Facile synthetic routes to all possible enantiomeric pairs of conduritol stereoisomers via efficient enzymatic resolution of conduritol B and C derivatives

Article abstract of DOI:10.1021/ol0164233

matrix presented The first synthesis of all possible enantiomeric pairs of conduritol stereoisomers has been accomplished by efficient enzymatic resolution of conduritol B and C derivatives, followed by oxidation/reduction and the Mitsunobu reaction in st

Full text of DOI:10.1021/ol0164233

ORGANIC
LETTERS
2001
Vol. 3, No. 19
3013-3016
Facile Synthetic Routes to All Possible
Enantiomeric Pairs of Conduritol
Stereoisomers via Efficient Enzymatic
Resolution of Conduritol B and C
Derivatives
Yong-Uk Kwon and Sung-Kee Chung*
Department of Chemistry, DiVision of Molecular and Life Sciences,
Pohang UniVersity of Science and Technology, Pohang 790-784, South Korea
skchung@postech.ac.kr
Received July 11, 2001
ABSTRACT
The first synthesis of all possible enantiomeric pairs of conduritol stereoisomers has been accomplished by efficient enzymatic resolution of
conduritol B and C derivatives, followed by oxidation/reduction and the Mitsunobu reaction in stereo- and regioselective manners.
Conduritols and their derivatives possess interesting biologi-
cal properties; conduritol epoxides and aminoconduritols act
as inhibitors of glycosidases,1 cyclophellitols have proved
to be potent inhibitors of human immunodeficiency virus
(HIV) and glycosidases,2 and conduritol A analogues modu-
late the release of insulin from isolated pancreatic islets in
the presence of varying concentrations of glucose.3 A number
of conduritol derivatives have also been found to possess
antibiotic, antileukemic, and growth-regulating activities.4 In
addition, conduritols have been widely used as intermediates
in chemical syntheses of inositols,5 quercitols,6 deoxyinosi-
tols,7 aminoconduritols,4,8 conduritol epoxides,4 cyclophel-
litol,9 pseudosugars,10 amino sugar analogues,11 sugar amino
acid analogues, etc. As pointed out in the recent reviews,4
however, a number of difficulties have been encountered in
the syntheses of conduritols. Conduritols are cyclohex-5-
ene-1,2,3,4-tetrols and exist as two meso compounds (con-
(5) (a) Brammer, L. E., Jr.; Hudlicky, T. Tetrahedron: Asymmetry 1998,
9, 2011-2014. (b) Desjardins, M.; Brammer, L. E., Jr.; Hudlicky, T.
Carbohydr. Res. 1997, 304, 39-42. (c) Hudlicky, T.; Mandel, M.; Rouden,
J.; Lee, R. S.; Bachmann, B.; Dudding, T.; Yost, K. J.; Merola, J. S. J.
Chem. Soc., Perkin Trans. 1 1994, 1553-1567. (d) Mandel, M.; Hudlicky,
T. J. Chem. Soc., Perkin Trans. 1 1993, 741-743.
(6) Hudlicky, T.; Cebulak, M. Cyclitols and DeriVatiVes; VCH: New
York, 1993.
(7) (a) Drian, C. L.; Vionnet, J. P.; Vogel, P. HelV. Chim. Acta 1990,
73, 161-168. (b) Drian, C. L.; Vieira, E.; Vogel, P. HelV. Chim. Acta 1989,
72, 338-347.
(8) (a) Sanfilippo, C.; Patti, A.; Piattelli, M.; Nicolosi, G. Tetrahedron:
Asymmetry 1997, 8, 1569-1573. (b) Hudlicky, T.; Luna, H.; Olivo, H. F.;
Andersen, C.; Nugent, T.; Price, J. D. J. Chem. Soc., Perkin Trans. 1 1991,
2907-2917.
(9) (a) Trost, B. M.; Hembre, E. J. Tetrahedron Lett. 1999, 40, 219-
222. (b) Takahashi, H.; Iimori, T.; Ikegami, S. Tetrahedron Lett. 1998, 39,
6939-6942.
(10) (a) Entwistle, D. A.; Hudlicky, T. Tetrahedron Lett. 1995, 36, 2591-
2594. (b) Pingli, L.; Vandewalle, M. Tetrahedron 1994, 50, 7061-7074.
(11) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc.
1994, 116, 5099-5107.
(1) (a) Legler, G.; Herrchen, M. FEBS Lett. 1981, 135, 139-144. (b)
Legler, G. Methods Enzymol. 1977, 46, 368-381. (c) Legler, G.; Bause,
E. Carbohydr. Res. 1973, 28, 45-52. (d) Legler, G. Mol. Cell. Biochem.
1973, 2, 31-38.
