Practical stereoselective synthesis of β-branched aα-amino acids through efficient kinetic resolution in the phase-transfer-catalyzed asymmetric alkylations

Article abstract of DOI:10.1021/ol701558e

Phase-transfer-catalyzed alkylation of glycinate Schiff base with racemic secondary alkyl halides proceeded with excellent levels of syn- and enantioselectivities under the influence of chiral quaternary ammonium bromide 1d and 18-crown-6. The alkylation

Full text of DOI:10.1021/ol701558e

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3945-3948
Practical Stereoselective Synthesis of
-Branched -Amino Acids through
â
r
Efficient Kinetic Resolution in the
Phase-Transfer-Catalyzed Asymmetric
Alkylations
Takashi Ooi,† Daisuke Kato, Koji Inamura, Kohsuke Ohmatsu, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received July 3, 2007
ABSTRACT
Phase-transfer-catalyzed alkylation of glycinate Schiff base with racemic secondary alkyl halides proceeded with excellent levels of syn- and
enantioselectivities under the influence of chiral quaternary ammonium bromide 1d and 18-crown-6. The alkylation product can be selectively
converted to the corresponding anti isomer, allowing the preparation of all the stereoisomers of
valuable chiral building block.
â-alkyl-r-amino acid derivatives, an extremely
Stereochemically homogeneous â-branched R-amino acids
have been regarded as extremely valuable, conformationally
constrained amino acids mainly because their incorporation
into peptides results in a significant influence on the
conformational preference, providing useful information for
the understanding of structure-activity relationships and for
the design of peptide analogues with enhanced pharmaco-
logical properties.1 In addition, they are often encountered
as components of naturally occurring peptides with unique
biological activities.2 Accordingly, numerous studies have
been made for the synthesis of the individual stereoisomer
of â-alkyl-R-amino acids (Figure 1), most of which rely on
† Current address: Department of Applied Chemistry, Graduate School
of Engineering, Nagoya University, Nagoya, 464-8603, Japan.
(1) For general reviews, see: (a) Giannis, A.; Kolter, T. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1244. (b) Gante, J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1699. See also: (c) Qian, X.; Shenderovich, M. D.; Ko¨ve´r, K.
E.; Davis, P.; Horva´th, R.; Zalewska, T.; Yamamura, H. I.; Porreca, F.;
Hruby, V. J. J. Am. Chem. Soc. 1996, 118, 7280. (d) Hruby, V. J. J. Med.
Chem. 2003, 46, 4215.
Figure 1. Four possible stereoisomers of â-branched R-amino acid.
the diastereoselective transformations involving substrates
with chiral auxiliaries3 or resolution of racemates.4 Hence,
to our knowledge, the catalytic asymmetric approach toward
10.1021/ol701558e CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/01/2007

