ASYMMETRIC PHASE-TRANSFER CATALYSIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 225

O

Ar N

O t -Bu

Me

O

( S )- 17a
(1 mol%)

25 (Ar = 4-Cl-C 6 H 4 )

Me

1. 1N HCl

Ar N

O t -Bu

+

N
H

CO 2 t -Bu

CsOH·H 2 O
Toluene
0°C, 6 h

2. Na 2 CO 3

Me

I Cl

Cl

30

87%

31

(ee = 99%)

Ar

-

F

Br

F

+

Bu
Bu

N Ar =

F

Ar

( S )- 17a

SCHEME 7.14

alkylated product 30 . Imine hydrolysis and subsequent treatment with Na 2 CO 3
facilitated intramolecular ring closure to give an -methylproline tert -butyl ester

31 with excellent enantioselectivity (Scheme 7.14) [40].

a

7.2.3. Alkylation of Peptides
Peptide modification is an essential yet flexible synthetic concept for efficient target
screening and optimization of lead structures in the application of naturally occurring
peptides as pharmaceuticals. The introduction of side chains directly to a peptide
backbone represents a powerful method for the preparation of unnatural peptides [41].
Achiral glycine subunits have generally been used for this purpose, and glycine
enolates, radicals, and glycine cation equivalents have been exploited as reactive
intermediates. However, control of the stereochemical outcome of these processes
in an absolute sense is a difficult task, especially in the modification of linear peptides,
and hence development of an efficient and practical approach to establish sufficient
stereoselectivity and general applicability has been an issue of central importance.
Upon facing the difficulty of the stereochemical control in the peptide alkyl-
ation event, we envisaged that chiral phase-transfer catalyst should play a crucial role
in achieving an efficient chirality transfer, and we examined the alkylation of the
dipeptide, Gly- L -Phe derivative 32 (Scheme 7.15) [42]. When a mixture of 32 and
tetrabutylammonium bromide (TBAB, 2 mol%) in toluene was treated with 50%
KOH aqueous solution and benzyl bromide at 0 C for 4 h, the corresponding
benzylation product 33 was obtained in 85% yield with a diastereomeric ratio
( DL - 33 : LL - 33 ) of 54:46 (8% de). In contrast, the reaction with chiral quaternary
ammonium bromide ( S , S )- 5c under similar conditions gave rise to 33 in 55% de. The
preferential formation of LL - 33 in lower de in the reaction with ( R , R )- 5c indicates that
( R , R )- 5c is a mismatched catalyst for this diastereofacial differentiation of 32 .
Changing the 3,3 0 -aromatic substituent (Ar) of the catalyst 5 dramatically increased
the stereoselectivity and almost complete diastereocontrol was realized with ( S , S )- 5g .
Asymmetric phase-transfer catalysis with ( S , S )- 5g can be successfully
extended to the stereoselective N -terminal alkylation of tetrapeptide DDL- 34 and