Synthesis of conformationally constrained C-glycosyl α- and β-amino acids and sugar-carbamino sugar hybrids via Diels-Alder Reaction

Article abstract of DOI:10.1021/ol052190u

(Chemical Equation Presented) Sugar-derived dienes undergo Diels-Alder reactions with methyl α-nitro acrylate and ethyl β-nitro acrylate to form the corresponding cycloadducts which have been converted into conformationally constrained C-glycosyl α- and β

Full text of DOI:10.1021/ol052190u

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5441-5444
Synthesis of Conformationally
Constrained C-Glycosyl - and
Acids and Sugar Carbamino Sugar
Hybrids via Diels
Alder Reaction†
r
â-Amino
−
−
K. Jayakanthan and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Vankar@iitk.ac.in
Received September 12, 2005
ABSTRACT
Sugar-derived dienes undergo Diels
which have been converted into conformationally constrained C-glycosyl
into sugar carbamino sugar hybrid molecules.
−
Alder reactions with methyl
r
-nitro acrylate and ethyl
â
-nitro acrylate to form the corresponding cycloadducts
r
- and -amino acids. Further, these â
â
-amino acids are converted
−
Naturally occurring O- and N-glycoconjugates play key roles
as carriers of biological information at the cellular level, such
as the adhesion of bacteria and viruses to cells and cell-
cell communication.1 Owing to their limited chemical and
enzymatic stabilities, recent efforts have been focused on
the synthesis of unnatural C-glycosyl amino acids with the
amino acid side chains connected to the sugar unit via linkers
such as triazoles,2a isoxazoles,2a,b acetylenes,2c alkyl chains,2d
phenyl ring,2e,f and spirolinkage.2d,g It is expected that these
may lead to chemically and metabolically more stable and
rigid analogues with potential biological activities. Encourag-
ing results of very similar binding constants and biological
properties of C-glycosides to those of oxygen counterparts
have been reported.3 In drug design, rigidity plays an
important role for the binding of a glycopeptide (or)
peptidomimetic to the target protein receptors. Compounds
that are too flexible may pay high entropic penalties on
binding such that the process becomes energetically unfavor-
able. Introducing annulation to the appropriate amino acid
residue is one of the ways to rigidify glycopeptides.4 Even
though glycosyl R-amino acids are fragments of several
natural products,5 the same is not generally true of glycosyl
â-amino acids. But â-peptides (non-natural oligomers of
â-amino acids) have been shown to fold into helices, sheets,
and turns, which are the main structural elements of proteins,
and in some instances, it has been found that they possess
even higher biological activities than their parent R-peptides.6
* To whom correspondence should be addressed. Fax: 0091-512-259
0007.
† Dedicated to Prof. S. Chandrasekaran on the occasion of his 60th
birthday.
(1) (a) Wong, C-H. Acc. Chem. Res. 1999, 32, 376. (b) Herzner, H.;
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A. Glycobiology 1993, 3, 97.
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Chem. 2000, 65, 2544. (c) Tsuruta, O.; Yuasa, H.; Kurono, S.; Hashimoto,
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2004, 6, 3123. (b) Dondoni, A.; Giovannini, P. P.; Massi, A. Org. Lett.
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10.1021/ol052190u CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/04/2005

