Sulfinyl moiety as an internal nucleophile. 1. Efficient stereoselective synthesis of fragment A of cryptophycin 3

Article abstract of DOI:10.1021/jo026802p

A novel, efficient, and stereoselective synthesis of fragment A of cryptophycin 3 is disclosed. The key step involves the regio- and stereoselective transformation of an unsaturated ester to a bromohydrin via anchimeric assistance by the sulfinyl group.

Full text of DOI:10.1021/jo026802p

significant clinical potential of the cryptophycins and
their relatively low natural abundance make them an
attractive target for total synthesis. By retrosynthetic
analysis, the structure of cryptophycins can be divided
into two halves, a hydroxy acid (fragment A) and a
peptidic subunit (fragment B). Herein we report a ste-
reocontrolled synthesis of fragment A of cryptophycin 3.
Su lfin yl Moiety a s a n In ter n a l Nu cleop h ile.
1. Efficien t Ster eoselective Syn th esis of
F r a gm en t A of Cr yp top h ycin 3†
Sadagopan Raghavan* and K. A. Tony
Organic Division I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India
purush101@yahoo.com
Received December 4, 2002
Abstr a ct: A novel, efficient, and stereoselective synthesis
of fragment A of cryptophycin 3 is disclosed. The key step
involves the regio- and stereoselective transformation of an
unsaturated ester to a bromohydrin via anchimeric as-
sistance by the sulfinyl group.
The synthesis of fragment A commenced from alcohol
9, which was prepared from the oxazolidinone 69 (Scheme
1). Acylation of 610 with methacraloyl chloride afforded
the imide 7. Titanium tetrachloride-promoted Michael
addition11 of thiophenol to oxazolidinone 7 afforded the
sulfide 8 and its diastereomer in a ratio of 92:8 (HPLC)
which were separated by column chromatography. Re-
duction of sulfide 8 with lithium aluminum hydride
afforded alcohol 912 and recovery of the chiral auxiliary 6.
Swern oxidation13 of alcohol 9 afforded the correspond-
ing aldehyde which without purification was subjected
to Wittig olefination using Still’s phosphonate14 to yield
predominantly the cis ester 10 along with the trans ester
in small quantity which were separated by column
chromatography. The stereochemical integrity of the
chiral center during the transformation of the alcohol 9
to the ester 10 was proven by a two-step transformation
of the latter to a diastereomerically homogeneous man-
delate ester 12. The sulfide 10 upon oxidation with
Cryptophycin 1 (1) is a macrocyclic depsipeptide iso-
lated from the blue-green alga belonging to the Nosto-
caceae.1 Its structure was established as 1 by Moore et
al.,2 who had isolated this and six other cryptophycins
independently from Nostoc sp. GSV 224. Among these
were cryptophycin 2 (2), cryptophycin 3 (3), and crypto-
phycin 4 (4).3 At about the same time, Kitagawa isolated
a depsipeptide from the marine sponge Dysidea arenaria4
that he named arenastatin which was found to be
identical to cryptophycin 24 (5). Moore and co-workers
have shown cryptophycin 1 to be a potent tumor-selective
cytotoxin.3,5 Its exceptional antiproliferative effects are
believed to be due to reversible high affinity binding to
microtubules.6
15
NaIO4 afforded an equimolar, inseparable mixture of
sulfoxides 13a and 13b. Treatment of the mixture of
unsaturated sulfoxides 13a and 13b with N-bromosuc-
ccinimide (NBS) in toluene as the solvent in the presence
of a stoichiometric quantity of water under an inert atmo-
(5) Golagoti, T.; Ogino, J .; Heltzel, C. E.; Husebo, T. L.; J ensen, C.
M.; Larsen, L. K.; Patterson, G. M. L.; Moore, R. E.; Mooberry, S. L.;
Corbett, T. H.; Valeriote, F. A.; J . Am. Chem. Soc. 1995, 117, 12030.
(6) Panda, D.; Himes, R. H.; Moore, R. E.; Wilson, L.; J ordan, M. A.
Biochemistry 1997, 36, 12948.
(7) Kobayashi, M.; Kurosu, M.; Wang, W.; Kitagawa, I. Chem.
Pharm. Bull. 1994, 42, 2394.
(8) (a) Rej, R.; Nguyen, D.; Go, B.; Fortin, S.; Lavallee, J .-F. J . Org.
