Asymmetrization of all-cis-3,5-dihydroxy-1-(methoxycarbonyl)cyclohexane and of the 4-methyl and 4-ethyl substituted homologues

Article abstract of DOI:10.1016/S0957-4166(00)00339-6

Enantiomerically pure mono acylated derivatives of cis,cis-3,5-dihydroxy-1-(methoxycarbonyl)cyclohexane 1, all-cis-3,5-dihydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane 2 and all-cis-3,5-dihydroxy-4-ethyl-1-(methoxycarbonyl)cyclohexane 3 were obtained upon lipase catalyzed asymmetrization. PPL-catalyzed transesterification of 1 with vinyl acetate led in high yield to the (S)-monoacetate (+)-13. With substrates 2 and 3 this process was slower and gave the (R)-monoacetates (-)-14 and (-)-15; the best results were obtained with SAM II lipase. On the other hand, enantiotoposelective hydrolysis of their diacetates and especially dibutyrates gave useful results only for the 4-substituted substrates and produced the (S)-monoesters. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00339-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3887–3900
Asymmetrization of all-cis-3,5-dihydroxy-
1-(methoxycarbonyl)cyclohexane and of the 4-methyl
and 4-ethyl substituted homologues
Yurui Zhao,a Yusheng Wu,a Pierre De Clercq,a Maurits Vandewalle,a,* Philippe Maillosb
and Jean-Claude Pascalb
aLaboratory of Organic Synthesis, Department of Organic Chemistry, University of Ghent, Krijgslaan 281 S4,
B-9000 Gent, Belgium
bR. & D. Chemical Department, The´ramex S.A., 4-6 Avenue du Prince He´re´ditaire Albert, F-98007 Monaco
Received 29 June 2000; accepted 24 August 2000
Abstract
Enantiomerically pure mono acylated derivatives of cis,cis-3,5-dihydroxy-1-(methoxycarbonyl)-
cyclohexane 1, all-cis-3,5-dihydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane 2 and all-cis-3,5-dihy-
droxy-4-ethyl-1-(methoxycarbonyl)cyclohexane 3 were obtained upon lipase catalyzed asymmetrization.
PPL-catalyzed transesterification of 1 with vinyl acetate led in high yield to the (S)-monoacetate (+)-13.
With substrates 2 and 3 this process was slower and gave the (R)-monoacetates (−)-14 and (−)-15; the best
results were obtained with SAM II lipase. On the other hand, enantiotoposelective hydrolysis of their
diacetates and especially dibutyrates gave useful results only for the 4-substituted substrates and produced
the (S)-monoesters. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
In the context of a program directed towards enantioselective total synthesis of natural
products and analogues thereof containing a cyclohexane ring, we decided to study the
asymmetrization of meso all-cis-3-5-dihydroxy-1-(methoxycarbonyl)cyclohexanes 1, 2 and 3. Of
special interest to us was the eventual synthesis of 19-nor vitamin D analogues in which the title
compounds could be precursors for the A-ring.1 Previously we have described the asymmetriza-
tion of 4,2 52 and 61 and the transformation of 6 into precursor 12 for the synthesis of
19-nor-1a,25-dihydroxy-vitamin D3 (11; R=H) (Scheme 1).
* Corresponding author. Tel: +32 (0)9 264 44 60; fax: +32 (0)9 264 49 98.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00339-6

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Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
Scheme 1.
2. Results and discussion
The all-cis substrates 1, 2 and 3 are readily available upon hydrogenation of the correspond-
ing methyl benzoates 8, 9 and 10. The formation of cis,cis-3,5-dihydroxy-1-(methoxycar-
bonyl)cyclohexane 1 has already been reported by Wang and Adams3 via Rh/Al2O3 catalyzed
hydrogenation of 3,5-dihydroxybenzoic acid. We found that hydrogenation of the methyl esters4
8, 9 and 10 is a superior method, e.g. starting from 8 essentially the same yield is obtained but
only half the amount of catalyst can be used and the process is quite clean (spot to spot on
TLC) allowing the recovery of circa 25–30% of the starting materials.
For the asymmetrization studies, both transesterifications of 1, 2 and 3 (Table 1) and
hydrolysis of the corresponding diacetates 16, 18, 20 (Table 2) and dibutyrates 17, 19 and 21
(Table 3) were investigated (Scheme 2). Vinyl acetate mediated acylation (Table 1) of cis,cis-3,5-
dihydroxy-1-(methoxycarbonyl)cyclohexane 1 led to an excellent result with PPL5 as the lipase
(Table 1, entry 2). Indeed after 24 h at room temperature enantiomerically pure monoacetate
(+)-13 was obtained in high yield, the hydroxy function on the (S)-stereogenic centre being
acylated (vide infra). This process has been carried out on a 400 g scale. The enantiomeric excess
(e.e.) was determined by subcritical fluid chromatography (SFC),6 no enantiomer could be
detected. The other enzymes5 tested gave unsatisfactory results (entries 3–7) as substantial
amounts of diacetate 16 were formed, while the enantiomeric excesses obtained for 13 were
lower than for PPL. As is shown for the reaction performed with SAM II lipase, formation of
16 could, to a large extent, be suppressed (compare entries 3, 4 and 5) upon lowering the
temperature. It is evident that mono-acetylation employing inexpensive PPL is the method of
choice for the asymmetrization of 1, also when compared to the enantioselective hydrolysis of
the diesters 16 and 17 (vide infra). The reaction was also carried out on 10 g scale with EtOAc
as solvent and 10 equiv. of vinyl acetate; the same result as shown in entry 2 was obtained.

Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
3889
Scheme 2.
Transesterification of the 4-alkyl substituted substrates 2 and 3 proceeds much slower and
leads, in contrast to 1, to the acetylation of the R hydroxy group (vide infra). Remarkably, PPL
did not catalyze the reaction of 2 and 3 (entries 8 and 14). As can be seen from Table 1, as a
general trend, the steric inhibition of the 4-ethyl substituent in 3 pushes the catalytic process to
its limits (compare for instance entries 13 and 18). Nevertheless SAM II lipase catalyzed
acetylation provides a practical process, as enantiopure monoacetates (−)-14 (entry 13) and
(−)-15 (entry 18) were obtained in 92 and 67% yield, respectively.
We then turned our attention to the enantiotoposelective hydrolysis of the respective
diacetates 16, 18 and 20 (Table 2) and dibutyrates 17, 19 and 21 (Table 3). The experiments were
carried out in phosphate buffer (0.1 M) at pH 7 by continuous addition of NaOH (1 M) and
monitored by a pH-stat-autotitrator. It was soon observed that the diesters 16 and 17 were poor
substrates. Depending on the enzymes tested, both enantiomers of 13 were obtained starting
from 16 (Table 2, entries 1–7). Only the lipases SAM II and PSL showed some selectivity (Table
2, entries 1 and 2) but unexpectedly produced (+)-13 and (+)-22 by hydrolysis of the (R)-acyloxy
group, thus providing the same enantiomeric series as the transesterification of 1.
In sharp contrast are the good to excellent selectivities obtained with several enzymes for the
4-substituted 3,5-diacyloxy-1-(methoxycarbonyl)cyclohexanes. In accordance with the general
trend the hydrolyses take place at the same stereocenter (R), as observed for the acylation of
diols 2 and 3, thus providing an entry to both enantiomeric series. When a methyl group is
present the diacetate 18 (Table 2, entries 8–13) is a poorer substrate than the dibutyrate 19
(Table 3, entries 8–13); in the latter case SAM II, PSL and CCL catalyzed hydrolysis gave

