An enantioselective synthesis of the core unit of the non-nucleoside reverse transcriptase inhibitor taurospongin A

Article abstract of DOI:10.1016/S0957-4166(03)00040-5

An enantioselective formal synthesis of taurospongin A has been achieved. The key steps involve chelation-controlled reductions of β-ketosulfoxide and β-hydroxy ketone intermediates and Sharpless asymmetric epoxidation to construct the tertiary alcohol st

Full text of DOI:10.1016/S0957-4166(03)00040-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 629–634
An enantioselective synthesis of the core unit of the
non-nucleoside reverse transcriptase inhibitor taurospongin A
Arun K. Ghosh* and Hui Lei
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 9 December 2002; accepted 20 December 2002
Abstract—An enantioselective formal synthesis of taurospongin A has been achieved. The key steps involve chelation-controlled
reductions of b-ketosulfoxide and b-hydroxy ketone intermediates and Sharpless asymmetric epoxidation to construct the tertiary
alcohol stereoselectively. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
gia sp. has very interesting biological properties:3 it
inhibits DNA polymerase b and HIV reverse transcrip-
tase with Ki values of 1.7 and 1.3 mM, respectively. The
initial structure elucidation and determination of the
absolute stereochemistry of taurospongin were carried
out through degradation studies.3 The structural fea-
tures of taurospongin A coupled with its potent reverse
transcriptase inhibitory properties stimulated our inter-
est in its synthesis and thus far, the only synthesis of
(+)-taurospongin A has been reported by Lebel and
Jacobsen.4 Herein, we report a stereocontrolled synthe-
sis of the C1–C10 fragment 2 which contains all three
stereocenters of taurospongin A. Segment 2 is an inter-
mediate of the previous synthesis of (+)-taurospongin
A.4 A highly stereoselective chelation-controlled reduc-
tion of an optically active b-ketosulfoxide followed by
diastereoselective reduction of the resulting b-hydroxy
ketone efficiently constructed the syn-1,3-diol function-
ality of compound 3. Sharpless epoxidation was then
used to efficiently install the stereochemistry of the C3
tertiary alcohol fragment of taurospongin. The key
coupling step leading to the synthesis of 2 was accom-
plished by opening epoxide 3 with the alkynyllithium
derived from 4.
Combination therapy consisting of both nucleoside and
non-nucleoside reverse transcriptase inhibitors and
protease inhibitors has become a standard treatment
for HIV infection.1 Because of numerous limitations of
current chemotherapies, the design and discovery of
novel, structurally diverse, agents is very important.2
Taurospongin A (Fig. 1), a unique fatty acid derivative
isolated from the Okinawan marine sponge Hippospon-
2. Results and discussion
The preparation of enantiomerically pure epoxide 3
is illustrated in Scheme 1. The known5 ketal 5 was
prepared in multigram quantities by heating methyl
acetoacetate and ethylene glycol in dry benzene for 3 h
in the presence of a catalytic amount of p-TsOH with
azeotropic removal of water. Treatment of 5 with the
Figure 1.
* Corresponding author. E-mail: arunghos@uic.edu
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00040-5

630
A. K. Ghosh, H. Lei / Tetrahedron: Asymmetry 14 (2003) 629–634
Scheme 1. Reagents, conditions (and yields): (a) LDA, (S)-
methyl-p-tolylsulfoxide, THF, 30 min (65%); (b) DIBAL,
−78°C, THF, 30 min; (c) oxalic acid, THF/H2O, 15 h (84%,
two steps); (d) Et2BOMe, NABH4, THF/MeOH, 6 h, then
H2O2, 10 h (92%); (e) PhCH(OMe)2, p-TsOH·H2O, CH2Cl2,
30 min; (f) DIBAL, 0–23°C, 6 h (74%, two steps); (g)
Me3OBF4, CH2Cl2; (h) K2CO3, H2O (70%, two steps).
Scheme 2. Reagents, conditions (and yields): (a) Ti(OiPr)4,
,
(+)-DET, t-BuOOH, 4 A MS, CH2Cl2, −30°C, 30 h (61%);
(b) LAH, ether, 0°C, 1 h; (c) cyclohexanone dimethyl ketal,
p-TsOH·H2O (cat.), CH2Cl2, 23°C, 3 h (71%, two steps); (d)
nBuLi, BF3·OEt2, THF, −78°C, then 3, 2 h (87%); (e) Ac2O,
Et3N, DMAP (cat.), CH2Cl2, 3 h (94%); (f) 10% Pd–C, H2,
EtOAc, 6 h (96%); (g) TBSOTf, 2,6-lutidine, CH2Cl2, 0°C,
30 min (95%); (h) PPTS (cat.), MeOH, 15 min (95%).
