Convergent synthesis of the spiroketal core of the HIV-1 protease inhibitors the didemnaketals

Article abstract of DOI:10.1039/b108512n

A stereocontrolled and efficient synthetic approach to the spiroketal compound 4a and its C1″-epimer 4b, the core of the HIV-protease inhibitor didemnaketals isolated from the ascidian Didemnum sp., is developed through a multistep approach from natural L

Full text of DOI:10.1039/b108512n

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Convergent synthesis of the spiroketal core of the HIV-1 protease
inhibitors the didemnaketals
Yanxing Jia, Xin Li, Pingzhen Wang, Bin Wu, Xuezhi Zhao and Yongqiang Tu*
1
Department of Chemistry & National Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, P. R. China
Received (in Cambridge) 19th September 2001, Accepted 12th December 2001
First published as an Advance Article on the web 29th January 2002
A stereocontrolled and efficient synthetic approach to the spiroketal compound 4a and its C1Љ-epimer 4b, the core of
the HIV-protease inhibitor didemnaketals isolated from the ascidian Didemnum sp., is developed through a multi-
step approach from natural -(Ϫ)-menthone. This route involves the highly diastereoselective construction of four
chiral carbon centers by intramolecular chiral induction.
(Ϫ)-menthone 8 could be employed as a starting material due to
the presence of a chiral methyl in 8. So our synthesis work
started from the construction of two intermediates 6 and 7.
The construction of intermediate 6 from 8 is shown in
Introduction
The didemnaketals, new complex, naturally occuring marine
spiroketal compounds isolated from the ascidian Didemnum sp.
by Faulkner and colleagues, have been found to inhibit HIV-1
protease, with IC50-values of 1 and 2 being 2 µM and 10 µM,
Scheme 2. Thus, the known α,β-unsaturated ketone 9 was pre-
pared from -(Ϫ)-menthone using a literature procedure,3
respectively.1 In addition, their structural features, which
and then was subjected to stereoselective epoxidation with
include the presence of two branching methyl groups at two β-
basic H2O2 to afford exclusively the epoxy ketone 10 in 71%
positions of the spiro center and a long side-chain bearing
multi-acetoxy groups, are significant. However, their synthesis
has not been reported previously, and it is important to perform
studies toward their total synthesis. Our research interest in the
yield.4 After several attempts to ring open 10 with hydrazine,
the key allylic alcohol intermediate 11 was prepared in
reasonable yield (65%).5 Direct ozonization of 11 without
protecting the hydroxy group by carefully monitoring the reac-
chemistry of this class of compound is focused on the develop-
tion formed the keto-aldehyde product, which was obtained
ment of an efficient synthetic approach, in which the construc-
tion of the key spiroketals 4a/4b is the challenging work. Since
the original report did not determine the absolute stereo-
chemistry of the naturally occurring didemnaketals, we selected
actually as an intramolecular hemiacetal 12 (2 isomers, ca. 1/1)
in 85% yield. Subsequent reduction of the ketone carbonyl of
12 with NaBH4 at low temperature gave the sole product 13 in
80% yield. Fortunately, the stereochemistry of the newly formed
a pair of epimers 4a/4b as the target molecules with such con-
hydroxy group of 13 was determined to have the α-hydroxy
figurations as shown in Scheme 1. In this paper we present a
configuration on the basis of the NOESY spectra for the
convergent stereocontrolled approach to the spiroketals 4a/4b.
acetonide of 14. Thus, all of the chiral carbon centers required
for the intermediate 6 were constructed. Trans-acetalization of
the hemiacetal 13 with propane-1,3-dithiol, followed by pro-
tection of the two hydroxy groups with TBSCl (tert-butyl-
Results and discussion
In developing a synthetic strategy to access 4a/4b (Scheme 1), the
synthesis of the key open-chain δ,δЈ-dihydroxy ketone inter-
mediate 5 was envisaged,2 which would be further disconnected
into two similar pieces 6 and 7, in terms of its structural sym-
metry. Both 6 and 7 contain the similar key ‘1-oxygen-3-methyl’
moiety, which reminded us that the abundant and natural -
dimethylsilyl chloride), and final deprotection of the aldehyde
carbonyl, afforded the intermediate 6 (52% yield, three steps).
Preparation of the intermediate 7 is presented in Scheme 3, in
which the initial reduction of the α,β-unsaturated ketone 9 with
NaBH4
furnished exclusively the allylic alcohol 16 in 90% yield.
The stereochemistry of the newly formed hydroxy group of 16
Scheme 1
DOI: 10.1039/b108512n
J. Chem. Soc., Perkin Trans. 1, 2002, 565–570
This journal is © The Royal Society of Chemistry 2002
565

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Scheme 2 Reagents and conditions (yields): (a) H2O2, NaOH, MeOH, 25 ЊC (71%); (b) 85% NH2NH2ؒH2O, HOAc, 25 ЊC (65%); (c) O3, CH2Cl2,
Ϫ78 ЊC; then Me2S (85%); (d) NaBH4, MeOH, Ϫ78 ЊC (80%); (e) propane-1,3-dithiol, BF3ؒOEt2, 0 ЊC (78%); (f ) TBDMSCl, imidazole, DMF, 90 ЊC;
(g) CaCO3, HgCl2, 80% MeCN–water (66%) (2 steps).
Scheme 3 Reagents and conditions (yields): (a) NaBH4, CeCl3ؒ7H2O, MeOH, 0 ЊC (90%); (b) O3, CH2Cl2, Ϫ78 ЊC; then Me2S (85%); (c) I2, IBDA,
hv, 25 ЊC (70%); (d) PhSO2Na, DMF (90%); (e) K2CO3, MeOH, 25 ЊC (88%); (f ) Zn(BH4)2, THF, 0 ЊC (93%); (g) NaBH4, MeOH, Ϫ78 ЊC (90%);
(h) K2CO3, MeOH, 25 ЊC; (i) acetone, PTSA (84%) (2 steps). IBDA = (Diacetoxyiodo)benzene.
was established to have the β-configuration from the literature.6
Direct ozonization of 16 in the same way as 11 afforded the
hemiacetal 17 (2 isomers, ca. 1/1) in 85% yield, which was
subjected to decarboxylation–iodination with (diacetoxyiodo)-
benzene (IBDA) to afford the iodide 18 (70%) bearing the C4-
formyloxy group.7 Sulphonation of 18 with PhSO2Na gave the
sulfone 19 in 90% yield.8 Deformylation of 19 with K2CO3–
MeOH followed by a regular reduction with NaBH4 gave the
diol 21 as a mixture of two isomers (ca. 1/1), which could not be
separated by column chromatography. The Zn(BH4)2 reduction
of the ketone carbonyl of 20 following a literature procedure
could furnish predominantly the product 21a with the α-
hydroxy configuration in 93% yield,8 but its epimer 21b with the
β-hydroxy configuration has not been obtained due to that no
direct procedure is available. Therefore, direct reduction of 19
afforded 22a and 22b in 90% yield, which could be separated by
column chromatography. Deformylation of 22a and 22b separ-
ately with K2CO3–MeOH then furnished 21a and 21b in the
same 88% yield, respectively. The stereochemistry of 21a was
further determined by the NOESY spectra of 7a. Thus, the
diastereoselective construction of two chiral carbon centers
bearing hydroxy groups was achieved. Protection of the two
hydroxy groups of 21a and 21b as an acetonide furnished the
intermediates 7a and 7b in the same 95% yield, respectively.
