories. The reaction involves the internal hydride migration from an alcohol or silyl protected alcohol to open an epoxide with inversion of configuration at the epoxide center. As the product is already protected during the course of this transformation, further modifications are not required in contrast to standard aldol reactions. The retrosynthetic disconnection of tedanolide’s backbone began with the cleavage at the lactone and scission at the C12eC13 bond to generate the common precursors 126 C1eC12 fragment and 125 C13eC23 fragment (Fig. 9). These intermediates should have been coupled either by an aldol reaction of the

aldehyde 125 (for tedanolide (1)) or an alkylation of the tosylate derived from 125 (for 13-deoxytedanolide (2)). The northern fragment 126 [14] was generated from the aldol coupling of the two intermediates 127 and 128 with TiCl4 and Hunig’s base (Scheme 20). It is worth mentioning that only the desired Felkin product was obtained in good yield. Other coupling reagents were unsuccessful. After protection of the free hydroxyl group and reduction of the ketone by L-Selectride compound 132 was obtained containing all the required chiral centers of the northern fragment of the tedanolides 1 and 2 (Scheme 21). The precursor of 127, namely ester 129 was prepared from commercially available L-ascorbic acid in three steps via diol protection with 2,2 dimethoxypropane, cleavage of the alkene and esterification with ethyl iodide [14]. The desired ketone 127 was obtained through reduction, epoxidation and regioselective epoxide opening with methyl magnesium bromide and copper iodide (Scheme 22).

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1436

aldol reaction macrolactonization

OH

TBSO

O

OH O

O

OMe O

O OH

O

R

OMe O

t-BuO2C OPMB

O

OTBS

OTBS

O

OH

+

114

OH

O

113 Paterson aldol reaction

aldol reaction R = OH tedanolide(1) R = H 13-deoxytedanolide (2)

TBSO TBDPSO

+

OPMB

O

115

72

O acetate aldol

Paterson aldol reaction TBSO O

OTBDPS OMe O

t-BuO

O 116

OTBS OTBDPS

+ t-BuO2C O

OMe O 117

118

Fig. 8. Retrosynthesis of tedanolide by Loh et al.

(Scheme 23) The synthesis of aldehyde 128, already containing the required stereogenic centers from C5 to C11, started from the commercially available Roche ester 131 and was completed in 13 steps. E-selective Wittig reaction was applied to install the C18eC19 olefin. NBS-promoted cyclization of the free homoallylic alcohol to the double bond generated the bromotetrahydrofuran 136 (which demonstrated the utility of

this protecting group as a masked homoallylic ketone). The protection of the alkene functionality was necessary to permit the application of the non-aldol aldol process. Thereby problems associated with allylic epoxide rearrangements were avoided. A second Eselective Wittig olefination, reduction to the allylic alcohol and Sharpless asymmetric epoxidation led to intermediate 130. The crucial non-aldol aldol TBSO TBDPSO

TBSO + TBDPSO

O 115

OPMB O

1) (c-hex)2BCl, Et3N Et2O, 72, -78 °C to 0 °C 2) 115, -78 °C to -20 °C 95%

72

119a (major)

+

OH

O

OPMB

O

OPMB

TBSO

TBDPSO 119b (minor)

Scheme 16. Boron-mediated aldol reaction.

OH

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446 TBSO

1437 TBSO

m-CPBA, NaHCO3

OH

OH

OPMB

CH2Cl2, -78 °C to -30 °C 54%

O

OH

120

OH

OPMB

121

Scheme 17. Epoxidation.

TBSO

Bu2BOTf, Et3N, CH2Cl2

+

OTBDPS

t-BuO2C OMe O

-78 °C to 0 °C, 35% 90% conversion

O 118

117

+

t-BuO2C OMe O

OH

t-BuO2C OMe O

OTBDPS

122a

OH

OTBDPS

122b

Scheme 18. Boron-mediated aldol reaction.

