Access to ring-expanded analogues of 2-amino sugars

Article abstract of DOI:10.1021/ol9018387

Ring-expanded 2-Nacetylamino sugar analogs of D-glucose, D-galactose, and D-mannose have been prepared by a new synthetic route. Aspects of the highly substituted a-amio aldehyde Intermediates made them central to the approach. First, they were accessed v

Full text of DOI:10.1021/ol9018387

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4482-4484
Access to Ring-Expanded Analogues of
2-Amino Sugars
Jaideep Saha and Mark W. Peczuh*
Department of Chemistry, UniVersity of Connecticut, 55 North EagleVille Road
U-3060, Storrs, Connecticut 06269
mark.peczuh@uconn.edu
Received August 7, 2009
ABSTRACT
Ring-expanded 2-N-acetylamino sugar analogs of D-glucose, D-galactose, and D-mannose have been prepared by a new synthetic route. Aspects
of the highly substituted r-amino aldehyde intermediates made them central to the approach. First, they were accessed via diastereoselective
addition of a vinyl Grignard onto protected glycosyl amines. Also, the sterics of the bis-protected amine favored the formation of only one
glycoside anomer. The new analogues reported here should prove useful in the development of tools to investigate the role of 2-amino sugars
in biology.
Carbohydrates that incorporate at least one 2-amino sugar
residue make up an important facet of glycobiology. The
diversity of examples ranges from small molecule natural
products1 to glycans,2 glycolipids,3 and glycoproteins.4
Functions mediated by these carbohydrates are similarly
broad and include antibiotic activity, biosynthesis, metabo-
lism, and cell-cell signaling. Among the most common
2-amino sugars are the N-acetylated gluco- (GlcNAc),
galacto- (GalNAc), and manno- (ManNAc) hexoses (1-3).
Analogues of 2-amino sugars have been utilized to explore
numerous aspects of glycobiology5 and also in the develop-
ment of new drugs.6
membered ring pyranoses to seven-membered ring septanoses
is akin to the homologation of purine and pyrimidine
nucleosides to their benzo-fused analogues9 or of R-amino
acids to ꢀ-amino acids.10 Syntheses of septanose carbohy-
drates to date have most commonly involved functionaliza-
tion of ring-expanded glycals (oxepines).11 Here we describe
a synthetic route for the preparation of 2-N-acetylamino
septanosides derived from D-glucose, D-galactose, and D-
mannose. Oxepines do not serve as intermediates in the
synthesis; rather, the expanded ring is formed via an
(4) (a) Weerapana, E.; Imperiali, B. Glycobiology 2006, 16, 91R. (b)
Slawson, C.; Housley, M. P.; Hart, G. W. J. Cell. Biochem. 2006, 97, 71.
(c) Dziadek, S.; Kunz, H. Chem. Record 2004, 3, 308.
(5) Agard, N. J.; Bertozzi, C. R. Acc. Chem. Res. 2009, 42, 788.
(6) Kondo, S.; Hotta, K. J. Infect. Chemother. 1999, 5, 1.
(7) (a) Markad, S.; Xia, S.; Surana, B.; Morton, M. D.; Hadad, C. M.;
Peczuh, M. W. J. Org. Chem. 2008, 73, 6341. (b) Castro, S.; Fyvie, W. S.;
Hatcher, S.; Peczuh, M. W. Org. Lett. 2005, 7, 4709.
(8) (a) Castro, S.; Duff, M.; Snyder, N.; Morton, M.; Kumar, C. V.;
Peczuh, M. W. Org. Biomol. Chem. 2005, 3, 3869. (b) DeMatteo, M.;
Snyder, N. L.; Morton, M.; Baldisseri, D. M.; Hadad, C. M.; Peczuh, M. W.
J. Org. Chem. 2005, 70, 24.
Our group has focused on the synthesis7 and characteriza-
tion8 of ring-expanded carbohydrates. Homologation of six-
(9) Kreuger, A. T.; Kool, E. T. Chem. Biol. 2009, 16, 242.
(10) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219. (b) Kritzer, J. A.; Stephens, O. M.; Gurracino, D. A.; Reznik,
S. K.; Schepartz, A. Bioorg. Med. Chem. 2005, 13, 11.
(1) Silva, J. G.; Carvalho, I. Curr. Med. Chem. 2007, 14, 1101.
(2) Imberty, A.; Lortat-Jacob, H.; Pe´rez, S. Carbohydr. Res. 2007, 342,
430.
(11) (a) Boone, M. A.; McDonald, F. E.; Lichter, J.; Lutz, S.; Cao, R.;
Hardcastle, K. I. Org. Lett. 2009, 11, 851. (b) Peczuh, M. W.; Snyder, N. L.;
Fyvie, W. S. Carbohydr. Res. 2004, 339, 1163. (c) Peczuh, M. W.; Snyder,
N. L. Tetrahedron Lett. 2003, 44, 4057.
(3) Lanctot, P. M.; Gage, F. H.; Varki, A. P. Curr. Opin. Chem. Biol.
2007, 11, 373.
10.1021/ol9018387 CCC: $40.75
Published on Web 09/01/2009
 2009 American Chemical Society

