LETTER
1185
Advantage of Anaerobic Conditions in the Highly Enantioselective Synthesis
of -Dialkyl- -Amino Acids by Chiral Phase-Transfer Catalysis
Takashi Ooi, Mifune Takeuchi, Daisuke Ohara, Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax +81-75-753-4041; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Received 19 April 2001
O
1) R1X, 2) R2X
Abstract: Intervention of the enolate oxidation in the catalytic
asymmetric phase-transfer alkylation of protected -amino acid de-
rivatives under aerobic conditions has been addressed, and anaero-
bic conditions have been introduced to obtain synthetically
satisfactory chemical yields as well as a high level of enantioselec-
tivity.
p-Cl-Ph
p-Cl-Ph
N
OBut
OBut
O
CsOH•H2O/toluene
-10~0 °C
+
1 (1 mol%)
H
H2N
OBut
O
R1 R2
1 (1 mol%), R2X
N
3
CsOH•H2O/toluene
-20~0 °C
58~85% yield
91~99% ee
R1
Key words: alkylation, anaerobic conditions, chiral phase-transfer
catalysis, protected -amino acid derivatives, oxidation
2
R
Br
Recently, we disclosed a broadly useful and practical pro-
cedure for the enantioselective synthesis of nonproteino-
N
genic
-dialkyl- -amino acids under solid-liquid phase-
Q
Br
R
1 (R = 3,4,5-F3-Ph)
transfer conditions using rationally designed C2-symmet-
ric chiral quaternary ammonium salts of type 1 as cata-
lysts [(S,S)-3,4,5-trifluorophenyl-NAS-bromide [54,838-
3] and (S,S)- -naphthyl-NAS-bromide [54,839-1] from
Aldrich Chemical Co. Ltd.].1,2 A wide variety of
-di-
CsOH•H2O experiences the extremely fast ion-exchange
with 1 to give the corresponding chiral enolate that reacts
with benzyl bromide in an asymmetric fashion as illustrat-
ed in Scheme 1.4 This is consistent with the fact that at-
tempted benzylation of 2 (R1 = i-Bu) in the absence of
catalyst under otherwise similar conditions afforded the
racemic product 3 (R1 = i-Bu, R2 = CH2Ph) in 51% yield.
Based on the plausible mechanistic profile, we assumed
that the initially formed cesium enolate could be rapidly
oxidized by molecular oxygen under aerobic conditions as
also shown in Scheme 1, and this pathway would compete
with the desired alkylation, lowering the chemical yield.
Actually, upon mixing 2 (R1 = i-Bu) and CsOH•H2O (5
equiv) in toluene at 0 °C, instantaneous consumption of
the starting Schiff base was observed to furnish a deterio-
rated mixture from which p-chlorobenzamide (4) was iso-
lated (23%),5,6 while almost complete preservation of 2
(R1 = i-Bu) was confirmed after similar treatment under
argon atmosphere.
alkyl- -amino acids can be efficiently prepared with
enantioselectivities as high as 99% ee either by the one-
pot, double alkylation of aldimine Schiff base of glycine
tert-butyl ester or by the simple alkylation of aldimine
Schiff base 2 derived from the corresponding -amino ac-
ids.3 Although excellent enantioselectivity was constantly
observed, the chemical yields of the products were varied
and generally modest, which prompted us to investigate
the fundamental reason for this in relation to the mecha-
nistic aspect of this asymmetric phase-transfer catalytic
alkylation. Since we performed the reaction under aerobic
conditions, it seemed conceivable that rapid oxidation of
the in situ generated enolate with molecular oxygen could
occur concurrently with the desired alkylation step, there-
by resulting in a certain decrease of the chemical yield. In
this letter, we address this problem and report the anaero-
bic conditions for the highly enantioselective alkylation of
protected -amino acid derivatives by chiral phase-trans-
fer catalysis.
To obtain more direct and compelling evidence for the in-
tervention of the enolate oxidation with molecular oxy-
gen, we prepared ester 5 as a carbon analogue of alanine-
derived Schiff base and examined its oxidation under aer-
obic conditions. Interestingly, simple treatment of 5 with
5 equiv of CsOH•H2O in toluene at room temperature for
3.5 h resulted in formation of the corresponding -hy-
droxy ester 6 in 41% yield, and the yield was improved to
63% by employing triethyl phosphite (1 equiv) as an ad-
ditive (Scheme 2).7
Alkylation of aldimine Schiff base derived from leucine
tert-butyl ester (2, R1 = i-Bu) with benzyl bromide (1.2
equiv) in the presence of the catalyst 1 (1 mol%) and
CsOH•H2O (5 equiv) in toluene proceeded smoothly at
0 °C under aerobic conditions to give the corresponding
benzylation product 3 (R1 = i-Bu, R2 = CH2Ph) in 64%
isolated yield with 92% ee.1 The observed asymmetric in-
duction can be interpreted for by the generally proposed
interfacial mechanism: the cesium enolate of 2 (R1 = i-Bu)
produced through interfacial deprotonation with
Synlett 2001, No. 7, 1185–1187 ISSN 0936-5214 © Thieme Stuttgart · New York