Chem. 1996, 61, 6289. (b) Salamonczyk, G. M.; Han, K.; Guo, Z. Sih,
C. J . Org. Chem. 1996, 61, 6893. (c) Dhokte, U. P.; Khan V. V.;
Hutchinson, D. R.; Martinelli, M. J . Tetrahedron Lett. 1998, 39, 8771.
(d) White, J . D.; Hong, J .; Robarge, L. A. Tetrahedron Lett. 1998, 39,
8779. (e) White, J . D.; Hong, J .; Robarge, L. A. J . Org. Chem. 1999,
64, 6206. (f) Patel, V. F.; Andis, S. L.; Kennedy, J . H.; Ray, J . E.; Shultz,
R. M. J . Med. Chem. 1999, 42, 2588. (g) Ghosh, A. K.; Bischoff, A. Org.
Lett. 2000, 2, 1573. (h) Eggen, M.; Mossman, C. J .; Buck, S. B.; Nair,
S. K.; Bhat, L.; Ali, S. M.; Reiff, E. A.; Boge, T. L.; Georg, G. I. J . Org.
Chem. 2000, 65, 7792. (i) Eggen, M.; Nair, S. K.; Georg, G. I. Org. Lett.
2001, 3, 1813. (j) Li, L.-H.; Tius, M. A. Org. Lett. 2002, 4, 1637.
(9) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 77.
The first synthesis of arenastatin was reported by
Kitagawa et al. in 1994,7 and thereafter many syntheses8
of cryptophycin 1 (1) and analogues were reported. The
† IICT Communication No. 021016.
(1) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J . E.; Chartrain,
M. J .; Leisch, J . M.; Yudin, K. J . Ind. Microbiol. 1990, 5, 113.
(2) Barrow, R. A.; Hemscheidt, T.; Liang, J .; Paik, S.; Moore, R. E.;
Tius, M. A. J . Am. Chem. Soc. 1995, 117, 2477.
(3) Trimurthulu, G.; Ohtani, I.; Patterson, G. M. L.; Moore, R. E.;
Corbett, T. H.; Valeriote, F. A.; Demchik, L. J . Am. Chem. Soc. 1994,
116, 4729.
(10) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 83.
(11) Tseng, T.-C.; Wu, M.-J . Tetrahedron: Asymmetry 1995, 6, 1633.
(12) For the preparation of the enantiomer of 9 refer: Baker, R.;
O’Mahony, M. J .; Swain, C. J . J . Chem. Soc., Perkin Trans. 1 1987,
1623.
(4) (a) Kobayashi, M.; Aoki, S.; Ohyabu, N.; Kurosu, M.; Wang, W.;
Kitagawa, I. Tetrahedron Lett. 1994, 35, 7969. (b) Kobayashi, M.;
Kurosu, M.; Ohyabu, N.; Wang, W.; Fujii, S.; Kitagawa, I. Chem.
Pharm. Bull. 1994, 42, 2196.
(13) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(14) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(15) Leonard, N. J .; J ohnson, C. R. J . Org. Chem. 1962, 27, 282.
10.1021/jo026802p CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/16/2003
5002
J . Org. Chem. 2003, 68, 5002-5005

SCHEME 1a
a
Reaction conditions: (a) n-BuLi, THF, -78 °C, 90%; (b) TiCl4,
PhSH, CH2Cl2, -78 °C, 88%, 92:8 of 8 and its diastereomer; (c)
LiAlH4, THF, 0 °C, 80%.
SCHEME 2a
F IGURE 1.
SCHEME 4a
a
Reaction conditions: (a) (COCl)2, DMSO, iPrNEt2, CH2Cl2, -60
°C; (b) NaH, (F3CH2O)2P(O)CH2CO2Me, THF, 0 °C, -78 °C,
aldehyde, 71% for two steps, 8.5:1.5 of cis ester 10:trans ester; (c)
DIBAL, CH2Cl2, -78 °C, 75%; (d) DCC, DMAP, (S)-methoxyman-
delic acid, CH2Cl2, 0 °C to rt, 75%; (e) NaIO4, MeOH, H2O, 0 °C to
rt, 95%; (f) NBS, toluene, H2O, rt, 80%; (g) m-CPBA, CH2Cl2, 0 °C
to rt, 80%.