(S)-methyl-p-tolylsulfoxide anion furnished the opti-
cally active b-ketosulfoxide 6 in 65% yield after chro-
matography.6 DIBAL reduction of 6 in THF at −78°C
as reported by Solladie et al.7 then afforded the corre-
sponding b-hydroxysulfoxide diastereoselectively. The
1H and 13C NMR analysis of the resulting b-hydroxy-
sulfoxide revealed that the reduction occurred with
excellent diastereoselectivity (>96% de). Removal of
the ketal by exposure to oxalic acid in a mixture of
THF and water furnished b-hydroxy ketone 7 in 84%
yield in two steps. For syn-selective reduction of 7, we
examined the chelation-controlled reduction protocol
developed by Prasad and co-workers8 utilizing diethyl-
methoxyborane and sodium borohydride at −78°C.9
This provided the syn-1,3-diol derivative 8 as a single
vided epoxide 11 enantioselectively. The enantiomeric
purity of 11 (98% ee, [h]2D0=−16.5 (c 0.85, CHCl3) was
determined by formation of the Mosher ester and 19F
NMR analysis.14 Reduction of the epoxide with LAH
in ether at 0°C afforded the corresponding 1,3-diol
which was treated with cyclohexanone dimethyl ketal
in the presence of a catalytic amount of p-TsOH·H2O
to provide ketal 4 in 71% yield from 11.
1
diastereomer (by H and 13C NMR analysis) in 92%
isolated yield. Treatment of 8 with benzaldehyde
dimethyl acetal in the presence of a catalytic amount
of p-TsOH·H2O afforded the corresponding benzyli-
dene acetal. Reduction of the resulting acetal with
DIBAL effected regioselective reduction of the acetal
as well as reduction of the sulfoxide moiety to the
sulfide. Benzyl ether 9 was isolated in 74% yield for
two steps. The b-hydroxysulfide functionality of 9 was
converted to the corresponding oxirane 3 in a one pot,
two-step sequence consisting of alkylation of 9 by
exposure to trimethyloxoniumtetrafluoroborate in
CH2Cl2 followed by treatment of the resulting mixture
with aqueous potassium carbonate, providing 3 in 70%
yield after chromatography.10
Treatment of alkyne 4 with nBuLi in THF at −78°C
for 20 min provided the alkynyl anion which was
reacted with epoxide 3 in the presence of BF3·OEt2 at
−78°C for 2 h to furnish alcohol 12 in 87% yield.
Acetylation of the alcohol with acetic anhydride and
triethylamine in the presence of a catalytic amount of
DMAP afforded acetate 13 in 94% yield. Hydrogena-
tion of 13 over 10% Pd–C in ethyl acetate effected
saturation of the triple bond as well as removal of the
benzyl group to afford alcohol 14. It was converted to
TBS ether 15 by reaction with TBSOTf in the presence
of 2,6-lutidine at 0°C for 30 min. Exposure of 15 to
PPTS in methanol at 23°C for 15 min removed the
cyclohexylidene ketal and provided diol 2 which has
been converted previously to (+)-taurospongin by
Lebel and Jacobsen.4 Spectral data (1H and 13C NMR)
for synthetic 2 ([h]D23=−3.8 (c 1.58, CHCl3), lit. [h]2D3=
−2.5 (c 1.73, CHCl3) are in full agreement with those
reported in the literature.4
The synthesis of compound 4 was carried out utilizing
Pattenden’s protocol as shown in Scheme 2.11 The
(Z)-enynol 10 was prepared in multi-gram quantities
using the method described in the literature.12 Sharp-
less asymmetric epoxidation13 of 10 with (+)-DET pro-

A. K. Ghosh, H. Lei / Tetrahedron: Asymmetry 14 (2003) 629–634
631
3. Conclusion
separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4 and evaporated under
reduced pressure to provide crude b-keto-a-hydroxysul-
foxide. An analytical sample was prepared after column
chromatography over silica gel (25% ethyl acetate in
In conclusion, an enantioselective formal synthesis of
(+)-taurospongin A has been accomplished utilizing
chelation-controlled reduction and Sharpless asymmet-
ric epoxidation as the key steps. The present synthesis
will provide further access to structural variants of
1
hexanes). H NMR (400 MHz, CDCl3): l 1.32 (s, 3H),
taurospongin
studies.
A
for important structure–activity
1.86 (dd, 1H, J=14.5, 3.8 Hz), 1.91 (dd, 1H, J=14.5,
7.9 Hz), 2.41 (s, 3H), 2.79 (dd, 1H, J=13.0, 3.0 Hz),
2.86 (dd, 1H, J=13.0, 9.5 Hz), 3.89–4.00 (m, 5H),
4.46–4.54 (m, 1H), 7.33 (d, 2H, J=8.4 Hz), 7.55 (d, 2H,
J=8.1 Hz); 13C NMR (100 MHz, CDCl3): l 21.4, 24.1,
44.5, 63.0, 64.3, 64.5, 109.6, 123.9, 129.9, 140.7, 141.4.
