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Tin triflate promoted synthesis of bicyclic and tricyclic sulfonyl dihydropyrans
Accepted Manuscript Tin triflate promoted synthesis of bicyclic and tricyclic sulfonyl dihydropyrans Chieh-Kai Chan, Yu-Hsin Chen, Meng-Yang Chang PII:
S0040-4020(16)30632-9
DOI:
10.1016/j.tet.2016.07.009
Reference:
TET 27905
To appear in:
Tetrahedron
Received Date: 17 May 2016 Revised Date:
29 June 2016
Accepted Date: 2 July 2016
Please cite this article as: Chan C-K, Chen Y-H, Chang M-Y, Tin triflate promoted synthesis of bicyclic and tricyclic sulfonyl dihydropyrans, Tetrahedron (2016), doi: 10.1016/j.tet.2016.07.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Tin Triflate Promoted Synthesis of Bicyclic and Tricyclic Sulfonyl Dihydropyrans Chieh-Kai Chan, Yu-Hsin Chen and Meng-Yang Chang*
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan Me R S Me O
2a O S O
R
Ar
O
O K2CO3, acetone R S Me O
O 1
Me Ar
Br 2b
MeNO2 Sn(OTf)2
Me O
Me
MeNO2 Me
4
TE D EP
Me
3 Me
Me
AC C
R Sn(OTf)2
Me
Me
O
H
S O
Me Me
Ar
O
O R S O Ar
Me
5
H
Me
Me
O
Me
6
M AN U
Ar
K2CO3, acetone
Me
O
SC
Me
Br
H Me
ACCEPTED MANUSCRIPT Tetrahedron
1
TETRAHEDRON Pergamon
RI PT
Tin Triflate Promoted Synthesis of Bicyclic and Tricyclic Sulfonyl Dihydropyrans Chieh-Kai Chan, Yu-Hsin Chen and Meng-Yang Chang*
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
SC
Abstract—Tin triflate-promoted one-pot intramolecular annulation of α-geranyl or α-farnesyl β-ketosulfones 3-4 affords the respective bicyclic or tricyclic sulfonyl dihydropyrans 5-6 in moderate to good yields via a cascade cation-olefin-carbonyl carbocyclization process. The starting materials 3 and 4 were obtained by K2CO3-mediated α-geranylation or α-farnesylation of β-ketosulfones 1 with bromides 2a or 2b. The structures of the key products were confirmed by X-ray crystallography. On the basis of unique enzyme-templated one-pot cascade intramolecular annulation of polyprenoids,8-9 a recent remarkable biosynthetic route of xiamycin has been demonstrated by Zhang et al.9a Despite extensive studies on LBA (Lewis acid-assisted chiral Bronsted acid; a complex of SnCl4 and BINOL derivative) catalyzed synthesis of Ambrox10 via a hydroxyl group triggered cation-olefin cyclization by Yamamoto et al.,7c-d a cascade process using a 1,3-dicarbonyl synthon-mediated cation-olefin oxycyclization has not yet been reported. Various catalysts have been employed to accelerate the formation of a carbon-carbon bond via a carbocation-like intermediate, as shown in Scheme 2. Our aim is to find an optimal metal triflate (M(OTf)n) as the catalyst to synthesize bicyclic sulfonyl dihydropyrans 5 and tricyclic sulfonyl dihydropyrans 6 (a Ambrox analogue) by the intramolecular bicyclization of α-geranyl β-ketosulfones 3 and tricyclization of α-farnesyl β-ketosulfones 4 via sixmembered chair-like conformations.
M AN U
1.
Introduction
AC C
EP
TE D
Metal complex-promoted one-pot carbocyclizations of polyolefin have attracted significant attention in the field of synthetic organic chemistry because the tandem approach results in the formation of unique polycycles (e.g., terpenes and steroids) bearing contiguous tertiary and quaternary stereogenic centers and new six-membered rings in a single catalytic pathway.1-2 Representative successful utilizations on the construction of natural molecules have been developed, including MeAlCl2-mediated synthesis of serratenediol,3a germanicol,3b lupeol,3c dammarenediol II,3d erythrodiol;3e Et2AlCl-mediated synthesis of walsucochin B;3f Sc(OTf)3-promoted synthesis of adociasulfate 1;3g InBr3-promoted synthesis of totarol;3h and Mn(OAc)3/Cu(OAc)2-catalyzed synthesis of oridamycins A and B.3i Other methodologies to Lewis acids (e.g., SnCl4,4a FeCl3,4b-c TiCl4,4d BF3·OEt24e-g), zeolites,5 radicals,6 and Bronsted acids7 mediated polycyclization have been documented as well. Scheme 1 illustrates general epoxideolefin-arene carbocyclization.
Scheme 2. Oxygen atom triggered cation-olefin cyclization Yamamoto work
Scheme 1. Epoxide initiated cation-arene carbocyclization epoxide-olefin-arene carbocyclization
O
Me
Me
Me
Ph4PBF3/HFIP7a tetracylization
Me
HO
Me
Me
MeAlCl23b
OMe
Me
Me
O
i-Pr
dicyclization
Me
K2CO3, acetone
Me
Ar
Me
Me
Me
Me O
Me
H
LBA
Me
Me O Me
Me
Ambrox
Me
Me O
Me
S O 1
R K2CO3, acetone
Me
Me
farnesyl bromide (2b)
i-Pr
Me
HO
Ar O S R O
M(OTf)n MeNO2
Me Me
4
O
Me 5 O
3
O
OMe
Me Me
Me
Me
This work
OMe InBr33h
Me O
Me
Me
Me
Me Me
geranyl bromide (2a)
OMe Me
LBA
Me Me
Me
HO
tricyclization
Me
O
O
Me
Me
Me O
Me
Me H Me
Me
O R O Me S Ph M(OTf) n O MeNO2
Ar O
S
R
R O S O Me Ph
Me Me
O Me
6
Me
———
2.
Keywords: Tin Triflate; β-Ketosulfones; Carbocyclization; Dihydropyrans. *Corresponding author. Tel.: +886 7 3121101 ext 2220 e-mail: [email protected]
Results and discussion
Our interest in the utilization of cascade protocols for metal triflate-mediated synthesis of diverse scaffolds has
ACCEPTED MANUSCRIPT Tetrahedron
Table 1. Metal triflates mediated reaction conditions Me
O
Me
S
Me
M(OTf)n
O Ph
O
Me
H
S
Me Me
O O
Me
solvent (5 mL) conditions
Ph
3a
O
Me 5a
AC C
EP
TE D
M AN U
entry catalyst (mol%) solvent temp (oC) time (h) 5a (%)b －c 1 AgOTf (10) MeNO2 25 20 －c 2 Mg(OTf)2 (10) MeNO2 25 20 －c 3 Ni(OTf)2 (10) MeNO2 25 20 4 Cu(OTf)2 (10) MeNO2 25 20 35d 5 Zn(OTf)2 (10) MeNO2 25 20 20d 6 Sn(OTf)2 (10) MeNO2 25 20 85 －c 7 Sm(OTf)3 (10) MeNO2 25 20 －e 8 Ga(OTf)3 (10) MeNO2 25 20 －c 9 La(OTf)3 (10) MeNO2 25 20 －c 10 Gd(OTf)3 (10) MeNO2 25 20 －c 11 Ce(OTf)3 (10) MeNO2 25 20 －c 12 Yb(OTf)3 (10) MeNO2 25 20 13 Fe(OTf)3 (10) MeNO2 25 20 81 14 Sc(OTf)3 (10) MeNO2 25 20 78 15 In(OTf)3 (10) MeNO2 25 20 80 16 Sn(OTf)2 (5) MeNO2 25 20 85 17 Fe(OTf)3 (5) MeNO2 25 20 80 18 Sc(OTf)3 (5) MeNO2 25 20 67 19 In(OTf)3 (5) MeNO2 25 20 68 20 Sn(OTf)2 (5) MeNO2 25 10 70 21 Fe(OTf)3 (5) MeNO2 25 10 52d －e 22 Sn(OTf)2 (5) MeNO2 101 10 23 Sn(OTf)2 (5) EtNO2 25 20 61 24 Sn(OTf)2 (5) CH2Cl2 25 20 36d －e 25 Sn(OTf)2 (5) DMF 25 20 －e 26 Sn(OTf)2 (5) DMSO 25 20 27 SnCl2 (5) MeNO2 25 20 20e 28 TfOH (5) MeNO2 25 20 71 a Reactions were run on 1a (0.5 mmol), solvent (5 mL). b Isolated yields. cNo reaction. d1a was recovered (for entry 4, 43%; for entry 5, 30%; for entry 19, 15%; for entry 21, 35%). eComplex mixture.
To the control one-pot annulation condition (25 oC, MeNO2, 20 h), the use of various commercially available metal triflates was investigated initially for the formation of bicyclic dihydropyran 5a (Table 1, entries 1-15). Among these screened catalysts, which included catalytic amounts (10 mol%) of AgOTf, Mg(OTf)2, Ni(OTf)2, Cu(OTf)2, Zn(OTf)2, Sn(OTf)2, Sm(OTf)3, Ga(OTf)3, La(OTf)3, Gd(OTf)3 Ce(OTf)3, Yb(OTf)3, Fe(OTf)3, Sc(OTf)3, and In(OTf)3, Zn(OTf)2 and Cu(OTf)2 provided low yields (35% and 20%) of 5a along with 43% and 30% yields of 3a, respectively (entries 4-5). As shown in entries 6 and 13-15, Sn(OTf)2, Fe(OTf)3, Sc(OTf)3, and In(OTf)3 provided better yields (85%, 81%, 78%, and 80%) of 5a under the above conditions. For the other shown metal triflates of Table 1 (entries 1-3 and 7-12), 5a was not isolated and the starting material 3a was recovered. After decreasing the catalytic amounts (10 5 mol%) of four reactive metal triflates (entries 16-19), Sn(OTf)2 and Fe(OTf)3 provided better yields (85% and 80%) of 5a than Sc(OTf)3 and In(OTf)3 (67% and 68%). Next, Sn(OTf)2 and Fe(OTf)3 exhibited low yields under a diminishing reaction time (20 10 h), as shown in entries 20-21. With the results in hand, we found that 5 mol% of Sn(OTf)2 belonged to the most reactive and used catalyst compared to other metal triflates derivatives. Furthermore, we studied the factors of temperature and solvent. In entry 22, a complex mixture occurred when elevating the temperature (25 101). After changing the solvents (from MeNO2 to EtNO2, CH2Cl2, DMF, and DMSO), different results were observed. In entry 23, the results showed that EtNO2 provided 5a in a 61% yields. Entry 24 showed that 36% of 5a was observed due to the poor polarity of CH2Cl2. With the involvement of high-polar solvents (DMSO and DMF), a complex mixture was detected (entries 25-26). Other type of tin(II) salt (e.g. SnCl2) was examined. In entry 27, 5a was isolated in only 20% yield. By the involvement of 2 mol% TfOH (entry 28), 71% of 5a was generated. The control experiment pointed out that the real catalyst was the trace amount of TfOH resulted from the hydrolysis of the metal triflates. According to the results, 5 mol% of Sn(OTf)2/MeNO2/rt condition would be an optimal combination for yielding 5a. Aside from the present one-pot carbonyl-triggered cationolefin oxycyclization, Sn(OTf)2 has also been reported as a catalyst for (3+2) annulation,14 aldol reaction,15 Mannishtype reaction,16 and rearrangement.17 Remarkably, only a few examples of Sn(OTf)2-mediated reactions have been performed in comparison with other commercially available tin (II) salts. On the basis of the above reaction conditions, we explored the substrate scope, with the results shown in Table 2. To adjust Ar and R groups of β-ketosulfones 1a-l, α-geranyl 3a-l and α-farnesyl 4a-l (Ar = Ph, 4-FC6H4, 4MeC6H4, 4-MeOC6H4, 4-CF3C6H4, 4-NO2C6H4, 4-PhC6H4, 2-naphthalene; R = Me, Ph, 4-MeC6H4, 4-MeOC6H4) were provided in moderate yields, as shown in entries 1-24. Next, the Sn(OTf)2-mediated intramolecular annulation of 3a-l and 4a-l produced bicyclic or tricyclic dihydropyrans 5 and 6. For the Ar group of 3 and 4, the phenyl ring with a
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led us to explore novel methodologies.11 As part of our efforts in the synthetic chemistry of β-ketosulfones 1,12-13 we streamlined the metal triflate-mediated one-pot facile synthesis of bicyclic and tricyclic sulfonyl dihydropyrans 5 and 6 via tandem intramolecular annulation of α-geranyl or α-farnesyl β-ketosulfones 3 and 4. According to previous reports,11-12 the starting materials 3 and 4 were obtained via K2CO3-mediated α-geranylation and α-farnesylation of βketosulfones 1 with geranyl bromide (2a) and farnesyl bromide (2b) in acetone at reflux. With this idea in mind, the catalytic amounts of several metal triflates were first examined for the model substrate 3a (R = Me, Ar = Ph), as shown in Table 1.
SC
2
ACCEPTED MANUSCRIPT Tetrahedron
Based on the results, a possible reaction mechanism is shown in Scheme 3. Mechanistically, the sequence initiates with the formation of intermediate A by complexation of a carbonyl motif of 3a with Sn(OTf)2. Deprotonation of A with in situ generated triflate anion gives B. Following the hydrolysis of B with the TfOH, tertiary carbocation C1 is obtained. Based on the six-membered chair conformation (C2), 5a is provided via SnOTf-chelated oxygen atom promoted an intramolecular stereochemical cyclization. Subsequently, Sn(OTf)2 is regenerated by complexation of SnOTf and triflate anion. Scheme 3. Proposed mechanism
Table 2. Synthesis of 5 and 6a-b Me R
S Ar
O O K 2CO3, acetone
Ar
Me
1 Br
3 Me
S
Me
O Me
2b
O
O
R
Ar
O Me
Sn(OTf)2
Ar O
R
O
Me 5
O
Me Me
6
Ph
Me H OTf
O
Me Sn
OTf
A
H
Me
Me
O
Me
B
S
Me H
O
Sn TfO
Ph
Me
O
Me Sn
Me OTf
5a
C2
OTf
TfO
C1
Scheme 4: Sn(OTf)2-mediated reactions of 8 Ph Ar
O
Me
Ph
NaH, 2a THF
Ar
7a, Ar = Ph 7b, Ar = 4-FC6H4
O
Me
O
Ar
O
THF
O NaH, 2a O
Me
MeNO2
8c, Ar = Ph (86%) 8d, Ar = 4-MeOC6H4 (85%)
O
Ph
O
THF
Ph
7e
O
Me
Me
H
Me Me
EtO Ar O Me 9c, Ar = Ph (75%) 9d, Ar = 4-MeOC6H4(ND) O
Sn(OTf)2
Me
Me
O Me 9a, Ar = Ph (ND) 9b, Ar = 4-FC6H4(ND)
Me
Ph
H
Ar
O Sn(OTf)2
Me Ar
7c, Ar = Ph 7d, Ar = 4-MeOC6H4
Ph
MeNO2
Me
NaH, 2a EtO
EtO
Ph
Sn(OTf)2
Me
8a, Ar = Ph (84%) 8b, Ar = 4-FC6H4 (86%)
O
EP
AC C
a The synthesis of 3 or 4 were run on 1 (1.0 mmol), 2a or 2b (1.05 equiv), K2CO3 (2.9 equiv), acetone (10 mL), reflux, 8 h. bThe synthesis of 5 or 6 was run on a 3 or 4 (0.5 mmol), Sn(OTf)2 (10 mg, 0.025 mmol), MeNO2 (5 mL), rt, 20 h. cIsolated yields. d6 was isolated as two isomers (d.r. = 9/1~2/1). eComplex mixture.
Ph
O
Sn(OTf)2
S
O
S
Me
c-d
TE D
1, Ar =, R =; 2a / 2b 3 / 4 (%) 5 / 6 (%) 1a, Ph, Me; 2a 3a, 84 5a, 85 1b, Ph, Ph; 2a 3b, 86 5b, 83 1c, Ph, 4-MeC6H4; 2a 3c, 82 5c, 85 1d, 4-FC6H4, 4-MeC6H4; 2a 3d, 86 5d, 82 1e, 4-MeC6H4, 4-MeC6H4; 2a 3e, 85 5e, 86 5f, －e 1f, 4-MeOC6H4, 4-MeC6H4; 2a 3f, 87 1g, 4-CF3C6H4, 4-MeC6H4; 2a 3g, 82 5g, 83 1h, 4-NO2C6H4, 4-MeC6H4; 2a 3h, 83 5h, 80 1i, 4-PhC6H4, 4-MeC6H4; 2a 3i, 84 5i, 85 1j, 2-naphthalene, 4-MeC6H4; 2a 3j, 86 5j, 83 1k, 4-MeC6H4, Me; 2a 3k, 83 5k, 81 1l, Ph, 4-MeOC6H4; 2a 3l, 85 5l, 18e 1a, Ph, Me; 2b 4a, 82 6a, 81 1b, Ph, Ph; 2b 4b, 83 6b, 81 1c, Ph, 4-MeC6H4; 2b 4c, 83 6c, 85 1d, 4-FC6H4, 4-MeC6H4; 2b 4d, 85 6d, 80 1e, 4-MeC6H4, 4-MeC6H4; 2b 4e, 83 6e, 83 6f, －e 1f, 4-MeOC6H4, 4-MeC6H4; 2b 4f, 86 1g, 4-CF3C6H4, 4-MeC6H4; 2b 4g, 80 6g, 80 1h, 4-NO2C6H4, 4-MeC6H4; 2b 4h, 81 6h, 77 1i, 4-PhC6H4, 4-MeC6H4; 2b 4i, 85 6i, 83 1j, 2-naphthalene, 4-MeC6H4; 2b 4j, 86 6j, 84 1k, 4-MeC6H4, Me; 2b 4k, 85 6k, 80 1l, Ph, 4-MeOC6H4; 2b 4l, 87 6l, <5e
O
Me
O
Me
Me Sn
O
O
Ph
c
Me
Me
Me
O
OTf
Me
Me
O
Ph
H
S
S
H
O
Me
3a
Me H Me
Me O
O
O
Me
Sn(OTf)2
Ph
H
S
Me
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
S
Me
OTf
Me
O
O Ar
Me
Me
O
Me
Me
O
Me MeNO2
MeNO2
H
S
Sn(OTf)2
Me 4
O
R Me
Me O
K 2CO3, acetone
S
Me
O
SC
2a
O
R
Me
M AN U
Br
RI PT
strong electron-withdrawing group (e.g. 4-FC6H4, 3NO2C6H4, or 4-CF3C6H4) provided the desired 5 and 6 in good yields, and the phenyl ring with an electron-neutral substituent (e.g., Ph, 4-MeC6H4, 4-PhC6H4, 2-naphthalene) also provided modest yields. In particular, the phenyl ring with an electron-donating group (for 3f and 4f, Ar = 4MeOC6H4) produced complex results and no 5f and 6f were formed. However, for the Sn(OTf)2-mediated reaction of 3l and 4l (R = 4-MeOC6H4), the desired 5l and 6l were yielded in 18% and trace amounts (<5%). The structures of 5d, 5g, 5h, 6b, 6c, 6d, and 6e were determined by singlecrystal X-ray crystallography.18
3
H
Me Me
Ph
MeNO2
Ph
8e (88%) O
O Me 9e (85%) H
Me Me
Me O
O NaH, 2a
Me Ph 7f
O
THF
Me
Me
Ph Sn(OTf)2
Me Ph
O 8f (84%)
Me
O
MeNO2
O Me 9f (35%) Me H Me
Ph Me
O Me 9g (40%)
Changing the starting substrates 1a-l with the sulfonyl groups (from β-ketosulfone) to compounds 7a-f with the aryl, ester or benzoyl substituents (from deoxybenzoin, βketoester, β-diketone), we studied the alkylation of 7a-f with geranyl bromide (2a) (Scheme 4). With the involvement of NaH, α-geranylation of 7a-f with 2a afforded 8a-f in a range of 84%-88%. During the Sn(OTf)2mediated annulation of 8a-e, only 9c and 9e could be generated as the sole product in 75 and 85% yields,
ACCEPTED MANUSCRIPT Tetrahedron
1472673 (6d) Monoclinic P 21/n 7.0592(3) 26.5040(10) 14.4311(5) 90 101.633(2) 90 4 2653.65(18) 296(2) 1.243 0.158 1064 1.054 0.15×0.11×0.10 1.537 to 26.390 21025 5425(R=0.0477) 0.0694, 0.1923 0.1157, 0.2322
1472674 (6e) Monoclinic P 21/n 6.9224(6) 27.150(2) 14.7171(13) 90 101.813(2) 90 4 2707.4(4) 296(2) 1.209 0.149 1064 1.002 0.10×0.08×0.08 1.500 to 26.415 21590 5568(R=0.0667) 0.0568, 0.1220 0.1230, 0.1487
M AN U
1473357 (9e) Monoclinic P 21/c 7.6511(6) 20.7338(18) 12.4531(9) 90 95.040(3) 90 4 1967.9(3) 100(2) 1.217 0.075 776 1.094 0.20×0.15×0.15 1.913 to 26.498 16774 4051(R=0.0370) 0.0398, 0.1041 0.0510, 0.1239
RF =Σ|Fo-Fc|/ΣFo|; RW (F2) =[ΣW|Fo2-Fc2|2/ΣW Fo4]1/2
4.
Experimental section
EP
a
Conclusion
In summary, we have developed a facile synthetic route of bicyclic or tricyclic sulfonyl dihydropyrans 5 and 6 via (1) K2CO3-mediated α-geranylation or α-farnesylation of βketosulfones 1 with 2a and 2b and (2) tin triflate-promoted intramolecular cation-olefin-carbonyl carbocyclization of α-geranyl or α-farnesyl β-ketosulfones 3-4. The structural frameworks of the key products were confirmed by X-ray crystallography. Further investigation regarding synthetic applications of β-ketosulfones will be conducted and published in due course.
1472672 (6c) Monoclinic P 21/n 7.0561(5) 26.349(2) 14.3583(11) 90 101.571(3) 90 4 2615.3(3) 296(2) 1.216 0.153 1032 1.035 0.20×0.10×0.10 1.546 to 26.411 18844 5362(R=0.0431) 0.0583, 0.1649 0.0949, 0.2022
TE D
Table 3. Crystal data for compounds 6b-e and 9e CCDC number 1479881 (6b) Crystal system Orthorhombic Space group P 21 21 21 a (Å) 6.2765(3) b (Å) 14.2655(7) c (Å) 27.0870(14) α (°) 90 90 β (°) 90 γ (°) Z 4 Volume (Å3) 2425.3(2) Temperature (K) 100(2) 1.272 Dcalcd (Mg/m3) Absorption coefficient (mm-1) 0.163 F(000) 1000 GOF 1.135 Crystal size (mm3) 0.30×0.25×0.21 θ range for data collection (°) 1.504 to 26.390 Reflections collected 19914 Independent reflections 4959(R=0.0404) 0.0355, 0.0891 RF, Rw (F2) (I > 2σ(I))a RF, Rw (F2) (all data)a 0.0414, 0.1045
3.
RI PT
respectively. The structure of 9e was determined by singlecrystal X-ray crystallography.18 As shown in Table 3, the single crystal X-ray diffraction analyses were employed to prove the constitution and relative configuration. For the annulation of 8a and 8b, no desired 9a and 9b were observed and a complex mixture was isolated in major products. Moreover, 9d with an electron-donating substituent (Ar = 4-MeOC6H4) provided a complex mixture. For the Sn(OTf)2-mediated annulation of 8f having an unsymmetrical dione group, two isomers 9f and 9g were produced in 35% and 40% yields, respectively. For the non-sulfonyl groups, the one-pot route also performed well.
SC
4
AC C
4.1. General. All other reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Melting points were determined with a SMP3 melting apparatus. 1H and 13C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 400 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the coupling constants (J) are given in Hertz. High resolution mass spectra (HRMS) were measured with a mass spectrometer Finnigan/Thermo Quest MAT 95XL. X-ray crystal structures were obtained with an Enraf-Nonius FR590 diffractometer (CAD4, Kappa CCD).