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Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
Table 1
Acylation with vinyl acetate
Entry
Subst.
Enz.5
t (h)
T (°C)
Ester (y %)a
Di
Conv. (%)b [h]2D0
% e.e.c
Mono
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1
1
1
1
1
1
1
2
2
2
2
2
2
3
3
3
3
3
PPL
PPL
SAM II
SAM II
SAM II
PSL
CCL
PPL
CCL
GCL
24
24
48
72
72
26
26
72
96
96
96
72
120
96
96
120
96
15
rt
35
25
15
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
35
(+)-13 (31)
(+)-13 (97)
41
95
98
95
85
95
95
+23.4
+23.6
\99
16 (95)
16 (30)
16 (ꢀ5)
16 (60)
16 (47)
(+)-13 (63)
(+)-13 (73)
(+)-13 (33)
(+)-13 (46)
+14
+14.5
+18
+22
(−)-14 (33)
35
−17
70
PSL
(−)-14 (50)
(−)-14 (42)
(−)-14 (92)
93
92
95
−21.5
−22.7
−22.5
93
\99
SAM II
SAM II
PPL
PSL
CCL
(−)-15 (19)
(−)-15 (53)
(−)-15 (67)
95
92
91
−46.4
−50.2
−51
SAM II
SAM II
\99
134
a Isolated yield of pure product.
b Calculated upon recovery of starting material.
c Determined by SFC6 for the processes leading to high specific rotations.
Table 2
Hydrolysis of diacetates 16, 18 and 20
Entry
Subst.
Enz.5
t (h)
T (°C)
Prod. (y)a
[h]2D0
% e.e.b
77
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
16
16
16
16
16
16
16
18
18
18
18
18
18
20
20
20
20
20
20
SAM II
PSL
PPL
90
47
86
6
rt
(+)-13 (39)
(+)-13 (37)
(−)-13 (26)
(−)-13 (31)
1
(−)-13 (11)
(−)-13 (25)
(+)-14 (49)
(+)-14 (72)
(−)-14 (49)
(+)-14 (37)
(−)-14 (63)
(+)-14 (54)
(+)-15 (38)
–
+18.1
+17.5
−4.3
25
30
rt
PLE
−9.7
CCL
GCL
CAL
SAM II
PSL
PPL
PLE
CCL
CAL
SAM II
PSL
1
rt
72
27
46
44
42
2
40
47
70
80
49
3
25
25
25
25
25
rt
25
rt
25
25
25
rt
−3.2
−4.1
+19.9
+19.8
−6.2
+18.8
−3
+12.6
+47.1
–
88
PPL
PLE
CCL
CAL
(+)-15 (25)
(+)-15 (72)
(+)-15 (58)
(+)-15 (76)
+41.1
+50.4
+48
\99
29
42
25
25
+48.5
a Isolated yield of pure product.
b Determined by SFC6 for the processes leading to high specific rotations.

Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
3891
Table 3
Hydrolysis of dibutyrates 17, 19 and 21
Entry
Subst.
Enz.5
t (h)
T (°C)
Prod. (y)a
[h]2D0
% e.e.b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
17
17
17
17
17
17
17
19
19
19
19
19
19
21
21
21
21
21
21
SAM II
PSL
PPL
17
20
15
5
3
63
3
18
23
21
3
18
10
69
48
22
2
rt
(+)-22 (69)
(+)-22 (63)
(+)-22 (74)
1
+15.9
+18.2
+8.9
66
25
30
rt
25
25
25
25
25
25
rt
25
25
25
25
25
rt
PLE
CCL
GCL
CAL
SAM II
PSL
PPL
PLE
CCL
CAL
SAM II
PSL
(−)-22 (31)
(−)-22 (13)
(+)-22 (48)
(+)-23 (91)
(+)-23 (89)
(+)-23 (65)
(+)-23 (15)
(+)-23 (53)
(+)-23 (89)
(+)-24 (88)
(+)-24 (84)
(+)-24 (49)
(+)-24 (26)
(+)-24 (78)
(+)-24 (82)
−3.0
−3.7
+6.5
+16.5
+16.4
+14.5
+15.2
+16.3
+12.9
+44.6
+44.4
+33.2
+38.5
+44.5
+42.2
\99
\99
PPL
PLE
CCL
CAL
87
23
10
25
25
a Isolated yield of pure product.
b Determined by SFC6 for the processes leading to high specific rotations.
enantiopure (+)-23 in high yield. The 4-ethyl substituted diesters 20 and 21 are the best
substrates, e.g. PLE mediated mono-hydrolysis (Table 2, entry 17) is fast and completely
enantiotoposelective. Similar to 19, dibutyrate 21 is hydrolyzed to pure (+)-24 by the same
enzymes (SAM II, PSL and CCL; Table 3, entries 14, 15 and 18).
In conclusion, preparatively useful enantioselectivies were found for the acylation of diol 1 for
the 4-methyl or 5-ethyl substituted homologues 2 and 3 (Table 1, entries 2, 13 and 18). In the
same case of 1 the (S)-acetate is formed, while 2 and 3 produced the (R)-acetates. This is a
formal discrepancy, as although, in 1 the 5-hydroxy group takes priority in the CIP rule, steric
inhibition via C-2 (larger 1-carbomethoxy) being more important. In 2 and 3 the difference in
substitution pattern around the hydroxy functions is more pronounced. Similar observations
have previously been made in the case of the asymmetrization process of 4, 5 and 6.1,2
Also the PLE-catalyzed selective hydrolysis of diacetate 20 (Table 2, entry 17) and of
dibutyrates 19 and 21, employing SAM II, PSL and CCL (Table 3, entries 8, 9, 12, 14, 15 and
18) provide a preparatively useful entry into the enantiomeric series. On the other hand,
hydrolysis of the 4-unsubstituted diesters 16 and 17 gave poor results, probably due to the
similar size of the acyloxy- and the methoxycarbonyl substituents. The best ones (Tables 2 and
3, entries 1 and 2) produced, respectively, the (R)-alcohols (+)-13 [as for 1 to (+)-13] and (+)-22.
It is noteworthy that while 3,5-dihydroxy-4-ethyl-1-(methoxycarbonyl)cyclohexane 3 was the
poor substrate in the transesterification process, the corresponding diacetate 20 and dibutyrate
21 are the better substrates in the enantiotoposelectivity hydrolysis. Seemingly the 4-ethyl

