Synthetic studies toward highly functionalized 5β-lanosterol derivatives: A versatile approach utilizing anionic cycloaddition

Article abstract of DOI:10.1021/jo0608725

Stereoselective synthesis of the potentially biologically valuable 5β-lanosteroidal-type backbone was achieved via anionic cycloaddition. Synthesis of the two new bicyclic Nazarov intermediates 14 and 40 and their cycloaddition with chiral cyclohexenone 2

Full text of DOI:10.1021/jo0608725

Synthetic Studies toward Highly Functionalized 5â-Lanosterol
Derivatives: A Versatile Approach Utilizing Anionic Cycloaddition
Sreekanth A. Ramachandran,† Rajendra K. Kharul,† Sylvain Marque,† Pierre Soucy,†
Fre´de´ric Jacques,‡ Robert Cheˆnevert,‡ and Pierre Deslongchamps*,†
Laboratoire de Synthe`se Organique, Institut de Pharmacologie de Sherbrooke, UniVersite´ de Sherbrooke,
Sherbrooke, Que´bec J1H 5N4, Canada, and De´partement de Chimie, Faculte´ des Sciences et de Ge´nie
UniVersite´ LaVal, Que´bec G1K 7P4, Canada
pierre.deslongchamps@usherbrooke.ca
ReceiVed April 26, 2006
Stereoselective synthesis of the potentially biologically valuable 5â-lanosteroidal-type backbone was
achieved via anionic cycloaddition. Synthesis of the two new bicyclic Nazarov intermediates 14 and 40
and their cycloaddition with chiral cyclohexenone 25 and further functional group manipulations resulted
in highly functionalized tetracyclic intermediates 28 and 44. These synthetic intermediates could lead to
the total synthesis of new lanosterol-based inhibitors.
Introduction
library of potential candidates for biological evaluation. In this
paper, we describe a general synthetic strategy for the stereo-
selective construction of 5â-analogues having a lanosterol-type
backbone via anionic cycloaddition.
Functionalized lanosterol derivatives present unique and
significant importance due to their interesting biological proper-
ties. Recent studies have shown that steroids having the general
structure 1 (Figure 1) exhibit 14R-demethylase inhibitory
activity1 and lanosterol derivatives such as 2 possess antitumor
properties.2 Studies from Merck laboratories have identified
recently isolated natural product clavaric acid 3, a similar
structural analogue, as a potential human farnesyl-protein
transferase (FPTase) inhibitor.3
Recently our laboratory was involved in developing a novel
methodology for the construction of a steroid backbone via
anionic cycloaddition between a functionalized cyclohexenone
and a bicyclic Nazarov intermediate resulting in stereoselective
formation of a highly functionalized tetracycle.4 A representative
example of this strategy is shown in Scheme 1.
It is worth noting that development of a common intermediate
possessing the basic skeleton of these steroids would lead to a
On the basis of this strategy we envisaged the construction
of a functionalized lanosterol moiety having an A-B cis-
junction, which could serve as a key intermediate for the
synthesis of a library of potential 14R-demethylase inhibitors.
The proposed retrosynthetic analysis (Scheme 2) revealed that
the intermediate 4 could be easily developed into potential
candidates, which in turn could be obtained from 5, the tetracylic
intermediate of anionic cycloaddtion between cyclohexenone
6 and Nazarov intermediate 7.
† Universite´ de Sherbrooke.
‡ Universite´ Laval.
(1) (a) Trzaskos, J. M.; Ko, S. S.; Magolda, R. L.; Favata, M. F.; Fischer,
R. T.; Stam, S. H.; Johnson, P. R.; Gaylor, J. L. Biochemistry 1995, 34,
9670. (b) Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347.
(2) (a) Sonoda, Y.; Ichinose, K.; Yoshimura, S.; Sato, Y.; Sasaki, T.
Chem. Pharm. Bull. 1991, 39, 100. (b) Sonoda, Y.; Obi, N.; Onoda, M.;
Sakakibara, Y.; Sato, Y. Chem. Pharm. Bull. 1992, 40, 2796.
(3) Jayasuriya, H.; Silverman, K. C.; Zink, D. L.; Jenkins, R. G.; Sanchez,
M.; Pelaez, F.; Vilella, D.; Lingham, R. B.; Singh, S. B. J. Nat. Prod. 1998,
61, 1568. (b) Lingham, R. B.; Silverman, K. C.; Jayasuriya, H.; Moon Kim,
B.; Amo, S. E.; Wilson, F. R.; Rew, D. J.; Schaber, M. D.; Bergstrom, J.
D.; Koblan, K. S.; Graham, S. L.; Kohl, N. E.; Gibbs, J. B.; Singh, S. B.
J. Med. Chem. 1998, 4492.
(4) (a) Lepage, O.; Stone, C.; Deslongchamps, P. Org. Lett. 2002, 4,
1091. (b) Yang. Z.; Shannon, D.; Truong, V. L.; Deslongchamps, P. Org.
Lett. 2002, 4, 4693. (c) Lepage, O.; Deslongchamps, P. J. Org. Chem. 2003,
68, 2183. (d) Guay, B. Deslongchamps, P. J. Org. Chem. 2003, 68, 6140.
10.1021/jo0608725 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/01/2006
J. Org. Chem. 2006, 71, 6149-6156
6149

Ramachandran et al.
FIGURE 1. Functionalized lanosterol-based inhibitors.
SCHEME 1a
With both components in hand, the anionic cycloaddition
between cyclohexenone 6 and Nazarov intermediate 14 was
studied (Scheme 4). Under optimized conditions, cycloaddition
carried out using Cs2CO3 in ethyl acetate followed by dealkoxy-
carbonylation13 and purification by silica gel chromatography
furnished the two diastereomers 15 and 16 in 4:1 ratio.