TBSO O

OTBS TBSO

t-BuO2C

OMe O

TBSO

(c-hex)2BCl, Et3N

+ H TESO

O 123

OTBS

t-BuO2C

114 O

OMe O

TBSO

Et2O, 47% 74:26 dr 59% 114 recovered TESO

O PMB

O

OH PMB

O

124

Scheme 19. Fragments coupling by Loh et al.

rearrangement of the epoxide provided the aldol product 137 as a single diastereomer. 2.16. The Iqbal approach A different synthetic plan was presented by Iqbal et al. [15] who reported a general approach for the synthesis of the C3eC16 segment of tedanolide (1) and 13-deoxytedanolide (2). The central idea was to introduce a C12eC13 double bond of 138 through metathesis and to transform it depending on the natural product to be synthesized, either to saturated

hydrocarbon 139 for 13-deoxytedanolide (2) or the corresponding epoxide 140 in the case of tedanolide (Fig. 10). The synthesis started with the reductive transformation of 141 and subsequent acetalization. Reductive opening, oxidation and Wittig olefination provided the corresponding extended ester 144. A second reduction/oxidation sequence finally provided the corresponding aldehyde which was subjected to an Evans aldol reaction (Scheme 24). Liberation of the aldehyde 146 and a second Evans aldol reaction provided stereoselectively the

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1438 OH

Me

O

OH O

Me

O

PMBO

OMe O

O

OTBS

+ O

OH

O

OH

O

O

O

OTES

MeO

CHO

Me

OTES

TBS

1

126

125

Me O

O

Me

Me Me

Br Me

O

O O

CO2Et

+

Et

O OTMS

O

O 127

129

Me

128 nonaldol aldol product

Br

L-absorbic acid Me

Me

TBSO O

O

NBS-promoted cyclization 130

OH

MeO2C 131

Fig. 9. Retrosynthesis of the tedanolides by Jung et al.

Br

Me Me

Me

O O

Et

+ O

O

O OTMS

Me Me

TiCl4 i-Pr2NEt

Me

Br Me

O O

-50 °C 60%

O

OH

128

127

O OTMS

132

Scheme 20. Aldol coupling of 127 and 128 with TiCl4 and Hunig’s base.

Me 132

1) TESOTf, -78°C; 95% 2) L-Selectride, -25°C; 75%

Me

Br Me

O O OH

O OTES OTMS 133

Scheme 21. Protection of the hydroxyl group and reduction with L-Selectride.

Me

Me

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446 Me Me

1) LAH 82% 2) TsCl, TEA, 83%

O O

CO2Et

Me Me

129

Me

O O

2) TPAP NMO 85%

O

OH

Me

1) MeMgBr CuI, 82%

O O

3) K2CO3 MeOH; 75%

1439

Et O

134

127

Scheme 22. Synthesis of ketone 127.

intermediate 147 (Scheme 25). A sequence of PMPacetalization/Dibal-H opening provided the precursor 149 for the pivotal cross metathesis reaction. During the course of their investigations it appeared that the free C5 allylic alcohol was necessary for the reaction. The final transformations for the different intermediates could be achieved through either DesseMartin oxidation and NiCl2-catalyzed reduction (139) or epoxidation of the allylic alcohol (140).

the time and they were elucidated by total synthesis. Their interesting biological activity (IC50 value of 100 ng/mL against L-1210 murine leukemia cells) as well as the similarities of their structure to the C10e C23 portion of tedanolide (1) suggests that the myriaporones are in fact naturally occurring analogues. The myriaporones would then share the same mode of action as tedanolide and their simpler structure renders them more attractive as drug candidates. Recently, a study established that like tedanolide, myriaporone 3/4 is a potent protein synthesis inhibitor selective for eukaryotes [17]. Surprisingly, despite the numerous methodologies developed for the synthesis of tedanolide, few groups applied them for the synthesis of myriaporone (Fig. 11).

2.17. Myriaporones Ten years after the discovery of the first tedanolide (1), Rinehart isolated from Myriapora truncata a closely related family of natural products, the myriaporones [16]. It appears that myriaporone 1 (151) and 2 (152) are isolation by-products of the natural compound, myriaporone 3/4 (153 and 154). Myriaporone 2 (152) arises from the opening of the epoxide by the C7 carbonyl in myriaporone 1 (151). Myriaporone 3/ 4 exists as a dynamic equilibrium between a closed and an open form due to the lability of the hemiketal moiety. The small amount isolated did not allow the determination of the stereochemistry at C5 and C6 at

