Iodine catalyzed one-pot diamination of glycals with chloramine-T: A new approach to 2-amino-β-glycosylamines for applications in N-glycopeptide synthesis

Article abstract of DOI:10.1039/b612151a

Iodine catalyzes a facile one-pot direct diamination of glycals with chloramine-T to afford stereoselectively 2-amino-β-glycosylamine derivatives that serve as convenient precursors for the synthesis of N-linked glycopeptides. The Royal Society of Chemist

Full text of DOI:10.1039/b612151a

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Iodine catalyzed one-pot diamination of glycals with chloramine-T: a
new approach to 2-amino-b-glycosylamines for applications in
N-glycopeptide synthesis{{
Vipin Kumar and Namakkal G. Ramesh*
Received (in Cambridge, UK) 23rd August 2006, Accepted 19th September 2006
First published as an Advance Article on the web 9th October 2006
DOI: 10.1039/b612151a
Iodine catalyzes a facile one-pot direct diamination of glycals
with chloramine-T to afford stereoselectively 2-amino-b-glyco-
sylamine derivatives that serve as convenient precursors for the
synthesis of N-linked glycopeptides.
With the emergence of glycobiology as an inter-disciplinary
aziridines could be opened up, in a domino process, by the
research domain, organic chemists are provided with ample
nucleophilic amino reagent itself, to afford 2-amino glycosylamines
opportunities to develop strategies for the synthesis of biologically
such as 5, directly in one-pot (Eq. 1). Given the fact that a
relevant glycoconjugates. N-Linked glycoproteins, typically con-
successful outcome would have significant prominence in the
taining a GlcNAc-b(1AN) linkage to Asn 1, are among the most
extensively explored glycoconjugates due to their implication in
synthesis of amino-substituted carbohydrate scaffolds, we began
identifying proper aziridination conditions that could directly lead
various biological processes.1 2-Amino-b-glycosylamines 2 are the
to 5. After extensive experimentation, we were finally successful in
central core in N-linked glycoproteins and glycopeptides and play
realizing our hypothesis when we investigated the aziridination
a crucial role in cell-recognition and signal transduction during
reaction of tri-O-acetyl-D-glucal 6 with chloramine-T9 in the
their biological processes. It has been further established that an
presence of iodine as a catalyst.10
acetamido group at C2 (2, R1 5 Ac) and the anomeric
b-stereochemistry are crucial in inducing a well-defined b-turn in
the peptide backbone of N-linked glycoproteins.2 2-Amino-
ð1Þ
glycosylamines 2 are also the key building blocks in the convergent
synthesis of N-linked glycopeptides and glycoproteins.1 Current
methods for the synthesis of 2 (R1 5 Ac, R2 5 H) such as
reduction of 2-acetamido glycosyl azides,1c,3 Kochetkov’s amina-
Treatment of 6 with 1 equiv. of chloramine-T and 15 mol% of
tion and its modification,4 reductive cyclization of d-hydroxyni-
triles5 all rely on the extensive synthetic modification of
glucosamine. Alternative strategies that efficiently introduce two
nitrogen substituents at C1 and C2 of a readily available glycal 3
are fewer in number despite the significant advantages.6 Synthetic
applications of these protocols are sometimes limited due to
protecting group (especially ester group) intolerance, lack of
substrate-generality, special reaction conditions and the use of
hazardous chemicals and/or reagents such as azides. In this
communication we report an efficient one-pot stereoselective
diamination of glycals using simple and inexpensive reagents
under very mild conditions.7 The reaction is functional group
tolerant, successful over a wide range of glycals including
disaccharides and amenable to large-scale synthesis.
