A versatile strategy for the synthesis of N-linked glycoamino acids from glycals

Article abstract of DOI:10.1039/b712841j

A versatile route for the synthesis of N-linked glycoamino acids from readily available glycals is reported. A variety of glycals possessing different carbohydrate templates (mono-, di- and trisaccharide glycals) were shown to undergo a novel iodine catal

Full text of DOI:10.1039/b712841j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A versatile strategy for the synthesis of N-linked glycoamino acids from
glycals†‡
Vipin Kumar and Namakkal G. Ramesh*
Received 20th August 2007, Accepted 2nd October 2007
First published as an Advance Article on the web 19th October 2007
DOI: 10.1039/b712841j
A versatile route for the synthesis of N-linked glycoamino acids from readily available glycals is
reported. A variety of glycals possessing different carbohydrate templates (mono-, di- and trisaccharide
glycals) were shown to undergo a novel iodine catalyzed stereoselective diamination reaction with
chloramine-T. Taking advantage of the difference in the reactivity between the anomeric and C2
sulfonamido groups of these diamines 7, 13, 15, 17 and 19, they could be protected differentially at the
C2 and anomeric nitrogen atoms. Thus, chemoselective acetylation of these diamines installed the C2
acetamido group, an essential functionality that plays a crucial role in inducing a b-turn in N-linked
glycoproteins. Subsequent protection of the anomeric nitrogens of 20a,b,e as their Alloc
(allyloxycarbonyl) derivatives followed by SmI2 mediated facile didetosylation afforded 24a–c.
Deprotection of the Alloc group of 24a and 24c and coupling of the liberated free amine with a variety
of protected amino acids provided N-linked glycoamino acids 25 and 27 in high yields. An illustrative
synthesis of an N-linked glycopeptide 29 is also reported.
However, a major hurdle in this direction is the existence of
Introduction
glycoproteins as a heterogeneous mixture of glycoforms and hence
It has now been well recognized that protein-glycosylation, which
isolation of pure homogeneous glycoproteins/glycopeptides from
is the most complex post-translational modification of proteins, is
natural sources has become a formidable task. As a consequence,
key to many biological processes such as cell–cell recognition,
presently, synthesis (both chemical and enzymatic) of glycopro-
cell adhesion, cellular differentiation etc.1–4 Significantly, it is
teins/glycopeptides with a tailored glycosylation pattern seems
the carbohydrate moiety in a glycoprotein that plays a crucial
to be the only solution to obtain well-defined homogeneous
role in protein-folding and transport, inhibiting their proteolysis
materials.4–6 N-Linked glycoproteins 1 (Fig. 1), one among the two
and improving the biological half-life of proteins.1–4 Protein
forms of protein glycosidation that are naturally found, typically
glycosylation has also been implicated in various physiological
possess a core pentasaccharide moiety which is always bound
processes including bacterial and viral infection, and hence
to the side chain of an asparagine amino acid of the protein
understanding their structure, stereochemistry and binding ability
moiety via an N-glycosidic linkage. It has also been established
would enable the development of carbohydrate based therapeutics.
that the acetamido group at C2 position and the anomeric b-
stereochemistry of 1 are decisive in ensuring a well-defined b-turn
Department of Chemistry, Indian Institute of Technology-Delhi, Hauz Khas,
in the peptide backbone of N-linked glycoproteins.7
New Delhi, 110016, India. E-mail: ramesh@chemistry.iitd.ac.in; Fax: +91-
N-Linked glycopeptides can be readily accessed through a solid
phase peptide synthesis where pre-formed glycosyl amino acid
building blocks are employed in a step-wise assembly of peptides.6,8
While this process provides the opportunity for automated syn-
thesis, non-availability of glycosyl amino acid building blocks with
complex oligosaccharide side chains, however, is often a matter of
11-26581102; Tel: +91-11-26596584
† This paper is dedicated to Professor Binne Zwanenburg on the occasion
of his 73rd birthday.
‡ Electronic supplementary information (ESI) available: Synthesis and
detailed characterization of compounds 7c, 7d, 13a, 13b, 20c, 20c, 20d,
23e, 24b, 24d, 25c, 25d and 27c and copies of 1H and 13C NMR spectra of
all compounds. See DOI: 10.1039/b712841j
Fig. 1 Examples of an N-linked glycoprotein containing the pentasaccharide core 1 and a 2-amino-b-glycosylamine 2.
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concern in this strategy. A convergent approach in which a complex
oligosaccharide is directly coupled to a peptide through the
anomeric nitrogen provides a very flexible alternative to the former
strategy.9–11 2-Amino-b-glycosylamines, such as 2 (Fig. 1), serve as
the basic carbohydrate building blocks in the convergent synthesis
of N-linked glycoproteins/glycopeptides. Literature strategies for
the synthesis of 2-amino-b-glycosylamines such as Kochetkov’s
amination and its modification,12,13 reduction of 2-acetamido
glycosyl azides,10,14 reductive cyclization of d-hydroxynitriles15 all
rely on the extensive synthetic modifications of D-glucosamine (2-
amino-2-deoxy glucose) or its derivatives by way of introducing
the second amino functionality at the anomeric position. While
2-amino derivatives of monosaccharides are easily accessible, it
is not the case with complex oligosaccharides. Since glycals of
mono-, di-, tri- and oligosaccharides are readily available and/or
easily prepared, strategies that introduce two amino functionalities
on to the double bond of a glycal moiety have significant
synthetic advantages. Notable among them are (a) Danishefsky’s
iodosulfonamidation followed by azidation;16 (b) Finney’s dipolar
cycloaddition–photochemical reaction;17 (c) Nicolaou’s synthesis
of 2-azido mannosylamine using Burgess reagent;18 one-pot
synthesis of 2-acetamido glycosyl azides by Gin;19 (e) Mn(OAc)3
catalyzed direct diazidation of glycals.20 Some of these protocols
suffer from drawbacks such as protecting group intolerance,
lack of substrate-generality and stereoselectivity, need for special
reaction conditions and use of hazardous chemicals such as azides.
Recently, we have briefly communicated our research work on a
facile and mild one-pot stereoselective diamination of a variety
of glycals using chloramine-T in presence of iodine as a catalyst
and demonstrated the synthetic scope of these diamines with
an illustrative synthesis of an N-linked glycoamino acid 25a.21
Subsequently, we have explored the efficacy of our methodology
and successfully realized the stereoselective synthesis of a variety
of N-linked glycoamino acids including glycosylasparagines in
high yields. We have also extended this methodology for a facile
synthesis of N-Ala-Asp linked glycopeptide. We herein describe
a full account of our research findings along with a plausible
mechanism for one-pot diamination of glycals.
hypothesis, when we treated tri-O-acetyl-D-glucal 6a with 15 mol%
of iodine and 2.3 eq. of chloramine-T.23–25 The expected diamine
7a was obtained in 69% yield as a single diastereomer having
the same stereochemistry (b-D-gluco configuration) as in naturally
occurring N-linked glycoproteins (Scheme 1). The stereochemistry
of 7a was established from detailed 1H-NMR studies.21
Scheme 1 Iodine catalyzed reaction of chloramine-T with tri-O-acetyl-
D-glucal 6a. Reagents and conditions: (i) chloramine-T (2.3 eq.), I2
(15 mol%), CH3CN, 0 ◦C, 14 h, 69%.
A plausible mechanism for the formation of 7a from 6a is
depicted in Fig. 3. Electrophilic attack of iodine (from the iodine–
chloramine-T complex 8)23 on to the double bond of 6a, exclusively
from the b-face, might provide the iodonium ion 9. Anionic
opening of the iodonium ion by the nucleophilic nitrogen atom
would then lead to intermediate 10, in which the C2 iodo and
anomeric N-chloro sulfonamido groups are properly oriented
(anti-periplanar) for an aziridine formation 11, which in fact
would very readily be facilitated by the iodide ion present in the
medium. SN2 type anionic ring opening of the aziridine 11 by
another molecule of chloramine-T from the b-face would then
afford the diamine 7a. Alternatively, opening of the aziridine ring
of 11 by the lone pair of electrons on the ring oxygen atom to
afford an oxocarbenium ion followed by nucleophilic attack by
another molecule of chloramine-T from the b-face would also
afford 7a. The iodine monochloride (ICl) generated during this
reaction would serve as a further source of iodonium ion and hence
only a catalytic amount of iodine is required for the reaction. This
was further supported from the fact that this reaction also works
well with stoichiometric amount ICl.
Success of our initial results prompted us to investigate the
diamination reaction with a variety of glycals possessing different
carbohydrate templates. As can be seen from Table 1, in all the
cases, the reaction proceeded smoothly affording the correspond-
ing diamines in good to moderate yields. The synthetic advantages
of our methodology are: (i) while the literature methodologies of
introducing two nitrogen functionalities onto the double bond
of glycals are protecting group specific, this reaction does not
depend on the nature of the protecting group and works well
with both ester as well as ether protected substrates (entries
1–8); (ii) the reaction conditions are mild and do not require
special experimentation; (iii) reagents are easily available and non-
hazardous; (iv) the reaction can be performed on a large scale
without loss in yield. Synthetically more rewarding is the facile
transformation of disaccharide glycals 14a–b,26 1626 and even a
trisaccharide glycal 1826 to their corresponding disulfonamides in
high yields. Among the various carbohydrates used, the maximum
yield (79%) obtained from the diamination of the complex
trisaccharide glycal 18 deserves special mention.