SCHEME 3a
a
Reaction conditions: (a) n-Bu3SnH, AIBN, PhH, 80 °C, 82%;
(b) TBDPS-Cl, imidazole, CH2Cl2, rt, 70%; (c) DIBAL, CH2Cl2, -78
°C, 85%; (d) Ph3PCHCO2Me, PhH, rt, 85%; (e) TFAA, Et3N,
CH3CN, then aq sat. NaHCO3; (f) (i) Ph3PCH2PhBr, n-BuLi, THF,
0 °C, aldehyde; (ii) PhSH, AIBN, PhH, 80 °C, 60% for three steps.
a
Reaction conditions: (a) DIBAL, CH2Cl2, -78 °C, 80%; (b)
TBDPS-Cl, imidazole, CH2Cl2, rt, 85%; (c) NBS, toluene, H2O, rt,
75%; (d)) m-CPBA, CH2Cl2, 0 °C to rt, 80%.
and subsequent hydrolysis of these by attack of water at
sulfur18 to yield bromohydrins 14a and 14b. The alter-
nate intermediates A′ and B′ would be disfavored for
steric reasons (A1,3 strain,19 Figure 1). The allyl substitu-
ent alone therefore influences the asymmetric induction,
and the sulfoxide configuration has no influence on the
stereochemical outcome.
The 5-exo nucleophilic attack by the sulfinyl group is
probably due to the inductive electron-withdrawing
nature of the carbomethoxy group which would destabi-
lize any partial positive charge developing at C2.20 The
cis olefin geometry predicates syn disposition of the
bromine and hydroxy groups due to the overall trans
addition of the electrophile and nucleophile across the
face of the olefin.
sphere afforded the bromohydrins 14a and 14b as an in-
separable mixture in high yield. Sulfoxides 14a and 14b
yielded sulfone 15 (Scheme 2) upon treatment with m-
CPBA, the 1H NMR spectrum of which revealed only one
set of signals, proving beyond doubt the isomeric char-
acter of 14a and 14b as a consequence of sulfur chirality.
The structure of bromohydrin 14 that has both the
stereocenters required for elaboration to fragment A was
unambiguously proven by transforming the sulfone 15
to the known silyl ether 17, elaborated earlier from the
allyl ether 1816 (Scheme 3).
The observed regio- and stereoselectivity in the reac-
tion of sulfoxide 13a and 13b with NBS can be explained
by invoking sulfoxonium intermediates A and B, respec-
tively, formed by the nucleophilic attack of the sulfinyl
group on the olefin complexed to the bromonium ion17
The bromohydrin 14 was transformed to fragment A
as depicted in Scheme 4. Thus debromination of 14 with
tributyltin hydride afforded sulfoxide 20 which revealed
(16) Raghavan, S.; Ramakrishna Reddy, S.; Tony, K. A.; Naveen
Kumar, Ch.; Varma, A. K.; Nangia, A. J . Org. Chem. 2002, 67, 5838.
(17) In the case of halogen additions, onoim intermediates are
generally freely reversible. See Guindon, Y.; Slassi, A.; Ghiro, E.;
Bantle, G.; J ung, G. Tetrahedron Lett. 1992, 33, 4257 and references
therein.
(18) Khuddus, M. A.; Swern, D. J . Am. Chem. Soc. 1973, 95, 8393.
(19) (a) J ohnson, F. Chem. Rev. 1968, 68, 375. (b) Hoffmann, R. W.
Chem. Rev. 1989, 89, 1841.