4.2. A representative synthetic procedure of skeleton 3 is as follows: K2CO3 (400 mg, 2.9 mmol) was added to a solution of β-ketosulfones 1 (1.0 mmol) in acetone (10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. Geranyl bromide 2a (227 mg, 1.05 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at reflux for 8 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 3. 4.2.1. 2-Methanesulfonyl-5,9-dimethyl-1-phenyldeca-4,8dien-1-one (3a). Yield = 84% (281 mg); Colorless gum; HRMS (ESI, M++1) calcd for C19H27O3S 335.1681, found 335.1685; 1H NMR (400 MHz, CDCl3): δ 7.97-7.94 (m, 2H), 7.62-7.57 (m, 1H), 7.49-7.45 (m, 2H), 4.96 (t, J = 7.2 Hz, 1H), 4.88-4.85 (m, 2H), 3.03-2.95 (m, 1H), 2.98 (s, 3H),
ACCEPTED MANUSCRIPT Tetrahedron
4.2.7. 5,9-Dimethyl-2-(toluene-4-sulfonyl)-1-(4trifluoromethylphenyl)deca-4,8-dien-1-one (3g). Yield = 82% (392 mg); Colorless gum; HRMS (ESI, M++1) calcd for C26H30F3O3S 479.1868, found 479.1865; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 5.10-5.05 (m, 1H), 4.87 (t, J = 6.8 Hz, 1H), 4.82 (t, J = 6.0 Hz, 1H), 2.86-2.75 (m, 2H), 2.37 (s, 3H), 1.90-1.76 (m, 4H), 1.53 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.88, 145.47, 140.24, 139.84, 134.59 (q, J = 32.6 Hz), 133.34, 129.51 (4x), 129.08 (2x), 125.53 (d, J = 3.0 Hz, 2x), 125.51 (d, J = 3.0 Hz, 2x), 123.36, 116.97, 69.83, 39.27, 26.88, 26.03, 25.24, 31.40, 17.32, 15.88.
M AN U
4.2.3. 5,9-Dimethyl-1-phenyl-2-(toluene-4-sulfonyl)deca4,8-dien-1-one (3c). Yield = 82% (336 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H31O3S 411.1994, found 411.2002; 1H NMR (400 MHz, CDCl3): δ 7.88-7.86 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.54-7.50 (m, 1H), 7.42-7.37 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.05 (dd, J = 6.4, 8.8 Hz, 1H), 4.89-4.82 (m, 2H), 2.81-2.77 (m, 2H), 2.36 (s, 3H), 1.83-1.77 (m, 4H), 1.52 (s, 3H), 1.48 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.43, 145.07, 139.75, 137.17, 133.55, 131.24, 129.45 (2x), 129.33 (3x), 128.62 (2x), 128.43 (2x), 123.44, 117.22, 69.31, 39.22, 26.92, 26.00, 25.28, 21.41, 17.34, 15.86.
RI PT
4.2.2. 2-Benzenesulfonyl-5,9-dimethyl-1-phenyldeca-4,8dien-1-one (3b). Yield = 86% (341 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H29O3S 397.1837, found 397.1833; 1H NMR (400 MHz, CDCl3): δ 7.90-7.87 (m, 2H), 7.82-7.79 (m, 2H), 7.64-7.60 (m, 1H), 7.58-7.54 (m, 1H), 7.52-7.48 (m, 2H), 7.46-7.41 (m, 2H), 5.05 (dd, J = 6.4, 8.4 Hz, 1H), 4.91-4.84 (m, 2H), 2.82-2.78 (m, 2H), 1.88-1.80 (m, 4H), 1.54 (br d, J = 0.8 Hz, 3H), 1.51 (s, 3H), 1.45 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 192.47, 140.11, 137.26, 136.66, 134.10, 133.78, 131.50, 129.63 (2x), 128.82 (2x), 128.76 (2x), 128.63 (2x), 123.56, 117.22, 69.49, 39.39, 27.07, 26.17, 25.43, 17.49, 16.02.
4.2.6. 1-(4-Methoxyphenyl)-5,9-dimethyl-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3f). Yield = 87% (383 mg); Colorless gum; HRMS (ESI, M++1) calcd for C26H33O4S 441.2100, found 441.2105; 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 9.2 Hz, 2H), 4.97 (dd, J = 4.4, 10.0 Hz, 1H), 4.89-4.85 (m, 2H), 3.86 (s, 3H), 2.78-2.72 (m, 2H), 2.42 (s, 3H), 1.88-1.80 (m, 4H), 1.54 (s, 3H), 1.52 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.55, 164.14, 145.11, 139.74, 133.60, 131.45, 131.39 (2x), 130.41, 129.70 (2x), 129.41 (2x), 123.65, 117.56, 113.84 (2x), 69.29, 55.51, 39.41, 27.11, 26.22, 25.45, 21.63, 17.51, 16.04.
SC
2.91-2.85 (m, 1H), 1.89-1.81 (m, 4H), 1.61 (s, 3H), 1.53 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 194.04, 140.39, 136.83, 134.15, 131.50, 128.89 (2x), 128.74 (2x), 123.45, 116.90, 68.41, 39.33, 37.54, 27.82, 26.11, 25.41, 17.46, 16.02.
5
AC C
EP
TE D
4.2.4. 1-(4-Fluorophenyl)-5,9-dimethyl-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3d). Yield = 86% (368 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H30FO3S 429.1900, found 429.1902; 1H NMR (400 MHz, CDCl3): δ 7.97-7.92 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.14-7.09 (m, 2H), 4.98 (dd, J = 5.2, 9.2 Hz, 1H), 4.88-4.84 (m, 2H), 2.78-2.74 (m, 2H), 2.41 (s, 3H), 1.88-1.80 (m, 4H), 1.53 (s, 3H), 1.51 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.94, 166.09 (d, J = 254.7 Hz), 145.35, 140.08, 133.77 (d, J = 3.0 Hz), 133.40, 131.65 (d, J = 9.8 Hz, 2x), 131.49, 129.64 (2x), 129.49 (2x), 123.51, 117.22, 115.79 (d, J = 22.0 Hz, 2x), 69.61, 39.36, 27.09, 26.16, 25.41, 21.60, 17.47, 16.01. 4.2.5. 5,9-Dimethyl-2-(toluene-4-sulfonyl)-1-p-tolyldeca4,8-dien-1-one (3e). Yield = 85% (361 mg); Colorless solid; mp = 75-76 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C26H33O3S 425.2150, found 425.2153; 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.01 (dd, J = 5.2, 9.2 Hz, 1H), 4.89-4.84 (m, 2H), 2.78-2.74 (m, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 1.871.79 (m, 4H), 1.54 (s, 3H), 1.51 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.95, 145.10, 144.80, 139.76, 134.85, 133.57, 131.37, 129.62 (2x), 129.38 (2x), 129.26 (2x), 129.04, 128.96 (2x), 123.57, 117.40, 69.34, 39.34, 27.07, 26.14, 25.37, 21.56, 17.43, 15.97.
4.2.8. 5,9-Dimethyl-1-(4-nitrophenyl)-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3h). Yield = 83% (378 mg); Colorless solid; mp = 74-76 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H30NO5S 456.1845, found 456.1852; 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.03 (t, J = 6.8 Hz, 1H), 4.87-4.82 (m, 2H), 2.76 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.85-1.80 (m, 4H), 1.53 (d, J = 0.8 Hz, 3H), 1.49 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.67, 150.39, 145.73, 141.62, 140.61, 133.09, 131.57, 129.85 (2x), 129.66 (2x), 129.61 (2x), 123.76 (2x), 123.38, 116.78, 70.31, 39.33, 27.11, 26.14, 25.41, 21.63, 17.46, 16.02. 4.2.9. 1-Biphenyl-4-yl-5,9-dimethyl-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3i). Yield = 84% (408 mg); Colorless gum; HRMS (ESI, M++1) calcd for C31H35O3S 487.2307, found 487.2311; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.8 Hz, 2H), 7.71-7.66 (m, 4H), 7.62-7.59 (m, 2H), 7.50-7.40 (m, 3H), 7.32 (d, J = 8.4 Hz, 2H), 5.08 (dd, J = 4.8, 8.8 Hz, 1H), 4.94-4.86 (m, 2H), 2.83-2.78 (m, 2H), 2.43 (s, 3H), 1.89-1.82 (m, 4H), 1.58 (s, 3H), 1.51 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.02, 146.50, 145.25, 139.98, 139.55, 136.01, 133.57, 131.50, 129.74 (2x), 129.52 (2x), 129.49 (2x), 128.95 (2x), 128.40, 127.27 (2x), 127.24 (2x), 123.60, 117.44, 69.65, 39.42, 27.14, 26.20, 25.43, 21.65, 17.52, 16.07. 4.2.10. 5,9-Dimethyl-1-naphthalen-2-yl-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3j). Yield = 86% (396 mg); Colorless gum; HRMS (ESI, M++1) calcd for C29H33O3S 461.2150, found 461.2155; 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 1.2 Hz, 1H), 7.96-7.93 (m, 2H), 7.86-7.83 (m,
ACCEPTED MANUSCRIPT Tetrahedron
4.2.11. 2-Methanesulfonyl-5,9-dimethyl-1-p-tolyl-deca-4,8dien-1-one (3k). Yield = 83% (289 mg); Colorless gum; HRMS (ESI, M++1) calcd for C20H29O3S 349.1837, found 349.1840; 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.95 (t, J = 7.2 Hz, 1H), 4.84 (dd, J = 3.6, 11.2 Hz, 2H), 3.01-2.93 (m, 1H), 2.96 (s, 3H), 2.89-2.83 (m, 1H), 2.37 (s, 3H), 1.87-1.80 (m, 1H), 1.83 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 193.34, 145.29, 140.15, 134.34, 131.36, 129.40 (2x), 129.03 (2x), 123.47, 116.99, 68.17, 39.29, 37.50, 27.71, 26.07, 25.33, 21.51, 17.37, 15.95.
4.3.2. 2-Benzenesulfonyl-5,9,13-trimethyl-1phenyltetradeca-4,8,12-trien-1-one (4b). Yield = 83% (385 mg); Colorless gum; HRMS (ESI, M++1) calcd for C29H37O3S 465.2463, found 465.2462; 1H NMR (400 MHz, CDCl3): δ 7.89-7.87 (m, 2H), 7.82-7.79 (m, 2H), 7.63-7.41 (m, 6H), 5.08-4.99 (m, 2H), 4.90 (br t, J = 6.4 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H), 1.99-1.94 (m, 2H), 1.88-1.80 (m, 6H), 1.65 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.43, 140.15, 137.22, 136.62, 135.10, 134.07, 133.76, 131.09, 129.59 (2x), 128.79 (2x), 128.72 (2x), 128.59 (2x), 124.18, 123.45, 117.16, 69.42, 39.45, 39.39, 27.03, 26.55, 26.14, 25.59, 17.56, 16.02, 15.76. 4.3.3. 5,9,13-Trimethyl-1-phenyl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4c). Yield = 83% (397 mg); Colorless gum; HRMS (ESI, M++1) calcd for C30H39O3S 479.2620, found 479.2624; 1H NMR (400 MHz, CDCl3): δ 7.91-7.88 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.597.55 (m, 1H), 7.47-7.42 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.05-5.00 (m, 2H), 4.90-4.87 (m, 2H), 2.80-2.75 (m, 2H), 2.42 (s, 3H), 1.99-1.94 (m, 2H), 1.89-1.81 (m, 6H), 1.66 (d, J = 1.2 Hz, 3H), 1.56 (s, 3H), 1.55 (d, J = 0.8 Hz, 3H), 1.46 (d, J = 0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 192.67, 145.25, 140.14, 137.38, 135.20, 133.75, 133.60, 131.22, 129.74 (2x), 129.49 (2x), 128.86 (2x), 128.64 (2x), 124.26, 123.54, 117.32, 69.62, 39.53, 39.47, 27.19, 26.63, 26.24, 25.66, 21.66, 17.64, 16.11, 15.83.
TE D
M AN U
4.2.12. 2-(4-Methoxybenzenesulfonyl)-5,9-dimethyl-1phenyl-deca-4,8-dien-1-one (3l). Yield = 85% (362 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H31O4S 427.1943, found 427.1940; 1H NMR (400 MHz, CDCl3): δ 7.90-7.87 (m, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.56-7.52 (m, 1H), 7.44-7.40 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.04 (dd, J = 6.4, 8.4 Hz, 1H), 4.90-4.83 (m, 2H), 3.82 (s, 3H), 2.79-2.75 (m, 2H), 1.86-1.79 (m, 4H), 1.54 (s, 3H), 1.49 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.72, 163.99, 139.83, 137.28, 133.64, 131.76 (2x), 131.37, 128.71 (2x), 128.53 (2x), 127.90, 123.51, 117.30, 113.96 (2x), 69.47, 55.53, 39.31, 27.09, 26.09, 25.36, 17.43, 15.96.
124.16, 123.39, 116.88, 68.46, 39.47, 39.39, 37.54, 27.86, 26.55, 26.15, 25.58, 17.57, 16.08, 15.76.
RI PT
2H), 7.70 (d, J = 8.4 Hz, 2H), 7.61-7.52 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.23 (dd, J = 6.0, 8.8 Hz, 1H), 4.97-4.93 (m, 1H), 4.84-4.81 (m, 1H), 2.90-2.86 (m, 2H), 2.33 (s, 3H), 1.85-1.79 (m, 4H), 1.59 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 192.34, 145.19, 139.93, 135.64, 134.60, 133.58, 132.15, 131.36, 131.22, 129.75, 129.61 (2x), 129.41 (2x), 128.94, 128.49, 127.58, 126.84, 123.80, 123.48, 117.40, 69.62, 39.34, 27.05, 26.13, 25.29, 21.46, 17.37, 16.04.
SC
6
AC C
EP
4.3. A representative synthetic procedure of skeleton 4 is as follows: K2CO3 (400 mg, 2.9 mmol) was added to a solution of β-ketosulfones 1 (1.0 mmol) in acetone (10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. Farnesyl bromide 2b (298 mg, 1.05 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at reflux for 8 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 4.
4.3.1. 2-Methanesulfonyl-5,9,13-trimethyl-1-phenyltetradeca-4,8,12-trien-1-one (4a). Yield = 82% (330 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H35O3S 403.2307, found 403.2310; 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.4 Hz, 2H), 7.63-7.58 (m, 1H), 7.50-7.46 (m, 2H), 5.05-4.90 (m, 3H), 4.86 (dd, J = 3.6, 10.8 Hz, 1H), 3.072.86 (m, 2H), 2.99 (s, 3H), 2.03-1.95 (m, 2H), 1.92-1.81 (m, 3H), 1.86 (s, 3H), 1.66 (s, 3H), 1.62 (s, 3H), 1.57 (s, 3H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 194.07, 140.53, 136.86, 135.20, 134.16, 131.13, 128.91 (2x), 128.77 (2x),
4.3.4. 1-(4-Fluorophenyl)-5,9,13-trimethyl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4d). Yield = 85% (422 mg); Colorless gum; HRMS (ESI, M++1) calcd for C30H38FO3S 497.2526, found 497.2530; 1H NMR (400 MHz, CDCl3): δ 7.98-7.93 (m, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.13-7.08 (m, 2H), 5.03-4.97 (m, 2H), 4.89-4.85 (m, 2H), 2.78-2.74 (m, 2H), 2.41 (s, 3H), 1.98-1.93 (m, 2H), 1.88-1.79 (m, 6H), 1.65 (d, J = 0.8 Hz, 3H), 1.55 (s, 3H), 1.54 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.89, 166.06 (d, J = 255.5 Hz), 145.30, 140.11, 135.11, 133.73 (d, J = 3.0 Hz), 133.41, 131.63 (d, J = 9.9 Hz, 2x), 131.13, 129.62 (2x), 129.47 (2x), 124.14, 123.40, 117.20, 115.76 (d, J = 21.9 Hz, 2x), 69.58, 39.46, 39.36, 27.05, 26.54, 26.11, 25.56, 21.56, 17.54, 16.02, 15.73. 4.3.5. 5,9,13-Trimethyl-2-(toluene-4-sulfonyl)-1-p-tolyltetradeca-4,8,12-trien-1-one (4e). Yield = 83% (409 mg); Colorless gum; HRMS (ESI, M++1) calcd for C31H41O3S 493.2776, found 493.2780; 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.03-4.99 (m, 2H), 4.90-4.86 (m, 2H), 2.78-2.74 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 1.99-1.94 (m, 2H), 1.88-1.80 (m, 6H), 1.65 (d, J = 1.2 Hz, 3H), 1.57 (s, 3H), 1.55 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.96, 145.10, 144.81, 139.88, 135.07, 134.88, 133.60, 131.12, 129.66 (2x), 129.40 (2x), 129.29 (2x), 129.09, 128.99 (2x), 124.20, 123.53, 117.40, 69.40, 39.46, 39.40, 27.11, 26.58, 26.16, 25.61, 21.60, 17.58, 16.05, 15.75.
ACCEPTED MANUSCRIPT Tetrahedron
7
mg); Colorless gum; HRMS (ESI, M++1) calcd for C34H41O3S 529.2776, found 529.2772; 1H NMR (400 MHz, CDCl3): δ 8.40 (br s, 1H), 7.95 (dt, J = 2.0, 8.4 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.62 (dt, J = 1.2, 8.4 Hz, 1H), 7.56 (dt, J = 1.2, 8.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 5.20 (dd, J = 4.8, 10.0 Hz, 1H), 4.96-4.92 (m, 2H), 4.87-4.85 (m, 1H), 2.88-2.83 (m, 2H), 2.37 (s, 3H), 1.93-1.68 (m, 8H), 1.63 (d, J = 0.8 Hz, 3H), 1.59 (s, 3H), 1.53 (s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.42, 145.28, 140.14, 135.76, 135.15, 134.69, 133.59, 132.25, 131.33, 131.14, 129.88, 129.75 (2x), 129.49 (2x), 129.03, 128.59, 127.70, 126.93, 124.21, 123.92, 123.49, 117.41, 69.75, 39.47, 39.45, 27.16, 26.56, 26.22, 25.64, 21.60, 17.60, 16.18, 15.74.
4.3.7. 5,9,13-Trimethyl-2-(toluene-4-sulfonyl)-1-(4trifluoromethylphenyl)tetradeca-4,8,12-trien-1-one (4g). Yield = 80% (437 mg); Colorless gum; HRMS (ESI, M++1) calcd for C31H38F3O3S 547.2494, found 547.2490; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.04-4.98 (m, 2H), 4.88-4.85 (m, 2H), 2.81-2.77 (m, 2H), 2.43 (s, 3H), 1.99-1.93 (m, 2H), 1.90-1.79 (m, 6H), 1.65 (s, 3H), 1.56 (br s, 6H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.97, 145.58, 140.53, 139.92, 135.27, 134.98, 133.29, 131.25, 129.67 (4x), 129.62 (2x), 129.17 (2x), 125.68 (q, J = 3.8 Hz), 124.13, 123.39, 116.98, 70.08, 39.50, 39.42, 27.03, 26.58, 26.17, 25.60, 21.61, 17.59, 16.09, 15.78.
4.3.11. 2-Methanesulfonyl-5,9,13-trimethyl-1-p-tolyltetradeca-4,8,12-trien-1-one (4k). Yield = 85% (354 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H37O3S 417.2463, found 417.2466; 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.04-4.82 (m, 4H), 3.02-2.84 (m, 2H), 2.97 (s, 3H), 2.38 (s, 3H), 2.021.92 (m, 2H), 1.90-1.81 (m, 6H), 1.65 (d, J = 1.2 Hz, 3H), 1.62 (s, 3H), 1.56 (s, 3H), 1.46 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 193.34, 145.31, 140.27, 135.07, 134.37, 131.05, 129.43 (2x), 129.06 (2x), 124.12, 123.40, 116.99, 68.22, 39.41, 39.34, 37.49, 27.73, 26.51, 26.08, 25.54, 21.55, 17.52, 16.02, 15.67.
M AN U
SC
RI PT
4.3.6. 1-(4-Methoxyphenyl)-5,9,13-trimethyl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4f). Yield = 86% (437 mg); Colorless gum; HRMS (ESI, M++1) calcd for C31H41O4S 509.2726, found 509.2730; 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.03-4.95 (m, 2H), 4.90-4.86 (m, 2H), 3.83 (s, 3H), 2.78-2.73 (m, 2H), 2.40 (s, 3H), 1.98-1.93 (m, 2H), 1.88-1.80 (m, 6H), 1.64 (s, 3H), 1.55 (s, 3H), 1.45 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.44, 164.05, 145.03, 139.71, 134.99, 133.57, 131.30 (2x), 131.06, 130.30, 129.59 (2x), 129.34 (2x), 124.15, 123.49, 117.46, 113.76 (2x), 69.16, 55.40, 39.43, 39.36, 27.00, 26.52, 26.12, 25.55, 21.53, 17.53, 16.00, 15.73.
EP
TE D
4.3.8. 5,9,13-Trimethyl-1-(4-nitrophenyl)-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4h). Yield = 81% (424 mg); Colorless gum; HRMS (ESI, M++1) calcd for C30H38NO5S 524.2471, found 524.2475; 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.02 (t, J = 7.6 Hz, 1H), 5.00-4.96 (m, 1H), 4.87-4.84 (m, 2H), 2.77 (t, J = 7.6 Hz, 2H), 2.44 (s, 3H), 1.96-1.77 (m, 8H), 1.64 (s, 3H), 1.54 (br s, 6H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.64, 150.41, 145.75, 141.60, 140.69, 135.29, 133.07, 131.30, 129.87 (2x), 129.68 (2x), 129.63 (2x), 124.04, 123.78 (2x), 123.26, 116.77, 70.34, 39.48, 39.37, 27.12, 26.54, 26.09, 25.57, 21.66, 17.57, 16.07, 15.80.
AC C
4.3.9. 1-Biphenyl-4-yl-5,9,13-trimethyl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4i). Yield = 85% (471 mg); Colorless gum; HRMS (ESI, M++1) calcd for C36H43O3S 555.2933, found 555.2930; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz, 2H), 7.71-7.66 (m, 4H), 7.637.60 (m, 2H), 7.50-7.46 (m, 2H), 7.44-7.39 (m, 1H), 7.32 (d, J = 8.4 Hz, 2H), 5.09 (dd, J = 5.2, 9.2 Hz, 1H), 5.03-4.98 (m, 1H), 4.95-4.92 (m, 2H), 2.84-2.80 (m, 2H), 2.43 (s, 3H), 2.02-1.77 (m, 8H), 1.64 (d, J = 0.8 Hz, 3H), 1.59 (s, 3H), 1.56 (s, 3H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.99, 146.45, 145.24, 140.04, 139.50, 135.98, 135.13, 133.54, 131.16, 129.71 (2x), 129.50 (2x), 129.48 (2x), 128.93 (2x), 128.39, 127.24 (2x), 127.22 (2x), 124.20, 123.51, 117.37, 69.60, 39.47, 39.44, 27.11, 26.58, 26.19, 25.60, 21.63, 17.60, 16.11, 15.80. 4.3.10. 5,9,13-Trimethyl-1-naphthalen-2-yl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4j). Yield = 86% (454
4.3.12. 2-(4-Methoxybenzenesulfonyl)-5,9,13-trimethyl-1phenyltetradeca-4,8,12-trien-1-one (4l). Yield = 87% (430 mg); Colorless gum; HRMS (ESI, M++1) calcd for C30H39O4S 495.2569, found 495.2570; 1H NMR (400 MHz, CDCl3): δ 7.91-7.89 (m, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.597.55 (m, 1H), 7.47-7.43 (m, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.05-5.00 (m, 2H), 4.91-4.88 (m, 2H), 3.87 (s, 3H), 2.79-2.74 (m, 2H), 1.99-1.94 (m, 2H), 1.89-1.81 (m, 6H), 1.66 (d, J = 0.8 Hz, 3H), 1.57 (s, 3H), 1.56 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.87, 164.11, 140.10, 137.42, 135.20, 133.76, 131.95 (2x), 131.24, 128.87 (2x), 128.65 (2x), 127.99, 124.26, 123.55, 117.35, 114.05 (2x), 69.68, 55.64, 39.54, 39.49, 27.27, 26.64, 26.26, 25.67, 17.65, 16.13, 15.84. 4.4. A representative synthetic procedure of skeleton 5 is as follows: Sn(OTf)2 (10 mg, 0.025 mmol) was added to a solution of 3 (0.5 mmol) in MeNO2 (5 mL) at 25 oC. The reaction mixture was stirred at 25 oC for 10 min. The reaction mixture was stirred at 25 oC for 20 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 5.
