Stereoselective synthesis of highly oxygenated cyclohexanes through a [3+3] annulation approach

Article abstract of DOI:10.1016/S0957-4166(00)00429-8

The synthesis of highly oxygenated cyclohexanes has been achieved through a Michael-Wittig protocol via a [3+3] annulation of the enal that is derived from 2,3-O-isopropylidene-(R)-glyceraldehyde. The γ-alkoxy enal system is responsible for the stereosele

Full text of DOI:10.1016/S0957-4166(00)00429-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4499–4507
Stereoselective synthesis of highly oxygenated cyclohexanes
through a [3+3] annulation approach†
G. V. M. Sharma,a,* T. Rajendra Prasad,a Palakodety Radha Krishna,a K. Krishnudu,a
M. H. V. Ramana Raob and A. C. Kunwarb
aDiscovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
bNMR Group, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 August 2000; accepted 16 October 2000
Abstract
The synthesis of highly oxygenated cyclohexanes has been achieved through a Michael–Wittig protocol
via a [3+3] annulation of the enal that is derived from 2,3-O-isopropylidene-(R)-glyceraldehyde. The
g-alkoxy enal system is responsible for the stereoselectivity. © 2000 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Highly functionalised cyclohexanes are useful intermediates for the synthesis of natural
products. Oxygenated cyclohexane derivatives,1,2 the pseudo sugars,3,4 are fragments5 of several
bioactive natural products such as antibiotics, enzyme inhibitors, etc., which play a vital role in
life processes. Because of the major significance of cyclohexane derivatives, several strategies have
been devised1,6 for their synthesis. In an attempt to develop simple methods for the synthesis of
functionalised cyclohexane derivatives, which could be precursors to plant growth regulators7 and
others, we describe herein a stereoselective [3+3] annulation protocol for the synthesis of 1–3 by
a Michael–Wittig reaction on the enal derived from 2,3-O-isopropylidene-(R)-glyceraldehyde.
* Corresponding author. E-mail: esmvee@iict.ap.nic.in
†
IICT Communication No. 4610.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00429-8

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2. Results and discussion
Michael addition8 of nucleophiles to a,b-unsaturated carbonyl ‘acceptors’, especially those
bearing a stereogenic oxygen substituted centre in the g-position, to obtain enantiomerically
pure products is a very useful tool in organic synthesis. From retrosynthetic analysis (Scheme 1)
it was envisaged that a [3+3] annulation on a chiral acceptor, through an initial Michael
addition followed by a Wittig reaction of the adduct, would result in the formation of
cyclohexenone derivatives. Thus, in the present study, enal 5, derived from 2,3-O-isoprop-
ylidene-(R)-glyceraldehyde 6, and ethyl 3-oxo(triphenylphosphorylidene)butanoate 79,10 are
chosen as appropriate synthons for performing the Michael–Wittig reaction en route to the
synthesis of 1–3 through the late stage intermediate 4, wherein the chirality is induced from the
g-alkoxy stereocentre of enal 5.
Scheme 1.
Accordingly, ester 9, prepared from 6 (Scheme 2), was reduced with DIBAL-H to the
corresponding alcohol 10,11 which on PDC oxidation gave enal 5 (72% yield). The crucial [3+3]
annulation reaction of 5 with ylide 7 in the presence of NaH in THF containing two drops of
water9 at 50°C for 15 min resulted in the formation of 4 and 11 (68%) as a keto–enol mixture,
1
as was evident from the H NMR spectrum (Scheme 3).
