Stereoselective synthesis of optically active cyclitol precursors via a chemoenzymatic method

Article abstract of DOI:10.1016/j.tetasy.2006.11.002

Racemic α′-acetoxy α,β-unsaturated cyclohexanone has been converted to the corresponding enantiomerically enriched α′-hydroxylated and acetoxylated compounds with 97% ee via enzymatic resolution with PLE. OsO₄-Catalyzed dihydroxylation of enant

Full text of DOI:10.1016/j.tetasy.2006.11.002

Tetrahedron: Asymmetry 17 (2006) 3004–3009
Stereoselective synthesis of optically active cyclitol precursors
via a chemoenzymatic method
Funda Og˘uzkaya,a Ertan Sahinb and Cihangir Tanyelia,*
ß
aDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
bDepartment of Chemistry, Atatu¨rk University, 25240 Erzurum, Turkey
Received 11 October 2006; revised 1 November 2006; accepted 2 November 2006
Available online 28 November 2006
Abstract—Racemic a0-acetoxy a,b-unsaturated cyclohexanone has been converted to the corresponding enantiomerically enriched
a0-hydroxylated and acetoxylated compounds with 97% ee via enzymatic resolution with PLE. OsO4-Catalyzed dihydroxylation of
enantiomerically enriched a0-acetoxylated compound afforded a single diastereomer in 85% chemical yield. The absolute configuration
of 2,3,6-triacetoxycylohexanone was determined by X-ray diffraction analysis. Subsequent Luche reduction allowed us to obtain corre-
sponding syn-type cyclitol precursors in a highly stereoselective manner as expected.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
access to cyclitols.10 Additionally, enzymatic resolution of
a hydroxyl group in the presence of an endoperoxide func-
tionality reported by Balcı and Tanyeli et al. provides enan-
tiomerically enriched cyclopentol derivatives.11
Polyhydroxylated cyclohexanes and their derivatives are
widespread constituents of biologically important com-
pounds, the most obvious instances being cyclitols,1 espe-
cially inositols.2 Carbasugars,3 carbacyclic analogues of
sugars first synthesized by McCasland et al.,4 with their
ability to function as glycosidase inhibitors, have potential
in many therapeutic areas. Polyhydroxylated cyclohexane
rings are also found in the amaryllidaceae family of natural
products, most notably pancratistatin, lycoridine and
narciclasine and their relatives.5 Cyclitols have attracted a
great deal of attention from synthetic chemists due to their
diverse biological activity and their versatility as synthetic
intermediates.6 Various methodologies have been devel-
oped for the synthesis of enantiopure cyclitols and their
derivatives. Recently, the synthesis of enantiopure cyclitols
was achieved via the transformation of other cyclitols.7 The
microbial oxidation of halobenzenes was employed by
Hudlickly et al. in the preparation of inositols.8 The Fer-
rier-II rearrangement and the free radical cyclization9 of
sugar derivatives are also useful methods developed by
Ikegami and Yadav et al., respectively. Furthermore, the
reduction of allylsilanes in combination with asymmetric
dihydroxylation reported by Landais et al. provides an easy
In connection with our work on the development of
novel procedures for the direct oxidation of a,b-unsatu-
12
rated cyclic ketones with Mn(OAc)3 in the synthesis of
( )-6-acetoxy-2-cyclohexen-1-one rac-1 and subsequent
PLE catalyzed enzymatic resolution into enantiomerically
enriched forms,13 we herein report the results of OsO4 cat-
alyzed dihydroxylation and then Luche reduction of the
corresponding ketones to obtain structurally very diverse
cyclitol precursors.
2. Results and discussion
2.1. Enzymatic hydrolysis of racemic substrate 1
The bioconversion of rac-1 was performed using PLE
according to the following procedure, which has already
been developed in our group (Scheme 1). To a stirred solu-
tion of rac-1 (9.1 mmol) in a phosphate buffer (pH 7.00,
50 mL), PLE (100 lL) was added in one portion and the
reaction mixture stirred at room temperature in a pH stat
unit. The conversion was monitored by TLC. After 8 h,
(S)-(ꢀ)-6-acetoxy-2-cyclohexen-1-one (S)-1 was obtained
with 97% ee in 49% chemical yield.
