iminosugars of type 7 were prepared in five-seven steps
from Cbz-protected furfurylamine 6. Both furans 4 and 6
were easily prepared as either enantiomer by the Sharpless
asymmetric dihydroxylation reaction (AD)14 and amino-
hydroxylation reaction (AA),15 respectively. Buoyed by this
success, we decided to investigate a related strategy toward
Cbz-protected 6-amino-6-deoxysugars 1 from pyran 2. Thus
we envisioned pyran 2 arising via an Achmatowicz strategy16
from furfuryl alcohol 3 (Scheme 1). Ultimately we envision
this route allowing access to unnatural C-2/C-3-dideoxy-6-
aminosugars.
Scheme 2
Traditionally, 6-amino-6-deoxysugars are obtained from
an azide displacement of a protected C-6-halosugar followed
by reduction to the free amine.2,17,18 Because we desired
access to both enantiomers of various 6-aminosugars, we
were interested in testing the viability of an Achmatowicz
approach (2 from 3) to these aminoglycoside intermediates16
(Scheme 1), where the initial asymmetry will be derived from
furan 3. Herein we report our successful efforts at the
conversion of furfural into either enantiomer of N-Cbz-
protected â-pivaloyl-6-aminomannose 1a and the corre-
sponding talose and gulose isomers 1b and 1c.
Previously we found that N-Cbz-protected amino alcohol
3 was produced (42% yield) as the major regioisomer (2:1
ratio) from the asymmetric aminohydroxylation (AA) of
vinylfuran, however in low enantioexcess.19 Using the
(DHQ)2PHAL ligand the minor isomer (+)-9 was pro-
duced in greater than 87% enantiomeric excess,20 while the
major isomer (+)-3 was formed with 14% enantiopurity
(Scheme 3). Accordingly, the pseudoenantiomeric ligand
logues will greatly increase our understanding of how to
control bacterial infections and resistance.9
Analysis of the aminoglycosides reveals two common
structural motifs, a 2-deoxystreptamine core and variously
substituted aminosugars (Scheme 1). Wong and Mobashery
have demonstrated the importance of the 6-amino-6-deoxy-
sugar for both ribosomal RNA binding and antibiotic
activity.5,10 Previous structure-activity studies of the ami-
noglycoside antibiotics have used semisynthesis techniques
to remove hydroxyl groups from the existing aminoglyco-
sides and strategically added functional groups of interest.11
We felt a complementary approach would be to start with a
drastically simplified structure and to sequentially increase
its stereochemical and functional complexity. To implement
this strategy, we desired a flexible route to D- and L-6-amino-
6-deoxysugars that allows for the synthesis of various
stereoisomers and deoxy analogues.
Recently, our group has had success at using asymmetric
catalysis for the synthesis of D- and L-sugars and iminosugars
from the achiral vinylfuran via chiral furans 4 and 6 (Scheme
2).12,13 Four hexoses of the type 5 were derived from
monoprotected diol 4 in four-six steps. Similarly, two
Scheme 3
(6) (a) Green, M. R. AIDS Res. ReV. 1993, 3, 41-55. (b) Alper, P. B.;
Hendrix, M.; Sears, P.; Wong, C.-H. J. Am. Chem. Soc. 1998, 120, 1965-
1978.
(7) Miller, G. H.; Sabatelli, F. J.; Hare, R. S.; Glupczynski, Y.; Mackey,
P.; Shlaes, D.; Shimizu, K.; Shaw, K. J.; Bauernfeind, A.; Schweighart, S.;
Shannon, K.; Patzer, J.; Molinari, G.; Schito, G. C.; Gomezlus, R.;
Gomezlus, S.; Ferreira, H.; Sousa, J. C.; Vaz, M. J. M.; Collatz, E.; Bismuth,
R.; Lambert, T.; Courvalin, P.; Minozzi, C.; Klugman, K. Clin. Infect. Dis.
1997, 24, S 46-S 62.
(8) For instance, worldwide Streptococcus pneumoniae is responsible
for 1.2 million deaths per year in children under the age of 5, see: (a)
Bruyn G. A. W.; Zegers, B. J. M.; van Furth, R. Clin. Infect. Dis. 1992,
14, 251-262. (b) Janoff, E. N.; Rubins, J. B. Microb. Drug Resist. 1997,
3, 215-232. Even more alarming is that Mycobacterium tuberculosis is
estimated to cause 3 million deaths per year, see: (c) Swartz, M. N. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 2420-2427.
(9) Umezawa, H.; Kondo, S. Mechanisms of Resistance to Aminogly-
coside Antibiotics. In Aminoglycoside Antibiotics; Hooper, I. R., Umezawa,
H., Eds.; Springer-Verlag: New York, 1982.
(DHQD)2PHAL provided the enantiomer (-)-3 in a slightly
higher enantiomeric excess (20%) and (-)-9 in a similar
enantiomeric excess (> 87%). Although the use of
(14) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(15) (a) Sharpless, K. B.; Patrick, D. W.; Truesdale, L. K.; Biller, S. A.
J. Am. Chem. Soc. 1975, 97, 2305-2306. (b) Li, G.; Chang, H.-T.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451-454.
(16) An Achmatowicz reaction is the oxidative rearrangement of furfuryl
alcohols to 2-substituted 6-hydroxy-2H-pyran-3(6H)-ones. (a) Achmatowicz,
O.; Bielski, R. Carbohydr. Res. 1977, 55, 165-176. (b) Grapsas, I., K.;
Couladouros, E. A.; Georgiadis, M. P. Pol. J. Chem. 1990, 64, 823-826.
For its use in carbohydrate synthesis, see: ref 12 and the following. (c)
Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863-866. (d) Balachari,
D.; O’Doherty, G. A. Org. Lett. 2000, 2, 4033-4036.
(17) (a) Ponpipom, M. M.; Hanessian, S. Can. J. Chem. 1972, 50, 246-
252. (b) Ponpipom, M. M.; Hanessian, S. Can. J. Chem. 1972, 50, 253-
258.
(10) Roestamadji, J.; Grapsas, I.; Mobashery, S. J. Am. Chem. Soc. 1995,
117, 11060-11074.
(11) (a) Umezawaa, S.; Tsuchiya, T. Total Synthesis and Chemical
Modification of the Aminoglycoside Antibiotics. In Aminoglycoside Anti-
biotics; Hooper, I. R., Umezawa, H., Eds.; Springer-Verlag: NewYork,
1982. (b) Okuda, T. Ito, Y. Biosynthesis and Mutasynthesis of Aminogly-
coside Antibiotics. In Aminoglycoside Antibiotics; Hooper, I. R., Umezawa,
H., Eds.; Springer-Verlag: NewYork, 1982.
(12) (a) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem.
1999, 64, 2982-2983. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.;
Young, V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17-36.
(13) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401-404.
(18) Recently, Herscovici reported the use of this approach to structures
related to 2 by a six-step route from triacetyl-D-glucal, see: Herscovici, J.;
Egron, M. J.; Quenot, A.; Leclercq, F.; Leforestier, N.; Mignet, N.; Wetzer,
B.; Scherman, D. Org. Lett. 2001, 3, 1893-1896.
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