Synthesis of protected sugar-amino acid hybrid molecules as platform for further derivatization

Article abstract of DOI:10.1016/j.tetlet.2012.10.042

The sugar-amino acid hybrid molecules with appropriate protecting groups were synthesized from sugar-derived lactones and ester of amino acids in five high yielding steps. The C-5 of the resultant hybrid molecule, upon selective deprotection, can be further derivatized to afford the linear depsipeptide.

Full text of DOI:10.1016/j.tetlet.2012.10.042

Tetrahedron Letters 53 (2012) 6957–6960
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of protected sugar-amino acid hybrid molecules as platform
for further derivatization
⇑
Han Liu, Xuechen Li
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2012
Revised 19 September 2012
Accepted 9 October 2012
Available online 17 October 2012
The sugar-amino acid hybrid molecules with appropriate protecting groups were synthesized from sugar-
derived lactones and ester of amino acids in five high yielding steps. The C-5 of the resultant hybrid mol-
ecule, upon selective deprotection, can be further derivatized to afford the linear depsipeptide.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hybrid molecule
Sugar
Amino acid
Depsipeptide
To face the challenge of developing new therapeutic reagents to
infectious and noninfectious diseases, the construction of small
molecules with diverse structures from simple building blocks
via short synthetic routes has became one of the important fields
of synthetic organic chemistry and medicinal chemistry.1 Besides
the design of novel multicomponent reactions and multistep reac-
tion sequences,2 another way of thinking is to synthesize the hy-
brid molecules between available building blocks such as
carbohydrates, amino acids and natural products.3 Considering
the availability and side-chain diversity (hydrophilic and hydro-
phobic side chains/functional groups) of amino acids, and the con-
densed chiral centres and modification sites on sugars, the
synthesis of sugar-amino acid hybrid molecules can be conceived
as a way for the rapid construction of potential bioactive molecules
with tunable and highly diverse structures.4,6a
The formation of the amide linkage between sugar compounds
and amines at oxidized C-1 position has been involved in the syn-
thesis of glycoconjugates.5,6 The reported synthetic approaches to-
wards the amide conjugates can be divided into two types, as
shown in Scheme 1. The most widely used approach for the simple
primary amine is the ring-opening of sugar-derived lactone with-
out protecting group.5 Full conversion can be obtained under a
mild heating condition even for polyamine nucleophiles,5b but
the reaction with the ester of amino acid is not feasible due to
the self-condensation. In recent years, the I2 mediated one-pot oxi-
dative amidation was applied to the conjugation step.6 In 2009,
Fang et al. reported the one-pot oxidative amidation of unpro-
tected aldoses and the decarboxylative amidation of a-keto acids
(sialic acid and KDO) with amino acids.6a The linkage at the oxi-
dized C-1 position was formed under mild condition. However,
only the reaction of unprotected sugar was compatible with amino
acid derived nucleophiles. When benzyl protected sugar was used
as substrate, only amino alcohols and some simple amines can give
good results.6c The hybrid molecules with C-1 amide linkage have
wide prospects for compatibility with all types of aldoses. How-
ever, the unprotected sugar segment used in the above mentioned
strategies hampered the further selective modification of the hy-
droxyl groups. To achieve the desired appropriately protected hy-
brid molecules, we designed a detoured but facile approach. In
this approach, the acid with the silyl protection of the released hy-
droxyl group is pursued as the pivotal intermediate (see Scheme 1).
As illustrated in Scheme 2, the benzylated lactone 1a7 derived
from glucose was first used as the model substrate. The lactone
ring can be opened via LiOH mediated saponification,8 but the hy-
droxyl acid 7 re-lactonized rapidly during the purification. When
the crude acid was used, the lactone 1a was re-formed as the sole
product under the silylation condition. The failure of the direct ap-
proach forced us to prepare the acid indirectly. The lactone ring
was opened by benzylamine in toluene under reflux.9 The reaction
time can be shortened from 12 to 1 h when microwave irradiation
(open vessel mode) was used. After removing the excess amine by
HCl (aq) washing, the crude product was silylated by TESCl/imidaz-
ole in DMF, and the product 3a was formed in 93% yield. To acti-
vate the amide bond towards hydrolysis,
a Boc group was
introduced onto the N atom.10 The reaction was slow and needed
2 days for a good conversion, but fortunately no side product was
formed and the unconverted 3a could be recovered. The resultant
⇑
Corresponding author.
E-mail address: xuechenl@hku.hk (X. Li).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.042

