N
H
Ar COOMe
O
O
R
O
O
N COOMe
R
Ar
EtOAc
N
H
O COOMe
R
Ph
H
2
N
Ar COOMe
O
O
R
+
1(a-f)
2
3(a-f)
4(a-f)
5 (a-c)
a. R = H
b. R = CH
3
c. R = CH
2
Ph
Ar R
a. Ph H
b. Ph Me
c. Ph CH
2
Ph
d. p-Cl-Ph H
e. p-Cl-Ph Me
f. p-Cl-Ph CH
2
Ph
Pd(OH)
2
, AcOH
TMED, LiBr
CH
3
CN
TMED= Tetramethylethylenediamine
TETRAHEDRON
LETTERS
Tetrahedron Letters 42 (2001) 7891–7892 Pergamon
Cycloaddition–hydrogenolysis strategy for the synthesis of
2,4-disubstituted pyroglutamates
†
Lalit N. Goswami, Stuti Srivastava, Sharad K. Panday and Dinesh K. Dikshit*
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 29 May 2001; revised 21 August 2001; accepted 30 August 2001
Abstract—1,3-Dipolar addition of amino acid derived dipoles with menthyl acrylate followed by hydrogenolysis of the adduct
gives chiral 2--substituted-4--arylmethyl-pyroglutamates. © 2001 Elsevier Science Ltd. All rights reserved.
Substituted prolines and pyroglutamates have been the
favored targets of many synthetic strategies due to their
importance as fragments of various bioactive substances.
1
There have been numerous reports describing strategies
for stereoselective functionalisation of C-4
2,3
C-3
4,5
and
C-2
6,7
of the pyroglutamate skeleton. Most of these
methodologies employ low temperature enolate
chemistry
3
and depend on the steric influence of the C-2
substituent.
6
This often results in a varying degree of
stereoselectivity. Moreover, there are limited methodolo-
gies for functionalisation at C-2 and almost none for
achieving a stereocontrolled C-2, C-4 di-substitution.
1,3-Dipolar cycloaddition of arylidene derivatives of
amino acid esters with various polarized olefins is known
to give a high order of stereoselection, and it is also
possible to introduce an element of chirality using chiral
auxiliaries.
8,9
We were intrigued by the possibility of
transforming these pyrrolidine adducts to pyroglutamates
having defined stereochemistry. In the present communi-
cation we report our initial results in this direction.
* Corresponding author. Fax: + (91 522) 223405, 223938, 229504; e-mail: dk
–
dikshit@yahoo.com
†
Communication No. 6183 from Central Drug Research Institute.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII:S0040-4039(01)01629-X