Results and discussion
Glycal aziridines such as 4 are highly unstable due to the presence
of the ring oxygen atom and are opened up immediately in
the presence of a nucleophile.17,22 Our quest for a simple and
general synthesis of 2-amino-b-glycosylamines prompted us to
take advantage of their instability and hence, we expected that
under suitable aziridination conditions and in the presence of
an appropriate nitrogen source, the unstable glycal aziridines
obtained from glycals 3 could be opened up, in a domino
process, by the nucleophilic amino reagent itself, to afford 2-
amino glycosylamines such as 5, directly in one-pot (Fig. 2).
After extensive experimentation, we successfully realized our
In general, while these disulfonamides should prove to be
versatile synthetic intermediates in carbohydrate chemistry, their
transformation into C2-acetamido-b-glycosylamines, such as 22
(or their stable equivalents), provides the vital glycodomain
for the convergent synthesis of N-linked glycoamino acids and
Fig. 2 Retro-synthetic route for diamination of glycals.
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Fig. 3 Proposed mechanism for one-pot diamination of glycals.
Table 1 Iodine catalyzed one-pot disulfonamidation of glycals with chloramine-Ta
Entry
Starting material
Product
Time/h
Yield (%)b
1
2
3
4
6a: R = Ac, R1 = OAc, R2 = H
6b: R = Bn, R1 = OBn, R2 = H
6c: R = Me, R1 = OMe, R2 = H
6d: R = Ac, R1 = H, R2 = OAc
7a
7b
7c
7d
14
13
13
72c
69
57
60
38d
5
6
12a: R = Ace
12b: R = Mee
13a
13b
14
14
63
60
7
8
14a: R = Acf
14b: R = Bnf
15a
15b
96
96
65g
51g,h
9
16f
17
96
71g
10
18f
19
100
79g
a Unless otherwise mentioned, all the reactions were performed at 0 ◦C using 2.3 eq. of chloramine-T and 15 mol% of iodine in acetonitrile. b Isolated
yield after column chromatography. c The reaction was incomplete. d Yield based on recovered starting material; isolated yield 21%. e For the synthesis
of glycals 12 see ref. 27. f For the synthesis of glycals 14, 16 and 18 see ref. 26. g 3.0 eq. of chloramine-T and 20 mol% of iodine were used. h Mixture of
diastereomers, at 0 ◦C dr was ∼1 : 1 and at −10 ◦C dr was ∼ 4 : 1.
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N-linked glycopeptides. For instance, synthesis of 22a from 7a
requires incorporation of an acetyl group exclusively at the C2
nitrogen followed by didetosylation. When acetylation of 7a was
attempted using acetic anhydride (2 eq.) in presence of DMAP
(1 eq.) and pyridine, we were pleasantly surprised to note that
acetylation occurred chemoselectively at C2 nitrogen to afford
monoacetylated compound 20a in 84% yield (Scheme 2) and the
anomeric nitrogen remained unaffected even with an excess of
acetic anhydride (up to 5 eq.) and prolonged reaction time. This
was confirmed from the splitting pattern of the H-2 proton in
the 1H-NMR spectrum of the product obtained which resonated
at d 4.29 as triplet with J = 9.0 Hz due to its coupling with
H-1 and H-3. Also, its splitting pattern remained unchanged
on exchange with D2O. On the other hand, the H-2 proton of
starting diamine 7a appeared at d 3.40 as quartet with J =
9.0 Hz due to its coupling with H-1, H-3 and NH protons.
Even though it may be rationalized that the selective acetylation
is due to poor nucleophilicity of the anomeric nitrogen (as
compared to the C2 nitrogen) dictated by the electron withdrawing
ring oxygen atom, to our knowledge such a selectivity has no
precedence. Further, this selective acetylation assumes enormous
synthetic significance since an acetamido group at C2 position is
an essential functionality of N-linked glycopeptides.7 A variety
of other disulfonamides 7b–c, 13a and 17 also underwent this
selective acetylation to afford the corresponding products 20b–e
in very high yields (Scheme 2)
In order to obtain the C2-acetamido-b-glycosylamines 22,
the carbohydrate moieties for N-linked glycoamino acids and
N-linked glycopeptides, didetosylation of compounds 20 was
necessary and since they were found to be extremely sensitive to
common acidic or basic desulfonating reagents, judicial choice of
the reagent was very crucial. Attempted detosylation of 20a and
20b with SmI2 (a mild reagent) in presence of water or HMPA
as a co-solvent,28 afforded 21a and 21b respectively wherein the
tertiary sulfonamide group at C2 was deprotected while leaving
the anomeric sulfonamide group intact (Scheme 3). Subsequent
attempts to detosylate 21a and 21b using a large excess of the
reagent or step-wise detosylation of 20a and 20b to obtain 22a
and 22b were in vain. Consequently, it appeared that protection of
the anomeric nitrogen of 20 before detosylation was essential.
After several unsuccessful attempts with various reagents, we
were finally able to protect the anomeric nitrogen of 20 as their
carbamates. Thus, a variety of carbamates 23a–e were prepared by
treating compounds 20a,b,e with 4 eq. of alkoxycarbonyl chloride
in presence of DMAP and Et3N (Table 2).
Scheme
3 Attempted synthesis of C2-acetamido glycosylamines.
Reagents and conditions: (i) SmI2 (8.5 eq.), H2O (50 eq.), rt, THF; (ii) SmI2
(5–8.5 eq.), HMPA (23–46 eq.), rt, THF; (iii) SmI2–DMPU.
On exposure to SmI2–water, these carbamates 23a–d underwent
a very facile didetosylation affording 24a–d in high yields (Table 2).
It was found that the carbamates of benzyl protected sugars
23b and 23d are quite unstable during purification by column
chromatography over silica gel, and hence were subjected to
didetosylation in the presence of SmI2–H2O without purification
to obtain 24b and 24d respectively in high yields. Unlike the
free glycosamines 22 that were reported to be unstable,11,13,29 the
carbamates 24a–d are quite stable with a long shelf life and thus
may serve as their stable synthetic equivalents. Since deprotection
of Alloc groups under very mild and neutral conditions is
Scheme 2 Chemoselective acetylation of disulfonamides. Reagents and
conditions: (i) Ac2O (2 eq.), DMAP (1 eq.), pyridine, rt, 24 h.
Table 2 Synthesis of differentially protected 2-amino-b-glycosylamines
Entry
Compd
R
R1
Product
R2
Time/h
Yielda (%)
Compd
Time/h
Yielda (%)
1
2
3
20a
20b
20e
Ac
Bn
Ac
Ac
Bn
23a
23b
23c
Allyl
Allyl
Allyl
9
12
12
79
60b
75
24a
24b
24c
1
1
1
90
78
88
4
5
20b
20a
Bn
Ac
Bn
Ac
23d
23e
Et
Et
6
6
67b
75
24d
—
0.5
—
85
—
c
a Isolated yield after column chromatography. b Crude yield, without isolation has been taken up to the next step. c Detosylation reaction not tried.
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well documented in literature,13,30 we preferentially attempted
the deprotection of Alloc derivatives 24a–c rather than the
ethoxycarbonyl derivative 24d. Thus, compound 24a was found
to undergo a facile deprotection with a catalytic amount of
Pd[(PPh3)]4 in presence of Et2NH to afford the free amine 22a
(vide TLC) which without isolation was successfully coupled
with Boc-glycine in presence of DCC and DMAP to obtain
the N-linked glycoamino acid 25a in 72% yield (for two steps)
(Scheme 4). Even though the coupling of incipient free amine 22a
with Boc-glycine proceeded smoothly, requirement of an excess
of the amino acid (1.5 eq.) posed a serious setback especially
during the synthesis of complex N-linked glycoamino acids using
expensive and/or synthetically precious amino acids. Later, we
have identified that use of HOBt as an auxiliary nucleophile in
place of DMAP circumvents this problem; the coupling reaction
could be efficiently realized with just equimolar amounts of the
amino acid and DCC. Using this procedure compound 25a was
obtained from 24a in almost the same yield as earlier (71% for
two steps) (Scheme 5). This two-step (one-pot) synthesis of N-
linked glycoamino acid from 24a was successful with a variety
of protected amino acids (Fmoc-alanine, Fmoc-valine and Fmoc-
leucine), the corresponding N-linked glycoamino acids 25b–d were
obtained in high yields (Scheme 5).
Scheme 5 Deprotection of 24a and in situ DCC–HOBt mediated coupling
with protected amino acids. Reagents and conditions: (i) Pd(PPh3)4
(10 mol%), Et2NH (10 eq.), THF, 20 min; (ii) DCC (1 eq.), HOBt (1 eq.),
rt, CH3CN, 16 h.
Since all the naturally occurring N-linked glycoproteins possess
carbohydrates that are invariably N-linked to the side chain of
asparagine, we next attempted and succeeded in synthesizing
protected glycosylasparagines using the same strategy as above.
