ASYMMETRIC PHASE-TRANSFER CATALYSIS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 230

interested in the development of Michael additions to nitroolefins. Although qua-
ternary ammonium salts as phase-transfer catalysts are generally believed to require
base additives for phase-transfer reactions, we discovered that even without any base
additives, the enantioselective phase-transfer Michael addition of 3-phenyloxindole
to

-nitrostyrene proceeded smoothly in the presence of a chiral bifunctional
ammonium bromide 46a under neutral conditions in water-rich solvent with both
high diastereo- and enantioselectivities (Scheme 7.20) [53].

b

7.4. ALDOL AND MANNICH REACTIONS

Although phase-transfer-catalyzed enantioselective direct aldol reactions of glycine
donors with aldehyde acceptors could provide an ideal method for the simultaneous
construction of the primary structure and stereochemical integrity of -hydroxy

b

-amino acids, which are extremely important chiral units especially from the
pharmaceutical viewpoint, the examples reported to date are very limited. We
developed an efficient, highly diastereo- and enantioselective direct aldol reaction
of 2a with a wide range of aliphatic aldehydes under mild phase-transfer conditions
employing N -spiro chiral quaternary ammonium salt 5h as a key catalyst, leading to
the establishment of a general and practical chemical process for the synthesis of
optically active anti -

a

-amino esters 47 (Scheme 7.21) [54].
Phase-transfer-catalyzed direct Mannich reaction of glycine Schiff base 2a with
a -imino ester 48 was achieved with high enantioselectivity by using N -spiro chiral
quaternary ammonium bromide 5e as the catalyst (Scheme 7.22) [55]. Amore general
and highly diastereoselective Mannich-type reaction was developed by Ohshima,
Shibasaki and coworkers. The original tartrate-derived diammonium salt 8 was
modified by introducing an aromatic ring at the acetal side chains, and 4-fluorophenyl-
substituted 8d was identified as an optimal catalyst for the reaction of 2a with various
N -Boc imines 49 under solid (Cs 2 CO 3 )-liquid (fluorobenzene) phase-transfer condi-
tions, as exemplified in Scheme 7.22 [56].

b -hydroxy a

( R , R )- 5h
(2 mol%)

O O OH O

1N HCl

Ph 2 C N +

O t -Bu R H R O t -Bu

1% NaOH aq
(15 mol%)
NH 4 Cl (10 mol%)
Toluene, 0°C

THF

NH 2

2a anti - 47

( anti / syn = 96:4)

F 3 C CF 3

R = Ph(CH 2 ) 2 : 82% (ee = 98%)

: 79% (ee = 97%)
: 73% (ee = 98%)
: 54% (ee = 99%)
c -Hex: 83% (ee = 98%)

Ar

-

Me(CH 2 ) 4
i -Pr 3 SiOCH 2
Me

Br

+

N

Ar =

CF 3

(CPME as solvent)

Ar

( R , R )- 5h

CF 3

SCHEME 7.21