(2) (a) Atsumi, S.; Iinuma, H.; Nosaka, C.; Umezawa, K. J. Antibiot.
1990, 43, 1579. (b) Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.;
Nakamura, H.; Iitaka, Y.; Takeuchi, T. J. Antibiot. 1990, 43, 49.
(3) Billington, D. C.; Perron-Sierra, F.; Beaubras, S.; Duhault, J.; Espinal,
J.; Challal, S. Bioorg. Med. Chem. Lett. 1994, 4, 2307-2312.
(4) (a) Balci, M. Pure Appl. Chem. 1997, 69, 97-104 and references
therein. (b) Balci, M.; Su¨tbeyaz, Y.; Sec¸en, H. Tetrahedron Lett. 1990, 46,
3715-3742 and references therein.
10.1021/ol0164233 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/21/2001

duritols A and D) and four enantiomeric pairs (conduritols
B, C, E, and F). Conduritols A and F are naturally occurring.
Conduritol isomers have been synthesized by several meth-
ods: microbial oxidation of benzene12 or halobenzenes,8b,13
followed by epoxidation-ring opening or dihydroxylation,
dedihydroxylation of inositol diols,14 and others.7,15 Although
considerable progress has been made from enantiopure
unsaturated cyclic cis-diols, obtained by microbial oxidation
of halobenzenes,8b,13 many other approaches result in racemic
mixtures. Recently, enantiopure conduritols have been
prepared by employing chiral starting materials such as sugar
alcohols16 and diethyl L-tartrate.17 Enantiopure conduritols
have also been obtained by chemical9,14b,18 or enzymatic8a,10b,19
resolution of racemic conduritol derivatives or their precur-
sors. However, the systematic and practical access to all
enantiopure conduritols has not been realized. Thus we
undertook the synthesis of all possible enantiomeric pairs
of conduritol stereoisomers via efficient enzymatic resolution
of conduritol B and C derivatives and herein report the
results.
Kazlauskas’ procedure.23 After 3 h the conversion reached
ca. 50% and the reaction mixture contained the unreacted
diacetate (+)-4 (49%, >95% ee) and the monoacetate (-)-5
(48%, 95% ee) (Scheme 1).
Scheme 1a
a (a) PPh3, imidazole, I2, toluene, vV, 77%; (b) NaOMe, MeOH,
vV, 96%; (c) Ac2O, pyridine 97.5%; (d) see Table 1; (e) NaOMe,
MeOH, quant; (f) 80% aq. AcOH, 100 °C, quant.
To obtain enantiopure conduritol stereoisomers, enanti-
oselective enzyme-catalyzed hydrolysis of conduritol B and
C derivatives was explored. First, conduritol C derivative
(2) was prepared from myo-inositol diol 120 under the
Samuelsson conditions.21,22 The diacetate 4, which was
derived from 2, was exposed to lipase from Candida rugosa
(CRL, Sigma) in a phosphate buffer (pH 7) according to the
This observation was at minor variance with Ba¨ckvall’s
results, which indicated the enzymatic resolution of the
diacetate 4 by CRL produced the unreacted diacetate (+)-4
and the diol (-)-3.19c It is clear that CRL shows R stereo-
preference. Methanolysis and successive acid-catalyzed
hydroysis of compounds (+)-4 and (-)-5 afforded (+)-cond-
uritol C [(+)-6] and (-)-conduritol C [(-)-6], respect-
ively.7b,13e,19c The reaction catalyzed by lipase from Pseudo-
monas cepacia (PCL, Amano) also gave comparable results
in terms of products, enantioselectivity, and reaction rate.
However, the alcoholysis of the diacetate 4 with Novozym
435 (CAL, immobilized lipase from Candida antarctica,
Novo Nordisk) or Lipozyme RM IM (RML, immobilized
lipase from Rhizomucor miehei, Novo Nordisk) in t-BME
did not work at all (Table 1).
To obtain enantiopure conduritol B derivatives, the con-
duritol B derivative 10 was prepared according to Samuels-
son’s olefination procedure21 from compound 9,20 which was
derived from compound 720 (Scheme 2). The diacetate 12,
prepared by methanolysis and subsequent acetylation of
compound 10, was exposed to CRL and PCL in a phosphate
buffer (pH 7), but the optical resolutions did not result.
