A rapid and efficient approach to chiral, nonracemic aza sugars from nonsugars. A formal synthesis of 1,4-dideoxy-1,4-imino-D-lyxitol

Full text of DOI:10.1021/jo960129k

2586
J . Org. Chem. 1996, 61, 2586-2587
A Ra p id a n d Efficien t Ap p r oa ch to Ch ir a l,
Non r a cem ic Aza Su ga r s fr om Non su ga r s. A
F or m a l Syn th esis of
1,4-Did eoxy-1,4-im in o-D-lyxitol
A. I. Meyers*, C. J . Andres, J ames E. Resek,
Maureen A. McLaughlin, Charlotte C. Woodall, and
P. H. Lee
required construction of the angularly substituted (ben-
zyloxy)methylene lactam 7 followed by subsequent ste-
reoselective steps leading to the appropriate diol 9. The
latter would then serve as the pivotal precursor, after
removal of the chiral phenylglycinol moiety, to (2R,3S,4R)-
1,4-dideoxy-1,4-imino-D-lyxitol, 3, a known1j,3,7 competi-
tive inhibitor of R-galactosidase (green coffee beans).1a
The synthetic route, depicted in Scheme 1, began with
the alkylation of dihydrofuran 4 by treatment with t-BuLi
in THF (0 °C) followed by benzyloxymethyl chloride
(BOM-Cl, Fluka, 60% purity) to give crude furan deriva-
tive 5. The crude substituted dihydrofuran 5 was then
simultaneously hydrolyzed and oxidized6d by treatment
with J ones reagent to furnish the keto acid 6. Cyclode-
hydration of the latter with (S)-phenylglycinol8 gave the
chiral lactam 7 in 38% overall yield from dihydrofuran 4
without purification or isolation of any of the intermedi-
ates (5 and 6). Introduction of the unsaturation to
produce 8 was accomplished in 85% yield by treatment
with methyl phenylsulfinate and potassium hydride in
THF, followed by thermal elimination of the intermediate
sulfoxides in refluxing toluene.9
Department of Chemistry, Colorado State University,
Fort Collins, Colorado 80523
Received J anuary 23, 1996
Azasugars 1 and 2 are particularly attractive synthetic
targets because of their important biological properties
which include glycosidase inhibition,1 tumor growth
inhibition,2 and anti-HIV3 behavior. The recent intense
activity targeting the synthesis of azasugars has pro-
duced a large number of elegant and efficient routes
based on carbohydrate4 and noncarbohydrate5 starting
materials. Most of these routes, however, suffer from
excessive length or from lack of selectivity.4h,5e
The key step to introduce the vicinal hydroxyl groups
was accomplished with a catalytic quantity of osmium
tetraoxide and stoichiometric N-methylmorpholine-N
oxide (NMO) in aqueous acetone. An 80% yield of a 87:
13 mixture of endo-exo diols 9 was obtained which was
readily purified by chromatography and crystallization
to provide the major component 9b in 64% yield. The
relative stereochemistry in 9b was confirmed by X-ray
crystallography which indicates preferential entry of the
OsO4 from the endo face. In preparation for the reductive
cleavage of the C-O bond, the acetonide 10 was formed
in 98% yield using dimethoxypropane and catalytic
p-toluensulfonic acid in CH2Cl2.10
As a continuation of our studies describing stereose-
lective additions of heteroatoms to unsaturated chiral
lactams,6 we explored the diastereoselective dihydroxyl-
ation of 8 as a potential route to these important aza
sugars, e.g., 3. The implementation of this sequence
(1) Sinnott, L. M. Chem. Rev. 1990, 90, 1171.