4. Experimental
All moisture sensitive reactions were carried out under
argon or nitrogen atmosphere. Anhydrous solvents
were obtained as follows: tetrahydrofuran and diethyl
ether, distilled from sodium and benzophenone;
dichloromethane, distilled from CaH2; triethylamine,
distilled from CaH2. All other solvents were HPLC
grade. Column chromatography was performed with
Whatman 240–400 mesh silica gel under low pressure of
5–10 psi. Thin-layer chromatography (TLC) was car-
To a stirred solution of the above alcohol in THF (5
mL) and H2O (10 mL) was added oxalic acid (581.1
mg, 4.6 mmol). The resulting mixture was stirred at
room temperature for 15 h and quenched with satu-
rated aqueous NaHCO3. The layers were separated and
the aqueous layer was extracted with EtOAc. The com-
bined organic layers were washed with brine, dried over
Na2SO4 and evaporated under reduced pressure. The
crude product was washed with ether to provide b-
hydroxy ketosulfoxide 7 as a white solid (406 mg, 84%
two steps). Mp 105°C; [h]2D3=−305 (c 0.34, CHCl3); IR
(film): 3379, 2921, 1710, 1084 cm−1; 1H NMR (300
MHz, CDCl3): l 2.05 (s, 3H), 2.28 (s, 3H), 2.51–2.67
(m, 2H), 2.71–2.89 (m, 2H), 4.53–4.60 (m, 1H), 4.76 (br,
1H), 7.20 (d, 2H, J=7.8 Hz), 7.44 (d, 2H, J=7.8 Hz);
13C NMR (75 MHz, CDCl3): l 21.0, 30.4, 49.4, 62.3,
63.0, 123.6, 129.7, 139.7, 141.2, 207.1
1
ried out with E. Merck silica gel 60 F-254 plates. H
and 13C NMR spectra were recorded on Bruker Avance
400 (400 MHz), Avance 500 (500 MHz) and Varian 300
(300 MHz) spectrometers.
4.1. (S)-4,4-(Ethylenedioxy)-1-(p-tolylsulfinyl)pentan-2-
one, 6
To a stirred solution of LDA [prepared from iPr2NH
(2.2 mL, 15.4 mmol) and nBuLi (8.1 mL, 13.0 mmol)]
in THF at 0°C was added (S)-methyl-p-tolylsulfoxide
(Aldrich, 0.91 g, 5.9 mmol) in THF (5 mL). The
resulting mixture was stirred for 30 min at 0°C and
added to a solution of methyl ester 5 (0.98 g, 6.1 mmol)
in THF (15 mL). The reaction mixture was stirred at
room temperature for 30 min and quenched with satu-
rated aqueous NH4Cl. The layers were separated and
the aqueous layer was extracted with EtOAc. The com-
bined organic layers were washed with brine, dried over
Na2SO4 and evaporated under reduced pressure. The
residue was purified by column chromatography (50%
EtOAc in hexanes) to provide the title compound (1.08
g, 65% yield) as a colorless oil. [h]2D3=−153 (c 0.81,
CHCl3); IR (film): 2981, 2893, 1710, 1040 cm−1; 1H
NMR (300 MHz, CDCl3): l 1.25 (s, 3H), 2.33 (s, 3H),
2.74 (ABq, 2H, J=13.2, Dw=28.6 Hz), 3.84–3.91 (m,
6H), 7.25 (d, 2H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz);
13C NMR (75 MHz, CDCl3): l 21.1, 24.2, 52.9, 64.2,
64.3, 68.6, 107.2, 123.8, 129.7, 139.5, 141.7, 198.9
4.3. (2R,4S,SS)-2,4-Dihydroxy-1-(p-tolylsulfinyl)pentane,
8
To a stirred solution of 7 (257 mg, 1.1 mmol) in THF
(20 mL) and methanol (4 mL) was added diethyl-
methoxyborane (0.17 mL, 1.3 mmol). After stirring for
15 min at room temperature, the reaction mixture was
cooled to −78°C and sodium borohydride (57 mg, 1.5
mmol) was added. The reaction mixture was stirred at
−78°C for additional 6 h and 50% aqueous H2O2 (0.5
mL) was added. The mixture was warmed to room
temperature and diluted with EtOAc and H2O. The
layers were separated and the aqueous layer was
extracted with EtOAc. The combined organic layers
were washed with saturated NaHCO3, Na2SO3, brine,
dried over Na2SO4 and evaporated under reduced pres-
sure. The resulting white solid (236 mg, 92% yield) was
sufficiently pure to be used for next step reaction with-
out further purification. Mp 122°C; [h]2D3=−291 (c 1.01,
CHCl3); IR (film): 3370, 2966, 2922, 1066, 1028, 1010
cm−1; 1H NMR (400 MHz, CDCl3): l 1.12 (d, 3H,
J=6.2 Hz), 1.48 (dt, 1H, J=14.2, 3.0 Hz), 1.64 (dt, 1H,
J=14.2, 9.5 Hz), 2.35 (s, 3H), 2.74 (dd, 1H, J=13.2,
2.3 Hz), 2.87 (dd, 1H, J=13.2, 9.9 Hz), 3.99–4.03 (m,
1H), 4.21 (s, 1H), 4.38–4.44 (m, 1H), 5.30 (d, 1H,
J=3.0 Hz), 7.27 (d, 2H, J=8.2 Hz), 7.48 (d, 2H, J=8.2
Hz); 13C NMR (100 MHz, CDCl3): l 21.3, 23.8, 44.4,
64.4, 66.3, 67.5, 123.9, 130.0, 139.8, 141.6; HRMS (EI)
m/z calcd for C12H18O3NaS (M++Na): 265.0874; found:
265.0874.