We then investigated the system with Novozym 435 and
n-BuOH in t-BME at 45 °C. After 30 min, the reaction
mixture was found to contain the unreacted diacetate (+)-
12, the monoacetate (-)-13, and the diol (-)-11. The
monoacetate (-)-13 was slowly converted to (-)-11. This
reveals that this enzyme also has R stereopreference and can
recognize both acetyl groups since the diacetate (-)-12 has
a C2 symmetry axis. After 3 h, the reaction mixture contained
(+)-12 (49.5%, 98% ee) and (-)-11 (48.5%, >99% ee).
Compound (+)-12 was treated with NaOMe in MeOH to
(12) (a) Billington, D. C.; Perron-Sierra, F.; Beaubras, S.; Duhault, J.;
Espinal, J.; Challal, S. Bioorg. Med. Chem. Lett. 1994, 4, 2307-2312. (b)
Carless, H. A. J. Tetrahedron: Asymmetry 1992, 3, 795-826 and references
therein. (c) Ley, S. V.; Parra, M.; Redgrave, A. J.; Sternfeld, F. Tetrahedron
1990, 46, 4995-5026. (d) Carless, H. A. J.; Oak, O. Z. Tetrahedron Lett.
1989, 30, 1719-1720.
(13) (a) Donohoe, T. J.; Moore, P. R.; Beddoes, R. L. J. Chem. Soc.,
Perkin Trans. 1 1997, 43-51. (b) Carless, H. A. J.; Busia, K.; Dove, Y.;
Malik, S. S. J. Chem. Soc., Perkin Trans. 1 1993, 2505-2506. (c) Carless,
H. A. J. J. Chem. Soc., Chem. Commun. 1992, 234-235. (d) Hudlicky, T.;
Price, J. D.; Olivo, H. F. Synlett 1991, 645-646. (e) Johnson, C. R.; Ple´,
P. A.; Adams, J. P. J. Chem. Soc., Chem. Commun. 1991, 1006-1007.
(14) (a) Mereyala, H. B.; Pannala, M. J. Chem. Soc., Perkin Trans. 1
1997, 1755-1758. (b) Innes, J. E.; Edwards, P. J.; Ley, S. V. J. Chem.
Soc., Perkin Trans. 1 1997, 795-796. (c) Mereyala, H. B.; Pannala, M.
Tetrahedron Lett. 1995, 36, 2121-2124. (d) Akiyama, T.; Shima, H.;
Ohnari, M.; Okazaki, T.; Ozaki, S. Bull. Chem. Soc. Jpn. 1993, 66, 3760-
3767.
(15) (a) Su¨tbeyaz, Y.; Sec¸en, H.; Balci, M. J. Chem. Soc., Chem.
Commun. 1988, 1330-1331. (b) Knapp, S.; Ornaf, R. M.; Rodriques, K.
E. J. Am. Chem. Soc. 1983, 105, 5494-5495.
(16) (a) Ackermann, L.; Tom, D. E.; Fu¨rstner, A. Tetrahedron 2000,
56, 2195-2202. (b) Cere`, V.; Mantovani, G.; Peri, F.; Pollicino, S.; Ricci,
A. Tetrahedron 2000, 56, 1225-1231. (c) Gallos, J. K.; Koftis, T. V.; Sarli,
V. C.; Litinas, K. E. J. Chem. Soc., Perkin Trans. 1 1999, 3075-3077. (d)
Cere`, V.; Peri, F.; Pollicino, S. Tetrahedron Lett. 2000, 38, 7797-7800.
(17) Lee, W. W.; Chang, S. Tetrahedron: Asymmetry 1999, 10, 4473-
4475.
(18) Trost, B. M.; Patterson, D. E.; Hembre, E. J. J. Am. Chem. Soc.
1999, 121, 10834-10835.
(19) (a) Sanfilippo, C.; Patti, A.; Nicolosi, G. Tetrahedron: Asymmetry
2000, 11, 1043-1045. (b) Sanfilippo, C.; Patti, A.; Nicolosi, G. Tetrahe-
dron: Asymmetry 1999, 10, 3273-3276. (c) Yoshizaki, H.; Ba¨ckvall, J. E.
J. Org. Chem. 1998, 63, 9339-9341. (d) Sanfilippo, C.; Patti, A.; Piattelli,
M.; Nicolosi, G. Tetrahedron: Asymmetry 1997, 8, 2083-2084.
(20) Chung, S. K.; Chang, Y. T. J. Chem. Soc., Chem. Commun. 1995,
11-12.