The structures of both diastereomers 15 and 16 were
confirmed by single-crystal X-ray analysis. The major dia-
stereomer 15 was then converted into an advanced intermediate
18 by the following transformations (Scheme 5). The aldehyde
at C10 (steroid numbering) was selectively reduced using NaBH4
in methanol to alcohol 17, which was then converted into the
corresponding xanthate derivative14 by standard procedure
followed by Barton-McCombie deoxygenation15 to furnish the
tetracycle 18. It is also interesting to note that the minor
diastereomer 16 obtained by anionic cycloaddition could well
serve as an advanced precursor for the synthesis of the unnatural
enantiomer of biologically active friedolanostanes.16
Recently we have shown that the use of enantiomerically pure
5-(trialkylsilyl)-2-cyclohexenones as ring A precursor will
efficiently control the stereoselectivity of anionic cycloaddi-
tion.17,18 Hence we decided to synthesize enatiomerically pure
5-(trialkylsilyl)-2-cyclohexenone 25 with a 4,4′-gem-dimethyl
group (Scheme 6). The synthesis starts with the 1,4-addition of
a dimethylphenylsilylzinc species to 4,4′-dimethyl-2-cyclo-
hexenone in the presence of catalytic CuI as previously
reported.19 The ketone 20 was then reduced diastereoselectively
using tri-tert-butoxylithiumalumium hydride to furnish syn-
alcohol 21 (syn:anti 9:1), which was separated from the anti-
alcohol by chromatography. Kinetic resolution of the racemic
syn-alcohol 21 using Lipase B Candida antarctica20 with vinyl
acetate as solvent furnished enantiomerically pure (+)-syn-
alcohol 22 in 48% yield and g98% ee21a along with acetate
enantiomer 22a. The absolute configuration of compounds 22
and 22a were determined on the basis of the empirical rule by
Kazlauskas,21b commonly used for the lipase-catalyzed enzy-
matic resolution reactions and later confirmed by X-ray analysis
a Reagents and conditions: (a) Cs2CO3, CH2Cl2, (b) Pd(PPh3)4, mor-
pholine, THF, 87% (2 steps).
Results and Discussion
Our investigation toward this goal was commenced by the
synthesis of Nazarov intermediate 14 (Scheme 3). The Hajos-
Parish ketone 85 was identified as the suitable starting material
for this purpose. The ketone 8 was transformed into nitrile 9 as
previously reported.6,4b The enone thus obtained was subjected
to carboxylation using magnesium methyl carbonate7 followed
by esterification with diazomethane8 to furnish â-keto ester 10
in 65-70% yield in two steps. To obtain the desired ester 12,
we opted for triflation of ester 10 followed by hydrogenolysis.
Under optimized conditions, ester 10 was transformed into
triflate 119 using N,N-diisopropylethylamine and triflic anhydride
at -78 °C. Hydrogenolysis of triflate 11 was achieved by a
standard protocol.10 The ester 12 was then saponified with KOH
to furnish acid 13. This acid was converted into the correspond-
ing acid chloride with oxalyl chloride11 in the presence of
catalytic DMF, and the product was then allowed to react with
the lithium enolate of allyl acetate prepared in situ to give the
desired Nazarov intermediate 14 in 78% yield from acid 13.
The functionalized cyclohexenone 6 that would serve as the
ring A precursor was synthesized according to the previously
reported procedure.12
(5) Hajos, Z. G.; Parrish, D. R. Org. Synth. 1985, 63, 26.
(6) (a) Caine, D.; Kotian, P. L. J. Org. Chem. 1992, 57, 6587. (b) Deng,
W.; Jensen, M. S.; Overman, L. E.; Rucker, P. V.; Vionnet, J. P. J. Org.
Chem. 1996, 61, 6760. (c) Yang. Z.; Shannon, D.; Truong, V. L.;
Deslongchamps, P. Org. Lett. 2002, 4, 4693.
(7) (a) Isaacs, R. C. A.; Di Grandi, M. J.; Danishefsky, S. J. J. Org.
Chem. 1993, 58, 3938. (b) Rychnovsky, S. D.; Mickus, D. E. J. Org. Chem.
1992, 57, 2732. (c) Kerwin, S. M.; Paul, A. G.; Heathcock, C. H. J. Org.
Chem. 1987, 52, 1686.
(8) (a) Arndt, F. Organic Syntheses; Wiley: New York, 1943; Collect.
Vol. II, p 165. (b) Nicolaou, K. C.; Paphatjis, D. P.; Claremon, D. A.; Dole,
R. E. J. Am. Chem. Soc. 1981, 103, 6967. (c) Fujisawa, T.; Sato, T.; Itoh,
T. Chem. Lett. 1982, 219.
(9) Evans, D. A.; Sjogren, E. B. Tetrahedron Lett. 1985, 26, 3787.
(10) Cacchi, S.; Morera, E.; Ortar, G. Org. Synth. 1990, 68, 138.
(11) (a) Marson, C. M. Tetrahedron 1992, 48, 3659. (b) Standler, P. A.
HelV. Chim. Acta. 1978, 61, 1675. (c) Ookawa, A.; Soai, K. J. Chem. Soc.,
Perkin Trans. 1 1987, 1465.
(13) (a) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org.
Synth. 1997, 74, 77. (b) Castedo, L.; Mourino, A.; Sarandeses, L. A.
Tetrahedron Lett. 1986, 27, 1523.
(14) (a) Chen, S. H.; Huang, S.; Kant, J.; Fairchild, C.; Wei, J.; Farina,
V. J. Org. Chem. 1993, 58, 5028. (b) Nace, H. R. Org. React. 1962, 12,
57. (c) Roberts, J. D.; Sauer, C. W. J. Am. Chem. Soc. 1949, 71, 3925.
(15) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(16) Vieira, L. M. M.; Kijjoa, A.; Wilairat, R.; Nascimento, M. S. J.;
Gales, L.; Damas, A. M.; Silva, A. M. S.; Mondranonddra, I.; Herz, W. J.
Nat. Prod. 2004, 67, 2043.
(17) Trudeau, S.; Deslongchamps, P. J. Org. Chem. 2004, 69, 832.
(18) (a) Sarakinos, G.; Corey, E. J. Org. Lett. 1999, 1, 811. (b) Stoltz,
B. M.; Kano, T.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9044.
(19) Oestreich, M.; Weiner, B. Synlett 2004, 12, 2139.
(20) Anderson, E. M.; Larsson, K. M.; Kirk, O. Biocatal. Biotransform.
1998, 16, 181.
(12) Rouillard, A.; Bonin, M. A.; Deslongchamps, P. HelV. Chim. Acta
2003, 86, 3730.
6150 J. Org. Chem., Vol. 71, No. 16, 2006

Studies toward Functionalized 5â-Lanosterol DeriVatiVes
SCHEME 2
SCHEME 3a
a Reagents and conditions: (a) NaBH4, MeOH, -15 °C, 94%, (b) p-TsCl, pyridine, DMAP, rt, 4 days, 90%, (c) NaCN, DMSO, rt, 3 h, 86%, (d)
MeOMgOCO2Me‚xCO2, 125-130 °C, DMF, 3 h, 75%, (e) CH2N2, Et2O/DCM, -78 °C, 30 min, 65% (f) DIPEA, Tf2O, CH2Cl2, - 78 °C, 92%, (g) Bu3N,
Pd(OAc)2, PPh3, DMF, HCO2H, 60 °C, 70%, (h) KOH, MeOH/H2O (1:1), rt, 6h, 85%, (i) (1) (COCl)2, cat. DMF, toluene, rt, 2 h, (2) allyl acetate, LHMDS,
THF, -78 °C, 78%.