4.2. (2R,SS)-2-Hydroxy-1-(p-tolylsulfinyl)pentan-4-one,
7
To a stirred solution of 6 (660 mg, 2.33 mmol) in THF
(30 mL) at −78°C was added DIBAL (4.67 mL 1 M
solution in hexane, 4.67 mmol) dropwise. The resulting
mixture was stirred for 30 min and quenched with
methanol and warmed to room temperature. The sol-
vent was removed under reduced pressure and the
residue was dissolved in EtOAc and 10% aqueous
potassium sodium tartrate solution. The layers were

632
A. K. Ghosh, H. Lei / Tetrahedron: Asymmetry 14 (2003) 629–634
4.4. (2R,4S)-4-Benzyloxy-2-hydroxy-1-(mercapto-p-
4.48 (d, 1H, J=11.7 Hz), 4.60 (d, 1H, J=11.7 Hz),
7.32–7.35 (m, 5H), 13C NMR (125 MHz, CDCl3): l
20.0, 39.7, 47.2, 50.0, 70.7, 73.0, 127.9, 127.9, 128.7,
139.1; HRMS (EI) m/z calcd for C12H16O2Na (M++
Na): 215.1048; found: 215.1050.
tolyl)pentane, 9
To a stirred solution of 8 (191 mg, 0.79 mmol) in
CH2Cl2 (10 mL) was added benzaldehyde dimethyl
acetal (0.24 mL, 1.6 mmol) and p-TsOH·H2O (15 mg,
0.1 mmol). The resulting mixture was stirred for 1 h
and quenched with saturated NaHCO3. The layers were
separated and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with
brine, dried over Na2SO4 and evaporated under
reduced pressure. The residue was purified by column
chromatography (50% EtOAc in hexanes) to provide
the corresponding benzylidene acetal. 1H NMR (500
MHz, CDCl3): l 1.33 (d, 3H, J=6.2 Hz), 1.48 (dt, 1H,
J=13.0, 11.1 Hz), 1.65 (dt, 1H, J=13.0, 2.4 Hz), 2.41
(s, 3H), 2.85–2.94 (m, 2H), 4.01–4.01 (m, 1H), 4.50–4.55
(m, 1H), 5.67 (s, 1H), 7.31–7.56 (m, 9H); 13C NMR
(125 MHz, CDCl3): l 21.8, 21.9, 38.5, 64.9, 70.9, 73.2,
101.0, 124.2, 126.5, 128.6, 129.2, 130.4, 138.5, 141.5,
141.9.