Scheme 1
this subject has been restricted to only two examples recently
event, simultaneous establishment of relative and absolute
stereochemistries of the target amino acid derivatives could
be achieved. In this Letter, we wish to disclose the realization
of this phase-transfer-catalyzed alkylation involving impres-
sive kinetic resolution, together with the highly selective
inversion of R-stereogenic carbon centers by a simple
deprotonation-protonation sequence, thereby providing a
versatile chemical process for the synthesis of all the
stereoisomers of â-methyl-R-amino acid derivatives (Scheme
1).
Asymmetric alkylation of glycinate Schiff base 3 using
chiral phase-transfer catalysts has been intensively studied
and rapidly developed into a powerful method for the
synthesis of optically active R-amino acids.8 Surprisingly,
however, the stereochemistry of the alkylation of 3 with
chiral electrophiles (alkyl halides), particularly those having
an asymmetric center on the electrophilic carbon itself, has
never been addressed.9 Our initial examination was therefore
focused on the search for the appropriate phase-transfer
conditions including catalyst structure to attain sufficient
reactivity and selectivity in the reaction of 3 with com-
mercially available, racemic 1-bromo-1-phenylethane (2a).
Attempted treatment of 3 with 2a (2 equiv) and (S,S)-1a,10
a promising catalyst for the asymmetric alkylation of 3 with
simple achiral alkyl halides, in toluene-50% KOH aqueous
reported. In 1995, Burk and co-workers pioneered the
enantioselective hydrogenation of â,â-disubstituted didehy-
droamino acids utilizing rhodium chiral bisphosphine com-
plexes,5 and Turner and co-workers elegantly combined it
with an amino acid oxidase (AAO) stereoinversion proce-
dure, offering a chemobiocatalytic method for the synthesis
of the possible four stereoisomers of â-methyl-â-arylalanine
analogues.6 However, this strategy based on the transition-
metal-catalyzed asymmetric hydrogenation inevitably re-
quires the stereoselective, multistep preparation of (E)- and
(Z)-isomers of the starting didehydroamino esters. In this
context, we have been interested in the possibility of direct
construction of â-alkyl-R-amino acid derivatives from a
glycine unit through the alkylation with readily available
racemic secondary alkyl halides under phase-transfer condi-
tions in the presence of chiral quaternary ammonium salts
of type 1 as catalyst.7 If the chiral ammonium cation of
appropriately modified 1 could precisely discriminate not
only the enantiofaces of the prochiral enolate but also the
central chirality of the halides during this bond-forming
(2) (a) Waisvisz, J. M.; van der Hoeven, M. G.; te Nijenhuis, B. J. Am.
Chem. Soc. 1957, 79, 4524. (b) Zlatopolskiy, B. D.; de Meijere, A. Chem.-
Eur. J. 2004, 10, 4718. (c) Saito, T.; Iwata, N.; Tsubuki, S.; Takaki, Y.;
Takano, J.; Huang, S.-M.; Suemoto, T.; Higuchi, M.; Saido, T. C. Nat.
Med. 2005, 11, 434.
(3) (a) Dharanipragada, R.; VanHulle, K.; Bannister, A.; Bear, S.;
Kennedy, L.; Hruby, V. J. Tetrahedron 1992, 48, 4733. (b) Pasto´, M.;
Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem. 1997, 62, 8425. (c)
Medina, E.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem. 1998,
63, 8574. (d) Schabbert, S.; Pierschbacher, M. D.; Mattern, R.-H.; Goodman,
M. Bioorg. Med. Chem. 2002, 10, 3331. (e) O’Donnell, M. J.; Cooper, J.
T.; Mader, M. M. J. Am. Chem. Soc. 2003, 125, 2370.
(4) Enzymatic process: (a) Ogawa, J.; Ryono, A.; Xie, S.-X.; Vohra, R.
M.; Indrati, R.; Miyakawa, H.; Ueno, T.; Ikenaka, Y.; Nanba, H.; Takahashi,
S.; Shimizu, S. Appl. Microbiol. Biotechnol. 1999, 52, 797. Recrystallization
of diastereomeric salts: (b) Erchegyi, J.; Penke, B.; Simon, L.; Michaelson,
S.; Wenger, S.; Waser, B.; Cescato, R.; Schaer, J.-C.; Reubi, J. C.; Rivier,
J. J. Med. Chem. 2003, 46, 5587.
(7) (a) Maruoka, K.; Ooi, T.; Kano, T. Chem. Commun. 2007, 1487.
For recent reviews on asymmetric phase-transfer catalysis, see: (b)
Albanese, D. Mini-ReV. Org. Chem. 2006, 3, 195. (c) Vachon, J.; Lacour,
J. Chimia 2006, 60, 266. (d) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed.
2007, 46, 4222.
(8) For recent reviews, see: (a) Maruoka, K.; Ooi, T. Chem. ReV. 2003,
103, 3013. (b) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506. (c) Lygo,
B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518. See also ref 7.
(9) The stereochemical outcome of the alkylation of 3 with â-chiral alkyl
halides has been investigated. See: (a) Le´pine, R.; Carbonnelle, A.-C.; Zhu,
J. Synlett 2003, 1455. (b) Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5,
2331. (c) Ooi, T.; Takeuchi, M.; Kato, D.; Uematsu, Y.; Tayama, E.; Sakai,
D.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 5073.
(5) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc. 1995,
117, 9375.
(6) Roff, G. J.; Lloyd, R. C.; Turner, N. J. J. Am. Chem. Soc. 2004, 126,
4098.
(10) (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228. (b) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 5139.
3946
Org. Lett., Vol. 9, No. 20, 2007