(21) (a) Liu, Z.; Classon, B.; Samuelsson, B. J. Org. Chem. 1990, 55,
4273-4275. (b) Pakulski, Z.; Zamojski, A. Carbohydr. Res. 1990, 205,
410-414. (c) Garegg, P. J.; Samuelsson, B. Synthesis 1979, 469-470; 813-
814.
(22) Chung, S. K.; Kwon, Y. U. Bioorg. Med. Chem. Lett. 1999, 9, 2135-
2140.
(23) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656-2665.
3014
Org. Lett., Vol. 3, No. 19, 2001

configurations. Accordingly, the procedures starting from
(+)-3 and (+)-11 only are described as the representative.
Because our initial synthetic plan for enantiopure cond-
uritol stereoisomers involved the inversion of the allylic
alcohol stereochemistry in selectively protected conduritol
derivatives under the Mitsunobu conditions, the monoben-
zoate (+)-15 was preferentially prepared by treatment of
(+)-3 with BzCl (1.0 equiv) in pyridine (Scheme 3).
Table 1. Lipases-Catalyzed Resolution of Conduritol B and C
Derivatives
time
(h)c
yield
(%)
enantioselectivity
of products (% ee)d
substrate
lipase
4
4
4
CRLa
PCLa
CALb
RMLb
CRLa
PCLa
CALb
RMLb
3
3
48
48
95 (>99)e
95 (>99)e
no rxn
no rxn
no rxn
no rxn
3
4
12
12
12
12
Scheme 3a
48.5
48.5
>99
>99
36
a CRL, lipase from Candida rugosa (Sigma); PCL, lipase from Pseudomo-
nas cepacia (Amano). Experimental conditions, enzyme (100 mg/substrate
1 mmol), 0.5 N buffer (pH 7.0, 5 mL/substrate 1 mmol), 0.5 N NaOH, rt.
b CAL, Novozym 435 (immobilized lipase from Candida antarctica, Novo
Nordisk); RML, Lipozyme RM IM (immobilized lipase from Rhizomucor
miehei, Novo Nordisk). Experimental conditions: enzyme (300 mg/substrate
1 mmol), n-BuOH (10 mmol/substrate 1 mmol), t-BME (15 mL/substrate
1 mmol), 45 °C. c At ca. 50% conversion. d Determined by NMR analysis
of the diacetates using Eu(hfc)3 as the NMR shift agent. e After recrystal-
lization.
give (+)-11. The reaction catalyzed by Lipozyme RM IM
gave comparable results in terms of products and enantio-
selectivity but showed a lower reaction rate (Table 1). The
enantiomerically pure trans-diols (+)-11 and (-)-11 were
hydrolyzed in 80% aqueous AcOH to yield (+)-conduritol
B [(+)-14] and (-)-conduritol B [(-)-14], respectively.7a,14d
Conversions of the enantiomeric diols (+)-3/(-)-3 and
(+)-11/(-)-11 to enantiomeric pairs of conduritol stereo-
isomers follow the same procedures except that the corre-
sponding products involved in each route have opposite
a (a) BzCl (1.0 equiv), pyridine; (b) SO3-pyridine complex, TEA,
DMSO; (c) NaBH4, MeOH-CH2Cl2, 74.5% from (+)-15; (d) (i)
NaOMe, MeOH, vV, (ii) 80% aq. AcOH, 100 °C, 92%; (e) (i)
MOMCl, (i-Pr)2NEt, (ii) NaOMe, MeOH, vV, 97.1%; (f) BzOH,
Ph3P, DEAD, toluene, 97.1%; (g) (i) NaOMe, MeOH, vV, (ii) 80%
aq. AcOH, 100 °C, 89%.
Scheme 2a
In the preliminary experiment, the Mitsunobu reaction of
the racemic monobenzoate 15 with BzOH, Ph3P, and DEAD
in toluene at room temperature was found to give the
expected conduritol D derivative 25 (8.5%) as the minor
product and the rearranged conduritol C derivative 26
(73.1%) as the major product in stereo- and regioselective
fashions. That is, the reaction was found to proceed
predominantly with both inversion and allylic rearrangement,
presumably via the intermediate 24 by SN2′ replacement to
afford compound 26 (Scheme 4). These unexpected results
suggest that the reaction of a carboxylate anion with an
alkoxy phosphonium salt is better described as proceeding
through an intimate ion pair rather than a free allylic
carbonium ion.24 When (()-(1,2,3/4)-1-O-methoxymethyl-
2,3-O-isopropylidene-cyclohex-5-ene-1,2,3,4-tetrol and (()-
(1,2,3/4)-1,2,3-tri-O-methoxymethylcyclohex-5-ene-1,2,3,4-
tetrol, derived from the racemate 3, were subjected to the
Mitsunobu conditions, similar results were obtained, indicat-
ing that the nature of the protecting groups made little
difference. The stereochemistry of the transformation does
not significantly depend on steric and electronic effects but
rather on the substrate structure.