4.4.1. 3-Methanesulfonyl-5,5,8a-trimethyl-2-phenyl4a,5,6,7,8,8a-hexahydro-4H-chromene (5a). Yield = 85% (142 mg); Colorless solid; mp = 173-175 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C19H27O3S 335.1681, found 335.1683; 1H NMR (400 MHz, CDCl3): δ 7.44-7.35 (m, 5H), 2.64 (dd, J = 4.4, 16.8 Hz, 1H), 2.63 (s, 3H), 2.27 (dd, J = 12.8, 16.8 Hz, 1H), 1.94-1.91 (m,
ACCEPTED MANUSCRIPT Tetrahedron
4.4.2. 3-Benzenesulfonyl-5,5,8a-trimethyl-2-phenyl4a,5,6,7,8,8a-hexahydro-4H-chromene (5b). Yield = 83% (165 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H29O3S 397.1837, found 397.1838; 1H NMR (400 MHz, CDCl3): δ 7.48-7.41 (m, 3H), 7.37-7.19 (m, 7H), 2.74 (dd, J = 4.4, 16.4 Hz, 1H), 2.19 (dd, J = 12.8, 16.4 Hz, 1H), 1.891.86 (m, 1H), 1.65 (dd, J = 4.8, 12.8 Hz, 1H), 1.63-1.59 (m, 1H), 1.52-1.46 (m, 3H), 1.32-1.25 (m, 1H), 1.21 (s, 3H), 1.03 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.62, 142.34, 134.27, 132.10, 129.59 (2x), 129.43, 128.36 (2x), 127.43 (2x), 126.89 (2x), 113.64, 79.94, 48.02, 41.07, 39.01, 33.54, 31.96, 21.48, 20.50, 19.51, 19.40.
4.4.6. 5,5,8a-Trimethyl-3-(toluene-4-sulfonyl)-2-(4trifluoromethylphenyl)-4a,5,6,7,8,8a-hexahydro-4Hchromene (5g). Yield = 83% (198 mg); Colorless solid; mp = 179-180 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C26H30F3O3S 479.1868, found 479.1870; 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.16 (dd, J = 12.8, 16.8 Hz, 1H), 1.89-1.86 (m, 1H), 1.64 (dd, J = 4.4, 7.6 Hz, 1H), 1.63-1.60 (m, 1H), 1.52-1.45 (m, 3H), 1.33-1.25 (m, 1H), 1.22 (s, 3H), 1.02 (s, 3H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.45, 143.30, 139.00, 138.05, 131.38, 131.06, 130.00 (2x), 129.21 (2x), 127.02 (2x), 124.45 (d, J = 3.0 Hz), 124.37 (d, J = 3.8 Hz), 114.90, 80.40, 47.99, 41.05, 38.99, 33.59, 31.96, 21.44, 21.32, 20.51, 19.53, 19.47. Single-crystal X-Ray diagram: crystal of compound 5g was grown by slow diffusion of EtOAc into a solution of compound 5g in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P b c n, a = 19.064(10) Å, b = 10.973(6) Å, c = 22.586(10) Å, V = 4725(4) Å3, Z = 8, dcalcd = 1.345 mg/cm3, F(000) = 2016, 2θ range 1.803~26.641o, R indices (all data) R1 = 0.1001, wR2 = 0.1674.
TE D
M AN U
4.4.3. 5,5,8a-Trimethyl-2-phenyl-3-(toluene-4-sulfonyl)4a,5,6,7,8,8a-hexahydro-4H-chromene (5c). Yield = 85% (174 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H31O3S 411.1994, found 411.1996; 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.0 Hz, 2H), 7.35-7.32 (m, 2H), 7.307.20 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 2.72 (dd, J = 4.8, 16.4 Hz, 1H), 2.36 (s, 3H), 2.17 (dd, J = 12.8, 16.4 Hz, 1H), 1.891.86 (m, 1H), 1.64 (dd, J = 4.8, 12.8 Hz, 1H), 1.51-1.42 (m, 3H), 1.34-1.29 (m, 2H), 1.21 (s, 3H), 1.03 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.26, 142.80, 139.49, 134.46, 129.59 (2x), 129.38, 129.02 (2x), 127.39 (2x), 126.99 (2x), 113.82, 79.84, 48.04, 41.11, 39.06, 33.57, 31.99, 21.48, 21.44, 20.53, 19.54, 19.42.
(ESI, M++1) calcd for C26H33O3S 425.2150, found 425.2154; H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.4 Hz, 2H), 7.18-7.08 (m, 6H), 2.68 (dd, J = 4.8, 16.4 Hz, 1H), 2.37 (s, 3H), 2.36 (s, 3H), 2.13 (dd, J = 12.8, 16.4 Hz, 1H), 1.88-1.85 (m, 1H), 1.64 (dd, J = 4.8, 12.8 Hz, 1H), 1.50-1.45 (m, 3H), 1.34-1.29 (m, 2H), 1.18 (s, 3H), 1.01 (s, 3H), 0.85 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 160.42, 139.52, 139.46, 131.66, 129.47 (2x), 128.96 (2x), 128.08 (2x), 127.00 (2x), 124.80, 113.23, 79.69, 48.01, 44.45, 41.09, 39.05, 33.50, 31.96, 21.49, 21.44, 20.50, 19.51, 19.38. 1
RI PT
1H), 1.65 (dd, J = 4.8, 12.8 Hz, 1H), 1.63-1.59 (m, 1H), 1.541.47 (m, 3H), 1.33-1.25 (m, 1H), 1.35 (s, 3H), 1.04 (s, 3H), 0.91 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.60, 134.28, 129.69, 129.18 (2x), 127.74 (2x), 113.29, 79.85, 47.80, 43.03, 40.98, 38.97, 33.44, 31.87, 20.96, 20.40, 19.40, 19.12.
SC
8
AC C
EP
4.4.4. 2-(4-Fluorophenyl)-5,5,8a-trimethyl-3-(toluene-4sulfonyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene (5d). Yield = 82% (175 mg); Colorless solid; mp = 129-130 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H30FO3S 429.1900, found 429.1901; 1H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.4 Hz, 2H), 7.23-7.19 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.98-6.93 (m, 2H), 2.71 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.13 (dd, J = 12.8, 16.4 Hz, 1H), 1.88-1.86 (m, 1H), 1.63 (dd, J = 4.8, 12.8 Hz, 1H), 1.501.45 (m, 3H), 1.28-1.23 (m, 2H), 1.18 (s, 3H), 1.02 (s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.31 (d, J = 247.8 Hz), 159.16, 143.03, 139.36, 131.73 (d, J = 8.4 Hz, 2x), 130.46 (d, J = 3.0 Hz), 129.08 (2x), 126.92 (2x), 114.46 (d, J = 21.3 Hz, 2x), 114.16, 80.00, 48.03, 41.07, 39.03, 33.54, 31.97, 21.53, 21.44, 20.50, 19.51, 19.39. Single-crystal XRay diagram: crystal of compound 5d was grown by slow diffusion of EtOAc into a solution of compound 5d in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P b c n, a =18.4792(14) Å, b = 10.7741(7) Å, c = 22.6790(16) Å, V = 4515.3(6) Å3, Z = 8, dcalcd = 1.261 mg/cm3, F(000) = 1824, 2θ range 1.796~26.417o, R indices (all data) R1 = 0.1152, wR2 = 0.1907. 4.4.5. 5,5,8a-Trimethyl-3-(toluene-4-sulfonyl)-2-p-tolyl4a,5,6,7,8,8a-hexahydro-4H-chromene (5e). Two isomers (ratio = 3 : 1); Yield = 86% (182 mg); Colorless gum; HRMS
4.4.7. 5,5,8a-Trimethyl-2-(4-nitrophenyl)-3-(toluene-4sulfonyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene (5h). Yield = 80% (182 mg); Colorless solid; mp = 207-208 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H30NO5S 456.1845, found 456.1848; 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.39 (s, 3H), 2.08 (dd, J = 12.8, 16.8 Hz, 1H), 1.89-1.86 (m, 1H), 1.63 (dd, J = 4.4, 7.6 Hz, 1H), 1.63-1.60 (m, 1H), 1.50-1.45 (m, 3H), 1.33-1.23 (m, 1H), 1.20 (s, 3H), 1.00 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.54, 148.16, 143.65, 141.02, 138.73, 130.59 (2x), 129.40 (2x), 126.97 (2x), 122.59 (2x), 114.88, 80.75, 47.85, 40.93, 38.89, 33.53, 31.87, 21.48, 21.29, 20.45, 19.48 (2x). Single-crystal X-Ray diagram: crystal of compound 5h was grown by slow diffusion of EtOAc into a solution of compound 5h in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P b c n, a = 18.8743(11) Å, b = 10.8665(5) Å, c = 22.3032(11) Å, V = 4574.3(4) Å3, Z = 8, dcalcd = 1.323 mg/cm3, F(000) = 1936, 2θ range 1.826~26.434o, R indices (all data) R1 = 0.0723, wR2 = 0.1585.
ACCEPTED MANUSCRIPT Tetrahedron
RI PT
4.5. A representative synthetic procedure of skeleton 6 is as follows: Sn(OTf)2 (10 mg, 0.025 mmol) was added to a solution of 4 (0.5 mmol) in MeNO2 (5 mL) at 25 oC. The reaction mixture was stirred at 25 oC for 10 min. The reaction mixture was stirred at 25 oC for 20 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 6. 4.5.1. 2-Methanesulfonyl-4a,7,7,10a-tetramethyl-3-phenyl4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6a). Two diastereomers (d.r. = 3/1); Yield = 81% (163 mg); Colorless solid; mp = 147-148 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C24H35O3S 403.2307, found 403.2310; 1H NMR (400 MHz, CDCl3): δ 7.43-7.38 (m, 5H), 2.64 (s, 3H), 2.57 (dd, J = 1.2, 16.8 Hz, 1H), 2.34-2.26 (m, 1H), 2.06-2.02 (m, 1H), 1.97-1.94 (m, 1H), 1.81-1.46 (m, 7H), 1.34 (s, 3H), 1.09-0.96 (m, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 159.65, 134.44, 129.86, 129.80, 129.29 (2x), 127.88 (2x), 113.17, 79.76, 55.86, 51.83, 43.14, 41.65, 40.24, 39.14, 37.01, 33.34, 21.46, 20.25, 20.21, 19.56, 18.35, 14.88.
TE D
M AN U
4.4.9. 5,5,8a-Trimethyl-2-naphthalen-2-yl-3-(toluene-4sulfonyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene (5j). Yield = 83% (191 mg); Colorless solid; mp = 136-137 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C29H33O3S 461.2150, found 461.2153; 1H NMR (400 MHz, CDCl3): δ 7.82-7.75 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.69 (br s, 1H), 7.52-7.47 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.25 (dd, J = 1.6, 8.4 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 2.79 (dd, J = 4.8, 16.8 Hz, 1H), 2.29 (s, 3H), 2.29 (dd, J = 6.0, 16.8 Hz, 1H), 1.92-1.89 (m, 1H), 1.70 (dd, J = 4.8, 12.8 Hz, 1H), 1.66-1.62 (m, 1H), 1.54-1.48 (m, 3H), 1.34-1.28 (m, 1H), 1.29 (s, 3H), 1.06 (s, 3H), 0.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.14, 142.82, 139.46, 133.53, 132.22, 131.72, 129.64, 128.87 (2x), 128.37, 127.59, 127.05, 127.02 (2x), 126.79, 126.48, 126.11, 114.47, 79.99, 48.14, 41.13, 39.08, 33.59, 32.01, 21.54, 21.36, 20.55, 19.55, 19.47.
55.47, 48.04, 41.10, 39.05, 33.53, 31.97, 21.45, 20.51, 19.53, 19.37.
SC
4.4.8. 2-Biphenyl-4-yl-5,5,8a-trimethyl-3-(toluene-4sulfonyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene (5i). Yield = 85% (206 mg); Colorless solid; mp = 160-162 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C31H35O3S 487.2307, found 487.2310; 1H NMR (400 MHz, CDCl3): δ 7.60-7.57 (m, 2H), 7.51-7.35 (m, 7H), 7.31 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 2.75 (dd, J = 4.8, 16.8 Hz, 1H), 2.36 (s, 3H), 2.20 (dd, J = 12.8, 16.8 Hz, 1H), 1.92-1.90 (m, 1H), 1.67 (dd, J = 4.8, 12.8 Hz, 1H), 1.541.47 (m, 3H), 1.28-1.24 (m, 2H), 1.24 (s, 3H), 1.05 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.90, 142.84, 142.28, 140.59, 139.42, 133.32, 130.08 (2x), 128.98 (2x), 128.74 (2x), 127.53, 127.13 (2x), 127.05 (2x), 126.15 (2x), 114.04, 79.91, 48.04, 41.09, 39.07, 33.55, 31.98, 21.50, 21.46, 20.52, 19.53, 19.42.
9
AC C
EP
4.4.10. 3-Methanesulfonyl-5,5,8a-trimethyl-2-p-tolyl4a,5,6,7,8,8a-hexahydro-4H-chromene (5k). Yield = 81% (141 mg); Colorless solid; mp = 146-147 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C20H29O3S 349.1837, found 349.1840; 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.64 (dd, J = 5.2, 16.8 Hz, 1H), 2.65 (s, 3H), 2.36 (s, 3H), 2.27 (dd, J = 12.8, 16.8 Hz, 1H), 1.94-1.92 (m, 1H), 1.64 (dd, J = 4.4, 12.8 Hz, 1H), 1.66-1.62 (m, 1H), 1.54-1.47 (m, 3H), 1.35 (s, 3H), 1.34-1.28 (m, 1H), 1.04 (s, 3H), 0.91 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 159.78, 139.95, 131.47, 129.21 (2x), 128.55 (2x), 113.13, 79.79, 47.91, 43.12, 41.08, 39.08, 33.51, 31.95, 21.35, 21.05, 20.47, 19.47, 19.18.
4.4.11. 3-(4-Methoxybenzenesulfonyl)-5,5,8a-trimethyl-2phenyl-4a,5,6,7,8,8a-hexahydro-4H-chromene (5l). Yield = 18% (38 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H31O4S 427.1943, found 427.1946; 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 8.8 Hz, 2H), 7.36-7.32 (m, 1H), 7.307.26 (m, 2H), 7.23-7.20 (m, 2H), 6.77 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 2.71 (dd, J = 4.8, 16.8 Hz, 1H), 2.17 (dd, J = 12.8, 16.8 Hz, 1H), 1.88-1.86 (m, 1H), 1.64 (dd, J = 4.4, 12.8 Hz, 1H), 1.66-1.62 (m, 1H), 1.50-1.42 (m, 3H), 1.38-1.24 (m, 1H), 1.21 (s, 3H), 1.02 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.42, 159.93, 134.50, 134.15, 129.59 (2x), 129.36, 129.05 (2x), 127.41 (2x), 114.19, 113.55 (2x), 79.76,
4.5.2. 2-Benzenesulfonyl-4a,7,7,10a-tetramethyl-3-phenyl4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6b). Two diastereomers (d.r. = 9/1); Yield = 81% (188 mg); Colorless solid; mp = 192-194 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C29H37O3S 465.2463, found 465.2466; 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 8.4 Hz, 2H), 7.44-7.42 (m, 1H), 7.37-7.18 (m, 7H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.20 (dd, J = 12.8, 16.8 Hz, 1H), 1.98 (dt, J = 3.2, 12.4 Hz, 1H), 1.73 (d, J = 13.2 Hz, 2H), 1.65-1.23 (m, 7H), 1.20 (s, 3H), 1.04-0.96 (m, 2H), 0.88 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 160.57, 142.39, 134.36, 132.10, 129.58 (2x), 129.40, 128.38 (2x), 127.45 (2x), 126.91 (2x), 113.30, 79.73, 55.83, 51.92, 41.67, 40.17, 39.08, 36.99, 33.34, 33.13, 21.48, 20.66, 20.38, 19.56, 18.38, 14.86. Single-crystal X-Ray diagram: crystal of compound 6b was grown by slow diffusion of EtOAc into a solution of compound 6b in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P 21 21 21, a = 6.2765(3) Å, b = 14.2655(7) Å, c = 27.0870(14) Å, V = 2425.3(2) Å3, Z = 4, dcalcd= 1.272 g/cm3, F(000) = 1000, 2θ range 1.504~26.390o, R indices (all data) R1 = 0.0414, wR2 = 0.1045. 4.5.3. 4a,7,7,10a-Tetramethyl-3-phenyl-2-(toluene-4sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6c). Two diastereomers (d.r. = 5/2); Yield = 85% (203 mg); Colorless solid; mp = 147-149 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C30H39O3S 479.2620, found 479.2621; 1H NMR
ACCEPTED MANUSCRIPT Tetrahedron
4.5.6. 4a,7,7,10a-Tetramethyl-2-(toluene-4-sulfonyl)-3-(4trifluoromethylphenyl)-4a,5,6,6a,7,8,9,10,10a,10bdecahydro-1H-benzo[f]chromene (6g). Two diastereomers (d.r. = 5/2); Yield = 80% (218 mg); Colorless solid; mp = 158-160 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C31H38F3O3S 547.2494, found 547.2493; 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 2.62 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.20-2.11 (m, 1H), 1.98-1.95 (m, 1H), 1.74-1.42 (m, 8H), 1.21 (s, 3H), 1.16-0.90 (m, 3H), 0.88 (s, 3H), 0.84 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.39, 131.28, 139.02, 138.13, 130.01, 129.97 (2x), 129.22 (2x), 127.03 (4x), 124.42 (q, J = 3.8 Hz), 114.55, 80.17, 55.84, 51.86, 41.65, 40.14, 39.08, 37.01, 35.12, 33.34, 33.14, 21.47, 20.50, 20.44, 19.58, 18.37, 14.89.
AC C
EP
TE D
M AN U
4.5.4. 3-(4-Fluorophenyl)-4a,7,7,10a-tetramethyl-2(toluene-4-sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro1H-benzo[f]chromene (6d). Two diastereomers (d.r. = 4/1); Yield = 80% (198 mg); Colorless solid; mp = 199-201 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C30H38FO3S 497.2526, found 497.2524; 1H NMR (400 MHz, CDCl3): δ 7.39-7.35 (m, 2H), 7.25-7.18 (m, 2H), 7.14 (d, J = 7.2 Hz, 2H), 6.99-6.94 (m, 2H), 2.62 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.18-2.09 (m, 1H), 1.97 (dt, J = 3.2, 12.8 Hz, 1H), 1.77-1.69 (m, 2H), 1.65-1.39 (m, 5H), 1.35-1.08 (m, 2H), 1.17 (s, 3H), 1.02-1.00 (m, 2H), 0.87 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.39 (d, J = 247.1 Hz), 159.08, 143.00, 139.38, 131.78, 131.70, 131.69 (d, J = 8.4 Hz, 2x), 130.52 (d, J = 3.0 Hz), 129.09 (2x), 126.92 (2x), 114.47 (d, J = 22.0 Hz, 2x), 113.81, 79.76, 55.82, 51.90, 41.65, 40.17, 39.08, 36.97, 33.33, 21.47, 20.68, 20.36, 19.55, 18.36, 14.84. Single-crystal X-Ray diagram: crystal of compound 6d was grown by slow diffusion of EtOAc into a solution of compound 6d in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/n, a = 7.0592(3) Å, b = 26.5040(10) Å, c = 14.4311(5) Å, V = 2653.65(18) Å3, Z = 4, dcalcd = 1.243 mg/cm3, F(000) = 1064, 2θ range 1.537~26.390o, R indices (all data) R1 = 0.1157, wR2 = 0.2322.
crystal X-Ray diagram: crystal of compound 6e was grown by slow diffusion of EtOAc into a solution of compound 6e in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/n, a = 6.9224(6) Å, b = 27.150(2) Å, c = 14.7171(13) Å, V = 2707.4(4) Å3, Z = 4, dcalcd = 1.209 mg/cm3, F(000) = 1064, 2θ range 1.500~26.415o, R indices (all data) R1 = 0.1230, wR2 = 0.1487.
RI PT
(400 MHz, CDCl3): δ 7.38-7.33 (m, 3H), 7.30-7.19 (m, 4H), 7.11 (d, J = 7.6 Hz, 2H), 2.62 (dd, J = 4.4, 16.8 Hz, 1H), 2.36 (s, 3H), 2.21-2.12 (m, 1H), 1.98 (dt, J = 3.2, 12.8 Hz, 1H), 1.76-1.70 (m, 2H), 1.66-1.38 (m, 5H), 1.35-1.08 (m, 2H), 1.02-1.00 (m, 2H), 1.19 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.23, 142.79, 139.55, 134.57, 129.59 (2x), 129.44, 129.37, 129.04 (2x), 127.43 (2x), 127.02 (2x), 113.49, 79.64, 55.87, 51.96, 41.71, 40.24, 39.12, 33.37, 33.16, 21.50, 21.47, 20.66, 20.42, 19.60, 18.41, 14.89. Single-crystal X-Ray diagram: crystal of compound 6c was grown by slow diffusion of EtOAc into a solution of compound 6c in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/n, a = 7.0561(5) Å, b = 26.349(2) Å, c = 14.3583(11) Å, V = 2615.3(3) Å3, Z = 4, dcalcd= 1.216 g/cm3, F(000) = 1032, 2θ range 1.546~26.411o, R indices (all data) R1 = 0.0949, wR2 = 0.2022.
SC
10
4.5.5. 4a,7,7,10a-Tetramethyl-2-(toluene-4-sulfonyl)-3-ptolyl-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6e). Two diastereomers (d.r. = 4/1); Yield = 83% (204 mg); Colorless solid; mp = 190-192 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C31H41O3S 493.2776, found 493.2774; 1H NMR (400 MHz, CDCl3): δ 7.42-7.38 (m, 2H), 7.16-7.08 (m, 6H), 2.59 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.36 (s, 3H), 2.17-2.10 (m, 1H), 1.97 (dt, J = 3.2, 12.8 Hz, 1H), 1.72-1.39 (m, 6H), 1.35-1.11 (m, 3H), 1.17 (s, 3H), 1.02-0.95 (m, 2H), 0.87 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.38, 142.75, 139.58, 139.44, 131.76, 129.51, 129.46 (2x), 128.99 (2x), 128.11 (2x), 127.04 (2x), 112.92, 79.49, 55.83, 51.92, 41.68, 40.22, 39.08, 38.96, 36.97, 33.35, 21.49, 21.44, 20.66, 20.38, 19.56, 18.39, 14.85. Single-
4.5.7. 4a,7,7,10a-Tetramethyl-3-(4-nitrophenyl)-2-(toluene4-sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6h). Two diastereomers (d.r. = 3/1); Yield = 77% (201 mg); Colorless solid; mp = 172-174 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C30H38NO5S 524.2471, found 524.2472; 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.8 Hz, 2H), 7.49-7.42 (m, 4H), 7.20 (d, J = 8.0 Hz, 2H), 2.60-2.54 (m, 1H), 2.40 (s, 3H), 2.14-1.96 (m, 2H), 1.71-1.22 (m, 11H), 1.19 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.51, 148.17, 143.65, 141.14, 138.77, 130.62, 130.58 (2x), 129.44 (2x), 127.01 (2x), 122.64 (2x), 114.60, 80.54, 55.81, 51.74, 41.60, 40.05, 39.02, 36.98, 33.31, 31.40, 21.52, 21.44, 20.47, 19.56, 18.34, 14.86. 4.5.8. 3-Biphenyl-4-yl-4a,7,7,10a-tetramethyl-2-(toluene-4sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6i). Two diastereomers (d.r. = 2/1); Yield = 83% (230 mg); Colorless gum; HRMS (ESI, M++1) calcd for C36H43O3S 555.2933, found 555.2930; 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.4 Hz, 2H), 7.51-7.35 (m, 7H), 7.29 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.36 (s, 3H), 2.24-2.15 (m, 1H), 2.091.99 (m, 1H), 1.83-1.48 (m, 9H), 1.26 (s, 3H), 1.07-0.90 (m, 2H), 0.88 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.86, 142.84, 142.27, 140.64, 139.47, 133.41, 130.06 (2x), 129.01 (2x), 128.77 (2x), 127.54, 127.18 (2x), 127.08 (2x), 126.18 (2x), 113.72, 79.65, 55.85, 51.95, 41.68, 40.24, 39.10, 37.01, 33.35, 31.43, 29.66, 21.50, 20.67, 20.42, 19.59, 18.40, 14.88. 4.5.9. 4a,7,7,10a-Tetramethyl-3-naphthalen-2-yl-2-(toluene4-sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6j). Two diastereomers (d.r. = 3/1); Yield
ACCEPTED MANUSCRIPT Tetrahedron
RI PT
4.6.3. 2-Benzoyl-5,9-dimethyldeca-4,8-dienoic acid ethyl ester (8c). Yield = 86% (282 mg); Colorless gum; HRMS (ESI, M++1) calcd for C21H29O3 329.2117, found 329.2115; 1 H NMR (400 MHz, CDCl3): δ 8.00-7.97 (m, 2H), 7.59-7.55 (m, 1H), 7.48-7.44 (m, 2H), 5.13-5.09 (m, 1H), 5.04-5.00 (m, 1H), 4.31 (t, J = 7.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.772.63 (m, 2H), 2.05-1.90 (m, 4H), 1.63 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 195.06, 169.68, 138.20, 136.36, 133.35, 131.39, 128.62 (2x), 128.55 (2x), 123.98, 119.97, 61.26, 54.43, 39.62, 27.64, 26.46, 25.57, 17.59, 16.05, 13.95. 4.6.4. 2-(4-Methoxybenzoyl)-5,9-dimethyldeca-4,8-dienoic acid ethyl ester (8d). Yield = 85% (304 mg); Colorless gum; HRMS (ESI, M++1) calcd for C22H31O4 359.2222, found 359.2218; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.10 (t, J = 7.2 Hz, 1H), 5.02 (t, J = 6.4 Hz, 1H), 4.26 (dd, J = 7.2, 8.0 Hz, 1H), 4.14 (dd, J = 1.6, 7.2 Hz, 1H), 4.10 (dd, J = 1.2, 7.2 Hz, 1H), 3.85 (s, 3H), 2.76-2.60 (m, 2H), 2.05-1.89 (m, 4H), 1.63 (s, 3H), 1.61 (s, 3H), 1.55 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 193.41, 169.88, 163.73, 138.02, 131.34, 130.95 (2x), 129.31, 124.01, 120.12, 113.77 (2x), 61.16, 55.42, 54.12, 39.62, 27.69, 26.48, 25.56, 17.58, 16.05, 13.98.