(20) Guindon, Y.; Soucy, F.; Yaokim, C.; Ogilvie, W. W.; Plamondon,
L. J . Org. Chem. 2001, 66, 8992.
J . Org. Chem, Vol. 68, No. 12, 2003 5003

in dry dichloromethane (8 mL) cooled at -78 °C was added the
solution of DMSO (1.09 g, 14 mmol) in dry dichloromethane (7
mL), and the mixture was stirred at the same temperature for
another 15 min. The solution of the alcohol 9 (1.82 g, 10 mmol)
in dry dichloromethane (10 mL) was added dropwise to the above
mixture, and stirring was continued at the same temperature
for 45 min. Hunig’s base (6.50 g, 50 mmol) was then added and
the reaction mixture allowed to warm to -10 °C. Water (50 mL)
was added, and the two layers were separated. The aqueous
layer was extracted with dichloromethane (2 × 25 mL). The
combined organic layers were washed with water and brine and
dried over Na2SO4. The solvent was evaporated under reduced
pressure keeping the water bath temperature around 20 °C to
afford the crude aldehyde which was taken ahead to the next
step without further purification. To a stirred suspension of NaH
(0.36 g, 50% in Nujol, 8 mmol) in dry THF (10 mL) cooled at 0
°C was added the solution of methyl (2,2,2-trifluoroethylphospho-
no)acetate (2.4 g, 7.5 mmol) in dry THF (5 mL) dropwise and
stirred for 30 min. The reaction mixture was then cooled to -78
°C, and the solution of the aldehyde in dry THF (5 mL) was
added and stirred at the same temperature for another 1 h. The
reaction was quenched by the addition of a saturated aq NH4Cl
solution (10 mL). The reaction mixture was diluted with EtOAc
(25 mL), and the organic layer was separated. The aqueous layer
was extracted with EtOAc (25 mL), and the combined organic
layers were washed with water and brine and dried over Na2-
SO4. The solvent was removed under reduced pressure to afford
the crude product as a mixture of the cis and the trans esters.
Separation of the esters by column chromatography using 3%
EtOAc/petroleum ether (v/v) as the eluent afforded cis ester 10
the presence of methylene protons adjacent to the car-
bomethoxy group as understood from an examination of
1
its H NMR and 13C NMR spectra, thereby also proving
the regioselectivity of bromohydrin formation.
Treatment of the debrominated alcohol 20 with tert-
butyldiphenylsilyl chloride afforded the silyl ether 21 as
an epimeric mixture of sulfoxides. Reduction of the carbo-
methoxy group with DIBAL afforded the aldehyde 22
which was taken ahead to the next step without further
purification. Two-carbon homologation by subjecting the
aldehyde to treatment with methyl(triphenylphosphoran-
ylidene)acetate in benzene afforded the trans ester 23
exclusively. Pummerer reaction21 followed by an aq sodium
bicarbonate workup of the resulting intermediate yielded
the aldehyde 24. Without further purification, Wittig
reaction of aldehyde 24 with the unstable ylide generated
from benzylphosphonium bromide afforded a mixture of
cis and trans isomers. The above mixture without sepa-
ration was subjected to treatment with thiophenol22 to
effect isomerization of the cis to the trans isomer to yield
dienoate 25. It is instructive to note that attempted
elaboration of the dienoate 25 by J ulia olefination of the
sulfone derived from the sulfoxide 23 failed. Attempted
condensation of the sulfone anion generated using a
variety of bases and employing different protocols, with
benzaldehyde only returned unreacted starting material.
The dienoate 25 was found to be possess physical
characteristics similar to the product elaborated by Tius
and co-workers.2
1
(1.68 g) in 71% yield. Liquid. H NMR (200 MHz, CDCl3) δ 1.98
(d, J ) 6.8 Hz, 3H), 2.92 (d, J ) 4.5 Hz, 2H), 3.68 (s, 3H), 3.80
(m, 1H), 5.78 (d, J ) 10.0 Hz, 1H), 6.20 (t, J ) 10.0 Hz, 1H),
7.12-7.26 (m, 5H); 13C NMR (50 MHz, CDCl3) δ 19.6, 32.6, 40.5,
51.0, 119.4, 125.9, 128.8, 129.4, 136.7, 152.9, 166.3. [R]D +65 (c
2.5 EtOAc). HRMS-FAB (m/z) [M]+ calcd for C13H16O2S 236.0871,
found 236.0872.
In conclusion, we have developed a novel, efficient, and
stereoselective route to fragment A of cryptophycin 3
employing the sulfinyl moiety as an intramolecular
nucleophile to functionalize an unsaturated ester in a key
step of the reaction sequence. The sulfinyl moiety has
been exploited to reveal an aldehyde group for further
elaboration.
