Enantiomerically enriched cryptone by lipase catalysed kinetic resolution

Article abstract of DOI:10.1016/j.tetasy.2005.12.012

Thiophenol was added to racemic cryptone (4-isopropyl-2-cyclohexene-1-one) and the resulting 1,4-addition products, cis- and trans-4-isopropyl-3- (phenylsulfanyl)cyclohexanone were separated and the latter reduced to rac-1,3-cis-1,4-trans-4-isopropyl-3-(p

Full text of DOI:10.1016/j.tetasy.2005.12.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 275–280
Enantiomerically enriched cryptone by lipase catalysed
kinetic resolution
Dan Isaksson, Kristina Sjo¨din and Hans-Erik Ho¨gberg*
Department of Natural Sciences, Mid Sweden University, 851 70 Sundsvall, Sweden
Received 18 November 2005; accepted 8 December 2005
Abstract—Thiophenol was added to racemic cryptone (4-isopropyl-2-cyclohexene-1-one) and the resulting 1,4-addition products,
cis- and trans-4-isopropyl-3-(phenylsulfanyl)cyclohexanone were separated and the latter reduced to rac-1,3-cis-1,4-trans-4-isopropyl-
3-(phenylsulfanyl)cyclohexanol, which was subjected to lipase catalysed resolution by acylation catalysed by CAL-B (Candida
antarctica lipase B). The alcohol enantiomers obtained were oxidised. The remaining alcohol was separated from the produced
acetate, which was hydrolysed to the alcohol. The initial products, probably sulfoxidoketones spontaneously decomposed to furnish
enantiomerically enriched (R)- and (S)-cryptone with up to 76% and 98% ee, respectively.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
which when subjected to lipase-catalysed resolution
and subsequent oxidation to the ketone would poten-
tially provide both enantiomers of cryptone 1 in high
ee. For a secondary alcohol to be resolved by a lipase it
is important that the lipase can differentiate between
the two enantiomers. The hydroxylated carbon must,
in addition to the hydroxyl group, be linked to two
groups which differ considerably in size.13 Simple race-
mic cyclo-2-hexenols are notoriously difficult to resolve
by lipase catalysed acylation.14,15 Similar resolutions of
rac-2- and/or 3-substituted cyclo-2-hexene-1-ols or simi-
larly substituted cyclohexanols are, however, usually suc-
cessful.14–16 As reported by Morgan et al.17 it is possible
to temporarily attach a large and removable group by
1,4-addition to a cyclohexenone and in this way create
the size difference required for a successful resolution
of the corresponding alcohol.17 Inspired by this work,
we hoped that thiophenol could be added diastereoselec-
tively to rac-cryptone 1 and that the product would after
reduction provide one diastereomer of alcohol 3 which
would be resolvable by lipase catalysed acylation (steps
a and b in Scheme 1). Oxidation of the enantiopure alco-
hol and oxidative elimination of thiophenol would then
provide the desired enantiomer of cryptone [(R)- or (S)-1].
The enantiomers of the nor-monoterpene cryptone (4-
isopropyl-2-cyclohexene-1-one, 1, Scheme 1) are of
interest as starting materials for the synthesis of natural
products.1–3 Several synthetic approaches to enantio-
merically enriched cryptone have been described.1,4–8
The resulting enantiomeric excesses (ees) range from
66% to 95%.
In the last 10 years, some marine natural products with a
cadinene-type skeleton have attracted considerable inter-
est among biochemists as well as synthetic chemists due
to their antifouling properties.9,10 Enantiomerically pure
(R)- and (S)-cryptone (R)- and (S)-1 could be suitable
starting materials for the enantioselective synthesis of
such biologically active compounds. Racemic cryptone
1 can easily be obtained from the readily available b-
pinene11 (regardless of the initial enantiomeric purity of
the b-pinene, the cryptone product is virtually racemic).