a (a) 80% aq. AcOH, 100 °C, quant; (b) 2-methoxypropene, TSA,
DMF, 43%; (c) PPh3, imidazole, I2, toluene, vV, 78%; (d) NaOMe,
MeOH, vV, 97.4%; (e) Ac2O, pyridine 98.8%; (f) see Table 1; (g)
NaOMe, MeOH, quant; (h) 80% aq. AcOH, 100 °C, quant.
(24) Grynkiewicz, G.; Burzynska, H. Tetrahedron 1976, 32, 2109-2111.
Org. Lett., Vol. 3, No. 19, 2001
3015

Scheme 4a
Scheme 5a
a (a) BzOH, Ph3P, DEAD, toluene; (b) (i) NaOMe, MeOH, vV,
(ii) 80% aq. AcOH, 100 °C, 90%; (c) BzCl (1.05 equiv), pyridine.
a (a) BzOH, Ph3P, DEAD, toluene.
(Scheme 5).8b,16b The monobenzoate (+)-29 was obtained
by treatment of the diol (+)-11 with BzCl (1.05 equiv) in
pyridine in 61% yield. The Mitsunobu reaction of (+)-29
with BzOH, Ph3P, and DEAD in toluene provided the
conduritol F derivative (-)-30 in 98% yield. All protecting
groups of (-)-30 were removed by methanolysis and
subsequent acid-catalyzed hydrolysis to yield conduritol F,
(-)-31.7a,13d,14d,16b
In sum, we successfully developed synthetic routes to
enantiomeric pairs of all possible stereoisomeric conduritol
derivatives by efficient enzymatic resolution of conduritol
B and C derivatives, followed by oxidation/reduction and
the Mitsunobu reaction in stereo- and regioselective manners.
We are currently examining the utility of enantiopure
conduritol stereoisomers in the syntheses of inositol stereo-
isomers and various cyclitols.
Thus, the possibility of obtaining conduritol D by way of
oxidation and subsequent stereoselective reduction of (+)-
15 was investigated (Scheme 3). Compound (+)-15 was
treated with SO3-pyridine complex and TEA in DMSO to
furnish an enone (+)-17. Although conduritol D itself is a
meso compound, reduction of the enone (+)-17 with NaBH4
gave stereoselectively an enantiopure conduritol D derivative
(-)-18 in 74.5% overall yield from (+)-15. Methanolysis
and successive acid-catalyzed hydrolysis of (-)-18 provided
achiral conduritol D (19).7b,12d,13a
On the other hand, the allylic alcohol (+)-20, derived from
(+)-15 by treatment with MOMCl and (i-Pr)2NEt in CHCl3,
followed by debenzoylation, was treated with BzOH, Ph3P,
and DEAD in toluene to afford the conduritol A derivative
(-)-21 with inversion of the stereochemistry but no allylic
rearrangement in 97.1% yield. All protecting groups of (-)-
21 were removed by treatment with NaOMe and subsequent
acid-catalyzed hydrolysis to give achiral conduritol A
(19).12d,15a
Acknowledgment. This work was supported by
POSTECH/POSCO and the Ministry of Education/Basic
Science Research Institute.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 2-4, (+)-
4, (-)-5, (+)/(-)-3, 10-12, (+)-12, (-)-13, (+)/(-)-11, (+)/
(-)-15, (+)/(-)-16, (+)/(-)-2, (+)/(-)-17, (+)/(-)-18, (+)/
(-)-20, (+)/(-)-21, 25, 26, (+)/(-)-27, (+)/(-)-29, (+)/
(-)-10, and (+)/(-)-30. This material is available free of
charge via the Internet at http://pubs.acs.org.
The double inversion of two allylic hydroxyl groups of
(+)-11 might be expected to give the conduritol E derivative.
The treatment of (+)-11 with BzOH, Ph3P, and DEAD in
toluene at room temperature indeed provided the (-)-
conduritol E derivative [(-)-27] without allylic rearrange-
ment in 90% yield. The protecting groups of (-)-27 were
removed by successive reactions with NaOMe in MeOH and
80% aqueous AcOH to yield (-)-conduritol E [(-)-28]
OL0164233
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Org. Lett., Vol. 3, No. 19, 2001