Met h yl 4-Met h yl-5-p h en ylsu lfin yl-(Z,4S)-2-p en t en oa t e
13. To the stirred solution of the ester 10 (2.36 g, 10 mmol) in
MeOH (100 mL) cooled at 0 °C was added dropwise a solution
of NaIO4 (2.35 g, 11 mmol) in water (50 mL), and the reaction
mixture was stirred overnight gradually allowing it to warm to
rt. The precipitated solid was filtered, and the methanol in the
filtrate was evaporated under reduced pressure. The aqueous
layer was then extracted with EtOAc (2 × 100 mL). The
combined organic layer was washed with brine and dried over
Na2SO4. The solvent was evaporated under reduced pressure to
afford the crude product which was then purified by column
chromatography using 4:6 EtOAc:petroleum ether as the eluent
to afford the sulfoxides 13a and 13b as an inseparable mixture
(2.39 g) in 95% yield. Solid. 1H NMR (400 MHz, CDCl3) δ 1.20
(d, J ) 7.2 Hz, 3H), 1.24 (d, J ) 7.2 Hz, 3H), 2.70 (m, 2H), 2.86
(m, 2H), 3.68 (s, 3H), 3.69 (s, 3H), 4.0 (m, 1H), 4.05 (m, 1H),
5.95 (d, J ) 9.2 Hz, 2H), 6.60 (t, J ) 9.2 Hz, 2H), 7.48 (m, 6H),
7.60 (m, 4H). 13C NMR (50 MHz, CDCl3) δ 20.0, 20.1, 29.0, 29.4,
51.2, 64.8, 119.5, 119.8, 124.0, 124.1, 128.1, 129.2, 131.0, 151.0,
166.1. HRMS-FAB (m/z) [M + H]+ calcd for C13H17O3S 253.0898,
found 253.0900
Meth yl 2-Br om o-3-h yd r oxy-4-m eth yl-5-p h en ylsu lfin yl-
(2S,3R,4S)-p en ta n oa te 14. To the stirred solution of the
unsaturated sulfoxide 13 (1.76 g, 7 mmol) in toluene (28 mL)
was added water (0.18 mL, 10 mmol) followed by NBS (1.37 g,
7.7 mmol) at rt. The reaction mixture was stirred at rt for 3 h
when TLC examination revealed the completion of the reaction.
The reaction mixture was diluted with EtOAc and washed
successively with saturated aq NaHCO3, water, and brine and
dried over Na2SO4. The solvent was removed under reduced
pressure to afford the crude product which was purified by
column chromatography using 4.5:5.5 EtOAc:petroleum ether
as the eluent to yield bromohydrin 14 (2.0 g) in 80% yield.
Viscous oil. 1H NMR (400 MHz, CDCl3) δ 1.12 (d, J ) 8.8 Hz,
3H), 1.20 (d, J ) 8.8 Hz, 3H), 2.37 (m, 2H), 2.65-3.1 (m, 4H),
3.80 (m, 5H), 3.82 (s, 3H), 4.45 (d, J ) 8.8 Hz, 2H), 7.50 (m,
6H), 7.62 (m, 4H). 13C NMR (50 MHz, CDCl3) δ 16.6, 17.2, 33.8,
Exp er im en ta l Section
NBS was freshly recrystallized from hot water before use.
NMR spectra were recorded on
a 200, 300, or 400 MHz
spectrometer. 1H NMR and 13C NMR samples were internally
referenced to TMS (0.00 ppm). Column chromatography was
performed with 60-120 mesh silica gel.
2-Met h yl-3-p h en ylsu lfa n yl-(2S)-p r op a n -1-ol 9. To the
stirred suspension of LAH (0.42 g, 11.3 mmol) in dry THF (5
mL), cooled at 0 °C, was added the solution of sulfide 8 (5.32 g,
15 mmol) in dry THF (15 mL) over a period of 5 min and stirred
at the same temperature for another 2 h. The reaction mixture
was diluted with ether, and excess LAH was quenched by adding
small pieces of ice and allowed to attain rt when a gel separated
out. The gel was filtered and washed with hot EtOAc (2 × 25
mL). The combined filtrates were evaporated under reduced
pressure, and the resulting crude product was purified by column
chromatography using 8% EtOAc/petroleum ether (v/v) as the
eluent to afford alcohol 9 (2.2 g) in 80% yield. Viscous liquid. 1H
NMR (200 MHz, CDCl3) δ 1.02 (d, J ) 7.3 Hz, 3H), 1.90 (m,
1H), 2.80 (dd, J ) 13.4, 7.3 Hz, 1H), 3.05 (dd, J ) 13.4, 7.3 Hz,
1H), 3.50 (br s, 2H), 7.30 (m, 5H). [R]D + 14.6 (c 1, CH2Cl2).
Rotation for the enantiomer: (([R]D -17 (c 1, CH2Cl2)).12 Anal.