Lipase catalysed acylation reactions were looked at as
a means to resolve rac-cryptone 1 into (R)- and (S)-1.
Highly enantioselective transesterification reactions of
enol esters with secondary alcohols can be catalysed by
lipases.12 Regio- and stereoselective reduction of rac-
cryptone 1 could furnish a secondary allylic alcohol,
2. Results and discussion
Bakuzis et al.18 have shown that Michael addition of
*
Corresponding author. Tel.: +46 60 148704; fax: +46 60 148802;
e-mail: Hans-Erik.Hogberg@miun.se
thiophenol to a,b-unsaturated cyclic ketones can be
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.012

276
D. Isaksson et al. / Tetrahedron: Asymmetry 17 (2006) 275–280
O
OH
OH
OAc
c
b
+
S
S
S
S
4
t-2
c,t-3
mp 88-91 oC
(+)-c,t-3
[α]2D0= +56.0
[α]2D0= -29.7
mp 51-54 oC
O
c
d
O
a
ratio t-2:c-2 = 2:1
by-product:
+
OH
OH
5
SPh
PhS
1
(+)-c,t-3
(-)-c,t-3
[α]2D0= -118
[α]2D0= +104
mp 91-93 oC
O
OH
mp 103-104 oC
b
e
e
S
S
O
O
c,c-3 + t,t-3
c-2
e, f
S
(R)-(-)-1
( )-(+)-1
[α]2D0= -69.8
[α]2D0= +89.9
Scheme 1. Reagents and conditions: (a) thiophenol (1 equiv), Et3N (0.05 equiv) in dichloromethane 0 ꢁC, 36% (isolated yield of t-2 calculated from
1); (b) NaBH4 (1 equiv), CeCl3Æ7H2O (1 equiv) in methanol 66% (isolated yield of c,t-3 calculated from t-2); (c) CAL-B, vinylacetate (5 equiv) in
diisopropylether; (d) 1 M NaOH in methanol, reflux (82% from 4); (e) (i) Jones reagent in acetone, (ii) NaHCO3 (aq) (86% yield from 3); (f) Et3N in
THF/H2O.
performed successfully. We found that the addition of
thiophenol to cryptone 1 (step a in Scheme 1) was
accompanied by the formation of substantial amounts
of a side-product, 4-isopropyl-3-cyclohexenone 5. By
using a catalytic amount of base and lowering the tem-
perature to ꢀ15 to 0 ꢁC, we suppressed the formation
of 5. Thus, two diastereomeric products were formed
in a 2:1 ratio. Relative to the isopropyl group, the ma-
jor product, t-2, had the phenylsulfanyl group trans,
whereas the minor one, c-2, was cis. The diastereo-
meric products t-2 and c-2 were separated by flash col-
umn chromatography. The low energy conformations
of t-2 and c-2 are shown in Figure 1 (calculated by
using Chem3Dꢂ). The relative configuration of the
to those observed in the spectrum of the trans-product
t-2.
When subjected to Luche reduction (NaBH4, CeCl3),
cyclic ketones can be stereoselectively reduced.19,20 Thus,
such a reduction of the major PhSH addition product t-2
gave a single crystalline product, the 1,3-cis-1,4-trans-
cyclohexanol c,t-3. In contrast, the minor Michael
addition product c-2 furnished two diastereomeric cyclo-
hexanols, the 1,3-cis-1,4-cis- and the 1,3-trans-1,4-trans
ones, c,c-3 and t,t-3, respectively (in a 1:1 ratio). We were
unable to separate the two products c,c-3 and t,t-3. As a
result, the lipase catalysed resolution of the cyclohexanol
c,t-3 only was studied. The relative configuration of c,t-3
was determined by 1H NMR and H,H-COSY. The signal
from the axial proton at carbon 2 (H2a) was an apparent
quartet due to three couplings of similar size, two
1
proposed major product t-2 was confirmed by its H
NMR and H,H-COSY spectrum. The proton at car-
bon 3 coupled to three protons, two at carbon 2 and
one at carbon 4 with one small (4.6 Hz) and two large
coupling constants. The latter were large enough to
indicate an axial–axial–axial relationship between the
protons at carbons 2, 3 and 4 and were equal in size
(ꢁ9.5 Hz). Thus, the signal for the proton at carbon
3 in t-2 appeared as a doublet of triplets thus
confirming the proposed structure (Fig. 1). On the
axial and one vicinal (JH2ꢀH3 ꢁ JH1ꢀH2 ꢁ JH2ꢀH2
ꢁ
a
a
a
a
11:2–12 Hz). The signal for H3a ina c,t-3 appeaered
as in t-2 as a doublet of triplets, confirming that there
was still an axial relationship between the protons at
the 2-, 3- and 4-positions. If the coupling constants
JH1ꢀH2 had been smaller and the signal for the axial pro-
a
ton 2awould have appeared as a doublet of triplets, the
diastereomeric alcohol could have been the product.
