Asymmetric desymmetrization of meso-cyclopentitol using a C2-symmetric bis-sulfoxide: A synthesis of (-)-allosamizoline

Article abstract of DOI:10.1016/S0957-4166(97)00625-3

A synthesis of (-)-allosamizoline was accomplished via asymmetric desymmetrization of a meso-cyclopentitol using the C₂-symmetric bis-sulfoxide 5 as a chiral auxiliary.

Full text of DOI:10.1016/S0957-4166(97)00625-3

Pergamon
Tetrahedron: Asymmetry 9 (1998) 179–182
Asymmetric desymmetrization of meso-cyclopentitol using a
C2-symmetric bis-sulfoxide: A synthesis of (−)-allosamizoline
Naoyoshi Maezaki, Atsunobu Sakamoto, Tetsuaki Tanaka and Chuzo Iwata ∗
Faculty of Pharmaceutical Sciences, Osaka University, 1–6 Yamadaoka, Suita, Osaka 565-0871, Japan
Received 7 November 1997; accepted 3 December 1997
Abstract
A synthesis of (−)-allosamizoline was accomplished via asymmetric desymmetrization of a meso-cyclopentitol
using the C2-symmetric bis-sulfoxide 5 as a chiral auxiliary. © 1998 Elsevier Science Ltd. All rights reserved.
Allosamizoline 1 is a naturally occurring N-acetyl-β-D-allosamine analogue and is part of the structure
of allosamidin 2, isolated from the mycelia of Stroptomyces sp. no. 17131 and from the fermentation broth
of sp. AJ 9463.2 Due to its unusual bicyclic structure and strong chitinase inhibiting activity,3 several
synthetic studies have been reported.4 The asymmetric syntheses previously studied can be categorized
into two approaches: (1) a chiral pool approach using sugar;4d–i and (2) an enzymatic desymmetrization
of meso-4-benzyloxymethyl-3,5-dihydroxycyclopentene.4j–l
Herein, we describe a novel approach using chemical asymmetric desymmetrization of a meso-
cyclopentitol derivative 4 as a key step and creating five stereogenic centers in 1 simultaneously. Our
synthetic plan is illustrated in Scheme 1. Although allosamizoline has a high density of functional groups
and multi-stereogenic centers on its cyclopentane ring, the molecule has inherent symmetry. A suitably
protected cyclopentitol derivative 3 is envisioned as a precursor of 1, which can be converted into 1
via SN2 displacement of the hydroxy group with an amino group followed by formation of an oxazoline
moiety. The cyclopentitol derivative 3 can be derived from a meso-cyclopentitol 4 by differentiation of an
enantiotopic hydroxy group. In this step, we planned to use the C2-symmetric bis-sulfoxide 5 which has
recently been developed in our laboratory as a novel chiral auxiliary for asymmetric desymmetrization
of meso-1,2-diols.5
meso-Diol 7 was prepared starting from the known meso-diol 66 via benzylation followed by di-
hydroxylation with a catalytic amount of OsO4 in the presence of N-methylmorpholine N-oxide (NMO)
(Scheme 2). Dihydroxylation proceeded diastereoselectively from the opposite side to the adjacent ben-
zyloxy groups to give the desired meso-diol 7 along with a diastereomer (ratio 8:1), which was separable
by column chromatography.7 Acetalization of the mono silyl ether of 7 with the (R,R)-bis-sulfoxide
∗
Corresponding author. E-mail: iwata@phs.osaka-u.ac.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00625-3

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Scheme 1.
55 in the presence of TMSOTf proceeded in good yield to give the acetal 8.8 On treatment of 8 with
KHMDS followed by benzylation, an acetal cleavage reaction proceeded with high diastereoselectivity
(>96% d.e.) to give the benzyl ether 9.9 Then, the chiral auxiliary was readily removed by hydrolysis
with dilute hydrochloric acid.10 The enantiomeric excess of the resulting alcohol 10 was determined as
95% e.e. by 1H-NMR spectroscopy after conversion into the Mosher’s ester. The absolute configuration
was determined as (1R,2S) by Mosher’s method.11 SN2 Displacement of the hydroxy group into the
amino group was carried out via triflation of 10 with triflic anhydride and pyridine followed by azidation
with n-Bu4NN3 to give the azide 11, which was transformed into the carbamate 12 by the sequence of
chemoselective reduction of the azide moiety in the presence of benzyl groups and methoxycarbonylation
of the resulting amine. After deprotection of the four benzyl groups on Pd(OH)2–C,12 the known
triacetate 134d–h was obtained via cyclization with MeONa in refluxing MeOH in the presence of 4 Å
molecular sieves13 followed by acetylation of the remaining alcohols with acetic anhydride in pyridine.
30
The spectroscopic data of the synthesized 13 {[α]D −26.0 (c=0.56, CHCl3), lit.4d [α]D −25, lit.4e
20
26
[α]D −29.4 (c=1.48, CHCl3), lit.4f,g [α]D −24.1 (c=0.46, CHCl3), lit.4h [α]D −25 (c=0.41, CHCl3)}
was consistent with authentic data.14 Since 13 leads to 1 in two steps,4h we achieved a formal synthesis
of (−)-1.
In conclusion, highly potent chitinase inhibitor, allosamizoline (1), was synthesized using asymmetric
desymmetrization of the meso-cyclopentitol derivative with the C2-symmetrical bis-sulfoxide as a key
step. Our approach should be effective for the synthesis of other cyclitols having a regioselectively
protected polyhydroxy structure, and thus for the synthesis of other naturally occurring sugar mimics and
their related analogs, which are of great interest as tools for biological research or as potential therapeutic
agents.
Acknowledgements
We thank Professor Kuniaki Tatsuta (Waseda University) for spectral data of the triacetate 13,
allosamizoline triacetate and allosamizoline.
References
1. Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, S. J. Antibiot. 1987, 40, 296–300.
2. Somers, P. J. B.; Yao, R. C.; Doolin, L. E.; McGowan, M. J.; Fukuda, D. S.; Mynderse, J. S. J. Antibiot. 1987, 40, 1751–1756.
3. Koga, D.; Isogai, A.; Sakuda, S.; Matsumoto, S.; Suzuki, A.; Kimura, S.; Ide, A. Agric. Biol. Chem. 1987, 51, 471–476.

