Design of new, chiral phase-transfer catalysts for practical, catalytic asymmetric synthesis

Article abstract of DOI:10.1016/S0022-1139(01)00472-9

Structurally rigid, chiral spiro ammonium salts of type 1 derived from commercially available (S)-binaphthol have been designed as a new C₂-symmetric chiral phase-transfer catalyst and successfully applied to the highly efficient, catalytic enantioselective alkylation of tert-butyl glycinate Schiff base under mild phase-transfer conditions to furnish a-alkyl-oc-amino acids and α,α-dialkyl-α-amino acids with excellent enantioselectivity. These ammonium salts have been also utilized for the in situ generation of chiral quaternary ammonium fluorides.

Full text of DOI:10.1016/S0022-1139(01)00472-9

Journal of Fluorine Chemistry 112 ꢀ2001)95±99
Design of new, chiral phase-transfer catalysts for practical, catalytic
asymmetric synthesis
*
Keiji Maruoka
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
Abstract
Structurally rigid, chiral spiro ammonium salts of type 1 derived from commercially available ꢀS)-binaphthol have been designed as a
new C -symmetric chiral phase-transfer catalyst and successfully applied to the highly ef®cient, catalytic enantioselective alkylation of tert-
2
butyl glycinate Schiff base under mild phase-transfer conditions to furnish a-alkyl-a-amino acids and a,a-dialkyl-a-amino acids with
excellent enantioselectivity. These ammonium salts have been also utilized for the in situ generation of chiral quaternary ammonium
¯
uorides. # 2001 Elsevier Science B.V. All rights reserved.
Keywords: Phase-transfer catalyst; Asymmetric alkylation; a-Amino acid; Tert-butyl glycinate; Quaternary ammonium ¯uoride
1
. Introduction
nate-benzophenone Schiff base under mild phase-transfer
conditions [11].
Since the pioneering work of O'Donnell et al. in 1989,
asymmetric synthesis of a-amino acids by phase-transfer
enantioselective alkylation of a prochiral protected glycine
derivative using a chiral catalyst has provided an attractive
method for the preparation of both natural and unnatural
amino acids [1]. Recently, the Corey and Lygo groups
independently reported an impressive departure from the
previous results in terms of enantioselectivity and general
applicability [2±7]. However, almost all the elaborated
chiral phase-transfer catalysts reported so far have been
restricted to cinchona alkaloid derivatives, which unfortu-
nately constitutes a major dif®culty in rationally designing
and ®ne-tuning of catalysts to attain suf®cient reactivity and
selectivity for various chemical transformations under
phase-transfer catalyzed conditions [8±10]. Accordingly,
structurally rigid, chiral spiro ammonium salts of type 1
derived from commercially available ꢀS)-binaphthol have
2. Results and discussion
The requisite catalyst 1 can be readily synthesized from
commercially available ꢀS)-binaphthol and the primary
structure of 1a was unambiguously determined by single-
crystal X-ray diffraction analysis. The asymmetric phase-
transfer alkylation of tert-butyl glycinate-benzophenone
Schiff base ꢀ2)using 1 mol% of 1a, benzyl bromide and
50% aqueous KOH/toluene proceeded smoothly at 08C
been designed as a new C -symmetric chiral phase-transfer
2
catalyst and successfully applied to the highly ef®cient,
catalytic enantioselective alkylation of tert-butyl glyci-
to furnish product 3 ꢀR ˆ CH Ph)in 73% after 6 h with
2
0
79% e.e. Interestingly, the profound effect of 3,3 -bisaryl
*
Tel.: ‡81-75-753-4041; fax: ‡81-75-753-4041.
E-mail address: maruoka@kuchem.kyoto-u.ac.jp ꢀK. Maruoka).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ꢀ 0 1 ) 0 0 4 7 2 - 9