The keto–enol mixture containing 4 and 11 was subjected to reduction with CeCl3–
NaBH4·7H2O in ethanol to afford a chromatographically (silica gel, 1:1 ethyl acetate:pet. ether)
separable mixture of alcohols 12, 13 and 14 in a 2:1:1.5 ratio, respectively. The formation of the
Scheme 2. Reagents: (a) Ph3PꢀCHCO2Et, MeOH, rt; (b) DIBAL-H, CH2Cl2; (c) PDC, CH2Cl2; (d)
Ph3PꢀCHCOCH2CO2Et, NaH, THF, two drops of water, 50°C

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 11 (2000) 4499–4507
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Scheme 3. Reagents: (a) CeCl3·7H2O, NaBH4, EtOH; (b) Ac2O, pyridine; (c) OsO4, NMO, acetone:water (3:1)
isomer 14 could be attributed to the epimerisation at H-1 followed by reduction under the
aforementioned reaction conditions. The carbinols 12–14, independently on reaction with
Ac2O–pyridine, were converted into the corresponding acetates 15, 16 and 17, respectively. The
structures of these compounds were unambiguously determined based on spectroscopic analysis.
Finally, stereoselective cis-hydroxylation of olefins in 15–17 was achieved by osmylation
(OsO4, NMO) to afford the diols 18, 19 and 20 with complete diastereocontrol,12,13 i.e. anti
relative to the adjacent -OAc group. The diols 18–20 were converted under standard reaction
conditions (Ac2O, pyridine) to the triacetates 1, 2 and 3, whose structures were thoroughly
established from spectroscopic analysis (Fig. 1).
The six-membered ring in 1 adopts a chair conformation (6C3) such that both the bulky
substituents are equatorial. Couplings are consistent with the structure shown in Fig. 1. This is
further supported by NOESY cross peaks H6ꢁH4, H6ꢁH5%b and H1ꢁH4%. The five-membered
ring exists in a twist conformation, consistent with the 3J4%,5%a, 3J4%,5%b and NOESY cross peaks
methyl (A)-H5%a, methyl (A)-H4% and methyl (B)-H5%b. NOESY cross peaks H6ꢁH5%b and
H1ꢁH4%, as well as J6,4 2.9 Hz, imply a single conformation about C6ꢁC4% with a
H6ꢁC6ꢁC4%ꢁH4% dihedral angle of about −110°.
6
For 2, the six-membered ring is in C3 chair conformation, with all the substituents in
equatorial positions except for the C-4 acyl group. NOESY experiments also show diaxial
disposition of protons H2ꢁH6, H5axꢁH3, H1ꢁH5ax and H1ꢁH3. The dihedral angle
H6ꢁC6ꢁC5ꢁH4%, as well as the five-membered ring conformation, is very similar to that of 1.
6
For molecule 3 in the C3 chair conformation, the five-membered ring is equatorial, while the
-CO2Et group adopts an axial position. The NOESY experiments show diaxial proximities of
H2ꢁH6 and H5aꢁH3. The five-membered ring adopts a conformation similar to that of 1 and
2. NOE cross peaks H6ꢁH5%b, H1ꢁH4% and H1ꢁH5%a and J6,4 7.6 Hz are consistent with a
dihedral angle H6ꢁC6ꢁC4%ꢁH4% of about −150°.

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G. V. M. Sharma et al. / Tetrahedron: Asymmetry 11 (2000) 4499–4507
Figure 1.
The configuration and conformational studies of the six-membered rings deduced in the
present work are identical to those observed in our earlier work.14 Interestingly the yields also
follow the same pattern.
Taking advantage of the existing stereocentre of the three-carbon synthon, the enal, derived
from 2,3-O-isopropylidene-(R)-glyceraldehyde, a Michael–Wittig protocol has been adopted for
the construction of a homochiral cyclohexene system en route to the synthesis of highly
functionalised cyclohexane derivatives. Since the two components of the [3+3] annulation viz.
the enal and the phosphonium salt are simple and easily accessible starting materials, the present
protocol should find wide use in the construction of carbocycles. Utilisation of the present
strategy for the synthesis of related bioactive carbocycles is in progress.
3. Experimental
1
Solvents were dried over standard drying agents and freshly distilled prior to use. H NMR
(200 MHz, 500 MHz) and 13C NMR (50 MHz, 125 MHz) spectra were recorded in deuteriochlo-
roform solution with tetramethylsilane as an internal reference on Varian Gemini-200 MHz and
INOVA-500 MHz spectrometers and J values are given in Hz. Optical rotations were measured
with a Jasco DIP-370 instrument and [h]D values are in units of 10−1 deg cm2 g−1. Organic
solutions were dried over anhydrous Na2SO4 and concentrated below 40°C in vacuo. HRMS
were recorded on a V G Autospec mass spectrometer at 5 or 7 K resolution using perfluoro
kerosene as an internal reference.