Calcd for C10H14OS: C, 65.90; H, 7.70; Found: C, 65.70; H, 7.52.
Meth yl 4-Meth yl-5-p h en ylsu lfa n yl-(Z,4S)-2-p en ten oa te
10. To the stirred solution of oxalyl chloride (1.40 g, 11.0 mmol)
(21) (a) Pummerer, R. Chem. Ber. 1909, 42, 2282. (b) Sugihara, H.;
Tanikaga, R.; Kaji, A. Synthesis 1978, 881. (c) Padwa, A.; Gunn, D.
E., J r.; Osterhout, M. H. Synthesis 1997, 1353.
(22) Schwarz, M.; Gaminski, G. F.; Waters, R. M. J . Org. Chem.
1986, 51, 260.
5004 J . Org. Chem., Vol. 68, No. 12, 2003

34.1, 50.7, 51.2, 53.3, 60.3, 61.4, 74.1, 74.3, 124.0, 124.1, 128.3,
131.1, 143.9, 177.5. HRMS-FAB (m/z) [M + H]+ calcd for
C13H18O4SBr 349.0109, found 349.0130.
under reduced pressure to afford a residue which was purified
by column chromatography using 3:7 EtOAc:petroleum ether as
the eluent to yield the unsaturated ester 23 (0.70 g) in an overall
yield of 72% for two steps. Viscous oil. 1H NMR (400 MHz,
CDCl3) δ 1.04 (s, 9H), 1.08 (d, J ) 8.1 Hz, 3H), 1.15 (d, J ) 8.1
Hz, 3H), 2.18-2.28 (m, 6H), 2.32-2.95 (m, 4H), 3.62-3.72 (m,
8H), 5.46 (d, J ) 16.2 Hz, 1H), 5.60 (d, J ) 16.2 Hz, 1H), 6.46
(m, 1H), 6.60 (m, 1H), 7.27-7.60 (m, 30H). 13C NMR (75 MHz,
CDCl3) δ 16.2, 17.0, 19.4, 27.0, 33.3, 33.8, 36.8, 36.9, 51.3, 60.6,
60.9, 75.6, 75.9, 123.5, 123.9, 124.1, 127.5, 127.6, 127.7, 129.2,
129.8, 129.9, 130.9, 131.2, 133.0, 133.5, 135.8, 135.9, 144.2, 144.3,
166.2, 166.3. HRMS-FAB (m/z) [M + H]+ calcd for C31H39O4SiS
535.2338, found 535.2331.
Meth yl 2-Br om o-3-h yd r oxy-4-m eth yl-5-p h en ylsu lfon yl-
(2S,3R,4S)-p en ta n oa te 15. To the stirred solution of the
sulfoxide 14 (0.174 g, 0.5 mmol) in dichloromethane (2 mL)
cooled at 0 °C was added m-CPBA (70%, 0.15 g, 0.6 mmol), and
the reaction was stirred overnight. The reaction mixture was
diluted with EtOAc (10 mL) and washed successively with
saturated aq sodium sulfite, saturated aq sodium bicarbonate,
water, and brine and dried over Na2SO4. The solvent was
removed under reduced pressure to afford the crude product
which was purified by column chromatography using 3:7 EtOAc:
petroleum ether to afford sulfone 15 (0.146 g) in 80% yield.
Viscous oil. 1H NMR (400 MHz, CDCl3) δ 1.20 (d, J ) 6.6 Hz,
3H), 2.35 (m, 1H), 2.95 (dd, J ) 14.1, 8.1 Hz, 1H), 3.55 (dd, J )
14.1, 2.8 Hz, 1H), 3.70 (dd, J ) 8.1, 3.7 Hz, 1H), 3.82 (s, 3H),
4.30 (d, J ) 3.7 Hz, 1H), 7.55-7.74 (m, 3H), 7.85-7.88 (m, 2H).
13C NMR (50 MHz, CDCl3) δ 16.5, 33.1, 49.5, 53.4, 57.7, 73.4,
127.8, 129.3, 133.7, 139.8, 169.4. [R]D -9.0 (c 1, EtOAc). Anal.
Calcd for C13H18O5BrS: C, 42.75; H, 4.69; S, 8.78. Found: C,
42.72; H, 4.62; S, 8.80.