addition-cyclization sequence. A detailed consideration of
the synthesis has provided insight into the factors that
contribute to cyclization of these molecules. Importantly, the
new analogues reported here should prove to be useful in
the development of tools to investigate the role of 2-amino
sugars in biology.
Scheme 2. Synthesis of 2-Amino Septanoside 13
The strategy employed for the synthesis of the 2-amino
sugar analogues is shown in Scheme 1. Cyclization of a
Scheme 1. 2-Amino Septanoside Retrosynthetic Analysis
prepared from D-galactose and D-mannose.15 Cyclization of
12 in an acidic methanol solution furnished the protected
methyl R-2-amino septanoside 13 in 74% yield. Overall, the
five-step process gave a combined yield of 29% or an average
of 79% yield per step. The same sequence of transformations
was used to prepare 14 and 15 in 38% and 26% overall
yields, respectively.
protected hydroxy aldehyde such as 6 and subsequent
glycosylation to form 4 were the central features of the
approach. Formation of 7 via stereoselective addition of a
vinyl Grignard onto a D-glucosyl amine (9) was prece-
dented12 and provided confidence that the glycosyl amines
prepared from D-galactose and D-mannose would react in a
predictable way (vida infra). Ozonolysis of 7 to give 6
seemed equally likely. It was critical that hemiacetal 5 be
an energetically favorable intermediate in the sequence.
Reaction of related R-silyloxy and R-hydro aldehydes13 (in
place of R-amino aldehyde 6) in acidic methanol provided
only the acyclic dimethyl acetal or a mixture of cyclic and
acyclic products. We wanted to know whether, under the
same conditions, 6 would deliver glycoside 4. In short, the
route would allow us to investigate the role of the R-sub-
stituent in the cyclization reaction and also would provide
the desired analogues.
For each case we investigated, one diastereomer of the
allyl amine was selectively obtained in the Grignard addi-
tion.16 In turn, each allyl amine delivered a single septanoside
meaning that only one anomer was formed. We ascribed the
selective glycoside formation to the steric bulk associated
with the bis-protected amine at C2. Such a model would
require that glycosylation went through a cyclic oxonium
ion derived from a hemiacetal (5). Preference for a cyclic
(methyl septanoside) rather than an acyclic (dimethyl acetal)
pathway was likely based on the stability of the products.
By considering together the absolute stereochemistry at C2
as predicted by the Cram-chelate model and the trans-1,2
nature of the methyl septanosides based on the bulk of the
amino substituents,17 we proposed structures 13-15 as the
The preparation of protected methyl 2-amino septanoside
13 from 8 illustrates the synthetic route (Scheme 2).14
Formation of glycosyl amine 9 and subsequent diastereose-
lective addition of a vinyl Grignard followed literature
conditions12 giving 10 in 47% yield (two steps). Syntheses
where acetyl or Cbz groups were used to protect the allyl
amine proved problematic during deprotection; instead,
amine 10 was protected as its Fmoc carbamate, giving 11
(91%). Ozonolyis of the alkene in 11 provided hydroxy
aldehyde 12 (90%). Analysis of the NMR spectra of 12
indicated that both the aldehyde and hemiacetal forms were
populated; this was also true for the hydroxy aldehydes
1
products of our synthetic route. Both the H and 13C NMR
spectra of 13-15 proved complicated. Specifically, 1H
spectra were essentially uninterpretable, and the 13C spectra
(15) The product of Fmoc removal from 12 was a cyclic hemiacetal
that gave simplified NMR spectra. See Supporting Information.
(16) For D-glucosyl amine (9) and D-galactosyl amine (9-Gal), only one
diastereomer was formed and isolated. For D-mannosyl amine (9-Mann), a
4:1 ratio of diastereomers was observed, but only the major isomer was
isolated. See Supporting Information for details.
(12) (a) Cipolla, L.; Lay, L.; Nicotra, F.; Pangrazio, C.; Panza, L.
Tetrahderon 1995, 51, 4679. (b) Cipolla, L.; Fernandes, M. R.; Gregori,
M.; Airoldi, C.; Nicotra, F. Carbohydr. Res. 2007, 342, 1813.
(13) Castro, S.; Peczuh, M. W. J. Org. Chem. 2005, 70, 3312.
(14) The Supporting Information contains schemes for the syntheses of
14 and 15.
(17) Hindsgaul, O.; Jiao, H. Angew. Chem., Int. Ed. 1999, 38, 346.
Org. Lett., Vol. 11, No. 19, 2009
4483