Thus, glucosylasparagine 27a was obtained in 75% yield from 24a
in two steps (Table 3) whose spectral data are identical with the
literature values.31–34 This also establishes that the anomeric b-
stereochemistry remained intact through out the entire synthetic
sequence. The methodology was also successfully extended to the
disaccharide derivative 24c to obtain the N-linked glycoamino
acids 27b and 27c in good yields (Table 3). It has been observed by
us that while with Boc-protected aspartic acid 26b, only a single
diastereomer 27b with b-anomeric stereochemistry was obtained,
Cbz-protected aspartic acid 26a afforded 27c as a mixture of
anomers in a ratio of 1 : 0.8.35 Lowering of temperature, however,
did not bring about any significant change in the anomeric
ratio.
Scheme 4 Deprotection of 24a and in situ DCC–DMAP mediated cou-
pling with Boc-glycine. Reagents and conditions: (i) Pd(PPh3)4 (10 mol%),
Et2NH (10 eq.), rt, THF, 20 min; (ii) DCC (1.8 eq.), DMAP (1.5 eq.),
Boc-glycine (1.5 eq.), rt, CH3CN, 12 h.
Table 3 Synthesis of glycosylasparagines
Entry
Reactant
R1
Product
R2
Yield (%)a (for two steps)
1
2
24a
24c
Ac
27a
27b
Cbz
Boc
75
64
3
24c
27c
Cbz
73b
a Isolated yield after column chromatography. b Mixture of diastereomers obtained with dr ∼ 1 : 0.8.
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The efficacy of our methodology was further demonstrated with
an illustrative synthesis of an N-linked glycopeptide 29. Thus,
Alloc deprotection of 24a followed by coupling of the liberated
free amine with Fmoc-Ala-Asp-OBn 28 afforded 29 in 55% yield
(Scheme 6). The success of the reaction clearly favors that the
methodology reported in this manuscript could be readily adapted
for the synthesis of more complex N-linked glycopeptides.
reaction mixture was allowed to stir at 0 ◦C until the reaction
was complete (as indicated by TLC). The reaction mixture was
diluted with CHCl3 and stirred for an additional 5 min. It was
then transferred into a separatory funnel containing aq. sodium
thiosulfate solution and shaken vigorously. The organic layer
was separated and the remaining aqueous layer was washed
with more CHCl3. The combined organic layer was washed with
brine solution and dried over anhydrous sodium sulfate and
concentrated. The product was purified by flash chromatography.
3,4,6-Tri-O-acetyl-1,2-dideoxy-1,2-di-(p-toluenesulfonamido)-b-
D-glucopyranose 7a. Compound 7a (7.76 g, 69%) was obtained
as a white solid from the reaction of tri-O-acetyl-D-glucal 6a
(5.00 g, 18.38 mmol) with chloramine-T (11.91 g, 42.27 mmol)
and iodine (0.701 g, 2.76 mmol) in CH3CN (50 mL) in 14 h as
per the general procedure. Flash chromatography of the crude
reaction mixture was performed with hexane : ethyl acetate
Scheme 6 Synthesis of an N-Ala-Asp linked glycopeptide 29. Reagents
and conditions: (i) Pd(PPh3)4 (10 mol%), Et2NH (10 eq.), THF, rt, 20 min;
(ii) 28 (1 eq.), DCC (1 eq.), HOBt (1 eq.), CH3CN, rt, 24 h.
◦
(2 : 1). Mp 191–192 C (from hot benzene); [a]2D8 +27.2 (c 1.12
in CHCl3) (Found: C, 50.97; H, 5.24; N, 4.78. C26H32N2O11S2
requires: C, 50.97; H, 5.26; N, 4.57%); vmax (KBr)/cm−1 3286,
2927, 1745, 1599, 1457, 1368, 1329, 1242, 1162, 1091, 1072, 1044;
dH (300 MHz, CDCl3) 7.82 (2 H, d, J 8.2), 7.71 (2 H, d, J 8.2),
7.32 (2 H, d, J 8.0), 7.29 (2 H, d, J 8.0), 6.35 (1 H, d, J 7.4, NH,
exchangeable with D2O), 5.34 (1 H, d, J 8.1, NH, exchangeable
with D2O), 4.97–4.87 (2 H, m), 4.67 (1 H, dd, J 8.7 and 7.8), 4.14
(1 H, dd, J 12.3 and 4.8), 3.96 (1 H, dd, J 12.3 and 1.8), 3.67–3.63
(1 H, m), 3.40 (1 H, q, J 9.0), 2.43 (3 H, s), 2.42 (3 H, s), 2.06
(3 H, s), 1.97 (3 H, s), 1.48 (3 H, s); dC (75 MHz, CDCl3) 171.1,
170.5, 169.4, 143.8, 143.6, 138.2, 137.6, 129.8, 129.4, 127.2, 127.1,
83.6, 72.9, 68.3, 61.7, 56.6, 21.4, 20.6, 20.5, 19.9.
Conclusions
In conclusion, we have developed a versatile strategy for the
synthesis of N-linked glycoamino acids from readily available
glycals with complete stereocontrol in all steps. Our methodology
describes an innovative but yet a simple way of obtaining
complex glycosylamines required for subsequent coupling with
amino acids/peptides. Synthesis of an N-linked glycopeptide 29
illustrates the accessibility of our methodology to such com-
pounds. The simplicity of the methodology coupled with the ready
availability of starting materials and stereoselectivity are likely to
contribute significantly to the research developments in the area
of glycobiology.
3,4,6-Tri-O-benzyl-1,2-dideoxy-1,2-di-(p-toluenesulfonamido)-
b-D-glucopyranose 7b. Compound 7b (5.18 g, 57%) was obtained
as a white solid from the reaction of tri-O-benzyl-D-glucal 6b
(5.00 g, 12.02 mmol) with chloramine-T (7.79 g, 27.65 mmol) and
iodine (0.457 g, 1.80 mmol) in CH3CN (40 mL) in 13 h as per the
general procedure. Flash chromatography of the crude reaction
mixture was performed with hexane : ethyl acetate (3 : 1). Mp
124 ◦C (from hot benzene); [a]2D8 +18.3 (c 2.29 in acetone) (Found:
C, 65.18; H, 5.79; N, 4.01. C41H44N2O8S2 requires: C, 65.06; H,
5.86; N, 3.70%); vmax (KBr)/cm−1 3266, 2869, 2362, 1456, 1327,
1160, 1090, 1063 cm−1; dH (300 MHz, CDCl3) 7.80 (2 H, d, J 8.1),
7.68 (2 H, d, J 8.1), 7.29–7.18 (13 H, m), 7.08 (2 H, d, J 8.1), 7.04–
6.98 (4 H, m), 6.21 (1 H, d, J 7.8, NH, exchangeable with D2O),
4.86 (1 H, d, J 7.7, NH, exchangeable with D2O), 4.63–4.58 (3 H,
m), 4.52 (1 H, d, J 11.4), 4.47–4.41 (2 H, m), 4.30 (1 H, d, J 12.1),
3.59 (2 H, dd, J 9.1 and 8.7), 3.43–3.38 (3 H, m), 3.30 (1 H, ddd, J
9.3, 8.7 and 8.4), 2.36 (3 H, s), 2.30 (3 H, s); dC (75 MHz, CDCl3)
143.8, 143.6, 139.2, 138.4, 138.2, 137.9, 130.0, 129.7, 129.3, 128.8,
128.7, 128.5, 128.1, 127.9, 127.5, 84.4, 82.5, 78.7, 76.6, 75.5, 75.0,
74.0, 68.7, 58.4, 21.9; HRMS (ESI): C41H44N2O8S2Na [M + Na]+
calcd: 779.2437, found 779.2439.
Experimental
General
All solvents were purified using standard procedures. Chloramine-
T purchased from Aldrich or Fluka Chemicals only was used
for consistency of results. Thin layer chromatography (TLC) was
performed on Merck silica gel pre-coated on aluminium plates.
Flash column chromatography was performed on 230–400 mesh
silica gel. Optical rotations were recorded on an Autopol II or
Autopol V (Rudolph Research Flanders, New Jersey) instrument.
All the rotations were measured at 589 nm (sodium Dꢀ line).
Melting points of the compounds are uncorrected. IR spectra were
taken within the range 4000–400 cm−1 as KBr pellets on a Nicolet
(Madison, USA) FT-IR spectrophotometer (Model Protege 460).
1
All the H and 13C NMR spectra were recorded on a 300 M
Bruker Spectrospin DPX FT-NMR. Chemical shifts are reported
as d values (ppm) relative to internal standard Me4Si. Elemental
analyses were performed on a Perkin Elmer 2400 series II analyzer.
Mass spectra were recorded using Waters Micro Mass Q-TOF
instrument.
4-O-[2,3,4,6-Tetra-O-acetyl-(a-D-glucopyranosyl)]-3,6-di-O-acetyl-
1,2-dideoxy-1,2-di-(p-toluenesulfonamido)-b-D-glucopyranose 15a.