SCHEME 4a
a Reagents and conditions: (a) Cs2CO3, EtOAc, rt, (b) (1) 5 mol % Pd(PPh3)4, morpholine, THF, 2 h, (2) toluene, reflux, 1 h, 59% (4:1) over 2 steps.
for cycloadduct 26. The alcohol 22 was then oxidized under
standard Swern conditions to give the ketone 23, which was
then subjected to formylation using ethyl formate in the presence
of NaH/KH to furnish the â-keto aldehyde 24. The introduction
of the double bond was carried out by the conversion of
aldehyde 24 to the selenium intermediate 24a, followed by
oxidation using H2O2 to furnish the ring A precursor 25.
Having achieved the synthesis of enantiomerically pure
cyclohexenone 25, we then tried the anionic cycloaddition with
Nazarov intermediate 14 (Scheme 7).
Under optimized conditions, the anionic cycloaddition fol-
lowed by dealkoxycarbonylation furnished a single diastereomer
26 in good yield. The structure and absolute configuration of
the tetracycle 26 was further confirmed by a single-crystal X-ray
analysis. Thus it became evident that the dimethylphenylsilyl
group in cyclohexenone controls the diastereoselectivity of
anionic cycloaddition. We believe that the anionic cyclization
takes place either via a highly asynchronous Diels-Alder
reaction or by two consecutive Michael additions where the first
step would be reversible. The fact that cycloaddition proceeded
only on the â face of the Nazarov reagent 14 can be explained
(21) (a) The enantiomeric excesses for compounds 22 and 22a were
determined using chiral HPLC (CHIRACEL OD-H, for 22 hexane/
isopropanol 99:1, flow 0.6 mL/min. Retention time (+)-alcohol, 20.1 min;
(-)-alcohol, 26.3 min. For 22a gradient 0-50 min (0.2 mL/min, hexane
100%) 50-60 min (hexane/isopropanol 95:5; flow 0.6 mL/min). Retention
time (+)-acetate, 54.2 min; (-)-acetate, 57.3 min). (b) Bornscheuer, U. T.;
Kazlauskas, R. J. Hydrolases in Organic Synthesis; Regio and Stereo-
selectiVe Biotransformations; Wiley-VCH: Weinheim, 1999.
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Ramachandran et al.
SCHEME 5a
a Reagents and conditions: (a) NaBH4, MeOH, -15 °C, 70%, (b) (1) NaH, CS2, MeI, THF, 60 °C, 84%, (2) 17a, n-Bu3SnH, AIBN (cat.), toluene, 120
°C, 2 h, 75%.
SCHEME 6a
a Reagents and conditions: (a) PhMe2SiLi, ZnCl2, CuI (5 mol %), toluene, -20 °C, 6 h, 84%, (b) LiAl(tBuO)3H, THF, -50 °C, 12 h, 96%, syn:anti (9:1),
(c) Lipase B Candida antarctica, vinyl acetate, rt, 48 h, 48%, (d) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 87%, (e) NaH, KH, EtOCHO, THF, rt, 4 h, 73%,
(f) PhSeCl, pyridine, CH2Cl2, (g) H2O2, CH2Cl2, rt, 78% over 2 steps.
SCHEME 7a
standard conditions and subjected to Barton-McCombie deoxy-
genation using tris-trimethylsilyl silane and AIBN to furnish
the tetracycle 28.
To have a functionalized side chain at C17 (steroid numbering)
of the tetracycle, we have prepared Nazarov intermediate 40
according to the following synthetic sequence (Scheme 9).
Vitamin D2 was selected as the starting material for this purpose,
which was converted to diol 29 by ozonolysis followed by
reduction according to the reported procedure.22 The primary
alcohol was selectively benzoylated as reported23 to furnish the
alcohol 30, which was dehydrated under Mitsunobu conditions
and further hydrolyzed with 1 M NaOH to afford the alcohol
31. The alcohol was then protected as PMB ether 32, which on
epoxidation followed by ring opening with KOH afforded a
mixture of diastereomeric diols (4:1), which were separated by
column chromatography. The major diastereomer 33 was then
transformed to the MOM-protected alcohol 34, which was then
oxidized using NMO and TPAP to furnish the ketone 35.
Trapping the enolate of ketone 35 using Comins’ reagent24
afforded the triflate 36, which was subjected to a one-carbon
homologation using a carbonylation reaction25 to furnish the
ester 37. Reduction of the ester using DIBAL-H followed by
Swern oxidation of the alcohol furnished the aldehyde 39.
a Reagents and conditions: (a) (i) Cs2CO3, EtOAc, rt, 6 h, 70%, (ii)
Pd(PPh3)4 (5 mol %), morpholine, THF, reflux, 2 h, 90%.
FIGURE 2. Comparison of the cycloaddition approaches for the
reaction of 14 with 25.
by the steric interaction created by the C3 SiPhMe2 group on
the cyclohexenone 25 and hence explains the diastereoselectivity
of the reaction (Figure 2; approach A is favored over approach
B).
The tetracyclic intermediate 26 thus obtained was further
transformed into the deoxygenated derivative 28 by the follow-
ing pathway (Scheme 8).
The aldehyde 26 was selectively reduced to alcohol 27 using
tetramethylammonium triacetoxyborohydride in CH3CN. The
alcohol thus formed was transformed into xanthate 27a under
(22) Sardina, F. J.; Mourino, A.; Castedo, L. J. Org. Chem. 1986, 51,
1264.
(23) Wovkulich, P. M.; Barcelos, F.; Batcho, A. D.; Sereno, J. F.;
Baggiolini, E. G.; Hennessy, B. M.; Uskokovic, M. R. Tetrahedron 1984,
40, 2283.
(24) (a) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org.
Synth. 1997, 74, 77. (b) Castedo, L.; Mourino, A.; Sarandeses, L. A.
Tetrahedron Lett. 1986, 27, 1523.
(25) Tius, M. A.; Kamali Kannangara, G. S. J. Org. Chem. 1990, 55,
5711.
6152 J. Org. Chem., Vol. 71, No. 16, 2006

Studies toward Functionalized 5â-Lanosterol DeriVatiVes
SCHEME 8a
a Reagents and conditions: (a) Me4NBH(OAc)3, CH3CN, -20 °C, 90%, (b) (1) n-BuLi, CS2, MeI, THF, -40 °C, 80%, (2) 27a, (Me3Si)3SiH, AIBN
(cat.), toluene, 120 °C, 2 h, 55%.
