exo-imino to endo-iminocyclitol rearrangement. A general route to five-membered antiviral azasugars

Article abstract of DOI:10.1021/ol061071r

A facile synthesis is reported for five-membered iminocyclitols which allows for variation in stereochemistry at all the chiral centers, diverse C₁- and N-substitution, and the potential for a three-component combinatorial process. The key step

Full text of DOI:10.1021/ol061071r

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3465-3467
exo-Imino to endo-Iminocyclitol
Rearrangement. A General Route to
Five-Membered Antiviral Azasugars
Robert M. Moriarty,*,† Carmen I. Mitan,† Norica Branzaˇ-Nichita,‡
|
Kenneth R. Phares,§ and Damon Parrish
UniVersity of Illinois at Chicago, Department of Chemistry, Chicago, Illinois 60607,
Institute of Biochemistry of the Romanian Academy, Splaiul Independentei 296,
77700 Bucharest, Romania, United Therapeutics Corporation Research, Triangle Park,
North Carolina 27709, and Laboratory for the Structure of Matter, Department of the
NaVy, NaVal Research Laboratory, Washington, D.C. 20375
moriarty@uic.edu
Received May 2, 2006
ABSTRACT
A facile synthesis is reported for five-membered iminocyclitols which allows for variation in stereochemistry at all the chiral centers, diverse
C1- and N-substitution, and the potential for a three-component combinatorial process. The key step is inversion at the C4 stereocenter ( -lyxo
sugar -ribono azasugar). The exo-imino to endo-iminocyclitol process was extended to the -lyxo and the - and -hexose series. Some
analogues were found to be more potent than N-butyl DNJ and N-nonyl DNJ in antiviral activity.
L
f
D
D
D
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Azasugars are of considerable interest in modern glyco-
biology.1 Recently, five-membered azasugars have assumed
high biological significance, even eclipsing that of the better
known six-membered deoxynojirimycin (DNJ)2 and deoxy-
galactojirimycin (DGJ).3 This is largely due to the work of
Wong et al. who reported that members of this class of
compounds were inhibitors of glycosidases and glycosyl-
transferases.4 These workers showed, using a small library
of five-membered C1 alkyl-substituted analogues made using
a Strecker synthesis, that selective inhibition of R-Glc-ase,
R-Man-ase, R-Gal-ase, and â-Gal-ase could be effected.4 The
pyrrolidine ring system had 2(R), 3(R), 4(S), and 5(R) stereo-
chemistries, and the ring could adopt either a galacto or a
manno conformation. Our interest is in azasugars as antiviral
compounds, e.g., hepatitis B virus (HBV),5 hepatitis C virus
(HCV),6 and human immunodeficiency virus (HIV).7 Among
pyrrolidine azasugars, LAB1 (1,4-dideoxy-1,4-imino-L-
arabinitol) was shown to inhibit both the cytopathic effect
of HIV and the yield of infectious viruses.8 A priori, one
would expect that interference with the host cellular process-
ing of carbohydrates by glucosidase inhibition could affect
the infectivity of the virus by producing defective envelope
glycoproteins.
† University of Illinois at Chicago.
‡ Institute of Biochemistry of the Romanian Academy.
§ United Therapeutics Corporation.
| Laboratory for the Structure of Matter.
(5) Mehta, A.; Carrouee, S.; Conyers, B.; Jordan, R.; Butters, T.; Dwek,
R. A.; Block, T. M. Hepatology 2001, 33, 1488.
(6) (a) Zitzmann, N.; Mehta, A. S.; Carroue´e, S.; Butters, T. D.; Platt,
F. M.; McCauley, J.; Blumberg, B. S.; Dwek, R. A.; Block, T. M. Proc.
Natl. Acad. Sci. U.S.A. 1999, 96, 11878. (b) Durantel, D.; Carroue´e-Durantel,
S.; Branza-Nichita, N.; Dwek, R. A.; Zitzmann, N. Antimicrob. Agents
Chemother. 2004, 48, 497.