The large coupling between the protons at carbons 1
and 2 and the apparent quartet for H2a shows that H1
1
other hand, in the H NMR spectrum of c-2, the signal
for the proton at carbon 3 was a non-resolved multi-
plet due to three smaller coupling constants compared

D. Isaksson et al. / Tetrahedron: Asymmetry 17 (2006) 275–280
277
Ph
H3
O
O
a
S
H
1
6
5
2
4
H2
H2
e
e
3
H3
H
S
e
H2
H4
a
H2
H4
a
a
a
Ph
t-2
c-2
H1
a
H3
a
H6
e
HO
H2
e
H6a
H
S
H2
H4
a
a
Ph
c,t-3
Figure 1. Relative stereochemistry of the products t-2, c-2 and c,t-3 determined by NMR.
has to be axial, thus proving the proposed structure of
c,t-3.
not complete. According to Evarts et al.,8 elimination
of phenylsulfinic acid is facilitated by base in combina-
tion with a polar solvent. Thus, in order to obtain a
reasonable yield of recycled cryptone, we had to use
Et3N in a solvent mixture of water and THF to achieve
complete elimination of the sulfinate from the mixture
after oxidation of c-2, c,c-3 and t,t-3. It is unclear why
the oxidative elimination of the sulfide moiety should
be more difficult from c-2 than from t-2.
With the masked cryptone in hand as its derivative c,t-3,
we turned our attention to the possibility of resolving it
using a lipase catalysed acylation with vinyl acetate.
Three different lipases were tested: CAL-B, Lipase PS
and PPL. Only CAL-B catalysed the acylation of the
alcohol. Hence, immobilised CAL-B was added to a
solution of vinyl acetate and the cyclohexanol c,t-3
and the conversion was monitored by GC. When it
reached 40%, the reaction was stopped by filtration,
which removed the immobilised CAL-B. Ester 4 and
alcohol (+)-c,t-3 were separated by chromatography.
In order to increase the enantiomeric purity of the
remaining substrate, alcohol (+)-c,t-3, was treated a sec-
ond time with vinyl acetate and CAL-B. The reaction
was very slow and after 25% conversion, it seemed to
stop spontaneously, indicating that most of the (ꢀ)-c,t-
3 was consumed. The remaining substrate after the sec-
ond esterification, alcohol (+)-c,t-3 was purified by
chromatography. Although the conversion in the
CAL-B catalysed resolution was determined relatively
easy by GC, we were unable to obtain good enantiosep-
arations for either the produced acetates or the remain-
ing alcohols. Thus we were unable to calculate any
E-values.