The coupling of 6 and 7a was performed as shown in Scheme
4. Deprotonation of the sulfone 7a with n-BuLi, followed by the
addition of aldehyde 6, led to the β-hydroxy sulfone 23a in 73%
yield.9 Oxidation of the hydroxy group of 23a with PDC,
followed by desulfonation with 6% sodium amalgam, gave the
precursor 24a (66%) for the spirocyclization,10 which corre-
sponded to the open-chain intermediate 5. Thus, treatment of
24a with a solution of 40% aq. hydrofluoric acid and acetonitrile
led to full deprotection–spirocyclization to form the target
spiroketal 4a in 67% yield.11 In the same way above, the epimer
4b also has been synthesized from the diastereoisomerically
pure 7b (30% yield, three steps via intermediates 23b and 24b).
In conclusion, an efficient synthetic approach to the
spiroketal core of the HIV-1 protease inhibitor didemnaketals
is described. Further studies concerning the total synthesis and
biological activity are ongoing.
Experimental
1H NMR and 13C NMR spectra were recorded for CDCl3 solu-
tions on a Bruker 200 MHz or a Bruker 400 MHz instrument
with TMS as internal standard. J-Values are in Hz. MS data
were measured with EI (70 eV) and HRMS data were measured
with FAB or ESI techniques. Optical rotations were determined
on Perkin-Elmer Model 341, and [α]D-values are given in units
of 10Ϫ1 deg cm2
g
Ϫ1. Compounds were purified by column
chromatography on silica gel H, from the Qingdao Marine
Chemical Factory, and elution with solvent mixtures of light
petroleum (distillation range 60–90 ЊC) and ethyl acetate. Ether
refers to diethyl ether.
(1R,4R,6R)-1-Isopropyl-4-methyl-7-oxa-bicyclo[4.1.0]heptan-2-
one 10
To a stirred solution of 9 (1.86 g, 12.2 mmol) and 30% hydrogen
peroxide (4.6 mL) in methanol (30 mL) was added 6 M NaOH
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(1.0 mL) at room temperature. The mixture was stirred for
7 h after which the solvent was removed in vacuo. The residue
was extracted with ether (3 × 30 mL) and the extracts
were washed with brine, dried over Na2SO4, and evaporated
in vacuo. The residue was purified by column chromatography
to give 10 (1.46 g, 71%), [α]2D5 ϩ61 (c 1.0 in MeOH);
δH(200 MHz) 3.46 (1H, br s, CH2CHO), 2.75–1.65 (6H, m,
CH2CHCH2 and CHMe2), 1.10 (6H, d, J 6.8, CHMe2), 0.90
(3H, d, J 6.5, CHCH3); δC(50 MHz) 205.5 (C), 63.6 (C), 57.2
(CH), 46.0, 31.7, 25.6, 23.7, 21.0, 18.4, 16.0 (2 × CH, 2 × CH2
and 3 × CH3).
mixture was stirred at Ϫ78 ЊC for 1.0 h, then the solvent was
removed in vacuo. The obtained residue was diluted with ether
(80 mL) and the extracts were washed successively with water
(20 mL) and brine, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by column chromatography to give 13
(0.89 g, 80%) as a mixture of two isomers in the ratio 1 : 1 as a
colorless oil. δH(400 MHz) (2 isomers) 5.37 (1H, d, J 2.5,
OCHOH), 4.77 (1H, dd, J 9.7 and 1.3, OCHOH), 4.07 (1H, dt,
J 9.7 and 2.5, CH2CHOCH), 3.54 (1H, ddd, J 11.5, 3.5 and 2.5,
CH2CHOCH), 3.38 (1H, dd, J 8.1 and 3.5, CHCHOHCH),
3.27 (1H, dd, J 8.1 and 3.5, CHCHOHCH), 1.90–1.07 (12H,
m, 2 × CH2CHCH2 and 2 × CHCMe2), 1.01 (6H, d, J 6.4,
CHCMe2), 1.00 (3H, d, J 6.4, CHCH3), 0.95 (3H, d, J 6.6,
CHMeAMeB), 0.88 (3H, d, J 6.6, CHMeAMeB), 0.86 (3H, d,
J 6.6, CHCH3); δC(100 MHz) 96.2 (CH), 92.2 (CH), 78.4 (CH),
78.1 (CH), 76.3 (CH), 69.7 (CH), 41.4, 38.4, 32.0, 31.4, 29.8,
29.3, 29.2, 28.7, 23.1, 22.3, 21.8, 19.0, 18.8, 18.7 (4 × CH, 4 ×
CH2 and 6 × CH3); m/z (2 isomers) (EI) 171 (Mϩ ϩ 1 Ϫ H2O,
8%), 170 (Mϩ Ϫ H2O, 13), 115 (92), 71 (100); HRMS (ESI)
Found: (M ϩ H)ϩ, 211.1144. C10H21O3 requires M ϩ H,
209.1148.
(1R,5S)-2-Isopropyl-5-methylcyclohex-2-enol 11
To a stirred solution of 10 (2.68 g, 16.0 mmol) and 85% hydra-
zine hydrate (18.0 mL) in methanol (40 mL) was added a
portion of acetic acid at 0 ЊC. After stirring of the mixture for
8 h at room temperature, the solvent was removed in vacuo. The
residue was extracted with ether (3 × 40 mL), and the extracts
were washed successively with saturated aq. NaHCO3 and
brine, dried over Na2SO4, and evaporated in vacuo. The residue
was purified by column chromatography to give 11 (1.58 g,
65%), [α]2D5 ϩ68 (c 0.57 in EtOH); δH(400 MHz) 5.53 (1H, m,
2-[(2R,4R,5R)-4,5-Dihydroxy-2,6-dimethylheptyl]-1,3-dithiane
14
CH CH᎐C), 4.11 (1H, br s, CCHOHCH ), 2.42 (1H, m,
᎐
2
2
CHCMe2), 2.15–1.24 (5H, m, CH2CHCH2), 1.05 (3H, d, J 7.0,
CHMeAMeB), 1.03 (3H, d, J 7.0, CHMeAMeB), 0.94 (3H, d,
J 6.5, CHCH3).
