Asymmetric synthesis of alpha,beta-dialkyl-alpha-phenylalanines via direct alkylation of a chiral alanine derivative with racemic alpha-alkylbenzyl bromides. A case of high enantiomer differentiation at room temperature.

Article abstract of DOI:10.1021/ol000330o

[figure: see text] This study demonstrates that the direct alkylation of a Ni(II)-complex of the chiral Schiff base of alanine with (S)-o-[N-(N-benzylprolyl)amino]- benzophenone, with racemic alpha-alkylbenzyl bromides, is a synthetically feasible and methodologically advantageous approach to the target alpha,beta-dialkylphenylalanines over previously reported methods. For the first time we report and rationalize a case of a high enantiomer differentiation process at room temperature.

Full text of DOI:10.1021/ol000330o

ORGANIC
LETTERS
2001
Vol. 3, No. 3
341-343
Asymmetric Synthesis of
r,â-Dialkyl-r-phenylalanines via Direct
Alkylation of a Chiral Alanine Derivative
with Racemic r-Alkylbenzyl Bromides. A
Case of High Enantiomer Differentiation
at Room Temperature
,†
,†
Vadim A. Soloshonok,* Xuejun Tang,† Victor J. Hruby,* and Luc Van Meervelt‡
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721, and
K. U. LeuVen - Department of Chemistry, Celestijnenlaan 200F,
B-3001 HeVerlee-LeuVen, Belgium
hruby@u.arizona.edu
Received October 27, 2000
ABSTRACT
This study demonstrates that the direct alkylation of a Ni(II)-complex of the chiral Schiff base of alanine with (S)-o-[N-(N-benzylprolyl)amino]-
benzophenone, with racemic r-alkylbenzyl bromides, is a synthetically feasible and methodologically advantageous approach to the target
r,â-dialkylphenylalanines over previously reported methods. For the first time we report and rationalize a case of a high enantiomer differentiation
process at room temperature.
R,â-Dialkyl-substituted R-amino acids are among the least
studied, yet potentially very important class of tailor-made
amino acids.1,2 Analysis of the relevant literature,3 including
our own experience in de noVo peptide design,4 suggests that
rational manipulation of the steric properties of the R- and
â-alkyl groups in such amino acids might allow for a
simultaneous control of the peptide backbone dihedral angles
φ (phi), ψ (psi), and ω (omega) and the torsional angles (chi)
ø1, ø2, etc., defining the position of side-chain functional
groups.3e,4a Since all these dihedral angles are of key
importance in determining the three-dimensional structure
(3) (a) Molecular Conformation and Biological Interactions; Balaram,
P., Ramaseshan, S., Eds.; Indian Academy of Science: Bangalore, 1991.
(b) Scheraga, H. A. Chem. ReV. 1971, 71, 195. (c) Ramachandran, G. N.;
Sasisekharan, V. AdV. Protein Chem. 1968, 23, 283. (d) Bloom, S. M.;
Fasman, G. D.; DeLoze, C.; Blout, E. R. J. Am. Chem. Soc. 1961, 84, 458.
(e) Gibson, S. E.; Guillo, N.; Tozer, M. J. Tetrahedron 1999, 55, 585.
(4) (a) Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich, M.
Biopolymers (Peptide Science) 1997, 43, 219. (b) Hruby, V. J. Life Sci.
1982, 31, 189. (c) Nicola´s, E.; Dharanipragada, R.; To´th, G.; Hruby, V. J.
Tetrahedron Lett. 1989, 30, 6841. (d) Hruby, V. J.; Slate, C. In AdVances
in Amino Acid Mimetics and Peptidomimetics; Abell, A., Ed.; JAI Press
Inc.: Greenwich, 1999; pp 191-220.
† University of Arizona.
‡ K. U. Leuven.
(1) For definition of “tailor-made amino acids”, see footnote 2 in the
following: Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L.
Tetrahedron 1999, 55, 12045.
(2) For general reviews on asymmetric synthesis of R-amino acids, see:
(a) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998,
9, 3517. (b) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry
2000, 11, 654. (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (d) Williams,
R. M. Synthesis of Optically ActiVe R-Amino Acids; Pergamon Press:
Oxford, 1989.
10.1021/ol000330o CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/11/2001