*
Corresponding author. Tel.: +90 312 210 3222; fax: +90 312 210 3200;
e-mail: tanyeli@metu.edu.tr
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.002

F. Og˘uzkaya et al. / Tetrahedron: Asymmetry 17 (2006) 3004–3009
3005
to stir for 26 h at ꢀ5 ꢁC until all the starting material had
been used. NaHSO3 (6.64 mmol), florosil (0.076 mol) and
H2O (0.465 mol) were also added and the resulting solution
allowed to stir for 12 h. The conversion was monitored by
TLC. The pH of the reaction mixture was adjusted to 2 by
using 1 M HCl and compound 3 was obtained as a single
diastereomer. This unusual diastereoselectivity is presum-
ably comes from a possible coordination of the a0-acetoxy
group to the OsO4 to afford a syn-dihydroxylation reaction.
Due to isolation problem, compound 3 was acetylated
in situ and (ꢀ)-4 was obtained in 85% chemical yield. By
adjusting the same process to (R)-(+)-6-acetoxy-2-cyclo-
hexen-1-one (R)-1, the corresponding diol ent-3 was also
obtained. Subsequent acetylation afforded (+)-4 in 81%
chemical yield (Scheme 2).
O
O
O
OAc
OAc
OH
PLE
pH7
phosphate buffer
(S
)-1
97%ee
(R)-2
rac-1
AcCl
pyridine
O
OAc
(
R
)-1
The absolute configuration of (ꢀ)-4 was determined by
X-ray analysis as (1R,2R,4S)-3-oxocyclohexane-1,2,4-triyl
triacetate. The absolute configurations of new stereogenic
centres formed, C1 and C2, were determined relatively by
taking the C4 centre as the reference point (Figs. 1 and 2).
92%ee
Scheme 1.
In our previous work,13 we showed that 6-hydroxy-2-
cyclohexen-1-one (R)-2 could not be isolated due to the
racemization and/or rearrangement of a0-hydroxylated
cyclic enones. With this in mind, substrate (R)-2 was imme-
diately subjected to acetylation to afford the corresponding
(R)-(+)-6-acetoxy-2-cyclohexen-1-one (R)-1 with 92% ee in
44% chemical yield.
2.2. Upjohn dihydroxylation of substrates (S)-1 and (R)-1
Osmium-catalyzed oxidation reaction is one of the most
useful methods for the dihydroxylation of olefins so as to
give the corresponding diols. The oxidation proceeds in
the presence of a catalytic amount of OsO4 with a cooxi-
dant, such as N-methylmorpholine N-oxide (Upjohn proce-
dure).14 The first dihydroxylation was performed with
substrate (S)-1 using OsO4 and NMO prepared in situ
according to the following general procedure. 4-Methyl-
morpholine-N-oxide monohydrate 97% (4.94 mmol) was
dissolved in H2O (0.23 mol) under inert atmosphere. The
temperature was adjusted to ꢀ5 ꢁC, then, 14.07 mL OsO4
(100 mg/40 mL) stock solution was added to the medium
including (S)-1 (4.46 mmol) in acetone and dissolved
NMO solution was slowly added. The mixture was allowed
Figure 1. The molecular structure of (1R,2R,4S)-3-oxocyclohexane-1,2,4-
triyl triacetate (ꢀ)-4. Displacement ellipsoids are plotted at the 50%
˚
probability level. Selected bond lengths (A) and angles (ꢁ): C3–O5
1.203(4), C2–C3 1.512(3), C1–C2 1.528(3), C4–O6 1.430(3), C2–O4
1.429(3), O1–C11 1.194(3), O4–C2–C3 108.09(9), C2–C3–O5 124.38(10),
C3–C4–C5 111.35(12), C2–C1–O3 107.45(10).
O
O
O
OsO4, NMO
acetone
OAc
HO
OAc
AcCl
AcO
AcO
OAc
pyridine
HO
(
S
)-1
3
4
(-)-
O
O
O
OsO4, NMO
acetone
OAc
HO
HO
OAc
AcO
AcO
OAc
AcCl
pyridine
ent-3
4
(+)-
(R
)-1
Scheme 2.