6958
H. Liu, X. Li / Tetrahedron Letters 53 (2012) 6957–6960
Literature approaches
OH
O
R'NH2
[O] & R'NH2
O
O
NHR'
RO
RO
RO
Ring-opening
Oxidative amidation
OH
R = H or Bn
O
R = H or Bn
For amino acids when R = H
For simple amines and polyamines
For amino alcohols and simple amines when R = Bn
Our approach
H2N
COOR'
∗
OSi
H
N
OSi
O
COOR'
R
∗
OH
PGO
PGO
PGO
amide coupling
O
O
O
R
Scheme 1. Approaches towards sugar-amino acid hybrid molecules.
OBn
OBn
OH
OBn
OTES
COOH
O
ii
vi
quant.
BnO
BnO
BnO
BnO
BnO
OH
BnO
O
BnO
1a
BnO
BnO
O
7
5a
i
quant.
OBn
OBn
OTES
CON(Boc)Bn
OBn
OTES
ii
93%
iii
OH
BnO
BnO
BnO
BnO
CONHBn
83%
(95% BRSM)
BnO
BnO
CONHBn
BnO
BnO
4a
BnO
2a
3a
OBn
OTES
OBn
OTES
iv
v
H
N
BnO
BnO
BnO
BnO
CO2Et
70-95%
COOH
93%
BnO
BnO
O
5a
Ph
6a
i) 5 eq. BnNH2, toluene, relux, 12 h; or 5 eq. BnNH2, toluene, microwave irradation, 150W, 110 oC, 1 h. ii) 3 eq.
TESCl, 6 eq. imidazole, DMF, 60 oC, 3 h. iii) 2 eq. Boc2O, 1 eq. DMAP, 1 eq. Et3N, THF, r.t., 48 h. iv) 10 eq. LiOH,
20 eq. H2O2, THF/H2O 4 : 1, r.t., 16 h. v)1.5 eq. PheOEt-HCl, 2 eq. EDCI, 1.5 eq. HOBt, 6 eq. Et3N, DCM, r.t., 2 h.
vi) 2 eq. LiOH, THF/H2O 2 : 1, 0 oC, 2 h.
Scheme 2. Synthesis of glucose-phenylalanine hybrid molecule.
imide 4a was treated with LiOOH (generated in situ by LiOH and
H2O2),11 and the acid 5a was formed smoothly. Compared with
other reported methods,12 our method for the acid preparation
gave better yield and it is amenable to the large-scale preparation.
However, the yield of 5a varied from batch to batch due to the
instability during the flash chromatography purification. The final
amide coupling with the ethyl ester of phenylalanine mediated
by EDCI was quite efficient, and the desired hybrid molecule 6a
was obtained in 93% yield. Considering the instability of the acid
5a (variable yields and inappropriate for storage), the coupling of
the crude intermediate was tested. As shown in Scheme 3, the cou-
pling using crude acid gave 92% yield over 2 steps. This simplified
process gave higher yield and better reproducibility than the for-
mer process, and was used in the synthesis of other hybrid
molecules.
With this encouraging result in hand, the hybrid molecules de-
rived from galactose, mannose, rhamnose and benzylidene pro-
tected glucose were synthesized following the optimized process
OBn
OBn
OBn
OTES
BnO
ii
OTES
CON(Boc)Bn
BnO
BnO
i
OTES
COOH
BnO
5a
BnO
BnO
NH
COOEt
BnO
93%
81%
BnO
BnO
O
Ph
4a
6a
i, ii
92% over 2 steps
i) 10 eq. LiOH, 20 eq. H2O2, THF/H2O 4 : 1, r.t., 16 h. ii)1.5 eq. PheOEt-HCl, 2 eq. EDCI, 1.5 eq. HOBt, 6
eq. Et3N, DCM, r.t., 2 h.
Scheme 3. Amide coupling using purified and crude acid intermediate.