To a solution of 13 (800 mg, 4.26 mmol) in CH2Cl2 (15 mL)
were added propane-1,3-dithiol (1.6 mL, 16.0 mmol) and
BF3ؒEt2O (0.20 mL). Stirring was continued for 1.5 h at 0 ЊC.
The mixture was diluted with CH2Cl2 and saturated aq.
NaHCO3. The aqueous layer was extracted with CH2Cl2 (3 ×
20 mL), and the combined organic layers were dried over
Na2SO4 and evaporated in vacuo. The residue was purified by
column chromatography to give 14 (0.88 g, 78%), [α]2D5 ϩ23
(c 1.0 in CHCl3); δH(400 MHz) 4.10 (1H, m, CH2CHS2), 3.98
(1H, m, CH2CHOHCH), 3.66 (1H, dd, J 8.1 and 3.8, CH-
CHOHCH), 2.91–2.79 (4H, m, SCH2CH2CH2S), 2.11–1.17
(8H, m, CH2CHCH2, SCH2CH2CH2S and CHCMe2), 1.04 (3H,
d, J 6.6, CHMeAMeB), 0.97 (3H, d, J 6.6, CHMeAMeB),
0.87 (3H, d, J 6.8, CHCH3); δC(100 MHz) 83.9 (CH), 75.0 (CH),
45.1 (CH), 43.9 (CH2), 35.9 (CH2), 30.8 (CH2), 30.6 (CH2), 28.8
(CH), 27.3 (CH2), 25.9 (CH), 20.4 (CH3), 19.0 (CH3), 18.7
(CH3); m/z (EI) 278 (Mϩ, 6%), 246 (56), 131 (59), 105 (100);
HRMS (FAB) Found: (M ϩ H)ϩ, 279.1200. C13H27O2S2
requires M ϩ H, 279.1212.
(4R,6R)-2-Hydroxy-4-methyl-6-(2Ј-methylpropionyl)tetra-
hydropyran 12
Into a cold (Ϫ78 ЊC) solution of compound 11 (1.0 g, 5.9 mmol)
in CH2Cl2 (50 mL) was bubbled ozone. When the reaction was
complete (TLC) the reaction mixture was treated with Me2S
(2 mL), stirred overnight, and evaporated in vacuo. The residue
was purified by column chromatography to give 12 (1.0 g, 85%)
as a mixture of two isomers in the ratio 1 : 1. δH(400 MHz)
(2 isomers) 5.47 (1H, d, J 3.2, OCHOH), 4.79 (1H, dd, J 9.4 and
1.9, OCHOH), 4.60 (1H, dd, J 12.2 and 2.4, CH2CHOCH),
4.04 (1H, dd, J 11.8 and 2.4, CH2CHOCH), 3.12 (1H, m,
CHCMe2), 2.99 (1H, m, CHCMe2), 2.25–0.90 (10H, m, 2 ×
CH2CHCH2), 1.08 (12H, d, J 6.8, 2 × CHCMe2), 1.01 (3H, d,
J 6.0, CHCH3), 0.95 (3H, d, J 6.0, CHCH3); δC(100 MHz) 213.8
(C), 213.0 (C), 96.4 (CH), 92.3 (CH), 79.6 (CH), 73.3 (CH),
41.0 (CH2), 37.8 (CH2), 37.4 (CH), 36.0 (CH), 35.8 (CH2),
35.4 (CH2), 30.0 (CH), 29.3 (CH), 23.8 (CH3), 22.0 (CH3),
21.6 (CH3), 18.3 (CH3), 18.2 (CH3), 14.1 (CH3); m/z (EI) 185
(Mϩ Ϫ 1, 4%), 169 (30), 115 (64), 71 (100); HRMS (ESI)
Found: (M ϩ Na)ϩ, 209.1144. C10H18O3Na requires M ϩ Na,
209.1148.
2-[(2R,4R,5R)-4,5-Isopropylidenedioxy-2,6-dimethylheptyl]-
1,3-dithiane, the acetonide of 14
To a solution of 14 (55 mg, 0.21 mmol) in dry acetone (2 mL)
was added a catalytic amount of PTSA. The mixture was
stirred for 8 h at room temperature, and was then diluted with
ether (30 mL) and washed successively with saturated aq.
NaHCO3 and brine, dried over Na2SO4, and evaporated in
vacuo. The residue was purified by column chromatography to
give the acetonide of 14 (50 mg, 79%), [α]2D5 ϩ69 (c 1.0 in
(4R,6R)-6-[(1R)-1-Hydroxy-2-methylpropyl)]-4-methyltetra-
hydropyran-2-ol 13
To a cooled (Ϫ78 ЊC), stirred solution of 12 (1.1 g, 5.90 mmol)
in MeOH (30 mL) was added NaBH4 (210 mg, 5.90 mmol). The
Scheme 4 Reagents and conditions (yields): (a) n-BuLi, THF, Ϫ78 ЊC, 30 min; then 6, Ϫ78 ЊC, 2.5 h (73%); (b) i) PDC, CH2Cl2; ii) Na(Hg), MeOH,
0 ЊC (66%); (c) 40% HF, MeCN, 25 ЊC (67%).
J. Chem. Soc., Perkin Trans. 1, 2002, 565–570
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CHCl3); δH(400 MHz) 4.05 (1H, ddd, J 11.6, 5.0 and 2.4,
CH2CHOHCH), 4.03 (1H, t, J 7.4, CH2CHS2), 3.59 (1H, dd,
J 9.8 and 5.0, CHCHOHCH), 2.91–2.70 (4H, m, SCH2CH2-
CH2S), 2.10–0.85 (8H, m, CHMe2, CH2CHCH2 and SCH2-
CH2CH2S), 1.38 (3H, s, CMeAMeB), 1.26 (3H, s, CMeAMeB),
0.97 (3H, d, J 6.5, CHMeAMeB), 0.89 (3H, d, J 6.5, CHMeA-
MeB), 0.78 (3H, d, J 6.6, CHCH3); δC(100 MHz) 107.5 (C),
83.9 (CH), 74.9 (CH), 45.2 (CH), 43.9 (CH2), 35.9 (CH2), 30.4
(2 × CH2), 28.7 (CH3), 27.2 (CH), 26.2 (CH3), 26.0 (CH2), 25.9
(CH), 20.4 (CH3), 19.0 (CH3), 18.7 (CH3); HRMS (FAB)
Found: (M ϩ H)ϩ, 319.1598. C16H31O2S2 requires M ϩ H,
319.1602.
