Palladium(II)-catalyzed cyclization of urethanes and total synthesis of 1-deoxymannojirimycin.

Article abstract of DOI:10.1021/ol0060432

The palladium(II)-catalyzed cyclization of the urethane 8, which was derived from D-mannitol, gave the cyclic compound 9 with excellent diastereoselectivity. During these transformations, the Pd(II) species are not reduced and thus the catalyst can recycle without its reoxidation. The cycloadduct 9 was converted to 1-deoxymannojirimycin.

Full text of DOI:10.1021/ol0060432

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2427-2429
Palladium(II)-Catalyzed Cyclization of
Urethanes and Total Synthesis of
1-Deoxymannojirimycin
Hajime Yokoyama, Kumiko Otaya, Hisatake Kobayashi, Masahiro Miyazawa,
Seiji Yamaguchi, and Yoshiro Hirai*
Department of Chemistry, Faculty of Science, Toyama UniVersity, 3190 Gofuku,
Toyama 930-8555, Japan
hirai@sci.toyama-u.ac.jp
Received May 11, 2000
ABSTRACT
The palladium(II)-catalyzed cyclization of the urethane 8, which was derived from D-mannitol, gave the cyclic compound 9 with excellent
diastereoselectivity. During these transformations, the Pd(II) species are not reduced and thus the catalyst can recycle without its reoxidation.
The cycloadduct 9 was converted to 1-deoxymannojirimycin.
Stereoselective amino cyclization of alkenylamines is one
of the most important methodologies for the stereoselective
construction of nitrogen hetero alicycles.1 Recently we
developed an intramolecular substitution of an allylic alcohol
by a heteroatom using a palladium catalyst without activation
of an allylic alcohol.2 As a continuation of this work, we
decided to investigate the synthesis of azasugars using this
reaction. Carbohydrates play an important role in many in
vivo biological phenomena. Recently many azasugars were
found to be efficient inhibitors of the carbohydrate hydro-
genase and transferase.3 In these azasugars, 1-deoxyman-
nojirimycin (1), isolated from Lonshocarpus sericeus by L.
E. Fellows in 1979,4 showed significant biological activity
as an inhibitor of R-L-fucosidase, R-D-mannnosidase and R-D-
glucosidase.5 As a result, much synthetic effort6 has been
directed toward the stereoselective synthesis of 1-deoxy-
mannojirimycin (1). Herein we report the preparation of the
optically active piperidine 9 using Pd(II)-catalyzed cycliza-
tion and the conversion of this piperidine 9 to 1-deoxy-
mannojirimycin (1).
(1) (a) Saitoh, Y.; Moriyama, Y.; Hirota, H.; Takahashi, T.; Khuong-
Huu, Q, Bull. Chem. Soc, Jpn. 1981, 54, 488. (b) Hirama, M.; Shigemoto,
T.; Yamazaki, Y.; Ito, S. J. Am. Chem. Soc. 1985, 107, 1797. (c) Knapp,
S.; Rodriques, K. E.; Levorse, A. T.; Ornaf, R. M. Tetrahedron Lett. 1985,
26, 1803. (d) Tamaru, Y.; Hojo, M.; Yoshida, Z. J. Org. Chem. 1988, 53,
5731 and references therein.
(2) Hirai, Y.; Watanabe, J.; Nozaki, T.; Yokoyama, H.; Yamaguchi, S.
J. Org. Chem. 1997, 62, 776. Hirai, Y.; Nagatsu, M. Chem. Lett. 1994, 21.
Hirai, Y.; Terada, T.; Momose, T. Tetrahedron Lett. 1992, 33, 7893.
(3) (a) Fleet, G. W. J.; et al. FEBS Lett. 1998, 237. (b) Baxter, E. W.;
Reitz, A. B. J. Org. Chem. 1994, 59, 3174. (c) Sinnott, L. M. Chem. ReV.
1990, 90, 1171. (d) Tsukamoro, K.; et al. Clin. Res. 1989, 37A, 722. (d)
Gruters, R. A.; Niefies, J. J.; Tersmette, M. I.; DeGroede, R. E.; Tulp, A.;
Heisman, H. G.; Miedema, F.; Ploegh, H. L. Nature 1987, 330, 74. (e)
Bermaki, R. J.; Korytnyk, W. Cancer Metastasis ReV. 1985, 4, 81.
Our starting material, 3,4-di-O-benzyl-5,6-O-isopropyl-
idene-D-mannitol (2), was prepared from D-mannitol by a
(4) Fellows, L. E.; Bell, E. A.; Lynn, D. G.; Pilkiewicz, F.; Miura, I.;
Nakanishi, K. J. Chem. Soc., Chem. Commun. 1979, 22, 977.
(5) (a) Evans, S. V.; Fellows, L. E.; Shing, T. K. M.; Fleet, G. W. J.
Phytochemistry 1985, 24. 1953.
10.1021/ol0060432 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/12/2000