Despite several efforts to improve the conditions for the
GC-analysis (chiral column, b-dex120) of racemic cryp-
tone 1 (prepared according to Queiroga et al.11), such
analysis gave, at best, two overlapping peaks without
base-line separation. Consequently, each of the enantio-
merically enriched cryptone products gave rise to what
appeared to be a single peak. Thus, we were unable to
use GC to accurately determine the enantiomeric purity
of the samples of (S)-(+)- or (R)-(ꢀ)-cryptone we had
prepared. Although optical rotation is not a very reli-
able way to assess ee-values, we ultimately had to use
this method. Thus, optical rotation measurements were
conducted using ethanol as solvent. Although a higher
rotation has been found for (ꢀ)-cryptone (Galloway
et al.21), the correct rotation of pure (ꢀ)-1 seems to have
been reliably determined by Gillespie et al.22 to be
20
½aꢂD ¼ ꢀ91:7 (c 2.2 EtOH). From the rotations we
obtained the enantiomeric purity which was determined
to be 76% ee and 98% ee for (R)-(ꢀ)-1 and (S)-(+)-1,
respectively.
Acetate, 4, that is the product from the first lipase catal-
ysed esterification, was then hydrolysed by treatment
with sodium hydroxide in refluxing methanol (step d
in Scheme 1).
3. Conclusion
Jones oxidation of each of the enantiomers of alcohol
c,t-3 gave the desired enantiomers of cryptone. Under
the conditions used, the sulfide was presumably oxidised
to a sulfoxide, which spontaneously underwent elimina-
tion to give a,b-unsaturated ketone 1 (step e in Scheme
1). As depicted in Scheme 1, racemic cryptone could also
be recovered from the products c-2, c,c-3 and t,t-3 by
Jones oxidation. In this case, however, elimination was
We have shown that it is possible to separate the enan-
tiomers of racemic cryptone in a five/six-step procedure.
The procedure involves a lipase catalysed resolution of
4-isopropyl-3-thiophenylcyclohexan-1-ol formed from
racemic cryptone. Enantiomerically enriched cryptone
is easily obtained from the resolved alcohols by simple
oxidation using Jones reagent.

278
D. Isaksson et al. / Tetrahedron: Asymmetry 17 (2006) 275–280
4. Experimental
atory funnel. After the addition of aqueous NaOH (1 M,
10 mL) and diethyl ether (30 mL), the phases were sha-
ken and separated, and the organic phase was washed
with water (2 · 10 mL) followed by 10 mL brine. The
combined water phases were extracted with Et2O
(10 mL). The combined organic phases were dried over
Na2SO4 overnight. Filtration, concentration, purifica-
tion by flash chromatography and recrystallization in
pentane gave crystalline t-2 (0.915 g, 51% yield). As
the product tended to decompose to cryptone and thio-
phenol on silica gel, the time spent on the column
was minimised. Racemic t-2: Anal. Calcd for
C15H20OS: C, 72.53; H, 8.12. Found: C, 72.8; H, 8.3.
mp 51–54 ꢁC. 1H NMR: d 0.88 (3H, d, J = 6.8 Hz,
CH3), 1.04 (3H, d, J = 6.9 Hz, CH3), 1.54 (1H, m),
1.66 (1H, m), 2.08 (1H, m), 2.25–2.33 (1H, dddd,
J = 1.1, 5.7, 11.6, 16.2 Hz), 2.35–2.43 (2H, m), 2.43–
2.51 (1H, m), 2.66 (1H, ddd, J = 1.9, 4.6, 14.8 Hz
CHeqH), 3.31 (1H, ddd, J = 4.6, ꢃ9.5, ꢃ9.5 Hz CH),
7.27–7.33 (3H, m, Ph), 7.42 (2H, m, Ph). 13C NMR: d
16.47 (CH3), 21.21 (CH3), 23.53 (CH2), 27.71 (CH),
39.84 (CH2), 45.44 (CH), 47.05 (CH2), 49.02 (CH),
127.94 (CH), 129.09 (2C, CH), 132.89 (C), 133.82 (2C,
CH), 209.45 (C@O). Cryptone and racemic c-2 (in total
0.642 g) were also recovered. Further purification by
4.1. General
Except for the resolution reactions, all reactions carried
out in dry solvents were performed under an argon
atmosphere in dry glassware.