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substituent in 20 and 21 provides optimum differentiation of the substitution pattern around C3
and (or) C5. In all cases, interference occurring from possible concomitant hydrolysis of the
carbomethoxy group was not observed. It can also be noted that no selectivity could be found
for either transesterification of 3,5-dihydroxy-1-methylcyclohexane 7 or hydrolysis of its
diacetate.
In order to ascertain that the monobutyrates (+)-22, (+)-23 and (+)-25 belonged to the same
enantiomeric series as the corresponding monoacetates (+)-13, (+)-14 and (+)-15, the respective
pairs were transformed into the TBDPS ethers (−)-25, (−)-26 and (−)-27 (Scheme 3). The
absolute configuration of (+)-13 was proven by transformation into (−)-12 via (−)-29 and
subsequent (i) acetate hydrolysis; (ii) Mitsunobu inversion at C-3; (iii) benzoate hydrolysis and
TBS ether formation; (iv) base induced cyclopropane formation; (v) reduction of the ester
function. The vitamin D A-ring precursor (−)-12 has previously been obtained from (−)-quinic
acid 28;1 identical specific rotations were observed.7
Scheme 3. a: (1) TBDPSCl, Imid., DMAP, DMF, rt, (2) K2CO3, MeOH, rt; b: DEAD, (Ph)3P, THF, rt; c: MeMgBr,
,
THF, −78°C; d: TPAP, NMO, 4 A MS, CH2Cl2, rt
The synthesis of the naturally occuring monoterpene cis-sobrerol (−)-318 starting from (−)-14
proved the absolute configuration (Scheme 3). Elimination under Mitsunobu conditions
afforded the substituted cyclohexene (−)-30, which upon treatment with MeMgBr gave cis-
sobrerol (−)-31 (same specific rotation).
Additional proof was obtained by oxidation of (−)-31 to (−)-32, previously synthesized by
Mori et al.9 from (R)-carvone. Also, application of the method of Horeau10 and of Kakisawa’s

Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
3893
rule11 (Fig. 1) based on Mosher’s12 method for determining the absolute configuration of
secondary alcohols via the MPTA esters led to the same conclusion that indeed the acetoxy
function in (−)-14 is at the (R)-stereogenic center.
Figure 1. Absolute sterochemistry determination: Dl values for the (S)- and (R)-Mosher’s esters of the respective
acetates (−)-14 and (−)-15 (Dl=lS−lR, 500 MHz)
Determination of the absolute configuration of 4-ethyl substituted (−)-15 follows from the
methods of Horeau and of Kakisawa, which with regard to the result obtained for (−)-14 can
thus be used safely. Furthermore, the behaviour of the 4-ethyl and 4-methyl homologues in
subcritical fluid chromatography and in polarimetry is consistent with identical absolute
configurations.
Synthetic applications of the enantiopure monoesters will be published elsewere.
3. Experimental
3.1. General remarks
All reactions were carried out under argon atmosphere with magnetic stirring. All solvents
were purified or dried according to standard literature procedures. Solutions were dried over
MgSO4 (unless otherwise specified) and solvent evaporations were carried out in a Rotavapor at
16 mmHg. Column chromatography was performed on SiO2. HPLC separations were performed
on a Knauer 64 or a Kontron 420 delivery system with RI detection. Optical rotations were
measured with a Perkin–Elmer 421 polarimeter. IR spectra were recorded on a Perkin–Elmer
1
FTIR-1600 spectrometer, mass spectra on a HP-5988 spectrometer. The H NMR spectra were
recorded at 500 MHz (Brucker AN-500), the 13C NMR spectra at 50 MHz (Varian Gemini-200).
The chemical shifts are expressed in ppm relative to TMS and coupling constants are in Hz.
Elemental analyses were carried out by ICHOR, Universite´ Pierre et Marie Curie (Paris,
France).
3.2. cis,cis-3,5-Dihydroxy-1-(methoxycarbonyl)cyclohexane 1
Methyl 3,5-dihydroxybenzoate 8 (90 g, 0.53 mol), 5% Rh/Al2O3 (9 g, 10%) in dry MeOH (750
mL) containing AcOH (2 mL) was added into an autoclave (1 L). The autoclave was flushed
twice with hydrogen (from 130 to 40 atm). The pressure of hydrogen was put at 130 atm and
the temperature was raised to 105°C during circa 2 h. In the process of raising the temperature,
the pressure of hydrogen decreased. After the pressure diminished to 90 atm the hydrogen
pressure was again brought to 130 atm. The hydrogenation was continued for an additional

