Practical catalytic enantioselective synthesis of α,α-dialkyl-α-amino acids by chiral phase-transfer catalysis [10]

Full text of DOI:10.1021/ja0007051

5228
J. Am. Chem. Soc. 2000, 122, 5228-5229
Scheme 1
Practical Catalytic Enantioselective Synthesis of
r,r-Dialkyl-r-amino Acids by Chiral Phase-Transfer
Catalysis
Takashi Ooi, Mifune Takeuchi, Minoru Kameda, and
Keiji Maruoka*
Table 1. Catalytic Enantioselective Double Alkylation of Aldimine
Department of Chemistry, Graduate School of Science
Hokkaido UniVersity, Sapporo 060-0810, Japan
Department of Chemistry, Graduate School of Science
Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Schiff Base Derived from Glycine under Phase-Transfer Conditionsa
ReceiVed February 28, 2000
Nonproteinogenic R,R-dialkyl-R-amino acids have played a
special role in the design of peptides with enhanced properties.1
This is not only because they possess stereochemically stable
quaternary carbon centers but also because their incorporation
into peptides results in the significant influence on the confor-
mational preferences, which eventually provides useful informa-
tion for the elucidation of enzymatic mechanisms.2 Furthermore,
R,R-dialkyl-R-amino acids themselves are often effective enzyme
inhibitors3 and also constitute a series of interesting building
blocks for the synthesis of various biologically active compounds.4
Accordingly, development of truly efficient methods for their
preparation, especially in an enantiomerically pure form, has
become of great importance and numerous studies have been made
for this purpose as seen in recent excellent reviews.5 However,
only a few catalytic systems have been reported with limited
general applicability.6,7 Herein we wish to disclose that R,R-
dialkyl-R-amino acids can be prepared in a highly enantioselective
manner by the one-pot, double alkylation of aldimine Schiff base
of glycine tert-butyl ester 1 under phase-transfer catalytic condi-
tions using our recently introduced C2-symmetric chiral quaternary
ammonium salts 3 as catalysts;8 thus paved the way for practical
asymmetric synthesis of R,R-dialkyl-R-amino acids from the
corresponding R-amino acids.
a The reaction was performed by the sequential treatment of aldimine
Schiff base 1 (0.5 mmol) with R1X (1 equiv) and R2X (1.2 equiv) under
the indicated reaction conditions in the presence of 1 mol % of 3b and
CsOH‚H2O (5 equiv) in toluene (2 mL). b Isolated yield. c Enantiopurity
was determined by HPLC analysis of the amino ester or its N-benzoate
using a chiral column [DAICEL Chiralpak AD (for entries 1 and 4)
and Chiralcel OD (for entry 2)] with hexane-2-propanol as solvent.
Capillary GC analysis with a chiral column (GL Science CP-Chirasil-
DEX CB) was employed for entry 3. d Absolute configuration was
determined by cleavage of the tert-butyl ester (6 N HCl) and comparison
of the optical rotation of the free amino acid with the literature value
[Vedejs, E.; Fields, S. C.; Hayashi, R.; Hitchcock, S. R.; Powell, D.
R.; Schrimpf, M. R. J. Am. Chem. Soc. 1999, 121, 2460 (for entries 1
and 4)].
focused on the search for the appropriate reaction conditions.
Attempted sequential alkylation of 1 with allyl bromide (1 equiv)
and benzyl bromide (1.2 equiv) in 50% aqueous KOH/toluene
(volume ratio ) 1:3) under the influence of 3a (R ) â-Naph) (1
The requisite aldimine Schiff base 1 was conveniently prepared
in a similar manner as previously reported7c and initial studies
(1) (a) Bellier, B.; McCort-Tranchenpain, I.; Ducos, B.; Danascimento, S.;
Meudal, H.; Noble, F.; Garbay, C.; Roques, B. P. J. Med. Chem. 1997, 40,
3947. (b) Mossel, E.; Formaggio, F.; Crisma, M.; Toniolo, C.; Broxterman,
Q. B.; Boesten, W. H. J.; Kamphuis, J.; Quaedflieg, P. J. L. M.; Temussi, P.
Tetrahedron: Asymmetry 1997, 8, 1305. (c) Dery, O.; Josien, H.; Grassi, J.;
Chassaing, G.; Couraud, J. Y.; Lavielle, S. Biopolymers 1996, 39, 67. (d)
Benedetti, E.; Gavuzzo, E.; Santini, A.; Kent, D. R.; Zhu, Y.-F.; Zhu, Q.;
Mahr, C.; Goodman, M. J. Pept. Sci. 1995, 1, 349. (e) Toniolo, C.; Formaggio,
F.; Crisma, M.; Valle, G.; Boesten, W. H. J.; Schoemaker, H. E.; Kamphuis,
J.; Temussi, P. A.; Becker, E. L.; Precigoux, G. Tetrahedron 1993, 49, 3641.