H. Liu, X. Li / Tetrahedron Letters 53 (2012) 6957–6960
6959
Table 1
Isolated yields of sugar-phenylalanine hybrid molecules and intermediatesa
Compounds 2b–2e
Compounds 3b–3e
Compounds 4b–4e
Compounds 6b–6e
OBn
BnO
OBn
BnO
OBn
BnO
OBn
BnO
OTES
H
N
OH
OTES
OTES
CO2Et
BnO
BnO
CONHBn
BnO
CONHBn
BnO
CON(Boc)Bn
BnO
6b
BnO
BnO
BnO
4b
O
3b
2b
Ph
Quant.
98%
75% (98% BRSM)
65%
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OH
CONHBn
OBn
OTES
CONHBn
OTESH
OTES
CON(Boc)Bn
BnO
BnO
BnO
BnO
BnO
BnO
N
CO2Et
BnO
BnO
O
3c
4c
6c
2c
Ph
Quant.
81%
88% (95% BRSM)
72%
Ph
O
OH
OTBS
OTBS
BnO CON(Boc)Bn
OTBS
BnO
CONHBn
BnO
CONHBn
BnO
N
CO2Et
BnO
BnO
BnO
BnO
H
BnO
BnO
BnO
BnO
4d
2d
3d
6d
Quant.
91%
88%
94%
O
O
O
O
OTBS
Ph
Ph
Ph
Ph
OTBS
CONHBn
OTBS
CON(Boc)Bn
OH
H
N
O
O
O
O
CO2Et
BnO
BnO
BnO
BnO
CONHBn
BnO
4e
67% (96% BRSM)
BnO
3e
BnO
BnO
2e
O
Ph
6e
94%
86%
91%
a
The products in this table were synthesized following the same reaction sequence as the synthesis of 2À4a and 6a. The details were provided in Supplementary
information.
OBn
OTES
OBn
OTES
OBn
OH
O
O
i, ii
H
iii
BnO
BnO
BnO
BnO
H
BnO
BnO
N
CON(Boc)Bn
N
O
88%
O
BnO
BnO
BnO
O
O
4a
Ph
8
9
Ph
NHBoc
O
O
OBn OBn
OBn O
H
BnO
BnO
O
N
iv
O
O
O
BocHN
H
N
95%
BnO
O
O
Ph
BnO
(2 steps)
BnO
O
Ph
Depsipeptide
10
i) 10 eq. LiOH, 20 eq. H2O2, THF/H2O 4 : 1, r.t., 16 h. ii)1.5 eq. PheOAll-HCl, 2 eq. EDCI, 1.5 eq. HOBt, 6 eq. Et3N,
DCM, r.t., 2 h. iii) 2 eq. TBAF, THF, r.t., 1 h. iv) 2 eq. BocAlaOH, 2 eq. DCC, 0.5 eq. DMAP, DCM, r.t., overnight.
Scheme 4. Synthesis of Ala-gluconic acid-Phe depsipeptide.
from the corresponding lactones.13 The results were summarized
in Table 1. In most cases, good yields can be achieved for both
intermediates and final products. The yields for galactose derived
6b and mannose derived 6c were lower than 6d and 6e, probably
due to the partial decomposition during the imide cleavage step.
For rhamnose and benzylidene protect glucose derived com-
pounds, the TBS was used instead of TES, in order to avoid the
Si–O bond cleavage during LiOOH treatment. Although the basic
condition was involved in several steps, no epimerization at C-2
position was observed.
After the establishment of the facile approach towards the su-
gar-amino acid hybrids, the derivatization of the hybrid molecule
was explored. The depsipeptide structure was chosen as our syn-
thetic target due to their important applications in peptide synthe-
sis14 and drug discovery.15 As illustrated in Scheme 4, the imide
intermediate 4a was transformed to 8 via two steps in 88% yield.
In the coupling step, the phenylalanine protected by an allyl ester
was chosen, for the orthogonal deprotection condition of the allyl
group. After the TBAF desilylation of 8, another amino acid BocA-
laOH was coupled to the hydroxyl amide 9 to generate depsipep-
tide 10 in 95% yield over 2 steps. The new hybrid molecule 10
can be used as a building block for the synthesis of more complex
linear depsipeptides. Further derivatization of the hybrid mole-
cules to complex linear and cyclic structures is now undergoing
in our laboratory.
In conclusion, a synthetic approach towards protected sugar-
amino acid hybrid molecules was established. All the synthetic
steps used cheap reagents and gave good yields, which was impor-
tant for the scale-up preparation. The derivatization of the hybrid
molecules was demonstrated by the synthesis of a linear depsipep-
tide. Further application of this approach to construct complex hy-
brid molecules will be reported in due course.
Acknowledgment
The work was supported by RGC General Research Fund
(703811P), the Area of Excellence Scheme of the University Grants
Committee (Grant AoE/M-12/06) and the National Basic Research

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H. Liu, X. Li / Tetrahedron Letters 53 (2012) 6957–6960
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Supplementary data
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