Glycosylative transcarbamylation: efficient transformation of tert-butyl carbamates to novel glycoconjugates

Article abstract of DOI:10.1016/j.tetlet.2007.01.027

Reaction of a variety of tert-butyl carbamates under glycosylation conditions gives rise to anomeric 2-deoxy-2-amino sugar carbamates in a good to excellent yields. The reaction exhibits good tolerance to several common protecting groups, and has been use

Full text of DOI:10.1016/j.tetlet.2007.01.027

Tetrahedron Letters 48 (2007) 1791–1794
Glycosylative transcarbamylation: efficient transformation
of tert-butyl carbamates to novel glycoconjugates
Kenneth J. Henry, Jr.* and Jayana P. Lineswala
Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Lilly Corporate Center,
Indianapolis, IN 46285, United States
Received 29 August 2006; revised 4 January 2007; accepted 5 January 2007
Available online 10 January 2007
Abstract—Reaction of a variety of tert-butyl carbamates under glycosylation conditions gives rise to anomeric 2-deoxy-2-amino
sugar carbamates in a good to excellent yields. The reaction exhibits good tolerance to several common protecting groups, and
has been used to generate unnatural glycopeptide building blocks.
Ó 2007 Published by Elsevier Ltd.
Protecting group strategies are central to the successful
synthesis of glycopeptides. It has long been recognized
that tert-butyl carbamates (Boc groups) are sometimes
poor protecting groups for glycosylation reactions,1
although there have been examples where the Boc group
has efficiently survived. Jiaang et al. have reported an
example where glycosylation in the presence of the
electron-rich p-methoxybenzyl carbamate (Moz) group
resulted in carbamate exchange; giving rise to an
anomerically linked glycosyl carbamate in an excellent
yield, and it was surmised that the same process could
occur with a Boc group.2
HO
O
HO
NH2
OH
O
NaO3S
O
NAc
OH
OH
OH
O
O
H
N
H
N
O
N
N
N
H
H
H
O
O
O
O
O
O
OH
NAc
HO
HO
OH
SQ-28546
amount of the unexpected product 4, which arose from
the glycosylation of the threonine residue, and subse-
quent exchange of the tert-butyl group of the carbamate
by a second sugar group (Eq. 1). It is worth noting that
Schmidt has reported very efficient glycosylation of the
free hydroxyl of Boc-threonine benzyl ester under condi-
tions which were nearly identical to ours with the excep-
tion that a single equivalent of glycosyl donor was used.
It seems likely therefore, that the unexpected formation
of 4 is solely due to the presence of an excess of reagent,
and the yield of 3 could have been substantially im-
proved by using a stoichiometric amount of donor. Nev-
ertheless, this intriguing suboptimal result prompted us
to further examine the reaction of Boc groups with 2.
As part of a synthesis of the peptide fragment of the
natural product SQ-28546,3 we attempted to glycosylate
the threonine residue of the protected tetrapeptide 1.4
Glycosylation with N-trichloroethoxycarbonyl-glucos-
aminyl trichloroacetimidates has been well studied.5
Their ease of synthesis, high selectivity for b-linkages,
and facile refunctionalization makes them a premier
choice for glycosyl donors. Glycosyl donor 2 was
prepared for this study by the published method.
Peptide 1 was treated with 2 equiv of donor 2 and cata-
lytic TMS-OTf (10%) in dichloromethane at ꢀ40 °C for
20 min, at which time the starting material was con-
sumed as judged by TLC. In addition to a modest yield
of the desired product 3, we also isolated an equivalent
The proton NMR spectrum of 4 was expectedly com-
plex, and the assignment was made primarily on the
basis of the parent ion in the mass spectrum, and on
the lack of a tert-butyl carbamate resonance in the
*
Corresponding author. E-mail: henryk@lilly.com
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.01.027