2.18. The Yonemitsu approach As previously mentioned, the stereochemistry at C5 and C6 was not assigned at the time of the isolation. In light of the structural similarities between myriaporone and tedanolide, one could have assumed the stereochemistry of these two centers to be identical to the corresponding carbons of tedanolide (C13

Br OH MeO2C

7 steps

NBS

OH

TBSO

131

Me

Me

1) epoxidation 2) protection (90% over 2 steps)

O

Br Me

TMSOTf

Br Me +

TBSO

HO

137

3) Ph3 PC(Me)CO2Et (79% over three steps) 4) DiBAl-H, 91%

O

136

Br

Br

O

130a

1) TBAF 2) Swern

Me

TBSO

88%

135

Me

Me

Me

O

O dr 10:1

Me

O O OTMS

128 Scheme 23. Synthesis of aldehyde 128.

Me

TBSO O

130b

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1440 OH O

O

OH

TBSO

OH O

OMe O

O

R

OTBS OH

OPMB

TBSDPSO

O

138

R = OH (1) R = H (2) epoxidation

TBSO

OTBS

reduction

TBSO

OTBS

OH

TBSDPSO

OPMB

OH

O

OH

OH

TBSDPSO

OPMB

140

O 139

Fig. 10. The Iqbal approach.

and C14). Yonemitsu, however, hypothesized the opposite configuration for C6 (C14 of tedanolide) [10i]. He also altered his route to the tedanolide and developed a new synthesis toward myriaporone 3/4. His retrosynthesis was based on the coupling of known vinyl iodide 157 and aldehyde 156. The C5eC9

aldehyde was generated from intermediate 158 which was developed for his synthesis of erythronolide A [10i]. The starting material for this synthesis was D-glucose (Fig. 12). The key methodology applied in this study was the regioselective opening of MP acetal 160 with MgBr2

Bn N OH

O

O O

141

1) NaBH4 THF/H2O, 90%

O

O

2) CSA, 96% MeO

1) DiBAl-H, CH2Cl2 0 °C, 80% 2) TEMPO, IBSA CH2Cl2, 95%

PMBO

OMe MeO

O

143

142 OMe

OEt Ph3P

1) DiBAl-H, CH2Cl2 OEt -78 °C, 93%

O CH2Cl2, 92% 24:1, E/Z

PMBO

O

144

2) MnO2, CH2Cl2, PMBO 95% 3) TiCl4, (-)-sparteine, 55 4) TBSCl; 83% 2 steps

Aux TBSO

O

145 Bn N O 55

Scheme 24. Synthesis of 145.

O O

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446 1) NaBH4 THF/H2O, 75%

Aux PMBO

TBSO

1441

2) TEMPO, IBSA CH2Cl2, 85%

O

PMBO

TBSO

O

146

145 Bn N

1) CSA, 85% MeO

O

OMe

O

O

MeO

152

1) (-)-spartein, 0 °C, CH2Cl2, 90% PMBO

2) NaBH4 THF/H2O, 90%

TBSO

OH

OH

2) DiBAl-H, CH2Cl2 0 °C, 90%

147

1) TBSCl, imidazole, DMF, 95% PMBO

TBSO

O

148

HO

2) DDQ, CH2Cl2/H2O

OH PMB

TBSO

TBSO

OTBS

75%

OTBS 1) Dess-Martin CH2Cl2, 90%

Grubbs II

O PMB

149

TBSO

OH

OTBS OH

2) NiCl2•6H2O NaBH4, MeOH/THF 0 °C, 88% TBSO

OPMB

TBDPSO

150

OPMB 138

HO

TBDPSO

OPMB

O

139

60% mCPBA, CH2Cl2 75%

TBSO

OTBS OH

TBDPSO

OPMB

O

HO

140

Scheme 25. Synthesis of 139 and 140.

and SnBu3H [10i]. The opening selectivity is governed by a five-membered ring chelation of the substrate, and thus opening occurs at the more hindered carbon. This is a good complement to the Dibal-H opening of acetals (Scheme 26). The total synthesis was not completed and only the intermediate 155 was generated. As it is now proven that his assumption of the stereochemistry was not

correct at C6, his synthesis will need to be revised to generate the natural product. 2.19. The Taylor approach The first approach envisioned for the introduction of C5eC9 hydroxypropionate unit was two successive stereocontrolled allylations (Fig. 13) [17a]. The known

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1442

O

OAc 5 O

5

O O

OH

OH O

OH O

OH OAc myriaporone 2 (152)

myriaporone 1 (151) OH O OH

OH

OH 5

5 O

OH O

O

OH

myriaporone 3 (153)

OH O

OH O

myriaporone 4 (154)

Fig. 11. The family of myriaporones.