of peptides and, thus, their mode of biological action,
incorporation of sterically defined R,â-dialkyl-substituted
R-amino acids into peptides would provide a powerful tool
for exploration of peptide-mediated biological information
transfer.3,4
Asymmetric synthesis of the target amino acids is virtually
undeveloped, however.2 To the best of our knowledge only
a recent report by the Davis group offers a relatively
generalized approach to R,â-dialkyl-substituted R-amino
acids via stepwise introduction of the required functional-
ities.5 A more methodologically concise approach to the
target amino acids would be by direct alkylation of chiral
derivatives of alanine with racemic sec-alkyl halides.6 In this
Letter, we report the reactions between a chiral Ni(II)-
complex of alanine (S)(S,R)-17 (Scheme 1) with a series of
alanine6 or glycine9 utilized reactions conducted at low
temperatures (-78 °C). Therefore, we were most interested
in developing a process which could be conducted at
synthetically more convenient, higher temperatures, ulti-
mately, room-temperature reactions.
The alkylations of the alanine complex (S)(S,R)-110 with
rac-2a-c (ratio 1/2.5, respectively) were conducted under
our standard conditions: in DMF solutions using powdered
NaOH as a base. The temperature of the reactions was varied
to study its influence on the stereochemical outcome. The
results obtained are given in Table 1. First of all, we were
Table 1. Reactions of (S)(S,R)-1 with 2a-ca
entry
2a -c
T, °C
time, min
yield,b %
ratioc 3/4
1
2
3
4
5
6
7
8
a
a
a
b
b
c
c
c
25
0
-10
25
-10
25
60
90
140
40
140
240
360
480
92
94
94
90
97
90
93
90
5.7/1d
6.2/1
19.0/1
14.9/1
17.0/1
3.0/1
Scheme 1
0
-10
6.0/1
12.0/1
a All reactions were run under an oxygen-free nitrogen atmosphere. Ratio
(S)(S,R)-1/2a-c was 1/2.5. b Combined yield of all diastereomeric products.
c Ratio of diastereomeric products (S)(2S,3R)-3/(S)(2S,3S)-4 was determined
on the crude reaction mixtures by 1H NMR (500 MHz). In particular,
characteristic and well-separated signals of aromatic protons in the region
8.00-8.25 ppm were used for the determination. d Some amounts (<5%)
of (2R)-configured product also were detected in the reaction mixture.
pleased to find that even at room temperature (25 °C) the
alkylation of the alanine complex (S)(S,R)-1 with racemic
R-methylbenzyl bromide (2a) occurred with substantial
stereoselectivity, giving rise to a mixture of diastereomeric
products (S)(2S,3S)-3a and (S)(2S,3R)-4a in a ratio of 5.7 to
1 (entry 1). Lowering the reaction temperature expectedly
decreased the rate of the alkylation (entries 2 and 3 vs 1)
but noticeably increased the enantiomer stereodifferentiation
process allowing preparation of (S)(2S,3S)-3a with syntheti-
cally meaningful diastereoselectivity (90% de) (entry 3). The
major product (S)(2S,3S)-3a was isolated in diastereomeri-
cally pure form simply by washing the reaction mixture with
diethyl ether and was decomposed to give the target (2S,3S)-
R,â-dimethylphenylalanine (5a) in 70% overall yield, along
with the recovered chiral ligand (S)-611 (96%) (Scheme 1).
Alkylation of alanine complex (S)(S,R)-1 at room temperature
with the more sterically demanding R-ethylbenzyl bromide
(2b) gave more impressive results, affording the major
product (S)(2S,3S)-3 with 93.7% diastereoselectivity (entry
4 vs 1). As observed in the reaction between (S)(S,R)-1 with
2a (entries 1-3), lowering the temperature (-10 °C)
increased the selectivity of the enantiomer differentiation
process in the alkylation of (S)(S,R)-1 with 2b (entry 5).
However, the observed diastereoselectivity was lower than
that obtained in the reaction between (S)(S,R)-1 and 2a (entry
5 vs 3). Unexpectedly, a further increase in the steric bulk
of the alkylating agent resulted in decreased diastereoselec-
tivity. Thus, alkylation of (S)(S,R)-1 with R-isobutylbenzyl
racemic 1-bromo-1-phenylalkanes 2a-c,8 which provide a
fast, generalized, and synthetically efficient access to the
target R,â-dialkyl-substituted R-amino acids.
A central issue for the stereochemical outcome of the
reactions between chiral derivatives of alanine with racemic
sec-alkyl halides is the enantiomer-differentiating ability of
the former. A handful of reports describing high enantiomer-
differentiation in the reactions between chiral derivatives of
(5) (a) Davis, F. A.; Liang, C.-H.; Liu, H. J. Org. Chem. 1997, 62, 3796.
(b) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y. J.
Org. Chem. 1999, 64, 7559.
(6) Kazmierski, W. M.; Urbanczyk-Lipkowska, Z.; Hruby, V. J. J. Org.
Chem. 1994, 59, 1789.
(7) A Ni(II)-complex of the chiral Schiff base of alanine with (S)-o-[N-
(N-benzylprolyl)amino]benzophenone (1) was available from a previous
study: Qiu, W.; Soloshonok, V. A.; Cai, C.; Tang, X.; Hruby, V. J.
Tetrahedron 2000, 56, 2577.
(8) rac-1-Bromo-1-phenylethane (1a) is commercially available; the other
1-bromo-1-phenylalkanes (1b,c) were prepared by dehydroxybromination
of the corresponding benzylic alcohols; see the Supporting Information.
(9) (a) Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277. (b) Seebach,
D.; Hoffmann, M. Eur. J. Org. Chem. 1998, 1337.
(10) Complex 1 prepared from racemic alanine and chiral ligand (S)-6
(see Scheme 1) was obtained and used as a mixture of (S)(R-S) and (S)-
(R-R) diastereomers in a ratio of 9 to 1.
(11) Ligand (S)-6, isolated stereochemically intact, was readily trans-
formed to the starting Ni(II)-complex (S)(S,R)-1.
342
Org. Lett., Vol. 3, No. 3, 2001