In this case 3 eq. of chloramine-T and 20 mol% iodine were
used. Compound 15a (1.00 g, 65%) was obtained as a white
solid from the reaction of hexa-O-acetyl-D-maltal 14a26 (1.00 g,
1.79 mmol) with chloramine-T (1.50 g, 5.34 mmol) and iodine
(0.09 g, 0.36 mmol) in CH3CN (6 mL) in 96 h as per the general
General procedure for diamination of glycals
To a 0 ◦C stirred suspension of glycal (1 eq.), chloramine-T
(2.3 eq.) in acetonitrile taken in a dried 100 mL round-bottomed
flask, was added a catalytic amount of iodine (15 mol%) and the
3852 | Org. Biomol. Chem., 2007, 5, 3847–3858
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procedure. Flash chromatography of the crude reaction mixture
was performed with hexane : ethyl acetate (1 : 1). Mp 168 ◦C (from
hot benzene); [a]D28 +68.1 (c 0.52, CHCl3); vmax (KBr)/cm−1 3297,
2926, 1749, 1457, 1333, 1234, 1163, 1088, 1046; dH (300 MHz,
CDCl3) 7.80 (2 H, d, J 7.8), 7.72 (2 H, t, J 7.8), 7.30 (4 H, m),
6.19 (1 H, d, J 7.5, NH, exchangeable with D2O), 5.30–5.25 (2 H,
m), 5.05–4.94 (3 H, m), 4.82 (1 H, dd, J 10.2 and 3.6), 4.63 (1 H,
t, J 8.5), 4.26–4.00 (4 H, m), 3.89–3.81 (2 H, m), 3.60 (1 H, d, J
9.6), 3.38 (1 H, q, J 9.0), 2.43 (6 H, s), 2.10 (3 H, s), 2.08 (3 H,
s), 2.01 (3 H, s), 1.97 (6 H, s), 1.59 (3 H, s); dC (75 MHz, CDCl3)
171.5, 170.4, 170.3, 170.2, 169.8, 169.3, 143.9, 143.5, 138.1, 137.4,
129.8, 129.3, 127.1, 95.3, 83.4, 75.1, 73.3, 72.7, 69.8, 69.2, 68.3,
67.8, 62.5, 61.3, 57.0, 21.4, 20.6, 20.5, 20.4, 20.3; HRMS (ESI):
C38H49N2O19S2 [M + H]+ calcd: 901.2371, found 901.2374.
21.5, 20.5, 20.2; HRMS (ESI): C38H48N2O19S2Na [M + Na]+
calcd: 923.2190, found 923.2173.
4-O-{[2,3,4,6-Tetra-O-acetyl-(a-D-glucopyranosyl)]-2,3,6-tri-O-
acetyl-(a-D-glucopyranosyl)}-1,2-dideoxy-1,2-di-(p-toluenesulfona-
mido)-b-D-glucopyranose 19. In this case 3 eq. of chloramine-T
and 20 mol% of iodine were used. Compound 19 (0.110 g, 79%)
was obtained as a white solid from the reaction of nona-O-acetyl
maltotrial 1826 (0.100 g, 0.118 mmol) with chloramine-T (0.100 g,
0.354 mmol) and iodine (0.006 g, 0.024 mmol) in CH3CN (50 mL)
in 100 h as per the general procedure. Flash chromatography of
the crude reaction mixture was performed with hexane : ethyl
acetate (1 : 1). Mp 108–110 ◦C (from CH2Cl2–hexane); [a]2D8 +80.9
(c 0.46 in CHCl3); vmax (KBr)/cm−1 3483, 3283, 2959, 1752, 1448,
1375, 1337, 1232, 1162, 1039; dH (300 MHz, CDCl3) 7.80 (2 H, d,
J 7.8), 7.72 (2 H, d, J 7.6), 7.34–7.30 (4 H, m), 6.19 (1 H, d, J 7.5,
-NH exchangeable with D2O), 5.38–5.31 (3 H, m), 5.17–5.07 (2 H,
m), 5.04 (1 H, d, J 7.9, -NH exchangeable with D2O), 4.99–4.70
(3 H, m), 4.63 (1 H, t, J 8.2), 4.46 (1 H, d, J 12.2), 4.19–3.80 (9 H,
m), 3.65 (1 H, m), 3.36 (1 H, q, J 8.5), 2.44 (3 H, s), 2.43 (3 H, s),
2.14 (3 H, s), 2.10 (3 H, s), 2.03 (9 H, s), 2.00 (3 H, s), 1.98 (3 H,
s), 1.94 (3 H, s), 1.56 (3 H, s); dC (75 MHz, CDCl3) 171.6, 170.5,
170.3, 169.8, 169.6, 169.4, 144.1, 143.6, 138.0, 137.2, 129.9, 129.4,
127.2, 95.6, 95.5, 83.4, 75.2, 73.4, 73.3, 72.3, 71.6, 70.1, 70.0,
69.2, 68.9, 68.4, 67.8, 62.6, 62.0, 61.3, 56.9, 21.5, 20.7, 20.5, 20.4;
HRMS (ESI): C50H64N2O27S2Na [M + Na]+ calcd: 1211.3036
found 1211.3075.
4-O-[2,3,4,6-Tetra-O-benzyl-(a-D-glucopyranosyl)]-3,6-di-O-benzyl-
1,2-dideoxy-1,2-di-(p-toluenesulfonamido)-b-D-glucopyranose 15b.
In this case 3 eq. of chloramine-T and 20 mol% iodine were
used. Compound 15b (0.098 g, 51%) was obtained as a white
solid from the reaction of hexa-O-benzyl-D-maltal 14a26 (0.138 g,
0.163 mmol) with chloramine-T (0.138 g, 0.489 mmol) and iodine
(0.008 g, 0.033 mmol) in CH3CN (3 mL) in 96 h as per the general
procedure. Flash chromatography of the crude reaction mixture
was performed with hexane : ethyl acetate (2 : 1). Diastereomeric
mixtures were obtained in dr = 1 : 1 at 0 ◦C and dr = 4 : 1 at
−10 ◦C. Mp 42 ◦C (from hot benzene) for diastereomeric mixture
4 : 1; [a]2D8 +18.3 (c 0.92 in CHCl3) for diastereomeric mixture 4 : 1;
vmax (KBr)/cm−1 3281, 3032, 2917, 2867, 1454, 1331, 1159, 1085;
dH (300 MHz, CDCl3) 7.73 (2 H, d, J 8.3), 7.70 (2 H, d, J 8.3),
7.32–7.08 (34 H, m), 6.24 (1 H, d, J 9.2, NH, exchangeable with
D2O), 5.47 (1 H, d, J 8.6, NH, exchangeable with D2O), 4.89–4.23
(14 H, m), 3.92–3.87 (2 H, m), 3.76–3.28 (10 H, m), 2.35 (3 H, s),
2.28 (3 H, s) for major diastereomer; dC (75 MHz, CDCl3) 171.5,
143.8, 143.5, 138.9, 138.7, 138.5, 138.4, 138.0, 137.9, 137.6, 130.0,
129.6, 128.8, 128.7, 128.4, 128.2, 128.1, 128.0, 127.9, 127.7, 127.5,
97.7, 83.5, 82.5, 80.0, 77.8, 76.0, 75.4, 73.7, 73.6, 72.6, 72.5, 71.5,
69.8, 68.2, 56.7, 21.8, 21.7 for major diastereomer; HRMS (ESI):
C68H72N2O13S2Na [M + Na]+ calcd: 211.4374, found 1211.4384.
General procedure for chemoselective acetylation of diamine at C2
nitrogen
To an ice cooled solution of a diamine (1 eq.) in pyridine were
added acetic anhydride (2 eq.) and DMAP (1 eq.) and the reaction
mixture was allowed to warm to room temperature and stirred for
24 h. The colour of the reaction mixture changed from colourless
to dark brown. It was then quenched with 10% HCl solution
and extracted with ethyl acetate and washed with water. The
organic layers were dried over sodium sulfate and concentrated.
The product was purified by flash chromatography.