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 11 (2000) 4499–4507
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3.1. 3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-(Z)-propenal 5
A solution of alcohol 10 (7.5 g, 47.4 mmol) in dry CH2Cl2 (80 mL) was treated with PDC
(26.94 g, 71.5 mmol) and heated at reflux for 2 h. The reaction mixture was brought to room
temperature, CH2Cl2 was removed under reduced pressure and the residue was filtered through
a silica gel bed using ether as eluent. Evaporation of solvent gave the enal 5 (4.8 g) in 65% yield
1
as a syrup, which was used as such for further reaction. [h]D=−33.75 (c 1.0, CHCl3); H NMR
(200 MHz, CDCl3): l 1.42, 1.45 (2s, 6H, CH3), 3.75 (t, 1H, J5%a,5%b 10.5, J4%,5%b 6.6 Hz, H-5%a), 4.25
(t, 1H, J4%,5%b 9.9 Hz, H-5%b), 4.80 (m, 1H, H-4%), 6.35 (dd, 1H, J2,3 16.5, J1,2 5.5 Hz, H-2), 6.78
(dd, 1H, J3,4% 5.5 Hz, H-3), 9.60 (d, 1H, H-1).
3.2. Michael–Wittig reaction on 5
A suspension of NaH (1.35 g, 58.9 mmol; 60% dispersion in mineral oil) was added to a
stirred solution of the above enal 5 (4.6 g, 29.4 mmol) and ylide 7 (15.27 g, 32.4 mmol) in dry
THF (70 mL) at 50°C under nitrogen followed by two drops of water and stirred for 15 min at
the same temperature. The reaction mixture was brought to room temperature, acidified by
adding a 5% aq. HCl solution (pH 6) and extracted with ether (3×50 mL). The combined ether
layers were washed with water (50 mL) and brine (50 mL) and dried (Na2SO4). Evaporation of
solvent under reduced pressure and purification of the residue by column chromatography (finer
than 200 mesh, Si-gel, ethyl acetate:pet. ether, 1:5) gave a keto–enol mixture, ethyl 6-[(4S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-2-oxo-(1S,6R)-3-cyclohexene-1-carboxylate 4 and ethyl 6-[(4S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-2-oxo-(1R,6R)-3-cyclohexene-1-carboxylate 11 (5.4 g) in 68% yield
1
as a syrup. H NMR (200 MHz, CDCl3): l 1.20–1.54 (m, 9H, CH3), 2.02–2.82 (m, 3H,
H-5a,5b,6), 3.35 (d, 1H, J1,6 9.6 Hz, H-1 of keto form), 3.60–3.80 (m, 2H, H-4%a, 5%a), 3.95–4.32
(m, 3H, H-5%b, -OCH2CH3), 6.02–6.15 (m, 1H, H-3), 6.95–7.08 (m, 1H, H-4), 12.33 (s, 1H, OH
of enolic form); EIMS (%): 253 (M+−15; 55), 167 (38), 121 (83), 101 (73), 43 (100); EI-HRMS:
calcd for C13H17O5 (M+−15): 253.107599, found: 253.108181.
3.3. Reduction of keto–enol mixture 4 and 11
To a stirred solution of 4 and 11 (3 g, 11.2 mmol) and CeCl3·7H2O (4.5 g, 12.3 mmol) in
ethanol (25 mL), sodium borohydride (0.82 g, 22.3 mmol) was added portionwise at 0°C. The
reaction mixture was brought to room temperature and stirred for 1 h. Ethanol was removed
under reduced pressure, the reaction mixture diluted with water (50 mL) and extracted with
ether (3×50 mL). The combined ether layers were washed with water (50 mL), brine (50 mL) and
dried (Na2SO4). Solvent was evaporated under reduced pressure and the resulting residue was
purified by column chromatography (finer than 200 mesh Si-gel, ethyl acetate:pet. ether 1:4) to
give 12, 13 and 14 in 2:1:1.5 ratio.