96
K. Maruoka / Journal of Fluorine Chemistry 112 ꢀ2001) 95±99
Table 1
substituents of 1 on the reactivity as well as enantioselec-
tivity was clearly observed. Thus, the benzylation of 2 under
the in¯uence of 1b ꢀ1 mol%)was completed within 30 min
at 08C, producing the alkylation product 3 ꢀR ˆ CH2Ph)in
Catalytic enantioselective phase-transfer alkylation of 2 under the
a
influence of spiro-type chiral phase-transfer catalyst 1c
b
Entry
RX
Condition
8C, h)
Yield
ꢀ%)
Percent of e.e.
ꢀconfiguration)
ꢀ
8
1% yield with 89% e.e. Use of 1c as catalyst further
increased the enantioselectivity to 96% e.e. ꢀ95% yield).
As revealed in Table 1, various alkyl halides ꢀRX)were
successfully employable where enantioselectivities gener-
ally exceeded 90% e.e., indicating the remarkable potential
and generality of the present system for the practical a-
amino acid synthesis [11].
With this basic information at hand, our attention has now
been focused on the a,a-dialkyl-a-amino acid synthesis.
Such non-proteinogenic a,a-dialkyl-a-amino acids have
played a special role in the design of peptides with enhanced
properties [12±15]. Furthermore, a,a-dialkyl-a-amino acids
themselves are often effective enzyme inhibitors and also
constitute a series of interesting building blocks for the
synthesis of various biologically active compounds. Accord-
ingly, development of truly ef®cient methods for their pre-
paration, especially in an enantiomerically pure form, has
become of great importance. In this context, we were suc-
cessfully able to realize the enantioselective one-pot, double
alkylation of aldimine Schiff base of glycine tert-butyl ester 4
1
2
3
4
PhCH Br
0, 0.5
0, 8
95
64
41
84
96 ꢀR)
90 ꢀR)
95 ꢀR)
94 ꢀR)
2
c
CH
CH
3
I
c
3
CH
2
I
0, 10
0, 1
5
6
7
0, 1
82
90
80
93 ꢀR)
95 ꢀR)
96 ꢀR)
0, 1
0, 0.5
8
9
0, 1
81
60
96 ꢀR)
96 ꢀR)
0, 1.5
a
Unless otherwise specified, the reaction was carried out with 1.2 eq.
of RX in the presence of 1 mol% of 1c in 50% aqueous KOH/toluene
ꢀvolume ratio ˆꢀ 1 : 3)under the given reaction conditions.
b
Isolated yield.
c
Use of 5 eq. of alkyl halide.
under phase-transfer catalytic conditions using C -sym-
2
metric chiral quaternary ammonium salt 1 as catalyst [16].
Initial treatment of the toluene solution of 4 and 1c
1 mol%)with allyl bromide and commercially available
enhanced the enantioselectivity to 98% e.e. ꢀ80% yield).
Other selected examples are listed in Table 2. The distinct
feature of this procedure is that it enables straightforward
asymmetric synthesis of various a,a-dialkyl-a-amino acids
including those otherwise inaccessible from the naturally
occurring amino acids. Notably, in the double alkylation of
4 by the addition of the halides in a reverse order, the
absolute configuration of the double alkylation product 5
ꢀ
CsOHÁH O ꢀ5 eq.)at À108C for 3.5 h and the subsequent
2
reaction with benzyl bromide at 08C for 30 min gave rise to,
after hydrolysis, the double alkylation product
1
5
2
ꢀ
R ˆ CH2CHˆCH2; R ˆ CH2Ph)in 61% yield with
8
7% e.e. Interestingly, use of newly designed, polyfluori-
nated 1d ꢀAr ˆ 3; 4; 5-F3-Ph)as catalyst significantly
Table 2
a
Catalytic enantioselective double alkylation of aldimine Schiff base derived from glycine under phase-transfer conditions
1
R X
2
R X
Entry
First alkylation
Second alkylation
Yield ꢀ%)Percent of e.e.
ꢀconfiguration)
condition ꢀ8C, h)
condition ꢀ8C, h)
1
2
CH
2
=CHCH
2
Br
À10, 3.5
PhCH
2
Br
0, 0.5
0, 0.7
80
60
98 ꢀR)
97
3
0, 0.5
58
74
96
4
PhCH Br
2
À10, 2
0, 0.3
92 ꢀS)
a
1
The reaction was performed by the sequential treatment of aldimine Schiff base 4 with R X ꢀ1 eq.)and R X ꢀ1.2 eq.)under the indicated reaction
2
conditions in the presence of 1 mol% of 1d and CsOHÁH
2
O ꢀ5 eq.)in toluene.