4-O-[2,3,4,6-Tetra-O-acetyl-(b-D-galactopyranosyl)]-3,6-di-O-
acetyl-1,2-dideoxy-1,2-di-(p-toluenesulfonamido)-b-D-glucopyranose
17. In this case 3 eq. of chloramine-T and 20 mol% of iodine
were used. Compound 17 (6.23 g, 71%) was obtained as a white
solid from the reaction of hexa-O-acetyl lactal 1626 (5.46 g,
9.75 mmol) with chloramine-T (8.24 g, 29.25 mmol) and iodine
(0.495 g, 1.95 mmol) in CH3CN (50 mL) in 96 h as per the general
procedure. Flash chromatography of the crude reaction mixture
was performed with hexane : ethyl acetate (1 : 1). Mp 107 ◦C
(from hot benzene); [a]2D8 +17.7 (c 1.21 in CHCl3); vmax (KBr)/cm−1
3479, 3279, 2927, 1751, 1456, 1371, 1338, 1227, 1162, 1048; dH
(300 MHz, CDCl3) 7.80 (2 H, d, J 8.12), 7.71 (2 H, t, J 8.1),
7.34 (2 H, t, J 7.2), 7.30 (2 H, t, J 8.5), 6.36 (1 H, d, J 6.9, NH,
exchangeable with D2O), 5.32 (1 H, br s), 5.06–4.81 (4 H, m),
4.54 (1 H, dd, J 8.4 and 7.9), 4.37 (1 H, d, J 7.8), 4.33 (1 H, m),
4.11–3.92 (3 H, m), 3.82–3.80 (1 H, m), 3.65–3.56 (2 H, m), 3.35
(1 H, q, J 9.4), 2.44 (6 H, s), 2.11 (3 H, s), 2.10 (3 H, s), 2.04 (3 H,
s), 2.03 (3 H, s), 1.95 (3 H, s), 1.57 (3 H, s); dC (75 MHz, CDCl3)
171.3, 170.0, 169.1, 144.1, 143.6, 137.3, 129.9, 129.4, 127.2, 100.8,
83.7, 75.7, 73.9, 72.9, 70.8, 70.6, 69.0, 66.6, 61.7, 60.7, 60.7, 56.8,
2-N-Acetyl-3,4,6-tri-O-acetyl-1,2-dideoxy-1,2-di-(p-toluenesul-
fonamido)-b-D-glucopyranose 20a. Compound 20a (4.20 g, 84%)
was obtained as a white crystalline solid by the acetylation of
7a (4.68 g, 7.64 mmol) using Ac2O (1.44 mL, 15.28 mmol) and
DMAP (0.932 g, 7.64 mmol) in pyridine (8 mL) as per the general
procedure. Flash chromatography of the crude reaction mixture
was performed with hexane : ethyl acetate (2 : 1). Mp 121 ◦C (from
benzene–hexane); [a]2D8 −23.2 (c 1.20 in CHCl3) (Found: C, 51.02;
H, 5.22; N, 3.90. C28H34N2O12S2 requires: C, 51.37; H, 5.23; N,
4.28%); vmax (KBr)/cm−1 3226, 2986, 2928, 1754, 1707, 1597, 1462,
1344, 1234, 1167, 1088, 1058; dH (300 MHz, CDCl3) 7.93 (2 H, d,
J 8.2), 7.77 (2 H, d, J 8.2), 7.40 (2 H, d, J 8.2), 7.28 (2 H, d, J
8.1), 5.80–5.71 (3 H, m), 4.99 (1 H, t, J 9.5), 4.29 (1 H, t, J 9.0),
4.09 (1 H, dd, J 12.3 and 4.3), 3.83 (1 H, dd, J 12.3 and 2.00),
3.73–3.68 (1 H, m), 2.45 (3 H, m), 2.42 (3 H, s), 2.07 (3 H, s), 2.04
(3 H, s), 1.98 (3 H, s), 1.79 (3 H, s); dC (75 MHz, CDCl3) 170.6,
170.5, 170.0, 169.4, 145.7, 143.7, 137.8, 135.8, 130.2, 129.4, 128.3,
127.3, 81.0, 73.1, 69.7, 69.0, 61.7, 60.9, 25.7, 21.6, 21.5, 20.6, 20.5,
20.4.
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4-O-[2,3,4,6-Tetra-O-acetyl-(b-D-galactopyranosyl)]-2-N-acetyl-
3,6-di-O-acetyl-1,2-dideoxy-1,2-di-(p-toluenesulfonamido)-b-D-gluco-
pyranose 20e. Compound 20e (2.82 g, 90%) was obtained
as a white solid by the reaction of 17 (3.00 g, 3.33 mmol)
using Ac2O (0.628 mL, 6.66 mmol) and DMAP (0.406 g,
3.33 mmol) in pyridine (6 mL) as per the general procedure. Flash
chromatography of the crude reaction mixture was performed
with hexane : ethyl acetate (1 : 1). Mp 90 ◦C (from CH2Cl2–
hexane); [a]D28 −12.3 (c 0.73 in CHCl3); vmax (KBr)/cm−1 3629,
3258, 2982, 1762, 1598, 1496, 1435, 1371, 1239, 1167, 1059; dH
(300 MHz, CDCl3) 7.94 (2 H, d, J 7.8), 7.75 (2 H, d, J 7.8), 7.40
(2 H, d, J 7.8), 7.27 (2 H, d, J 7.8), 5.76–5.69 (2 H, m), 5.51 (1 H,
d, J 10.3, NH, exchangeable with D2O), 5.33 (1 H, s), 5.06 (1 H,
dd, J 9.5 and 8.4), 4.92 (1 H, d, J 10.3), 4.44 (1 H, d, J 7.5),
4.20–3.94 (5 H, m), 3.86–3.67 (3 H, s), 2.46 (3 H, s), 2.43 (3 H, s),
2.13 (3 H, s), 2.07 (6 H, s), 2.05 (3 H, s), 2.02 (3 H, s), 1.95 (3 H,
s), 1.90 (3 H, s); dC (75 MHz, CDCl3) 170.4, 170.3, 170.0, 169.7,
168.8, 145.6, 143.6, 137.7, 135.7, 130.1, 129.3, 128.2, 127.2, 100.5,
80.8, 76.8, 73.8, 70.9, 70.5, 69.5, 68.9, 66.5, 61.8, 61.0, 60.7, 25.5,
21.5, 21.4, 20.6, 20.5; HRMS (ESI): C40H51N2O20S2 [M + H]+
calcd: 943.2477, found 943.2465.
chromatography of the resulting residue provided corresponding
detosylated compound.
2-Acetamido-3,4,6-tri-O-acetyl-1,2-dideoxy-1-(p-toluenesulfo-
namido)-b-D-glucopyranose 21a. Procedure A: Compound 21a
(0.068 g, 88%) was obtained as a white solid in 30 min from
the reaction of 20a (0.100 g, 0.153 mmol) with 8.5 eq. of SmI2
(preformed) in dry THF (10 mL) and HMPA (1.22 mL, 7.04 mmol)
using general procedure A. Flash chromatography of the crude
reaction mixture was performed with hexane : ethyl acetate (1 : 1).
Procedure B: Compound 21a (0.102 g, 89%) was obtained as a
white solid in 25 min. from the reaction of 20a (0.150 g, 0.23 mmol)
with 8.5 eq. of SmI2 (preformed) in dry THF (10 mL) and degassed
water (0.206 g, 11.45 mmol) as per the general procedure B. Flash
chromatography of the crude reaction mixture was performed with
hexane : ethyl acetate (1 : 1). Mp 160–162 ◦C (decomp.) (from
CH2Cl2–hexane); [a]D28 +31.0 (c 0.59 in THF); vmax (KBr)/cm−1
3294, 1746, 1658, 1543, 1459, 1377, 1333, 1238, 1157, 1086, 1049;
dH (300 MHz, CDCl3) 7.76 (2 H, d, J 7.8), 7.27 (2 H, d, J 7.8), 6.54
(1 H, d, J 7.8, NH, exchangeable with D2O), 6.00 (1 H, d, J 7.8,
NH, exchangeable with D2O), 5.02 (2 H, d, J 8.8), 4.72 (1 H, t, J
8.7), 4.14–3.97 (3 H, m), 3.65 (1 H, br s), 2.41 (3 H, s), 2.05 (6 H,
s), 2.03 (3 H, s), 1.91 (3 H, s); dC (75 MHz, CDCl3) 172.4, 171.5,
170.5, 169.3, 143.4, 138.6, 129.3, 127.0, 84.4, 73.0, 72.6, 68.1, 61.9,
53.2, 22.9, 21.5, 20.6; HRMS (ESI): C21H28N2O10SNa [M + Na]+
calcd: 523.1358, found 523.1362.
General procedure for SmI2 mediated detosylation
Procedure A. Using SmI2 and HMPA: Powdered samarium
metal (5–10 eq.) was added to a flame dried 100 mL three-
necked round bottomed flask and further heated under an argon
atmosphere. After cooling under an argon atmosphere, dry THF
and CH2I2 (5–8.5 eq.) were added to it and the reaction flask was
sonicated at room temperature. A deep blue colour was obtained
in 5 minutes. After 20 min (1 h for large scale preparation), the
reaction flask was taken out and starting compound (1 eq.) was
added. No colour change was observed. After 5 minutes HMPA
(23–46 eq.) was added dropwise under an argon atmosphere and
the colour of the reaction mixture started fading and changed to
grey black. After 15 minutes a yellow-brown colour was obtained.
After completion of the reaction (as indicated by TLC), the
reaction mixture was quenched with saturated NH4Cl solution and
extracted with CHCl3. The combined organic layer was washed
with water and dried over sodium sulfate and concentrated. Flash
chromatography of the resulting residue provided corresponding
detosylated compound.
2-Acetamido-3,4,6-tri-O-benzyl-1,2-dideoxy-1-(p-toluenesulfona-
mido)-b-D-glucopyranose 21b. Procedure A: Compound 21b
(0.062 g, yield 77%) was obtained as a white solid in 30 min from
the reaction of 20b (0.100 g, 0.125 mmol) with 5 eq. of SmI2 (pre-
formed) in dry THF (10 mL) and HMPA (0.500 mL, 2.87 mmol)
using general procedure A. Flash chromatography of the crude
reaction mixture was performed with hexane : ethyl acetate (1 : 1).