(7) Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong,
S. K.; Ramsden, N. G.; Jacob, G. S.; Rademacher, T. W. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 9229.
(8) Behling, J. R.; Campbell, A. L.; Babiak, K. A.; Ng, J. S.; Medich,
J.; Farid, P.; Fleet, G. W. J. Tetrahedron 1993, 49, 3359.
(1) (a) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199. (b)
Look, G. C.; Fotsch, C. H.; Wong, C. H. Acc. Chem. Res. 1993, 26, 182.
(c) Pearson, M. S. M.; Mathe´-Allainmat, M.; Fargeas, V.; Lebreton, J. Eur.
J. Org. Chem. 2005, 11, 2159.
(2) Mehta, A.; Ouzounov, S.; Jordan, R.; Simsek, E.; Lu, X.; Moriarty,
R. M.; Jacob, G.; Dwek, R. A.; Block, T. M. AntiViral Chem. Chemother.
2002, 13, 299.
(3) Mehta, A.; Conyers, B.; Tyrrell, D. L. J.; Walters, K.-A.; Tipples,
G. A.; Dwek, R. A.; Block, T. M. Antimicrob. Agents Chemother. 2002,
46, 4004.
(4) Saotome, C.; Wong, C.-H.; Kanie, O. Chem. Biol. 2001, 8, 1061.
10.1021/ol061071r CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/15/2006

The mechanism of action of R-glucosidase inhibitors such
as N-butyl and N-nonyl-DNJ upon HBV and bovine viral
diarrhea virus (BVDV, a surrogate for HCV which causes
human hepatitis C) is known in detail.9 All of these
flaviviridaes gain their glycoprotein envelope in the endo-
plasmic reticulum (ER). An obligate step is cleavage of the
terminal glucose from oligosaccharide (Gla)3(Man)9(GlcNAc)2
from an N-linked glycoprotein.10
Scheme 2. Synthesis of
N-n-Nonyl-C1-alkyl-1,4-imino-1,4-dideoxy-L-ribitols
We report now a general synthesis of five-membered
iminocyclitols which allows for variation in the stereochem-
istry at all the chiral centers, diverse C1- and N-substitution,
and the potential for a three-component combinatorial
process.11
anti hepatitis B agent, and the relationship between the linear
acyclic ceramide structure and the cyclic azasugars has been
pursued with respect to antiviral activity and glucosidase
inhibitors.14
Figure 1. Basic reaction and X-ray structure of 2a.
Scheme 3. Mechanism of exo-Imino to endo-Imino
Rearrangement
Figure 1 exemplifies the key step in the exo-imino to endo-
iminocyclitol rearrangement in which the L-lyxo sugar (1a)
is converted to the D-ribo iminocyclitol (2a). The X-ray
structure of the D-ribo iminocyclitol (2a) is as shown. The
reaction was generalized in the L-lyxo f D-ribo series
(Scheme 1) with diversity in the C1 alkyl substituent
eventuating in the series of analogues 6a-d.12 The N-alkyl
substituent is constant, C9H19, but this is independently
variable based on the aldehyde used in the reductive
amination step (5 f 6).13
Scheme 1. Synthesis of
N-n-Nonyl-C1-alkyl-1,4-imino-1,4-dideoxy-D-ribitols
The mechanism of 4 f 2 is shown in Scheme 3 with the
key step being the intramolecular 5-exo-tet ring opening of
the epoxide with inversion of configuration at C4.15a-d
(9) (a) Block, T. M.; Lu, X.; Platt, F. M.; Foster, G. R.; Gerlich, W. H.;
Blumberg, B. S.; Dwek, R. A. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 2235.
(b) Branza-Nichita, N.; Durantel, D.; Carroue´e-Durantel, S.; Dwek, R. A.;
Zitzmann, N. J. Virol. 2001, 75, 3527. (c) Durantel, D.; Branza-Nichita,
N.; Carroue´e-Durantel, S.; Butters, T. D.; Dwek, R. A.; Zitzmann, N. J.
Virol. 2001, 75, 8987.