SCHEME 9a
a Reagents and conditions: (a) (1) DEAD, PPh3, THF, reflux, (2) NaOH 1 M, MeOH, rt, 93% (over 2 steps), (b) NaH, PMBCl, TBAI, THF, reflux, 74%,
(c) (1) m-CPBA, CH2Cl2, -15 °C, (2) KOH, DMSO/H2O, 140 °C, 58% (4:1) (over 2 steps), (d) (1) TMSCl, Et3N, THF, rt, (2) MOMCl, DIPEA, DMAP,
CH2Cl2, rt, (3) TBAF, THF, rt, 84% (over 3 steps), (e) TPAP, NMO, 4 Å MS, CH2Cl2, rt, 98%, (f) LHMDS, Comin’s reagent, THF, -10 °C, 81%, (g)
PdCl2(PPh3)2, CO (24 atm), Et3N, MeOH, DMF, 55 °C, 87%, (h) DIBAL-H, CH2Cl2, -78 °C, 79%, (i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 98%, (j)
(1) allyl acetate, LHMDS, THF, -78 °C, (2) 39, THF, -78 °C, 94%, (3) 39a, Dess-Martin periodinane, CH2Cl2, rt, 79%.
SCHEME 10a
a Reagents and conditions: (a) (i) Cs2CO3, CH3CN, rt, 3 h, 55%, (ii) Pd(PPh3)4, morpholine, THF, reflux, 2 h, 90%.
Finally an aldol condensation of the aldehyde 39 with the lithium
enolate of allyl acetate followed by oxidation of the resulting
alcohol afforded the desired Nazarov intermediate 40.
We then investigated the anionic cycloaddition reaction
between the newly synthesized Nazarov intermediate 40 and
the cyclohexenone 25 (Scheme 10).
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Ramachandran et al.
SCHEME 11a
a Reagents and conditions: (a) Me4NBH(OAc)3, CH3CN, -20 °C to rt, 6 h, 60%, (b) NaH, CS2, MeI, THF, 60 °C, 6 h, 61%, (c) (Me3Si)3SiH, AIBN
(cat.), toluene, reflux, 50%.
with EtOAc (100 mL), and the organic phase was washed with
water (3 × 20 mL) and saturated NH4Cl solution (20 mL), dried
over MgSO4, and filtered. The solvent was removed in vacuo, and
then the crude product was chromatographed over SiO2 (eluent 1:4
EtOAc/hexane) to furnish the two diasteromers 15a (406 mg, 52%)
and 16a (95 mg, 12%).
Pd(PPh3)4 (52 mg, 45 µmol, 5 mol %) was added followed by
morpholine (375 mg, 0.37 mL, 4.3 mmol) in THF (2 mL) to a
stirring solution of aldehyde 15a or 16a (400 mg, 0.86 mmol) in
THF (40 mL). The reaction mixture was stirred for 2 h at room
temperature. The solvent was then removed in vacuo, and toluene
was added (30 mL). The reaction mixture was refluxed for 1 h and
diluted with EtOAc (50 mL). The organic layer was washed with
water (2 × 20 mL) and brine (20 mL), dried over MgSO4, and
filtered. The solvent was removed in vacuo followed by chroma-
tography over SiO2 (eluent 3:7 EtOAc/hexane) to furnish pure
aldehyde 15 (270 mg, 88%) and 16 (280 mg, 90%).
Diastereomer 15. [R]20D ) -10° (c ) 1.6, CHCl3). IR (CHCl3,
ν, cm-1): 2919, 2853, 2227, 1722, 1683, 1638, 1599, 1459, 1353,
1218, 754. 1H NMR (300 MHz, CDCl3): δ 9.75 (1H, s); 5.39 (1H,
s); 3.76 (3H, s); 3.25-3.18 (1H, m); 2.98-2.95 (1H, m); 2.77-
2.55 (3H, m); 2.43-2.32 (2H, m); 2.22-2.02 (4H, m); 1.86-1.78
(1H, m); 1.37-1.30 (1H, m); 1.26 (3H, s); 1.24 (3H, s); 1.20 (3H,
s). 13C NMR (75 MHz, CDCl3): δ 200.5; 198.8; 196.7; 181.9;
159.7; 125.1; 119.8; 99.3; 61.5; 56.5; 46.3; 40.8; 40.4; 39.8; 39.2;
38.9; 33.5; 29.9; 29.7; 26.3; 22.9; 21.6; 21.3 EI-MS m/z (% rel
int): 381 (M+); 369 (10); 352 (M - CHO)+; 338; 310; 277. HRMS
(m/z): calcd for C23H27NO4 381.1940, found 381.1947 ( 0.0011.
Diastereomer 16. [R]20D: +61.5 ° (c ) 1.1, CHCl3). IR (CHCl3,
ν, cm-1): 2919, 2853, 2227, 1722, 1683, 1638, 1599, 1459, 1353,
1218, 754. 1H NMR (300 MHz, CDCl3): δ 9.90 (1H, s); 5.36 (1H,
s); 3.75 (3H, s); 3.11-3.00 (1H, m); 2.94-2.89 (1H, m); 2.82-
2.68 (1H, m); 2.64-2.51 (3H, m); 2.48-2.35 (2H, m); 2.28-2.06
(2H, m); 1.92-1.78 (2H, m); 1.37-1.20 (1H, m); 1.16 (3H, s);
1.15 (3H, s); 1.12 (3H, s). 13C NMR (75 MHz, CDCl3): δ 201.9;
198.9; 196.8; 181.5; 161.4; 125.8; 119.8; 98.9; 61.9; 56.4; 46.2;
40.8; 39.9; 39.1; 38.1; 37.7; 31.4; 30.5; 26.4; 22.8; 19.9; 19.7. EI-
MS m/z (rel int): 381 (M+); 369 (10); 352 (M - CHO)+; 338;
310; 277. HRMS (m/z): calcd for C23H27NO4 381.1940, found
381.1947 ( 0.0011
The best results were obtained when acetonitrile was used
as a solvent and Cs2CO3 as base, affording the tetracycle 41
after dealkoxycarbonylation as a single diastereomer. The
tetracycle 41 was further transformed into the advanced
intermediate 44 according to the following reactions (Scheme
11). The â-keto aldehyde 41 was selectively reduced to 1,3-
diol 42 as a single diastereomer using tetramethylammonium
triacetoxy borohydride in CH3CN. The diol 42 was then
converted to bis-xanthate 43 by standard protocol in good yield.