(f) Schiller, P. W.; Weltrowska, G.; Nguyen, T. M.-D.; Lemieux, C.; Chung,
N. N.; Marsden, B. J.; Wilkes, B. C. J. Med. Chem. 1991, 34, 3125.
(2) (a) Paradisi, M. P.; Torrini, I.; Zecchini, G. P.; Lucente, G.; Gavuzzo,
E.; Mazza, F.; Pochetti, G. Tetrahedron 1995, 51, 2379. (b) Burgess, K.; Ho,
K.-K.; Pal, B. J. Am. Chem. Soc. 1995, 117, 3808. (c) Giannis, A.; Kolter, T.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (d) Balaram, P. Curr. Opin.
Struct. Biol. 1992, 2, 845.
(3) For example, see: (a) Zhelyaskov, D. K.; Levitt, M.; Uddenfriend, S.
Mol. Pharmacol. 1968, 4, 445. (a) Sourkers, T. L. Arch. Biochem. Biophys.
1945, 51, 444.
(4) Review: Koert, U. Nachr. Chem. Technol. Lab. 1995, 43, 347.
(5) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (b) Seebach, D.; Sting,
A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. (c) Wirth,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225. (d) Cativiela, C.; Diaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517.
mol %) proceeded very reluctantly at room temperature. After
the solution was stirred for 12 h, hydrolysis with 0.5 M citric
acid in THF afforded R-allyl phenylalanine tert-butyl ester (2;
R1 ) CH2CHdCH2, R2 ) CH2Ph) in 28% isolated yield with
83% ee. This result prompted us to examine solid-liquid phase-
transfer conditions in order to attain sufficient reactivity as well
as selectivity.9 Thorough optimization of the reaction conditions
eventually revealed that initial treatment of the toluene solution
of 1 and 3a (R ) â-Naph) (1 mol %) with allyl bromide (1 equiv)
and commercially available CsOH‚H2O (5 equiv) at -10 °C for
3.5 h and the subsequent reaction with benzyl bromide (1.2 equiv)
at 0 °C for 30 min resulted in formation of the double alkylation
product 2 (R1 ) CH2CHdCH2, R2 ) CH2Ph) in 61% yield with
higher enantiomeric excess (87% ee). Here, it should be particu-
larly emphasized that tuning of electronic property of the catalyst
(6) (a) Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi,
T. Tetrahedron 1988, 44, 5253. (b) Ito, Y.; Sawamura, M.; Matsuoka, M.;
Matsumoto, Y.; Hayashi, T. Tetrahedron Lett. 1987, 28, 4849.
(7) For recent examples under PTC conditions, see: (a) Lygo, B.; Crosby,
J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671. (b) Belokon, Y. N.; North,
M.; Kublitski, V. S.; Ikonnikov, N. S.; Krasik, P. E.; Maleev, V. I. Tetrahedron
Lett. 1999, 40, 6105. (c) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Parmar, V. S.; Kumar,
R.; Kagan, H. B. Tetrahedron: Asymmetry 1998, 9, 851. (d) O’Donnell, J.
M.; Wu, S. Tetrahedron: Asymmetry 1992, 3, 591.
(9) For recent impressive reports on solid-liquid phase-transfer reactions,
see: (a) Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Chem. Commun. 1999, 49.
(b) Corey, E. J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1998, 120,
13000. (c) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414. (d) Eddine, J. J.; Cherqaoui, M. Tetrahedron: Asymmetry 1995, 6,
1225. See also ref 7.
(8) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519.