iodine in acetonitrile at 0 uC, although affording a product (in 30%
yield), did not lead to the completion of the reaction. Such an
observation was consistent with our proposition, as the formation
of the expected diamine 7 requires two equivalents of chloramine-
T. Upon careful analysis, the product was indeed identified to be
the disulfonamidated compound 7. Subsequently, on treatment
with 2.3 equiv. of chloramine-T and 15% of iodine, 6 was
completely converted to 7, in 14 h in an isolated yield of 69%, as a
single diastereomer possessing essentially the same stereochemistry
as in 1 (Scheme 1).11 The chloramine-T–iodine combination
proved to be the best choice of reagent for this transformation,
without the need for any buffer.10,12,13 Interestingly, products
arising out of iodine catalyzed Ferrier rearrangement have not
been observed under these conditions.14
Taking advantage of the instability of glycal aziridines 4,6a,8 we
envisaged that under suitable aziridination conditions and in the
presence of an appropriate nitrogen source, these incipient glycal
Encouraged by the initial results, we tested the reaction with a
variety of glycals possessing different carbohydrate templates. In
Department of Chemistry, Indian Institute of Technology – Delhi, Hauz
Khas, New Delhi – 110016, India. E-mail: ramesh@chemistry.iitd.ac.in;
Fax: +91 11 26581102; Tel: +91 11 26596584
{ Electronic supplementary information (ESI) available: Experimental
procedure; spectral data for all compounds; 1H-NMR and 13C-NMR for
important compounds. See DOI: 10.1039/b612151a
Scheme 1
{ Dedicated to Prof. Alfred Hassner on the occasion of his 76th birthday.
4952 | Chem. Commun., 2006, 4952–4954
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all the cases, the reaction proceeded smoothly affording the
corresponding hitherto unknown disulfonamides as a single
diastereomer in good yields (Table 1); the only exception being
tri-O-acetyl-D-galactal where the yield was moderate. The nature
of the protecting group seems to have little effect on the reaction
time as well as the yield; the reaction works equally well with ester
and ether protected substrates (Entries 1–5). Synthetically reward-
ing is the facile transformation of disaccharide glycals 18 and 20 to
the corresponding disulfonamides 19 and 21, in high yields. To our
knowledge, direct introduction of two nitrogen functionalities onto
a disaccharide glycal in one-pot has no precedence. A salient
feature is that the reaction has been performed with a few glycals
on a five-gram scale without much loss in the efficiency. The
success of the reaction with dihydropyran 22 demonstrates its
application to other enol ethers. The formation of a diastereomeric
mixture in this case may be attributed to its conformational
flexibility.
Scheme 2 Reagents and conditions: i) Ac2O (2 equiv.), DMAP (1 equiv.),
pyridine, RT, 24 h; ii) SmI2 (8.5 equiv.), H2O (50 equiv.), RT, 25 min; iii)
Alloc chloride (4 equiv.), DMAP (20 mol%), Et3N (2 equiv.), RT, 9–12 h;
iv) SmI2 (13–17 equiv.), H2O (75–100 equiv.), RT, 1 h.
In order to utilize these disulfonamides in N-glycopeptide
synthesis, it is essential to transform them into 2-acetamido-
glycosylamines such as 27, which requires the incorporation of an
acetyl group at C2 nitrogen. As revealed through the selective
examples, an unprecedented chemoselective acetylation of these
disulfonamides, for instance 7 and 19, installed the essential acetyl
group exclusively at C2 nitrogen in excellent yields (Scheme 2).15
Judicious choice of the reagent was found to be crucial for
subsequent detosylation of 24. Compound 24 and even its benzyl-
protected analogue were found to be extremely sensitive to
common acidic or basic desulfonating reagents. With SmI2 in the
presence of water or HMPA as
N-detosylation of tertiary sulfonamide at C2 to afford 26 was
a
co-solvent,16 mono
Table 1 Iodine catalyzed direct disulfonamidation of glycals with chloramine-Ta
Entry
Starting Material
Product
Time (h)
Yield (%)b
1
2
3
6 R 5 Ac
8 R 5 Bn
10 R 5 Me
7
9
11
14
13
13
69
57
60
4
5
12 R 5 Ac
14 R 5 Me
13
15
14
14
63
60
6
7
16
18
17
19
72c
38d
96
71e
8
20
22
21
96
14
65e
61
9
23f
a
Unless otherwise mentioned, all reactions were performed at 0 uC using 2.3 equiv. of chloramine-T and 15 mol% of iodine in acetonitrile.
Isolated yield after column chromatography. The reaction was incomplete. Yield based on recovered starting material; isolated yield 21%.
3.0 equiv. of chloramine-T and 20 mol% of iodine were used. Mixture of diastereomers, at 0 uC dr was 1 : 1 and at 225 uC dr was y 4 : 1.
b
e
c
d
f
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4 (a) L. M. Likhosherstov, O. S. Novikova, V. A. Derevitskaja and
N. K. Kochetkov, Carbohydr. Res., 1986, 146, C1; (b)
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7 Part of this work was presented as a poster at the IUPAC International
Conference on Biodiversity and Natural Products (ICOB-5 and ISCNP-
25), Kyoto, Japan, July 23–28, 2006.