Exposing the product to the silyl radical generated from
(Me3Si)3SiH and AIBN resulted in a double deoxygenation to
afford the tetracycle 44 in moderate yield.
Having achieved the synthesis of an advanced intermediate
44, we are planning to introduce R-C14 functional groups and
to evaluate the biological activity of these steroidal derivatives
against different cell lines. Work toward this direction will be
reported in due course.
Conclusion
In summary, we have explored the scope and utility of anionic
cycloaddition as a powerful synthetic tool for the stereoselective
construction of tetracyclic intermediates having a lanosteroidal-
type framework. It was shown that the use of a chiral ring A
precursor with a dimethylphenyl silyl group imparts a complete
stereocontrol for the anionic cycloaddition reaction. We were
also able to achieve the synthesis of advanced intermediates 18
and 28 along with a C17 functionalized tetracyclic intermediate
44. It would be worth noting that this methodology will allow
the synthesis of C1, C7, C10, and C14 functionalized (steroid
numbering) steroid analogues of lanosterol, which are otherwise
difficult to synthesize starting from lanosterol itself. It is
conceivable that these 5â-analogues should provide interesting
insight into the structure-activity relationship of lanosterol-
based inhibitors.
Experimental Section
Alcohol 17. Powdered NaBH4 (12 mg, 0.32 mmol) was added
in one portion to the stirring solution of aldehyde 15 (240 mg, 0.63
mmol) in mixed solvent system THF/MeOH (10:5 mL) at -15 °C.
The reaction mixture was stirred at the same temperature for 2 h.
The excess NaBH4 was quenched by addition of acetone (2 mL) at
the same temperature. Then the reaction mixture was allowed to
Tetracycles 15 and 16. Cs2CO3 (547 mg, 1.678 mmol) was added
to a stirring solution of Nazarov intermediate 14 (478 mg, 1.678
mmol) in EtOAc (110 mL), and stirred for 5 min. Cyclohexenone
6 (303 mg, 1.678 mmol) was added, and the mixture was stirred
for 1.5 h at room temperature. The reaction mixture was then diluted
6154 J. Org. Chem., Vol. 71, No. 16, 2006

Studies toward Functionalized 5â-Lanosterol DeriVatiVes
warm to room temperature, the solvent was removed in vacuo, and
the residue was dissolved in EtOAc (40 mL). The organic layer
was washed with water (10 mL) and brine (10 mL), dried over
MgSO4, and filtered. The solvent was removed in vacuo, and the
crude product was chromatographed over SiO2 (eluent 3:2 EtOAc/
2H), 2.72-2.38 (m, 2H), 2.26-2.03 (m, 4H), 1.57-1.32 (m, 3H),
1.29 (s, 3H), 1.26-1.15 (m, 1H), 1.08 (s, 3H), 1.03 (s, 3H), 1.00-
0.87 (m, 1H), 0.45 (s, 3H), 0.42 (s, 3H).
Pd(PPh3)4 (0.077 g, 0.06 mmol, 5 mol %) was added followed
by morpholine (0.59 mL, 6.65 mmol) to a stirring solution of
carboxyallyl cycloadduct 26a (0.76 g, 1.3 mmol) obtained above
in THF (20 mL), and the resulting solution was refluxed for 1 h.
Solvent was evaporated off, and the residue was column chromato-
graphed over silica gel to give the tetracycle 26 (0.58 g, 90%) as
a colorless crystalline solid. Mp: 110-112°C. [R]20D: +52.27° (c
) 1.1, CHCl3). IR (CHCl3, ν, cm-1): 2962, 2236, 1718, 1689, 1624,
1261, 811, 736. 1H NMR (300 MHz, CDCl3): δ 9.85 (s, 1H), 7.52-
7.24 (m, 5H), 3.07-2.88 (m, 3H), 2.62-1.56 (m, 12H), 1.37-
1.23 (m, 1H), 1.16 (s, 3H), 0.93 (s, 3H), 0.82 (s, 3H), 0.42 (s, 3H),
0.40 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 218.1, 200.9, 199.7,
158.1, 133.7, 129.4, 128.9, 128.1, 125.6, 119.5, 48.3, 46.0, 40.3,
39.9, 39.2, 37.8, 36.8, 33.9, 30.0, 28.9, 27.0, 26.3, 26.1, 21.4, 20.5,
-1.9, -2.2. EI-MS m/z (rel int): 458 (60), 390 (10), 219 (10),
135 (100), 107 (10). HRMS m/z: calcd for C30H37N1O3Si 487.2543,
found 487.2540 ( 0.0014.
hexane) and furnished pure alcohol 17 (168 mg, 70%). [R]20
:
D
-76.77° (c ) 1.3, CHCl3). IR (CHCl3, ν, cm-1): 3550-3265
(broad peak); 2968, 2363, 2232, 1677, 1642; 1606, 1463, 1363,
1244, 1214, 1167, 1042, 912, 846. H NMR (300 MHz, CDCl3):
1
δ 5.37 (1H, s); 4.54 (1H, d, J ) 11.7 Hz); 3.73 (3H, s); 3.39 (1H,
d, J ) 11.7 Hz); 3.35-3.22 (1H, m); 3.08-2.99 (1H, m); 2.75-
2.64 (4H, m); 2.39 (1H, dd, J ) 12.06, 7.32 Hz); 2.26-1.79 (5H,
m); 1.49-1.40 (1H, m); 1.34-1.28 (1H, m); 1.25 (3H, s); 1.22
(3H, s); 1.16 (3H, s). 13C NMR (75 MHz, CDCl3): δ 200.7; 200.4;
181.1; 159.2; 125.7; 119.7; 99.5; 59.3; 56.1; 51.8; 46.1; 40.2; 39.3;
39.3; 39.2; 38.5; 33.1; 29.6; 29.2; 26.1; 23.2; 21.9; 20.4. EI-MS
m/z (rel int): 383 (M+); 365 (M - H2O)+; 352 (100). HRMS m/z:
calcd for C23H29NO4 383.2096, found 383.2093 ( 0.0011.
Xanthate 17a. NaH (36 mg, 940 µmol, 60% dispersion in oil)
was successively washed with hexanes and then cooled to 0 °C.
Alcohol 17 (80 mg, 208.8 µmol) in THF (10 mL) was added
dropwise to the NaH, and it was stirred at 0 °C for 15 min and
then at room temperature for 1 h. CS2 (160 mg, 0.13 mL, 940 µmol)
in THF (2 mL) was added, and the solution was stirred for 1 h at
room temperature followed by addition of MeI (296 mg, 0.13 mL).