4.6. (2S,3R)-3-Ethynyl-3-methyloxiranyl)methanol, 11
,
To a stirred suspension of powdered 4 A molecular
sieves (1.5 g) in CH2Cl2 (60 mL) cooled at −23°C were
sequentially added (+)-DET (0.5 mL 2.8 mmol),
Ti(OiPr)4 (0.69 mL, 2.3 mmol) and the resulting mix-
ture was stirred for 20 min at −23°C. After this period,
a solution of (Z)-3-methylpent-2-en-4-yn-1-ol 10 (1.5 g,
15.6 mmol) dissolved in CH2Cl2 (10 mL) was added
dropwise. After 20 min, TBHP (10.4 mL, 3.3 M solu-
tion in benzene, 34.4 mmol) was added and the result-
ing mixture was kept at −23°C for 30 h. After this
period, 30% aqueous NaOH (20 mL) was added and
the mixture was stirred at 0°C for 1 h. The resulting
suspension was filtered through Celite. The filtrate was
diluted with H2O and EtOAc. The layers were sepa-
rated and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated under reduced
pressure. The residue oil was purified by column chro-
matography (30% EtOAc in hexanes) to provide com-
pound 11 as a colorless oil (1.07 g, 61%). [h]2D3=−16.5
(c 0.85 CHCl3); IR (film): 3396, 2982, 2359, 1444, 1381,
1017 cm−1; 1H NMR (300 MHz, CDCl3): l 1.53 (s, 3H),
2.39 (s, 1H), 2.82 (br, 1H), 3.07 (dd, 1H, J=6.3, 4.8
Hz), 3.76 (dd, 1H, J=12.3, 6.3 Hz), 3.88 (dd, 1H,
J=12.3, 4.8 Hz); 13C NMR (75 MHz, CDCl3): l 22.7,
51.2, 61.9, 63.5, 72.9, 80.4; MS (ESI) m/z 135.0 (M++
Na).
The above benzylidene acetal was dissolved in CH2Cl2
(20 mL) and cooled to 0°C. DIBAL (7.9 mL, 1 M
solution in hexane, 7.9 mmol) was added dropwise. The
resulting mixture was warmed to room temperature and
stirred for an additional 6 h. The reaction mixture was
quenched with 1N HCl. The layers were separated and
the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with saturated
NaHCO3, brine, dried over Na2SO4 and evaporated
under reduced pressure. The residue was purified by
column chromatography (30% EtOAc in hexanes) to
provide 9 as a colorless oil (176 mg, 74%). [h]2D3=−36.5
(c 0.46, CHCl3); IR (film): 3421, 2921, 1641 cm−1; H
1
NMR (500 MHz, CDCl3): l 1.25 (d, 3H, J=6.1 Hz),
1.73–1.84 (m, 2H), 2.35 (s, 3H), 2.93 (dd, 1H, J=13.4,
5.9 Hz), 3.00 (dd, 1H, J=13.4, 6.6 Hz), 3.78–3.82 (m,
1H), 3.90–3.93 (m, 1H), 4.40 (d, 1H, J=11.4 Hz), 4.64
(d, 1H, J=11.4 Hz), 7.09 (d, 2H, J=7.9 Hz), 7.28–7.34
(m, 7H); 13C NMR (125 MHz, CDCl3): l 20.0, 21.4,
42.0, 42.9, 70.0, 70.7, 75.6, 128.2, 128.9, 130.1, 130.3,
130.5, 132.6, 136.7, 138.4; HRMS (EI) m/z calcd for
C19H24O2NaS (M++Na): 339.1395; found: 339.1406.
4.7. (S)-3-Methyl-1,3-O-cyclohexylidenepent-4-yne, 4
To a stirred solution of epoxide 11 (0.96 g, 8.6 mmol) in
ether (20 mL) at 0°C was added LiAlH4 (812 mg, 21.4
mmol). After stirring at 0°C for one hour, the reaction
was quenched with 10% aqueous potassium sodium
tartrate solution. The layers were separated and the
aqueous layer was saturated with NaCl and extracted
with EtOAc. The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure.
The residue oil was purified by column chromatogra-
phy (45% EtOAc in hexanes) to provide the corre-
4.5. (2R,4S)-4-Benzyloxy-1,2-epoxypentane, 3
To a stirred solution of 9 (54 mg, 0.18 mmol) in CH2Cl2
(4 mL) was added trimethyloxonium tetrafluoroborate
(32 mg, 0.22 mmol) and the resulting mixture was
stirred for 2 h at room temperature. An aqueous solu-
tion of K2CO3 (50 mg in 2 mL H2O) was added and
stirring was continued for 30 h. The aqueous layer was
extracted with CH2Cl2. The combined organic layers
were washed with brine, dried over Na2SO4 and evapo-
rated under reduced pressure. The residue was purified
by column chromatography (15% EtOAc in hexanes) to
provided 3 as a colorless oil (24 mg, 70% for two steps).
[h]2D3=−20.1 (c 0.69, CHCl3); IR (film): 2918, 2854,
sponding diol as
a colorless oil (0.91 g, 93%).
[h]2D3=−6.0 (c 1.0 CHCl3); IR (film): 3344, 2980, 1417,
1373, 1133, 1094, 1053 cm−1; 1H NMR (300 MHz,
CDCl3): l 1.47 (s, 3H), 1.76 (td, 1H, J=14.4, 3.9 Hz),
1.93 (ddd, 1H, J=14.4, 9.4, 4.8 Hz), 2.46 (s, 1H), 3.83
(td, 1H, J=11.4, 4.8 Hz), 4.18–4.23 (m, 1H); 13C NMR
(75 MHz, CDCl3): l 30.1, 43.0, 59.8, 68.1, 71.6, 86.7;
MS (ESI) m/z 81.0, 137.1 (M++Na).