First eluted was ethyl 6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-(1S,2R,6R)-3-cyclo-
1
hexene-1-carboxylate 12 (0.98 g) in 33.4% yield as a syrup. [h]D=−152.0 (c 0.5, CHCl3); H
NMR (200 MHz,CDCl3): l 1.22–1.42 (m, 9H, CH3), 2.20–2.32 (m, 3H, H-5a,5b,6), 2.84 (t, 1H,
J1,6 4.2, J1,2 4.1 Hz, H-1), 3.60 (t, 1H, J4%,5% 6.1, J5a%,5b% 7.3 Hz, H-5%a), 4.08–4.30 (m, 3H, H-5%b,
-OCH2CH3), 4.30–4.48 (m, 2H, H-2,4%), 5.69–5.89 (m, 2H, H-3,4); EIMS (%): 255 (M+−15; 10),
195 (26), 121 (23), 101 (23), 79 (45), 43 (100).

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Second eluted was ethyl 6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-(1S,2S,6R)-3-
1
cyclohexene-1-carboxylate 13 (0.485 g) in 16.5% yield as a syrup. [h]D=−4.8 (c 1.5, CHCl3); H
NMR (200 MHz,CDCl3): l 1.20–1.45 (m, 9H, CH3), 2.00–2.20 (m, 3H, H-5a,5b,6), 2.42 (t, 1H,
J1,2 8.9, J1,6 9.2 Hz, H-1), 3.56 (t, 1H, J5a%,5b% 8.7, J4%,5b% 7.6 Hz, H-5%a), 3.88 (t, 1H, J4%,6 8.2 Hz,
H-4), 3.92–4.18 (m, 1H, H-5%b), 4.20 (q, 2H, J 7.2 Hz, -OCH2CH3), 4.35–4.49 (m, 1H, H-2),
5.60–5.82 (m, 2H, H-3,4); EIMS (%): 255 (M+−15; 12), 149 (38), 101 (86), 79 (32), 43 (100);
EI-HRMS: calcd for C13H19O5 (M+−15): 255.123249, found: 255.122625.
Third eluted was ethyl 6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-(1R,2S,6R)-3-cyclo-
1
hexene-1-carboxylate 14 (0.735 g) in 25% yield as a syrup. [h]D=−148.2 (c 0.9, CHCl3); H
NMR (200 MHz, CDCl3): l 1.22–1.41 (m, 9H, CH3), 2.12–2.38 (m, 3H, H-5a,5b,6), 2.65 (dd,
1H, J1,2 5.2, J1,6 12.3 Hz, H-1), 3.66 (t, 1H, J4%,5%a 8.6, J5%a,5%b 8.9 Hz, H-5%a), 3.98 (t, 1H, J4%,5% 7.3,
J4%,6 10.9 Hz, H-4%), 4.22–4.35 (m, 4H, H-2,5%b, -OCH2CH3), 5.80–5.92 (m, 2H, H-3,4); EIMS
(%): 255 (M+−15; 8), 195 (18), 149 (35), 121 (25), 101 (78).