was removed in vacuo to give 16 (9.1 g, 90%), which was directly
used in the next reaction. [α]2D5 Ϫ43.9 (c 2.5 in CHCl3); δH(400
MHz) 5.40 (1H, m, C᎐CHCH ), 4.29 (1H, t, J 6.7, CH CH-
᎐
2
2
OHC), 2.59–0.89 (6H, m, CH2CHCH2 and CHMe2), 1.01 (3H,
d, J 6.8, CHMeAMeB), 1.0 (3H, d, J 6.8, CHMeAMeB), 0.91
(3H, d, J 7.6, CHCH3); δC(100 MHz) 145.9 (C), 120.3 (CH),
68.6 (CH), 42.3 (CH2), 34.3 (CH2), 28.2 (2 × CH), 22.6 (CH3),
21.8 (CH3), 20.8 (CH3); m/z (EI) 154 (Mϩ, 4%), 139 (22), 111
(100), 43 (38).
(4S,6R)-2-Hydroxy-4-methyl-6-(2Ј-meth ylpropionyl)tetra-
hydropyran 17
Into a cold (Ϫ78 ЊC) solution of compound 16 (1.0 g, 5.9 mmol)
in CH2Cl2 (50 mL) was bubbled ozone. When the reaction was
complete (TLC) the reaction mixture was treated with Me2S
(2 mL), stirred overnight, and evaporated in vacuo. The residue
was purified by column chromatography to give 17 (1.0 g, 85%)
as a mixture of two isomers. δH(400 MHz) (2 isomers) 5.15
(2H, m, 2 × OCHOH), 4.66 (1H, t, J 5.2, CH2CHOCH), 4.41
(1H, dd, J 7.0 and 4.9, CH2CHOCH), 3.14 (1H, m, CHMe2),
3.01 (1H, m, CHMe2), 2.53–0.90 (10H, m, 2 × CH2CHCH2),
1.10–1.02 (18H, m, 2 × CHCH3 and 2 × CHMe2); δC(100 MHz)
215.4 (C), 215.3 (C), 93.0 (CH), 92.4 (CH), 75.4 (CH), 74.8
(CH), 40.9 (CH2), 39.8 (CH2), 35.9 (CH), 35.6 (CH), 32.5 (2 ×
CH2), 25.1 (CH), 22.5 (CH), 21.4 (CH3), 20.0 (CH3), 18.8
(CH3), 18.7 (CH3), 18.2 (CH3), 18.1 (CH3); m/z (EI) 186 (Mϩ,
1%), 168 (1), 143 (1), 115 (28), 71 (100), 43 (38); HRMS (ESI)
Found: (M ϩ Na)ϩ, 209.1144. C10H18O3Na requires M ϩ Na,
209.1148.
2-[(2R,4R,5R)-4,5-Bis(tert-butyldimethylsilyloxy)-2,6-dimethyl-
heptyl]-1,3-dithiane 15
To a solution of diols 14 (840 mg, 3.02 mmol) in DMF (5 mL)
were added imidazole (1.03 g, 15.2 mmol) and TBDMSCl
(1.09 g, 7.2 mmol). The reaction mixture was stirred for 24 h
at 90 ЊC, then diluted with ether (80 mL), washed successively
with water (3 × 20 mL) and brine, dried over Na2SO4, and
evaporated in vacuo. The residue was purified by column
chromatography to give 15 (1.26 g, 82%), [α]2D5 ϩ12.0 (c 1.26 in
CHCl3); δH(400 MHz) 4.08 (1H, dd, J 6.8 and 8.1, CH2CHS2),
3.76 (1H, d, J 9.7, CHOH), 3.34 (1H, d, J 7.6, CHOH),
2.91–2.78 (4H, m, SCH2CH2CH2S), 2.10–1.10 (8H, m, CHMe2,
CH2CHCH2 and SCH2CH2CH2S), 0.91–0.86 (27H, m, 2 ×
CMe3, CHCH3 and CHMe2), 0.12 (3H, s, SiCH3), 0.07 (3H, s,
SiCH3), 0.06 (3H, s, SiCH3), 0.04 (3H, s, SiCH3); δC(100 MHz)
83.0 (CH), 72.7 (CH), 45.6 (CH), 43.7 (CH2), 39.8 (CH2), 31.8
(CH2), 30.6 (CH), 30.5 (CH2), 26.2 (6 × CH3, CH2), 25.8 (CH),
20.3 (CH3), 19.3 (CH3), 18.9 (CH3), 18.5 (C), 18.1 (C), Ϫ3.4
(CH3), Ϫ3.5 (CH3), Ϫ4.6 (CH3), Ϫ4.8 (CH3); m/z (EI) 449
(Mϩ Ϫ 57, 3%), 319 (20), 185 (50), 147 (59), 84 (100).
(1R)-1-[(2S)-3-Iodo-2-methylpropyl]-3-methyl-2-oxobutyl
formate 18
To a mixture of lactol 17 (2.0 g, 9.6 mmol) in cyclohexane
(50 mL) were added iodosylbenzene diacetate (IBDA) (5.56 g,
17.3 mmol) and iodine (2.92 g, 11.5 mmol). The reaction
mixture was stirred under argon and irradiation with two
100 W tungsten-filament bulbs for 1.0 h, and then diluted with
ether (100 mL), washed successively with aq. Na2S2O3 and
brine, and dried over Na2SO4. The solvent was removed in
vacuo to give 18 (2.1 g, 70%), [α]2D5 Ϫ3.8 (c 1.75 in CHCl3);
δH(400 MHz) 8.11 (1H, s, OCHO), 5.27 (1H, dd, J 10.3 and
3.1, CH2CHOC), 3.29 (2H, d, J 4.1, CHCH2I), 2.9 (1H, m,
CHMe2), 1.83–1.50 (3H, m, ICH2CHCH2CHO), 1.21 (3H, d,
J 7.1, CHCH3), 1.12 (3H, d, J 6.6, CHMeAMeB), 1.02 (3H, d,
J 6.6, CHMeAMeB); δC(100 MHz) 209.3 (C), 160.0 (CH), 74.4
(CH), 37.1 (CH), 36.4 (CH2), 30.0 (CH), 21.4 (CH3), 19.1
(CH3), 17.8 (CH3), 16.4 (CH2); m/z (EI) 312 (Mϩ, 1%), 241 (6),
169 (17), 139 (25), 71 (100).