known procedure.7 Oxidative cleavage of the diol 2 followed
by Horner-Wadsworth-Emmons reaction afforded the R,â-
unsaturated ester 3 in 70% overall yield (Scheme 1).
mixtures 99a and 109b in 86% yield, the ratio of which was
>26:1 (Scheme 2). The structure of the major product 9 was
Scheme 2
Scheme 1
confirmed by its spectral data. The stereoselective formation
of 9 could be explained by assuming the cyclization proceed
via transition state A. Transition state B, which leads to 10,
would be disadvantageous because of nonbonding gauche
repulsion between the Boc group and the π-allyl-oxy
palladium complex.
Conversion of 9 to 1-deoxymannojirimycin (1) was
effected by the three-step sequence shown in Scheme 3.
Scheme 3
Reduction of the ester group of 3 and protection of the
resulting alcohol by the pivaloyl (Piv) group gave, in 88%
yield, the pivaloyl ester, which was treated with hydrochloric
acid to give the diol 4 in 95% yield. Tosylation of the diol
4 followed by treatment with potassium carbonate gave the
epoxide 5 in 76% yield.
Regioselective ring-opening of 5 with sodium azide and
subsequent protection of the resulting alcohol with the
methoxy methyl group gave the azide 6 in 39% yield.
Reduction by PPh3 and protection of the resulting amine
gave, in 44% yield, the pivaloyl ester 7, the pivaloyl group
of which was deprotected to afford the allyl alcohol 8 in a
quantitative yield.8
The allyl alcohol 8 was treated with 15 mol % PdCl2(CH3-
CN)2 in THF at room temperature to give the cyclized
Ozonolysis of 9 and reductive workup (NaBH4) gave the
alcohol 11 in 92% yield. Removal of the benzyl group and
the N-tert-butoxy carbonyl group (Boc) in 11 [TFA, CH2-
Cl2; H2, Pd/C, EtOH] afforded 1-deoxymannojirimycin (1),
(6) (a) Meyers, A. I.; Andres, C. J.; Resek, J. E.; Woodall, C. C.;
McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron 1999, 55, 8931.
(b) Cook, G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59, 3575.
(7) This procedure was three steps (overall 25% yield). cf. Takano, S.;
Ogasawara, K. J. Synth. Org. Chem., Jpn. 1987, 45, 1157 and references
therein.
1
(9) (a) Data of 9: [R]26 -1.21° (c 1.16, CHCl3); H NMR (400 MHz,
D
CDCl3) δ ) 7.39-7.22 (m, 10H), 6.00 (ddd, J ) 6.2, 10.0, 17.6 Hz, 1H),
5.08 (dd, J ) 2.5, 11, 7 Hz, 1H), 5.00-4.75 (br, 1H), 4.73-4.62 (m, 4H),
4.58 (d, J ) 12.2 Hz, 1H), 4.43 (d, J ) 12.0 Hz, 1H), 4.06 (brd, 1H), 3.94
(ddd, J ) 3.0, 4.9, 11.2, Hz, 1H), 3.82 (t, J ) 3.1 Hz, 1H), 3.72-3.61 (m,