3006
F. Og˘uzkaya et al. / Tetrahedron: Asymmetry 17 (2006) 3004–3009
Figure 2. View of intermolecular C–Hꢁ ꢁ ꢁO bonds and molecular packing through a-axis in compound (1R,2R,4S)-3-oxocyclohexane-1,2,4-triyl triacetate
a
b
1
2
1
1
2
(ꢀ)-4. [C10–Hꢁ ꢁ ꢁO1 , (a) 12 þ x; ꢀ y; z; Dꢁ ꢁ ꢁA = 3.314(5) A, D–Hꢁ ꢁ ꢁA = 146ꢁ; C8–Hꢁ ꢁ ꢁO2 , (b) 2 þ ꢀx; y; þ z; Dꢁ ꢁ ꢁA = 3.346(5) A, D–Hꢁ ꢁ ꢁA = 136ꢁ].
˚
˚
2.3. Luche reduction of substrates (ꢀ)-4 and (+)-4
triacetate (+)-4, single diastereomer in the absolute config-
uration of (1S,2R,3R,4R)-3-hydroxycyclohexane-1,2,4-triyl
triacetate (+)-5 was obtained in 80% chemical yield.
Luche reduction of compound (ꢀ)-4 gave compound (ꢀ)-5
as a single diastereomer in 82% chemical yield. The reduc-
tion was performed according to the following general
procedure. To a cooled solution, ꢀ78 ꢁC, of (1R,2R,4S)-
3-oxocyclohexane-1,2,4-triyl triacetate (ꢀ)-4 (0.4 mmol) in
methanol (0.1 mol), NaBH4 (0.4 mmol). and CeCl3Æ7H2O
(0.4 mmol) were added and allowed to stir. After 3 h, the
reaction was quenched with H2O (0.17 mol). The corre-
sponding product (ꢀ)-5 was obtained in 82% chemical
yield (Scheme 3). Due to identification problems, protec-
tion via direct acetylation was performed to assign clearly
the configuration of compound (ꢀ)-5 and the formation
of the resulting meso-6 in 84% chemical yield estimated that
such reduction provided us only a single diastereomer in
the absolute configuration of (1R,2S,3S,4S)-3-hydroxy-
cyclohexane-1,2,4-triyl triacetate (ꢀ)-5. By applying the
same process for (1S,2S,4R)-3-oxocyclohexane-1,2,4-triyl
3. Conclusion
Herein, we have improved the direct stereoselective dihydr-
oxylation of enantiomerically enriched a0-acetoxy a,b-
unsaturated cyclohexanones (S)-1 and (R)-1 using OsO4
and NMO in good yields, and have shown that six-mem-
bered enone afforded only syn-diastereomer 3 from (S)-1
and ent-3 from (R)-1. The absolute configuration of
(1R,2R,4S)-(ꢀ)-4 was determined by X-ray analysis. The
enantiomer (1S,2S,4R)-(+)-4 was also obtained by OsO4
catalyzed dihydroxylation reaction and subsequent protec-
tion and findings confirmed the results obtained in the
first set of experiments. Subsequent Luche reduction of
compounds (ꢀ)-4 and (+)-4 allowed structurally very diverse
O
OH
OAc
OAc
AcO
AcO
NaBH4
OAc
OAc
AcO
AcO
AcO
AcO
AcCl
CeCl3.7H2O
pyridine
(-)-4
meso-6
(-)-5
O
OAc
OH
AcO
AcO
OAc
OAc
OAc
AcO
AcO
NaBH4
AcO
AcO
AcCl
CeCl3.7H2O
pyridine
(+)-4
(+)-5
meso-6
Scheme 3.