(3R,5R,6R)-5,6-Bis(tert-butyldimethylsilyloxy)-3,7-dimethyl-
octanal 6
A solution of the dithiane 15 (900 mg, 1.78 mmol) in 80%
acetonitrile (25 mL) was added to an efficiently stirred solution
of mercuric chloride (2.01 g, 7.48 mmol) and powdered calcium
carbonate (748 mg, 7.48 mmol) in 80% acetonitrile (30 mL).
The mixture was stirred and heated at reflux under nitrogen for
24 h, cooled, and filtered through Super Cel., and the filter cake
was washed thoroughly with ether. The organic phase of the
filtrate was washed successively with 5 M aq. NH4OAc, water,
and brine, dried over anhydrous Na2SO4, and evaporated in
vacuo. The residue was purified by column chromatography to
give 6 (600 mg, 81%), [α]2D5 ϩ22.0 (c 2.7 in CHCl3); δH(400 MHz)
9.72 (1H, t, J 2.5, CH2CHO), 3.80 (1H, dd, J 8.4 and 1.3,
CHOTBDMS), 3.35 (1H, dd, J 6.6 and 1.1, CHOTBDMS),
2.31–1.23 (6H, m, CHMe2, CH2CHCH2), 0.96–0.86 (27H, m,
2 × CMe3, CHCH3 and CHMe2), 0.09 (3H, s, SiCH3), 0.08 (3H,
s, SiCH3), 0.07 (3H, s, SiCH3), 0.04 (3H, s, SiCH3); δC(100 MHz)
202.6 (CH), 82.8 (CH), 72.8 (CH), 52.1 (CH2), 39.9 (CH), 31.9
(CH2), 28.9 (6 × CH3), 24.4 (CH), 20.2 (CH3), 19.2 (CH3), 19.1
(CH3), 18.4 (C), 18.2 (C), Ϫ3.4 (CH3), Ϫ3.4 (CH3), Ϫ4.7 (CH3),
Ϫ4.9 (CH3); m/z (EI) 401 (Mϩ Ϫ Me, 1%), 359 (Mϩ Ϫ 57, 2),
303 (2), 259 (2), 187 (44), 84 (100); HRMS (ESI) Found:
(M ϩ H)ϩ, 417.3213. C22H49O3Si2 requires M ϩ H, 417.3215.
(2S,4R)-4-Formyloxy-2,6-dimethyl-5-oxoheptyl phenyl sulfone
19
To a solution of the above iodide 18 (1.60 g, 5.13 mmol)
in DMF (6 mL) was added sodium benzenesulfinate (1.54 g,
9.23 mmol) and the solution was stirred for 12 h at 60 ЊC. The
reaction mixture was poured into water (20 mL) and extracted
with ether (3 × 30 mL). The ethereal layer was washed with
brine (30 mL), dried over Na2SO4, and evaporated in vacuo. The
residue was purified by column chromatography to give 19 (1.51
g, 90%), [α]2D5 Ϫ9.0 (c 0.9 in CHCl3); δH(400 MHz) 8.01 (1H, s,
OCHO), 7.91–7.60 (5H, m, ArH), 5.31 (1H, dd, J 9.8 and 3.1,
CH2CHOCHO), 3.20 (1H, dd, J 14.2 and 4.6, CHCHACHBS),
3.01 (1H, dd, J 14.1 and 7.3, CHCHACHBS), 2.83 (1H, m,
CHMe2), 2.31–1.70 (3H, m, CH2CHCH2CHO), 1.21 (3H, d,
J 7.0, CHMeAMeB), 1.17 (3H, d, J 7.0, CHMeAMeB), 1.07 (3H,
d, J 6.6, CHCH3); δC(100 MHz) 209.4 (C), 159.8 (CH), 139.9
(C), 133.8 (CH), 129.4 (2 × CH), 127.7 (2 × CH), 74.7 (CH),
61.2 (CH2), 36.9, 36.5, 26.2, 20.8, 19.0, 17.8 (2 × CH, CH2 and
3 × CH3); m/z (EI) 298 (Mϩ ϩ 1 Ϫ CHO, 8%), 255 (8), 227
(1R,5R)-Menth-4-en-3-ol 16
To an ice–water-bath-cooled mixture of (Ϫ)-menth-4-en-3-one
9 (10 g, 66 mmol) and cerous choride (24.5 g, 66 mmol) in
MeOH (150 mL) was added NaBH4 (2.5 g, 66 mol) and the
mixture was stirred for 30 min, then the solvent was removed
in vacuo, the obtained residue was diluted with ether and 5% aq.
HCl, and the aqueous layer was extracted with ether. The
combined organic layer was washed successively with saturated
aq. NaHCO3 and brine, and dried over Na2SO4. The solvent
568
J. Chem. Soc., Perkin Trans. 1, 2002, 565–570

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(100), 143 (18), 71 (48); HRMS (ESI) Found: (M ϩ Na)ϩ,
349.1080. C16H22O5SNa requires M ϩ Na, 349.1080.
(2S,4R,5R)-4,5-Dihydroxy-2,6-dimethylheptyl phenyl sulfone
21b
Following the same procedure as for 21a, compound 22b
(640 mg, 1.95 mmol) afforded 21b (520 mg, 88%), [α]2D5 ϩ6.1
(c 0.93 in CHCl3); δH(400 MHz) 7.90 (2H, d, J 7.6, ArH), 7.64
(1H, t, J 7.7, ArH), 7.55 (2H, t, J 7.9, ArH), 3.66 (1H, m,
CH2CHOHCH), 3.27 (1H, dd, J 14.5 and 5.4, CHCHACHBS),
3.06 (1H, t, J 5.3, CHCHOHCH), 3.00 (1H, dd, J 14.1 and
6.6, CHCHACHBS), 2.35 (1H, m, CHMe2), 1.73 (1H, m, CH-
CH3), 1.57 (2H, m, CH2CHCH2CHOH), 1.09 (3H, d, J 6.7,
CHMeAMeB), 0.93 (3H, d, J 6.9, CHCH3), 0.90 (3H, d, J 6.7,
CHMeAMeB); δC(100 MHz) 139.8 (C), 133.6 (CH), 129.3 (2 ×
CH), 127.7 (2 × CH), 78.8 (CH), 68.9 (CH), 61.7 (CH2), 40.1,
29.9, 25.4, 21.0, 19.7, 16.9 (2 × CH, CH2 and 3 × CH3); m/z (EI)
282 (Mϩ Ϫ H2O, 1%), 267 (2), 257 (4), 239 (11), 227 (100), 143
(55); HRMS (ESI) Found: (M ϩ H)ϩ, 301.1467. C15H23O4S
requires M ϩ H, 301.1468.