8 D. A. Griffith and S. J. Danishefsky, J. Am. Chem. Soc., 1990, 112,
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9 Chloramine-T used was purchased from Aldrich or Fluka Chemicals.
10 T. Ando, D. Kano, S. Minakata, I. Ryu and M. Komatsu, Tetrahedron,
1998, 54, 13485.
Scheme 3 Reagents and conditions: i) Pd(PPh3)4 (10 mol%), Et2NH
(10 equiv.), RT, 20 min; ii) Boc-glycine (1.5 equiv.), DCC (1.8 equiv.),
DMAP (1.5 equiv.), RT, 12 h, 72% for two steps.
the sole reaction and the anomeric sulfonamide group remained
unaffected. Use of a large excess of the reagent or step-wise
detosylation in attempts to obtain 27 did not meet with success.
Consequently, protection of the anomeric nitrogen of 24 and 25
before detosylation is imperative. Gratifyingly, this could be
achieved smoothly by way of allyloxycarbonyl protection to obtain
28 and 29 in good yields. Subsequently, on exposure to SmI2–
water, compounds 28 and 29 readily underwent a very facile
didetosylation affording 30 and 31 respectively, as stable N-glycans
for glycopeptide synthesis, in excellent yields (Scheme 2). While
free glycosylamines such as 27 are known to be highly unstable
and prone to facile anomerization,1c,4c,17 the Alloc derivatives 30
and 31 are notably stable with a long shelf-life. Preferential choice
of Alloc protection was influenced by the availability of well-
established deprotection protocols.18,19 As an illustrative example,
compound 30 was smoothly deprotected using a catalytic amount
of Pd(PPh3)4 and the liberated free amine, without isolation, was
coupled with Boc-glycine in one-pot to obtain the N-linked
glycopeptide 32 in a high yield (72% for two steps) (Scheme 3). It is
noteworthy that the anomeric-b-stereochemistry remained intact
during the entire synthetic sequence.
11 The b-D-gluco stereochemistry of 7 was established from the coupling
constants between H-1 and H-2 (see ESI{) as well as by detailed NOE
experiments. Thus, NOE irradiation of the H-1 signal resulted in an
enhancement of the signals of H-3 and H-5 by 8.3% and 11.8%
respectively. Similarly, irradiation of the signal due to H-2 enhanced the
signal due to H-4 by 10%. Structure 7 showing NOE experiment details:
:
In conclusion, we have reported a new and stereoselective
approach to 2-amino-b-glycosylamines for use in the convergent
synthesis of N-linked glycopeptides via iodine-catalyzed one-pot
disulfonamidation of glycals with chloramine-T as the key step.
The simplicity of the protocol and scope for further expansion to
complex oligosaccharides are likely to contribute to the research
developments in the area of glycobiology.
12 We have observed that a stoichiometric amount of iodine monochloride
also effects the reaction. However, it has obvious operational
disadvantages as compared to iodine.
13 Very recently, a tin(II) iodide catalyzed aziridination or diamination of
simple olefins with chloramine-T under reflux conditions was reported,
see: Y. Masuyama, M. Ohtsuka, M. Harima and K. Yasuhiko,
Heterocycles, 2006, 67, 503.
14 For reports on iodine catalyzed Ferrier rearrangement see: (a)
J. S. Yadav, B. V. Subba Reddy, K. Premalatha and T. Swamy,
Tetrahedron Lett., 2005, 46, 2687; (b) B. K. Banik, O. Zegrocka,
M. S. Manhas and A. K. Bose, Heterocycles, 1997, 46, 173; (c)
B. K. Banik, M. S. Manhas and A. K. Bose, Tetrahedron Lett., 1997, 38,
5077; (d) M. Koreeda, T. A. Houston, B. K. Shull, E. Klemke and
R. J. Tuinman, Synlett, 1995, 90.
We are grateful to the DST, India for financial support and the
CSIR, India for a fellowship to V. K. We are also grateful to
Dr. K. P. Kaliappan for helping us with the HRMS data.
Notes and references
15 Other disulfonamides also underwent chemoselective acetylation in
yields ranging from 82–87%.
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4954 | Chem. Commun., 2006, 4952–4954
This journal is ß The Royal Society of Chemistry 2006