Met h yl 3-H yd r oxy-4-m et h yl-5-p h en ylsu lfin yl-(3S,4S)-
p en ta n oa te 20. To the stirred solution of the sulfoxide14 (1.40
g, 4.0 mmol) in dry benzene (16 mL) maintained at 80 °C was
added AIBN (65 mg, 0.4 mmol) followed by tributyltin hydride
(1,28 g, 4.4 mmol), and reaction was stirred at the same
temperature under a nitrogen atmosphere for 3 h when TLC
examination revealed completion of the reaction. The solvent
was removed under reduced pressure and the residue purified
by column chromatography using 4.5:5.5 EtOAc:petroleum ether
as the eluent to yield the debrominated product 20 (0.88 g) in
82% yield. Viscous oil. 1H NMR (400 MHz, CDCl3) δ 1.13 (d, J
) 7.8 Hz, 3H), 1.25 (d, J ) 7.8 Hz, 3H), 2.20 (m, 2H), 2.40-3.05
(m, 8H), 3.72 (s, 6H), 3.94 (m, 2H), 7.45-7.58 (m, 6H), 7.62-
7.70 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 16.5, 17.3, 34.5, 35.3,
38.9, 39.3, 51.8, 61.2, 61.5, 71.3, 123.9, 124.0, 129.2, 129.3, 131.0,
143.7, 144.3, 172.7, 173.0. ms [EI] 271.
Meth yl 3-ter t-Bu tyld ip h en ysilyloxy-4-m eth yl-5-p h en yl-
su lfin yl-(3S,4S)-p en ta n oa te 21. To the solution of the alcohol
20 (0.78 g, 2.9 mmol) in dry dichloromethane (3.5 mL) was added
imidazole (0.47 g, 7.0 mmol) followed by TBDP-Cl (0.88 g, 3.2
mmol) and the mixture stirred at rt for 24 h. The reaction
mixture was diluted with ether (50 mL), washed with water and
brine, and dried over Na2SO4. The solvent was removed under
reduced pressure to afford the crude product which was purified
by column chromatography using 1:3 EtOAc:petroleum ether as
the eluent to yield the silyl ether 21 (1.02 g) in 70% yield. 1H
NMR (400 MHz, CDCl3) δ 1.02 (s, 18H), 1.06 (d, J ) 8.0 Hz,
3H), 1.14 (d, J ) 8.0 Hz, 3H), 2.04-2.26 (m, 2H), 2.25-2.88 (m,
8H), 3.40 (s, 6H), 4.08-4.20 (m, 2H), 7.25-7.72 (m, 30H). 13C
NMR (75 MHz, CDCl3) δ 15.6, 16.1, 19.3, 19.4, 27.0, 27.9, 34.2,
34.7, 38.6, 39.3, 51.4, 60.9, 61.0, 73.0, 73.4, 123.9, 124.1, 127.4,
127.5, 127.6, 129.2, 129.6, 129.7, 130.9, 131.0, 132.9, 133.0, 133.7,
133.8, 135.8, 135.9, 136.0, 144.2, 144.5, 171.2. HRMS-FAB
(m/z) [M + H]+ calcd for C29H37O4SiS 509.2181, found 509.2181.
Meth yl 5-ter t-Bu tyld ip h en ylsilyloxy-6-m eth yl-7-p h en yl-
su lfin yl-(E,5S,6S)-2-h ep ten oa te 23. To the solution of the silyl
ether 21 (0.912 g, 1.8 mmol) in dry dichloromethane (4.0 mL)
cooled at -78 °C was added DIBAL (2.0 M/toluene, 0.9 mL, 1.8
mmol), and the mixture was stirred at the same temperature
for 30 min. Ether (10 mL) followed by a few drops of water was
added and the reaction mixture allowed to warm to rt. The gel
was filtered and washed with hot EtOAc (2 × 10 mL). The
combined filtrates were dried over Na2SO4, and the solvent was
removed under reduced pressure to afford the crude aldehyde
22 (0.73 g) in 85% yield which was used in the next step without
further purification. 1H NMR (400 MHz, CDCl3) δ 0.98 (s, 18H),
1.0 (d, J ) 6.6 Hz, 3H), 1.05 (d, J ) 6.6 Hz, 3H), 1.98-2.02 (m,
4H), 2.20-2.85 (m, 6H), 4.02-4.20 (m, 2H), 7.20-7.70 (m, 30H),
9.30 (m, 2H).