3.4. Ethyl 2-acetoxy-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-(1S,2R,6R)-3-cyclohexene-1-carb-
oxylate 15
A solution of alcohol 12 (0.9 g, 3.3 mmol) in pyridine (5 mL) containing DMAP (0.040 g, 0.3
mmol) was treated with acetic anhydride (0.34 mL, 3.6 mmol) at 0°C and stirred for 1 h at room
temperature. The reaction mixture was diluted with a saturated aqueous NaHCO3 solution (25
mL) and extracted with CH2Cl2 (2×25 mL). The combined CH2Cl2 layers were washed with an
aq. saturated CuSO4 solution (25 mL), water (25 mL), followed by brine (25 mL) and dried
(Na2SO4). Solvent was evaporated under reduced pressure and residue on purification by
column chromatography (60–120 mesh, Si-gel, ethyl acetate:pet. ether 1:4) gave the acetate 15
1
quantitatively as a syrup. [h]D=+27.0 (c 0.6, CHCl3); H NMR (200 MHz, CDCl3): l 1.25–1.40
(m, 9H, CH3), 2.05 (s, 3H, -OAc), 2.05–2.45 (m, 3H, H-5a,5b,6), 2.95–3.05 (m, 1H, H-1), 3.65
(t, 1H, J4%,5%a 7.4, J5%a,5%b 8.4 Hz, H-5%a), 3.86 (m, 4H, H-4%, 5%b, -OCH2CH3), 5.48–5.60 (m, 2H,
H-3, 4), 5.91–6.02 (m, 1H, H-2); 13C NMR (50 MHz, CDCl3): l 14.25, 20.95, 25.72, 26.75, 29.64,
38.49, 43.57, 60.35, 67.83, 69.34, 77.68, 109.0, 123.77, 130.28, 169.88, 170.293; EIMS (%): 297
(M+−15; 12), 195 (8), 121 (12), 101 (12), 79 (25), 72 (15), 43 (100); EI-HRMS: calcd for C15H21O6
(M+−15): 297.133814, found: 297.133015.
3.5. Ethyl 2-acetoxy-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-(1S,2S,6R)-3-cyclohexene-1-carb-
oxylate 16
A solution of alcohol 13 (0.5 g, 1.8 mmol) in pyridine (2 mL) was treated with acetic
anhydride (0.2 mL, 2.0 mmol) at 0°C, worked up and purified as described for 15 to give acetate
1
16 in quantitative yield as a syrup. [h]D=+148.8 (c 0.5, CHCl3); H NMR (200 MHz, CDCl3):
l 1.20–1.45 (m, 9H, CH3), 1.98–2.25 (m, 6H, H-5a,5b,6, -OAc), 2.58–2.70 (m, 1H, H-1), 3.62 (t,
1H, J5%a,5%b 8.6, J4%,5%a 7.8 Hz, H-5%a), 3.93 (t, 1H, J4%,6 8.6 Hz, H-4%), 4.00–4.25 (m, 3H, -OCH2CH3,
H-5%b), 5.52–5.62 (m, 2H, H-3,4), 5.82–5.96 (m, 1H, H-2); 13C NMR (50 MHz, CDCl3): l 14.16,
20.99, 24.68, 25.08, 26.25, 37.73, 49.32, 60.89, 66.80, 71.32, 75.94, 108.93, 125.22, 129.24, 170.20,
172.92; EIMS (%): 297 (M+−15; 5), 237 (10), 149 (15), 121 (18), 101 (50), 43 (100); EI-HRMS:
calcd for C15H21O6 (M+−15): 297.133814, found: 297.133690.

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4505
3.6. Ethyl 2-acetoxy-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-(1R,2S,6R)-3-cyclohexene-1-carb-
oxylate 17
A solution of alcohol 14 (0.5 g, 1.8 mmol) in pyridine (2 mL) was treated with acetic
anhydride (0.19 mL, 2.0 mmol) at 0°C, worked up and purified as described for 15 to give
1
acetate 17 (0.46 g) in 93% yield as a syrup. [h]D=−132.3 (c 0.5, CHCl3); H NMR (200 MHz,
CDCl3): l 1.25–1.48 (m, 9H, CH3), 2.02–2.38 (m, 6H, -OAc, H-5a,5b,6), 2.82 (dd, 1H, J1,2 4.5,
J1,6 11.3 Hz, H-1), 3.76 (dd, 1H, J5%a,4% 5.4, J5%a,5%b 9.0 Hz, H-5%a), 3.98–4.25 (m, 3H, H-5%b,
-OCH2CH3), 4.45 (td, 1H, J4%,6 5.4, J4%,5% 6.7 Hz, H-4%), 5.58 (t, 1H, J2,3 5.4 Hz, H-2), 5.78–5.90
(m, 1H, H-3), 6.02–6.12 (m, 1H, H-4); 13C NMR (50 MHz, CDCl3): l 14.01, 20.89, 23.49, 24.72,
26.02, 31.72, 45.91, 60.55, 66.55, 66.74, 75.40, 108.78, 122.76, 132.53, 170.13, 171.33; EIMS (%):
297 (M+−15; 20), 195 (17), 149 (31), 121 (48), 101 (64), 435 (100); EI-HRMS: calcd for C15H21O6
(M+−15); 297.133814, found: 297.133470.