F. Og˘uzkaya et al. / Tetrahedron: Asymmetry 17 (2006) 3004–3009
3007
syn-type cyclitol precursors (1R,2S,3S,4S)-3-hydroxycyclo-
hexane-1,2,4-triyl triacetate (ꢀ)-5 and (1S,2R,3R,4R)-3-
hydroxycyclohexane-1,2,4-triyl triacetate (+)-5 to be obtained
respectively.
under argon atmosphere. The temperature of (S)-(ꢀ)-6-
acetoxy-2-cyclohexen-1-one (S)-(ꢀ)-1 (0.690 g, 4.46 mmol)
was adjusted to ꢀ5 ꢁC and dry acetone (9.9 g, 0.062 mol)
was added. NMO was allowed to dissolve completely in
water. Then, 14.07 mL OsO4 (100 mg/40 mL) stock solu-
tion was added to the medium including (S)-(ꢀ)-6-acet-
oxy-2-cyclohexen-1-one (S)-(ꢀ)-1 in acetone and the
subsequent dissolved NMO solution was slowly added.
The mixture was allowed to stir for 26 h at ꢀ5 ꢁC by
TLC monitoring. After the required conversion was
obtained, NaHSO3 (0.690 g, 6.64 mmol), florosil (4.29 g,
0.076 mol) and H2O (8.37 g, 0.465 mol) were also added
and allowed the resulting solution to stir for additional
12 h. The pH of the reaction mixture was adjusted to 2
by using 1 M HCl. The solution was diluted with an equal
amount of ethyl acetate and the organic phase was dried
over MgSO4 and evaporated in vacuo. The product was
purified by flash column chromatography (EtOAc/hexane,
1:3) and the corresponding diol 3 was obtained (0.630 g,
75% chemical yield).
4. Experimental
1
The H and 13C NMR spectra were recorded in CDCl3 on
a Brucker Spectrospin Avance DPX 400 spectrometer.
Chemical shifts are given in parts per million downfield
from tetramethylsilane. Apparent splittings are given in
all cases. Infrared spectra were obtained from KBr pellets
on a Mattson 1000 FT-IR spectrophotometer. Optical
rotations were measured in a 1 dm cell using a Rudolph
Research Analytical Autopol III polarimeter at 20 ꢁC.
HPLC measurements were performed with Thermo-
Finnigan Spectra System instrument. Separations were
carried out on Chiralcel OD-H analytical column
(250 · 4.60 mm) with hexane/2-propyl alcohol as eluent.
Column chromatography was performed on silica gel
(60-mesh, Merck). TLC was carried out on Merck 0.2-
mm silica gel 60 F254 analytical aluminium plates. PLE
(Pig Liver Esterase) was purchased from Sigma as a
suspension in ammonium sulfate solution (3.2 mol/L).
By adjusting the same process to (R)-(+)-6-acetoxy-2-
cyclohexen-1-one (R)-(+)-1, corresponding diol ent-3
(0.175 g, 72% chemical yield) was obtained. The corre-
sponding diols were subjected to acetylation. Compound
3 (0.630 g, 3.35 mmol), was mixed with (1.32 g, 13.4 mol)
dry pyridine in CH2Cl2 (25 mL) under an inert atmosphere,
at 0 ꢁC for 1/2 h. Then, acetylchloride (0.79 g, 10.1 mol)
was added and mixed for 16 h at room temperature. The
organic phase was extracted with 0.1 M HCl (3 · 20 mL),
NaHCO3 (3 · 20 mL), brine (3 · 20 mL), respectively, then
dried over MgSO4, filtrated and evaporated. The crude
product was separated by flash column chromatography
using ethyl acetate/hexane (1:2) as the eluent to afford
(1R,2R,4S)-3-oxocyclohexane-1,2,4-triyl triacetate (ꢀ)-4
(0.780 g, 85%). (1S,2S,4R)-3-Oxocyclohexane-1,2,4-triyl
triacetate (+)-4 (0.205 g, 81%) was also obtained by apply-
ing the same procedure.