Meth yl 5-ter t-Bu tyld ip h en ylsilyloxy-6-m eth yl-8-p h en yl-
(2E,5S,6R,7E)-2,7-octa d ien oa te 25. To the solution of the ester
23 (0.15 g, 0.28 mmol) in dry acetonitrile (2.8 mL) was added
Et3N (0.23 g, 2.24 mmol) followed by TFAA (0.35 g, 1.68 mmol)
at rt, and the mixture was stirred for 30 min. A solution of
NaHCO3 (0.24 g, mmol) in water (3 mL) was added at 0° C, and
stirring was continued, gradually allowing it to attain rt. The
reaction mixture was diluted with ether (10 mL) and the aqueous
layer separated. The aqueous layer was extracted with ether (2
× 10 mL), and the combined organic layers were washed with
brine and dried over Na2SO4. The solvent was removed under
reduced, keeping the water bath temperature around 20 °C to
afford the crude aldehyde 24 (0.14 g) which was taken ahead to
the next step without further purification. To the suspension of
benzyltriphenylphosphonium bromide (0.4 g, 0.8 mmol) in dry
THF (3.2 mL) was added n-BuLi (1.6 M/hexanes, 0.35 mL, 0.56
mmol) at 0 °C and the mixture stirred for 15 min. The solution
of the aldehyde in dry THF (1.2 mL) was then added and stirring
continued for 30 min at 0 °C. The reaction was quenched with
a saturated aqueous solution of NH4Cl. The organic layer was
separated and the aqueous layer was extracted with ether (2 ×
10 mL). The combined organic layers were washed with water
and brine and dried over Na2SO4. The solvent was removed
under reduced pressure to afford the crude product which was
purified by column chromatography using 1:9 EtOAc:petroleum
ether as the eluent to yield the dienoate 25 and the cis isomer.
This mixture was dissolved in benzene (0.5 mL), thiophenol (5
mg) was added, and the mixture was heated at 80 °C. AIBN (2
mg) was added and the mixture heated at reflux for 3 h.
Evaporation of the solvent afforded the crude product which was
purified by column chromatography using 1:9 EtOAc:petroleum
ether as the eluent to yield dienoate 25 (70 mg) in 60% overall
1
yield for three steps. Viscous oil. H NMR (400 MHz, CDCl3) δ
1.88 (s, 9H), 1.12 (d, J ) 5.9 Hz, 3H), 2.35 (m, 2H), 2.42 (m,
1H), 3.68 (s, 3H), 3.82 (m, 1H), 5.66 (d, J ) 11.8 Hz, 1H), 6.15
(dd, J ) 11.8, 5.9 Hz, 1H), 6.25 (d, J ) 11.8 Hz, 1H), 6.77 (dt, J
) Hz, 1H), 7.12-7.50 (m, 11H), 7.68-7.71 (m, 4H). 13C NMR
(75 MHz, CDCl3) δ 16.2, 19.5, 27.1, 37.2, 42.2, 51.3, 76.3, 122.9,
126.1, 127.1, 127.5, 127.6, 128.5, 129.7, 129.8, 130.7, 131.8, 133.7,
134.1, 136.0, 137.6, 145.9, 166.7. [R]D + 74 (c 1, CHCl3) (([R]D
+
76 (c 0.4, CHCl3)).2a HRMS-FAB (m/z) [M - H]+ calcd for
C
32H37O3Si 497.2512, found 497.2508.
Ack n ow led gm en t. S.R. is thankful to Dr. J . S.
Yadav, Head, Organic Div. I, and Dr. K. V. Raghavan,
Director, IICT, for constant support and encouragement,
to Dr. A. C. Kunwar for NMR spectra, and Dr. M.
Vairamani for the mass spectra. K.A.T. is thankful to
CSIR (New Delhi) for the senior research fellowship.
Financial assistance from DST is gratefully acknowl-
edged.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of compounds 7, 8, 11, and 12
(including analytical data) and copies of 1H and 13C NMR data
of all the reported compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
To the solution of the above aldehyde in dry benzene (6.0 mL)
was added methyl (triphenylphosphoranylidene)acetate (0.62 g,
1.84 mmol) and stirred at rt for 30 min. The solvent was removed
J O026802P
J . Org. Chem, Vol. 68, No. 12, 2003 5005