(10) (a) Lu, X.; Mehta, A.; Dwek, R.; Butters, T.; Block, T. Virology
1995, 213, 660. (b) Lu, X.; Mehta, A.; Dadmarz, M.; Dwek, R.; Blumberg,
B. S.; Block, T. M. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2380.
(11) For other recent combinatorial approaches, see: Chapman, T. M.;
Davies, I. G.; Gu, B.; Block, T. M.; Scopes, D. I. C.; Hay, P. A.; Courtney,
S. M.; McNeill, L. A.; Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc.
2005, 127, 506.
(12) For related iminocyclitols, see: (a) Sifferlen, Th.; Defoin, A.; Streith,
J.; Le Noue¨n, D.; Tarnus, C.; Dosbaaˆ, I.; Foglietti, M.-J. Tetrahedron 2000,
56, 971. (b) Wang, Y.-F.; Dumas, D. P.; Wong, C.-H. Tetrahedron Lett.
1993, 34, 403.
Members of the enantiomeric series of compounds have
been made in the D-lyxo f L-ribo series (Scheme 2).12 This
is important because the C4 (S) stereochemistry is the same
as that for the C2 amino carbon of R- and â-galactosyl
ceramide as well as that for the C3 and C4 hydroxyl groups
of R-galactosyl ceramide. R-Galactosyl ceramide is a potent
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Org. Lett., Vol. 8, No. 16, 2006

Wasserman et al. have shown that δ,ꢀ-epoxyimines undergo
intramolecular cyclization. Thus, 6,7-epoxy-2-heptanone
upon treatment with benzylamine yielded N-benzyl-6-oxa-
8-azabicyclo[3.2.1]octane. In contrast to 10 f 2, in the epoxy
heptanone system, the hydroxymethyl group adds intra-
molecularly to the imino double bond to yield the oxa-
tropane.15e No evidence of such an intramolecular addition
in the present epoxy imine system (10) was observed.
The exo-imino to endo-iminocyclitol process works equally
efficiently in the D- and L-hexose series with the interesting
consequence that a double inversion occurs at two carbon
atoms, namely, C4 and C5. This process is illustrated by the
conversion of the L-gulono analogue (11) to the 1,4-imino-
1,4-dideoxy-D-talitol (13) (Scheme 4) and of the D-mannono
Scheme 5. Synthesis of
N-n-Nonyl-C1-methyl-1,4-imino-1,4-dideoxy L-allitol
Scheme 4. Synthesis of
C1-Octyl-1,4-imino-1,4-dideoxy-D-talitol
logues 6d (IC50 ) 4.6 µM) and 9c (IC50 ) 8.2 µM) in the
D-ribo and L-ribitol series, respectively, were less active
relative to the N-desalkyl (NH) compound 8b.
The general route to azasugars disclosed in this report fits
within the context of other methods for their synthesis. For
example, a number of C1-substituted iminocyclitols have been
synthesized from 5-O-TBDMS-1-N-dehydro-1,4-imino-2,3-
O-isopropylidene-D-ribitol, which is formed by dehydro-
chlorination of the N-chloroamine and subsequent nucleo-
philic addition of lithium alkyls, aryls, and heteroaryls.17-19
The C1 aryl compounds are powerful inhibitors for the
nonspecific nucleoside N-ribohydrolases.18 The C1 nucleo-
sides are called immucillins and are important PNP inhibi-
tors.19 In the present synthesis, the C1 substituent is installed
at an earlier stage and the troublesome dimerization and
trimerization of the C1-unsubstituted 1-N-pyrrolidines, used
as starting materials, are avoided.
analogue (14) to the 1,4-imino-1,4-dideoxy-L-allitol (16)
(Scheme 5).16
The antiviral activity of selected C1 monoalkyl and N,C1
dialkyl analogues was evaluated in the bovine viral diarrhea
virus assay (BVDV).2 Compound 8b having no alkyl group
on nitrogen possesses an IC50 value of 1.5 µM. This value
is superior to that for N-n-butyl DNJ (IC50 ) 125 µM) and
N-n-nonyl DNJ (IC50 ) 10 µM).9 The N-C1-Dialkyl ana-
Acknowledgment. We thank the United Therapeutics Cor-
poration (UTC) for support of this work under an unrestricted
gift to the University of Illinois at Chicago. We are also
grateful for valuable discussions of the biological results with
scientists at UTC, Raymond A. Dwek and Terry D. Butters
at the Department of Biochemistry, Oxford University, as
well as insightful discussions of the chemistry with George
Fleet of the Chemistry Department, Oxford University.