bromide (2c) at room temperature gave a mixture of the
corresponding diastereomeric products (2S,3S)-3a and (S)-
(2S,3R)-4a in a ratio of 3:1, respectively (entry 6). While a
decrease of the reaction temperature allowed us to reach a
respectable level of diastereoselectivity (92.3%) (entries 7
and 8), the results of the enantiomer differentiation process
obtained in this series were noticeably lower as compared
with the data observed in the alkylations of (S)(S,R)-1 with
2a,b (entries 6-8 vs 1-3 and 4 and 5). These data allow us
to arrive at the surprising conclusion that an increase in the
steric bulk of the alkylating agents 2a-c results in a lowering
of the enantiomer differentiation selectivity. On the other
hand, the high level of the diastereoselectivity, especially at
room temperature, observed in the reactions suggests that
the present methodology is definitely synthetically superior
to the previously described methods, providing a reliable
access to this family of R,â-dialkyl amino acids.
Figure 1. Possible TSs in the reactions between (S,R)-1 and
2a-c.
The absolute configuration of the R-stereogenic center of
the newly formed amino acids in products 3 and 4 was
determined to be (S) on the basis of their chiroptical
properties and NMR data.12 Accordingly, complexes 3 and
4 could be considered as diastereomers, differing in the
absolute configuration at the â-stereogenic center. It follows
that attack by the alkylating agent 2a-c occurs almost
exclusively13 on the si-face of the enolate derived from the
complex 1. As mentioned above, decomposition of the
complex 3a to the free amino acid (2S,3S)-5a allowed us to
determine the (2S,3S) stereochemistry of the former. More-
over, taking into account the surprising observation that an
increase in the steric bulk of the alkylating agent reduced
the stereodifferentiation between the enantiomers of 2a-c,
we performed single-crystal X-ray analysis of the major
product 3b obtained in the reaction between (S)(S,R)-1 and
2b which confirmed its (2S,3S) absolute configuration. On
unfavorable nonbonding steric interaction with the ketimine
phenyl of the complex. Moreover, TS A perfectly accounts
for the unexpected observation that an increase in the steric
bulk of the substituent R interferes with a high level of an
enantiomer differentiation process. Thus, in TS A the
substituent R points directly to the Ni ion and, as one can
expect, increases in the steric bulk of R would bring
correspondingly unfavorable nonbonding interactions desta-
bilizing TS A. On the basis of the results obtained, we
conclude that while the steric bulk of methyl and ethyl groups
could be accommodated by TS A, the stereochemical
requirements of the isobutyl substituent are definitely larger,
decreasing the thermodynamic difference between TSs A and
F.
1
the basis of the obvious similarity in the H NMR spectra
In summary, this study has demonstrated that direct
alkylation of alanine complex (S)(S,R)-1 with racemic 2a-c
is a synthetically feasible and methodologically advantageous
approach to the target R,â-dialkylphenylalanines over the
previously reported methods.2,5 For the first time we report
and rationalize a case of a high enantiomer differentiation
process at room temperature. Because of the simplicity of
the experimental procedure, the low cost of the required
reagents, and the high chemical and optical yields of the
targeted products, this method is immediately useful for
preparing R,â-dialkyl-substituted R-amino acids.
between 3a,b and 3c, and on the other hand between 4a,b
and 4c, we confidently assigned a (2S,3S)-configuration to
3c and a (2S,3R) stereochemistry to 4c.
With the assigned stereochemistry of the products, we are
in position to discuss the mechanism of these alkylation
reactions. Considering the three possible transition states
(TSs) A-C (Figure 1), with the approach geometry unlike,
leading to the products of (2S,3S) absolute configuration 3a-
c, and the three TSs D-F, of approach geometry like,
affording the (S)(2S,3R) configured products 4a-c, we
suggest that the TSs A and F are the most plausible to
account for the formation of products (S)(2S,3S)-3a-c and
(S)(2S,3R)-4a-c, respectively. Thus, in the TSs A and F the
phenyl of the alkylating agent occupies the position of the
largest group, avoiding unfavorable steric interactions with
the ketimine phenyl and the Ni atom of the alanine complex
(TSs A and F vs B-E). On the other hand, TS A should be
regarded more thermodynamically favorable relative to F,
as in the latter the substituent R experiences a direct
Acknowledgment. This work was supported by grants
from U.S. Public Health Service (DK 17420) and the
National Institute of Drug Abuse (DA 06284 and DA 13449).
The authors thank Dr. Dominic McGrath of the University
of Arizona for kindly letting us use his polarimeter. The
views expressed are those of the authors and not necessarily
those of the USPHS.
Supporting Information Available: Experimental pro-
cedures and characterization of the compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) For details on determination of the absolute configuration of the
R-stereogenic center in complexes of type 3 and 4, see: Soloshonok, V.
A.; Cai, C.; Hruby, V. J.; Meervelt, L. V.; Mischenko, N. Tetrahedron 1999,
55, 12031.
(13) See footnote d in Table 1.
OL000330O
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