were characterized by a proliferation of each carbon signal
into multiple signals. Restricted rotation of the C-N bond
of the bis-substituted amino group was responsible for this
effect.18
To test our rationale for the complicated NMR spectra and
also to prepare more relevant derivatives, we proceeded with
the stepwise deprotection of methyl septanosides 13-15. For
clarity, the deprotection sequence is shown only for D-
galactose derived septanoside 14 (Scheme 3).19 The Fmoc
the benzylic groups from oxygen and the second to remove
the benzylic group from the nitrogen, provided methyl R-2-
amino septanoside 18 in 89% yield over two steps. 3J
Coupling constant analysis on 18 proved the stereochemical
3
assignment at C1 and C2. Specifically, JH1,H2 (7.6 Hz) and
3JH2,H3 (10.0 Hz) indicated an anti relationship between H1
and H2 as well as between H2 and H3. Peracetylation of 18
then provided methyl R-2-N-acetylamino septanoside 19 in
75% yield (56% overall). The same sequence applied to 13
and 15 provided 20 and 21 in 54% and 42% yields.
Scheme 3. Formation of 2-N-Acetylamino Septanoside 19
We have demonstrated a rapid and efficient route to
2-amino septanosides from protected pyranoses. The steric
bulk of the bis-substituted amine at C2 of the hydroxy
aldehyde directed both cyclization and formation of a single
glycosidic linkage. The new ring-expanded sugar analogues
should serve as valuable tools in glycobiology. They can be
used as novel substrates in metabolic pathways or inhibitors
of glycosyl transferases and glycosidases. Similarly, they may
be used to assess the specificity of lectins in a number of
biological contexts. A key challenge that we are currently
addressing is the ability to attach other relevant aglycones
in place of a methyl group which will broaden the utility of
the analogues.
carbamate was first removed under standard conditions12b
to give 16 (84%). In the absence of the Fmoc group, the
NMR spectra of the per-benzylated systems (e.g., 16)
simplified considerably and allowed for standard interpreta-
tion. A two-step debenzylation sequence, the first to remove
Acknowledgment. Courtney S. Johnson (U. of Con-
necticut) conducted experiments on the R-silyloxy aldehyde
cited here. We thank Srikanth Rapole (HRMS) and Martha
Morton (NMR) (U. of Connecticut) for technical assistance.
M.W.P. thanks NSF for a CAREER award (CHE-0546311).
Supporting Information Available: Additional synthetic
schemes, experimental procedures, and characterization data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) (a) Smith, B. D.; Goodenough-Lashau, D. M.; D’Souza, C. J. E.;
Norton, K. J.; Schmidt, L. M.; Tung, J. C. Tetrahedron Lett. 2004, 45,
2747. (b) Murphy, P. V.; Bradley, H.; Tosin, M.; Pitt, N.; Fitzpatrick, G.;
Glass, W. K. J. Org. Chem. 2003, 68, 5692. (c) Sirasani, G.; Andrade,
R. B. Org. Lett. 2009, 11, 2085.
(19) The Supporting Information contains schemes for the syntheses of
20 and 21.
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