10.1021/ja0007051 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/16/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 21, 2000 5229
Table 2. Catalytic Enantioselective Synthesis of
Scheme 2
R,R-Dialkyl-R-amino Acids by Phase-Transfer Alkylationa
applicable to the asymmetric alkylation of aldimine Schiff base
4 derived from the corresponding R-amino acids. Indeed, rapid
benzylation of DL-alanine-derived imine 4 (R1 ) Me) occurred
at 0 °C in toluene with benzyl bromide (R2 ) CH2Ph) (1.2 equiv)
and CsOH‚H2O (5 equiv) using 3b (R ) 3,4,5-F3-Ph) (1 mol %)
as a catalyst, giving the alkylation product 2 (R1 ) Me, R2 )
CH2Ph; 85%) (entry 1 in Table 2) in an almost enantiomerically
pure form (98% ee) as illustrated in Scheme 2.10
Other selected examples of the alkylation of 4 using 1 mol %
of catalyst 3b (R ) 3,4,5-F3-Ph) listed in Table 2 clearly
demonstrate the remarkable efficiency and generality of our
approach. Not only benzylation and allylation, but also alkylation
of 4 (R1 ) Me) with simple alkyl halide such as ethyl iodide
proceeded smoothly at 0 °C to furnish the corresponding R,R-
dialkyl-R-amino acid tert-butyl ester 2 (R1 ) Me, R2 ) Et) with
virtually complete enantiofacial control (entry 3). Use of R-bromo
tert-butyl acetate as an alkylating agent allows facile enantiose-
lective access to R-methyl aspartic acid (entry 4).11 Asymmetric
synthesis of R-methyl tryptophan, an important amino acid for
the design of dipeptoid with high affinity for the central
cholecystokinin receptor,12 can be realized by the present method
(entry 5). Moreover, the phase-transfer catalytic alkylation of
aldimine Schiff base derived from other R-amino acids such as
DL-phenylalanine (R1 ) PhCH2) and DL-leucine (R1 ) i-Bu) also
appeared to be feasible with high efficiency, providing the desired
noncoded amino acid esters 2, where excellent asymmetric
induction was uniformly observed (entries 6-8).
In summary, we have devised a broadly useful procedure for
the asymmetric synthesis of a wide variety of R,R-dialkyl-R-amino
acids based on the highly enantioselective solid-liquid phase-
transfer catalytic alkylation of aldimine Schiff base of amino acid
tert-butyl esters using structurally well-defined C2-symmetric
chiral quaternary ammonium bromides. This unprecedentedly
general and practical method should have vast synthetic potential
even from an industrial point of view.
a Unless otherwise specified, the reaction was carried out with R2X
(1.2 equiv) in the presence of 1 mol % of 3b and CsOH‚H2O (5 equiv)
in toluene (0.25 M) under the given reaction conditions. b Isolated yield.
c Enantiopurity was determined by HPLC analysis of the amino ester
or its N-benzoate using a chiral column [(DAICEL Chiralpak AD (for
entries 1, 3, 5-7) and Chiralcel OD (for entries 2, 4, 8)] with hexane-
2-propanol as solvent. d Absolute configuration was determined as noted
in Table 1 [Alonso, F.; Gavies, S. G.; Elend, A. S.; Haggitt, J. L. J.
Chem. Soc., Perkin Trans. 1, 1998, 257 (for entries 1 and 2), Studer,
A.; Seebach, D. Liebigs Ann. 1995, 217 (for entry 3), Cativiela, C.;
Diaz-de-Villegas, M. D.; Galvez, J. A.; Lapena, Y. Tetrahedron 1997,
53, 5891 (for entry 4), Gander-Coquoz, M.; Seebach, D. HelV. Chim.
Acta 1988, 71, 221 (for entry 5), See Table 1 for entry 6]. e Use of 5
equiv of alkyl halide.
by introducing 3,4,5-trifluorophenyl substituent on 3,3′-positions
of the binaphthyl structure further enhanced the enantioselectivity,
that is, the reaction in the presence of 3b (R ) 3,4,5-F3-Ph) (1
mol %) under otherwise similar conditions gave rise to the R,R-
dialkyl-R-amino acid 2 (R1 ) CH2CHdCH2, R2 ) CH2Ph; 80%)
in 98% ee (Scheme 1, entry 1 in Table 1). The distinct feature of
this procedure is that it enables straightforward asymmetric
synthesis of various R,R-dialkyl-R-amino acids including those
otherwise inaccessible from the naturally occurring amino acids
as exemplified in Table 1. Notably, in the double alkylation of 1
by the addition of the halides in a reverse order, the absolute
configuration of the product 2 was confirmed to be opposite,
indicating the intervention of the expected chiral ammonium
enolate in the second alkylation stage (entry 1 vs 4).
Acknowledgment. This work was partially supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education, Science,
Sports and Culture, Japan.
Supporting Information Available: Representative experimental
procedures as well as spectroscopic characterization of catalyst 3b and
all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA0007051
(10) The benzylation of either D-alanine- or L-alanine-derived imine gave
almost the same results.
(11) Kiick, D. M.; Cook, P. F. Biochemistry 1983, 22, 375.
(12) Horwell, D. C.; Hughes, J.; Hunter, J. C.; Pritchard, M. C.; Richardson,
R. S.; Roberts, E.; Woodruff, G. N. J. Med. Chem. 1991, 34, 404.
Since the stereochemistry of the newly created quaternary
carbon center was apparently determined in the second alkylation
process, we envisaged that the core of our method should be