Procedure B: Compound 21b (0.143 g, 76%) was obtained
as a white solid in 30 min from the reaction of 20b (0.231 g,
0.29 mmol) with 8.5 eq. of SmI2 (preformed) in dry THF (15 mL)
and degassed water (0.261 mL, 14.50 mmol) as per the general
procedure B. Flash chromatography of the crude reaction mixture
was performed with hexane : ethyl acetate (1 : 1). Mp 160 ◦C (from
CH2Cl2–hexane); [a]D28 +11.5 (c 0.46 in acetone); vmax (KBr)/cm−1
3242, 3029, 2913, 2868, 1655, 1544, 1454, 1330, 1306, 1155, 1090,
1059; dH (300 MHz, CDCl3) 7.74 (2 H, d, J 7.8), 7.39–7.14 (17 H,
m), 6.62 (1 H, d, J 7.2, NH, exchangeable with D2O), 5.00 (1 H,
d, J 7.5, NH, exchangeable with D2O), 4.80 (2 H, t, J 12.3), 4.61–
4.42 (4 H, m), 4.31 (1 H, d, J 12.3), 3.82 (1 H, q, J 9.3), 3.68–3.62
(2 H, m), 3.49–3.38 (3 H, m), 2.33 (3 H, s), 1.71 (3 H, s); dC
(75 MHz, CDCl3) 172.5, 143.0, 139.0, 138.0, 137.9, 137.8, 129.2,
128.8, 128.5, 128.4, 128.0, 127.6, 127.1, 84.7, 80.8, 78.3, 76.3, 74.9,
74.5, 73.6, 68.4, 53.8, 23.0, 21.4; HRMS (ESI): C36H40N2O7SNa
[M + Na]+ calcd: 667.2454 found 667.2451.
Procedure B. Using SmI2 and H2O: Powdered samarium metal
(5–20 eq.) was added to a flame dried 100 mL three-necked round
bottomed flask and further heated under an argon atmosphere.
After cooling under an argon atmosphere, dry THF and CH2I2
(5–20 eq.) were added to it and the reaction flask was sonicated
at room temperature. A deep blue colour was obtained in 5–
20 minutes. After 20 min (1 h for large scale preparation), the
reaction flask was taken out and starting compound (1 eq.) was
added. No colour change was observed. After 5 minutes H2O
(25–100 eq.) was added dropwise under an argon atmosphere and
the colour of the reaction mixture started fading and changed to
grey black. After 15 minutes a yellow-brown colour was obtained.
After 0.5–1 h the reaction was complete (as indicated by TLC). The
reaction mixture was quenched with saturated NH4Cl solution and
extracted with CHCl3. The combined organic layer was washed
by water and dried over sodium sulfate and concentrated. Flash
General procedure for the protection of anomeric nitrogen atom of
20a,b,e as their carbamates
Starting compound (1 eq.) was added to a flame dried 50 mL
three-necked round bottomed flask and dissolved in dry CH2Cl2
under a N2 atmosphere. To this, DMAP (20 mol%) and Et3N
(2 eq.) were added and the reaction mixture was cooled in an ice–
salt bath. (4 eq.) was injected into the reaction mixture drop-wise.
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hexane); [a]2D8 −9.3 (c 0.59 in CHCl3); vmax (KBr)/cm−1 3325, 3268,
2925, 1749, 1709, 1655, 1542, 1224, 1046; dH (300 MHz, CDCl3)
6.23 (1 H, d, J 8.7, NH, exchangeable with D2O), 5.99 (1 H, br d,
NH, exchangeable with D2O), 5.94–5.81 (1 H, m), 5.27 (1 H, d, J
17.1), 5.20 (1 H, d, J 10.5), 5.16–5.02 (2 H, m), 4.86 (1 H, t, J 9.3),
4.56 (2 H, d, J 5.4), 4.30 (1 H, dd, J 12.3 and 3.9), 4.19–4.07 (2 H,
m), 3.74 (1 H, br d), 2.09 (3 H, s), 2.07 (3 H, s), 2.04 (3 H, s), 1.96
(3 H, s); dC (75 MHz, CDCl3) 171.5, 170.7, 169.3, 155.8, 132.2,
117.7, 82.2, 73.1, 68.0, 65.9, 61.8, 52.7, 23.0, 20.6, 20.5; HRMS
(ESI): C18H27N2O10 [M + H]+ calcd: 431.1666, found 431.1667.
After complete addition of alkoxycarbonyl chloride, the reaction
mixture was warmed to 30 C and stirred until the reaction was
◦
over (as indicated by TLC). The reaction mixture was quenched
with saturated NH4Cl solution and extracted with CHCl3. The
combined organic layers were washed with water and dried over
sodium sulfate and concentrated. Flash chromatography of the
resulting residue provided corresponding carbamates.
2-N-Acetyl-3,4,6-tri-O-acetyl-1-N-allyloxycarbonyl-1,2-dideoxy-
1,2-di-(p-toluenesulfonamido)-b-D-glucopyranose
23a. Com-
pound 23a (2.58 g, 79%) was obtained as a white solid in 9 h from
the reaction of 20a (2.89 g, 4.42 mmol) with DMAP (0.108 g,
0.88 mmol), Et3N (1.23 mL, 8.84 mmol) and allyloxycarbonyl
chloride (1.89 ml, 17.68 mmol) in 10 mL of dry CH2Cl2 as per
the general procedure described above. Flash chromatography
of the crude reaction mixture was performed with hexane : ethyl
4-O-[2,3,4,6-Tetra-O-acetyl-(b-D-galactopyranosyl)]-2-acetamido-
3,6-di-O-acetyl-1-N-allyloxycarbonyl-2-deoxy-b-D-glucopyrano-
sylamine 24c. Compound 24c (0.123 g, 88%) was obtained as a
white solid in 1 h from the reaction 23c (0.200 g, 0.195 mmol) with
17 eq. of SmI2 (preformed) in dry THF (20 mL) and degassed
water (0.351 mL, 19.50 mmol) using general procedure B for
detosylation as described above. Flash chromatography of the
crude reaction mixture was performed with hexane : ethyl acetate
◦
acetate (3 : 1). Mp 52 C (from CH2Cl2–hexane); [a]2D8 −33.4 (c
0.64 in CHCl3); vmax (KBr)/cm−1 3029, 2957, 1749, 1708, 1449,
1369, 1235, 1168, 1086, 1054; dH (300 MHz, CDCl3) 7.87 (2 H, d,
J 8.1), 7.76 (2 H, d, J 8.1), 7.33 (2 H, d, J 8.7), 7.29 (2 H, d, J
8.4), 6.76 (1 H, d, J 9.3), 5.99 (1 H, t, J 9.6), 5.90–5.77 (1 H, m),
5.57 (1 H, t, J 9.6), 5.33 (1 H, d, J 17.1), 5.23 (1 H, d, J 10.5),
5.11 (1 H, t, J 9.6), 4.68 (1 H, dd, J 13.2 and 5.4), 4.52 (1 H, dd, J
13.2 and 5.4), 4.13 (2 H, s), 3.99–3.95 (1 H, m), 2.43 (6 H, s), 2.15
(3 H, s), 2.07 (3 H, s), 2.04 (3 H, s), 2.02 (3 H, s); dC (75 MHz,
CDCl3) 171.5, 170.4, 169.4, 150.9, 145.3, 144.9, 136.1, 135.8,
130.2, 129.3, 128.6, 128.0, 119, 82.5, 73.9, 70.2, 69.0, 68.1, 62.2,
58.2, 26.1, 21.6, 21.5, 20.7, 20.6; HRMS (ESI): C32H39N2O14S2
[M + H]+ calcd: 739.1843, found 739.1847.
◦
(1 : 2). Mp 94 C (from CH2Cl2–hexane); [a]2D8 +5.4 (c 0.58 in
CHCl3); vmax (KBr)/cm−1 3369, 2927, 1747, 1540, 1370, 1227,
1048; dH (300 MHz, CDCl3) 6.17 (1 H, d, J 7.4, NH, exchangeable
with D2O), 6.02 (1 H, d, J 7.8, NH, exchangeable with D2O),
5.92–5.81 (1 H, m), 5.33 (2 H, d, J 17.0), 5.22 (1 H, dd, J 10.4
and 8.7), 5.14–4.95 (3 H, m), 4.79 (1 H, t, J 8.0), 4.56–4.41 (4 H,
m), 4.15–3.96 (4 H, m), 3.89–3.67 (3 H, m), 2.15 (3 H, s), 2.12
(3 H, s), 2.10 (3 H, s), 2.06 (6 H, s), 1.97 (3 H, s), 1.96 (3 H, s); dC
(75 MHz, CDCl3) 171.8, 171.4, 170.3, 170.2, 170.0, 169.1, 155.6,
132.2, 117.7, 101.0, 82.3, 75.7, 73.9, 73.1, 70.8, 70.6, 69.0, 66.6,
65.9, 62.0, 60.8, 53.1, 22.9, 20.7, 20.5; HRMS (ESI): C30H43N2O18
[M + H]+ calcd: 719.2511, found 719.2523.