To a stirred solution of the above diol (730 mg, 6.4
mmol) in CH2Cl2 (40 mL) was added cyclohexanone
dimethyl ketal (2.14 mL, 14.0 mmol) and p-TsOH·H2O
(121.8 mg, 0.64 mmol). The resulting mixture was
stirred for 3 h and quenched with saturated aqueous
NaHCO3. The layers were separated and the aqueous
1
1452, 1064 cm−1; H NMR (500 MHz, CDCl3): l 1.29
(d, 3H, J=6.2 Hz), 1.69 (dt, 1H, J=14.2, 5.5 Hz), 1.87
(dt, 1H, J=14.2, 6.2 Hz), 2.48 (dd, 1H, J=5.0, 2.7 Hz),
2.75 (t, 1H, J=4.7 Hz), 3.05 (m, 1H), 3.74 (m, 1H),

A. K. Ghosh, H. Lei / Tetrahedron: Asymmetry 14 (2003) 629–634
633
layer was extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The residue oil
was purified by column chromatography (5% EtOAc in
hexanes) to provide compound 4 as a colorless oil (944
mg, 76%). [h]2D3=+10.0 (c 1.0 CHCl3); IR (film): 3305,
1.51–1.64 (m, 7H), 1.77–1.86 (m, 2H), 1.98 (s, 3H),
1.99–2.04 (m, 1H), 2.2 (br, 2H), 2.40 (dd, 1H, J=16.9,
5.3 Hz), 2.50 (ddd, 1H, J=16.9, 5.8, 3.5 Hz), 3.56–3.60
(m, 1H), 3.74–3.78 (m, 1H), 4.16–4.23 (m, 1H), 4.41 (d,
1H, J=11.7 Hz), 4.57 (d, 1H, J=11.7 Hz), 5.03–5.06
(m, 1H), 7.29–7.34 (m, 5H); 13C NMR (125 MHz,
CDCl3): l 19.9, 21.5, 23.1, 23.5, 24.7, 26.0, 31.2, 33.0,
38.3, 40.2, 40.3, 57.4, 66.1, 70.0, 70.5, 72.1, 79.4, 86.8,
99.8, 127.9, 128.0, 128.7, 138.9, 170.7; MS (ESI) m/z
271.1, 451.3 (M++Na).
1
2935, 1368, 1123, 1094, 948 cm−1; H NMR (500 MHz,
CDCl3): l 1.32–1.37 (m, 4H), 1.45 (s, 3H), 1.48–1.55
(m, 6H), 1.64 (td, 1H, J=13.2, 2.2 Hz), 1.82 (dt, 1H,
J=12.9, 5.0 Hz), 2.37 (s, 1H), 3.77 (ddd, 1H, J=12.0,
5.1, 1.8 Hz), 4.24 (dt, 1H, J=12.0, 2.4 Hz); 13C NMR
(125 MHz, CDCl3): l 22.7, 22.9, 25.6, 30.7, 32.4, 37.5,
39.6, 56.7, 65.4, 71.8, 88.2, 100.0; MS (ESI) m/z 233.1
(M++K).
4.10. (3R,7S,9R)-7-Acetoxy-1,3-O-cyclohexylidene-9-
hydroxy-3-methyldecane, 14
A solution of 13 (90 mg, 0.21 mmol) in EtOAc (10 mL)
containing Pd/C (18 mg) was put under a H2 balloon.
The solution was stirred for 6 h and filtered through
Celite. The filtrate was concentrated under reduced
pressure and the residue oil was purified by column
chromatography (35% EtOAc in hexanes) to provide
the title compound as a colorless oil (68.9 mg, 96%).
[h]2D3=−5.3 (c 1.5 CHCl3); IR (film); 3454, 2934, 2859,
4.8. (3S,7S,9R)-9-Benzyloxy-7-hydroxy-1,3-O-cyclo-
hexylidene-3-methyldec-4-yne, 12
To a stirred solution of alkyne 4 (242 mg, 0.62 mmol)
in THF (5 mL) cooled to −78°C was added nBuLi (0.82
mL, 1.6 M solution in hexane, 1.30 mmol) dropwise.