K. Maruoka / Journal of Fluorine Chemistry 112 ꢀ2001) 95±99
97
was confirmed to be opposite, indicating the intervention of
the expected chiral ammonium enolate in the second alky-
lation stage ꢀentry 1 versus 4).
KOH aqueous solution ꢀvolume ratio ˆ 3 : 1)proceeded
smoothly at 08C in the presence of ꢀR)-1c ꢀ1 mol%)to furnish
fully protected L-Dopa tert-butyl ester, which was subse-
quently treated with a 1 M citric acid in THF at room
temperature for 10 h to afford the corresponding amino ester
Further, our approach has been successfully applied to the
catalytic asymmetric alkylation of aldimine Schiff base
derived from the corresponding a-alkyl-a-amino acids,
where its remarkable ef®ciency and general applicability
have been clearly demonstrated. The present practical meth-
ods should have vast synthetic potential, being able to
provide a wide variety of a,a-dialkyl-a-amino acids 5 in
an enantiomerically pure form [16].
3
7 ꢀR ˆ OBn)in 80% isolated yield. Although the enantio-
meric excess was determined to be 90% e.e. by chiral HPLC
analysis, it did not seem fully satisfactory because further
puri®cation such as recrystallization would be required to
increase the enantiomeric purity. Therefore, we employed
ꢀR)-1d as a catalyst and found that the alkylation of 2 with
3
Since both enantiomers of the catalyst of type 1 can be
readily assembled in exactly the same manner starting from
either ꢀR) - or Sꢀ )-binaphthol, a wide variety of natural and
unnatural a-amino acids can be synthesized in an enantio-
merically pure form by the phase-transfer catalytic alkyla-
tion of substrate 2. The successful utilization of this
advantage is illustrated for the facile synthesis of L-Dopa
ꢀR)-1d ꢀ1 mol%)and 6 ꢀR ˆ OBn; 1.2 eq.)under otherwise
3
identicalconditionsgaverisetotheaminoester7ꢀR ˆ OBn)
with excellent enantioselectivity ꢀ98% e.e.). Debenzylation
3
of 7 ꢀR ˆ OBn)under catalytic hydrogenation conditions
3
produced the desired L-Dopa tert-butyl ester ꢀ8; R ˆ OH)in
93%yield. Beingexempli®edbythefeasibilityofasymmetric
3
synthesis of natural tyrosine tert-butyl ester ꢀ8; R ˆ H), the
ꢀ
L-3,4-dihydroxyphenylalanine)esters, which have usually
present concise and practical procedures should enable highly
enantioselective synthesis of various L-Dopa analogues and
related a-amino acids.
been prepared in an enzymatic way and tested as potential
drugs for the treatment of Parkinson's disease [17±20].
The simple synthetic route to L-Dopa esters is shown as
follows [21]. Catalytic phase-transfer alkylation of 2 with
benzyl bromide 6 ꢀR ˆ OBn)ꢀ1.2 eq.)in toluene with 50%
Our chiral phase-transfer chemistry has been further
extended to the synthetic utility of the in situ-generated
quaternary ammonium ¯uorides [22]. Thus, quaternary
3

98
K. Maruoka / Journal of Fluorine Chemistry 112 ꢀ2001) 95±99
ammonium ¯uorides can be generated in situ from the corre-
sponding ammonium salts by stirring with commercially
Bu NHSO orKFÁ2H Ounderotherwiseidenticalconditions.
4
4
2
Noteworthy is that this phase-transfer system is advantageous
especially when the reaction was conducted with a reduced
amount of Bu NHSO ꢀ1 mol%), where the catalytic activity
available KFÁ2H O in THF, and directly used as a ¯uoride
2
source for the generation of carbon nucleophiles from orga-
nosilicon compounds. We have studied the most effective
ammonium salt which can generate the corresponding ammo-
nium ¯uoride. The ef®ciency of such anion exchange is
surveyed by performing aldol reaction of benzaldehyde and
4
4
of the in situ generated Bu NF was found to be markedly
4
enhanced compared to 1 mol% of Bu NF itself.
4
1
-trimethlysiloxycyclohexene. Thus, a mixture of Bu NX
4
ꢀ
10 mol%)and commercially available KF Á2H O ꢀ5 eq.)in
2
THF was well-stirred at room temperature for 1 h and then
benzaldehyde ꢀ1.2 eq.)and 1-trimethlysiloxycyclohexene
ꢀ1 eq.)were added sequentially at À788C. Monitoring the
reactionsrevealedthattheef®ciencyoftheinsitugenerationof
Bu NF was profoundly in¯uenced by the anion moiety ꢀX)as
4
summarized below. Use of Bu NX ꢀX ˆ I, Br, IO , ClO ,
4
4
4
BPh , OTf)resulted in only trace amounts of aldol products.
4
Althoughtheexpectedanionexchangewascertainlyachieved
with Bu NCl to catalyze the present cross aldol reaction, the
This method can be applied to the preparation of structu-
rally well-de®ned, C -symmetric chiral quaternary ammo-
4
reactivity was far less than that of Bu NF itself. Interestingly,
4
2
comparable catalytic activity was attained by use of
Bu NHSO as a precursor, where the aldol reaction was
nium ¯uorides of type 10 from the corresponding
ammonium hydrogensulfates 9 [22]. The in situ-generated
chiral ammonium ¯uorides 10 enhanced the reactivity of
ammonium enolates and allowed catalytic enantioselective
Mukaiyama-type aldol reactions under mild conditions,
giving chiral b-hydroxy ketones 12 in high yields with up
to 91% e.e. as illustrated in Table 3.
4
4
completed within 30 min at À788C and desired b-hydroxy
ketonewasobtainedin91%isolatedyield.Optimizationofthe
reaction conditions showed that 0.5 eq. of KFÁ2H O was
2
suf®cient for the smooth reaction. It should be added that
the aldol reaction did notproceed at all in the absence of either
Table 3
a
2
Asymmetric aldol reactions of 11 with aldehydes catalyzed by in situ generated C -symmetric chiral quaternary ammonium fluorides 10
0
b
Entry
Aldehyde ꢀR )Chiral ammonium
Yield
Erythro/threo
ratio
Percent of e.e.
hydrogensulfate
of 12 ꢀ%)
ꢀconfiguration)
1
2
3
4
Ph
9a
84
92
90
90
57:42
70:30
83:17
94:6
31 ꢀR, R)
76 ꢀR, R)
84 ꢀR, R)
91 ꢀR, R)
9b
9c
9c
a-Naph
a
Unless otherwise specified, the reaction was carried out with 1.2 eq. of aldehyde and 1 eq. of enol trimethylsilyl ether 11 in the presence of 2 mol% of 9
O in THF at À788C for 0.5 h.
The enantiomeric excess of the major erythro isomer in 12.
and 0.5 eq. of KFÁ2H
2
b