The reaction mixture was stirred for 1 h and then warmed in a
preheated oil bath at 55-60 °C for 2 h. The reaction mixture was
then cooled to room temperature and quenched with addition of
2-3 drops of saturated NH4Cl. The solvent was removed in vacuo,
and the residue was dissolved in EtOAc (20 mL). The organic layer
washed with water (5 mL) and saturated NH4Cl solution (5 mL),
dried over MgSO4, and filtered. The solvent was removed in vacuo
followed by chromatography over SiO2 (eluent 2:3 EtOAc/hexane)
to yield xanthate derivate 17a (85 mg, 84%). 1H NMR (300 MHz,
CDCl3): δ 5.40 (1H, s); 5.30 (1H, dd, J ) 11.19 Hz); 4.67 (1H, d,
J ) 11.18 Hz); 3.74 (3H, s); 3.28-3.26 (1H, m); 3.08-3.06 (1H,
m); 2.70-2.68 (1H, m); 2.64-2.44 (3H, m); 2.51 (3H, s); 2.37-
1.99 (3H, m); 1.82-1.77 (1H, m); 1.58-1.56 (1H, m); 1.35-1.31
(1H, m); 1.27 (3H, s); 1.22 (3H, s); 1.19 (3H, s).
Tetracycle 18. n-Bu3SnH (50 mg, 168 µmol) was added to a
stirring solution of xanthate 17a (53 mg, 112 µmol) and catalytic
amount of AIBN (0.1 equiv) in toluene (5 mL) at room temperature.
The reaction mixture was degassed twice and then refluxed for 2
h. It was cooled to room temperature, the solvent was removed in
vacuo, and the residue was purified by chromatography (eluent 3:7
EtOAc/hexane) to furnish 18 (30 mg, 73%). [R]20D: -106.57° (c
) 1.4, CHCl3). IR (CHCl3, ν, cm-1): 2972, 2363, 2319, 2242, 1678,
1645, 1612, 1595, 1456, 1351, 1224, 1191, 1168, 1130, 986, 914,
726, 671. 1H NMR (300 MHz, CDCl3): δ 5.35 (1H, s); 3.72 (3H,
s); 3.35-3.27 (1H, m); 2.95-2.89 (1H, m); 2.75-2.71 (1H, m);
2.67-2.60 (2H, m); 2.40 (1H, dd, J ) 12, 7.48 Hz); 2.30-2.06
(3H, m); 1.98 (1H, dt, J ) 7.4, 3.4 Hz); 1.76-1.69 (1H, m); 1.45-
1.30 (2H, m); 1.23 (3H, s); 1.20 (3H, s); 1.18 (3H, s); 1.17 (3H, s).
13C NMR (75 MHz, CDCl3): δ 200.8; 200.4; 179.9; 159.5; 126.2;
119.8; 98.9; 56.0; 47.7; 47.2; 46.1; 40.8; 40.4; 39.6; 39.1; 32.9;
29.6; 29.3; 26.2; 22.9; 21.9; 21.1; 16.9. EI-MS m/z (rel int): 367
(M+); 352 (90); 324 (15); 269 (14); 240; 167 (100). HRMS m/z:
calcd for C23H29NO3 367.2147, found 367.2150 ( 0.0011.
Alcohol 27. To a stirred solution of aldehyde 26 (0.1 g, 0.2
mmol) in CH3CN (10 mL) at -20 °C was added Me4NBH(OAc)3
(0.054 g, 0.2 mmol), and the reaction mixture was stirred at that
temperature for 1 h. The reaction was quenched by the addition of
saturated NaHCO3, extracted with ethyl acetate, dried, and column
chromatographed over silica gel to afford the alcohol 27 (0.09 g,
90%) as a colorless oil. [R]20D: +102.8° (c ) 1.5, CHCl3). IR
(CHCl3, ν, cm-1): 3510, 2966, 2240, 1686, 1627, 1258, 1184, 911,
1
810. H NMR (300 MHz, CDCl3): δ 7.53-7.50 (m, 2H), 7.38-
7.34 (m, 3H), 3.82 (dd, J ) 9.0, 5.6 Hz, 1H), 3.14-3.12 (m, 1H),
2.98-2.82 (m, 2H), 2.70-1.88 (m, 12H), 1.56-1.23 (m, 3H), 1.17
(s, 3H), 0.86 (s, 3H), 0.81 (s, 3H), 0.41 (s, 3H), 0.38 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 218.8, 200.4, 158.3, 138.0, 133.7, 129.3,
128.0, 125.7, 119.5, 64.1, 53.7, 49.9, 45.8, 40.2, 40.1, 39.1, 39.0,
38.5, 37.4, 33.9, 29.6, 28.6, 28.4, 27.4, 26.2, 25.8, 20.7, -1.9, -2.2.
EI-MS m/z (rel int): 471 (30), 460 (13), 458 (30), 428 (3) HRMS
m/z: calcd for C30H39NO3Si 489.2699, found 489.2693 ( 0.0014.
Xanthate 27a. To a stirred solution of alcohol 27 (0.069 g, 0.14
mmol) in THF (5 mL) at - 40 °C was added n-BuLi (0.087 mL,
0.14 mmol, 1.6M), and the mixture was stirred for 10 min. To this
was added CS2 (0.017 mL, 0.28 mmol) followed by MeI (0.017
mL, 0.28 mmol), and the reaction mixture was stirred for 1 h, slowly
warming to room temperature. The reaction was quenched by the
addition of saturated NH4Cl, extracted with EtOAc, dried, and
column chromatographed over silica gel to afford the xanthate 27a
(0.065 g, 80%). [R]20D: +60.4° (c ) 1.2, CHCl3). IR (CHCl3, ν,
1
cm-1): 2966, 2239, 1690, 1628, 1208, 1072, 910, 811, 733. H
NMR (300 MHz, CDCl3): δ 7.53-7.50 (m, 2H), 7.39-7.34 (m,
3H), 4.67 (d, J ) 11.4 Hz, 1H), 4.44 (d, J ) 11.4 Hz, 1H), 3.11-
2.88 (m, 2H), 2.76-2.67 (m, 1H), 2.49 (s, 3H), 2.34-2.00 (m,
8H), 1.70-1.65 (m, 2H), 1.40-1.23 (m, 3H), 1.11 (s, 3H), 0.89
(s, 3H), 0.42 (s, 3H), 0.39 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
216.0, 213.0, 199.7, 158.1, 138.0, 133.7, 129.3, 128.0, 125.6, 119.5,
74.3, 60.3, 52.3, 50.0, 45.7, 40.3, 40.1, 38.7, 37.8, 37.4, 33.6, 29.8,
28.7, 26.4, 26.3, 25.9, 20.8, 20.5, 19.2, -1.9, -2.2. EI-MS m/z
(rel int): 562 (10), 471 (25), 147 (40), 135 (100), 91 (40). HRMS
m/z: calcd for C32H42NO3S2Si 580.2375, found 580.2381 ( 0.0017.