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Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
20 h at 105°C. The catalyst was filtered off over Celite. The filtrate was concentrated and the
residue was crystallized from EtOAc:isooctane (4:1) giving 1 (55 g, 59%). Circa 25% of 8 can be
recuperated from the mother liquor upon crystallization from water.
Rf 0.20 (isooctane:acetone, 1:1). Crystals from isooctane/EtOAc. Mp 132–135°C. IR (KBr):
1
3287, 2934, 1732, 1457, 1281, 1017 cm−1. H NMR (500 MHz, D2O, l ppm): 3.73 (m, 2H), 3.72
(s, 3H), 2.53 (dt, J=12.2, 3.4 Hz, 1H), 2.26 (d, J=11.30 Hz, 1H), 2.17 (d, J=11.7 Hz, 2H), 1.30
(q, J=12.0 Hz, 2H), 1.23 (q, J=11.4 Hz, 1H). MS m/z (%): 156 (M+−H2O, 9), 137 (8), 113 (78),
97 (44), 87 (100), 55 (72).
3.3. All-cis-3,5-dihydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane 2
From 9 as described for 1 from 8. Yield 62%. Crystals from isooctane/EtOAc. Rf 0.21
(isooctane:EtOAc, 3:2). Mp 127–128°C. IR (KBr) 3382, 2913, 1731, 1439, 1361, 1268, 1198,
1
1020, 739, 695 cm−1. H NMR (500 MHz, CDCl3, l ppm): 3.85 (br.s, 2H), 3.32 (s, 3H), 2.61 (t,
J=5.4 Hz, 1H), 2.21 (br.s, 2H), 1.85–1.80 (m, 4H), 1.10 (d, J=7.1 Hz, 3H). MS m/z (%): 189
(M++1, 2), 170 (11), 152 (16), 127 (86), 111 (98), 95 (58), 87 (100), 67 (71), 55 (80).
3.4. All-cis-3,5-dihydroxy-4-ethyl-1-(methoxycarbonyl)cyclohexane 3
From 10 as described for 1 from 8. Crystals from isooctane/EtOAc. Yield 57%. Rf 0.26
(isooctane:EtOAc, 3:2). Mp 95–96°C. IR (KBr): 3395, 2956, 2854, 1722, 1433, 1267, 1011 cm−1.
1H NMR (500 MHz, MeOD, l ppm): 3.72 (dt, J=10.9, 4.7 Hz, 2H), 3.66 (s, 3H), 2.42 (m, 1H),
1.86 (br.s, 1H), 1.79 (dt, J=12.8, 4.1 Hz, 2H), 1.59 (d, J=9.0 Hz, 2H), 1.46 (m, 2H), 1.02 (t,
J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3, l ppm): 179.3, 68.9, 52.4, 45.3, 34.9, 33.6, 21.4,
11.7. MS m/z (%): 202 (M+, 1), 184 (11), 166 (15), 152 (14), 141 (73), 124 (28), 111 (89), 97 (29),
87 (79), 55 (100).
3.5. (1S,3S,5R)-3-Acetoxy-5-hydroxy-1-(methoxycarbonyl)cyclohexane (+)-13
To diol 1 (412 g, 2.31 mmol) and PPL (246 g, 21 U/mg) in a 20 L round-bottom flask was
added vinyl acetate (12.3 L) at rt. The resulting suspension was stirred under N2 at rt (18–22°C)
for 24 h in the dark. The residue was crystallized from i-Prop2O (1.4 L) yielding 13 (436.06 g).
The mother liquor was evaporated and the residue purified by flash chromatography
(Tol.:EtOAc, 7:3). Solvent evaporation and recrystallization from i-Prop2O (250 mL) gave
another 61.3 g. The combined yield of (+)-13 is 496.3 g (97.7%). Rf 0.20 (isooctane:acetone; 7:3).
[h]rDt=+23.6 (c 1.60, CHCl3). Mp 54–55°C. IR (KBr): 3437, 2954, 1732, 1367, 1244, 1029 cm−1.
1H NMR (500 MHz, CDCl3, d ppm): 4.74 (dt, J=11.4, 4.3 Hz, 1H), 3.74 (m, 1H), 3.69 (s, 3H),
2.41 (dt, J=12.6, 3.5 Hz, 1H), 2.30 (m, 1H), 2.24 (m, 2H), 2.05 (s, 3H), 1.40 (m, 3H). 13C NMR
(50 MHz, CDCl3, l ppm): 174.5, 170.7, 69.8, 67.7, 52.3, 40.5, 38.4, 37.1, 33.3, 21.5. MS m/z (%):
216 (M+, 1), 199 (1), 156 (12), 125 (17). Anal. calcd for C10H16O5: C, 55.55; H, 7.46. Found: C,
55.36; H, 7.65.
3.6. (1R,3S,4S,5R)-5-Acetoxy-3-hydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane (−)-14
A suspension of diol 2 (0.10 g, 0.55 mmol) and SAM-II (64.3 mg, 42.5 U/mg) in vinyl acetate
(4 mL) was stirred in the dark at 25–30°C. The reaction was monitored by TLC. After

Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
3895
completion, the reaction mixture was filtered through a pad of Celite. The filtrate was
concentrated and the residue was purified by column chromatography (isooctane:EtOAc, 3:2)
giving (−)-14 (0.11 g, 89%) as a colorless oil. Rf 0.39 (isooctane:EtOAc, 1:1). [h]rDt=−22.7 (c 0.38,
CHCl3). IR (film): 3434, 1731, 1439, 1243, 1027 cm−1. 1H NMR (500 MHz, CDCl3, l ppm): 4.84
(dt, J=11.1, 4.3 Hz, 1H), 3.82 (m, 1H), 3.69 (s, 3H), 2.45 (m, 1H), 2.32 (d, J=6.4 Hz, 1H), 2.05
(s, 3H), 1.92 (dt, J=13.0, 4.0 Hz, 2H), 1.77 (m, 3H), 0.96 (d, J=7.0 Hz, 3H). 13C NMR (50
MHz, CDCl3, l ppm): 174, 170.1, 71.9, 69.3, 51.7, 37.6, 37.3, 30.1, 26.9, 20.1, 5.0. MS m/z (%):
231 (M++1, 1), 213 (1), 199 (2), 186 (4), 170 (15), 152 (21), 127 (34), 111(67), 93 (69), 87 (40),
86 (42), 43 (100).
3.7. (1R,3S,4S,5R)-5-Acetoxy-4-ethyl-3-hydroxy-1-(methoxycarbonyl)cyclohexane (−)-15
From 3 as described for (−)-14 from 2. Colorless oil. Yield 63%. Rf 0.35 (isooctane:EtOAc,
1:1). [h]rDt=−50.2 (c 0.47, CHCl3). IR (film): 3421, 2958, 2360, 1733, 1437, 1239, 1027, 739 cm−1.
1H NMR (500 MHz, CDCl3, l ppm): 4.98 (t, J=4.1, 1H), 3.87 (m, 1H), 3.69 (s, 3H), 2.60 (br.s,
1H), 2.16 (m, 2H), 2.02 (s, 3H), 1.84 (m, 2H), 1.72 (br.s, 1H), 1.59 (m, 2H), 1.47 (m, 1H), 0.97
(t, J=7.5, 3H). MS m/z (%): 245 (M++1, 1), 233 (2), 206 (3), 184 (21), 166 (25), 141 (45), 125
(38), 111 (48), 95 (68), 43 (100).
3.8. cis,cis-3,5-Diacetoxy-1-(methoxycarbonyl)cyclohexane 16
To a solution of diol 1 (0.58 g, 3.333 mmol) in CH2Cl2 (10 mL) was added acetic anhydride
(0.95 mL, 10.0 mmol) at rt, followed by a solution of TMSOTf (0.30 mL, 1 M in CH2Cl2). The
mixture was stirred at rt for 30 min. MeOH (2.5 mL) was added and stirring was continuned for
1 h. After quenching with 5% NaHCO3, the solution was washed with brine (3×5 mL), dried and
concentrated. The residue was purified by chromatography (isooctane:EtOAc, 9:1) affording
diacetate 16 (0.84 g, 98.8%) as a colorless oil. Rf 0.30 (isooctane:EtOAc, 4:1). IR (film): 2964,
1
2876, 1732, 1437, 1384, 1363, 1285, 1255, 1180, 1090, 1029, 988 cm−1. H NMR (500 MHz,
CDCl3, l ppm): 4.76 (tt, J=11.6, 4.2 Hz, 2H), 3.67 (s, 3H), 2.45 (tt, J=12.8, 3.5 Hz, 1H),
2.29–2.26 (m, 3H), 2.03 (s, 6H), 1.47–1.38 (m, 3H). MS m/z (%): 259 (M++1, 1), 227 (2), 215 (1),
198 (11), 185 (18), 172 (8), 157 (12), 156 (100), 125 (34), 138 (12), 113 (8).
3.9. cis,cis-3,5-Dibutanoyloxy-1-(methoxycarbonyl)cyclohexane 17
From 1 and butyric anhydride as described for 16. Colorless oil. Yield 98%. Rf 0.32
(isooctane:EtOAc, 4:1). IR (film): 2964, 2876, 1732, 1468, 1384, 1358, 1285, 1256, 1179, 1090,
1
1046, 989 cm−1. H NMR (500 MHz, CDCl3, l ppm): 4.79 (m, 2H), 3.68 (s, 3H), 2.46 (m, 1H),
2.25 (m, 6H), 1.59 (m, 5H), 1.42 (m, 3H), 0.95 (t, J=7.4 Hz, 6H). MS m/z (%): 313 (M+−1, 1),
305 (5), 283 (13), 278 (4), 263 (2), 254 (2), 245 (10), 226 (95), 213 (100), 198 (18), 194 (25), 183
(12), 166 (85), 156 (16), 138 (10), 107 (10).
3.10. cis,cis-3,5-Diacetoxy-4-methyl-1-(methoxycarbonyl)cyclohexane 18
As described for 16. Colorless oil. Yield 98%. Rf 0.25 (isooctane:EtOAc, 4:1). IR (film): 2955,
1
1738, 1436, 1365, 1236, 1199, 1139, 1025, 979 cm−1. H NMR (500 MHz, CDCl3, l ppm): 4.85
(dt, J=12.1, 4.5 Hz, 2H), 3.68 (s, 3H), 2.46 (m, 2H), 2.05 (s, 6H), 1.98 (dt, J=12.8, 4.0 Hz, 2H),

