TETRAHEDRON:
ASYMMETRY
Tetrahedron: Asymmetry 14 (2003) 399–405 Pergamon
Synthesis of enantiopure (Me)Dip and other -methylated
-branched amino acid derivatives
Alberto Avenoza,
a,
* Jesu ´s H. Busto,
a
Carlos Cativiela,
b
Jesu ´ s M. Peregrina,
a,
* David Sucunza
a
and
Marı ´a M. Zurbano
a
a
Departamento de Quı ´mica, Universidad de La Rioja, Grupo de Sı ´ntesis Quı ´mica de La Rioja, U.A.-C.S.I.C.,
26006 Logron ˜o, Spain
b
Departamento de Quı ´mica Orga ´nica, Instituto de Ciencia de Materiales de Arago ´n, Universidad de Zaragoza -C.S.I.C.,
50009 Zaragoza, Spain
Received 14 November 2002; accepted 3 December 2002
Abstract—This report describes the synthesis of the two enantiomerically pure -methylated -branched phenylalanine derivatives,
(S )- and (R )--methyl-,-diphenylalanine—(Me)Dip—starting from the chiral building blocks (R )- and (S )-N-Boc-N,O-iso-
propylidene--methylserine methyl esters, respectively. The key step involves a double alkylation with a Grignard reagent on an
ester group. The use of the same protocol for the preparation of other -methylated -branched serine derivatives is also
described. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
In the last few years the synthesis of quaternary -
amino acids has received a great deal of attention,
1,2
particularly -methylated -amino acids since they are
capable of stabilising certain conformations when they
are incorporated into peptides.
3–5
In this context, sev-
eral authors have focused their interest on the special
case of -methylated -amino acids with a -branched
side chain.
6,7
For example, -methyl-,-diphenylala-
nine—(Me)Dip—has been the subject of several theo-
retical calculations and these indicate a marked
preference for folded conformations.
8
This predicted
behaviour has been demonstrated experimentally by
incorporation of this unit into peptides.
9
However,
(Me)Dip has only been synthesised on two occasions.
The R -isomer was obtained by asymmetric synthesis
from highly stereoselective enolate trapping of lithium
(1S,2R,4R )-10-dicyclohexylsulfamoylisobornyl-2-cyano-
3,3-diphenylpropanoate combined with the appropriate
rearrangement process.
10
More recently, both isomers
of (Me)Dip were obtained by HPLC resolution of a
racemic precursor, followed by the convenient transfor-
mation of each enantiomerically pure compound.
11
Taking into account the importance of the -methyl-
ated -branched -amino acids (S )- and (R )-1, as well
as our experience in the synthesis of quaternary -
amino acids from the chiral building blocks N -Boc-
N,O -isopropylidene--methylserinals (S )- and
(R )-2,
12–15
we wanted in the first instance to develop a
new and straightforward synthesis of both enantiomers
of (Me)Dip (Fig. 1).
Figure 1. (S )- and (R )--Methyl-,-diphenylalanines and
chiral building blocks (R )- and (S )-2.
* Corresponding authors. Tel./fax: +34-941-299655; e-mail: alberto.
avenoza@dq.unirioja.es; jesusmanuel.peregrina@dq.unirioja.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII:S0957-4166(02)00828-5