After stirring for 20 min, BF3·OEt2 (0.16 mL, 1.30
mmol) and (2R,4S)-4-benzyloxy-1,2-epoxypentane 3
(119 mg, 0.62 mmol) dissolved in THF (1 mL) were
sequentially added. The reaction mixture was stirred at
−78°C for 2 h and quenched with saturated aqueous
NH4Cl. The layers were separated and the aqueous
layer was extracted with EtOAc. The combined organic
layers were washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The residue oil
was purified by column chromatography (15% EtOAc
in hexanes) to provide 12 as a colorless oil (208 mg,
87%). [h]2D3=−29.4 (c 1.7 CHCl3); IR (film): 3468, 2933,
1
1735, 1246, 1107 cm−1; H NMR (500 MHz, C6D6): l
1.18 (d, 3H, J=6.0 Hz), 1.24 (s, 3H), 1.32–1.77 (m,
18H), 1.71 (s, 3H), 1.93–1.98 (m, 2H), 3.51–3.59 (m,
1H), 3.65–3.88 (m, 2H), 5.22–5.28 (m, 1H); 13C NMR
(125 MHz, C6D6): l 19.2, 20.6, 23.2, 23.4, 25.8, 26.8,
30.0, 34.3, 35.1, 36.0, 38.6, 43.9, 44.1, 55.7, 65.2, 71.7,
72.1, 97.8, 170.1; MS (ESI) m/z 285.7, 365.2 (M++Na).
4.11. (3R,7S,9R)-7-Acetoxy-9-O-tert-butyldimethylsilyl-
1,3-O-cyclohexylidene-3-methyldecane, 15
1
2861, 1449, 1123, 1094, 945 cm−1; H NMR (500 MHz,
To a stirred solution of 14 (64.5 mg, 0.19 mmol) in
CH2Cl2 (3 mL) was added 2,6-lutidine (33 mL, 0.29
mmol) and TBSOTf (50 mL, 0.23 mmol). The reaction
mixture was stirred for 30 min and quenched with
saturated aqueous NH4Cl. The layers were separated
and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried
over Na2SO4 and concentrated under reduced pressure.
The residue oil was purified by column chromatogra-
phy (10% EtOAc in hexanes) to provide compound 15
as a colorless oil (83 mg, 95%). [h]2D3=−1.3 ( c 1.5,
CHCl3); IR (film): 2933, 2857, 1738, 1463, 1246, 1135,
C6D6): l 1.06 (dd, 3H, J=6.0, 2.7 Hz), 1.44–1.58 (m,
4H), 1.63 (s, 3H), 1.68–1.97 (m, 10H), 2.37 (td, 1H,
J=16.4, 7.6 Hz), 2.49 (ddd, 1H, J=16.4, 5.2, 1.4 Hz),
2.58 (br, 1H), 3.55–3.63 (m, 1H), 3.71–3.75 (m, 1H),
3.97–4.01 (m, 1H), 4.16 (dd, 1H, J=11.7, 2.2 Hz),
4.31–4.39 (m, 1H), 4.41 (d, 1H, J=11.7 Hz), 7.22–7.30
(m, 5H); 13C NMR (125 MHz, C6D6): l 19.7, 23.3,
23.8, 26.4, 28.2, 31.7, 33.2, 38.5, 40.6, 43.5, 53.4, 57.2,
66.3, 70.4, 75.5, 81.1, 86.9, 99.8, 128.2, 128.4, 128.9,
138.8; MS (ESI) m/z 409.3 (M++Na).
1
4.9. (3S,7S,9R)-7-Acetoxy-9-benzyloxy-1,3-O-cyclo-
hexylidene-3-methyldec-4-yne, 13
1108 cm−1; H NMR (500 MHz, C6D6): l 0.17 (s, 3H),
0.20 (s, 3H), 1.10 (s, 9H), 1.11 (d, 3H, J=6.0 Hz), 1.20
(s, 3H), 1.26–1.31 (m, 5H), 1.59–1.74 (m, 12H), 1.84 (s,
3H), 1.96–2.05 (m, 3H), 3.69–3.74 (m, 1H), 3.77–3.83
(m, 1H), 3.96–4.00 (m, 1H), 5.33–5.36 (m, 1H); 13C
NMR (125 MHz, C6D6): l −5.3, −3.9, 14.5, 18.4, 19.6,
20.9, 23.6, 23.9, 26.2, 27.1, 30.3, 34.9, 35.7, 36.4, 39.1,
44.7, 45.2, 56.1, 66.4, 70.6, 72.1, 98.2, 170.0; MS (ESI)
m/z 184.0, 341.1, 479.3 (M+Na)+; HRMS (EI) m/z
calcd for C25H48O5NaSi (M++Na): 479.3161; found:
479.6164.