M AN U
4.5.10. 2-Methanesulfonyl-4a,7,7,10a-tetramethyl-3-p-tolyl4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6k). Two diastereomers (d.r. = 4/1); Yield = 80% (166 mg); Colorless solid; mp = 80-82 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H37O3S 417.2463, found 417.2460; 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.64 (s, 3H), 2.56 (dd, J = 5.2, 16.8 Hz, 1H), 2.36 (s, 3H), 2.33-2.24 (m, 1H), 2.06-2.01 (m, 1H), 1.76-1.35 (m, 7H), 1.33 (s, 3H), 1.31-1.10 (m, 2H), 1.09-0.94 (m, 2H), 0.90 (s, 3H), 0.89 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.78, 139.98, 131.56, 129.25 (2x), 128.62 (2x), 112.92, 79.62, 55.87, 51.86, 43.17, 41.66, 40.27, 39.15, 37.01, 33.34, 33.13, 21.47, 21.41, 20.28, 20.20, 19.57, 18.37, 14.87.
(m, 2H), 5.10 (t, J = 7.2 Hz, 1H), 5.01 (t, J = 6.8 Hz, 1H), 4.49 (t, J = 7.2 Hz, 1H), 2.90-2.83 (m, 1H), 2.57-2.50 (m, 1H), 2.02-1.90 (m, 4H), 1.63 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 198.17, 165.41 (d, J = 252.4 Hz), 139.33, 137.36, 133.26 (d, J = 3.0 Hz), 131.26 (d, J = 9.1 Hz, 2x), 131.25, 128.82 (2x), 128.15 (2x), 127.01, 124.14, 121.27, 115.49 (d, J = 21.3 Hz, 2x), 54.05, 39.66, 32.54, 26.53, 25.57, 17.59, 15.97.
SC
= 84% (222 mg); Colorless gum; HRMS (ESI, M++1) calcd for C34H41O3S 529.2776, found 529.2773; 1H NMR (400 MHz, CDCl3): δ 7.82-7.75 (m, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.52-7.46 (m, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 2.69 (dd, J = 5.2, 16.8 Hz, 1H), 2.38-2.22 (m, 2H), 2.30 (s, 3H), 2.05-1.98 (m, 1H), 1.82-1.41 (m, 8H), 1.26 (s, 3H), 1.17-0.90 (m, 2H), 0.88 (br s, 6H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.09, 142.81, 139.51, 133.54, 132.25, 131.82, 129.59, 128.90 (2x), 128.39, 127.62, 127.05 (2x), 126.79, 126.52, 126.11, 114.14, 79.77, 55.87, 52.05, 41.70, 40.24, 39.14, 37.04, 33.37, 33.16, 29.67, 21.50, 21.39, 20.72, 20.45, 19.60, 18.42, 14.91.
11
EP
TE D
4.6. A representative synthetic procedure of skeleton 8 is as follows: NaH (60% in oil, 120 mg, 3.0 mmol) was added to a solution of 7 (1.0 mmol) in THF (10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. Geranyl bromide 2b (298 mg, 1.05 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at reflux for 8 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 8.
AC C
4.6.1. 5,9-Dimethyl-1,2-diphenyldeca-4,8-dien-1-one (8a). Yield = 84% (279 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H29O 333.2219, found 333.2220; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 2H), 7.50-7.45 (m, 1H), 7.40-7.27 (m, 6H), 7.22-7.18 (m, 1H), 5.11 (t, J = 7.2 Hz, 1H), 5.03 (t, J = 6.4 Hz, 1H), 4.56 (t, J = 7.2 Hz, 1H), 2.922.85 (m, 1H), 2.59-2.51 (m, 1H), 2.02-1.89 (m, 2H), 1.771.67 (m, 2H), 1.64 (s, 3H), 1.57 (s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 199.79, 139.48, 137.24, 132.69, 131.24, 128.74 (2x), 128.64 (2x), 128.42 (2x), 128.24 (2x), 126.89, 124.17, 121.42, 54.00, 39.67, 32.59, 26.55, 26.50, 25.57, 17.60, 15.99. 4.6.2. 1-(4-Fluoro-phenyl)-5,9-dimethyl-2-phenyldeca-4,8dien-1-one (8b). Yield = 86% (301 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H28FO 351.2124, found 351.2120; 1H NMR (400 MHz, CDCl3): δ 8.01-7.96 (m, 2H), 7.30 (br s, 2H), 7.29 (br s, 2H), 7.24-7.19 (m, 1H), 7.07-7.01
4.6.5. 2-(3,7-Dimethylocta-2,6-dienyl)-1,3-diphenylpropane1,3-dione (8e). Yield = 88% (317 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H29O2 361.2168, found 361.2170; 1H NMR (400 MHz, CDCl3): δ 7.99-7.95 (m, 4H), 7.57-7.53 (m, 2H), 7.45-7.41 (m, 4H), 5.25 (t, J = 6.8 Hz, 1H), 5.19 (t, J = 7.2 Hz, 1H), 5.02-4.99 (m, 1H), 2.84 (t, J = 6.8 Hz, 2H), 1.96-1.88 (m, 4H), 1.62 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H);13C NMR (100 MHz, CDCl3): δ 195.91 (2x), 137.93, 136.11, 133.34 (2x), 131.34, 128.73 (4x), 128.52 (4x), 127.08, 123.97, 120.60, 57.07, 39.55, 28.21, 26.37, 25.53, 17.57, 16.05. 4.6.6. 2-(3,7-Dimethyl-octa-2,6-dienyl)-1-phenylbutane-1,3dione (8f). Yield = 84% (250 mg); Colorless gum; HRMS (ESI, M++1) calcd for C20H26O2 299.2011, found 299.2015; 1 H NMR (400 MHz, CDCl3): δ 7.98-7.96 (m, 2H), 7.61-7.56 (m, 1H), 7.50-7.42 (m, 2H), 5.05 (t, J = 7.2 Hz, 1H), 4.99 (t, J = 7.2 Hz, 1H), 4.46 (t, J = 7.2 Hz, 1H), 2.69 (t, J = 7.2 Hz, 2H), 2.14 (s, 3H), 1.99-1.86 (m, 4H), 1.62 (s, 3H), 1.61 (s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 204.11, 196.35, 138.30, 136.55, 133.60, 131.48, 128.78 (2x), 128.69 (2x), 123.92, 119.86, 63.30, 39.59, 28.07, 27.75, 26.40, 25.58, 17.62, 16.09. 4.7. A representative synthetic procedure of skeleton 9 is as follows: Sn(OTf)2 (10 mg, 0.025 mmol) was added to a solution of 8 (0.5 mmol) in MeNO2 (5 mL) at 25 oC. The
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CDCl3): δ 7.64-7.62 (m, 2H), 7.50-7.44 (m, 1H), 7.42-7.38 (m, 2H), 2.59 (dd, J = 4.4, 16.8 Hz, 1H), 2.05-1.91 (m, 2H), 1.73-1.63 (m, 1H), 1.64 (s, 3H), 1.55-1.45 (m, 4H), 1.30 (s, 3H), 1.32-1.28 (m, 1H), 0.97 (s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 198.48, 160.10, 141.31, 131.33, 128.43 (2x), 128.33 (2x), 110.43, 78.46, 47.82, 41.40, 39.45, 33.34, 32.08, 21.52, 21.28, 20.52, 19.66, 19.56.
4.7.1. 5,5,8a-Trimethyl-2-phenyl-4a,5,6,7,8,8a-hexahydro4H-chromene-3-carboxylic acid ethyl ester (9c). Yield = 75% (123 mg); Colorless gum; HRMS (ESI, M++1) calcd for C21H29O3 329.2117, found 329.2115; 1H NMR (400 MHz, CDCl3): δ 7.34-7.31 (m, 5H), 3.95-3.87 (m, 2H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.07 (dd, J = 13.2, 16.8 Hz, 1H), 1.681.42 (m, 6H), 1.34 (s, 3H), 1.30-1.22 (m, 1H), 1.04 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.78, 161.26, 137.52, 128.61, 128.53 (2x), 128.26, 127.55 (2x), 102.93, 79.19, 59.61, 47.69, 41.37, 39.42, 32.13, 21.08, 20.54, 19.72, 19.32, 13.66.
Acknowledgments The authors would like to thank the Ministry of Science and Technology of the Republic of China for its financial support (MOST 104-2113-M-037-012). References and notes
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For a review on the biomimetic total synthesis of terpenes and steroids, see: Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730-4756. For leading references on the polycyclizations, see: (a) Kurti, L.; Chein, R.-J.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 9031-9036. (b) Rajendar, G.; Corey, E. J. J. Am. Chem. Soc. 2015, 137, 58375844. (c) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew. Chem., Int. Ed. 2000, 39, 2812-2833. (d) Liu, W.; Li, H.; Cai, P.-J.; Wang, Z.; Yu, Z.-X.; Lei, X. Angew. Chem., Int. Ed. 2016, 55, 3112-3116. Representative examples on the synthesis of natural products by metal complex-mediated ployolefin carbocyclizations, for serratenediol, see: (a) Zhang, J.-H.; Corey, E. J. Org. Lett. 2001, 3, 3215-3216. For germanicol, see: (b) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8865-8869. For lupeol, see: (c) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2009, 131, 13928-13929. For dammarenediol II, see: (d) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765-8766. For erythrodiol, see: (e) Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874. For walsucochin B, see: (f) Xu, S.; Gu, J.; Li, H.; Ma, D.; Xie, X.; She, X. Org. Lett. 2014, 16, 1996-1999. For adociasulfate 1, see: (g) Bogenstatter, M.; Limberg, A.; Overman, L. E.; Tomasi, A. L. J. Am. Chem. Soc. 1999, 121, 12206-12207. For totarol, see: (h) Kim, M.; Shaw, J. T. Org. Lett. 2010, 12, 3324-3327. For oridamycins A and B, see: (i) Trotta, A. H. Org. Lett. 2015, 17, 3358-3361. For SnCl4, see: (a) van Tamelen, E. E.; Willet, J.; Schwartz, M.; Nadeau, R. J. Am. Chem. Soc. 1966, 88, 5937-5938. For FeCl3, see: (b) Sen, S. E.; Roach, S. L.; Smith, S. M.; Zhang, Y.-Z. Tetrahedron Lett. 1998, 39, 3969-3972. (c) Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 9019-9022. For TiCl4, see: (d) Corey, E. J.; Liu, K. J. Am. Chem. Soc. 1997, 119, 9929-9930. For BF3·OEt2, see: (e) van Tamelen, E. E.; Carlson, J. G.; Russell, R. K.; Zawacky, S. R. J. Am. Chem. Soc. 1981, 103, 4615-4616. (f) van Tamelen, E. E.; Leiden, T. M. J. Am. Chem. Soc. 1982, 104, 20612062. (g) Tanis, S. P. J. Org. Chem. 1988, 53, 4929-4938. For zeolites, see: (a) Sen, S. E.; Zhang, Y.-Z.; Roach, S. L. J. Org. Chem. 1996, 61, 9534-9537. (b) Sen, S. E.; Zhang, Y.-Z.; Smith, S. M. J. Org. Chem. 1998, 63, 4459-4465. For radicals, see: (a) Justicia, J.; Rosales, A.; Buñuel, E.; OllerLópez, J. L.; Valdivia, M.; Haïdour, A.; Oltra, J. E.; Barrero, A. F.; Cárdenas, D. J.; Cuerva, J. M. Chem. Eur. J. 2004, 10, 1778-1788. (b) Domingo, V.; Arteaga, J. F.; Perez, J. L. L.; Pelaez, R.; Quilez del Moral, J. F.; Barrero, A. F. J. Org. Chem. 2012, 77, 341-350. (c) Rosales, A.; Foley, L. A. R.; Padial, N. M. Munoz-Bascon, J.; Sancho-Sanz, I.; Roldan-Molina, E.; Pozo-Morales, L.; Irias-Alvarez, A.; Rodríguez-Maecker, R.; Rodriguez-Garcia, I.; Oltra, J. E. Synlett 2016, 27, 369-374. For Bronsted acids, see: (a) Tain, Y.; Xu, X.; Zhang, L.; Qu, J. Org. Lett. 2016, 18, 268-271. (b) Suzuki, K.; Yamakoshi, H.; Nakamura, S. Chem. Eur. J. 2015, 21, 17605-17609. (c) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 3647-3655. (d) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999,
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4.7.2. Phenyl-(5,5,8a-trimethyl-2-phenyl-4a,5,6,7,8,8ahexahydro-4H-chromen-3-yl)methanone (9e). Yield = 85% (153 mg); Colorless solid; mp = 137-138 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H29O2 361.2168, found 361.2170; 1H NMR (400 MHz, CDCl3): δ 7.47-7.44 (m, 2H), 7.20-7.18 (m, 2H), 7.15-7.11 (m, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.03-6.99 (m, 3H), 3.03 (dd, J = 5.2, 17.2 Hz, 1H), 2.12 (d, J = 17.2 Hz, 1H), 2.09 (d, J = 17.2 Hz, 1H), 1.68 (dd, J = 5.2, 12.8 Hz, 2H), 1.64-1.59 (m, 2H), 1.52 (s, 3H), 1.37-1.27 (m, 2H), 1.08 (s, 3H), 0.93 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 198.59, 159.87, 139.59, 135.93, 130.87, 129.56 (2x), 129.13, 129.09 (2x), 127.48 (2x), 127.42 (2x), 111.94, 78.89, 47.85, 41.40, 39.37, 33.41, 32.12, 22.32, 20.44, 19.71, 19.26. Single-crystal X-Ray diagram: crystal of compound 9e was grown by slow diffusion of EtOAc into a solution of compound 9e in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/c, a = 7.6511(6) Å, b = 20.7338(18) Å, c = 12.4531(9) Å, V = 1967.9(3) Å3, Z = 4, dcalcd = 1.217 mg/cm3, F(000) = 776, 2θ range 1.913~26.498o, R indices (all data) R1 = 0.0510, wR2 = 0.1239.
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reaction mixture was stirred at 25 oC for 10 min. The reaction mixture was stirred at 25 oC for 20 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 9.
4.7.3. 1-(5,5,8a-Trimethyl-2-phenyl-4a,5,6,7,8,8ahexahydro-4H-chromen-3-yl)ethanone (9f). Yield = 35% (52 mg); Colorless gum; HRMS (ESI, M++1) calcd for C20H27O2 299.2011, found 299.2010; 1H NMR (400 MHz, CDCl3): δ 7.44-7.34 (m, 5H), 2.77 (dd, J = 5.2, 17.2 Hz, 1H), 1.96 (d, J = 13.2 Hz, 1H), 1.92 (d, J = 13.2 Hz, 1H), 1.66 (s, 3H), 1.57-1.44 (m, 4H), 1.32 (s, 3H), 1.30-1.20 (m, 2H), 1.03 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 200.30, 163.00, 137.14, 129.87, 129.35 (2x), 128.36 (2x), 115.22, 79.50, 47.79, 41.36, 39.39, 33.44, 32.09, 30.34, 20.84, 20.41, 19.71, 19.09. 4.7.4. Phenyl-(2,5,5,8a-tetramethyl-4a,5,6,7,8,8ahexahydro-4H-chromen-3-yl)methanone (9g). Yield = 40% (60 mg); Colorless gum; HRMS (ESI, M++1) calcd for C20H27O2 299.2011, found 299.2008; 1H NMR (400 MHz,
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(h) Lu, Q.; Zhang, J.; Zhao, G.; Qi, Y.; Wang, H.; Lei, W. J. Am. Chem. Soc. 2013, 135, 11481-11484. (i) Handa, S.; Fennewald, J. C.; Lipshutz, B. H. Angew. Chem. Int. Ed. 2014, 53, 3432-3435. (j) Tang, X.; Huang, L.; Xu, Y.; Yang, J.; Wu, W.; Jiang, H. Angew. Chem., Int. Ed. 2014, 53, 4205-4208. (k) Chawla, R.; Singh, A. K.; Yadav, L. D. S. Eur. J. Org. Chem. 2014, 10, 2032-2036. (l) Singh, A. K.; Chawla, R.; Yadav, L. D. S. Tetrahedron Lett. 2014, 55, 4742-4746. (m) Shi, X.; Ren, X.; Ren, Z.; Li, J.; Wang, Y.; Yang, S.; Gu, J.; Gao, Q.; Huang, G. Eur. J. Org. Chem. 2014, 10, 5083-5088. (n) Xuan, J.; Feng, Z.-J.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J. Chem. Eur. J. 2014, 20, 3045-3049. (o) Singh, A. K.; Chawla, A. K.; Chawla, R.; Keshari, T.; Yadav, V. K.; Yadav, L. D. S. Org. Biomol. Chem. 2014, 12, 8550-8554. (p) Saraiva, M. T.; Costa, G. P.; Seus, N.; Schumacher, R. F.; Perin, G.; Paixao, M. W.; Luque, R.; Alves, D. Org. Lett. 2015, 17, 6206-6209. (q) Yadav, V. K.; Srivastava, V. P.; Yadav, L. D. Synlett 2016, 27, 427-431. Sn(OTf)2-mediated annulations, see: (a) Smith, A. G.; Slade, M. C.; Johnson, J. S. Org. Lett. 2011, 13, 1996-1999. (b) Kranz, D. P.; Meierzu, G. A.; El Sheikh, S.; Neudrfl, J. M.; Schmalz, H. G. Eur. J. Org. Chem. 2011, 15, 2860-2866. (c) Goldberg, A. F. G.; O’Connor, N. R.; Craig, R. A. II; Stoltz, B. M. Org. Lett. 2012, 14, 5314-5317. Sn(OTf)2-mediated aldol reaction, see: Kobayashi, S.; Hachiya, I. J. Org. Chem. 1992, 57, 1324-1326. Sn(OTf)2-mediated Mannish-type reactions, see: (a) Kulkarni, N. A.; Chen, K. Tetrahedron Lett. 2006, 47, 611-613. (b) Yang, Y.; Phillips, D. P.; Pan, S. Tetrahedron Lett. 2011, 52, 1549-1552. Sn(OTf)2-mediated rearrangements, see: (a) Xu, G.-C.; Ma, M.; Liu, L.-P.; Shi, M. Synlett 2005, 1869-1872. (b) Lambert, T. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 13646-13647. CCDC 1472669 (5d), 1472670 (5g), 1472671 (5h), 1479881 (6b), 1472672 (6c), 1472673 (6d), 1472674 (6e) and 1473357 (9e) contain the supplementary crystallographic data for this paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033; email: [email protected]).
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121, 4906-4907. (e) van Tamelen, E. E.; Hwu, J. R. J. Am. Chem. Soc. 1983, 105, 2490-2491. For a review on the biosynthetic cyclization of polyprenoids, see: Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. Rev. 1993, 93, 21892206. (a) Li, H.; Sun, Y.; Zhang, Q.; Zhu, Y.; Li, S.-M.; Li, A.; Zhang, C. Org. Lett. 2015, 17, 306-309. (b) Tanaka, H.; Noguchi, H.; Abe, I. Org. Lett. 2005, 7, 5873-5876. For the synthesis of ambrox, see: (a) Zoretic, P. A.; Fang, H.; Ribeiro, A. A. J. Org. Chem. 1998, 63, 4779-4785. (b) Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.; Ramos, J. M.; Salido, S. J. Org. Chem. 1996, 61, 2215-2218. (c) Snowden, R. L.; Eichenberger, J. C.; Linder, S. M.; Sonnay, P.; Vial, C.; Schulte-Elte, K. H. J. Org. Chem. 1992, 57, 955-960. For metal triflate mediated synthesis by the authors, for Sc(OTf)3, see: (a) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K.; Huang, G. G. Tetrahedron 2015, 71, 2095-2104. For In(OTf)3, see: (b) Chang, M.Y.; Lu, Y.-J.; Cheng, Y.-C. Tetrahedron 2015, 71, 6840-6845. For Fe(OTf)3, see: (c) Chang, M.-Y.; Chen, Y.-H.; Cheng, Y.-C. Tetrahedron 2016, 72, 518-524. For Bi(OTf)3, see: (d) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2015, 17, 1264-1267. (e) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2015, 17, 3142-3145. (f) Chang, M.-Y.; Cheng, Y.-C. Org. Lett. 2015, 17, 5702-5705. For synthetic applications on β-ketosulfones by the authors, for (E)styrylsulfones, see: (a) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Synlett 2014, 25, 1739-1744. For vinylcyclopropanes, see: (b) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Tetrahedron 2014, 70, 8908-8913. For 2,5-diaryltetrahydrofurans, see: (c) Chang, M.-Y.; Cheng, Y.-C. Synlett 2016, 27, 854-858. For 2,6-diaryltetrahydropyrans, see: (d) Chang, M.-Y.; Lu, Y.-J.; Cheng, Y.-C. Tetrahedron 2015, 71, 11921201. For 2-arylpyrroles, see: (e) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2014, 16, 6252-6255. For 2-vinylfurans, see: (f) Chan, C.-K.; Lu, Y.-J.; Chang, M.-Y. Tetrahedron 2015, 71, 95449549. For tetralins and benzosuberans, see: (g) Chang, M.-Y.; Cheng, Y.-C. Org. Lett. 2016, 18, 608-611. For phenanthrenes, see: (h) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Tetrahedron 2015, 71, 782791. For phenanthrofurans, see: (i) Chan, C.-K.; Chen, Y.-C.; Chen, Y.-L.; Chang, M.-Y. Tetrahedron 2015, 71, 9187-9195. For recent synthesis of β-ketosulfones, see: (a) Zhou, G.; Ting, P. T.; Aslanian, R. G. Tetrahedron Lett. 2010, 51, 939-941. (b) Pospisil, J.; Sato, H.; J. Org. Chem. 2011, 76, 2269-2272. (c) Kumar, A.; Muthyala, M. K. Tetrahedron Lett. 2011, 52, 5368-5370. (d) Tsui, G. C.; Glenadel, Q.; Lau, C.; Lautens, M. Org. Lett. 2011, 13, 208-211. (e) Kumar, R.; Namboothiri, I. N. N. Org. Lett. 2011, 13, 4016-4019. (f) Sreedhar, B.; Rawat, V. S. Synlett 2012, 23, 413-417. (g) Bouhlel, A.; Curti, C.; Tabele, C.; Vanelle, P. Molecules 2013, 18, 4293-4307.
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Supplementary Material Experimental procedure and scanned photocopies of NMR (CDCl3) spectral data were supported.