Flash column chromatography was performed on silica
gel (Merck 60, 0.040–0.063 mm) using a gradient system
of pentane and ether as eluent according to the follow-
ing: Diethyl ether vol% in pentane: 0, 1.25, 2.5, 5, 10,
20, 40, 80 and 100 (the volume of each mixture was
the same as the column void volume).
All chemicals and enzymes were used as received from
suppliers unless otherwise stated. Dichloromethane
and diisopropylether was dried over 4 A molecular
˚
sieves prior to use.
CAL-B: (Candida antarctica lipase B) Novozym 435,
Novonordisk Batch no LC2 00009;
PPL: (crude from porcine pancreas) Sigma, [9001-62-1],
Lot 108H1379;
Lipase PS: (Pseudomonas cepacia) Amano PS, Amano
Enzyme Inc.
1
flash chromatography provided pure c-2: H NMR: d
1.04 (3H, d, J = 6.6 Hz, CH3), 1.13 (3H, d, J = 6.5 Hz,
CH3), 1.70–1.92 (2H, m), 2.17 (1H, m), 2.26–2.33
(2H, m), 2.47–2.58 (3H, m), 3.81 (1H, m), 7.25–7.32
(3H, m), 7.43 (2H, m). 13C NMR: d 20.82 (CH3),
21.36 (CH3), 26.19 (CH2), 29.83 (CH), 40.76 (CH2),
46.25 (CH2), 47.37 (CH), 50.25 (CH), 127.67 (CH),
129.14 (2C, CH), 133.36 (C), 133.70 (2C, CH), 209.21
(C@O).
Gas chromatography: Glass capillary columns, either a
Varian 3400 (Column: EC-1, 30 m, 0.32 mm i.d.,
df = 0.25 lm, carrier gas N2, 13 psi, air + N2 243 mL/
min, split 1:50, program: 50 ꢁC, 3 min, 10 ꢁC/min to
250 ꢁC) or a Varian 3300 (Column: b-dex 120, 30 m,
0.25 mm i.d., df = 0.25 lm, carrier gas He, Air + He
292 mL/min, split 1:6, program 100 ꢁC, 0 min, 0.5 ꢁC/
min to 180 ꢁC).
4.3.2. 4-Isopropyl-3-(phenylsulfanyl)cyclohexanol c,t-3.
To a methanol solution (10 mL) of NaBH4 (0.152 g,
4.0 mmol) and CeCl3Æ7H2O (1.40 g 3.8 mmol) was
added t-2 (0.915 g, 3.7 mmol). After stirring for
1 h, hydrochloric acid (ꢃ1 mL, 0.1 M, aq) was added
to quench the reaction. After mixing with brine
(20 mL) and diethyl ether (20 mL), the phases were sepa-
rated and the water phase extracted with Et2O
(2 · 10 mL). The combined organic phases were dried
over Na2SO4, filtered, concentrated and purified by flash
chromatography to give colourless crystalline solid c,t-3
(0.611 g, 66%, >95% by GC). Anal. Calcd for
C15H22OS: C, 71.95; H, 8.86. Found: C, 71.9; H, 9.0.
NMR spectra were recorded on a Bruker Avance 500
1
(500 MHz H, 125.7 MHz 13C) using CDCl3 as solvent
and TMS as internal reference. Optical rotation was
determined using a Perkin–Elmer model 341 with a
1 cm cell. Elemental analyses were performed by Mikro-
kemi AB (www.mikrokemi.se).
4.2. Response factors
Alcohol c,t-3 (3.47 mg, 1.39 10ꢀ5 mol) and the corre-
*
sponding acetate 4 (3.11 mg, 1.06 10ꢀ5 mol) were dis-
*
solved in diethyl ether. Three injections were
performed on GC to determine the integrated areas.