(2) (a) Bernacki, R. J .; Korytnyk, W. Cancer Metastasis Rev. 1985,
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A.; Neefies, J . J .; Tersmette, M; DeGroede, R. E.; Tulp, A.; Huisman,
H. G.; Miedema, F.; Ploegh, H. L. Nature 1987, 330, 74.
Reductive cleavage of the oxazolidine C-O bond in 10
was the final crucial step in the synthesis. This step had
to proceed with high stereoselectivity to prevent the
formation of 11 as an epimeric mixture at C-2 of the
pyrrolidine ring. We have previously described related
reductions of the fused aziridine6c lactam 13 and the
fused cyclobutane6d lactam 14 which proceeded with a
high degree of inversion of configuration at C-5 (Scheme
2). These results were interesting based on our previous
observation of clean retention of configuration in reduc-
tions of simple unsubstituted bicyclic lactams.11 By
forming the acetonide in 10, we had, in effect, added
(4) (a) Fleet, G. W. J .; Nicholas, S. J .; Smith, P. N.; Evans, S. V.;
Fellows, L. E.; Nash, R. J . Tetrahedron Lett. 1985, 26, 3127. (b) Fleet,
G. W. J .; Son, J .-C.; Green, D. St. C.; d. Bello, I. C.; Winchester, B.
Tetrahedron 1988, 44, 2649. (c) Son, J .-C.; Fleet, G. W. J . Tetrahedron
1988, 44, 2637. (d) Setoi, H.; Kayakiri, H.; Takeno, H.; Hashimoto, M.
Chem. Pharm. Bull. 1987, 35, 3995. (e) Buchanan, J . G.; Edgar, A. R.;
Hewitt, B. D. J . Chem. Soc. Perkin Trans. 1 1987, 2371. (f) Wehner,
V.; J a¨ger, B. Angew Chem., Int. Ed. Engl. 1990, 29, 1169. (g) Moss, W.
O.; Bradbury, R. H.; Hales, N. J .; Gallagher, T. J . Chem. Soc., Perkin
Trans. 1 1992, 1901. (h) Baxter, E. W.; Reitz, A. B. J . Org. Chem. 1994,
59, 3175 and references cited therein. (i) Wong, C.-H.; Provencher, L.;
Porco, J .; J ung, S.-H.; Wang, Y.-F.; Chen, L.; Wang, R.; Steensma, D.
H. J . Org. Chem. 1995, 60, 1492. (j) Ryu, Y.; Kim, G. J . Org. Chem.
1995, 60, 103.
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DeShong, P.; Sidler, D. R.; Kell, D. A.; Aronson, N. N. Tetrahedron
Lett. 1985, 26, 3747. (c) Ziegler, T.; Straub, A.; Effenberger, F. Angew
Chem., Int. Ed. Engl. 1988, 27, 716. (d) Takahata, H.; Banba, Y.;
Tajima, M.; Momose, T. J Org. Chem. 1991, 56, 240. (e) Takano, S.;
Moriya, M.; Ogasawara, K. Tetrahedron Asymmetry 1992, 3, 681. (f)
Hudliky, T.; Rouden, J .; Luna, H. J . Org. Chem. 1993, 58, 985. (g)
Wang, Y.-F.; Dumas, D. P.; Wong, C-H Tetrahedron Lett. 1993, 34,
403. (h) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acct. Chem. Res. 1993,
26, 182. (i) Blanco, M. J .; Sardina, F. J . Tetrahedron Lett. 1994, 35,
8493. (j) Griffart-Brunet, D.; Langlois, N. Tetrahedron Lett. 1994, 35,
119, 2889. (k) Hassner, A.; Falk, E.; Nudelman, A.; Albeck, A.; Gottlieb,
H. E. Tetrahedron Lett. 1994, 35, 2397. (l) Dondoni, A.; Pierrone, D.
J . Org. Chem. 1995, 60, 4749. (m) Huwe, C. M.; Blechert, S. Tetrahe-
dron Lett. 1995, 1621. (n) Zhi-cai, S.; Chun-min, Z.; Guo-qiang, L.
Heterocycles 1995, 41, 277. (o) Altenbach, H.-J .; Wischnat, R. Tetra-
hedron Lett. 1995, 36, 4983. (p) Park, K. H. Heterocycles 1995, 41, 1715.