4.1. General procedure for the enzymatic hydrolysis of rac-1
To a stirred solution of (1.4 g, 9.1 mmol) rac-1, in 50 mL of
pH 7.00 phosphate buffer, 100 lL PLE was added in one
portion and the reaction mixture stirred at 20 ꢁC in a pH stat
unit. The conversion was monitored by TLC. The reaction
mixture were extracted with ethyl acetate, dried over MgSO4
and concentrated under reduced pressure. The product was
purified by flash column chromatography (EtOAc/hexane,
1:3). Compound (S)-(ꢀ)-1 was isolated and is in accordance
with the literature data.13 The isolated product (R)-2 was
directly subjected to an acetylation reaction to prevent its
complete racemization. To a stirred solution of (R)-2
(0.191 g, 1.71 mmol) in CH2Cl2 (25 mL), dry pyridine
(0.268 g, 3.39 mmol) was added at 0 ꢁC and stirred for
30 min. Acetylchloride (0.202 g, 2.56 mmol) was then added
dropwise. The resultant mixture was stirred for 12 h at room
temperature. The organic phase was extracted with 0.1 M
HCl (3 · 20 mL), saturated NaHCO3 (3 · 20 mL) and brine
(2 · 20 mL), dried over MgSO4 and the solvent was
evaporated under reduced pressure to afford quantitatively
(R)-(+)-1. All are in accordance with the literature data.13
4.2.1. (1S,3R,4R)-3,4-Dihydroxy-2-oxocyclohexyl acetate
5.19 (dd, J = 6.8 and
3. 1H NMR (CDCl3):
d
J = 12.2 Hz, 1H), 4.32 (br s, 1H), 4.23 (br s, 1H), 3.72
(br s, 1H), 2.60 (br s, 1H), 2.14–2.15 (m, 2H), 2.11 (s,
3H), 1.80–1.86 (m, 2H).
4.2.2. (1R,2R,4S)-3-Oxocyclohexane-1,2,4-triyl triacetate
(ꢀ)-4. (0.780 g, 85% yield) as white crystals, mp: 104–
20
1
106 ꢁC; ½aꢂD ¼ ꢀ7:25 (c 0.02, CHCl3). H NMR (CDCl3):
d 5.65 (br s, 1H), 5.41 (d, J = 3.3 Hz, 1H), 5.34 (dd,
J = 4.9 and J = 6.8 Hz, 1H), 2.17–2.24 (m, 2H), 2.19 (s,
3H), 2.16 (s, 3H), 2.10 (s, 3H), 1.91–2.16 (m, 2H). 13C
NMR (CDCl3): d 195.8, 169.8, 160.5, 169.4, 75.4, 74.5,
72.3, 26.8, 25.0, 20.8, 20.5, 20.4.
4.1.1.
(S)-(ꢀ)-6-Acetoxy-2-cyclohexenone
(S)-(ꢀ)-1.
20
(0.690 g, 49%) as a colourless oil; 97% ee ½aꢂD ¼ ꢀ88:7 (c
0.5, MeOH).
4.1.2.
(R)-(+)-6-Acetoxy-2-cyclohexenone
(R)-(+)-1.
20
(0.116 g, 44%) as a colourless oil; 92% ee, ½aꢂD ¼ þ84:2
4.2.3. (1S,2S,4R)-3-Oxocyclohexane-1,2,4-triyl triacetate
¼
20
(c 0.5, MeOH).
(+)-4. (0.205 g, 81% yield) as white crystals; ½aꢂD
þ6:75 (c 0.02, CHCl3).
4.2. General procedure for the dihydroxylation of (S)-(ꢀ)-1
and (R)-(+)-1
4.3. General procedure for the reduction of (ꢀ)-4 and (+)-4
4-Methylmorpholine-N-oxide monohydrate 97% (0.668 g,
4.94 mmol) was dissolved in H2O (4.19 mL, 0.23 mol)
To a cooled solution, ꢀ78 ꢁC of (1R,2R,4S)-3-oxocyclo-
hexane-1,2,4-triyl triacetate (ꢀ)-4 (0.109 g, 0.4 mmol) in

3008
F. Og˘uzkaya et al. / Tetrahedron: Asymmetry 17 (2006) 3004–3009
methanol (4.04 mL, 0.1 mol), NaBH4 (0.016 g, 0.4 mmol)
and CeCl3Æ7H2O (0.156 g, 0.4 mmol) were added and
allowed to stir for 3 h. The reaction was quenched with
H2O (3 mL, 0.17 mol), and then diluted with the equal
amount of Et2O, washed with brine and dried over MgSO4,
filtrated and evaporated. The crude product was separated
by flash column chromatography using ethyl acetate/
hexane (1:2) to afford compound (1R,2S,3S,4S)-3-hydroxy-
parameters: 4048/0/179; goodness-of-fit on F2: 1.557; final
R indices [I > 2r(I)]: R1 = 0.094, wR2 = 0.120; R indices
(all data): R1=0.113, wR2 = 0.135; extinction coefficieꢀn3t:
˚
0.0003; largest diff. peak and hole: 0.232 and ꢀ0.162 e A
.