3.7. Ethyl 2-acetoxy-3,4-dihydroxy-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-(1S,2S,3S,4S,6R)-
cyclohexane-1-carboxylate 18
To a stirred solution of compound 15 (0.85 g, 2.7 mmol) and NMO (0.35 g, 2.9 mmol, 50%
aqueous solution) in acetone:water (3:1, 10 mL), OsO4 (five drops, 0.04N solution in toluene)
was added and stirred for 12 h at room temperature in darkness. Excess solid NaHSO3 (100 mg)
was added, stirred for 20 min, diluted with water (50 mL) and extracted in ethyl acetate (3×25
mL). The combined ethyl acetate layers were washed with brine (50 mL) and dried (Na2SO4).
Evaporation of solvent under reduced pressure and purification of residue by column chro-
matography (60–120 mesh Si-gel, ethyl acetate:pet. ether 2:3) gave the diol 18 (0.68 g) in 88%
1
yield as a syrup. [h]D=−113.4 (c 0.7, CHCl3); H NMR (200 MHz, CDCl3): l 1.20–1.42 (m, 9H,
CH3), 1.80–2.40 (m, 6H, -OAc, H-5a,5b,6), 3.05 (t, 1H, J1,6 5.9 J1,2 4.2 Hz, H-1), 3.65 (t, 1H,
J5%a,5%b 8.4, J5%a,4% 7.5 Hz, H-5%a), 3.82–3.86 (m, 1H, H-4), 4.00–4.28 (m, 4H, H-4%,5%b, -OCH2CH3),
4.32–4.44 (m, 1H, H-3), 5.05 (dd, 1H, J2,3 9.5 Hz, H-2); EIMS (%): 331 (M+−15; 38), 228 (22),
183 (18), 165 (20), 101 (25), 43 (100).
3.8. Ethyl 2-acetoxy-3,4-dihydroxy-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-(1S,2R,3R,4R,6R)-
cyclohexane-1-carboxylate 19
To a stirred solution of compound 16 (0.55 g, 1.7 mmol) and NMO (0.207 g, 1.7 mmol, 50%
aqueous solution) in acetone:water (3:1, 10 mL), OsO4 (five drops, 0.04N solution in toluene)
was added, worked up and purified as described for 18 to give the diol 19 (0.52 g) in 88% yield
1
as a syrup. [h]D=−37.0 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3): l 1.20–1.41 (m, 9H, CH3),
2.0–2.4 (m, 6H, -OAc, H-5a,5b,6), 2.5–2.65 (m, 1H, H-1), 3.49–3.69 (m, 1H, H-5%a), 3.86–4.28
(m, 6H, H-3,4,4%,5%b, -OCH2CH3), 5.28 (t, 1H, J1,2 10.7, J2,3 9.3, H-2); EIMS (%): 331 (M+−15;
27), 271 (20), 165 (30), 91 (34), 108 (100), 43 (98).