To a stirred solution of alcohol 12 (122 mg, 0.31 mmol)
in CH2Cl2 (5 mL) were sequentially added triethylamine
(0.12 mL, 0.93 mmol), acetic anhydride (74 mL, 0.78
mmol) and 4-dimethylaminopyridine (18.9 mg, 0.15
mmol). The reaction mixture was stirred for 3 h and
quenched with aqueous saturated NH4Cl. The layers
were separated and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were washed
with brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue oil was purified by
column chromatography (10% EtOAc in hexanes) to
provide 13 as a colorless oil (125 mg, 94%). [h]2D3=
+13.9 (c 1.8 CHCl3); IR (film): 2932, 2360, 1739, 1372,
4.12. (3R,7S,9R)-7-Acetoxy-9-O-tert-butyldimethylsilyl-
3-methyldecane-1,3-diol, 2
To a stirred solution of 15 (42 mg, 0.09 mmol) in
MeOH (3 mL) was added PPTS (5.1 mg, 0.02 mmol).
The reaction mixture was stirred for 15 min and
1
1195 cm−1; H NMR (500 MHz, CDCl3): l 1.23 (dd,
3H, J=6.1, 1.1 Hz), 1.35–1.43 (m, 2H), 1.45 (s, 3H),

634
A. K. Ghosh, H. Lei / Tetrahedron: Asymmetry 14 (2003) 629–634
quenched with saturated aqueous NaHCO3 and diluted
with EtOAc. The layers were separated and the
aqueous layer was extracted with EtOAc. The com-
bined organic layers were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The
residue oil was purified by column chromatography
(50% EtOAc in hexanes) to provide 2 as a colorless oil
(33 mg, 95%). [h]2D3=−3.8 (c 1.58 CHCl3); IR (film):
3380, 2955, 2930, 2860, 1740, 1460, 1375, 1250, 1140
2. Cihlar, T.; Bischofberger, N. N. Ann. Rep. Med. Chem.
2000, 35, 177.
3. Ishiyama, H.; Ishibashi, M.; Ogawa, A.; Yoshida, S.;
Kobayashi, J. J. Org. Chem. 1997, 62, 3831.
4. Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.
5. Cavallaro, R. A.; Filocamo, L.; Galuppi, A.; Galione, A.;
Brufani, M.; Genazzani, A. A. J. Med. Chem. 1999, 42,
2527.
6. Solladie, G.; Greck, C.; Demailly, G.; Solladie-Cavallo,
A. Tetrahedron Lett. 1982, 23, 5047.
1
cm−1; H NMR (500 MHz, CDCl3): l 0.05 (s, 6H), 0.88
(s, 9H), 1.15 (d, 3H, J=6.1 Hz), 1.22 (s, 3H), 1.23–1.37
(m, 2H), 1.46–1.59 (m, 5H), 1.60–1.67 (m, 1H), 1.75–
1.90 (m, 2H), 2.03 (s, 3H), 2.45 (s, 2H), 3.80–3.93 (m,
3H), 4.95–5.01 (m, 1H); 13C NMR (125 MHz, CDCl3):
l −4.4, −3.9, 18.5, 20.9, 21.8, 23.8, 26.2, 27.1, 35.3, 41.8,
42.0, 44.7, 60.3, 66.0, 71.9, 74.0, 171.1; HRMS (EI) m/z
calcd for C19H40O5NaSi (M++Na): 399.2543; found:
399.2547.
7. For application of this protocol, see: (a) Solladie, G.;
Salom-Roig, X. J.; Hanquet, G. Tetrahedron Lett. 2000,
41, 551; (b) Solladie, G.; Ghiatou, N. Bull. Chim. Soc. Fr.
1994, 131, 575 and references cited therein.
8. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.;
Shapiro, M. Tetrahedron Lett. 1987, 28, 155.
9. For other related reductions, see: (a) Narasaka, K.; Pai,
F. C. Tetrahedron 1984, 40, 2233; (b) Kathawala, F. G.;
Prager, B.; Prasad, K.; Repic, O.; Shapiro, M. J.; Stabler,
R. S.; Widler, L. Helv. Chim. Acta 1986, 69, 803.
10. (a) Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K.
B.; Viti, S. M. J. Org. Chem. 1982, 47, 1378; (b)
Fugisawa, T.; Sato, T.; Kawara, T.; Ohashi, K. Tetra-
hedron Lett. 1981, 22, 4823 and references cited therein.
11. Pattenden, G.; Cid, M. B. Synlett 1998, 540.
12. Mori, K.; Ohki, M.; Sato, A.; Matsui, M. Tetrahedron
1972, 28, 3739.
Acknowledgements
Financial support for this work was provided by the
National Institutes of Health. We thank Dr. Geoffrey
Bilcer for helpful discussions and Mr. Joseph T. Kim
for experimental assistance.
13. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: New York, 1993; p. 103.
14. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543.
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