I

OTBDPS

MP OH

OH

O

O

157

O

+ MP

OTBDPS O

OH

O

OH

O

PivO

OPiv

O

155

154

PivO

MPMO

H

O

O

156

OPiv

OH

O O

D-glucose O OBn 159

MPMO

OPiv

PivO

OBn 158

Fig. 12. The Yonemitsu approach of myriaporone 3/4.

MP O O

HO H

MPMO O

O O

HO O

MgBr2 n-Bu3SnH 95%

OBn 160

O OBn 161

Scheme 26. Opening of MP acetal 160.

intermediate 162 was in turn generated via an alternative approach using a thionyl chloride rearrangement (Scheme 27). The epoxide was chosen to be introduced prior to C9 installation even though such an early epoxidation was expected to render the synthetic intermediates more sensitive. This choice was motivated by the

report depicting anti-selectivity for epoxidation of secondary allylic alcohols by Sharpless et al. [18]. Although the thionyl chloride rearrangement mechanism was already known, its application in synthesis was not common [17b]. The key reaction depended upon an intramolecular cyclic rearrangement to provide the primary allylic chloride selectively. The zirconium-mediated allylation, however, was not selective due to the steric hindrance generated by the a-methyl of the aldehyde. Despite the lower activity of myriaporone 1 (151) compared to myriaporone 3/4, Taylor also decided to target the former [17c]. With C6 being sp2 hybridized in myriaporone 1, only the stereochemistry at C5 remained unknown, and thus, only two diastereomers needed to be synthesized (Fig. 14).

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446 OH

15

OH 5

O

OH

1443

O

OH

PMBO

HO

OH

CO2Et

O

O

163

162

154 iterative Zr allylation

Fig. 13. The Taylor approach.

Li 1) SOCl2, 70-80% 2) Cs(OAc)2

O

PMBO

PMBO OH

48

PMBO

OH

3) K2CO3, MeOH 50 % 2 steps

91% 165

6

Scheme 27. Thionyl chloride rearrangement.

OAc

OAc

OAc

PMBO O

OH

O

OH

PMBO O

O

151

O

O O TBS TMS

O

N

166

O

O TBS

167

Fig. 14. Retrosynthesis of myriaporone 1.

OH

OH

O

OH

OTBS OTBS PMBO

O

OH

154

O

PMBO

O 169

TBS

O

O

O

N

170

iterative Evans aldol

Fig. 15. Retrosynthesis of myriaporone 3/4.

The C5eC7 b-hydroxyketone was masked as an isoxazoline. Formation of the C6eC7 bond was envisioned to be made by a homoallenylation. The main drawback of this route was the sensitivity of aldehyde 167. It was generated via an Evans aldol reaction using a chiral auxiliary which proved to be selective and high yielding. C6eC7 bond formation was attempted using NozakieHiyamaeKishi coupling and several homoallenylation conditions. The best results were obtained using Brown conditions giving only a moderate yield. The isoxazoline in 166 was then

introduced in a 3:1 selectivity via an inverse dipolar cycloaddition. The amount of material generated was not sufficient to finish the synthesis. Myriaporone 1 was unexpectedly generated during the synthesis of myriaporone 3/4 (vide infra) [17d] (Fig. 15). Due to the excessive sensitivity of the epoxyaldehydes and encouraged by the promising epoxidation of Loh [12a], the synthetic plan for myriaporone 3/4 was revised as well as the timing of epoxidation.

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446

1444 OAc

OAc

B(OPr)2

C

PhNCO PrNO2

1) PMBO

PMBO O

2) TMSCl O 40% 2 steps

O

O

60% O

TBS

O TBS TMS

168

167 OAc PMBO O O

O O TBS TMS

N

166

Scheme 28. Toward myriaporone 1.

