Novel conformationally restricted glycoamino acids from glyco-α-aminonitriles as potent turn mimics in peptide synthesis

Article abstract of DOI:10.1016/S0040-4039(02)00689-5

Our previously described glycoaminocyanation procedure using Ti(OiPr)₄ and TMSiCN has been applied to introduce amino acid and peptide moieties on a monosaccharide. Selective reduction using NaNH₄-CoCl₂ and Pd(C), respectively, is described. Restricted conformation of the new glycoamino acids favours intramolecular cyclisation to give the corresponding oxopiperazine 5a-b and 12a-b. The target acyclic compound I was obtained when the peptide derivative was displaced from the complex using KCN. Hydrolysis of the glycospirohydantoin 18 to give the glycoamino acid II is also described.

Full text of DOI:10.1016/S0040-4039(02)00689-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3805–3808
Novel conformationally restricted glycoamino acids from
glyco-a-aminonitriles as potent turn mimics in peptide synthesis
Albert Nguyen Van Nhien, He´le`ne Ducatel, Christophe Len and Denis Postel*
Laboratoire des Glucides Universite´ de Picardie-Jules Verne, 33 rue Saint Leu, 80039 Amiens, France
Received 26 March 2002; revised 8 April 2002; accepted 9 April 2002
Abstract—Our previously described glycoaminocyanation procedure using Ti(OiPr)4 and TMSiCN has been applied to introduce
amino acid and peptide moieties on a monosaccharide. Selective reduction using NaNH4–CoCl2 and Pd(C), respectively, is
described. Restricted conformation of the new glycoamino acids favours intramolecular cyclisation to give the corresponding
oxopiperazine 5a–b and 12a–b. The target acyclic compound I was obtained when the peptide derivative was displaced from the
complex using KCN. Hydrolysis of the glycospirohydantoin 18 to give the glycoamino acid II is also described. © 2002 Published
by Elsevier Science Ltd.
More recently there has been an increased interest in
unnatural a-amino acids.1–5 A particular class within
this family is the conformationally restricted amino
acids, which are known as b-turn mimics.5–7 Such com-
pounds have been used to study enzymatic reaction
mechanisms and as optically active starting materials
for a variety of synthetic applications. Numerous differ-
ent types of unnatural aminoacids have been reported
tial to induce b-bends and a/310 helices in peptides and
to allow better control of the spatial organisation of
these metal receptors in peptide supramolecular
architectures.5,18,19
In the course of our ongoing interest in the introduc-
tion of a-aminonitriles at non-anomeric positions of
monosaccharides, we have explored various stereoselec-
tive routes to new chiral sugar a-amino acids incorpo-
rating Ca as one of the carbon atoms of the sugar ring.
This paper shows that the previously reported20–23
amino cyanation procedure can provide ready access to
key intermediates in routes to new GAAs derivatives of
the types I and II (Fig. 1).
in the last decade using
a variety of synthetic
approaches.8–10 An interesting class of turn mimics is
the glycoamino acids (GAAs), which are intended to
function as conformationally restricted dipeptide
isosters.11–16 The GAAs described in this paper are
characterised by having the amino and carboxylic acid
functionalities on two distinct positions of the saccha-
ride backbone. Recently, Steiner reported the hydroly-
sis of spirohydantoin derivatives of protected
In keeping with our earlier work, we have introduced
a-aminoacids on the saccharide moiety such that they
possess an N-terminal amino group in common with
4,6-dideoxy-L-talopyranoside and D-allopyranoside to
obtain the corresponding a-aminoacids with one of the
standard a-aminoacids. Thus,
L-alanine and glycine
were firstly protected by conversion into their methyl
esters using classical conditions ((MeO)2C(Me)2; HCl–
carbon atoms of the sugar ring being Ca.17
The concept of a,a-disubstituted a-aminoacids as build-
ing blocks for peptide scaffolds and conformational
restrained peptidomimetics, has been applied to the
synthesis of new chiral axial disymmetric compounds.
Wakselman prepared various biphenyl-, binaphthyl-
and 4,5-diazafluorene derivatives to study their poten-
Keywords: glyco-a-aminonitriles; glyco-a-amino acids; selective
reduction; oxopiperazine; glycopeptides; turn mimics.
* Corresponding author. Tel.: 03 22 82 75 70; fax: 03 22 82 75 68;
e-mail: denis.postel@sc.u-picardie.fr
Figure 1. Target glycoamino acid structures.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00689-5