4-O-[2,3,4,6-Tetra-O-acetyl-(b-D-galactopyranosyl)]-2-N-acetyl-
1-N-allyloxycarbonyl-3,6-di-O-acetyl-1,2-dideoxy-1,2-di-(p-toluene-
sulfonamido)-b-D-glucopyranose 23c. Compound 23c (1.63 g,
75%) was obtained as a white solid in 12 h from the reaction of
20e (2.00 g, 2.12 mmol) with DMAP (0.052 g, 0.424 mmol), Et3N
(0.589 mL, 4.24 mmol) and allyloxycarbonyl chloride (0.904 g,
8.48 mmol) in dry CH2Cl2 (10 mL) as per the general procedure
described above. Flash chromatography of the crude reaction
mixture was performed with hexane–ethyl acetate (2 : 1). Mp
General procedure for synthesis of N-linked glycoamino acids
25a–d, 27a–c and an N-linked glycopeptide 29
Procedure A using DCC–DMAP: Starting compound (1 eq.) was
added to a flame dried 50 mL three-necked round bottomed flask
and dissolved in dry THF under an argon atmosphere. To this,
Pd(PPh3)4 (10 mol%) was added followed by drop-wise addition
of Et2NH (10 eq.). The reaction mixture was allowed to stir at
room temperature. After completion of the reaction (20 minutes,
as indicated by TLC), the THF was evaporated completely. The
residue was then dissolved in dry CH2Cl2 and transferred drop-
wise to a suspension of protected amino acid (1.5 eq.), DCC
(1.8 eq.) and DMAP (1.5 eq.) in dry CH2Cl2 that was pre-
stirred for 2 h. The reaction mixture was then allowed to stir
at 30 ◦C for 12 h, after which it was filtered and the residue
was washed with more CH2Cl2. The organic layer was washed
with 5% NaHCO3, saturated NH4Cl, dried over sodium sulfate
and concentrated. Flash chromatography of the resulting residue
provided the corresponding N-linked glycoamino acids.
◦
79 C (from CH2Cl2–hexane); [a]2D8 −27.7 (c 0.49 in CHCl3); vmax
(KBr)/cm−1 2983, 1747, 1597, 1433, 1370, 1228, 1170, 1063; dH
(300 MHz, CDCl3) 7.85 (2 H, d, J 7.5), 7.77 (2 H, d, J 7.5), 7.31
(4 H, m), 6.74 (1 H, d, J 9.3), 5.97 (1 H, t, J 9.0), 5.80–5.71 (1 H,
m), 5.52 (1 H, t, J 9.3), 5.36–5.10 (4 H, m), 4.97 (1 H, d, J 10.2),
4.64–4.44 (4 H, m), 4.18–4.03 (4 H, m), 3.93–3.79 (2 H, m), 2.44
(6 H, s), 2.16 (3 H, s), 2.13 (3 H, s), 2.09 (9 H, s), 2.06 (3 H, s),
1.97 (3 H, s); dC (75 MHz, CDCl3) 171.2, 170.2, 170.1, 170.0,
169.8, 150.6, 145.0, 144.6, 136.1, 135.9, 130.0, 129.2, 128.3, 127.8,
118.7, 100.4, 82.3, 76.7, 74.6, 70.9, 70.6, 69.6, 69.0, 67.7, 66.7,
61.9, 60.8, 58.2, 25.8, 21.4, 20.8, 20.6, 20.4, 20.3; HRMS (ESI):
C44H55N2O22S2 [M + H]+ calcd: 1027.2688, found 1027.2697.
Procedure B using DCC–HOBt: Starting compound (1 eq.) was
added to a flame dried 50 mL three-necked round bottomed flask
and dissolved in dry THF under an argon atmosphere. To this,
Pd(PPh3)4 (10 mol%) was added followed by drop-wise addition
of Et2NH (10 eq.). The reaction mixture was allowed to stir at
room temperature. After completion of the reaction (20 minutes,
as indicated by TLC), the THF was evaporated completely. The
residue was then dissolved in dry CH3CN and transferred drop-
wise to a suspension of protected amino acid (1 eq.), DCC (1 eq.)
2-Acetamido-3,4,6-tri-O-acetyl-1-N-allyloxycarbonyl-2-deoxy-
b-D-glucopyranosylamine 24a. Compound 24a (0.105 g, 90%)
was obtained as a white solid in 1 h from the reaction 23a
(0.200 g, 0.27 mmol) with 13 eq. of SmI2 (preformed) in dry
THF (20 mL) and degassed water (0.366 mL, 20.32 mmol) using
general procedure B for detosylation as described above. Flash
chromatography of the crude reaction mixture was performed with
hexane : ethyl acetate (1 : 1). Mp 164 ◦C (decomp.) (from CH2Cl2–
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and 1-hydroxybenzotriazole (HOBt) (1 eq.) in dry CH3CN that
was pre-stirred for 2 h. The reaction mixture was then allowed
to stir at 30 ◦C for 12–24 h, after which it was filtered and the
residue was washed with CH2Cl2. The organic layer was washed
with 5% NaHCO3, saturated NH4Cl, dried over sodium sulfate
and concentrated. Flash chromatography of the resulting residue
provided the corresponding N-linked glycoamino acids.
(0.037 g, 0.032 mmol), Et2NH (0.337 mL, 3.25 mmol), 1-benzyl
N-(benzyloxycarbonyl)-L-aspartate 26a (0.116 g, 0.325 mmol),
DCC (0.044 g, 0.325 mmol) and HOBt (0.067 g, 0.325 mmol)
in dry CH3CN (10 mL) as per the general procedure B. Flash
chromatography of the crude reaction mixture was performed
with hexane : ethyl acetate (1 : 3).◦Mp 222–224 ◦C (from ethyl
◦
◦
acetate–hexane) {lit. mp 213–215 C,31 225 C,32 214–215 C33
and 213–217 ◦C34}; [a]D28 +6.3 (c 0.58 in CHCl3) {lit. [a]D +9 (c 1 in
CHCl3),31 +7 (c 1 in CHCl3),32 +10 (c 0.5 in CHCl3)33 and +12 (c
0.5 in CHCl3)34} (Found: C, 57.81; H, 5.78; N, 6.06. C33H39N3O13
requires: C, 57.80; H, 5.73; N, 6.13%); vmax (KBr)/cm−1 3307,
1743, 1697, 1661, 1546, 1376, 1229; dH (300 MHz, CDCl3)
7.36–7.33 (10 H, m), 7.17 (1 H, d, J 7.8, NH, exchangeable with
D2O), 6.02 (1 H, d, J 8.7, NH, exchangeable with D2O), 5.78
(1 H, d, J 7.9, NH, exchangeable with D2O), 5.23–5.07 (5 H, m),
5.01–4.90 (2 H, m), 4.68–4.65 (1 H, m), 4.27 (1 H, dd, J 12.5 and
4.2), 4.08–4.00 (2 H, m), 3.72–3.70 (1 H, m), 2.86 (1 H, dd, J 16.5
and 4.5), 2.70 (1 H, dd, J 16.0 and 4.5), 2.07 (3 H, s), 2.06 (3 H,
s), 2.05 (3 H, s), 1.82 (3 H, s); dC (75 MHz, CDCl3) 172.4, 171.7,
170.9, 170.7, 169.2, 156.1, 136.1, 135.5, 128.5, 128.3, 128.1, 128.0,
80.1, 73.5, 72.7, 67.7, 67.2, 67.0, 61.7, 53.1, 50.6, 37.7, 22.8, 20.7,
20.6, 20.5; HRMS (ESI): C33H40N3O13 [M + H]+ calcd: 686.2561
found 686.2554.
2-Acetamido-3,4,6-tri-O-acetyl-1-N-[N-tert-butyloxycarbonyl-
L-glycyl]-2-deoxy-b-D-glucopyranosylamine 25a. Procedure A:
Compound 25a (0.167 g, 72%) was obtained as a white solid in
12 h from the reaction of 24a (0.198 g, 0.460 mmol) with Pd(PPh3)4
(0.058 g, 0.05 mmol), Et2NH (0.477 mL, 4.60 mmol), N-Boc-
glycine (0.184 g, 0.690 mmol), DCC (0.171 g, 0.830 mmol) and
DMAP (0.084 g, 0.69 mmol) in dry CH2Cl2 (6 mL) as per the
general procedure A. Flash chromatography of the crude reaction
mixture was performed with ethyl acetate. Mp 85 ◦C (from ethyl
acetate–hexane); [a]2D8 +3.4 (c 0.24 in CHCl3); vmax (KBr)/cm−1
3319, 2976, 2359, 1747, 1665, 1533, 1376, 1241, 1169, 1047; dH
(300 MHz, CDCl3) 7.46 (1 H, d, J 7.6, NH, exchangeable with
D2O), 6.26 (1 H, d, J 8.3, NH, exchangeable with D2O), 5.16–5.09
(4 H, m), 4.28 (1 H, dd, J 12.3 and 4.2), 4.21–4.13 (1 H, m), 4.08
(1 H, dd, J 12.3 and 1.8), 3.81–3.80 (3 H, m), 2.09 (3 H, s), 2.06
(3 H, s), 2.04 (3 H, s), 1.94 (3 H, s), 1.46 (9 H, s); dC (75 MHz,
CDCl3): 172.0, 171.6, 170.7, 170.7, 169.3, 155.7, 80.0, 73.5, 72.8,
67.9, 61.8, 53.1, 44.1, 28.3, 22.9, 20.7, 20.6, 20.5; HRMS (ESI):
C21H34N3O11 [M + H]+ calcd: 504.2193, found 504.2204.