(2S,4R)-4-Hydroxy-2,6-dimethyl-5-oxoheptyl phenyl sulfone 20
Compound 19 (326 mg, 1.00 mmol) was dissolved in MeOH
(4 mL), then the solution was added to a suspension of K2CO3
(220 mg, 1.60 mmol) in MeOH (4 mL) and stirred for 2 h at
room temperature. The reaction mixture was diluted with
EtOAc (80 mL) and washed with brine (3 × 20 mL), dried over
anhydrous Na2SO4, and evaporated in vacuo. The residue was
purified by column chromatography to afford 21a (262 mg,
88%), δH(400 MHz) 7.93 (2H, d, J 7.8, ArH), 7.67 (1H, t, J 7.8,
ArH), 7.58 (2H, t, J 7.8, ArH), 4.37 (1H, dd, J 9.97 and 2.5,
CH2CHOHC), 3.35 (1H, dd, J 14.1 and 5.0, CHCHACHBS),
3.10 (1H, dd, J 14.4 and 7.1, CHCHACHBS), 2.84 (1H, m,
CHMe2), 2.46–1.43 (3H, m, CH2CHCH2CHOH), 1.21 (3H, d,
J 6.7, CHMeAMeB), 1.13 (3H, d, J 6.6, CHCH3), 1.10 (3H, d,
J 6.7, CHMeAMeB); δC(100 MHz) 215.8 (C), 140.1 (C), 133.6
(CH), 129.3 (2 × CH), 127.8 (2 × CH), 73.3 (CH), 61.4 (CH2),
39.3, 35.9, 26.7, 20.6, 19.4, 17.6 (2 × CH, CH2 and 3 × CH3);
m/z (EI) 298 (Mϩ, 1%), 227 (100), 143 (22).
(2S,4R,5S)-4,5-Isopropylidenedioxy-2,6-dimethylheptyl phenyl
sulfone 7a
To a solution of the above product 21a (540 mg, 1.8 mmol) in
dry acetone (5 mL) were added DMP (2,2-dimethoxypropane)
(2 mL) and a catalytic amount of PTSA and the mixture was
stirred at room temperature for 12 h. The reaction mixture
was diluted with ether (80 mL) and washed successively with
saturated aq. NaHCO3 (20 mL) and brine (20 mL), dried over
anhydrous Na2SO4, and evaporated in vacuo. The residue
was purified by column chromatography to afford 7a (580 mg,
95%), [α]2D5 ϩ42.2 (c 0.67 in CHCl3); δH(400 MHz) 7.91 (2H, d,
J 7.2, ArH), 7.62 (1H, t, J 7.3, ArH), 7.55 (2H, t, J 7.3, ArH),
4.05 (1H, m, CH2CHOHCH), 3.62 (1H, dd, J 5.2 and 9.3,
CHCHOHCH), 3.25 (1H, dd, J 4.5 and 14.3, CHCHACHBS),
3.00 (1H, dd, J 7.9 and 14.1, CHCHACHBS), 2.35 (1H, m,
CHMe2), 1.71 (1H, m, CHCH3), 1.52 (2H, m, CH2CHCH2-
CHOH), 1.33 (3H, s, CMeAMeB), 1.26 (3H, s, CMeAMeB), 1.19
(3H, d, J 6.9, CHCH3), 1.00 (3H, d, J 6.6, CHMeAMeB), 0.84
(3H, d, J 6.6, CHMeAMeB); δC(100 MHz) 140.2 (C), 133.4
(CH), 129.1 (2 × CH), 127.8 (2 × CH), 107.5 (C), 83.7 (CH),
74.9 (CH), 61.3 (CH2), 35.7, 28.3, 27.3, 26.3, 25.9, 20.7, 20.1,
19.1 (2 × CH, CH2 and 5 × CH3); m/z (EI) 325 (Mϩ Ϫ Me,
32%), 283 (35), 239 (51), 123 (100); HRMS (ESI) Found:
(M ϩ H)ϩ, 341.1782. C18H29O4S requires M ϩ H, 341.1785.
(2S,4R,5S)-4-Formyloxy-5-hydroxy-2,6-dimethylheptyl phenyl
sulfone 22a and (2S,4R,5R)-4-formyloxy-5-hydroxy-2,6-
dimethylheptyl phenyl sulfone 22b
To a cooled (Ϫ78 ЊC), stirred solution of 19 (1.51 g, 4.62 mmol)
in MeOH (20 mL) was added NaBH4 (176 mg, 4.62 mmol). The
mixture was stirred for 1 h at Ϫ78 ЊC, then diluted with EtOAc
(30 mL) and saturated aq. NH4Cl. The aqueous layer was
extracted with EtOAc (2 × 20 mL) and the combined organic
layer was washed with H2O and brine, dried over Na2SO4
and evaporated in vacuo. The residue was purified by column
chromatography to give 22a and 22b (680 mg and 680 mg,
90%), which were directly used in the next step.
(2S,4R,5S)-4,5-Dihydroxy-2,6-dimethylheptyl phenyl sulfone 21a
Method A. To a solution of 20 (300 mg, 1.0 mmol) in dry
THF (5 mL) was added Zn(BH4)2 in THF at 0 ЊC. The mixture
was stirred for 1.0 h, and then diluted with ether (50 mL) and
washed with brine, dried over anhydrous Na2SO4, and evapor-
ated in vacuo. The residue was purified by column chromato-
graphy to afford 21a (280 mg, 93%), δH(400 MHz) 7.88 (2H,
d, J 7.7, ArH), 7.63 (1H, t, J 7.4, ArH), 7.54 (2H, t, J 7.8, ArH),
3.70 (1H, dd, J 3.6 and 8.1, CHOH), 3.26 (2H, m, CHOH and
CHCHACHBS), 2.96 (1H, dd, J 14.3 and 6.9, CHCHACHBS),
2.41 (1H, m, CHMe2), 2.44–1.47 (3H, m, CH2CHCH2CHOH),
1.06 (3H, d, J 6.9, CHCH3), 0.94 (3H, d, J 6.7, CHMeAMeB),
0.83 (3H, d, J 6.7, CHMeAMeB).