S0040-4020(16)30632-9
DOI:
10.1016/j.tet.2016.07.009
Reference:
TET 27905
To appear in:
Tetrahedron
Received Date: 17 May 2016 Revised Date:
29 June 2016
Accepted Date: 2 July 2016
Please cite this article as: Chan C-K, Chen Y-H, Chang M-Y, Tin triflate promoted synthesis of bicyclic and tricyclic sulfonyl dihydropyrans, Tetrahedron (2016), doi: 10.1016/j.tet.2016.07.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Tin Triflate Promoted Synthesis of Bicyclic and Tricyclic Sulfonyl Dihydropyrans Chieh-Kai Chan, Yu-Hsin Chen and Meng-Yang Chang*
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan Me R S Me O
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Tin Triflate Promoted Synthesis of Bicyclic and Tricyclic Sulfonyl Dihydropyrans Chieh-Kai Chan, Yu-Hsin Chen and Meng-Yang Chang*
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Abstract—Tin triflate-promoted one-pot intramolecular annulation of α-geranyl or α-farnesyl β-ketosulfones 3-4 affords the respective bicyclic or tricyclic sulfonyl dihydropyrans 5-6 in moderate to good yields via a cascade cation-olefin-carbonyl carbocyclization process. The starting materials 3 and 4 were obtained by K2CO3-mediated α-geranylation or α-farnesylation of β-ketosulfones 1 with bromides 2a or 2b. The structures of the key products were confirmed by X-ray crystallography. On the basis of unique enzyme-templated one-pot cascade intramolecular annulation of polyprenoids,8-9 a recent remarkable biosynthetic route of xiamycin has been demonstrated by Zhang et al.9a Despite extensive studies on LBA (Lewis acid-assisted chiral Bronsted acid; a complex of SnCl4 and BINOL derivative) catalyzed synthesis of Ambrox10 via a hydroxyl group triggered cation-olefin cyclization by Yamamoto et al.,7c-d a cascade process using a 1,3-dicarbonyl synthon-mediated cation-olefin oxycyclization has not yet been reported. Various catalysts have been employed to accelerate the formation of a carbon-carbon bond via a carbocation-like intermediate, as shown in Scheme 2. Our aim is to find an optimal metal triflate (M(OTf)n) as the catalyst to synthesize bicyclic sulfonyl dihydropyrans 5 and tricyclic sulfonyl dihydropyrans 6 (a Ambrox analogue) by the intramolecular bicyclization of α-geranyl β-ketosulfones 3 and tricyclization of α-farnesyl β-ketosulfones 4 via sixmembered chair-like conformations.
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Metal complex-promoted one-pot carbocyclizations of polyolefin have attracted significant attention in the field of synthetic organic chemistry because the tandem approach results in the formation of unique polycycles (e.g., terpenes and steroids) bearing contiguous tertiary and quaternary stereogenic centers and new six-membered rings in a single catalytic pathway.1-2 Representative successful utilizations on the construction of natural molecules have been developed, including MeAlCl2-mediated synthesis of serratenediol,3a germanicol,3b lupeol,3c dammarenediol II,3d erythrodiol;3e Et2AlCl-mediated synthesis of walsucochin B;3f Sc(OTf)3-promoted synthesis of adociasulfate 1;3g InBr3-promoted synthesis of totarol;3h and Mn(OAc)3/Cu(OAc)2-catalyzed synthesis of oridamycins A and B.3i Other methodologies to Lewis acids (e.g., SnCl4,4a FeCl3,4b-c TiCl4,4d BF3·OEt24e-g), zeolites,5 radicals,6 and Bronsted acids7 mediated polycyclization have been documented as well. Scheme 1 illustrates general epoxideolefin-arene carbocyclization.
Scheme 2. Oxygen atom triggered cation-olefin cyclization Yamamoto work
Scheme 1. Epoxide initiated cation-arene carbocyclization epoxide-olefin-arene carbocyclization
O
Me
Me
Me
Ph4PBF3/HFIP7a tetracylization
Me
HO
Me
Me
MeAlCl23b
OMe
Me
Me
O
i-Pr
dicyclization
Me
K2CO3, acetone
Me
Ar
Me
Me
Me
Me O
Me
H
LBA
Me
Me O Me
Me
Ambrox
Me
Me O
Me
S O 1
R K2CO3, acetone
Me
Me
farnesyl bromide (2b)
i-Pr
Me
HO
Ar O S R O
M(OTf)n MeNO2
Me Me
4
O
Me 5 O
3
O
OMe
Me Me
Me
Me
This work
OMe InBr33h
Me O
Me
Me
Me
Me Me
geranyl bromide (2a)
OMe Me
LBA
Me Me
Me
HO
tricyclization
Me
O
O
Me
Me
Me O
Me
Me H Me
Me
O R O Me S Ph M(OTf) n O MeNO2
Ar O
S
R
R O S O Me Ph
Me Me
O Me
6
Me
———
2.
Keywords: Tin Triflate; β-Ketosulfones; Carbocyclization; Dihydropyrans. *Corresponding author. Tel.: +886 7 3121101 ext 2220 e-mail: [email protected]
Results and discussion
Our interest in the utilization of cascade protocols for metal triflate-mediated synthesis of diverse scaffolds has
ACCEPTED MANUSCRIPT Tetrahedron
Table 1. Metal triflates mediated reaction conditions Me
O
Me
S
Me
M(OTf)n
O Ph
O
Me
H
S
Me Me
O O
Me
solvent (5 mL) conditions
Ph
3a
O
Me 5a
AC C
EP
TE D
M AN U
entry catalyst (mol%) solvent temp (oC) time (h) 5a (%)b －c 1 AgOTf (10) MeNO2 25 20 －c 2 Mg(OTf)2 (10) MeNO2 25 20 －c 3 Ni(OTf)2 (10) MeNO2 25 20 4 Cu(OTf)2 (10) MeNO2 25 20 35d 5 Zn(OTf)2 (10) MeNO2 25 20 20d 6 Sn(OTf)2 (10) MeNO2 25 20 85 －c 7 Sm(OTf)3 (10) MeNO2 25 20 －e 8 Ga(OTf)3 (10) MeNO2 25 20 －c 9 La(OTf)3 (10) MeNO2 25 20 －c 10 Gd(OTf)3 (10) MeNO2 25 20 －c 11 Ce(OTf)3 (10) MeNO2 25 20 －c 12 Yb(OTf)3 (10) MeNO2 25 20 13 Fe(OTf)3 (10) MeNO2 25 20 81 14 Sc(OTf)3 (10) MeNO2 25 20 78 15 In(OTf)3 (10) MeNO2 25 20 80 16 Sn(OTf)2 (5) MeNO2 25 20 85 17 Fe(OTf)3 (5) MeNO2 25 20 80 18 Sc(OTf)3 (5) MeNO2 25 20 67 19 In(OTf)3 (5) MeNO2 25 20 68 20 Sn(OTf)2 (5) MeNO2 25 10 70 21 Fe(OTf)3 (5) MeNO2 25 10 52d －e 22 Sn(OTf)2 (5) MeNO2 101 10 23 Sn(OTf)2 (5) EtNO2 25 20 61 24 Sn(OTf)2 (5) CH2Cl2 25 20 36d －e 25 Sn(OTf)2 (5) DMF 25 20 －e 26 Sn(OTf)2 (5) DMSO 25 20 27 SnCl2 (5) MeNO2 25 20 20e 28 TfOH (5) MeNO2 25 20 71 a Reactions were run on 1a (0.5 mmol), solvent (5 mL). b Isolated yields. cNo reaction. d1a was recovered (for entry 4, 43%; for entry 5, 30%; for entry 19, 15%; for entry 21, 35%). eComplex mixture.
To the control one-pot annulation condition (25 oC, MeNO2, 20 h), the use of various commercially available metal triflates was investigated initially for the formation of bicyclic dihydropyran 5a (Table 1, entries 1-15). Among these screened catalysts, which included catalytic amounts (10 mol%) of AgOTf, Mg(OTf)2, Ni(OTf)2, Cu(OTf)2, Zn(OTf)2, Sn(OTf)2, Sm(OTf)3, Ga(OTf)3, La(OTf)3, Gd(OTf)3 Ce(OTf)3, Yb(OTf)3, Fe(OTf)3, Sc(OTf)3, and In(OTf)3, Zn(OTf)2 and Cu(OTf)2 provided low yields (35% and 20%) of 5a along with 43% and 30% yields of 3a, respectively (entries 4-5). As shown in entries 6 and 13-15, Sn(OTf)2, Fe(OTf)3, Sc(OTf)3, and In(OTf)3 provided better yields (85%, 81%, 78%, and 80%) of 5a under the above conditions. For the other shown metal triflates of Table 1 (entries 1-3 and 7-12), 5a was not isolated and the starting material 3a was recovered. After decreasing the catalytic amounts (10 5 mol%) of four reactive metal triflates (entries 16-19), Sn(OTf)2 and Fe(OTf)3 provided better yields (85% and 80%) of 5a than Sc(OTf)3 and In(OTf)3 (67% and 68%). Next, Sn(OTf)2 and Fe(OTf)3 exhibited low yields under a diminishing reaction time (20 10 h), as shown in entries 20-21. With the results in hand, we found that 5 mol% of Sn(OTf)2 belonged to the most reactive and used catalyst compared to other metal triflates derivatives. Furthermore, we studied the factors of temperature and solvent. In entry 22, a complex mixture occurred when elevating the temperature (25 101). After changing the solvents (from MeNO2 to EtNO2, CH2Cl2, DMF, and DMSO), different results were observed. In entry 23, the results showed that EtNO2 provided 5a in a 61% yields. Entry 24 showed that 36% of 5a was observed due to the poor polarity of CH2Cl2. With the involvement of high-polar solvents (DMSO and DMF), a complex mixture was detected (entries 25-26). Other type of tin(II) salt (e.g. SnCl2) was examined. In entry 27, 5a was isolated in only 20% yield. By the involvement of 2 mol% TfOH (entry 28), 71% of 5a was generated. The control experiment pointed out that the real catalyst was the trace amount of TfOH resulted from the hydrolysis of the metal triflates. According to the results, 5 mol% of Sn(OTf)2/MeNO2/rt condition would be an optimal combination for yielding 5a. Aside from the present one-pot carbonyl-triggered cationolefin oxycyclization, Sn(OTf)2 has also been reported as a catalyst for (3+2) annulation,14 aldol reaction,15 Mannishtype reaction,16 and rearrangement.17 Remarkably, only a few examples of Sn(OTf)2-mediated reactions have been performed in comparison with other commercially available tin (II) salts. On the basis of the above reaction conditions, we explored the substrate scope, with the results shown in Table 2. To adjust Ar and R groups of β-ketosulfones 1a-l, α-geranyl 3a-l and α-farnesyl 4a-l (Ar = Ph, 4-FC6H4, 4MeC6H4, 4-MeOC6H4, 4-CF3C6H4, 4-NO2C6H4, 4-PhC6H4, 2-naphthalene; R = Me, Ph, 4-MeC6H4, 4-MeOC6H4) were provided in moderate yields, as shown in entries 1-24. Next, the Sn(OTf)2-mediated intramolecular annulation of 3a-l and 4a-l produced bicyclic or tricyclic dihydropyrans 5 and 6. For the Ar group of 3 and 4, the phenyl ring with a
RI PT
led us to explore novel methodologies.11 As part of our efforts in the synthetic chemistry of β-ketosulfones 1,12-13 we streamlined the metal triflate-mediated one-pot facile synthesis of bicyclic and tricyclic sulfonyl dihydropyrans 5 and 6 via tandem intramolecular annulation of α-geranyl or α-farnesyl β-ketosulfones 3 and 4. According to previous reports,11-12 the starting materials 3 and 4 were obtained via K2CO3-mediated α-geranylation and α-farnesylation of βketosulfones 1 with geranyl bromide (2a) and farnesyl bromide (2b) in acetone at reflux. With this idea in mind, the catalytic amounts of several metal triflates were first examined for the model substrate 3a (R = Me, Ar = Ph), as shown in Table 1.
SC
2
ACCEPTED MANUSCRIPT Tetrahedron
Based on the results, a possible reaction mechanism is shown in Scheme 3. Mechanistically, the sequence initiates with the formation of intermediate A by complexation of a carbonyl motif of 3a with Sn(OTf)2. Deprotonation of A with in situ generated triflate anion gives B. Following the hydrolysis of B with the TfOH, tertiary carbocation C1 is obtained. Based on the six-membered chair conformation (C2), 5a is provided via SnOTf-chelated oxygen atom promoted an intramolecular stereochemical cyclization. Subsequently, Sn(OTf)2 is regenerated by complexation of SnOTf and triflate anion. Scheme 3. Proposed mechanism
Table 2. Synthesis of 5 and 6a-b Me R
S Ar
O O K 2CO3, acetone
Ar
Me
1 Br
3 Me
S
Me
O Me
2b
O
O
R
Ar
O Me
Sn(OTf)2
Ar O
R
O
Me 5
O
Me Me
6
Ph
Me H OTf
O
Me Sn
OTf
A
H
Me
Me
O
Me
B
S
Me H
O
Sn TfO
Ph
Me
O
Me Sn
Me OTf
5a
C2
OTf
TfO
C1
Scheme 4: Sn(OTf)2-mediated reactions of 8 Ph Ar
O
Me
Ph
NaH, 2a THF
Ar
7a, Ar = Ph 7b, Ar = 4-FC6H4
O
Me
O
Ar
O
THF
O NaH, 2a O
Me
MeNO2
8c, Ar = Ph (86%) 8d, Ar = 4-MeOC6H4 (85%)
O
Ph
O
THF
Ph
7e
O
Me
Me
H
Me Me
EtO Ar O Me 9c, Ar = Ph (75%) 9d, Ar = 4-MeOC6H4(ND) O
Sn(OTf)2
Me
Me
O Me 9a, Ar = Ph (ND) 9b, Ar = 4-FC6H4(ND)
Me
Ph
H
Ar
O Sn(OTf)2
Me Ar
7c, Ar = Ph 7d, Ar = 4-MeOC6H4
Ph
MeNO2
Me
NaH, 2a EtO
EtO
Ph
Sn(OTf)2
Me
8a, Ar = Ph (84%) 8b, Ar = 4-FC6H4 (86%)
O
EP
AC C
a The synthesis of 3 or 4 were run on 1 (1.0 mmol), 2a or 2b (1.05 equiv), K2CO3 (2.9 equiv), acetone (10 mL), reflux, 8 h. bThe synthesis of 5 or 6 was run on a 3 or 4 (0.5 mmol), Sn(OTf)2 (10 mg, 0.025 mmol), MeNO2 (5 mL), rt, 20 h. cIsolated yields. d6 was isolated as two isomers (d.r. = 9/1~2/1). eComplex mixture.
Ph
O
Sn(OTf)2
S
O
S
Me
c-d
TE D
1, Ar =, R =; 2a / 2b 3 / 4 (%) 5 / 6 (%) 1a, Ph, Me; 2a 3a, 84 5a, 85 1b, Ph, Ph; 2a 3b, 86 5b, 83 1c, Ph, 4-MeC6H4; 2a 3c, 82 5c, 85 1d, 4-FC6H4, 4-MeC6H4; 2a 3d, 86 5d, 82 1e, 4-MeC6H4, 4-MeC6H4; 2a 3e, 85 5e, 86 5f, －e 1f, 4-MeOC6H4, 4-MeC6H4; 2a 3f, 87 1g, 4-CF3C6H4, 4-MeC6H4; 2a 3g, 82 5g, 83 1h, 4-NO2C6H4, 4-MeC6H4; 2a 3h, 83 5h, 80 1i, 4-PhC6H4, 4-MeC6H4; 2a 3i, 84 5i, 85 1j, 2-naphthalene, 4-MeC6H4; 2a 3j, 86 5j, 83 1k, 4-MeC6H4, Me; 2a 3k, 83 5k, 81 1l, Ph, 4-MeOC6H4; 2a 3l, 85 5l, 18e 1a, Ph, Me; 2b 4a, 82 6a, 81 1b, Ph, Ph; 2b 4b, 83 6b, 81 1c, Ph, 4-MeC6H4; 2b 4c, 83 6c, 85 1d, 4-FC6H4, 4-MeC6H4; 2b 4d, 85 6d, 80 1e, 4-MeC6H4, 4-MeC6H4; 2b 4e, 83 6e, 83 6f, －e 1f, 4-MeOC6H4, 4-MeC6H4; 2b 4f, 86 1g, 4-CF3C6H4, 4-MeC6H4; 2b 4g, 80 6g, 80 1h, 4-NO2C6H4, 4-MeC6H4; 2b 4h, 81 6h, 77 1i, 4-PhC6H4, 4-MeC6H4; 2b 4i, 85 6i, 83 1j, 2-naphthalene, 4-MeC6H4; 2b 4j, 86 6j, 84 1k, 4-MeC6H4, Me; 2b 4k, 85 6k, 80 1l, Ph, 4-MeOC6H4; 2b 4l, 87 6l, <5e
O
Me
O
Me
Me Sn
O
O
Ph
c
Me
Me
Me
O
OTf
Me
Me
O
Ph
H
S
S
H
O
Me
3a
Me H Me
Me O
O
O
Me
Sn(OTf)2
Ph
H
S
Me
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
S
Me
OTf
Me
O
O Ar
Me
Me
O
Me
Me
O
Me MeNO2
MeNO2
H
S
Sn(OTf)2
Me 4
O
R Me
Me O
K 2CO3, acetone
S
Me
O
SC
2a
O
R
Me
M AN U
Br
RI PT
strong electron-withdrawing group (e.g. 4-FC6H4, 3NO2C6H4, or 4-CF3C6H4) provided the desired 5 and 6 in good yields, and the phenyl ring with an electron-neutral substituent (e.g., Ph, 4-MeC6H4, 4-PhC6H4, 2-naphthalene) also provided modest yields. In particular, the phenyl ring with an electron-donating group (for 3f and 4f, Ar = 4MeOC6H4) produced complex results and no 5f and 6f were formed. However, for the Sn(OTf)2-mediated reaction of 3l and 4l (R = 4-MeOC6H4), the desired 5l and 6l were yielded in 18% and trace amounts (<5%). The structures of 5d, 5g, 5h, 6b, 6c, 6d, and 6e were determined by singlecrystal X-ray crystallography.18
3
H
Me Me
Ph
MeNO2
Ph
8e (88%) O
O Me 9e (85%) H
Me Me
Me O
O NaH, 2a
Me Ph 7f
O
THF
Me
Me
Ph Sn(OTf)2
Me Ph
O 8f (84%)
Me
O
MeNO2
O Me 9f (35%) Me H Me
Ph Me
O Me 9g (40%)
Changing the starting substrates 1a-l with the sulfonyl groups (from β-ketosulfone) to compounds 7a-f with the aryl, ester or benzoyl substituents (from deoxybenzoin, βketoester, β-diketone), we studied the alkylation of 7a-f with geranyl bromide (2a) (Scheme 4). With the involvement of NaH, α-geranylation of 7a-f with 2a afforded 8a-f in a range of 84%-88%. During the Sn(OTf)2mediated annulation of 8a-e, only 9c and 9e could be generated as the sole product in 75 and 85% yields,
ACCEPTED MANUSCRIPT Tetrahedron
1472673 (6d) Monoclinic P 21/n 7.0592(3) 26.5040(10) 14.4311(5) 90 101.633(2) 90 4 2653.65(18) 296(2) 1.243 0.158 1064 1.054 0.15×0.11×0.10 1.537 to 26.390 21025 5425(R=0.0477) 0.0694, 0.1923 0.1157, 0.2322
1472674 (6e) Monoclinic P 21/n 6.9224(6) 27.150(2) 14.7171(13) 90 101.813(2) 90 4 2707.4(4) 296(2) 1.209 0.149 1064 1.002 0.10×0.08×0.08 1.500 to 26.415 21590 5568(R=0.0667) 0.0568, 0.1220 0.1230, 0.1487
M AN U
1473357 (9e) Monoclinic P 21/c 7.6511(6) 20.7338(18) 12.4531(9) 90 95.040(3) 90 4 1967.9(3) 100(2) 1.217 0.075 776 1.094 0.20×0.15×0.15 1.913 to 26.498 16774 4051(R=0.0370) 0.0398, 0.1041 0.0510, 0.1239
RF =Σ|Fo-Fc|/ΣFo|; RW (F2) =[ΣW|Fo2-Fc2|2/ΣW Fo4]1/2
4.
Experimental section
EP
a
Conclusion
In summary, we have developed a facile synthetic route of bicyclic or tricyclic sulfonyl dihydropyrans 5 and 6 via (1) K2CO3-mediated α-geranylation or α-farnesylation of βketosulfones 1 with 2a and 2b and (2) tin triflate-promoted intramolecular cation-olefin-carbonyl carbocyclization of α-geranyl or α-farnesyl β-ketosulfones 3-4. The structural frameworks of the key products were confirmed by X-ray crystallography. Further investigation regarding synthetic applications of β-ketosulfones will be conducted and published in due course.
1472672 (6c) Monoclinic P 21/n 7.0561(5) 26.349(2) 14.3583(11) 90 101.571(3) 90 4 2615.3(3) 296(2) 1.216 0.153 1032 1.035 0.20×0.10×0.10 1.546 to 26.411 18844 5362(R=0.0431) 0.0583, 0.1649 0.0949, 0.2022
TE D
Table 3. Crystal data for compounds 6b-e and 9e CCDC number 1479881 (6b) Crystal system Orthorhombic Space group P 21 21 21 a (Å) 6.2765(3) b (Å) 14.2655(7) c (Å) 27.0870(14) α (°) 90 90 β (°) 90 γ (°) Z 4 Volume (Å3) 2425.3(2) Temperature (K) 100(2) 1.272 Dcalcd (Mg/m3) Absorption coefficient (mm-1) 0.163 F(000) 1000 GOF 1.135 Crystal size (mm3) 0.30×0.25×0.21 θ range for data collection (°) 1.504 to 26.390 Reflections collected 19914 Independent reflections 4959(R=0.0404) 0.0355, 0.0891 RF, Rw (F2) (I > 2σ(I))a RF, Rw (F2) (all data)a 0.0414, 0.1045
3.
RI PT
respectively. The structure of 9e was determined by singlecrystal X-ray crystallography.18 As shown in Table 3, the single crystal X-ray diffraction analyses were employed to prove the constitution and relative configuration. For the annulation of 8a and 8b, no desired 9a and 9b were observed and a complex mixture was isolated in major products. Moreover, 9d with an electron-donating substituent (Ar = 4-MeOC6H4) provided a complex mixture. For the Sn(OTf)2-mediated annulation of 8f having an unsymmetrical dione group, two isomers 9f and 9g were produced in 35% and 40% yields, respectively. For the non-sulfonyl groups, the one-pot route also performed well.
SC
4
AC C
4.1. General. All other reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Melting points were determined with a SMP3 melting apparatus. 1H and 13C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 400 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the coupling constants (J) are given in Hertz. High resolution mass spectra (HRMS) were measured with a mass spectrometer Finnigan/Thermo Quest MAT 95XL. X-ray crystal structures were obtained with an Enraf-Nonius FR590 diffractometer (CAD4, Kappa CCD).
4.2. A representative synthetic procedure of skeleton 3 is as follows: K2CO3 (400 mg, 2.9 mmol) was added to a solution of β-ketosulfones 1 (1.0 mmol) in acetone (10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. Geranyl bromide 2a (227 mg, 1.05 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at reflux for 8 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 3. 4.2.1. 2-Methanesulfonyl-5,9-dimethyl-1-phenyldeca-4,8dien-1-one (3a). Yield = 84% (281 mg); Colorless gum; HRMS (ESI, M++1) calcd for C19H27O3S 335.1681, found 335.1685; 1H NMR (400 MHz, CDCl3): δ 7.97-7.94 (m, 2H), 7.62-7.57 (m, 1H), 7.49-7.45 (m, 2H), 4.96 (t, J = 7.2 Hz, 1H), 4.88-4.85 (m, 2H), 3.03-2.95 (m, 1H), 2.98 (s, 3H),
ACCEPTED MANUSCRIPT Tetrahedron
4.2.7. 5,9-Dimethyl-2-(toluene-4-sulfonyl)-1-(4trifluoromethylphenyl)deca-4,8-dien-1-one (3g). Yield = 82% (392 mg); Colorless gum; HRMS (ESI, M++1) calcd for C26H30F3O3S 479.1868, found 479.1865; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 5.10-5.05 (m, 1H), 4.87 (t, J = 6.8 Hz, 1H), 4.82 (t, J = 6.0 Hz, 1H), 2.86-2.75 (m, 2H), 2.37 (s, 3H), 1.90-1.76 (m, 4H), 1.53 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.88, 145.47, 140.24, 139.84, 134.59 (q, J = 32.6 Hz), 133.34, 129.51 (4x), 129.08 (2x), 125.53 (d, J = 3.0 Hz, 2x), 125.51 (d, J = 3.0 Hz, 2x), 123.36, 116.97, 69.83, 39.27, 26.88, 26.03, 25.24, 31.40, 17.32, 15.88.