(q) J ohnson, C. R.; Nerukar, B M.; Golebiowski, A.; Sundram H.; Esker,
J . L. J . Chem. Soc., Chem. Commun. 1995, 1139.
(6) (a) Andres, C. J .; Spetseris, N.; Norton, J . R.; Meyers, A. I.
Tetrahedron Lett. 1995, 36, 1613. (b) Andres, C. J .; Lee, P. H.; Nguyen,
T. H.; Meyers, A. I. J . Org. Chem. 1995, 60, 3189. (c) Andres, C. J .;
Meyers A. I. Tetrahedron Lett. 1995, 36, 3491. (d) For other diastero-
facial additions in this series see: Meyers, A. I.; Tschantz, M. A.;
Brengel, G. P. J . Org. Chem. 1995, 60, 4359. (e) Brengel, G. P., Rithner,
C.; Meyers, A. I. J . Org. Chem. 1994, 59, 5144.
(7) Boshyal, B. P.; Fleet, G. W. J .; Gough, M. J .; Smith, P. W.
Tetrahedron 1987, 43, 3083.
(8) For synthetic procedures using phenylglycinol and 2-alkyldihy-
drofurans to generate various angularly substituted chiral bicyclic
lactams, see: Tschantz, M. A.; Burgess, L. E.; Meyers, A. I. Organic
Syntheses; Wiley: New York, 1994; Vol. 73, p 221.
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0022-3263/96/1961-2586$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 8, 1996 2587
Sch em e 1
Sch em e 2
with the alkoxide salts. Use of titanium-assisted silane
reductions (Scheme 2) resulted in a variety of undesired
side reactions including reduction of the acetonide ketal
center. The problem of selectivity was finally overcome
by reduction of the acetonide 10 with 9-BBN (THF,
reflux, 10 equiv) which produced a single diastereomer
of 11 in 81% yield. Subsequent hydrogenolysis of 11 with
Pd(OH)2 in the presence of di-tert-butyl dicarbonate
(Boc2O) gave, after chromatography, the N-Boc-lyxitol 12
in 75% yield, whose physical constants were identical to
those previously reported.7 The fact that (2R,3S,4R)-12
was obtained confirmed that the 9-BBN reduction of the
tricyclic intermediate 10 also proceeded with inversion
at the angular benzyloxy group. Furthermore, the
9-BBN also conveniently reduced the lactam carbonyl,
while the hydrogenation step (11 f 12) proceeded with
simultaneous removal of the N and O-benzyl groups.
In summary, the asymmetric synthesis of 12, well-
known to be carried forward to 3,7 was accomplished in
eight steps (12.3% from dihydrofuran) and in high
enantiomeric purity from nonsugar precursors. Subse-
quent reports will describe synthetic routes to other
members of these biologically important systems.
another “steric control element”12 which was anticipated
to also direct the reduction, via inversion of the benzyl-
oxymethyl substituent, to the all-cis pyrrolidine, 11.
However, when the acetonide 10 was treated with alane
under standard conditions,11 the pyrrolidine 11 was
formed in 85% yield but as a 2:1 mixture epimeric at C-2.
A variety of conditions (solvents, temperature, different
diol and angular protecting groups) failed to improve this
disappointing ratio. Additional effort was directed at
reducing the unmasked diol, 9b, in the hope that the
dialkoxyaluminum salt would itself serve as a bulky unit
to enhance facial selectivity. However, the reaction
proceeded poorly due to solubility problems associated
Ack n ow led gm en t. The authors are grateful to
Professor G. W. J . Fleet for comparison spectra and
helpful discussions. Financial support from the National
Institutes of Health is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and NMR spectra for 7-12 (11 pages).
(12) The deliberate use of an appended ring to serve as a steric
control factor has been known for almost 40 years; Woodward, R. B.;
Bader, E. F.; Bickel, H.; Frey, A. J .; Kierstead, R. W. Tetrahedron 1958,
2, 1.
J O960129K