The C5eC9 hydroxypropionate unit of 171 was installed by two iterative Evans aldol reactions. The isoxazoline was then introduced without any diastereoselectivity. At the time of the synthesis, the stereochemistry at C5 was still unknown and both isomers were needed for spectroscopic comparison with the natural product. In later work, the selectivity was increased to 3:1 toward the desired isomer. The Z-olefin was installed via selective Wittig reaction to provide 173 and after protecting group manipulations, the isoxazoline was reductively cleaved to unmask the b-hydroxyketone. The final key epoxidation was highly

OTBS OTBS PMBO

TBS

O

PrNO2 PhNCO

selective according to Yonemitsu’s precedence. Myriaporone 3/4 (153/154) was thus completed in 2.1% over 25 linear steps. When acetate-protecting groups were used instead of TBS, the final deprotection led to an elimination reaction, thus providing myriaporone 1 (151) (Schemes 28e30). 2.20. The Cuevas approach Concomitantly with the Taylor synthesis, Cuevas et al. published their own synthesis in the same journal

OTBS OTBS

64% 1:1

OH

1) DDQ, 88% 2) IBX

PMBO

TBS

171

O

O

OH

3. Ph3PCHCH3 63% 2 steps

N

172 OTBS OTBS

OTBS OTBS 1) DMP, 98% 2) HF • Et3N, 83%

TBS

O

OH

O

3) TBSCl, 81%

N

OH

O

O

N

174

173

1) Mo(CO)6, 65% 2) m-CPBA, 62% 3) TASF, 70%

O

OH

O

O

OH

OH

O OH

153 Scheme 29. Taylor synthesis of myriaporone 3/4.

OH

OH

OH

O

OH

154

O

N. Schu¨bel et al. / C. R. Chimie 11 (2008) 1419e1446 OAc

1445 OAc

OAc KCN

O

66% OH

O

OH

O

O

OH

O

175

OH

O

151

Scheme 30. Taylor synthesis of myriaporone 1.

OTBS OTBS 1) O , 82% 3 PMBO

TBS

O

N

OH

O OMe

LDA O 91%, 1:2.5

176

N

PMBO

2) O

O

OH

O TBS

O

O

178

O

O TBS

OH

OMe

2) TBAF, AcOH, THF 80%

O

177

O 1) EtMgBr, 68%

4) DMP 5) Ph3PChCH3 60% 2 steps

OMe

TBS

OTBS OTBS N

1) TBSOTf, 81% 2) DMP 3) DDQ, 51% 2 steps

OTBS OTBS

OH

OH

OH

O

OH

O

154

O

OH

OH

OH

O

O

OH

153 Scheme 31. Cuevas synthesis of myriaporone 3/4.

issue [19]. The synthesis developed was also linear and its beginning was similar to the Taylor synthesis. The main difference resided in the choice of an early epoxidation and the installation of the C1eC5 b-hydroxyketone moiety (Scheme 31). The aldol reaction to form the C4eC5 bond gave 177 with a selectivity of 1:2.5 in favor of the unnatural isomer at C5. This is thus not a valuable selectivity a posteriori. Selective monoprotection discriminating between two secondary alcohols was performed to subsequently oxidize only C7. The carbon backbone was then completed via an Z-selective Wittig olefination to provide 178 and a Grignard addition to the Weinreb amide. Global deprotection gave myriaporone 3/4. The synthesis was completed in 24 linear steps (one step shorter than the Taylor synthesis) but with only 0.3% yield. Partial dehydration on silica gel (not observed by the Taylor group) and subsequent acetate protection of the dehydrated by-product provided them with myriaporone 1. The facility of elimination tends to prove

that myriaporone 1 is indeed an isolation by-product of myriaporone 3/4. 3. Conclusion In summary, the tedanolides are fascinating compounds due to their unprecedented biosynthetic origin, complex architecture and promising biological activity. For more than 20 years, a variety of new strategies to address the challenges offered by tedanolide were developed, completing the established set of tools available for polyketide synthesis. Additionally, completing the total synthesis of tedanolide opens the door to structureeactivity relationship studies, providing analogues that cannot be accessed from natural sources or degradation experiments. A fortiori, myriaporone 3/4 appears to be a simpler version of tedanolide that retains the latter’s potency, thus suggesting that myriaporone 3/4 is a naturally occurring analogue of tedanolide. Both families represent

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