M AN U
4.2.3. 5,9-Dimethyl-1-phenyl-2-(toluene-4-sulfonyl)deca4,8-dien-1-one (3c). Yield = 82% (336 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H31O3S 411.1994, found 411.2002; 1H NMR (400 MHz, CDCl3): δ 7.88-7.86 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.54-7.50 (m, 1H), 7.42-7.37 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.05 (dd, J = 6.4, 8.8 Hz, 1H), 4.89-4.82 (m, 2H), 2.81-2.77 (m, 2H), 2.36 (s, 3H), 1.83-1.77 (m, 4H), 1.52 (s, 3H), 1.48 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.43, 145.07, 139.75, 137.17, 133.55, 131.24, 129.45 (2x), 129.33 (3x), 128.62 (2x), 128.43 (2x), 123.44, 117.22, 69.31, 39.22, 26.92, 26.00, 25.28, 21.41, 17.34, 15.86.
RI PT
4.2.2. 2-Benzenesulfonyl-5,9-dimethyl-1-phenyldeca-4,8dien-1-one (3b). Yield = 86% (341 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H29O3S 397.1837, found 397.1833; 1H NMR (400 MHz, CDCl3): δ 7.90-7.87 (m, 2H), 7.82-7.79 (m, 2H), 7.64-7.60 (m, 1H), 7.58-7.54 (m, 1H), 7.52-7.48 (m, 2H), 7.46-7.41 (m, 2H), 5.05 (dd, J = 6.4, 8.4 Hz, 1H), 4.91-4.84 (m, 2H), 2.82-2.78 (m, 2H), 1.88-1.80 (m, 4H), 1.54 (br d, J = 0.8 Hz, 3H), 1.51 (s, 3H), 1.45 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 192.47, 140.11, 137.26, 136.66, 134.10, 133.78, 131.50, 129.63 (2x), 128.82 (2x), 128.76 (2x), 128.63 (2x), 123.56, 117.22, 69.49, 39.39, 27.07, 26.17, 25.43, 17.49, 16.02.
4.2.6. 1-(4-Methoxyphenyl)-5,9-dimethyl-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3f). Yield = 87% (383 mg); Colorless gum; HRMS (ESI, M++1) calcd for C26H33O4S 441.2100, found 441.2105; 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 9.2 Hz, 2H), 4.97 (dd, J = 4.4, 10.0 Hz, 1H), 4.89-4.85 (m, 2H), 3.86 (s, 3H), 2.78-2.72 (m, 2H), 2.42 (s, 3H), 1.88-1.80 (m, 4H), 1.54 (s, 3H), 1.52 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.55, 164.14, 145.11, 139.74, 133.60, 131.45, 131.39 (2x), 130.41, 129.70 (2x), 129.41 (2x), 123.65, 117.56, 113.84 (2x), 69.29, 55.51, 39.41, 27.11, 26.22, 25.45, 21.63, 17.51, 16.04.
SC
2.91-2.85 (m, 1H), 1.89-1.81 (m, 4H), 1.61 (s, 3H), 1.53 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 194.04, 140.39, 136.83, 134.15, 131.50, 128.89 (2x), 128.74 (2x), 123.45, 116.90, 68.41, 39.33, 37.54, 27.82, 26.11, 25.41, 17.46, 16.02.
5
AC C
EP
TE D
4.2.4. 1-(4-Fluorophenyl)-5,9-dimethyl-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3d). Yield = 86% (368 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H30FO3S 429.1900, found 429.1902; 1H NMR (400 MHz, CDCl3): δ 7.97-7.92 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.14-7.09 (m, 2H), 4.98 (dd, J = 5.2, 9.2 Hz, 1H), 4.88-4.84 (m, 2H), 2.78-2.74 (m, 2H), 2.41 (s, 3H), 1.88-1.80 (m, 4H), 1.53 (s, 3H), 1.51 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.94, 166.09 (d, J = 254.7 Hz), 145.35, 140.08, 133.77 (d, J = 3.0 Hz), 133.40, 131.65 (d, J = 9.8 Hz, 2x), 131.49, 129.64 (2x), 129.49 (2x), 123.51, 117.22, 115.79 (d, J = 22.0 Hz, 2x), 69.61, 39.36, 27.09, 26.16, 25.41, 21.60, 17.47, 16.01. 4.2.5. 5,9-Dimethyl-2-(toluene-4-sulfonyl)-1-p-tolyldeca4,8-dien-1-one (3e). Yield = 85% (361 mg); Colorless solid; mp = 75-76 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C26H33O3S 425.2150, found 425.2153; 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.01 (dd, J = 5.2, 9.2 Hz, 1H), 4.89-4.84 (m, 2H), 2.78-2.74 (m, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 1.871.79 (m, 4H), 1.54 (s, 3H), 1.51 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.95, 145.10, 144.80, 139.76, 134.85, 133.57, 131.37, 129.62 (2x), 129.38 (2x), 129.26 (2x), 129.04, 128.96 (2x), 123.57, 117.40, 69.34, 39.34, 27.07, 26.14, 25.37, 21.56, 17.43, 15.97.
4.2.8. 5,9-Dimethyl-1-(4-nitrophenyl)-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3h). Yield = 83% (378 mg); Colorless solid; mp = 74-76 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H30NO5S 456.1845, found 456.1852; 1H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.03 (t, J = 6.8 Hz, 1H), 4.87-4.82 (m, 2H), 2.76 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 1.85-1.80 (m, 4H), 1.53 (d, J = 0.8 Hz, 3H), 1.49 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.67, 150.39, 145.73, 141.62, 140.61, 133.09, 131.57, 129.85 (2x), 129.66 (2x), 129.61 (2x), 123.76 (2x), 123.38, 116.78, 70.31, 39.33, 27.11, 26.14, 25.41, 21.63, 17.46, 16.02. 4.2.9. 1-Biphenyl-4-yl-5,9-dimethyl-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3i). Yield = 84% (408 mg); Colorless gum; HRMS (ESI, M++1) calcd for C31H35O3S 487.2307, found 487.2311; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.8 Hz, 2H), 7.71-7.66 (m, 4H), 7.62-7.59 (m, 2H), 7.50-7.40 (m, 3H), 7.32 (d, J = 8.4 Hz, 2H), 5.08 (dd, J = 4.8, 8.8 Hz, 1H), 4.94-4.86 (m, 2H), 2.83-2.78 (m, 2H), 2.43 (s, 3H), 1.89-1.82 (m, 4H), 1.58 (s, 3H), 1.51 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.02, 146.50, 145.25, 139.98, 139.55, 136.01, 133.57, 131.50, 129.74 (2x), 129.52 (2x), 129.49 (2x), 128.95 (2x), 128.40, 127.27 (2x), 127.24 (2x), 123.60, 117.44, 69.65, 39.42, 27.14, 26.20, 25.43, 21.65, 17.52, 16.07. 4.2.10. 5,9-Dimethyl-1-naphthalen-2-yl-2-(toluene-4sulfonyl)deca-4,8-dien-1-one (3j). Yield = 86% (396 mg); Colorless gum; HRMS (ESI, M++1) calcd for C29H33O3S 461.2150, found 461.2155; 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 1.2 Hz, 1H), 7.96-7.93 (m, 2H), 7.86-7.83 (m,
ACCEPTED MANUSCRIPT Tetrahedron
4.2.11. 2-Methanesulfonyl-5,9-dimethyl-1-p-tolyl-deca-4,8dien-1-one (3k). Yield = 83% (289 mg); Colorless gum; HRMS (ESI, M++1) calcd for C20H29O3S 349.1837, found 349.1840; 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.95 (t, J = 7.2 Hz, 1H), 4.84 (dd, J = 3.6, 11.2 Hz, 2H), 3.01-2.93 (m, 1H), 2.96 (s, 3H), 2.89-2.83 (m, 1H), 2.37 (s, 3H), 1.87-1.80 (m, 1H), 1.83 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 193.34, 145.29, 140.15, 134.34, 131.36, 129.40 (2x), 129.03 (2x), 123.47, 116.99, 68.17, 39.29, 37.50, 27.71, 26.07, 25.33, 21.51, 17.37, 15.95.
4.3.2. 2-Benzenesulfonyl-5,9,13-trimethyl-1phenyltetradeca-4,8,12-trien-1-one (4b). Yield = 83% (385 mg); Colorless gum; HRMS (ESI, M++1) calcd for C29H37O3S 465.2463, found 465.2462; 1H NMR (400 MHz, CDCl3): δ 7.89-7.87 (m, 2H), 7.82-7.79 (m, 2H), 7.63-7.41 (m, 6H), 5.08-4.99 (m, 2H), 4.90 (br t, J = 6.4 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H), 1.99-1.94 (m, 2H), 1.88-1.80 (m, 6H), 1.65 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.43, 140.15, 137.22, 136.62, 135.10, 134.07, 133.76, 131.09, 129.59 (2x), 128.79 (2x), 128.72 (2x), 128.59 (2x), 124.18, 123.45, 117.16, 69.42, 39.45, 39.39, 27.03, 26.55, 26.14, 25.59, 17.56, 16.02, 15.76. 4.3.3. 5,9,13-Trimethyl-1-phenyl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4c). Yield = 83% (397 mg); Colorless gum; HRMS (ESI, M++1) calcd for C30H39O3S 479.2620, found 479.2624; 1H NMR (400 MHz, CDCl3): δ 7.91-7.88 (m, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.597.55 (m, 1H), 7.47-7.42 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H), 5.05-5.00 (m, 2H), 4.90-4.87 (m, 2H), 2.80-2.75 (m, 2H), 2.42 (s, 3H), 1.99-1.94 (m, 2H), 1.89-1.81 (m, 6H), 1.66 (d, J = 1.2 Hz, 3H), 1.56 (s, 3H), 1.55 (d, J = 0.8 Hz, 3H), 1.46 (d, J = 0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 192.67, 145.25, 140.14, 137.38, 135.20, 133.75, 133.60, 131.22, 129.74 (2x), 129.49 (2x), 128.86 (2x), 128.64 (2x), 124.26, 123.54, 117.32, 69.62, 39.53, 39.47, 27.19, 26.63, 26.24, 25.66, 21.66, 17.64, 16.11, 15.83.
TE D
M AN U
4.2.12. 2-(4-Methoxybenzenesulfonyl)-5,9-dimethyl-1phenyl-deca-4,8-dien-1-one (3l). Yield = 85% (362 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H31O4S 427.1943, found 427.1940; 1H NMR (400 MHz, CDCl3): δ 7.90-7.87 (m, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.56-7.52 (m, 1H), 7.44-7.40 (m, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.04 (dd, J = 6.4, 8.4 Hz, 1H), 4.90-4.83 (m, 2H), 3.82 (s, 3H), 2.79-2.75 (m, 2H), 1.86-1.79 (m, 4H), 1.54 (s, 3H), 1.49 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.72, 163.99, 139.83, 137.28, 133.64, 131.76 (2x), 131.37, 128.71 (2x), 128.53 (2x), 127.90, 123.51, 117.30, 113.96 (2x), 69.47, 55.53, 39.31, 27.09, 26.09, 25.36, 17.43, 15.96.
124.16, 123.39, 116.88, 68.46, 39.47, 39.39, 37.54, 27.86, 26.55, 26.15, 25.58, 17.57, 16.08, 15.76.
RI PT
2H), 7.70 (d, J = 8.4 Hz, 2H), 7.61-7.52 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.23 (dd, J = 6.0, 8.8 Hz, 1H), 4.97-4.93 (m, 1H), 4.84-4.81 (m, 1H), 2.90-2.86 (m, 2H), 2.33 (s, 3H), 1.85-1.79 (m, 4H), 1.59 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 192.34, 145.19, 139.93, 135.64, 134.60, 133.58, 132.15, 131.36, 131.22, 129.75, 129.61 (2x), 129.41 (2x), 128.94, 128.49, 127.58, 126.84, 123.80, 123.48, 117.40, 69.62, 39.34, 27.05, 26.13, 25.29, 21.46, 17.37, 16.04.
SC
6
AC C
EP
4.3. A representative synthetic procedure of skeleton 4 is as follows: K2CO3 (400 mg, 2.9 mmol) was added to a solution of β-ketosulfones 1 (1.0 mmol) in acetone (10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. Farnesyl bromide 2b (298 mg, 1.05 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at reflux for 8 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 4.
4.3.1. 2-Methanesulfonyl-5,9,13-trimethyl-1-phenyltetradeca-4,8,12-trien-1-one (4a). Yield = 82% (330 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H35O3S 403.2307, found 403.2310; 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.4 Hz, 2H), 7.63-7.58 (m, 1H), 7.50-7.46 (m, 2H), 5.05-4.90 (m, 3H), 4.86 (dd, J = 3.6, 10.8 Hz, 1H), 3.072.86 (m, 2H), 2.99 (s, 3H), 2.03-1.95 (m, 2H), 1.92-1.81 (m, 3H), 1.86 (s, 3H), 1.66 (s, 3H), 1.62 (s, 3H), 1.57 (s, 3H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 194.07, 140.53, 136.86, 135.20, 134.16, 131.13, 128.91 (2x), 128.77 (2x),
4.3.4. 1-(4-Fluorophenyl)-5,9,13-trimethyl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4d). Yield = 85% (422 mg); Colorless gum; HRMS (ESI, M++1) calcd for C30H38FO3S 497.2526, found 497.2530; 1H NMR (400 MHz, CDCl3): δ 7.98-7.93 (m, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.13-7.08 (m, 2H), 5.03-4.97 (m, 2H), 4.89-4.85 (m, 2H), 2.78-2.74 (m, 2H), 2.41 (s, 3H), 1.98-1.93 (m, 2H), 1.88-1.79 (m, 6H), 1.65 (d, J = 0.8 Hz, 3H), 1.55 (s, 3H), 1.54 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.89, 166.06 (d, J = 255.5 Hz), 145.30, 140.11, 135.11, 133.73 (d, J = 3.0 Hz), 133.41, 131.63 (d, J = 9.9 Hz, 2x), 131.13, 129.62 (2x), 129.47 (2x), 124.14, 123.40, 117.20, 115.76 (d, J = 21.9 Hz, 2x), 69.58, 39.46, 39.36, 27.05, 26.54, 26.11, 25.56, 21.56, 17.54, 16.02, 15.73. 4.3.5. 5,9,13-Trimethyl-2-(toluene-4-sulfonyl)-1-p-tolyltetradeca-4,8,12-trien-1-one (4e). Yield = 83% (409 mg); Colorless gum; HRMS (ESI, M++1) calcd for C31H41O3S 493.2776, found 493.2780; 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.03-4.99 (m, 2H), 4.90-4.86 (m, 2H), 2.78-2.74 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 1.99-1.94 (m, 2H), 1.88-1.80 (m, 6H), 1.65 (d, J = 1.2 Hz, 3H), 1.57 (s, 3H), 1.55 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.96, 145.10, 144.81, 139.88, 135.07, 134.88, 133.60, 131.12, 129.66 (2x), 129.40 (2x), 129.29 (2x), 129.09, 128.99 (2x), 124.20, 123.53, 117.40, 69.40, 39.46, 39.40, 27.11, 26.58, 26.16, 25.61, 21.60, 17.58, 16.05, 15.75.
ACCEPTED MANUSCRIPT Tetrahedron
7
mg); Colorless gum; HRMS (ESI, M++1) calcd for C34H41O3S 529.2776, found 529.2772; 1H NMR (400 MHz, CDCl3): δ 8.40 (br s, 1H), 7.95 (dt, J = 2.0, 8.4 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.62 (dt, J = 1.2, 8.4 Hz, 1H), 7.56 (dt, J = 1.2, 8.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 5.20 (dd, J = 4.8, 10.0 Hz, 1H), 4.96-4.92 (m, 2H), 4.87-4.85 (m, 1H), 2.88-2.83 (m, 2H), 2.37 (s, 3H), 1.93-1.68 (m, 8H), 1.63 (d, J = 0.8 Hz, 3H), 1.59 (s, 3H), 1.53 (s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.42, 145.28, 140.14, 135.76, 135.15, 134.69, 133.59, 132.25, 131.33, 131.14, 129.88, 129.75 (2x), 129.49 (2x), 129.03, 128.59, 127.70, 126.93, 124.21, 123.92, 123.49, 117.41, 69.75, 39.47, 39.45, 27.16, 26.56, 26.22, 25.64, 21.60, 17.60, 16.18, 15.74.
4.3.7. 5,9,13-Trimethyl-2-(toluene-4-sulfonyl)-1-(4trifluoromethylphenyl)tetradeca-4,8,12-trien-1-one (4g). Yield = 80% (437 mg); Colorless gum; HRMS (ESI, M++1) calcd for C31H38F3O3S 547.2494, found 547.2490; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.04-4.98 (m, 2H), 4.88-4.85 (m, 2H), 2.81-2.77 (m, 2H), 2.43 (s, 3H), 1.99-1.93 (m, 2H), 1.90-1.79 (m, 6H), 1.65 (s, 3H), 1.56 (br s, 6H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.97, 145.58, 140.53, 139.92, 135.27, 134.98, 133.29, 131.25, 129.67 (4x), 129.62 (2x), 129.17 (2x), 125.68 (q, J = 3.8 Hz), 124.13, 123.39, 116.98, 70.08, 39.50, 39.42, 27.03, 26.58, 26.17, 25.60, 21.61, 17.59, 16.09, 15.78.
4.3.11. 2-Methanesulfonyl-5,9,13-trimethyl-1-p-tolyltetradeca-4,8,12-trien-1-one (4k). Yield = 85% (354 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H37O3S 417.2463, found 417.2466; 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.04-4.82 (m, 4H), 3.02-2.84 (m, 2H), 2.97 (s, 3H), 2.38 (s, 3H), 2.021.92 (m, 2H), 1.90-1.81 (m, 6H), 1.65 (d, J = 1.2 Hz, 3H), 1.62 (s, 3H), 1.56 (s, 3H), 1.46 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 193.34, 145.31, 140.27, 135.07, 134.37, 131.05, 129.43 (2x), 129.06 (2x), 124.12, 123.40, 116.99, 68.22, 39.41, 39.34, 37.49, 27.73, 26.51, 26.08, 25.54, 21.55, 17.52, 16.02, 15.67.
M AN U
SC
RI PT
4.3.6. 1-(4-Methoxyphenyl)-5,9,13-trimethyl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4f). Yield = 86% (437 mg); Colorless gum; HRMS (ESI, M++1) calcd for C31H41O4S 509.2726, found 509.2730; 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.03-4.95 (m, 2H), 4.90-4.86 (m, 2H), 3.83 (s, 3H), 2.78-2.73 (m, 2H), 2.40 (s, 3H), 1.98-1.93 (m, 2H), 1.88-1.80 (m, 6H), 1.64 (s, 3H), 1.55 (s, 3H), 1.45 (s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 190.44, 164.05, 145.03, 139.71, 134.99, 133.57, 131.30 (2x), 131.06, 130.30, 129.59 (2x), 129.34 (2x), 124.15, 123.49, 117.46, 113.76 (2x), 69.16, 55.40, 39.43, 39.36, 27.00, 26.52, 26.12, 25.55, 21.53, 17.53, 16.00, 15.73.
EP
TE D
4.3.8. 5,9,13-Trimethyl-1-(4-nitrophenyl)-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4h). Yield = 81% (424 mg); Colorless gum; HRMS (ESI, M++1) calcd for C30H38NO5S 524.2471, found 524.2475; 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 5.02 (t, J = 7.6 Hz, 1H), 5.00-4.96 (m, 1H), 4.87-4.84 (m, 2H), 2.77 (t, J = 7.6 Hz, 2H), 2.44 (s, 3H), 1.96-1.77 (m, 8H), 1.64 (s, 3H), 1.54 (br s, 6H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.64, 150.41, 145.75, 141.60, 140.69, 135.29, 133.07, 131.30, 129.87 (2x), 129.68 (2x), 129.63 (2x), 124.04, 123.78 (2x), 123.26, 116.77, 70.34, 39.48, 39.37, 27.12, 26.54, 26.09, 25.57, 21.66, 17.57, 16.07, 15.80.
AC C
4.3.9. 1-Biphenyl-4-yl-5,9,13-trimethyl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4i). Yield = 85% (471 mg); Colorless gum; HRMS (ESI, M++1) calcd for C36H43O3S 555.2933, found 555.2930; 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz, 2H), 7.71-7.66 (m, 4H), 7.637.60 (m, 2H), 7.50-7.46 (m, 2H), 7.44-7.39 (m, 1H), 7.32 (d, J = 8.4 Hz, 2H), 5.09 (dd, J = 5.2, 9.2 Hz, 1H), 5.03-4.98 (m, 1H), 4.95-4.92 (m, 2H), 2.84-2.80 (m, 2H), 2.43 (s, 3H), 2.02-1.77 (m, 8H), 1.64 (d, J = 0.8 Hz, 3H), 1.59 (s, 3H), 1.56 (s, 3H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 191.99, 146.45, 145.24, 140.04, 139.50, 135.98, 135.13, 133.54, 131.16, 129.71 (2x), 129.50 (2x), 129.48 (2x), 128.93 (2x), 128.39, 127.24 (2x), 127.22 (2x), 124.20, 123.51, 117.37, 69.60, 39.47, 39.44, 27.11, 26.58, 26.19, 25.60, 21.63, 17.60, 16.11, 15.80. 4.3.10. 5,9,13-Trimethyl-1-naphthalen-2-yl-2-(toluene-4sulfonyl)tetradeca-4,8,12-trien-1-one (4j). Yield = 86% (454
4.3.12. 2-(4-Methoxybenzenesulfonyl)-5,9,13-trimethyl-1phenyltetradeca-4,8,12-trien-1-one (4l). Yield = 87% (430 mg); Colorless gum; HRMS (ESI, M++1) calcd for C30H39O4S 495.2569, found 495.2570; 1H NMR (400 MHz, CDCl3): δ 7.91-7.89 (m, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.597.55 (m, 1H), 7.47-7.43 (m, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.05-5.00 (m, 2H), 4.91-4.88 (m, 2H), 3.87 (s, 3H), 2.79-2.74 (m, 2H), 1.99-1.94 (m, 2H), 1.89-1.81 (m, 6H), 1.66 (d, J = 0.8 Hz, 3H), 1.57 (s, 3H), 1.56 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 192.87, 164.11, 140.10, 137.42, 135.20, 133.76, 131.95 (2x), 131.24, 128.87 (2x), 128.65 (2x), 127.99, 124.26, 123.55, 117.35, 114.05 (2x), 69.68, 55.64, 39.54, 39.49, 27.27, 26.64, 26.26, 25.67, 17.65, 16.13, 15.84. 4.4. A representative synthetic procedure of skeleton 5 is as follows: Sn(OTf)2 (10 mg, 0.025 mmol) was added to a solution of 3 (0.5 mmol) in MeNO2 (5 mL) at 25 oC. The reaction mixture was stirred at 25 oC for 10 min. The reaction mixture was stirred at 25 oC for 20 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 5.
4.4.1. 3-Methanesulfonyl-5,5,8a-trimethyl-2-phenyl4a,5,6,7,8,8a-hexahydro-4H-chromene (5a). Yield = 85% (142 mg); Colorless solid; mp = 173-175 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C19H27O3S 335.1681, found 335.1683; 1H NMR (400 MHz, CDCl3): δ 7.44-7.35 (m, 5H), 2.64 (dd, J = 4.4, 16.8 Hz, 1H), 2.63 (s, 3H), 2.27 (dd, J = 12.8, 16.8 Hz, 1H), 1.94-1.91 (m,
ACCEPTED MANUSCRIPT Tetrahedron
4.4.2. 3-Benzenesulfonyl-5,5,8a-trimethyl-2-phenyl4a,5,6,7,8,8a-hexahydro-4H-chromene (5b). Yield = 83% (165 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H29O3S 397.1837, found 397.1838; 1H NMR (400 MHz, CDCl3): δ 7.48-7.41 (m, 3H), 7.37-7.19 (m, 7H), 2.74 (dd, J = 4.4, 16.4 Hz, 1H), 2.19 (dd, J = 12.8, 16.4 Hz, 1H), 1.891.86 (m, 1H), 1.65 (dd, J = 4.8, 12.8 Hz, 1H), 1.63-1.59 (m, 1H), 1.52-1.46 (m, 3H), 1.32-1.25 (m, 1H), 1.21 (s, 3H), 1.03 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.62, 142.34, 134.27, 132.10, 129.59 (2x), 129.43, 128.36 (2x), 127.43 (2x), 126.89 (2x), 113.64, 79.94, 48.02, 41.07, 39.01, 33.54, 31.96, 21.48, 20.50, 19.51, 19.40.
