A new approach to peptide synthesis
Christopher J. Moody,a,b Leigh Ferris,b David Haighc and Elizabeth Swanna
a Department of Chemistry, University of Exeter, Stocker Road, Exeter, Devon, UK EX4 4QD
b Department of Chemistry, Loughborough University, Loughborough, Leicestershire, UK LE11 3TU
c Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North), Coldharbour
Road, The Pinnacles, Harlow, Essex, UK CM19 5AD
CO2R3
A new approach to the synthesis of dipeptides is described
based on the formation of the NHCHR1CONH–CHR2CO
bond by carbenoid N–H insertion, rather than the formation
of the peptide bond itself.
R1
H
N
N2
cat. RhII
P
P
CO2R3
R2
(a)
N
H
R1
O
O
R2
P
NH2
2
N
H
Peptides and proteins play a central role in all living organisms,
and hence the synthesis of such compounds has emerged as a
subject in its own right.1 In fact peptide synthesis is so highly
developed that chemists rarely, if ever, consider any approach
other than the formation of the amide bond (Fig. 1, disconnec-
tion 1). We now report a new approach to peptide synthesis
which involves for formation of the CONH–CHRCO bond by a
metal carbene N–H insertion reaction (Fig. 1, disconnection 2),
and its application in the synthesis of dipeptides of dehydro
amino acids, including the protected dehydro dipeptide compo-
nent of the tunichrome Mm-2.
R1
H
N
O
(b)
CO2R3
PO(OR3)2
cat. RhII
1
N
H
N2
CO2R3
PO(OR3)2
3
base,
R2CHO
R1
H
P
N
CO2R3
N
H
The N–H insertion reactions of metallocarbenoids, first
described in 1952,2 have found use in synthesis particularly in
the construction of bicyclic b-lactams.3 We have recently
described the application of such N–H insertion reactions in the
preparation of a-amino acids, a-aminophosphonates and phos-
phonoglycines,4,5 and therefore were attracted by the possibility
of using carbenoid N–H insertions in a synthesis of dipeptides
which, unusually, does not rely on formation of the peptide
bond itself. Two approaches starting from readily available
N-protected amino acid amides 1 were considered (Scheme 1).
Firstly, the use of diazo esters which would lead directly to
dipeptides 2 [Scheme 1(a)]. There is one reported example of
this approach which resulted in the synthesis of Z-Phe-a,a,a-
trifluoroAla-OMe 2 (P = Z, R1 = Bn, R2 = CF3, R3 = Me)
from methyl 2-diazo-3,3,3-trifluoropropionate,6 and we have
used both methyl 2-diazo-2-phenylacetate and methyl 2-diazo
O
R2
4
P = Protecting group
Scheme 1
observed. Although related phosphonates have been prepared
previously by synthesis of the corresponding a-amino-
phosphonate followed by peptide coupling,10 the simplicity of
this new method gives it some advantages. Wadsworth–
Emmons reaction of the phosphonates 6 with a range of
aldehydes using DBU as base11 gave the corresponding dehydro
dipeptides 7 in good yield (Scheme 2, Table 2). In each case a
N2
CO2Et
R1
R1
H
N
PO(OEt)2
R2
NH2
R2
CO2Et
3-oxobutanoate to give dipeptides 2 (R2
= Ph and Ac
N
P
N
P
Rh2(OAc)4
respectively).7,8 In the latter case the dipeptides 2 (R2 = Ac)
were cyclodehydrated to give oxazoles.8,9 The second ap-
proach, which is reported herein, involves the rhodium(ii)-
catalysed reaction of diazophosphonoacetate to give phospho-
nates 3, Wadsworth–Emmons reaction of which leads to the
dehydro dipeptide 4 [Scheme 1(b)].
O
toluene, heat
O
PO(OEt)2
5
6
DBU, CH2Cl2
R3CHO
R
2 = H
R1
H
N
The key N–H insertion reaction was carried out by treating a
mixture of the N-protected amino acid amide 5 and triethyl
diazophosphonoacetate with a catalytic amount of rhodium(ii)
acetate in toluene, and resulted in the formation of the
phosphonates 6 in good yield (Scheme 2, Table 1). The N–H
insertion reaction was completely regioselective, in that no
competing insertion into the carbamate N–H bond was
P
CO2Et
N
H
O
R3
7
Scheme 2
Table 1 Formation of phosphonates 6 from amides 5
➀ Peptide bond formation
Amide
P
R1
R2
Phosphonate
Yield (%)
R1
O
H
N
5a
5b
5c
5d
5e
5f
Z
Boc
Z
Boc
Boc
Z
H
H
H
H
H
H
6a
6b
6c
6d
6e
6f
81
88
80
80
82
80
N
H
Me
Me
Pri
Bui
O
R2
➁ Carbene N–H insertion
–(CH2)3–
Fig. 1
Chem. Commun., 1997
2391
Moody, Christopher J.