1H), 3.35 and 3.34 (two s, 3H), 3.23 (t, J ) 12.0 Hz, 1H), 1.45 (s, 9H); IR
(neat) 1694(CdO) cm-1. Anal. Calcd for C28H37NO6: C, 69.54; H, 7.71;
N, 2.90. Found: C, 69.54; H, 7.70; N, 2.66. (b) Data of 10: 1H NMR (400
MHz, CDCl3) δ ) 7.41-7.21 (m, 10H), 6.08 (ddd, J ) 3.7, 10.7, 17.6 Hz,
1H), 5.27 (brd, 1H), 5.13 (brd, 1H), 4.86-4.66 (m, 7H), 4.20-4.03 (m,
2H), 3.99-3.92 (m, 1H), 3.45 (dd, J ) 3.2, 10.2 Hz, 1H), 3.41 (s, 3H),
2.96-2.73 (m, 1H), 1.45 (s, 9H).
(8) Data of 8: [R]28D 35.1° (c 1.15, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.36-7.24 (m, 10H), 5.99 (ddd, J ) 4.6, 5.9, 15.6 Hz, 1H), 5.66 (dd, J
) 8.1, 15.6 Hz, 1H), 5.14-5.06 (m, 1H), 4.76 (d, J ) 12.0 Hz, 1H), 4.73
(d, J ) 12.0 Hz, 1H), 4.61 (d, J ) 6.8 Hz, 1H), 4.59 (d, J ) 11.7 Hz, 1H),
4.54 (d, J ) 6.8 Hz, 1H), 4.38 (d, J ) 11.7 Hz, 1H), 4.20 (dd, J ) 4.6,
13.4 Hz, 1H), 4.14 (dd, J ) 5.9, 13.4 Hz, 1H), 3.97 (brt, 1H), 3.81-3.74
(m, 2H), 3.53 (ddd, J ) 2.4, 8.1, 14.4 Hz, 1H), 3.36 (s, 3H), 3.13 (ddd, J
) 4.4, 8.1, 14.4 Hz, 1H), 1.41 (s, 9H); IR (neat) 3434 (NH, OH), 1695
(CdO) cm-1. Anal. Calcd for C28H39NO7: C, 67.04; H, 7.84; N, 2.79; O,
22.33. Found: C, 67.22; H, 8.08; N, 2.54; O, 22.16
2428
Org. Lett., Vol. 2, No. 16, 2000

this reaction is shown in Scheme 4. Transition state C would
be disadvantageous because of nonbonding gauche repulsion
between the Boc group and the pivaloyl group.
Scheme 4
In conclusion, we have described a novel asymmetric
synthesis of 1-deoxymannnojirimycin (1), the R-glycosidase
inhibitor, started from D-mannitol (16 steps, overall 2% yield
from 2). The key step in the sequence is the palladium(II)-
catalyzed cyclization of the urethane 8.
Acknowledgment. We are grateful to Dr. John R.Stille,
Eli Lilly and Company, for kindly providing us with NMR
data of the natural 1-deoxymannojirimycin. This work was
supported by a grant-in-aid for Scientific Research (C) from
the Ministry of Education, Science, Sports, and Culture of
Japan.
whose structure was established by comparison of its NMR
data with that of the natural compound.6b
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
We also examined the Pd(II)-catalyzed cyclization of the
pivaloyl ester 7. Compound 7 was treated with 20 mol %
PdCl2(CH3CN)2 in THF at room temperature to give the
piperidines 9 and 10 in 36% yield (76% conversion yield),
the ratio of which was 2:9. The transition state model for
OL0060432
Org. Lett., Vol. 2, No. 16, 2000
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