Supporting Information Available: Experimental pro-
cedures and compound characterization data are available
in a PDF file, and X-ray crystallographic data are available
in a CIF for 2a. This material is available free of charge via
the Internet at http://pubs.acs.org
(13) N-Alkylation, preferably C8-C9 is a requisite for BVDV and HCV
activity. See: Mellor, H. R.; Nolan, J.; Pickering, L.; Wormald, M. R.;
Platt, R. A.; Dwek, R. A.; Fleet, G. J.; Butters, T. D. Biochem. J. 2002
366, 225. (CF3CO)2O/H2O acts as a solvent for the substrate. The water
affords a slow release of CF3COOH necessary for hydrolysis.
(14) (a) Mehta, A. S.; Gu, B.; Conyers, B.; Ouzounov, S.; Wang, L.;
Moriarty, R. M.; Dwek, R. A.; Block, T. M. Antimicrob. Agents Chemother.
2004, 48, 2085. (b) Boucheron, C.; Desvergnes, V.; Compain, P.; Martin,
O. R.; Lavi, A.; Mackeen, M.; Wormald, M.; Dwek, R.; Butters, T. D.
Tetrahedron: Asymmetry 2005, 16, 1747.
OL061071R
(15) (a) Tenud, L.; Farooq, S.; Seibl, J.; Eschenmoser, A. HelV. Chim.
Acta 1970, 53, 2059. (b) Baldwin, J. E. J. Chem. Soc., Chem. Commun.
1976, 18, 734. (c) A similar epoxide intermediate has been observed in the
base hydrolysis of 7. Treatment of 7 with aqueous ammonia takes a different
pathway yielding the six-membered lactam, 5-amino-7-deoxy-2,3-O-iso-
propylidene, 1,5-lactam. See: Godskesen, M.; Lundt, I.; Madsen, R.;
Winchester, B. Bioorg. Med. Chem. 1996, 4, 1857. (d) In the case of hydro-
xylamine, a five-membered nitrone is formed. See: Duff, F. J.; Vivien, V.;
Wightman, R. H. J. Chem. Soc., Chem. Commun. 2000, 21, 2127. (e) Was-
serman, H. H.; Thyes, M.; Wolff, S.; Rusiecki, V. Tetrahedron Lett. 1988,
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(16) (a) Cenci di Bello, I.; Fleet, G. W. J.; Namgoong, S. K.; Tadano,
K.; Winchester, B. Biochem. J. 1989, 259, 855. (b) Al Daher, S.; Fleet, G.;
Nagmoong, S. K.; Winchester, B. Biochem. J. 1989, 258, 613. (c) Lundt,
I.; Madsen, R.; Al Daher, S.; Winchester, B. Tetrahedron 1994, 50, 7513.
(17) For a review of polyhydroxylated pyrrolidine cyclic imines, see:
Chapman, T. M.; Davies, I. G.; Gu, B.; Block, T. M.; Scopes, D. I. C.;
Hay, P. A.; Courtney, S. M.; McNeill, L. A.; Schofield, C. J.; Davis, B. G.
J. Am. Chem. Soc. 2005, 127, 506.
(18) (a) Horenstein, B. A.; Zabinski, R. F.; Schramm, V. L. Tetrahedron
Lett. 1993, 34, 7213. (b) Furneaux, R. H.; Limberg, G.; Tyler, P. C.;
Schramm, V. L. Tetrahedron 1997, 53, 2915.
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L.; Tyler, P. C. Tetrahedron 2000, 56, 3053. (b) Evans, G. B.; Furneaux,
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