A new approach to peptide synthesis

Article abstract of DOI:10.1039/a706658i

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.

Full text of DOI:10.1039/a706658i

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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

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(Scheme 3) to the protected dehydro dipeptide 9 (Ar2 = 3,4-
dibenzyloxyphenyl) differs from the published strategy. The
phosphonate 10, prepared from N-Boc-leucinamide and tri-
methyl phosphonoacetate in exactly the same way as its triethyl
analogue 6e, reacted readily with 3,4-dibenzyloxybenzaldehyde
to give the required dipeptide 11 (Ar2 = 3,4-dibenzyloxy-
phenyl) as a single Z-diasteromer. Hydrolysis of ester 11 gave
the required acid 9 in 95% yield (Scheme 3).
Table 2 Formation of dehydro dipeptides 7 from phosphonates 6
Phosphonate
P
R1 R3 Dehydro dipeptide
Yield (%)
6a
6b
6e
6e
6e
Z
H Ph Z-Gly-DPhe-OEt
7a 82
Boc Me Ph Boc-Ala-DPhe-OEt
Boc Bui Ph Boc-Leu-DPhe-OEt
Boc Bui Pri Boc-Leu-DLeu-OEt
Boc Bui Ara Boc-Leu-DTrp-OEt
7b 88
7c 88
7d 82
7e 80
In summary, we have shown that carbenoid N–H insertion
reactions can be applied in a new approach to peptides which
does not involve the formation of the peptide bond itself; such
an approach may offer advantages in some cases.
a Ar = N-Boc-indol-3-yl.
H2N
BocHN
We thank Loughborough University and SmithKline
Beecham Pharmaceuticals for their support.
O
H
N
O
NH
NH
Ar2
HO
Ar2
Footnote and References
Ar1
* E-mail: c.j.moody@exeter.ac.uk
O
O
8
9
1 For example, J. Jones, The Chemical Synthesis of Peptides, Clarendon,
Oxford, 1991.
LiOH,
aq. THF
(95%)
2 P. Yates, J. Am. Chem. Soc., 1952, 74, 5376.
3 For a compilation of references, see ref. 4.
4 E. Aller, R. T. Buck, M. J. Drysdale, L. Ferris, D. Haigh, C. J. Moody,
N. D. Pearson and J. B. Sanghera, J. Chem. Soc., Perkin Trans. 1, 1996,
2879.
BocHN
BocHN
DBU, CH2Cl2
O
O
NH
NH
Ar2CHO
(68%)
5 L. Ferris, D. Haigh and C. J. Moody, J. Chem. Soc., Perkin Trans. 1,
1996, 2885.
MeO
MeO
Ar2
PO(OMe)2
6 S. N. Osipov, N. Sewald, A. F. Kolomiets, A. V. Fokin and K. Burger,
Tetrahedron Lett., 1996, 37, 615.
7 C. J. Moody and R. T. Buck, unpublished results.
8 M. C. Bagley, R. T. Buck, S. L. Hind, C. J. Moody and A. M. Z. Slawin,
Synlett, 1996, 825.
O
10
O
11
Scheme 3
9 C. J. Moody and M. C. Bagley, Synlett, 1996, 1171.
10 U. Schmidt and B. Riedl, Synthesis, 1993, 815.
11 U. Schmidt, H. Griesser, V. Leitenberger, A. Lieberknecht, R. Mangold,
R. Meyer and B. Riedl, Synthesis, 1992, 487.
12 D. Kim, Y. Li, B. A. Horenstein and K. Nakanishi, Tetrahedron Lett.,
1990, 31, 7119.
single diastereoisomer was formed which on the basis of
literature precedent was assigned the Z-configuration.
Finally, the new approach to dipeptides was applied to the
synthesis of the dehydro dipeptide fragment of Mm-2 8 (Ar1 =
Ar2 = 3,4-dihydroxyphenyl), a blood pigment of the tunicate
Molgula manhattensis.12 Although this compound has been
synthesised previously,12 the projected disconnection
Received in Cambridge, UK, 15th September 1997; 7/06658I
2392
Chem. Commun., 1997