K. Maruoka / Journal of Fluorine Chemistry 112 ꢀ2001) 95±99
99
[
[
[
12] E. Benedetti, E. Gavuzzo, A. Santini, D.R. Kent, Y.-F. Zhu, Q. Zhu,
C. Mahr, M.J. Goodman, Pept. Sci. 1 ꢀ1995)349.
References
13] O. Dery, H. Josien, J. Grassi, G. Chassaing, J.Y. Couraud, S. Lavielle,
Biopolymers 39 ꢀ1996)67.
[
[
1] M.J. O'Donnell, W.D. Benett, S. Wu, J. Am. Chem. Soc. 111 ꢀ1989)
353.
2] E.J. Corey, F. Xu, M.C. Noe, J. Am. Chem. Soc. 119 ꢀ1997)
2414.
2
14] E. Mossel, F. Formaggio, M. Crisma, C. Toniolo, Q.B. Broxterman,
W.H.J. Boesten, J. Kamphuis, P.J.L.M. Quaedflieg, P. Temussi,
Tetrahedron Asymmetry 8 ꢀ1997)1305.
1
[
[
3] E.J. Corey, M.C. Noe, F. Xu, Tetrahedron Lett. 39 ꢀ1998)5347.
4] E.J. Corey, Y. Bo, J. Busch-Petersen, J. Am. Chem. Soc. 120 ꢀ1998)
[
15] B. Bellier, I. McCort-Tranchenpain, B. Ducos, S. Danascimento, H.
Meudal, F. Noble, C. Garbay, B.P. Roques, J. Med. Chem. 40 ꢀ1997)
13000.
3
947.
16] T. Ooi, M. Takeuchi, M. Kameda, K. Maruoka, J. Am. Chem. Soc.
22 ꢀ2000)5228.
[
[
5] B. Lygo, P.G. Wainwright, Tetrahedron Lett. 38 ꢀ1997)8595.
[
[
6] B. Lygo, J. Crosby, J.A. Peterson, Tetrahedron Lett. 40 ꢀ1999)
1
1385.
17] E.N. Vulfson, G. Ahmed, I. Gill, P.W. Goodenough, I.A. Kozlov,
B.A. Law, Biotech. Lett. 13 ꢀ1991)91.
[
[
7] B. Lygo, Tetrahedron Lett. 40 ꢀ1999)1389.
8] M.J. O'Donnell, Reviews of chiral PTC, in: I. Ojima ꢀEd.), Catalytic
Asymmetric Synthesis, Verlag Chemie, New York, 1993 ꢀChapter 8).
[
[
[
18] G. Ahmed, E.N. Vulfson, Biotech. Lett. 16 ꢀ1994)367.
19] M.J. Milewska, A. Chimiak, Amino Acids 7 ꢀ1994)89.
20] M. Brunner-Guenat, P.-A. Carrupt, G. Lisa, B. Yeata, S. Rose, K.
Thomas, P. Jenner, P.J. Ventura, Pharm. Pharmacol. 47 ꢀ1995)861.
21] T. Ooi, M. Kameda, H. Tannai, K. Maruoka, Tetrahedron Lett. 41
Â
See also: M.J.O Donnell, Aldrichimica Acta 34 ꢀ2001)3.
[9] T. Shioiri, in: Y. Sasson, R. Neumann ꢀEds.), Handbook of Phase
Transfer Catalysis, Blackie, London, 1997 ꢀChapter 14).
10] S. Ebrahim, M. Wills, Tetrahedron Asymmetry 8 ꢀ1997)3163.
11] T. Ooi, M. Kameda, K. Maruoka, J. Am. Chem. Soc. 121 ꢀ1999)
[
[
[
[
ꢀ
2000)8339.
22] T. ooi, K. Doda, K. Maruoka, Org. Lett. 3 ꢀ2001)1273.
6519.