Tetracycle 28. To a stirred solution of above xanthate 27a (0.015
g, 0.025 mmol) in toluene (1 mL) at room temperature was added
(Me3Si)3SiH (0.024 mL, 0.078 mmol) and catalytic AIBN. The
reaction mixture was then refluxed for 2 h, solvent was evaporated
off, and the residue was then column chromatographed over silica
gel to afford the tetracycle 28 (0.006 g, 55%). [R]20D: +48.2° (c
) 1, CHCl3). IR (CHCl3, ν, cm-1): 2961, 2239, 1691, 1627, 1260,
Tetracycle 26. To a stirred solution of Nazarov intermediate 14
(0.6 g, 2.1 mmol) and cyclohexenone 25 (0.603 g, 2.1 mmol) in
EtOAc (100 mL) was added Cs2CO3 (0.685 g, 2.1 mmol), and the
reaction mixture was stirred at room temperature for 6 h. Water
was added to quench the reaction, which was extracted with EtOAc,
dried, and column chromatographed over silica gel to afford the
carboxyallyl cycloadduct 26a (0.85 g, 70%) as a viscous liquid.
1
1112, 916, 811. H NMR (300 MHz, CDCl3): δ 7.53-7.50 (m,
1
[R]20D: + 52.2° (c ) 1.1, CHCl3). H NMR (300 MHz, CDCl3):
2H), 7.38-7.33 (m, 3H), 3.0-2.88 (m, 2H), 2.73-2.64 (m, 1H),
2.53-1.97 (m, 8H), 1.69-1.54 (m, 2H), 1.42-1.28 (m, 3H), 1.25
(s, 3H), 1.14 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H), 0.41 (s, 3H), 0.38
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 216.3, 200.1, 158.0, 138.2,
δ 12.94 (s, 1H, enol proton), 9.01 (s, 1H), 7.52-7.48 (m, 2H),
7.37-7.31 (m, 3H), 5.96-5.88 (m, 1H), 5.38-5.28 (m, 2H), 4.61
(d, J ) 8.52 Hz, 2H), 3.46 (d, J ) 3.96 Hz, 1H), 3.13-2.91 (m,
J. Org. Chem, Vol. 71, No. 16, 2006 6155

Ramachandran et al.
133.7, 129.2, 128.0, 125.5, 119.3, 56.5, 49.9, 45.6, 40.3, 40.0, 39.7,
39.1, 38.4, 37.3, 33.7, 29.6, 28.6, 26.3, 25.9, 20.9, 20.6, 19.5, 19.2,
-1.9, -2.2. EI-MS m/z (rel int): 458 (40), 395 (35), 326 (25),
259 (25), 135 (100), 91 (30). HRMS m/z: calcd for C30H39NO2Si
473.2750, found 473.2760 ( 0.0014.
127.7, 113.6, 104.1, 74.8, 72.7, 62.3, 61.8, 55.2, 52.3, 48.0, 45.1,
40.8, 39.2, 37.5, 35.1, 34.2, 31.9, 29.6, 26.8, 17.8, 17.3, 14.0, -1.8,
-2.3. HRMS m/z: calcd for C40H56O5Si 644.3897, found: 644.3891
( 0.0014.
bis-Xanthate 43. To a stirred solution of 1,3-diol 42 (0.039 g,
0.06 mmol) in THF (5 mL) was added NaH (0.014 g, 0.3 mmol,
60% in mineral oil) at room temperature, and the reaction mixture
was stirred for 1 h. To this was added CS2 (0.01 mL, 0.18 mmol)
followed by MeI (0.011 mL, 0.18 mmol), and the reaction mixture
stirred at room temperature for 1 h and then heated at 60 °C for 6
h. The reaction mixture was cooled to room temperature, quenched
with saturated NH4Cl, extracted with ether, dried, and column
chromatographed over silica gel to afford the bis-xanthate 43 (0.03
g, 61%). [R]20D: -5.1° (c ) 1, CHCl3). IR (CHCl3, ν, cm-1): 2919,
Tetracycle 41. To a stirred solution of cyclohexenone 25 (0.064
g, 0.22 mmol) and Nazarov reagent 40 (0.112 g, 0.22 mmol) in
CH3CN (15 mL) was added Cs2CO3 (0.007 g, 0.022 mmol), and
the reaction mixture was stirred for 6 h at room temperature. It
was quenched by the addition of water, extracted with EtOAc, dried,
and column chromatographed over silica gel to afford the carboxy-
allyl cycloadduct 41a (0.090 g, 55%). [R]20D: +41.2° (c ) 1,
CHCl3). IR (CHCl3, ν, cm-1): 2957, 1743, 1686, 1613, 1512, 1248,
1
1034, 821. H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 7.51-
1
7.48 (m, 2H), 7.38-7.34 (m, 3H), 7.26-7.21 (m, 2H), 6.86 (d, J
) 8.6 Hz, 2H), 5.99-5.89 (m, 1H), 5.37-5.21 (m, 2H), 4.68-
4.65 (m, 2H), 4.39 (d, J ) 11.6 Hz, 2H), 3.80 (s, 3H), 3.68 (d, J
) 10.8 Hz, 1H), 3.42-3.38 (m, 1H), 3.27-3.15 (m, 3H), 2.69-
2.66 (m, 1H), 2.48-2.28 (m, 2H), 2.08-1.95 (m, 3H), 1.81-1.72
(m, 2H), 1.49-1.28 (m, 3H), 1.25 (s, 3H), 1.06 (d, J ) 6.6 Hz,
3H), 0.94 (s, 3H), 0.84 (s, 3H), 0.41 (s, 3H), 0.39 (s, 3H).