Rfc,t-3 was set to 1 and a mean value of Rfacetate 4 was
determined to be 0.71 (mol/mol).
1
Mp 88–91 ꢁC. H NMR: d 0.80 (3H, d, J = 6.8 CH3),
0.96 (3H, d, J = 7.0 CH3), 1.03–1.30 (3H, m), 1.39
(1H, ddd (app q), J ꢁ 11.2, 12, 12), 1.45 (1H, s, OH),
1.78 (1H, m), 2.0 (1H, m), 2.28 (1H, m), 2.52 (1H, m),
2.88 (1H, ddd, J = 3.7, 11.5, 11.5 Hz, CHSPh), 3.5
(1H, m, CHOH) 7.25–7.32 (3H, m), 7.42 (2H, m). 13C
NMR: d 15.23 (CH3), 21.36 (CH3), 22.22 (CH2), 27.20
(CH), 34.89 (CH2), 43.60 (CH2), 46.25 (CH), 48.35
(CH), 70.19 (CH), 127.34 (CH), 128.86 (2C, CH),
133.82 (2C, CH), 134.03 (C).
4.3. Experimental procedures
4.3.1. 4-Isopropyl-3-(phenylsulfanyl)cyclohexanone 2.
Racemic cryptone (rac-1, 0.997 g 7.2 mmol) and thio-
phenol (0.74 mL, 7.2 mmol) were dissolved in dichloro-
methane (7 mL) in a 25 mL round-bottomed flask. After
cooling to ꢀ15 ꢁC in an ice/acetone bath, triethylamine
(0.05 mL, 0.36 mmol) was added and the reaction mix-
ture stirred at ꢀ15 ꢁC. After 1 h, the temperature was
ꢀ8 ꢁC. Saturated NaHCO3 (10 mL, aq) was added and
the mixture stirred for 5 min and transferred to a separ-
4.3.3.
(1R,3R,4S)-4-Isopropyl-3-(phenylsulfanyl)cyclo-
hexyl acetate 4. Vinyl acetate (0.370 mL, 4 mmol)
was added to a solution of c,t-3 (0.206 g, 0.8 mmol) in
diisopropylether (10 mL) in a 16 mL vial. The reaction

D. Isaksson et al. / Tetrahedron: Asymmetry 17 (2006) 275–280
279
20
was started by addition of CAL-B (9.7 mg) and stirred
by putting the vial on a roller board. The conversion
was followed by GC analysis of samples withdrawn
every hour. Response factors (see 4.2) had to be
used in order to estimate the conversion of c,t-3 to 4.
After 2 h (ꢃ40% conversion), the lipase was removed
by filtration through a glass filter funnel. The filtrate
was concentrated and purified by flash chromatography
(R)-1]. ½aꢂD ¼ þ89:9 (c 2.27, EtOH). Similarly (+)-c,
t-3 was converted to (ꢀ)-cryptone [(ꢀ)-(S)-1].
20
20
½aꢂD ¼ ꢀ69:7 (c 1.85, EtOH) {lit.22: ½aꢂD ¼ ꢀ91:7 (c
2.2, EtOH)}. The spectroscopic data were identical to
that previously published.
4.3.7. Recycling of cryptone from rac-1 from c-2, c,c- and
t,t-3. Using Jones reagent as described under 4.3.6,
mixtures of c-2, c,c-3 and t,t-3 were oxidised. However
in this case, cryptone 1 did not form spontaneously.
Therefore, the reaction product was dissolved in THF
(100 mL) and water (40 mL) and triethylamine (1 mL)
was added. The mixture was left stirring overnight.
Et2O (50 mL) was added and the phases separated.
The water phase was extracted with Et2O (30 mL).