Also recently, certain C-glycosyl â-amino acids have been
shown to be a new class of antitubercular agents.7 In addition,
some cyclic R-amino acid derivatives have been found to
be valuable enzyme inhibitors8a-c and serve as “chiral
auxiliaries” in asymmetric Diels-Alder reactions.8d On the
other hand, some cyclic â-amino acids have a range of
structural and biological properties9a including antifungal
activity.9b In view of these important effects, we now report
new methods to prepare some cyclic R- and â-amino acids
fused to a sugar moiety via a C-glycosidic linkage. These
molecules constitute another class of rigidified C-glycosyl
R- and â-amino acids.
There are several notable contributions to the area of
carbohydrate annulation involving ring-closing metathesis
(especially by Jenkins);10 Robinson annulation,11 intra-
molecular aldol condensation,12 radical cyclization,13 and
Diels-Alder cycloadditions have also been used for carbo-
hydrate annulation.14 Our approach to conformationally
constrained (annulated)-C-glycosyl R- and â-amino acids
would be based upon the Diels-Alder reaction of pyranose
dienes with R- and â-nitro acrylic esters. Accordingly, the
known pyranose diene 1a15 (Scheme 1) was reacted with
worthy in view of the fact that cycloadditions of cyclopenta-
diene or Danishefsky diene to 2 lead16a to the corresponding
cycloadducts as 85:15 and 70:30 mixtures of diastereomers
in favor of the endo nitro group. This is possibly due to the
presence of â-substituents at C-3, C-4, and C-5 which block
the â-face for high endo nitro group selectivity. Reduction
of the double bond as well as that of the nitro group was
achieved with Pd-C under H2 atmosphere, followed by
acetylation of the free amine with pyridine-Ac2O to obtain
the fused bicyclic C-glycosyl R-amino acid 4 as a single
stereoisomer in 53% yield. The moderate yield in the
hydrogenation step led us to use platinized Raney-Ni T416b
in place of Pd-C which gave the N-acetyl R-amino ester 4
in 92% yield as the sole product.
The stereoselectivity of the reduction of the hindered
double bond is consistent with similar reported observa-
tions,17 and the overall stereochemistry was confirmed by
2D NMR experiments, particularly NOESY.
There was no NOE correlation between H-1 and H-2 in
4, and J1,2 ) 10.0 Hz revealed a trans diaxial relationship
between these hydrogens (and a consequential diequatorial
relationship between the C-substitutents at the ring junctions
in 4). Subsequent NOE correlations between H-2 and amide
proton (NH) and H-2 and H-4 protons further suggested a
cis relationship between them. Additionally, no NOE cor-
relations were observed between H-1 and this NH, or H-1
and the H-5/H-3 protons, suggesting that these protons were
all trans related.
Scheme 1
Under the same conditions, the dienes 1b and 1c reacted
with 2 (Scheme 2) to give a separable mixture (82% yield)
of cycloadducts 5 and 6 in a 7:1 ratio. By way of contrast,
the stereoisomeric mixture 7 (77% yield, 7:1 ratio) was
Scheme 2
the in situ generated R-nitro methyl acrylate 216a to give the
regio- and stereoselectively controlled cycloadduct 3 in 80%
yield. The complete diastereoselectivity observed is note-
(7) Tripathi, R. P.; Tripathi, R.; Tiwari, V. K.; Bala, L.; Sinha, S.;
Srivastava, A.; Srivastava, R.; Srivastava, B. S. Eur. J. Med. Chem. 2002,
37, 773.
(8) (a) Satoru, N.; Takahiro, Y.; Takeshi, S. Jpn. Kokai Tokkyo Koho
2004, 137 pp; Chem. Abstr. 2004, 141, 277889. (b) Wook, L. J.; Yong, L.
B.; Ho, L. C.; Yun, H.; Dong, H. T.; Kyoung, K. H.; Won, Y. S.; Young,
S. J.; In, L. J.; Ho, S. M.; Sung, Y. J.; Kyung, K. M. PcT Int. Appl. 2004,
158 pp; Chem. Abstr. 2004, 140, 146014. (c) Schoepfer, J.; Gay, B.; End,
N.; Muller, E.; Scheffel, G.; Caravatti, G.; Furet, P. Bioorg. Med. Chem.
Lett. 2001, 11, 1201. (d) Avenoza, A.; Cativiela, C.; Par´ıs, M.; Peregrina,
J. M. Tetrahedron 1996, 52, 4839.
(9) (a) Fu¨lo¨p, F. Chem. ReV. 2001, 101, 2181. (b) Mittendorf, J.; Kunisch,
F.; Matzke, M.; Militzer, H.-S.; Schmidt, A.; Scho¨nfeld, W. Bioorg. Med.
Chem. Lett. 2003, 13, 433.
(10) (a) Holt, D. J.; Barker, W. D.; Jenkins, P. R.; Davies, D. L.; Garratt,
J.; Fawcett, J.; Russell, D. R.; Ghosh, S. Angew. Chem., Int. Ed. 1998, 37,
3298. (b) Holt, D. J.; Barker, W. D.; Jenkins, P. R. J. Org. Chem. 2000,
65, 482.
(11) Bonnert, R. V.; Jenkins, P. R. J. Chem. Soc., Chem. Commun. 1987,
6.
(12) Wood, A. J.; Jenkins, P. R.; Fawcett, J.; Russell, D. R. J. Chem.
Soc., Chem. Commun. 1995, 1567.
5442
Org. Lett., Vol. 7, No. 24, 2005