(2S,4R,5R)-4,5-Isopropylidenedioxy-2,6-dimethylheptyl phenyl
sulfone 7b
Following the same procedure as for 7a, compound 21b
(520 mg, 1.73 mmol) afforded 7b (509 mg, 87%), [α]2D5 ϩ16.5
(c 0.70 in CHCl3); δH(400 MHz) 7.91 (2H, d, J 7.6, ArH), 7.63
(1H, t, J 7.5, ArH), 7.55 (2H, t, J 7.7, ArH), 3.73 (1H, m,
CH2CHOHCH), 3.31 (2H, m, CHCHOHCH and CHCHA-
CHBS), 3.00 (1H, dd, J 7.4 and 14.3, CHCHACHBS), 2.31 (1H,
m, CHMe2), 1.71 (2H, m, CH2CHCH2CHOH), 1.53 (1H, m,
CHCH3), 1.30 (3H, s, CMeAMeB), 1.28 (3H, s, CMeAMeB), 1.16
(3H, d, J 6.8, CHMeAMeB), 0.94 (3H, d, J 6.8, CHMeAMeB),
0.90 (3H, d, J 6.9, CHCH3); δC(100 MHz) 140.1 (C), 133.4
(CH), 129.2 (2 × CH), 127.8 (2 × CH), 107.9 (C), 86.0 (CH),
76.4 (CH), 61.8 (CH2), 40.3, 30.5, 27.3, 27.0, 27.0, 20.3, 19.2,
18.2 (2 × CH, CH2 and 5 × CH3); m/z (EI) 325 (Mϩ Ϫ Me,
45%), 283 (9), 239 (48), 149 (34), 123 (100); HRMS (ESI)
Found: (M ϩ H)ϩ, 341.1782. C18H29O4S requires M ϩ H,
341.1785.
Method B. Compound 22a (680 mg, 2.07 mmol) was dis-
solved in MeOH (6 mL) then the solution was added to a sus-
pension of K2CO3 (450 mg, 3.25 mmol) in MeOH (4 mL) and
stirred for 2 h at room temperature. The reaction mixture
was diluted with EtOAc (100 mL) and washed with brine (3 ×
20 mL), dried over anhydrous Na2SO4, and evaporated in vacuo.
The residue was purified by column chromatography to afford
21a (546 mg, 88%), [α]2D5 ϩ14.2 (c 0.70 in CHCl3); δH(400 MHz)
7.90 (2H, d, J 7.7, ArH), 7.65 (1H, t, J 7.4, ArH), 7.56 (2H, t,
J 7.8, ArH), 3.72 (1H, dd, J 3.6 and 8.1, CHOH), 3.28 (2H, m,
CHOH and CHCHACHBS), 2.98 (1H, dd, J 14.3 and 6.9,
CHCHACHBS), 2.43 (1H, m, CHMe2), 2.44–1.49 (3H, m,
CH2CHCH2CHOH), 1.08 (3H, d, J 6.9, CHCH3), 0.96 (3H,
d, J 6.7, CHMeAMeB), 0.85 (3H, d, J 6.7, CHMeAMeB);
δC(100 MHz) 139.7 (C), 133.7 (CH), 129.3 (2 × CH), 127.8 (2
× CH), 79.9 (CH), 69.3 (CH), 61.6 (CH2), 36.8, 29.7, 25.4,
21.4, 19.0, 18.4 (2 × CH, CH2 and 3 × CH3); m/z (EI) 283
(Mϩ ϩ 1 Ϫ H2O, 1%), 267 (2), 239 (5), 227 (91), 143 (100), 85
(91), 77 (72); HRMS (ESI) Found: (M ϩ H)ϩ, 301.1467.
C15H23O4S requires M ϩ H, 301.1468.
(3R,4R,6R,10S,12R,13S)-3,4-Bis(tert-butyldimethylsilyloxy)-
12,13-isopropylidenedioxy-2,6,10,14-tetramethylpentadecan-8-
one 24a
To a solution of sulfone 7a (283 mg, 0.83 mmol) in THF (4 mL)
at Ϫ78 ЊC under Ar was added dropwise 1.60 M n-butyllithium
J. Chem. Soc., Perkin Trans. 1, 2002, 565–570
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(0.55 mL, 0.88 mmol) and the solution was stirred at the same
temperature for 30 min. To the solution at Ϫ78 ЊC was added
dropwise the aldehyde 6 (380 mg, 0.92 mmol) dissolved in THF
(3 mL) and the mixture was stirred at the same temperature for
2.5 h. The reaction was quenched with saturated aq. NH4Cl
(2 mL) and the temperature was allowed to warm to ambient.
The reaction mixture was poured into water (10 mL)
and extracted with ether (3 × 20 mL). The ethereal layer was
washed with brine (20 mL), dried with anhydrous Na2SO4,
and evaporated in vacuo. The residue was purified by column
chromatography to give coupling product 23a (458 mg, 73%),
which was directly used in the next reaction.
was carried out by spotting liquid directly onto a silica gel plate.
When deprotection was complete, ether and water were added.
The aqueous phase was extracted with ether (3 × 20 mL), and
the combined extracts were washed successively with NaHCO3
and brine, dried over anhydrous Na2SO4, and evaporated in
vacuo. The residue was purified by column chromatography to
give 4a (92 mg, 67%), [α]2D5 Ϫ39.8 (c 2.15 in CHCl3); δH(400
MHz) 3.82 (1H, ddd, J 3.3, 4.2 and 12.0, CH2CHOC), 3.69
(1H, ddd, J 2.4, 4.2 and 11.6, CH2CHOC), 3.28 (2H, m, 2 ×
CHCHOH), 2.15–0.85 (12H, m, 4 × CH and 4 × CH2), 1.17
(3H, d, J 7.2, CHCH3), 0.99 (3H, d, J 6.6, CHCH3), 0.97 (3H, d,
J 6.7, CHMeAMeB), 0.89 (3H, d, J 6.7, CHMeAMeB), 0.88 (3H,
d, J 6.8, CHMeAMeB), 0.87 (3H, d, J 6.8, CHMeAMeB); δC(100
MHz) 98.5 (C), 78.9 (CH), 78.7 (CH), 70.6 (CH), 65.4 (CH),
44.4 (CH2), 40.7 (CH2), 31.9 (CH2), 29.5 (CH2), 29.1, 29.0, 24.6,
24.5, 22.2, 20.8, 19.0, 19.0, 18.6, 18.4 (4 × CH and 6 × CH3);
m/z (EI) 328 (Mϩ, 1%), 285 (1), 255 (65), 149 (34), 43 (100);
HRMS (ESI) Found: (M ϩ H)ϩ, 329.2682. C19H37O4 requires
M ϩ H, 329.2686.
To a magnetically stirred solution of PDC (945 mg,
3.66 mmol) in CH2Cl2 (10 mL) was added a solution of 23a
(458 mg, 0.61 mmol) in CH2Cl2 (5 mL) at room temperature.
The reaction mixture was stirred for 15 min, the solution was
passed through a short column of Al2O3, and the solvent
was evaporated in vacuo. The residue was purified by column
chromatography to furnish the α-sulfonyl ketone (421 mg,
0.56 mmol), which was directly used in the next reaction.