3.9. Ethyl 2-acetoxy-3,4-dihydroxy-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-(1R,2R,3R,4R,6R)-
cyclohexane-1-carboxylate 20
To a stirred solution of compound 17 (0.45 g, 1.44 mmol) and NMO (0.186 g, 1.58 mmol,
50% aqueous solution) in acetone:water (3:1, 10 mL), OsO4 (five drops, 0.04N solution in

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G. V. M. Sharma et al. / Tetrahedron: Asymmetry 11 (2000) 4499–4507
toluene) was added, worked up and purified as described for 18 to give the diol 20 (0.43 g) in
1
82% yield as a syrup. [h]D=−8.8 (c 1.0, CHCl3); H NMR (200 MHz, CDCl3): l 1.20–1.46 (m,
9H, CH3), 1.95–2.24 (m, 6H, H-5a,5b,6, -OAc), 2.92 (dd, 1H, J1,2 10.4, J1,6 2.8 Hz, H-1), 3.70
(dd, 1H, J4%,5%a, 7.6, J5%a,5%b 8.6 Hz, H-5%a), 3.85–4.24 (m, 6H, H-3,4,4%,5%b, -OCH2CH3), 5.39–5.43
(m, 1H, H-2); EIMS (%): 331 (M+−15; 40), 228 (20), 183 (17), 165 (19), 165 (17), 137 (12), 101
(28), 72 (28), 43 (100).
3.10. Ethyl 6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,3,4-triacetoxy-(1S,2S,3S,4S,6R)-cyclo-
hexane-1-carboxylate 1
Acetic anhydride (0.26 mL, 2.8 mmol) was added to a stirred solution of diol 18 (0.5 g, 1.44
mmol) in pyridine (3 mL) containing DMAP (0.017 g, 0.14 mmol), worked up and purified as
1
described for 15 to gave 3 (0.52 g) in 85% yield. [h]D=+6.6 (c 0.45, CHCl3); H NMR (500
MHz, CDCl3): 1.25 (t, 3H, J 7.2 Hz, OCH2CH3), 1.31 (s, 3H, CH3(A)), 1.44 (s, 3H, CH3(B)),
1.80–1.84 (m, 2H, H-5ax,5eq), 2.01, 2.07, 2.15 (3s, 9H, -OAc), 2.31 (ddt, 1H, J4%,6 2.9, J5a,6 11.7,
J5e,6 5.0, J1,6 11.5 Hz, H-6), 2.88 (dd, 1H, J1,2 2.9 Hz, H-1), 3.73 (dd, 1H, J5%a,5%b 8.5, J4%,5%a 6.8 Hz,
H-5%a), 4.00 (dd, 1H, J4%,5%b 6.2 Hz, H-5%b), 4.11 (q, 2H, OCH2CH3), 4.20 (td, 1H, H-4%), 5.17
(ddd, 1H, J4,5a 11.2, J4,5e 5.9, J3,4 2.9 Hz, H-4), 5.24 (t, 1H, J2,3 4.2 Hz, H-3), 5.40 (t, 1H, H-2);
13C NMR (125 MHz, CDCl3): 14.24, 20.73, 20.74, 20.99, 25.52, 26.66, 27.19, 36.36, 46.13, 60.99,
67.71, 68.75, 69.48, 69.61, 76.79, 109.39, 169.92 (2C), 170.11, 170.18; FABMS (%): 453 (M+23;
5), 431 (M+1; 8), 415 (12), 373 (24), 313 (10), 221 (10), 207 (15), 147 (35), 123 (50), 109 (100);
FAB-HRMS: calcd for (M++1) C20H31O10: 431.191723, found: 431.191376.