inseparable. Clearly, the absence of a substitutent at C-3
appears to be responsible for the low stereoselectivity
observed. Compounds 5 and 6 were separated chromato-
graphically and carried separately through the sequence of
reactions as shown in Scheme-2. Single pot reduction of the
nitro group and olefinic bond in compound 5 with Raney
Ni followed by acetylation gave the R-linked C-glycosyl
R-amino ester 8 (87%) and the â-linked c-glycosyl R-amino
ester 9 (83%) respectively whose NOESY spectra18a were
in accord with the stereochemical assignments made.
Likewise, the inseparable nitro ester 7 was converted under
the same conditions to the corresponding C-glycosyl R-amino
esters 10 and 11 in 73% and 10% yield, respectively, which
were readily separable by chromatography. Structures of
these compounds were again assigned on the basis of
Scheme 4
1
NOESY and H NMR data.18a
Diels-Alder reaction of glucal derived diene 1d15 (Scheme
3) with R-nitro methyl acrylate 2 under similar experimental
Scheme 3
reduction with Zn/HCl followed by addition of a large excess
of Et3N and Boc2O in 73-84% yields through three steps.
The major isomer in each case was separated from the
inseparable mixture of minor diastereomers (8-10%) by
SiO2 column chromatography. Exposure of the unsaturated
amino esters 15a-d to OsO4 and NMO led to dihydroxyl-
ation and the corresponding annulated C-glycosyl â-amino
esters 16a-d were obtained in good yields. Structures of
these annulated products were assigned on the basis of their
1H NMR and NOE data.18a
In every case, the H-9 proton showed a doublet (J ) 3-4
Hz) of a triplet (which is basically an overlapping doublet
of a doublet with J ) 11-12 Hz) at δ ∼2.73, indi-
cating that H-9 is flanked by two axial protons (H-10 and
one of the H-8) and one equatorial proton (the other H-8)
while H-9 itself being axial (structure 16d,18b Scheme 4).
On the other hand, H-1 appeared as a doublet with J ) 2.68
Hz or as a broad singlet indicating that H-1 must be cis to
H-10.
conditions led to cycloadduct 12 as an inseparable stereo-
isomeric mixture. However, hydrogenation of 12 followed
by acetylation gave chromatographically separable major
product â-C-glycoside 13 and minor R-C-glycoside 14 in
52% and 15% yield, respectively, whose structures were
1
established based on their H NMR data and the NOESY
experiments.18a
For the synthesis of annulated â-amino acids, dienes 1a-d
were reacted with ethyl â-nitro acrylate19 (Scheme 4) to
afford the corresponding cycloadducts as inseparable stereo-
isomers. The crude products were subsequently converted
to the corresponding carbamates 15a-d sequentially by
(13) Wood, A. J.; Jenkins, P. R. Tetrahedron Lett. 1997, 38, 1853.
(14) Giuliano, R. B.; Jordan, A. D., Jr.; Gauthier, A. D.; Hoogsteen, K.
J. Org. Chem. 1993, 58, 4979 and references therein.
(15) Ben-Ami, F.; Kasuto, K. I.; Anke, G.; Sarah, A.; Schmidt, R. R. J.
Carbohydr. Chem. 2000, 19, 661.
(16) (a) Wade, P. A.; Murray, J. K., Jr.; Shah-Patel, S.; Carroll, P. J.
Tetrahedron Lett. 2002, 43, 2585. (b) Nishimura, S. Bull. Chem. Soc. Jpn.
1959, 32, 61.
(17) Masesane, I. B.; Steel, P. G. Synlett 2003, 735.
(18) (a) See the Supporting Information. (b) Spectral data for compounds
16a-c are given in the Supporting Information.
(19) Jayakanthan, K.; Madhusudanan, K. P.; Vankar, Y. D. Tetrahedron
2004, 60, 397.
Reduction of compounds 16a-d with LiAlH4 led to the
formation of the corresponding triols 17a-d, whose struc-
tures were based on the spectral data obtained18a for these
compounds. These molecules represent hybrid20 structures
of D-galactose or D-glucose with 4-deoxycarbasugars. In view
of the fact that carbasugars and their hybrids act21 as
(20) Mehta, G.; Singh, V.; Chem. Soc. ReV. 2002, 31, 324.
(21) Mehta, G.; Ramesh, S. S. Chem. Commun. 2000, 2429.
Org. Lett., Vol. 7, No. 24, 2005
5443

glycosidase inhibitors and our interest in synthesizing hybrid
molecules22 of sugars with azasugars, compounds 17a-d
appear interesting.
To the best of our knowledge, this is the first report of
the synthesis of annulated C-glycosyl R- and â-amino acids.
It is expected that these molecules would be useful in
modifying the properties of certain oligopetides by virtue of
their being rigid and metabolically stable (being annulated
C-glycosides).
Acknowledgment. We thank the Department of Science
and Technology, New Delhi, for financial support (Grant
No. SP/S1/G-21/2001). K.J. thanks IIT Kanpur for a senior
research fellowship.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Reddy, B. G.; Vankar, Y. D. Angew. Chem., Int. Ed. 2005, 44, 2001.
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