The combined organic phase was washed with brine
(20 mL) and dried over MgSO4, filtered and concen-
trated to furnish racemic cryptone rac-1.
to give ester 4 as a colourless oil (83 mg, 34.5%, 99.6%
20
pure by GC). ½aꢂD ¼ ꢀ29:7 (c 2.19, EtOH). 1H NMR: d
0.79 (3H, d, J = 6.9 Hz, CH3), 0.95 (3H, d, J = 7.0 Hz,
CH3), 1.1–1.3 (3H, m), 1.49 (1H, (app q) ddd J ꢁ 11.9,
11.9, 11.9), 1.79 (1H, m), 2.0 (4H, m), 2.28 (1H, m), 2.54
(1H, m), 2.93 (1H, (app dt) ddd, J = 3.8, ꢃ11.7, ꢃ11.8),
4.6 (1H, m), 7.27 (3H, m), 7.41 (2H, m). 13C NMR: d
15.12 (CH3), 21.30 (CH3), 21.31 (CH3), 22.12 (CH2),
27.18 (CH), 31.21 (CH2), 39.81 (CH2), 46.23 (CH),
48.05 (CH), 72.01 (CH), 127.29 (CH), 128.89 (2C,
CH), 133.16 (2C, CH), 133.96 (C), 170.38 (C@O). The
residual alcohol substrate (+)-c,t-3 from the resolution
above (113 mg), was subjected to a second resolution
step, see below.
Acknowledgements
We thank EU, Objective 1 the Region of South Forest
Counties And Mid Sweden University for financial sup-
port and Ms. Asa Ulander for technical assistance.
4.3.4.
(1R,3R,4S)-4-Isopropyl-3-(phenylsulfanyl)cyclo-
hexanol (ꢀ)-c,t-3. Acetate 4 (ꢃ83 mg) was refluxed
for 1 h in methanol (5 mL) containing aqueous NaOH
(1 M, 1 mL). After mixing with water (10 mL) and
Et2O (10 mL), the phases were separated. The organic
phase was then washed with brine (10 mL). The com-
bined aqueous phase was extracted with Et2O (5 mL).
The combined organic phase was dried over Na2SO4.
˚
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20
(ꢀ)-c,t-3 (58 mg, 82%, 99.4% (pure by GC), ½aꢂD
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ꢀ118 (c 1.94, EtOH), mp 103.3–104.2 ꢁC)
4.3.5.
(1S,3S,4R)-4-Isopropyl-3-(phenylsulfanyl)cyclo-
hexanol (+)-c,t-3. The residual alcohol substrate (+)-
c,t-3 from the resolution above (113 mg), 87.9% (pure
20
by GC), ½aꢂD ¼ þ56:0 (c 2.11, EtOH), was subjected to
a second resolution step with CAL-B and vinyl acetate
in an effort to improve both the enantiomeric and chemi-
cal purity. After 25% conversion (7 h) no further reac-
tion took place and the acetate was removed by flash
chromatography to furnish crystalline (+)-c,t-3, 63 mg,
20
56%, 92.7% (pure by GC), ½aꢂD ¼ þ104 (c 1.95
g/100 mL, EtOH), mp 91–93 ꢁC.
4.3.6. Formation of cryptone 1 from c,t-3 general
procedure. Jones reagent [267 g CrO3 dissolved in a
mixture of concd. H2SO4 (230 mL) and H2O (400 mL),
diluted to 1 L with water] was added dropwise to a solu-
tion of c,t-3 (47 mg, 0.19 mmol) in acetone (5 mL). After
the addition of 15 drops, the solution remained orange
and the reaction mixture was stirred for 10 min. Metha-
nol (0.5 mL) was added to quench the residual Jones re-
agent. The mixture was diluted with water (10 mL) and
Et2O (20 mL). The water phase was then extracted with
Et2O (2 · 5 mL). The combined organic phases were
washed with saturated Na2CO3 (5 mL) and brine
(5 mL) and dried over Na2SO4. Filtration followed by
concentration of the filtrate and flash chromatography
provided cryptone 1 (22.4 mg, 86%). Using the same
procedure (ꢀ)-c,t-3 was converted to (+)-cryptone [(+)-
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