3.11. Ethyl 6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,3,4-triacetoxy-(1S,2R,3R,4R,6R)-cyclo-
hexane-1-carboxylate 2
Acetic anhydride (0.217 mL, 2.31 mmol) was added to a stirred solution of diol 19 (0.4 g, 1.44
mmol) in pyridine (2.5 mL) containing DMAP (0.017 g, 0.14 mmol), worked up and purified as
1
described for 15 to give 1 (0.58 g) in quantitative yield as a syrup. [h]D=40.3 (c 0.5, CHCl3). H
NMR (500 MHz, CDCl3): l 1.27 (t, 3H, J 7.1 Hz, -OCH2CH3), 1.30 (s, 3H, CH3(A)), 1.39 (s, 3H,
CH3(B)), 1.66 (ddd, 1H, J5a,6 12.7, J5a,5e 15.1, J4,5a 2.3 Hz, H-5ax), 1.96 (dt, 1H, J5e,6 3.6, J4,5e 4.4
Hz, H-5eq), 1.99, 2.00, 2.14 (3s, 9H, OAc), 2.34 (tt, 1H, J1,6 11.7 Hz, H-6), 2.68 (t, 1H, J1,2 11.0
Hz, H-1), 3.60 (dd, 1H, J4%,5%a 6.7, J5%a,5%b 8.2 Hz, H-5%a), 3.95 (dd, 1H, J4%,5%b 6.2 Hz, H-5%b), 4.02
(dt, 1H, J4%,6 3.2 Hz, H-4%), 4.17 (q, 2H, -OCH2CH3), 4.87 (dd, 1H, J3,4 3.0, J2,3 10.2 Hz, H-3),
5.48 (m, 1H, H-4), 5.51 (t, 1H, H-2); 13C NMR (125 MHz, CDCl3) l: 14.10, 20.59, 20.66, 21.06,
24.73, 25.94, 27.25, 35.57, 50.44, 61.21, 66.56, 68.29, 70.11, 72.94, 75.35, 109.25, 169.45, 170.09,
170.18, 171.38; FABMS (%): 431 (M+1; 28), 415 (37), 373 (100), 313 (28), 211 (25), 165 (35), 154
(32), 137 (59), 107 (38); FAB-HRMS: calcd for (M++1) C20H31O10: 431.191723, found:
431.191677.
3.12. Ethyl 6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,3,4-triacetoxy-(1R,2R,3R,4R,6R)-cyclo-
hexane-1-carboxylate 3
Acetic anhydride (0.32 mL, 3.46 mmol) was added to a stirred solution of diol 20 (0.6 g, 1.73
mmol) in pyridine (5 mL) containing DMAP (0.021 g, 0.17 mmol), worked up and purified as
1
described for 15 to give 16 (0.55 g) in 75% yield as a syrup. [h]D=−10.8 (c 0.50, CHCl3); H

G. V. M. Sharma et al. / Tetrahedron: Asymmetry 11 (2000) 4499–4507
4507
NMR (500 MHz, CDCl3): l 1.27 (t, 3H, J 7.0 Hz, -OCH2CH3), 1.31 (s, 3H, CH3(A)), 1.37 (s, 3H,
CH3(B)), 1.98, 2.01, 2.09 (3s, 9H, OAc), 2.02 (dt, 1H, J5e,6 3.0, J5a,5e 12.9, J4,5e 3.5 Hz, H-5eq),
2.17 (td, 1H, J4a,6 12.9, J4,5a 2.3 Hz, H-5ax), 2.23 (ddd, 1H, J4%,6 7.6, J1,6 5.0 Hz, H-6), 3.11 (br.
t, 1H, J1,2 5.9 Hz, H-1), 3.67 (dd, 1H, J5%a,5%b 8.2, J4%5%a 6.8 Hz, H-5%a), 3.83 (dd, 1H, J4%,5%b 5.9 Hz,
H-4), 4.05 (dd, 1H, H-5%b), 4.17 (m, 2H, -OCH2CH3), 5.26 (dd, 1H, J2,3 10.6 Hz, H-2), 5.57 (m,
1H, J3,4 3.5 Hz, H-4), 5.71 (dd, 1H, H-3); 13C NMR (125 MHz, CDCl3): 13.96, 20.64, 20.81,
20.90, 23.31, 24.71, 25.97, 34.45, 43.84, 61.11, 66.65, 67.63, 68.43, 69.68, 75.41, 109.11, 169.02,
169.27, 170.06, 171.20; FABMS (%): 453 (M+23; 10), 431 (M+1; 8), 415 (M−15; 30), 373 (62),
165 (44), 147 (68), 109 (100); FAB-HRMS: calcd for (M++1) C20H31O10: 431.191723, found:
431.190130.
Acknowledgements
The authors T. Rajendra Prasad and M. H. V. Ramana Rao are thankful to CSIR, New
Delhi, for the financial assistance.
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