2-Acetamido-3,6-di-O-acetyl-N-[1-benzyl-N-(tert-butyloxycar-
bonyl)-L-aspart-4-oyl]-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-b-D-
galactopyranosyl)-b-D-glucopyranosylamine
27b. Compound
27b (0.084 g, 64%) was obtained as a white solid in 24 h from
the reaction of 24d (0.100 g, 0.139 mmol) with Pd(PPh3)4
(0.016 g, 0.014 mmol), Et2NH (0.144 mL, 1.39 mmol), 1-benzyl
N-(tert-butyloxycarbonyl)-L-aspartate 26b (0.045 g, 0.139 mmol),
DCC (0.029 g, 0.139 mmol) and HOBt (0.019 g, 0.139 mmol)
in dry CH3CN (10 mL) as per the general procedure B. Flash
chromatography of the crude reaction mixture was performed
with hexane : ethyl acetate (1 : 4). Mp 92 ◦C (from ethyl
acetate–hexane); [a]2D8 +9.7 (c 0.52 in CHCl3); vmax (KBr)/cm−1
3365, 2978, 2933, 1750, 1666, 1545, 1374, 1226, 1169, 1055; dH
(300 MHz, CDCl3) 7.36–7.34 (5 H, m), 7.12 (1 H, d, J 7.8, NH,
exchangeable with D2O), 5.82 (1 H, d, J 7.8, NH, exchangeable
with D2O), 5.75 (1 H, d, J 9.1, NH, exchangeable with D2O), 5.36
(1 H, br s), 5.25–5.07 (3 H, m), 4.99–4.93 (2 H, m), 4.88 (1 H, t, J
9.1), 4.57–4.55 (1 H, m), 4.47 (1 H, d, J 7.8), 4.40 (1 H, d, J 11.6),
4.14–3.94 (4 H, m), 3.87 (1 H, t, J 6.8), 3.76 (1 H, t, J 9.2), 3.64
(1 H, m), 2.84 (1 H, dd, J 16.3 and 3.7), 2.65 (1 H, dd, J 16.1 and
3.8), 2.16 (3 H, s), 2.12 (3 H, s), 2.10 (3 H, s), 2.06 (6 H, s), 1.98
(3 H, s), 1.84 (3 H, s), 1.42 (9 H, s); dC (75 MHz, CDCl3) 172.6,
171.6, 171.3, 171.1, 170.3, 170.0, 169.2, 155.5, 135.6, 128.4, 128.3,
128.0, 101.0, 80.0, 75.6, 74.3, 72.9, 70.8, 70.6, 68.9, 67.0, 66.5,
62.0, 60.8, 53.3, 50.0, 37.7, 28.2, 22.9, 20.8, 20.6; HRMS (ESI):
C42H58N3O21 [M + H]+ calcd: 940.3563, found 940.3600.
Procedure B: Compound 25a (0.164 g, 71%) was obtained in
16 h from the reaction of 24a (0.198 g, 0.46 mmol) with Pd(PPh3)4
(0.053 g, 0.046 mmol), Et2NH (0.477 mL, 4.60 mmol), N-Boc-
glycine (0.080 g, 0.460 mmol), DCC (0.095 g, 0.460 mmol) and
HOBt (0.062 g, 0.460 mmol) in dry CH3CN (10 mL) as per the
general procedure B.
2-Acetamido-3,4,6-tri-O-acetyl-1-N-[N-(fluorenylmethoxycar-
bonyl-L-alanyl]-2-deoxy-b-D-glucopyranosylamine
25b. Com-
pound 25b (0.281 g, 76%) was obtained as an off white solid
in 16 h from the reaction of 24a (0.250 g, 0.581 mmol) with
Pd(PPh3)4 (0.067 g, 0.058 mmol), Et2NH (0.603 mL, 5.81 mmol),
Fmoc-alanine (0.181 g, 0.581 mmol), DCC (0.119 g, 0.581 mmol)
and HOBt (0.078 g, 0.581 mmol) in dry CH3CN (15 mL) as per
the general procedure B. Flash chromatography of the crude
reaction mixture ◦was performed with hexane : ethyl acetate (1 :
2). Mp 204–206 C (from CH2Cl2–hexane); [a]2D8 −5.02 (c 0.55
in CHCl3); vmax (KBr)/cm−1 3306, 1748, 1670, 1541, 1374, 1236,
1044; dH (300 M, CDCl3) 7.76 (2 H, d, J 7.3), 7.60 (2 H, d, J 7.0),
7.44 (1 H, d, J 8.4, NH, exchangeable with D2O), 7.40 (2 H, t, J
7.5), 7.31 (2 H, t, J 7.5), 6.11 (1 H, d, J 7.8, NH, exchangeable
with D2O), 5.42 (1 H, d, J 6.9, NH, exchangeable with D2O),
5.12–5.04 (3 H, m), 4.39–4.05 (7 H, m), 3.77 (1 H, br s), 2.06 (6 H,
s), 2.04 (3 H, s), 1.90 (3 H, s), 1.38 (3 H, d, J 6.1); dC (75 MHz,
CDCl3) 173.4, 172.2, 171.7, 170.6, 169.2, 155.7, 143.8, 141.3,
127.7, 127.0, 125.2, 125.1, 119.9, 80.2, 73.6, 72.8, 67.9, 67.1, 61.7,
53.5, 50.7, 47.1, 23.0, 20.7, 20.5, 18.3; HRMS (ESI): C32H38N3O11
[M + H]+ calcd: 640.2506, found 640.2535.
2-Acetamido-3,4,6-tri-O-acetyl-1-N-{1-benzyl-2-N-[N-(fluorenyl-
methoxycarbonyl-L-alanyl)]-L-aspart-4-oyl}-2-deoxy-b-D-glucopy-
ranosylamine 29. Compound 29 (0.179 g, 55%) was obtained
as a white solid in 24 h from the reaction of 24a (0.166 g,
0.386 mmol) with Pd(PPh3)4 (0.044 g, 0.036 mmol), Et2NH
(0.401 mL, 3.86 mmol), Fmoc-Ala-Asp-OBn 28 (0.199 g,
0.386 mmol), DCC (0.079 g, 0.386 mmol) and HOBt (0.052 g,
0.386 mmol) in dry CH3CN (10 mL) as per the general procedure
B. Flash chromatography of the crude reaction mixture was
2-Acetamido-3,4,6-tri-O-acetyl-1-N-[1-benzyl-N-(benzyloxy)-
carbonyl-L-aspart-4-oyl]-2-deoxy-b-D-glucopyranosylamine 27a.
Compound 27a (0.167 g, 75%) was obtained as a white solid in
24 h from the reaction of 24a (0.140 g, 0.325 mmol) with Pd(PPh3)4
3856 | Org. Biomol. Chem., 2007, 5, 3847–3858
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performed with hexane : ethyl acetate (1 : 4). Mp 228–230 ◦C
(from DMSO–H2O); [a]2D8 +7.3 (c 0.11 in CHCl3); vmax (KBr)/cm−1
3307, 1746, 1665, 1538, 1449, 1375, 1236, 1044; dH (300 MHz,
CDCl3) 7.78 (2 H, d, J 7.9), 7.63 (2 H, br s), 7.44–7.28 (10 H, m),
5.88 (1 H, d, J 7.9, NH, exchangeable with D2O), 5.61 (1 H, d, J
5.8, NH, exchangeable with D2O), 5.18–4.89 (7 H, m), 4.42–4.24
(5 H, m), 4.13–4.04 (2 H, m), 3.65 (1 H, d, J 8.3), 2.90 (1 H, dd,
J 16.4 and 4.3), 2.73 (1 H, dd, J 16.3 and 3.3), 2.07 (3 H, s), 2.06
(6 H, s), 1.86 (3 H, s), 1.38 (3 H, d, J 6.0); dC (75 MHz, DMSO-d6)
172.6, 170.9, 170.0, 169.6, 169.5, 169.3, 155.6, 143.9, 143.8, 140.7,
135.9, 128.3, 127.9, 127.6, 127.1, 125.3, 120.1, 78.0, 73.3, 72.3,
68.3, 66.0, 65.6, 61.8, 52.2, 49.8, 48.3, 46.6, 36.7, 22.6, 20.5, 20.4,
20.3, 18.2; HRMS (ESI): C43H49N4O14 [M + H]+ calcd: 845.3245,
found 845.3257.
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Acknowledgements
We are grateful to the Department of Science and Technology,
India for financial support. V. K. thanks the Council of Scientific
and Industrial Research, India for a research fellowship. We are
also thankful to Dr K. P. Kaliappan and Dr N. Jayaraman for
helping us with the HRMS data.
10 C. M. Kaneshiro and K. Michael, Angew. Chem., Int. Ed., 2006, 45,
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