1792
K. J. Henry, Jr., J. P. Lineswala / Tetrahedron Letters 48 (2007) 1791–1794
OTIPS
OTIPS
O
O
H
BocN
N
OMe
OTIPS
OTIPS
OMe
O
N
H
N
H
O
O
AcO
H
O
O
3, 41%
O
O
NTroc
BocN
HO
N
AcO
AcO
N
H
N
H
O
O
OMe
1
TMS-OTf
CH2Cl2, -40 °C
O
OMe
+
+
OAc
O
ð1Þ
OTIPS
OTIPS
OMe
O
HN CCl3
O
O
OAc
H
H
AcO
AcO
O
N
N
O
O
N
N
O
H
H
NTroc
AcO
O
O
4, 39%
O
AcO
N
H
O
CCl3
OAc
O
NTroc
O
OMe
2
OAc
OAc
proton NMR.6 Therefore, the result was corroborated
with a much simpler substrate. When the tert-butyl
carbamate of 2-methylpiperidine (5) was treated under
similar conditions (1.5 equiv of donor 2, 10% TMS-OTf,
that the reaction proceeds by way of electrophilic attack
of the glycosyl cation on the carbonyl oxygen of the tert-
butyl carbamate, and subsequent loss of the more stable
tert-butyl cation.
˚
powdered 4 A molecular sieves, dichloromethane,
ꢀ35°C), glycosyl carbamate 6 was isolated in an 85%
yield (Eq. 2) as an inseparable mixture of isomers. Car-
bon NMR of 6 and subsequent derivatives clearly
showed two sets of carbamate resonances, which further
solidified the assignment of the new compound as a gly-
cosyl carbamate.
The application to protected amino acid derivatives was
also successful, affording high yields of glycosyl carb-
amates (Table 2). The reaction is highly selective for
t-butyl carbamates, and fails to react with Cbz or Fmoc
groups. Benzyl esters, and even t-butyl esters and penta-
fluororphenyl esters are compatible with the chemistry.
Finally, we demonstrated that the deprotection and
refunctionalization of a select number of these N-tri-
chloroethoxycarbonyl glucosaminyl carbamates with
zinc powder and acetic anhydride following the proce-
dure of Schmidt5 affords the expected 2-deoxy-2-amino
sugars in a good yield (Table 3).
O
N
O
OAc
N
+
O
O
2
O
ð2Þ
O
AcO
N
H
O
CCl3
OAc
5
6
We have further examined the scope, limitations and
some of the protecting group tolerances for this reac-
tion. The reaction of a series of tert-butyl carbamates
of simple anilines was instructive (Table 1). Consistent
with a strong dependence on the electronic composition
of the carbamate, an electron rich aryl group afforded a
superior yield, whereas electron deficient substrates
failed to react.7 This observation suggests the likelihood
In conclusion, we have uncovered an efficient means of
converting tert-butyl carbamates to unnatural glycoside
analogs. The reactions proceed in a very good yield, and
exhibits an excellent protecting group selectivity. Fur-
thermore, we have demonstrated that the carbamate
linkage tolerates conditions for unveiling of the parent
sugar. This methodology will provide access to novel
unnatural glycoconjugates.
Table 1.
HN CCl3
OAc
H
AcO
H
O
N
O
O
O
N
O
O
AcO
+
AcO
O
NH
R
O
AcO
N
H
O
CCl3
Troc
R
OAc
2
7a-e
8a-e
R
Yield (%)
a
b
c
d
e
H
Me
OMe
NO2
CO2Et
84
95
98
NR
NR

K. J. Henry, Jr., J. P. Lineswala / Tetrahedron Letters 48 (2007) 1791–1794
1793
Table 2.
Substrate
Product
Compound (% yield)
AcO
O
O
H
N
O
O
O
Boc-Leu-OtBu
Boc-Phe-OMe
Boc-Phe-OBn
9 (87)
AcO
AcO
O
O
NH
O
O
Troc
AcO
H
N
O
AcO
AcO
10 (90)
NH
Troc
AcO
O
O
H
N
O
O
O
AcO
AcO
O
11 (90)
NH
O
O
Troc
AcO
H
N
O
AcO
AcO
O
O
NH
Boc-Glu(OtBu)-OtBu
12 (87)
13 (58)
14 (56)
Troc
O
AcO
O
H
N
O
O
O
AcO
AcO
Boc-Lys(Z)-OtBu
O
NH
O
O
Troc
NCbz
AcO
H
N
O
AcO
AcO
NH
F
F
F
F
Troc
Fmoc-Lys(Boc)-OPfp
Fmoc'
O
F
N
H
O
Table 3.
AcO
AcO
H
HO
H
O
O
H
N
O
O
N
R
O
NaOH/MeOH
Zn(0), Ac2O, HOAc
AcO
AcO
AcO
AcO
R
N
R
O
HO
HO
NH
Troc
NH
O
NH
O
O
Ac
Ac
Compound
Step 1 yield (%)
Step 2 yield (%)
6
71
85
76
71
64
78
37a
89
50
51
33
50
65
—
8a
8b
8c
12
13
14
a Low yield due in part to incomplete conversion of starting material.
Supplementary data
References and notes
1. Lacombe, J. M.;Pavia, A. A. J. Org. Chem. 1983,48, 2557–2563.
2. Jiaang, W.-T.; Hsiao, K.-F.; Chen, S.-T.; Wang, K.-T.
Synthesis 1999, 9, 1687–1690.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.01.027.

1794
K. J. Henry, Jr., J. P. Lineswala / Tetrahedron Letters 48 (2007) 1791–1794
1
3. (a) Cooper, R.; Unger, S. J. Org. Chem. 1986, 51, 3942; (b)
Cooper, R.; Wells, J. S.; Sykes, R. B. J. Antibiotics 1985, 38,
449.
4. Prepared in 7 steps by standard solution-phase peptide
synthesis.
5. (a) Dullenkopf, W.; Castro-Palomino, J. C.; Manzoni, L.;
Schmidt, R. R. Carbohydr. Res. 1996, 296, 135–147; (b)
Saha, U. K.; Schmidt, R. R. J. Chem. Soc., Perkin Trans. 1
1997, 1855–1860.
6. All compounds were characterized by H NMR and MS,
and yields refer to isolated, homogeneous products.
7. It is noteworthy that our ability to perform the transcarbam-
ylation reaction roughly mimicked the ease with which the
parent amine reacted with di-tert-butyl dicarbonate to afford
the carbamate. Ethyl p-aminobenzoate is only carbamylated
under forcing conditions, and p-nitroaniline is inert to carba-
mylation, requiring a different route to starting material 7d:
Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1994, 20, 2975.