Crystallographic data (excluding structure factors) for the
structure of (ꢀ)-4 in this paper have been deposited with
the Cambridge Crystallographic Data Center as supple-
mentary publication number CCDC 622254. Copies of
the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
cyclohexane-1,2,4-triyl triacetate (ꢀ)-5 in 82% chemical
25
yield; ½aꢂD ¼ ꢀ1:3 (c 0.02, CHCl3). Compound (+)-5 was
25
obtained in 80% chemical yield; ½aꢂD ¼ þ1:1 (c 0.02,
CHCl3). Compound (ꢀ)-5 (0.089 g, 0.3 mmol) was mixed
with dry pyridine (0.048 g, 0.6 mmol) in 25 mL CH2Cl2
under inert atmosphere, at 0 ꢁC for 1/2 h. Then, acetylchlo-
ride (0.036 g, 0.5 mol) was added and mixed for 5 h at
room temperature. The organic phase was extracted with
0.1 M HCl (3 · 20 mL), NaHCO3 (3 · 20 mL), brine
(3 · 20 mL), respectively, dried over MgSO4, filtrated and
evaporated. The crude product was separated by flash
column chromatography using ethyl acetate/hexane (1:2)
as eluent to afford (1R,2R,3S,4S)-cyclohexane-1,2,3,4-
tetrayl tetraacetate meso-6 (0.088 g, 87%).
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4.3.1. (1R,2R,3S,4S)-Cyclohexane-1,2,3,4-tetrayl tetra-
acetate meso-6. (0.088 g, 87% yield) as a yellowish liquid;
25
1
½aꢂD ¼ 0 (c 0.02, CHCl3); H NMR (CDCl3): d 5.97 (br s,
2H), 5.22 (m, 2H), 2.08 (s, 6H), 2.07 (s, 6H), 1.65–1.78
(m, 4H). 13C NMR (CDCl3): d 169.9, 69.0, 68.4, 22.9,
20.9, 20.7.
4.4. X-ray structure analysis
For the crystal structure determination, a single crystal of
compound C12H16O7 (ꢀ)-4 was used for data collection
on a four-circle Rigaku R-AXIS RAPID-S diffractometer
equipped with a two-dimensional area IP detector.
The graphite-monochromatized MoKa radiation (k =
˚
0.71073 A) and oscillation scans technique with Dx = 5ꢁ
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for one image were used for data collection. Image for
(ꢀ)-4 was taken successfully by varying x with three sets
of different v and / values. For each compounds the 108
images for six different runs covering about 99.8% of the
Ewald spheres were performed. The lattice parameters were
determined by the least-squares methods on the basis of all
reflections with F2 > 2r(F2). Integration of the intensities,
correction for Lorentz and polarization effects and cell
refinement was performed using CrystalClear software.15
The structures were solved by direct methods (SHELXS-
97)16 and non-H atoms were refined by full-matrix least-
squares method with anisotropic temperature factors
(SHELXL-97).16
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4.5. Crystal data for compound (ꢀ)-4
C12H16O7, crystal system, space group: orthorhombic,
Pcab; (no: 61); unit cell dimensions: a = 9.6841(8),
˚
b = 12.3287(9), c = 22.2173(9) A, b = 90ꢁ; volume:
3
2652.58(2) A ; Z = 8; calculated density: 1.36 mg/m3;
˚
absorption coefficient: 0.113 mmꢀ1; F(000): 1152; crystal
size: 0.025 · 0.018 · 0.014 mm3; h range for data collection
2.8–30.6ꢁ; completeness to h: 30.6ꢁ, 99.8%; refinement
method: full-matrix least-square on F2; data/restraints/
9. Yadav, J. S.; Maiti, A.; Sankar, A. R.; Kunwar, A. C. J. Org.
Chem. 2001, 66, 8370–8378.

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Asymmetry 2004, 15, 1729–1733.
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