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Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
1.69 (q, J=12.6 Hz, 2H), 0.96 (s, 3H). MS m/z (%): 241 (M+−31, 1), 230 (2), 199 (10), 170 (45),
153 (12), 127 (10), 111 (15), 93 (42), 43 (100).
3.11. All-cis-3,5-dibutanoyloxy-4-methyl-1-(methoxycarbonyl)cyclohexane 19
As described for 17. Colorless oil. Yield 97%. Rf 0.13 (isooctane:EtOAc, 9:1). IR (film):
1
2965, 2877, 1737, 1451, 1436, 1359, 1282, 1250, 1178, 1091, 985 cm−1. H NMR (500 MHz,
CDCl3, l ppm): 4.87 (dt, J=12.1, 4.5 Hz, 2H), 3.68 (s, 3H), 2.47 (m, 2H), 2.27 (t, J=7.4
Hz, 4H), 1.97 (dt, J=12.7, 4.1 Hz, 2H), 1.66 (m, 6H), 0.95 (m, 9H). MS m/z (%): 297
(M+−31, 2), 261 (1), 240 (5), 227 (8), 197 (2), 170 (38), 153 (18), 127 (8), 111 (10), 71 (100).
3.12. All-cis-3,5-diacetoxy-4-ethyl-1-(methoxycarbonyl)cyclohexane 20
As described for 16. Colorless oil. Yield 98%. Rf 0.28 (isooctane:EtOAc, 4:1). IR (film):
1
2959, 2879, 1732, 1464, 1436, 1365, 1239, 1187, 1180, 1137, 1027, 981 cm−1. H NMR (500
MHz, CDCl3, l ppm): 4.87 (dt, J=11.1, 4.2 Hz, 2H), 3.67 (s, 3H), 2.48 (tt, J=11.5, 4.4 Hz,
1H), 2.11 (t, J=4.3 Hz, 1H), 2.04 (s, 6H), 1.95 (dt, J=12.9, 4.1 Hz, 2H), 1.79 (q, J=23.3,
11.5 Hz, 2H), 1.54 (m, 2H), 0.96 (t, J=7.6 Hz, 3H). MS m/z (%): 285 (M+−1, 1), 244 (2),
226 (1), 213 (5), 184 (20), 166 (15), 125 (25), 107 (30), 43 (100).
3.13. All-cis-3,5-dibutanoyloxy-4-ethyl-1-(methoxycarbonyl)cyclohexane 21
As described for 17. Colorless oil. Yield 97%. Rf 0.25 (isooctane:EtOAc, 4:1). IR (film):
1
2965, 2877, 1732, 1462, 1436, 1249, 1178, 1094, 1043, 988 cm−1. H NMR (500 MHz, CDCl3,
l ppm): 4.89 (dt, J=11.0, 4.1 Hz, 2H), 3.66 (s, 3H), 2.48 (tt, J=11.5, 4.3 Hz, 1H), 2.26 (t,
J=7.2 Hz, 4H), 2.09 (br.s, 1H), 1.94 (dt, J=12.9, 4.2 Hz, 2H), 1.77 (q, J=11.3 Hz, 2H),
1.64 (m, 4H), 1.53 (m, 2H), 0.94 (m, 9H). MS m/z (%): 311 (M+−31, 1), 272 (2), 241 (5), 211
(1), 184 (45), 166 (15), 125 (10), 107 (38), 71 (100).
3.14. (1R,3S,4S,5R)-3-Acetoxy-5-hydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane (+)-14
To a solution of meso-diacetate 18 (118 mg, 0.433 mmol) in CH3CN (3 mL) was added
27.0 mL of phosphate buffer (pH 7.00), followed by the addition of PSL (88 mg, 40 U/mg).
The mixture was stirred at rt and the pH was maintained at 7.00 by addition of NaOH (1.0
M). After completion, the reaction was saturated with NaCl and extracted with EtOAc (3×50
mL). The combined organic layers were washed with brine (3×10 mL), dried and concen-
trated. The residue was purified with HPLC (isooctane:EtOAc, 75:25) affording (+)-14
(71 mg, 72%) as a colorless oil. Rf 0.35 (isooctane:EtOAc, 1:1). [h]rDt=+19.8 (c 1.04, CHCl3).
IR (film): 3456, 2955, 1732, 1472, 1437, 1365, 1243, 1198, 1178, 1132, 1079, 1028, 981 cm−1.
1H NMR (500 MHz, CDCl3, l ppm): 4.83 (dt, J=10.9, 4.3 Hz, 1H), 3.82 (dt, J=10.8, 4.4
Hz, 1H), 3.69 (s, 3H), 2.46 (tt, J=7.3, 4.3 Hz, 1H), 2.32 (d, J=6.4 Hz, 1H), 2.05 (s, 3H),
1.91 (dt, J=13.0, 4.0 Hz, 2H), 1.81–1.71 (m, 3H), 0.96 (d, J=7.1 Hz, 3H). MS m/z (%): 217
(1), 199 (2), 198 (15), 185 (25), 172 (12), 157 (10), 156 (100), 138 (85), 125 (25), 113 (8), 97
(15).

Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
3897
3.15. (1R,3S,4S,5R)-5-Acetoxy-4-ethyl-3-hydroxy-1-(methoxycarbonyl)cyclohexane (+)-15
From 20 and PLE as described for (+)-14. Colorless oil. Yield 72%. Rf 0.35 (isooctane:EtOAc,
1:1). [h]rDt=+50.4 (c 0.83, CHCl3). IR (film): 3439, 2959, 2875, 1732, 1467, 1437, 1359, 1284,
1
1258, 1184, 1143, 1075, 992 cm−1. H NMR (500 MHz, CDCl3, l ppm): 4.97 (t, J=3.5 Hz, 1H),
3.87 (dt, J=6.8, 4.0 Hz, 1H), 3.68 (s, 3H), 2.59 (t, J=2.5 Hz, 1H), 2.14 (br.s, 2H), 2.01 (s, 3H),
1.83 (m, 2H), 1.71 (br.s, 1H), 1.58 (m, 1H), 1.45 (m, 1H), 0.96 (t, J=7.4 Hz). 13C NMR (50
MHz, CDCl3, l ppm): 176.1, 170.3, 71.6, 68.5, 52.0, 45.3, 36.5, 31.6, 29.7, 21.1, 18.2, 13.4. MS
m/z (%): 244 (M+, 1), 235 (1), 212 (12), 199 (5), 184 (20), 171 (12), 166 (42), 153 (38), 141 (100),
120 (32), 125 (85), 111(28), 107 (3).
3.16. (1S,3S,5R)-3-Butanoyloxy-5-hydroxy-1-(methoxycarbonyl)cyclohexane (+)-22
From 17 and PSL as described for (+)-14. Colorless oil. Yield 63%. Rf 0.24 (isooctane:EtOAc,
3:2). [h]rDt=+18.2 (c 0.74, CHCl3). IR (film): 3465, 2959, 2878, 1732, 1463, 1436, 1365, 1240,
1
1197, 1178, 1082, 1028 cm−1. H NMR (500 MHz, CDCl3, l ppm): 4.75 (tt, J=11.4, 3.9 Hz,
1H), 3.73 (tt, J=11.1, 3.9 Hz, 1H), 3.69 (s, 3H), 2.42 (tt, J=12.7, 3.4 Hz, 1H), 2.32–2.20 (m,
5H), 1.79 (br.s, 1H), 1.64 (dd, J=14.8, 7.2 Hz, 2H), 1.47–1.32 (m, 3H), 0.94 (t, J=7.4, 3H). 13C
NMR (50 MHz, CDCl3, l ppm): 174.8, 173.6, 69.8, 68.1, 52.6, 40.9, 38.8, 37.5, 36.9, 33.7, 19.1,
14.2. MS m/z (%): 245 (M++1, 1), 226 (2), 216 (1), 200 (15), 194 (10), 183 (12), 173 (11), 169 (10),
156 (75), 143 (45), 136 (90), 125 (100), 113 (35).
3.17. (1S,3S,4R,5R)-3-Butanoyloxy-5-hydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane
(+)-23
From 19 (125 mg, 0.381 mmol) and PSL as described for (+)-14. Crystals from n-hexane/acet-
one. Yield 89%. Rf 0.25 (isooctane:EtOAc, 3:2). Mp 41–42°C. [h]rDt=+16.5 (c 0.79, CHCl3). IR
1
(film): 3477, 2960, 2876, 1732, 1436, 1360, 1258, 1182, 1084, 1022, 989 cm−1. H NMR (500
MHz, CDCl3, l ppm): 4.85 (dt, J=11.1, 4.1 Hz, 1H), 3.83 (dt, J=10.7, 4.4 Hz, 1H), 3.69 (s,
3H), 2.45 (m, 1H), 2.32 (m, 1H), 2.28 (t, J=7.5 Hz, 2H), 1.91 (m, 2H), 1.75 (m, 2H), 1.65 (m,
3H), 0.95 (t, J=7.1 Hz, 3H), 0.94 (d, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3, l ppm):
174.7, 172.9, 71.8, 69.6, 52.0, 38.0, 37.7, 36.4, 30.4, 27.3, 18.5, 13.7, 6.2. MS m/z (%): 257 (M+−1,
1), 239 (1), 214 (1), 199 (2), 170 (10), 152 (12), 139 (15), 127 (30), 110 (60), 93 (70), 71 (65). Anal.
calcd for C13H22O5: C, 60.45; H, 8.58. Found: C, 60.16; H, 8.65.
3.18. (1S,3S,4R,5R)-3-Butanoyloxy-4-ethyl-5-hydroxy-1-(methoxycarbonyl)cyclohexane (+)-24
From 21 and SAM-II as described for (+)-14. Colorless oil. Yield 88%. Rf 0.26 (iso-
octane:EtOAc, 7:3). [h]rDt=+44.6 (c 1.04, CHCl3). IR (film): 3476, 2963, 2876, 1732, 1461, 1436,
1
1357, 1240, 1182, 1092, 1027, 992, 933 cm−1. H NMR (500 MHz, CDCl3, l ppm): 4.99 (t,
J=3.3 Hz, 1H), 3.88 (dt, J=6.9, 4.1 Hz, 1H), 3.68 (s, 3H), 2.60 (t, J=3.0 Hz, 1H), 2.24 (m, 2H),
2.11 (br.s, 2H), 1.84 (m, 2H), 1.70 (br.s, 1H), 1.63 (m, 2H), 1.57 (m, 2H), 1.45 (m, 1H), 0.96 (t,
J=7.5 Hz, 3H), 0.93 (t, J=7.4 Hz, 3H). 13C NMR (50 MHz, CDCl3, l ppm): 175.7, 172.7, 71.2,
66.4, 51.8, 45.2, 36.5, 36.1, 31.3, 29.2, 18.1, 17.8, 13.4, 13.4. MS m/z (%): 240 (M+−31-H, 1), 201
(1), 184 (12), 165 (15), 141 (55), 125 (48), 107 (72), 87 (50), 71 (85), 43 (100). Anal. calcd for
C14H24O5: C, 61.74; H, 8.88. Found: C, 61.57; H, 8.98.