4.4.6. 5,5,8a-Trimethyl-3-(toluene-4-sulfonyl)-2-(4trifluoromethylphenyl)-4a,5,6,7,8,8a-hexahydro-4Hchromene (5g). Yield = 83% (198 mg); Colorless solid; mp = 179-180 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C26H30F3O3S 479.1868, found 479.1870; 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.16 (dd, J = 12.8, 16.8 Hz, 1H), 1.89-1.86 (m, 1H), 1.64 (dd, J = 4.4, 7.6 Hz, 1H), 1.63-1.60 (m, 1H), 1.52-1.45 (m, 3H), 1.33-1.25 (m, 1H), 1.22 (s, 3H), 1.02 (s, 3H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.45, 143.30, 139.00, 138.05, 131.38, 131.06, 130.00 (2x), 129.21 (2x), 127.02 (2x), 124.45 (d, J = 3.0 Hz), 124.37 (d, J = 3.8 Hz), 114.90, 80.40, 47.99, 41.05, 38.99, 33.59, 31.96, 21.44, 21.32, 20.51, 19.53, 19.47. Single-crystal X-Ray diagram: crystal of compound 5g was grown by slow diffusion of EtOAc into a solution of compound 5g in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P b c n, a = 19.064(10) Å, b = 10.973(6) Å, c = 22.586(10) Å, V = 4725(4) Å3, Z = 8, dcalcd = 1.345 mg/cm3, F(000) = 2016, 2θ range 1.803~26.641o, R indices (all data) R1 = 0.1001, wR2 = 0.1674.
TE D
M AN U
4.4.3. 5,5,8a-Trimethyl-2-phenyl-3-(toluene-4-sulfonyl)4a,5,6,7,8,8a-hexahydro-4H-chromene (5c). Yield = 85% (174 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H31O3S 411.1994, found 411.1996; 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.0 Hz, 2H), 7.35-7.32 (m, 2H), 7.307.20 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 2.72 (dd, J = 4.8, 16.4 Hz, 1H), 2.36 (s, 3H), 2.17 (dd, J = 12.8, 16.4 Hz, 1H), 1.891.86 (m, 1H), 1.64 (dd, J = 4.8, 12.8 Hz, 1H), 1.51-1.42 (m, 3H), 1.34-1.29 (m, 2H), 1.21 (s, 3H), 1.03 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.26, 142.80, 139.49, 134.46, 129.59 (2x), 129.38, 129.02 (2x), 127.39 (2x), 126.99 (2x), 113.82, 79.84, 48.04, 41.11, 39.06, 33.57, 31.99, 21.48, 21.44, 20.53, 19.54, 19.42.
(ESI, M++1) calcd for C26H33O3S 425.2150, found 425.2154; H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.4 Hz, 2H), 7.18-7.08 (m, 6H), 2.68 (dd, J = 4.8, 16.4 Hz, 1H), 2.37 (s, 3H), 2.36 (s, 3H), 2.13 (dd, J = 12.8, 16.4 Hz, 1H), 1.88-1.85 (m, 1H), 1.64 (dd, J = 4.8, 12.8 Hz, 1H), 1.50-1.45 (m, 3H), 1.34-1.29 (m, 2H), 1.18 (s, 3H), 1.01 (s, 3H), 0.85 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 160.42, 139.52, 139.46, 131.66, 129.47 (2x), 128.96 (2x), 128.08 (2x), 127.00 (2x), 124.80, 113.23, 79.69, 48.01, 44.45, 41.09, 39.05, 33.50, 31.96, 21.49, 21.44, 20.50, 19.51, 19.38. 1
RI PT
1H), 1.65 (dd, J = 4.8, 12.8 Hz, 1H), 1.63-1.59 (m, 1H), 1.541.47 (m, 3H), 1.33-1.25 (m, 1H), 1.35 (s, 3H), 1.04 (s, 3H), 0.91 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.60, 134.28, 129.69, 129.18 (2x), 127.74 (2x), 113.29, 79.85, 47.80, 43.03, 40.98, 38.97, 33.44, 31.87, 20.96, 20.40, 19.40, 19.12.
SC
8
AC C
EP
4.4.4. 2-(4-Fluorophenyl)-5,5,8a-trimethyl-3-(toluene-4sulfonyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene (5d). Yield = 82% (175 mg); Colorless solid; mp = 129-130 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H30FO3S 429.1900, found 429.1901; 1H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.4 Hz, 2H), 7.23-7.19 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.98-6.93 (m, 2H), 2.71 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.13 (dd, J = 12.8, 16.4 Hz, 1H), 1.88-1.86 (m, 1H), 1.63 (dd, J = 4.8, 12.8 Hz, 1H), 1.501.45 (m, 3H), 1.28-1.23 (m, 2H), 1.18 (s, 3H), 1.02 (s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.31 (d, J = 247.8 Hz), 159.16, 143.03, 139.36, 131.73 (d, J = 8.4 Hz, 2x), 130.46 (d, J = 3.0 Hz), 129.08 (2x), 126.92 (2x), 114.46 (d, J = 21.3 Hz, 2x), 114.16, 80.00, 48.03, 41.07, 39.03, 33.54, 31.97, 21.53, 21.44, 20.50, 19.51, 19.39. Single-crystal XRay diagram: crystal of compound 5d was grown by slow diffusion of EtOAc into a solution of compound 5d in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P b c n, a =18.4792(14) Å, b = 10.7741(7) Å, c = 22.6790(16) Å, V = 4515.3(6) Å3, Z = 8, dcalcd = 1.261 mg/cm3, F(000) = 1824, 2θ range 1.796~26.417o, R indices (all data) R1 = 0.1152, wR2 = 0.1907. 4.4.5. 5,5,8a-Trimethyl-3-(toluene-4-sulfonyl)-2-p-tolyl4a,5,6,7,8,8a-hexahydro-4H-chromene (5e). Two isomers (ratio = 3 : 1); Yield = 86% (182 mg); Colorless gum; HRMS
4.4.7. 5,5,8a-Trimethyl-2-(4-nitrophenyl)-3-(toluene-4sulfonyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene (5h). Yield = 80% (182 mg); Colorless solid; mp = 207-208 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H30NO5S 456.1845, found 456.1848; 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.39 (s, 3H), 2.08 (dd, J = 12.8, 16.8 Hz, 1H), 1.89-1.86 (m, 1H), 1.63 (dd, J = 4.4, 7.6 Hz, 1H), 1.63-1.60 (m, 1H), 1.50-1.45 (m, 3H), 1.33-1.23 (m, 1H), 1.20 (s, 3H), 1.00 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.54, 148.16, 143.65, 141.02, 138.73, 130.59 (2x), 129.40 (2x), 126.97 (2x), 122.59 (2x), 114.88, 80.75, 47.85, 40.93, 38.89, 33.53, 31.87, 21.48, 21.29, 20.45, 19.48 (2x). Single-crystal X-Ray diagram: crystal of compound 5h was grown by slow diffusion of EtOAc into a solution of compound 5h in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P b c n, a = 18.8743(11) Å, b = 10.8665(5) Å, c = 22.3032(11) Å, V = 4574.3(4) Å3, Z = 8, dcalcd = 1.323 mg/cm3, F(000) = 1936, 2θ range 1.826~26.434o, R indices (all data) R1 = 0.0723, wR2 = 0.1585.
ACCEPTED MANUSCRIPT Tetrahedron
RI PT
4.5. A representative synthetic procedure of skeleton 6 is as follows: Sn(OTf)2 (10 mg, 0.025 mmol) was added to a solution of 4 (0.5 mmol) in MeNO2 (5 mL) at 25 oC. The reaction mixture was stirred at 25 oC for 10 min. The reaction mixture was stirred at 25 oC for 20 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 6. 4.5.1. 2-Methanesulfonyl-4a,7,7,10a-tetramethyl-3-phenyl4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6a). Two diastereomers (d.r. = 3/1); Yield = 81% (163 mg); Colorless solid; mp = 147-148 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C24H35O3S 403.2307, found 403.2310; 1H NMR (400 MHz, CDCl3): δ 7.43-7.38 (m, 5H), 2.64 (s, 3H), 2.57 (dd, J = 1.2, 16.8 Hz, 1H), 2.34-2.26 (m, 1H), 2.06-2.02 (m, 1H), 1.97-1.94 (m, 1H), 1.81-1.46 (m, 7H), 1.34 (s, 3H), 1.09-0.96 (m, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 159.65, 134.44, 129.86, 129.80, 129.29 (2x), 127.88 (2x), 113.17, 79.76, 55.86, 51.83, 43.14, 41.65, 40.24, 39.14, 37.01, 33.34, 21.46, 20.25, 20.21, 19.56, 18.35, 14.88.
TE D
M AN U
4.4.9. 5,5,8a-Trimethyl-2-naphthalen-2-yl-3-(toluene-4sulfonyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene (5j). Yield = 83% (191 mg); Colorless solid; mp = 136-137 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C29H33O3S 461.2150, found 461.2153; 1H NMR (400 MHz, CDCl3): δ 7.82-7.75 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.69 (br s, 1H), 7.52-7.47 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.25 (dd, J = 1.6, 8.4 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 2.79 (dd, J = 4.8, 16.8 Hz, 1H), 2.29 (s, 3H), 2.29 (dd, J = 6.0, 16.8 Hz, 1H), 1.92-1.89 (m, 1H), 1.70 (dd, J = 4.8, 12.8 Hz, 1H), 1.66-1.62 (m, 1H), 1.54-1.48 (m, 3H), 1.34-1.28 (m, 1H), 1.29 (s, 3H), 1.06 (s, 3H), 0.90 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.14, 142.82, 139.46, 133.53, 132.22, 131.72, 129.64, 128.87 (2x), 128.37, 127.59, 127.05, 127.02 (2x), 126.79, 126.48, 126.11, 114.47, 79.99, 48.14, 41.13, 39.08, 33.59, 32.01, 21.54, 21.36, 20.55, 19.55, 19.47.
55.47, 48.04, 41.10, 39.05, 33.53, 31.97, 21.45, 20.51, 19.53, 19.37.
SC
4.4.8. 2-Biphenyl-4-yl-5,5,8a-trimethyl-3-(toluene-4sulfonyl)-4a,5,6,7,8,8a-hexahydro-4H-chromene (5i). Yield = 85% (206 mg); Colorless solid; mp = 160-162 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C31H35O3S 487.2307, found 487.2310; 1H NMR (400 MHz, CDCl3): δ 7.60-7.57 (m, 2H), 7.51-7.35 (m, 7H), 7.31 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 2.75 (dd, J = 4.8, 16.8 Hz, 1H), 2.36 (s, 3H), 2.20 (dd, J = 12.8, 16.8 Hz, 1H), 1.92-1.90 (m, 1H), 1.67 (dd, J = 4.8, 12.8 Hz, 1H), 1.541.47 (m, 3H), 1.28-1.24 (m, 2H), 1.24 (s, 3H), 1.05 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.90, 142.84, 142.28, 140.59, 139.42, 133.32, 130.08 (2x), 128.98 (2x), 128.74 (2x), 127.53, 127.13 (2x), 127.05 (2x), 126.15 (2x), 114.04, 79.91, 48.04, 41.09, 39.07, 33.55, 31.98, 21.50, 21.46, 20.52, 19.53, 19.42.
9
AC C
EP
4.4.10. 3-Methanesulfonyl-5,5,8a-trimethyl-2-p-tolyl4a,5,6,7,8,8a-hexahydro-4H-chromene (5k). Yield = 81% (141 mg); Colorless solid; mp = 146-147 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C20H29O3S 349.1837, found 349.1840; 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.64 (dd, J = 5.2, 16.8 Hz, 1H), 2.65 (s, 3H), 2.36 (s, 3H), 2.27 (dd, J = 12.8, 16.8 Hz, 1H), 1.94-1.92 (m, 1H), 1.64 (dd, J = 4.4, 12.8 Hz, 1H), 1.66-1.62 (m, 1H), 1.54-1.47 (m, 3H), 1.35 (s, 3H), 1.34-1.28 (m, 1H), 1.04 (s, 3H), 0.91 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 159.78, 139.95, 131.47, 129.21 (2x), 128.55 (2x), 113.13, 79.79, 47.91, 43.12, 41.08, 39.08, 33.51, 31.95, 21.35, 21.05, 20.47, 19.47, 19.18.
4.4.11. 3-(4-Methoxybenzenesulfonyl)-5,5,8a-trimethyl-2phenyl-4a,5,6,7,8,8a-hexahydro-4H-chromene (5l). Yield = 18% (38 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H31O4S 427.1943, found 427.1946; 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 8.8 Hz, 2H), 7.36-7.32 (m, 1H), 7.307.26 (m, 2H), 7.23-7.20 (m, 2H), 6.77 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 2.71 (dd, J = 4.8, 16.8 Hz, 1H), 2.17 (dd, J = 12.8, 16.8 Hz, 1H), 1.88-1.86 (m, 1H), 1.64 (dd, J = 4.4, 12.8 Hz, 1H), 1.66-1.62 (m, 1H), 1.50-1.42 (m, 3H), 1.38-1.24 (m, 1H), 1.21 (s, 3H), 1.02 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.42, 159.93, 134.50, 134.15, 129.59 (2x), 129.36, 129.05 (2x), 127.41 (2x), 114.19, 113.55 (2x), 79.76,
4.5.2. 2-Benzenesulfonyl-4a,7,7,10a-tetramethyl-3-phenyl4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6b). Two diastereomers (d.r. = 9/1); Yield = 81% (188 mg); Colorless solid; mp = 192-194 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C29H37O3S 465.2463, found 465.2466; 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 8.4 Hz, 2H), 7.44-7.42 (m, 1H), 7.37-7.18 (m, 7H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.20 (dd, J = 12.8, 16.8 Hz, 1H), 1.98 (dt, J = 3.2, 12.4 Hz, 1H), 1.73 (d, J = 13.2 Hz, 2H), 1.65-1.23 (m, 7H), 1.20 (s, 3H), 1.04-0.96 (m, 2H), 0.88 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 160.57, 142.39, 134.36, 132.10, 129.58 (2x), 129.40, 128.38 (2x), 127.45 (2x), 126.91 (2x), 113.30, 79.73, 55.83, 51.92, 41.67, 40.17, 39.08, 36.99, 33.34, 33.13, 21.48, 20.66, 20.38, 19.56, 18.38, 14.86. Single-crystal X-Ray diagram: crystal of compound 6b was grown by slow diffusion of EtOAc into a solution of compound 6b in CH2Cl2 to yield colorless prisms. The compound crystallizes in the orthorhombic crystal system, space group P 21 21 21, a = 6.2765(3) Å, b = 14.2655(7) Å, c = 27.0870(14) Å, V = 2425.3(2) Å3, Z = 4, dcalcd= 1.272 g/cm3, F(000) = 1000, 2θ range 1.504~26.390o, R indices (all data) R1 = 0.0414, wR2 = 0.1045. 4.5.3. 4a,7,7,10a-Tetramethyl-3-phenyl-2-(toluene-4sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6c). Two diastereomers (d.r. = 5/2); Yield = 85% (203 mg); Colorless solid; mp = 147-149 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C30H39O3S 479.2620, found 479.2621; 1H NMR
ACCEPTED MANUSCRIPT Tetrahedron
4.5.6. 4a,7,7,10a-Tetramethyl-2-(toluene-4-sulfonyl)-3-(4trifluoromethylphenyl)-4a,5,6,6a,7,8,9,10,10a,10bdecahydro-1H-benzo[f]chromene (6g). Two diastereomers (d.r. = 5/2); Yield = 80% (218 mg); Colorless solid; mp = 158-160 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C31H38F3O3S 547.2494, found 547.2493; 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 2.62 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.20-2.11 (m, 1H), 1.98-1.95 (m, 1H), 1.74-1.42 (m, 8H), 1.21 (s, 3H), 1.16-0.90 (m, 3H), 0.88 (s, 3H), 0.84 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.39, 131.28, 139.02, 138.13, 130.01, 129.97 (2x), 129.22 (2x), 127.03 (4x), 124.42 (q, J = 3.8 Hz), 114.55, 80.17, 55.84, 51.86, 41.65, 40.14, 39.08, 37.01, 35.12, 33.34, 33.14, 21.47, 20.50, 20.44, 19.58, 18.37, 14.89.
AC C
EP
TE D
M AN U
4.5.4. 3-(4-Fluorophenyl)-4a,7,7,10a-tetramethyl-2(toluene-4-sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro1H-benzo[f]chromene (6d). Two diastereomers (d.r. = 4/1); Yield = 80% (198 mg); Colorless solid; mp = 199-201 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C30H38FO3S 497.2526, found 497.2524; 1H NMR (400 MHz, CDCl3): δ 7.39-7.35 (m, 2H), 7.25-7.18 (m, 2H), 7.14 (d, J = 7.2 Hz, 2H), 6.99-6.94 (m, 2H), 2.62 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.18-2.09 (m, 1H), 1.97 (dt, J = 3.2, 12.8 Hz, 1H), 1.77-1.69 (m, 2H), 1.65-1.39 (m, 5H), 1.35-1.08 (m, 2H), 1.17 (s, 3H), 1.02-1.00 (m, 2H), 0.87 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.39 (d, J = 247.1 Hz), 159.08, 143.00, 139.38, 131.78, 131.70, 131.69 (d, J = 8.4 Hz, 2x), 130.52 (d, J = 3.0 Hz), 129.09 (2x), 126.92 (2x), 114.47 (d, J = 22.0 Hz, 2x), 113.81, 79.76, 55.82, 51.90, 41.65, 40.17, 39.08, 36.97, 33.33, 21.47, 20.68, 20.36, 19.55, 18.36, 14.84. Single-crystal X-Ray diagram: crystal of compound 6d was grown by slow diffusion of EtOAc into a solution of compound 6d in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/n, a = 7.0592(3) Å, b = 26.5040(10) Å, c = 14.4311(5) Å, V = 2653.65(18) Å3, Z = 4, dcalcd = 1.243 mg/cm3, F(000) = 1064, 2θ range 1.537~26.390o, R indices (all data) R1 = 0.1157, wR2 = 0.2322.
crystal X-Ray diagram: crystal of compound 6e was grown by slow diffusion of EtOAc into a solution of compound 6e in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/n, a = 6.9224(6) Å, b = 27.150(2) Å, c = 14.7171(13) Å, V = 2707.4(4) Å3, Z = 4, dcalcd = 1.209 mg/cm3, F(000) = 1064, 2θ range 1.500~26.415o, R indices (all data) R1 = 0.1230, wR2 = 0.1487.
RI PT
(400 MHz, CDCl3): δ 7.38-7.33 (m, 3H), 7.30-7.19 (m, 4H), 7.11 (d, J = 7.6 Hz, 2H), 2.62 (dd, J = 4.4, 16.8 Hz, 1H), 2.36 (s, 3H), 2.21-2.12 (m, 1H), 1.98 (dt, J = 3.2, 12.8 Hz, 1H), 1.76-1.70 (m, 2H), 1.66-1.38 (m, 5H), 1.35-1.08 (m, 2H), 1.02-1.00 (m, 2H), 1.19 (s, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.23, 142.79, 139.55, 134.57, 129.59 (2x), 129.44, 129.37, 129.04 (2x), 127.43 (2x), 127.02 (2x), 113.49, 79.64, 55.87, 51.96, 41.71, 40.24, 39.12, 33.37, 33.16, 21.50, 21.47, 20.66, 20.42, 19.60, 18.41, 14.89. Single-crystal X-Ray diagram: crystal of compound 6c was grown by slow diffusion of EtOAc into a solution of compound 6c in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/n, a = 7.0561(5) Å, b = 26.349(2) Å, c = 14.3583(11) Å, V = 2615.3(3) Å3, Z = 4, dcalcd= 1.216 g/cm3, F(000) = 1032, 2θ range 1.546~26.411o, R indices (all data) R1 = 0.0949, wR2 = 0.2022.
SC
10
4.5.5. 4a,7,7,10a-Tetramethyl-2-(toluene-4-sulfonyl)-3-ptolyl-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6e). Two diastereomers (d.r. = 4/1); Yield = 83% (204 mg); Colorless solid; mp = 190-192 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C31H41O3S 493.2776, found 493.2774; 1H NMR (400 MHz, CDCl3): δ 7.42-7.38 (m, 2H), 7.16-7.08 (m, 6H), 2.59 (dd, J = 4.8, 16.8 Hz, 1H), 2.37 (s, 3H), 2.36 (s, 3H), 2.17-2.10 (m, 1H), 1.97 (dt, J = 3.2, 12.8 Hz, 1H), 1.72-1.39 (m, 6H), 1.35-1.11 (m, 3H), 1.17 (s, 3H), 1.02-0.95 (m, 2H), 0.87 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.38, 142.75, 139.58, 139.44, 131.76, 129.51, 129.46 (2x), 128.99 (2x), 128.11 (2x), 127.04 (2x), 112.92, 79.49, 55.83, 51.92, 41.68, 40.22, 39.08, 38.96, 36.97, 33.35, 21.49, 21.44, 20.66, 20.38, 19.56, 18.39, 14.85. Single-
4.5.7. 4a,7,7,10a-Tetramethyl-3-(4-nitrophenyl)-2-(toluene4-sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6h). Two diastereomers (d.r. = 3/1); Yield = 77% (201 mg); Colorless solid; mp = 172-174 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C30H38NO5S 524.2471, found 524.2472; 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.8 Hz, 2H), 7.49-7.42 (m, 4H), 7.20 (d, J = 8.0 Hz, 2H), 2.60-2.54 (m, 1H), 2.40 (s, 3H), 2.14-1.96 (m, 2H), 1.71-1.22 (m, 11H), 1.19 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 157.51, 148.17, 143.65, 141.14, 138.77, 130.62, 130.58 (2x), 129.44 (2x), 127.01 (2x), 122.64 (2x), 114.60, 80.54, 55.81, 51.74, 41.60, 40.05, 39.02, 36.98, 33.31, 31.40, 21.52, 21.44, 20.47, 19.56, 18.34, 14.86. 4.5.8. 3-Biphenyl-4-yl-4a,7,7,10a-tetramethyl-2-(toluene-4sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6i). Two diastereomers (d.r. = 2/1); Yield = 83% (230 mg); Colorless gum; HRMS (ESI, M++1) calcd for C36H43O3S 555.2933, found 555.2930; 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.4 Hz, 2H), 7.51-7.35 (m, 7H), 7.29 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.36 (s, 3H), 2.24-2.15 (m, 1H), 2.091.99 (m, 1H), 1.83-1.48 (m, 9H), 1.26 (s, 3H), 1.07-0.90 (m, 2H), 0.88 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.86, 142.84, 142.27, 140.64, 139.47, 133.41, 130.06 (2x), 129.01 (2x), 128.77 (2x), 127.54, 127.18 (2x), 127.08 (2x), 126.18 (2x), 113.72, 79.65, 55.85, 51.95, 41.68, 40.24, 39.10, 37.01, 33.35, 31.43, 29.66, 21.50, 20.67, 20.42, 19.59, 18.40, 14.88. 4.5.9. 4a,7,7,10a-Tetramethyl-3-naphthalen-2-yl-2-(toluene4-sulfonyl)-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6j). Two diastereomers (d.r. = 3/1); Yield
ACCEPTED MANUSCRIPT Tetrahedron
RI PT
4.6.3. 2-Benzoyl-5,9-dimethyldeca-4,8-dienoic acid ethyl ester (8c). Yield = 86% (282 mg); Colorless gum; HRMS (ESI, M++1) calcd for C21H29O3 329.2117, found 329.2115; 1 H NMR (400 MHz, CDCl3): δ 8.00-7.97 (m, 2H), 7.59-7.55 (m, 1H), 7.48-7.44 (m, 2H), 5.13-5.09 (m, 1H), 5.04-5.00 (m, 1H), 4.31 (t, J = 7.6 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.772.63 (m, 2H), 2.05-1.90 (m, 4H), 1.63 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 195.06, 169.68, 138.20, 136.36, 133.35, 131.39, 128.62 (2x), 128.55 (2x), 123.98, 119.97, 61.26, 54.43, 39.62, 27.64, 26.46, 25.57, 17.59, 16.05, 13.95. 4.6.4. 2-(4-Methoxybenzoyl)-5,9-dimethyldeca-4,8-dienoic acid ethyl ester (8d). Yield = 85% (304 mg); Colorless gum; HRMS (ESI, M++1) calcd for C22H31O4 359.2222, found 359.2218; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.10 (t, J = 7.2 Hz, 1H), 5.02 (t, J = 6.4 Hz, 1H), 4.26 (dd, J = 7.2, 8.0 Hz, 1H), 4.14 (dd, J = 1.6, 7.2 Hz, 1H), 4.10 (dd, J = 1.2, 7.2 Hz, 1H), 3.85 (s, 3H), 2.76-2.60 (m, 2H), 2.05-1.89 (m, 4H), 1.63 (s, 3H), 1.61 (s, 3H), 1.55 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 193.41, 169.88, 163.73, 138.02, 131.34, 130.95 (2x), 129.31, 124.01, 120.12, 113.77 (2x), 61.16, 55.42, 54.12, 39.62, 27.69, 26.48, 25.56, 17.58, 16.05, 13.98.