N. Maezaki et al. / Tetrahedron: Asymmetry 9 (1998) 179–182
181
Scheme 2.
4. For synthesis of racemic allosamizoline, (a) Goering, B. K.; Ganem, B. Tetrahedron Lett. 1994, 35, 6997–7000; (b) Trost, B.
M.; Vranken, D. L. V. J. Am. Chem. Soc. 1993, 115, 444–458; (c) Trost, B. M.; Vranken, D. L. V. J. Am. Chem. Soc. 1990,
112, 1261–1263. For synthesis of (−)-allosamizoline from sugar: (d) Blattner, R.; Furneaux, R. H.; Kemmitt, T.; Tyler, P.
C.; Ferrier, R. J.; Tiden, A.-K. J. Chem. Soc., Perkin Trans. 1 1994, 3411–3421; (e) Kitahara, T.; Suzuki, N.; Koseki, K.;
Mori, K. Biosci. Biotech. Biochem. 1993, 57, 1906–1909; (f) Simpkins, N. S.; Stokes, S.; Whittle, A. J. J. Chem. Soc.,
Perkin Trans. 1 1992, 2471–2477; (g) Simpkins, N. S.; Stokes, S.; Whittle, A. J. Tetrahedron Lett. 1992, 33, 793–796; (h)
Nakata, M.; Akazawa S.; Kitamura, S.; Tatsuta, K. Tetrahedron Lett. 1991, 32, 5363–5366; (i) Takahishi, S.; Terayama, H.;
Kuzuhara, H. Tetrahedron Lett. 1991, 38, 5123–5126. For synthesis of (−)-allosamizoline via enzymatic desymmetrization:
(j) Shrader, W. D.; Imperiali, B. Tetrahedron Lett. 1996, 37, 599–602; (k) Griffith, D. A.; Danishefsky, S. J.; Samuel, J. J.
Am. Chem. Soc. 1996, 118, 9526–8538; (l) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1991, 113, 5863–5864.
5. Maezaki, N.; Sakamoto, A.; Soejima, M.; Sakamoto, I.; Li, Y.-X.; Tanaka, T.; Ohishi, H.; Sakaguchi, K.; Iwata, C.
Tetrahedron: Asymmetry 1996, 7, 2787–2790 and references cited therein.
6. Madhavan, G. V. B.; Martin, J. C. J. Org. Chem. 1986, 51, 1287–1293.
7. The stereochemistry of the diastereomeric isomers was determined by examining the nuclear Overhauser effect (NOE).
By irradiating the α-methine proton of the benzyloxymethyl group, NOE was registered on the α-methine protons of the
hydroxy groups in the major product and the hydroxy protons in the minor products, respectively.
8. The reaction should be carried out at 4°C in the shortest possible time. Partial racemization of sulfurs was observed at higher
temperature and with longer reaction times.
9. The diastereomeric excess of 9 was determined by 1H-NMR spectroscopy.
10. The chiral auxiliary was recovered without decreasing the enantiomeric excess.
11. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543–2549. The chemical shifts due to the C2 and C5 methine protons of the (R)-(+)-MTPA ester of 10 are 4.27 ppm
and 3.73 ppm, respectively. The corresponding protons of the (S)-(−)-MTPA ester of 10 are 4.19 ppm and 3.85 ppm,
respectively.
12. Lin, C.-C.; Weitz-Schmidt, G.; Wong, C.-H. J. Am. Chem. Soc. 1996, 118, 6826–6840. Debenzylation using 10% Pd–C for
5 days gave the complex mixture.

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13. The reaction conditions were the same as those in Ferrier’s,4d except that molecular sieves were used in order to obtain
reproducible results.
30
14. Data for compound 13: [α]D −26.0 (c=0.56, CHCl3). δH (500 MHz, CDCl3) 2.10 (s, 3H, OAc), 2.11 (s, 3H, OAc), 2.12
(s, 3H, OAc), 2.60–2.65 (m, 1H, 5-H), 3.95 (dd, 1H, J=9.2, 4.3 Hz, 2-H), 4.22 (d, 2H, J=4.9 Hz, 6-H), 4.76 (dd, 1H, J=7.3,
4.3 Hz, 3-H), 4.87 (dd, 1H, J=9.2, 6.1 Hz, 1-H), 5.24 (dd, 1H, J=9.8, 7.3 Hz, 4-H), 5.70 (br s, 1H, NH). δC (67.8 MHz,
CDCl3) 20.65, 20.69, 20.72, 47.99, 59.28, 60.68, 72.53, 77.47, 83.49, 157.29, 169.90, 170.57, 171.36. νmax (KBr) 3336,
2924, 2854, 1743, 1371, 1230, 1041 cm−1. HR-FAB-MS m/z: 316.1036 (calcd for C13H17NO8+H+: 316.1032).