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Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
3.19. (4R,6R)-6-Acetoxy-1-methyl-4-(methoxycarbonyl)cyclohexene (−)-30
To a stirred solution of monoacetate (−)-14 (0.20 g, 0.869 mmol) and (Ph)3P (0.94, 3.584
mmol) in THF (10 mL) at rt was added dropwise DEAD (0.66 mL, 3.56 mmol). After stirring
overnight at rt, the solution was concentrated. The residue was purified by column chromatog-
raphy (pentane:Et2O, 9:1–4:1) affording 30 (170 mg, 94%). Rf 0.41 (isooctane:Et2O, 4:1).
[h]rt=−52.7 (c 1.83, CHCl3). IR (film): 3070, 2951, 2850, 1736, 1456, 1436, 1370, 1343, 1239,
1171, 1074, 1028, 987, 932 cm−1. 1H NMR (500 MHz, CDCl3, l ppm): 5.58 (d, J=1.5, 1H), 5.35
(br.s, 1H), 3.67 (s, 3H), 2.67 (m, 1H), 2.35–2.24 (m, 3H), 2.05 (s, 3H), 1.80 (m, 1H), 1.63 (s, 3H).
13C NMR (50 MHz, CDCl3, l ppm): 174.7, 170.8, 132.7, 124.7, 71.1, 51.7, 37.6, 31.0, 27.3, 21.0,
19.1. MS m/z (%): 212 (M+, 5), 199 (8), 184 (8), 170 (95), 152 (85), 139 (62), 121 (45), 111 (75),
93 (100), 77 (80).
3.20. (4R,6R)-6-Hydroxy-4-(1-hydroxyisopropyl)-1-methylcyclohexene (−)-31
To a stirred solution of (−)-30 (75 mg, 0.354 mmol) in THF (3 mL) at −78°C was added
dropwise MeMgBr solution (2.0 mL, 3.0 M in Et2O). The resulting mixture was stirred for 6 h
at −78°C, and then allowed to warm to rt overnight. The reaction was quenched with saturated
NH4Cl (3 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed
with brine (3×5 mL), dried, and concentrated. The residue was purified by HPLC (iso-
octane:EtOAc, 55:45) affording (−)-31 (51 mg, 85%). Crystals from CHCl3. Mp 109–110°C. Rf
0.18 (isooctane:EtOAc, 1:1). [h]rDt=−20.8 (c 0.29, CHCl3) {lit.8: [h]D=−16}. IR (KBr): 3283,
1
2969, 2944, 2886, 2849, 1454, 1383, 1320, 1256, 1167, 1148, 1109, 1037, 974, 922 cm−1. H NMR
(500 MHz, CDCl3, l ppm): 5.47 (t, J=1.4 Hz, 1H), 4.16 (br.s, 1H), 2.23–2.19 (m, 1H), 2.05 (m,
1H), 1.89–1.84 (m, 1H), 1.74 (s, 3H), 1.68–1.62 (m, 1H), 1.54 (br.s, 2H), 1.32 (m, 1H), 1.19 (s,
3H), 1.19 (s, 3H). 13C NMR (50 MHz, CDCl3, l ppm): 136.3, 123.6, 72.2, 70.8, 43.8, 34.2, 27.3,
26.9, 26.4, 18.7. MS m/z (%): 169 (M+−1, 4), 152 (13), 149 (4), 137 (16), 119 (11), 109 (59), 94
(57), 79 (60), 69 (34), 59 (100).
3.21. (4R)-1-Methyl-4-(1-hydroxyisopropyl)cyclohexene-6-one (−)-32
,
To a stirred solution of (−)-31 (80 mg, 0.471 mmol), NMO (85 mg, 0.706 mmol) and (4 A)
molecular sieves (236 mg) in CH2Cl2 (6 mL) at rt was added TPAP (8.3 mg, 0.024 mmol). The
resulting mixture was stirred for 2 h. After filtration on Celite and solvent evaporation, the
residue was purified by HPLC (isooctane:EtOAc, 3:2) affording (−)-32 (77 mg, 98%). Rf 0.31
(isooctane:EtOAc, 7:3). Mp 39–41°C. [h]2D0=−39.7 (c 0.54, EtOH) {lit.9: [h]2D4=−42.7 (c 6.94,
EtOH)}. IR (film): 3443, 2975, 2927, 1661, 1452, 1434, 1369, 1300, 1146, 1113, 1059, 905, 815
1
cm−1. H NMR (500 MHz, CDCl3, l ppm): 6.75 (dd, J=5.7, 1.1 Hz, 1H), 2.61–2.57 (m, 1H),
2.46–2.41 (m, 1H), 2.22 (m, 2H), 2.07–2.01 (m, 1H), 1.75 (s, 3H), 1.52 (br.s, 1H), 1.21 (s, 3H),
1.20 (s, 3H). 13C NMR (50 MHz, CDCl3, l ppm): 200.0, 144.8, 134.9, 71.3, 45.8, 39.4, 27.1, 26.9,
26.8, 15.4. MS m/z (%): 168 (M+, 1), 150 (113), 138 (4), 135 (7), 123 (2), 110 (39), 95 (38), 91
(14), 82 (21), 67 (20), 59 (100).
3.22. (R)-MTPA ester of (−)-14
To a stirred solution of (−)-14 (8.5 mg, 0.039 mmol), DMAP (2 mg) and Et3N (15.4 mL, 0.110
mmol) in CH2Cl2 (4 mL) was added dropwise (S)-(+)-MTPACl (13.8 mL, 0.074 mmol) at rt. The

Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
3899
resulting mixture was stirred overnight. The solution was diluted with Et2O (15 mL), washed
with NaHCO3 (2×5 mL) and brine (2×5 mL), dried and concentrated giving a residue. HPLC
purification (isooctane:AcOEt, 9:1) gave the (R)-MTPA ester (14 mg, 89%) as a colorless oil. Rf
0.19 (isooctane:EtOAc, 4:1). [h]rDt=+36.2 (c 0.56, CHCl3). IR (film): 2953, 1738, 1453, 1361,
1
1244, 1179, 1109, 1015, 720 cm−1. H NMR (500 MHz, CDCl3, l ppm): 7.50–7.30 (m, 5H), 5.12
(dt, J=12.2, 4.5 Hz, 1H), 4.88 (dt, J=12.1, 4.4 Hz, 1H), 3.70 (s, 3H), 3.55 (s, 3H), 2.51 (m, 2H),
2.09 (dt, J=12.7, 4.1 Hz, 1H), 2.05 (s, 3H), 2.01 (dt, J=12.9, 4.2 Hz, 1H), 1.82 (q, J=12.6 Hz,
1H), 1.70 (J=12.7 Hz, 1H), 0.85 (d, J=7.0 Hz, 3H). 13C NMR (50 MHz, CDCl3, l ppm): 173.5,
170.0, 165.4, 132.1, 129.6, 129.4, 128.4, 127.1, 73.8, 71.0, 55.4, 52.1, 37.5, 35.1, 26.8, 26.7, 21.0,
5.9. MS m/z (%): 415 (M+−31, 1), 373 (1), 341 (2), 321 (1), 253 (2), 223 (2), 189 (34), 171 (28),
139 (19), 93 (45), 43 (100).
3.23. (S)-MTPA ester of (−)-14
From (−)-14 and (R)-(−)-MTPACl. Colorless oil. Yield 90%. Rf 0.19 (isooctane:EtOAc, 4:1).
[h]rDt=−26.7 (c 0.19, CHCl3). IR (film): 2953, 1739, 1585, 1451, 1366, 1241, 1181, 1121, 1020, 722
1
cm−1. H NMR (500 MHz, CDCl3, l ppm): 7.50–7.36 (m, 5H), 5.12 (dt, J=12.1, 4.5 Hz, 1H),
4.89 (dt, J=11.9, 4.6 Hz, 1H), 3.69 (s, 3H), 3.52 (s, 3H), 2.56 (m, 1H), 2.50 (tt, J=12.9, 3.9 Hz,
1H), 2.06 (s, 3H), 2.04 (m, 1H), 1.99 (dt, J=12.9, 3.9 Hz, 1H), 1.75 (m, 1H), 1.69 (m, 1H), 0.95
(d, J=6.9 Hz, 3H). 13C NMR (50 MHz, CDCl3, l ppm): 173.1, 170.0, 165.5, 131.9, 129.7, 129.4,
128.5, 127.4, 73.9, 71.2, 55.2, 52.1, 37.5, 35.5, 26.8, 26.5, 21.2, 6.2. MS m/z (%): 416 (M+−31+H,
1), 373 (5), 341 (1), 321 (1), 260 (1), 247 (1), 213 (15), 189 (28), 153 (34), 139 (37), 93 (64), 43
(100).
3.24. (R)-MTPA ester of (−)-15
From (−)-15 and (S)-(+)-MTPACl. Colorless oil. Yield 88%. Rf 0.21 (isooctane:EtOAc, 4:1).
[h]rDt=+42.8 (c 0.68, CHCl3). IR (film): 2954, 1738, 1572, 1452, 1366, 1240, 1180, 1122, 1082,
1
1023, 921, 767, 722 cm−1. H NMR (500 MHz, CDCl3, l ppm): 7.50–7.39 (m, 5H), 5.09 (dt,
J=11.5, 4.3 Hz, 1H), 4.89 (dt, J=11.4, 4.3 Hz, 1H), 3.67 (s, 3H), 3.55 (s, 3H), 2.50 (m, 1H), 2.12
(t, J=4.8 Hz, 1H), 2.07 (dt, J=12.5, 3.5 Hz, 1H), 2.02 (s, 3H), 1.99 (dt, J=13.6, 3.5 Hz, 1H),
1.80 (m, 1H), 1.77 (m, 1H), 1.42 (m, 2H), 0.74 (t, J=7.5 Hz, 3H). 13C NMR (500 MHz, CDCl3,
l ppm): 173.5, 170.1, 165.6, 132.2, 129.7, 129.1, 128.5, 127.5, 74.2, 71.5, 55.5, 52.2, 43.0, 37.3,
28.0, 27.7, 21.0, 16.2, 14.3. MS m/z (%): 413 (1), 387 (4), 355 (1), 296 (2), 261 (1), 227 (10), 189
(38), 167 (35), 135 (34), 107 (85), 43 (100).
3.25. (S)-MTPA ester of (−)-15
From (−)-15 and (R)-(−)-MTPACl. Colorless oil. Yield 90%. Rf 0.21 (isooctane:EtOAc, 4:1).
[h]rDt=−23.1 (c 0.82, CHCl3). IR (film): 2954, 1738, 1572, 1452, 1365, 1239, 1175, 1122, 1020, 723
1
cm−1. H NMR (500 MHz, CDCl3, l ppm): 7.49–7.39 (m, 5H), 5.09 (dt, J=11.4, 4.3 Hz, 1H),
4.91 (dt, J=11.5, 4.3 Hz, 1H), 3.66 (s, 3H), 3.51 (s, 3H), 2.49 (tt, J=13.2, 4.5 Hz, 1H), 2.19 (t,
J=4.7 Hz, 1H), 2.04 (s, 3H), 2.03 (dt, J=11.3, 4.5 Hz, 1H), 1.97 (dt, J=13.1, 3.5 Hz, 1H), 1.78
(m, 1H), 1.72 (m, 1H), 1.49 (m, 2H), 0.87 (t, J=7.5 Hz, 3H). 13C NMR (50 MHz, CDCl3, l
ppm): 173.5, 170.2, 165.8, 132.1, 129.7, 128.5, 128.2, 127.4, 74.3, 71.6, 55.3, 52.2, 43.3, 37.3, 27.9,
27.7, 21.2, 16.4, 14.5. MS m/z (%): 431 (M+−31+2H, 1), 412 (1), 387 (4), 355 (1), 302 (1), 256
(3), 227 (9), 189 (15), 167 (14), 135 (17), 107 (49), 43 (100).

3900
Y. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3887–3900
3.26. Horeau’s partial resolution method for determination of the absolute configuration of
(−)-14 and (−)-15
To a stirred solution of (−)-14 (17 mg, 0.076 mmol) was added dropwise 2-phenylbutyric acid
anhydride (44 mL, 0.150 mmol) at rt. The resultant mixture was stirred at rt for 16 h. Then H2O
(0.2 mL) was added and the stirring was continuned for 0.5 h. The mixture was poured into
aqueous NaOH solution (0.1N, 15 mL) and benzene(15 mL). The aqueous layer was separated
and extracted with benzene (2×10 mL). The aqueous layer was acidified by addition of aqueous
HCl (1N) and extracted with benzene (3×10 mL). The combined organic layers were dried,
filtered and the volume was adjusted to 1 mL for optical measurements. The [h]rDt is −0.35,
indicating the S absolute configuration at C3. Starting from (−)-15, an [h]rDt −0.30 was found,
also indicating the S absolute configuration at C3.
Acknowledgements
Y. Zhao, Y. Wu, P. De Clercq and M. Vandewalle thank the ‘F.W.O.’ and the ‘Ministerie
voor Wetenschapsbeleid’ for financial support to the laboratory.
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