2849, 1681, 1611, 1512, 1463, 1207, 1056, 813. H NMR (300
MHz, CDCl3): δ 7.50-7.47 (m, 2H), 7.35-7.30 (m, 3H), 7.26-
7.22 (m, 2H), 6.86 (d, J ) 8.6 Hz, 2H), 4.67-4.34 (m, 4H), 3.80
(s, 3H), 3.43 (dd, J ) 3.4, 9.0 Hz, 1H), 3.25-3.23 (m, 1H), 2.68-
2.60 (m, 1H), 2.56 (s, 3H), 2.49 (s, 3H), 2.22-1.72 (m, 10H), 1.47-
1.28 (m, 5H), 1.06 (d, J ) 6.6 Hz, 3H), 1.01 (s, 3H), 0.98 (s, 3H),
0.92 (s, 3H), 0.52 (s, 3H), 0.37 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 195.9, 177.3, 159.1, 155.3, 138.5, 133.7, 129.1, 128.0,
127.3, 113.6, 104.5, 74.6, 72.7, 63.1, 61.2, 60.0, 55.2, 52.2, 48.0,
45.3, 40.5, 39.6, 38.0, 35.1, 34.2, 31.8, 29.7, 26.9, 25.1, 18.0, 17.3,
14.0, -1.8, -2.4. HRMS m/z: calcd for C43H57O5S3Si (M - SCH3)
777.3137, found 777.3122 ( 0.0023.
To a stirred solution of carboxyallyl cycloadduct 41a (0.040 g,
0.05 mmol) in THF (5 mL) was added Pd(PPh3)4 (0.003 g, 0.002
mmol) followed by morpholine (0.01 mL, 0.11 mmol), and the
reaction mixture was refluxed for 2 h. Solvent was evaporated off,
and the residue was column chromatographed over silica gel to
afford the tetracycle 41 (0.031 g, 90%). [R]20D: +44.0° (c ) 1.1,
CHCl3). IR (CHCl3, ν, cm-1): 2923, 1723, 1687, 1613, 1512, 1248,
Tetracycle 44. To a stirred solution of bis-xanthate 43 (0.010
g, 0.012 mmol) in toluene (1 mL) was added catalytic AIBN
followed by (Me3Si)3SiH (0.019 mL, 0.06 mmol), and the reaction
mixture was refluxed for 2 h. The solvent was evaporated off, and
the residue was column chromatographed over silica gel to afford
the tetracycle 44 (3.7 mg, 50%). [R]20D: +21.2° (c ) 1, CHCl3).
IR (CHCl3, ν, cm-1): 2921, 2850, 1671, 1514, 1458, 1249, 1079,
1
1111, 1034. H NMR (300 MHz, CDCl3): δ 9.93 (s, 1H), 7.52-
7.49 (m, 2H), 7.39-7.34 (m, 3H), 7.26-7.21 (m, 2H), 6.86 (d, J
) 8.6 Hz, 2H), 4.40 (dd, J ) 23.2, 11.6 Hz, 2H), 3.80 (s, 3H),
3.41 (dd, J ) 8.8, 3.2 Hz, 1H), 3.27-3.21 (m, 1H), 3.12-3.06 (m,
1H), 2.74-2.37 (m, 6H), 2.05-1.71 (m, 5H), 1.46-1.25 (m, 3H),
1.05 (d, J ) 6.6 Hz, 3H), 0.92 (s, 3H), 0.88 (s, 3H), 0.79 (s, 3H),
0.41 (s, 3H), 0.38 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 213.0,
201.9, 199.5, 168.5, 159.0, 155.2, 133.7, 129.3, 129.0, 128.0, 122.5,
113.6, 104.6, 74.7, 72.7, 61.9, 55.2, 52.5, 48.0, 45.6, 40.3, 39.6,
38.1, 36.8, 36.2, 35.0, 30.4, 28.9, 27.0, 26.1, 21.6, 18.2, 17.8, -1.8,
-2.4. HRMS m/z: calcd for C40H52O5Si 640.3584, found 640.3589
( 0.0019.
1
814. H NMR (300 MHz, CDCl3): δ 7.53-7.50 (m, 2H), 7.35-
7.30 (m, 3H), 6.86 (d, J ) 8.6 Hz, 2H), 4.40 (d, J ) 10.5 Hz, 2H),
3.80 (s, 3H), 2.48-2.40 (m, 1H), 2.21-1.70 (m, 12H), 1.42-1.28
(m, 6H), 1.06 (d, J ) 6.6 Hz, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.95
(s, 3H), 0.92 (s, 3H), 0.44 (s, 3H), 0.40 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 197.3, 168.5, 158.9, 155.8, 135.0, 130.1, 129.5,
127.8, 127.1, 113.0, 104.1, 74.6, 52.3, 48.0, 45.1, 40.7, 39.3, 37.1,
35.2, 34.0, 31.5, 30.1, 29.6, 28.5, 26.8, 25.7, 23.2, 20.0, 17.8, 17.1,
-1.8, -2.4. HRMS m/z: calcd for C40H56O3Si 612.3999, found
612.3985 ( 0.0014.
1,3-Diol 42. To a stirred solution of â-keto aldehyde 41 (0.061
g, 0.09 mmol) in CH3CN (5 mL) at - 20 °C was added Me4NBH-
(OAc)3 (0.075 g, 0.29 mmol), and the reaction mixture was stirred
for 6 h, slowly warming to room temperature. The reaction mixture
was quenched by the addition of saturated NaHCO3 solution (2
mL), extracted with EtOAc, washed with water, dried, and column
chromatographed over silica gel to afford the 1,3-diol 42 (0.037 g,
60%). [R]20D: -6.8° (c ) 1.1, CHCl3). IR (CHCl3, ν, cm-1): 3422,
Acknowledgment. Research chair in organic chemistry
granted to Pr. Pierre Deslongchamps by BioChem Pharma Inc.
and financial support from NSERC (Canada) are highly ap-
preciated.
1
2960, 1670, 1512, 1364, 1247. H NMR (300 MHz, CDCl3): δ
Supporting Information Available: Experimental details and
characterization data for compounds 10-14, 21-25, and 31-40
and X-ray crystal structure data in CIF format for compounds 15,
7.54-7.51 (m, 2H), 7.36-7.32 (m, 3H), 7.25-7.21 (m, 2H), 6.86
(d, J ) 8.6 Hz, 2H), 4.40 (d, J ) 11.5 Hz, 2H), 4.13 (dd, J ) 12.0,
3.5 Hz, 2H), 3.80 (s, 3H), 3.54-3.19 (m, 3H), 3.10-2.92 (m, 1H),
2.53-2.17 (m, 2H), 2.04-1.92 (m, 3H), 1.84-1.68 (m, 4H), 1.48-
1.28 (m, 6H), 1.06 (d, J ) 6.7 Hz, 3H), 1.04 (s, 3H), 0.97 (s, 3H),
0.93 (s, 3H), 0.46 (s, 3H), 0.42 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 201.2, 168.3, 159.5, 155.0, 133.6, 130.7, 129.1, 127.8,
1
16, and 26. Copies of H NMR for all new compounds are also
included. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0608725
6156 J. Org. Chem., Vol. 71, No. 16, 2006