M AN U
4.5.10. 2-Methanesulfonyl-4a,7,7,10a-tetramethyl-3-p-tolyl4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1Hbenzo[f]chromene (6k). Two diastereomers (d.r. = 4/1); Yield = 80% (166 mg); Colorless solid; mp = 80-82 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H37O3S 417.2463, found 417.2460; 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.64 (s, 3H), 2.56 (dd, J = 5.2, 16.8 Hz, 1H), 2.36 (s, 3H), 2.33-2.24 (m, 1H), 2.06-2.01 (m, 1H), 1.76-1.35 (m, 7H), 1.33 (s, 3H), 1.31-1.10 (m, 2H), 1.09-0.94 (m, 2H), 0.90 (s, 3H), 0.89 (s, 3H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.78, 139.98, 131.56, 129.25 (2x), 128.62 (2x), 112.92, 79.62, 55.87, 51.86, 43.17, 41.66, 40.27, 39.15, 37.01, 33.34, 33.13, 21.47, 21.41, 20.28, 20.20, 19.57, 18.37, 14.87.
(m, 2H), 5.10 (t, J = 7.2 Hz, 1H), 5.01 (t, J = 6.8 Hz, 1H), 4.49 (t, J = 7.2 Hz, 1H), 2.90-2.83 (m, 1H), 2.57-2.50 (m, 1H), 2.02-1.90 (m, 4H), 1.63 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 198.17, 165.41 (d, J = 252.4 Hz), 139.33, 137.36, 133.26 (d, J = 3.0 Hz), 131.26 (d, J = 9.1 Hz, 2x), 131.25, 128.82 (2x), 128.15 (2x), 127.01, 124.14, 121.27, 115.49 (d, J = 21.3 Hz, 2x), 54.05, 39.66, 32.54, 26.53, 25.57, 17.59, 15.97.
SC
= 84% (222 mg); Colorless gum; HRMS (ESI, M++1) calcd for C34H41O3S 529.2776, found 529.2773; 1H NMR (400 MHz, CDCl3): δ 7.82-7.75 (m, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.52-7.46 (m, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 2.69 (dd, J = 5.2, 16.8 Hz, 1H), 2.38-2.22 (m, 2H), 2.30 (s, 3H), 2.05-1.98 (m, 1H), 1.82-1.41 (m, 8H), 1.26 (s, 3H), 1.17-0.90 (m, 2H), 0.88 (br s, 6H), 0.83 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 160.09, 142.81, 139.51, 133.54, 132.25, 131.82, 129.59, 128.90 (2x), 128.39, 127.62, 127.05 (2x), 126.79, 126.52, 126.11, 114.14, 79.77, 55.87, 52.05, 41.70, 40.24, 39.14, 37.04, 33.37, 33.16, 29.67, 21.50, 21.39, 20.72, 20.45, 19.60, 18.42, 14.91.
11
EP
TE D
4.6. A representative synthetic procedure of skeleton 8 is as follows: NaH (60% in oil, 120 mg, 3.0 mmol) was added to a solution of 7 (1.0 mmol) in THF (10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. Geranyl bromide 2b (298 mg, 1.05 mmol) was added to the reaction mixture at 25 oC. The reaction mixture was stirred at reflux for 8 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 8.
AC C
4.6.1. 5,9-Dimethyl-1,2-diphenyldeca-4,8-dien-1-one (8a). Yield = 84% (279 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H29O 333.2219, found 333.2220; 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 2H), 7.50-7.45 (m, 1H), 7.40-7.27 (m, 6H), 7.22-7.18 (m, 1H), 5.11 (t, J = 7.2 Hz, 1H), 5.03 (t, J = 6.4 Hz, 1H), 4.56 (t, J = 7.2 Hz, 1H), 2.922.85 (m, 1H), 2.59-2.51 (m, 1H), 2.02-1.89 (m, 2H), 1.771.67 (m, 2H), 1.64 (s, 3H), 1.57 (s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 199.79, 139.48, 137.24, 132.69, 131.24, 128.74 (2x), 128.64 (2x), 128.42 (2x), 128.24 (2x), 126.89, 124.17, 121.42, 54.00, 39.67, 32.59, 26.55, 26.50, 25.57, 17.60, 15.99. 4.6.2. 1-(4-Fluoro-phenyl)-5,9-dimethyl-2-phenyldeca-4,8dien-1-one (8b). Yield = 86% (301 mg); Colorless gum; HRMS (ESI, M++1) calcd for C24H28FO 351.2124, found 351.2120; 1H NMR (400 MHz, CDCl3): δ 8.01-7.96 (m, 2H), 7.30 (br s, 2H), 7.29 (br s, 2H), 7.24-7.19 (m, 1H), 7.07-7.01
4.6.5. 2-(3,7-Dimethylocta-2,6-dienyl)-1,3-diphenylpropane1,3-dione (8e). Yield = 88% (317 mg); Colorless gum; HRMS (ESI, M++1) calcd for C25H29O2 361.2168, found 361.2170; 1H NMR (400 MHz, CDCl3): δ 7.99-7.95 (m, 4H), 7.57-7.53 (m, 2H), 7.45-7.41 (m, 4H), 5.25 (t, J = 6.8 Hz, 1H), 5.19 (t, J = 7.2 Hz, 1H), 5.02-4.99 (m, 1H), 2.84 (t, J = 6.8 Hz, 2H), 1.96-1.88 (m, 4H), 1.62 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H);13C NMR (100 MHz, CDCl3): δ 195.91 (2x), 137.93, 136.11, 133.34 (2x), 131.34, 128.73 (4x), 128.52 (4x), 127.08, 123.97, 120.60, 57.07, 39.55, 28.21, 26.37, 25.53, 17.57, 16.05. 4.6.6. 2-(3,7-Dimethyl-octa-2,6-dienyl)-1-phenylbutane-1,3dione (8f). Yield = 84% (250 mg); Colorless gum; HRMS (ESI, M++1) calcd for C20H26O2 299.2011, found 299.2015; 1 H NMR (400 MHz, CDCl3): δ 7.98-7.96 (m, 2H), 7.61-7.56 (m, 1H), 7.50-7.42 (m, 2H), 5.05 (t, J = 7.2 Hz, 1H), 4.99 (t, J = 7.2 Hz, 1H), 4.46 (t, J = 7.2 Hz, 1H), 2.69 (t, J = 7.2 Hz, 2H), 2.14 (s, 3H), 1.99-1.86 (m, 4H), 1.62 (s, 3H), 1.61 (s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 204.11, 196.35, 138.30, 136.55, 133.60, 131.48, 128.78 (2x), 128.69 (2x), 123.92, 119.86, 63.30, 39.59, 28.07, 27.75, 26.40, 25.58, 17.62, 16.09. 4.7. A representative synthetic procedure of skeleton 9 is as follows: Sn(OTf)2 (10 mg, 0.025 mmol) was added to a solution of 8 (0.5 mmol) in MeNO2 (5 mL) at 25 oC. The
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CDCl3): δ 7.64-7.62 (m, 2H), 7.50-7.44 (m, 1H), 7.42-7.38 (m, 2H), 2.59 (dd, J = 4.4, 16.8 Hz, 1H), 2.05-1.91 (m, 2H), 1.73-1.63 (m, 1H), 1.64 (s, 3H), 1.55-1.45 (m, 4H), 1.30 (s, 3H), 1.32-1.28 (m, 1H), 0.97 (s, 3H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 198.48, 160.10, 141.31, 131.33, 128.43 (2x), 128.33 (2x), 110.43, 78.46, 47.82, 41.40, 39.45, 33.34, 32.08, 21.52, 21.28, 20.52, 19.66, 19.56.
4.7.1. 5,5,8a-Trimethyl-2-phenyl-4a,5,6,7,8,8a-hexahydro4H-chromene-3-carboxylic acid ethyl ester (9c). Yield = 75% (123 mg); Colorless gum; HRMS (ESI, M++1) calcd for C21H29O3 329.2117, found 329.2115; 1H NMR (400 MHz, CDCl3): δ 7.34-7.31 (m, 5H), 3.95-3.87 (m, 2H), 2.65 (dd, J = 4.8, 16.8 Hz, 1H), 2.07 (dd, J = 13.2, 16.8 Hz, 1H), 1.681.42 (m, 6H), 1.34 (s, 3H), 1.30-1.22 (m, 1H), 1.04 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.78, 161.26, 137.52, 128.61, 128.53 (2x), 128.26, 127.55 (2x), 102.93, 79.19, 59.61, 47.69, 41.37, 39.42, 32.13, 21.08, 20.54, 19.72, 19.32, 13.66.
Acknowledgments The authors would like to thank the Ministry of Science and Technology of the Republic of China for its financial support (MOST 104-2113-M-037-012). References and notes
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For a review on the biomimetic total synthesis of terpenes and steroids, see: Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730-4756. For leading references on the polycyclizations, see: (a) Kurti, L.; Chein, R.-J.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 9031-9036. (b) Rajendar, G.; Corey, E. J. J. Am. Chem. Soc. 2015, 137, 58375844. (c) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew. Chem., Int. Ed. 2000, 39, 2812-2833. (d) Liu, W.; Li, H.; Cai, P.-J.; Wang, Z.; Yu, Z.-X.; Lei, X. Angew. Chem., Int. Ed. 2016, 55, 3112-3116. Representative examples on the synthesis of natural products by metal complex-mediated ployolefin carbocyclizations, for serratenediol, see: (a) Zhang, J.-H.; Corey, E. J. Org. Lett. 2001, 3, 3215-3216. For germanicol, see: (b) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8865-8869. For lupeol, see: (c) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2009, 131, 13928-13929. For dammarenediol II, see: (d) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765-8766. For erythrodiol, see: (e) Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874. For walsucochin B, see: (f) Xu, S.; Gu, J.; Li, H.; Ma, D.; Xie, X.; She, X. Org. Lett. 2014, 16, 1996-1999. For adociasulfate 1, see: (g) Bogenstatter, M.; Limberg, A.; Overman, L. E.; Tomasi, A. L. J. Am. Chem. Soc. 1999, 121, 12206-12207. For totarol, see: (h) Kim, M.; Shaw, J. T. Org. Lett. 2010, 12, 3324-3327. For oridamycins A and B, see: (i) Trotta, A. H. Org. Lett. 2015, 17, 3358-3361. For SnCl4, see: (a) van Tamelen, E. E.; Willet, J.; Schwartz, M.; Nadeau, R. J. Am. Chem. Soc. 1966, 88, 5937-5938. For FeCl3, see: (b) Sen, S. E.; Roach, S. L.; Smith, S. M.; Zhang, Y.-Z. Tetrahedron Lett. 1998, 39, 3969-3972. (c) Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 9019-9022. For TiCl4, see: (d) Corey, E. J.; Liu, K. J. Am. Chem. Soc. 1997, 119, 9929-9930. For BF3·OEt2, see: (e) van Tamelen, E. E.; Carlson, J. G.; Russell, R. K.; Zawacky, S. R. J. Am. Chem. Soc. 1981, 103, 4615-4616. (f) van Tamelen, E. E.; Leiden, T. M. J. Am. Chem. Soc. 1982, 104, 20612062. (g) Tanis, S. P. J. Org. Chem. 1988, 53, 4929-4938. For zeolites, see: (a) Sen, S. E.; Zhang, Y.-Z.; Roach, S. L. J. Org. Chem. 1996, 61, 9534-9537. (b) Sen, S. E.; Zhang, Y.-Z.; Smith, S. M. J. Org. Chem. 1998, 63, 4459-4465. For radicals, see: (a) Justicia, J.; Rosales, A.; Buñuel, E.; OllerLópez, J. L.; Valdivia, M.; Haïdour, A.; Oltra, J. E.; Barrero, A. F.; Cárdenas, D. J.; Cuerva, J. M. Chem. Eur. J. 2004, 10, 1778-1788. (b) Domingo, V.; Arteaga, J. F.; Perez, J. L. L.; Pelaez, R.; Quilez del Moral, J. F.; Barrero, A. F. J. Org. Chem. 2012, 77, 341-350. (c) Rosales, A.; Foley, L. A. R.; Padial, N. M. Munoz-Bascon, J.; Sancho-Sanz, I.; Roldan-Molina, E.; Pozo-Morales, L.; Irias-Alvarez, A.; Rodríguez-Maecker, R.; Rodriguez-Garcia, I.; Oltra, J. E. Synlett 2016, 27, 369-374. For Bronsted acids, see: (a) Tain, Y.; Xu, X.; Zhang, L.; Qu, J. Org. Lett. 2016, 18, 268-271. (b) Suzuki, K.; Yamakoshi, H.; Nakamura, S. Chem. Eur. J. 2015, 21, 17605-17609. (c) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 3647-3655. (d) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999,
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4.7.2. Phenyl-(5,5,8a-trimethyl-2-phenyl-4a,5,6,7,8,8ahexahydro-4H-chromen-3-yl)methanone (9e). Yield = 85% (153 mg); Colorless solid; mp = 137-138 oC (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C25H29O2 361.2168, found 361.2170; 1H NMR (400 MHz, CDCl3): δ 7.47-7.44 (m, 2H), 7.20-7.18 (m, 2H), 7.15-7.11 (m, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.03-6.99 (m, 3H), 3.03 (dd, J = 5.2, 17.2 Hz, 1H), 2.12 (d, J = 17.2 Hz, 1H), 2.09 (d, J = 17.2 Hz, 1H), 1.68 (dd, J = 5.2, 12.8 Hz, 2H), 1.64-1.59 (m, 2H), 1.52 (s, 3H), 1.37-1.27 (m, 2H), 1.08 (s, 3H), 0.93 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 198.59, 159.87, 139.59, 135.93, 130.87, 129.56 (2x), 129.13, 129.09 (2x), 127.48 (2x), 127.42 (2x), 111.94, 78.89, 47.85, 41.40, 39.37, 33.41, 32.12, 22.32, 20.44, 19.71, 19.26. Single-crystal X-Ray diagram: crystal of compound 9e was grown by slow diffusion of EtOAc into a solution of compound 9e in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/c, a = 7.6511(6) Å, b = 20.7338(18) Å, c = 12.4531(9) Å, V = 1967.9(3) Å3, Z = 4, dcalcd = 1.217 mg/cm3, F(000) = 776, 2θ range 1.913~26.498o, R indices (all data) R1 = 0.0510, wR2 = 0.1239.
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reaction mixture was stirred at 25 oC for 10 min. The reaction mixture was stirred at 25 oC for 20 h. The reaction mixture was cooled to 25 oC and the solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc = 8/1~4/1) afforded 9.
4.7.3. 1-(5,5,8a-Trimethyl-2-phenyl-4a,5,6,7,8,8ahexahydro-4H-chromen-3-yl)ethanone (9f). Yield = 35% (52 mg); Colorless gum; HRMS (ESI, M++1) calcd for C20H27O2 299.2011, found 299.2010; 1H NMR (400 MHz, CDCl3): δ 7.44-7.34 (m, 5H), 2.77 (dd, J = 5.2, 17.2 Hz, 1H), 1.96 (d, J = 13.2 Hz, 1H), 1.92 (d, J = 13.2 Hz, 1H), 1.66 (s, 3H), 1.57-1.44 (m, 4H), 1.32 (s, 3H), 1.30-1.20 (m, 2H), 1.03 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 200.30, 163.00, 137.14, 129.87, 129.35 (2x), 128.36 (2x), 115.22, 79.50, 47.79, 41.36, 39.39, 33.44, 32.09, 30.34, 20.84, 20.41, 19.71, 19.09. 4.7.4. Phenyl-(2,5,5,8a-tetramethyl-4a,5,6,7,8,8ahexahydro-4H-chromen-3-yl)methanone (9g). Yield = 40% (60 mg); Colorless gum; HRMS (ESI, M++1) calcd for C20H27O2 299.2011, found 299.2008; 1H NMR (400 MHz,
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(h) Lu, Q.; Zhang, J.; Zhao, G.; Qi, Y.; Wang, H.; Lei, W. J. Am. Chem. Soc. 2013, 135, 11481-11484. (i) Handa, S.; Fennewald, J. C.; Lipshutz, B. H. Angew. Chem. Int. Ed. 2014, 53, 3432-3435. (j) Tang, X.; Huang, L.; Xu, Y.; Yang, J.; Wu, W.; Jiang, H. Angew. Chem., Int. Ed. 2014, 53, 4205-4208. (k) Chawla, R.; Singh, A. K.; Yadav, L. D. S. Eur. J. Org. Chem. 2014, 10, 2032-2036. (l) Singh, A. K.; Chawla, R.; Yadav, L. D. S. Tetrahedron Lett. 2014, 55, 4742-4746. (m) Shi, X.; Ren, X.; Ren, Z.; Li, J.; Wang, Y.; Yang, S.; Gu, J.; Gao, Q.; Huang, G. Eur. J. Org. Chem. 2014, 10, 5083-5088. (n) Xuan, J.; Feng, Z.-J.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J. Chem. Eur. J. 2014, 20, 3045-3049. (o) Singh, A. K.; Chawla, A. K.; Chawla, R.; Keshari, T.; Yadav, V. K.; Yadav, L. D. S. Org. Biomol. Chem. 2014, 12, 8550-8554. (p) Saraiva, M. T.; Costa, G. P.; Seus, N.; Schumacher, R. F.; Perin, G.; Paixao, M. W.; Luque, R.; Alves, D. Org. Lett. 2015, 17, 6206-6209. (q) Yadav, V. K.; Srivastava, V. P.; Yadav, L. D. Synlett 2016, 27, 427-431. Sn(OTf)2-mediated annulations, see: (a) Smith, A. G.; Slade, M. C.; Johnson, J. S. Org. Lett. 2011, 13, 1996-1999. (b) Kranz, D. P.; Meierzu, G. A.; El Sheikh, S.; Neudrfl, J. M.; Schmalz, H. G. Eur. J. Org. Chem. 2011, 15, 2860-2866. (c) Goldberg, A. F. G.; O’Connor, N. R.; Craig, R. A. II; Stoltz, B. M. Org. Lett. 2012, 14, 5314-5317. Sn(OTf)2-mediated aldol reaction, see: Kobayashi, S.; Hachiya, I. J. Org. Chem. 1992, 57, 1324-1326. Sn(OTf)2-mediated Mannish-type reactions, see: (a) Kulkarni, N. A.; Chen, K. Tetrahedron Lett. 2006, 47, 611-613. (b) Yang, Y.; Phillips, D. P.; Pan, S. Tetrahedron Lett. 2011, 52, 1549-1552. Sn(OTf)2-mediated rearrangements, see: (a) Xu, G.-C.; Ma, M.; Liu, L.-P.; Shi, M. Synlett 2005, 1869-1872. (b) Lambert, T. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 13646-13647. CCDC 1472669 (5d), 1472670 (5g), 1472671 (5h), 1479881 (6b), 1472672 (6c), 1472673 (6d), 1472674 (6e) and 1473357 (9e) contain the supplementary crystallographic data for this paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033; email: [email protected]).
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121, 4906-4907. (e) van Tamelen, E. E.; Hwu, J. R. J. Am. Chem. Soc. 1983, 105, 2490-2491. For a review on the biosynthetic cyclization of polyprenoids, see: Abe, I.; Rohmer, M.; Prestwich, G. D. Chem. Rev. 1993, 93, 21892206. (a) Li, H.; Sun, Y.; Zhang, Q.; Zhu, Y.; Li, S.-M.; Li, A.; Zhang, C. Org. Lett. 2015, 17, 306-309. (b) Tanaka, H.; Noguchi, H.; Abe, I. Org. Lett. 2005, 7, 5873-5876. For the synthesis of ambrox, see: (a) Zoretic, P. A.; Fang, H.; Ribeiro, A. A. J. Org. Chem. 1998, 63, 4779-4785. (b) Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.; Ramos, J. M.; Salido, S. J. Org. Chem. 1996, 61, 2215-2218. (c) Snowden, R. L.; Eichenberger, J. C.; Linder, S. M.; Sonnay, P.; Vial, C.; Schulte-Elte, K. H. J. Org. Chem. 1992, 57, 955-960. For metal triflate mediated synthesis by the authors, for Sc(OTf)3, see: (a) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K.; Huang, G. G. Tetrahedron 2015, 71, 2095-2104. For In(OTf)3, see: (b) Chang, M.Y.; Lu, Y.-J.; Cheng, Y.-C. Tetrahedron 2015, 71, 6840-6845. For Fe(OTf)3, see: (c) Chang, M.-Y.; Chen, Y.-H.; Cheng, Y.-C. Tetrahedron 2016, 72, 518-524. For Bi(OTf)3, see: (d) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2015, 17, 1264-1267. (e) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2015, 17, 3142-3145. (f) Chang, M.-Y.; Cheng, Y.-C. Org. Lett. 2015, 17, 5702-5705. For synthetic applications on β-ketosulfones by the authors, for (E)styrylsulfones, see: (a) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Synlett 2014, 25, 1739-1744. For vinylcyclopropanes, see: (b) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Tetrahedron 2014, 70, 8908-8913. For 2,5-diaryltetrahydrofurans, see: (c) Chang, M.-Y.; Cheng, Y.-C. Synlett 2016, 27, 854-858. For 2,6-diaryltetrahydropyrans, see: (d) Chang, M.-Y.; Lu, Y.-J.; Cheng, Y.-C. Tetrahedron 2015, 71, 11921201. For 2-arylpyrroles, see: (e) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J. Org. Lett. 2014, 16, 6252-6255. For 2-vinylfurans, see: (f) Chan, C.-K.; Lu, Y.-J.; Chang, M.-Y. Tetrahedron 2015, 71, 95449549. For tetralins and benzosuberans, see: (g) Chang, M.-Y.; Cheng, Y.-C. Org. Lett. 2016, 18, 608-611. For phenanthrenes, see: (h) Chang, M.-Y.; Chen, Y.-C.; Chan, C.-K. Tetrahedron 2015, 71, 782791. For phenanthrofurans, see: (i) Chan, C.-K.; Chen, Y.-C.; Chen, Y.-L.; Chang, M.-Y. Tetrahedron 2015, 71, 9187-9195. For recent synthesis of β-ketosulfones, see: (a) Zhou, G.; Ting, P. T.; Aslanian, R. G. Tetrahedron Lett. 2010, 51, 939-941. (b) Pospisil, J.; Sato, H.; J. Org. Chem. 2011, 76, 2269-2272. (c) Kumar, A.; Muthyala, M. K. Tetrahedron Lett. 2011, 52, 5368-5370. (d) Tsui, G. C.; Glenadel, Q.; Lau, C.; Lautens, M. Org. Lett. 2011, 13, 208-211. (e) Kumar, R.; Namboothiri, I. N. N. Org. Lett. 2011, 13, 4016-4019. (f) Sreedhar, B.; Rawat, V. S. Synlett 2012, 23, 413-417. (g) Bouhlel, A.; Curti, C.; Tabele, C.; Vanelle, P. Molecules 2013, 18, 4293-4307.
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Supplementary Material Experimental procedure and scanned photocopies of NMR (CDCl3) spectral data were supported.