To a stirred solution of above product (421 mg, 0.56 mmol)
and anhydrous Na2HPO4 (319 mg, 2.24 mmol) in MeOH
(10 mL) was added pulverized 6% sodium amalgam (1.0 g) at
room temperature. The reaction mixture was vigorously stirred
for 1 h until TLC showed complete conversion. The mixture
was poured into saturated aq. NH4Cl (10 mL) and extracted
with ether (3 × 20 mL), the combined extracts were washed with
brine, dried over anhydrous Na2SO4, and evaporated in vacuo.
The residue was purified by column chromatography to give
24a (255 mg, 50% in overall yield in three steps), [α]2D5 ϩ27.0
(c 3.3 in CHCl3); δH(400 MHz) 4.07 (1H, m, CH2CHOTB-
DMS), 3.76 (1H, d, J 9.6, CHOC), 3.63 (1H, dd, J 5.0 and 9.1,
CHCHOTBDMS), 3.32 (1H, d, J 6.6, CHOC), 2.52–0.85 (12H,
m, 4 × CH and 4 × CH2), 1.41 (3H, s, CMeAMeB), 1.31 (3H, s,
CMeAMeB), 1.01 (3H, d, J 6.5, CHCH3), 0.97 (3H, d, J 5.9,
CHCH3), 0.93–0.84 (30H, m, 2 × CMe3 and 2 × CHMe2), 0.09
(3H, s, SiCH3), 0.08 (3H, s, SiCH3), 0.07 (3H, s, SiCH3), 0.03
(3H, s, SiCH3); δC(100 MHz) 210.2 (C), 107.5 (C), 83.8 (CH),
82.9 (CH), 75.7 (CH), 72.9 (CH), 52.3 (CH2), 49.0 (CH2), 40.0
(CH2), 36.0 (CH2), 31.9, 28.5, 27.4, 26.3, 26.1 (6 × CH3), 25.9,
25.6, 21.1, 20.3, 20.2, 19.4, 19.3, 19.2 (4 × CH and 8 × CH3),
18.5 (C), 18.2 (C), Ϫ3.4 (CH3), Ϫ3.5 (CH3), Ϫ4.6 (CH3), Ϫ4.9
(CH3); HRMS (ESI) Found: Mϩ, 614.4762. C34H70O5Si2
requires M, 614.4754.
(1R)-1-{(2R,4R,6S,8R,10S)-8-[(1S)-1-Hydroxy-2-methyl-
propyl)]-4,10-dimethyl-1,7-dioxaspiro[5.5]undecan-2-yl}-2-
methylpropan-1-ol 4b
Following the same procedure as for 4a, compound 24b
(230 mg, 0.37 mmol) gave 4b (82 mg, 67%), [α]2D5 Ϫ28.5 (c 2.0
in CHCl3); δH(400 MHz) 3.83 (1H, ddd, J 3.3, 5.1 and 11.6,
CH2CHOC), 3.74 (1H, dt, J 2.9 and 11.6, CH2CHOC),
3.28 (1H, dd, J 3.6 and 8.2, CHCHOH), 3.74 (1H, t, J 4.9,
CHCHOH), 2.15–0.85 (12H, m, 4 × CH and 4 × CH2), 1.19
(3H, d, J 7.1, CHCH3), 1.02 (3H, d, J 6.6, CHMeAMeB), 0.97
(3H, d, J 6.9, CHCH3), 0.94 (3H, d, J 6.7, CHMeAMeB), 0.89
(3H, d, J 6.7, CHMeAMeB), 0.86 (3H, d, J 6.7, CHMeAMeB);
δC(100 MHz) 98.2 (C), 78.8 (CH), 78.7 (CH), 70.7 (CH), 65.4
(CH), 44.4 (CH2), 40.5 (CH2), 32.9 (CH2), 31.5 (CH2), 29.8,
29.2, 24.8, 24.7, 22.2, 20.8, 20.1, 19.0, 18.9, 16.8 (4 × CH and
6 × CH3); m/z (EI) 328 (Mϩ, 1%), 285 (3), 255 (66), 43 (100);
HRMS (ESI) Found: (M ϩ H)ϩ, 329.2682. C19H37O4 requires
M ϩ H, 329.2686.
Acknowledgements
This work was supported by NSFC (No. 29972019, 29925205
and QT program), FUKTME of China, the Young Teachers’
Fund of the Ministry of Education and the Fund of the
Ministry of Education (No. 99209).
(3R,4R,6R,10S,12R,13R)-3,4-Bis(tert-butyldimethylsilyloxy)-
12,13-isopropylidenedioxy-2,6,10,14-tetramethylpentadecan-8-
one 24b
References
Following the same procedure as for 24a, compound 7b
(390 mg, 0.52 mmol) gave 24b (320 mg, 50% overall yield in
three steps), [α]2D5 ϩ12.1 (c 3.0 in CHCl3); δH(400 MHz) 3.78
(2H, m, CH2CHOTBDMS and CHOC), 3.38 (1H, t, J 6.7,
CHCHOTBDMS), 3.33 (1H, d, J 6.7, CHOC), 2.53–0.87 (12H,
m, 4 × CH and 4 × CH2), 1.35 (6H, s, CMe2), 0.97 (3H, d, J 6.6,
CHCH3), 0.94 (3H, d, J 6.9, CHCH3), 0.93–0.84 (30H, m, 2 ×
CMe3 and 2 × CHMe2), 0.09 (3H, s, SiCH3), 0.08 (3H, s,
SiCH3), 0.07 (3H, s, SiCH3), 0.04 (3H, s, SiCH3); δC(100 MHz)
210.0 (C), 107.9 (C), 86.3 (CH), 82.9 (CH), 77.1 (CH), 72.9
(CH), 52.3 (CH2), 49.6 (CH2), 41.0 (CH2), 40.0 (CH2), 31.9,
30.7, 27.4, 27.2, 27.1, 27.0 (6 × CH3), 25.9, 25.6, 20.6, 20.3, 19.4,
19.3, 18.5 (C), 18.4 (C), 18.2 (4 × CH and 8 × CH3), Ϫ3.3
(CH3), Ϫ3.4 (CH3), Ϫ4.6 (CH3), Ϫ4.8 (CH3); HRMS (FAB)
Found: Mϩ, 614.4762. C34H70O5Si2 requires M, 614.4754.
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26, 681.
(1R)-1-{(2R,4R,6S,8R,10S)-8-[(1R)-1-Hydroxy-2-methyl-
propyl)]-4,10-dimethyl-1,7-dioxaspiro[5.5]undecan-2-yl}-2-
methylpropan-1-ol 4a
The substrate 24a (255 mg, 0.42 mmol) was dissolved in
acetonitrile containing 40% aq. HF (1 mL). TLC monitoring
570
J. Chem. Soc., Perkin Trans. 1, 2002, 565–570