3806
A. Nguyen Van Nhien et al. / Tetrahedron Letters 43 (2002) 3805–3808
Scheme 1. Reagents: (i)
L-Ala-OMe, HCl or L-Gly-OMe, HCl; TEA; Ti(OiPr)4; MeOH then TMSiCN; (ii) CoCl2; NaBH4;
MeOH.
Selective reduction of the cyano groups of 16 was
achieved in the same fashion as used for 2a–b and 9a–b.
Contrary to previous experiments, the CoII-glycopep-
tide complex of I appeared to be relatively stable, such
that filtration through a layer of silica was found to be
inefficient in removing the cobalt moiety. However,
extraction using aqueous HCl (0.5N) gave exclusively
the cyclic oxopiperazine 5b in a low yield (34%). These
results demonstrate the effective and selective reduction
of the cyano group without affecting the carbonyl
group and the capability of the subsequent amines to
efficiently cyclise to give the required piperazine deriva-
tives. It has been proposed27 that the high reactivity is
due to the formation of a cobalt–aminoacid complex
involving the oxygen and nitrogen atoms of the same
aminoacid unit. Two different approaches were used to
access to the acyclic target compound I.28
H2O) and then stereoselectively coupled with the uloses
1 and 8 using our aminocyanation procedure which
employs Ti(OiPr)4 as mild and effective Lewis acid
catalyst. Relatively low yields of the L-alanine deriva-
tives 2a and 9a (23 and 47%, respectively) were
obtained. In contrast, higher yields (53 and 80%,
respectively) were afforded of the glycine derivatives
2b24 and 9b using the same reaction conditions.
Increases in either the number of equivalents of
aminoacid or that of Ti(OiPr)4 did not permit an
improvement in the yield. In the second case, the
isopropylesters 3 (2b: 43%; 3: 38%) and 10 (9b: 23%; 10:
12%) were observed as by-products. Selective reduction
of the CN group of 2a–b and 9a–b with NaBH4–CoIICl2
system5 gave the corresponding amino derivatives 4a–b
and 11a–b, which spontaneously cyclised to the corre-
sponding oxopiperazines 5a (75%), 5b (78%),25 12a
(50%) and 12b (60%) as outlined in Scheme 1. Removal
of CoII derivatives was achieved in all cases by filtration
through a silica gel pad. The same strategy was applied
to obtain the ulose derivative 1 starting from t-butyl
ester protected aminoacid derivatives that are less sub-
ject to aminolysis. a-Aminonitrile 6 was obtained in
35% yield. Reduction of the CN group of 6 and subse-
quent cyclisation gave 5b in 82% yield.
The first protocol involves displacement of the peptide
derivative from the complex by adding KCN followed
by extraction into CHCl3.29 Application of this proce-
dure to the dipeptide derivative 16 led successfully to
the target compound I in 35% yield. The glycine and
alanine derivatives 2a–b and 9a–b, were exclusively
converted into the cyclic oxopiperzine 5a–b and 12a–b
in high yield (60–75%).
The second route involved the selective reduction of the
cyano group without formation of the CoII derivative.
Pd(C)-catalysed hydrogenation of 2b in either pure
MeOH or MeOH–AcOH (1:1) yielded the cyclic deriva-
tive 5b in 44 and 57%, respectively. The Herranz
method,30 which involves hydrogenation in the presence
To avoid spontaneous intramolecular aminolysis aided
by the formation of a stable pyranose ring, we chose to
use the dipeptide glycylglycine in the route instead of a
monomeric aminoacid. Thus, the corresponding gly-
copeptidonitrile 16 was obtained in 38% yield.26

A. Nguyen Van Nhien et al. / Tetrahedron Letters 43 (2002) 3805–3808
3807
Scheme 2. Reagents: (i) CoCl2; NaBH4; MeOH then KCN.
Scheme 3. Reagents and conditions: (i) aqueous HCl (1N); (ii): Ba(OH)2; H2O reflux then Dowex 50X8-200 ion-exchange resin.
of di-tert-butyl-dicarbonate to give an (N-Boc)-pro-
tected derivative, was found to be ineffective in the this
case; thus 5b was obtained from 2b in 71%. Compound
16 appeared to be stable during Pd(C)-catalysed hydro-
genation in MeOH and a low yield (32%) of 5b was
observed (Scheme 2).
tion is being evaluated. Further derivatisations are
being explored using various amino acids in the
aminocyanation step and in subsequent peptide cou-
pling reactions involving I and II are in progress.
Acknowledgements
Compound II was synthesised via the corresponding
hydantoin derivative 17. In our previous paper we
described the synthesis of novel spirohydantoins of
We thank the Conseil Re´gional de Picardie and the
Ministe`re Franc¸ais de la Recherche for financial sup-
port, M. Pillon for technical support and G. Mackenzie
for helpful discussions.
D
-allose and
D
-ribose derived from glyco-a-aminoni-
triles.22,23 The preliminary study concerning the conver-
sion of these derivatives into the corresponding amino
acids was achieved on the partially deprotected D-allose
derivative 18 which was obtained in 67% yield from 17
using aqueous 1 M HCl. Hydrolysis of the hydantoin
ring with aqueous barium hydroxide (72 h; reflux) gave,
after treatment of the resulting barium carboxylate
derivative on Dowex 50X8-200 acidic resin, the target
compound II in 82% yield.31 It should be noted that a
shorter reaction time led to a mixture of II and of the
ureic derivative 19 (Scheme 3).
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