solution at 0 °C for 11 h gave rise to â-methylphenylalanine
(â-MePhe) derivative 4a in only 12% isolated yield as a 57:
43 mixture of syn and anti isomers, whose enantiomeric
excesses were determined to be 96% ee and 98% ee,
respectively (entry 1 in Table 1). In contrast, syn-4a was
The optimized reaction condition was used for investigat-
ing the applicability of this method for the synthesis of
various â-methyl-R-amino acid derivatives. As listed in Table
2, a series of 1-bromo-1-arylethanes with substituents of
Table 2. Scope of Secondary Alkyl Halides 2a
Table 1. Optimization of the Reaction Conditions in the
Phase-Transfer-Catalyzed Alkylation of 3 with Racemic
1-Bromo-1-phenylethane (2a) Using (S,S)-1 as Catalysta
time yieldb
eed,e
entry
R1
(h)
(%)
syn/antic (%) product
1
2
3
4
5
p-F-C6H4
p-Me-C6H4
2-Naph
PhCtC
t-BuO2C
4.5
3.5
7
3.5
5
93
82
65
80
45
>95:5
>95:5
>95:5
>95:5
86:14
97
99
86
97
91
4b
4c
4d
4e
4f
catalyst concn time yieldb
eed,e
(%)
entry
(1)
(M)
(h)
(%)
syn/antic
1
2
3
4
5
6g
1a
1b
1c
1d
1d
1d
0.17
11
14
10
8
8
6
12
47
30
44
73
88
57:43
91:9
93:7
95:5
>95:5
95:5
96 (98)f
81
91
94
95
a
The reaction was carried out with 2 equiv of 2 and 1 mol % each of
(S,S)-1d and 18-crown-6 in toluene-50% KOH aqueous solution at 0 °C
for the given reaction time. Isolated yield. Determined by 1H NMR
analysis. d Enantiopurity of syn-4 was determined by HPLC using a chiral
column (DAICEL chiralpak AD-H) after derivatization to N-benzoate (syn-
5). For details, see the Supporting Information. e Assignment of the absolute
configuration was deduced from that of syn-4a.
b
c
0.33
95
a
Unless otherwise noted, the reaction was conducted with 2 equiv of
2a and 1 mol % of (S,S)-1 in toluene-50% KOH aqueous solution at 0 °C
b
c
for the given reaction time. Isolated yield. Determined by 1H NMR
analysis. d Enantiopurity of syn-4a, which was determined by HPLC using
a chiral column (DAICEL chiralpak AD-H) with hexane-2-propanol as
solvent after derivatization to N-benzoate (syn-5a). e Absolute configuration
of syn-4a was assigned to be (2R,3S). For details, see the Supporting
different electronic properties were employable, allowing the
preparation of diverse â-MePhe analogues including â-meth-
yl-3-(2-naphthyl)alanine (â-Me2Nal) (entries 1-3). Asym-
metric construction of â-alkynyl-R-amino acid ester and
â-methylaspartate can also be achieved in a similar manner
with appropriate secondary alkyl bromides, though relatively
lower chemical yield and diastereoselectivity were observed
in the reaction with tert-butyl 2-bromopropionate (entries 4
and 5).
Given the present highly diastereo- and enantioselective
alkylation protocol that enables the preparation of both
enantiomers of syn-â-methyl-R-amino acid esters using either
(S,S)- or (R,R)-1d as catalyst, we further envisaged providing
a ready access to anti diastereomers by configurational
inversion of the R-stereocenter of the syn isomers. Our
strategy to this end is the simple deprotonation of syn-5 and
selective reprotonation of the resulting enolates bearing a
stereochemically defined â-chiral center, and we tested the
feasibility with syn-5a (95% ee, syn/anti ) 95:5) as a model
substrate (Table 3).13 Complete deprotonation of syn-5a was
realized by the treatment with 3 equiv of LDA in THF at
-78 to -20 °C for 0.5 h, and subsequent protonation by
the addition of H2O at the same temperature furnished 5a
with high preference to the anti isomer (syn/anti ) 17:83)
(entry 1). While switching the proton source to methanol
showed a similar degree of diastereoselectivity (entry 2),
increasing the steric size of an alcohol substituent appeared
beneficial for the enhancement of the anti selectivity, and
anti-5a was obtained predominantly (syn/anti ) 8:92) with
89% ee by the use of triphenylmethanol (entries 3 and 4).14
f
g
Information. Enantiomeric excess of anti-4a is shown in parentheses.
With 1 mol % of 18-crown-6.
obtained predominantly in higher chemical yield (47%) but
with decreased enantioselectivity (81% ee) when the catalyst
1b9c bearing a 3,5-di-tert-butylphenyl group at the 3,3′-
position of one binaphthyl subunit (Ar) was employed (entry
2). Here, the importance of the steric effect of the Ar moiety
for establishing kinetic resolution of 2a as well as enantio-
facial discrimination of the enolate of 3 turned out to be
evident from the enhanced diastereo- and enantioselectivities
of the reaction under the influence of 1c9c with a radially
extended 3,5-bis(3,5-di-tert-butylphenyl)phenyl substituent
(entry 3). Furthermore, introduction of electron-withdrawing
trifluoromethyl functionality in place of the tert-butyl group
(1d)11 was found to provide the highest levels of both
diastereo- and enantiocontrols (entry 4), and increasing the
substrate concentration delivered substantial rate acceleration
without sacrificing the stereoselectivities (entry 5). Although
the chemical yield was still insufficient at this stage, use of
18-crown-6 as an achiral cocatalyst fortunately solved this
problem.12 Thus, vigorous stirring of a mixture of 3, 2a (2
equiv), and 1 mol % each of (S,S)-1d and 18-crown-6 in
toluene (0.33 M substrate concentration)-50% KOH aqueous
solution at 0 °C for 6 h led to the almost exclusive formation
of syn-4a in 88% yield with 95% ee (entry 6).
(11) (a) Ooi, T.; Fujioka, S.; Maruoka, K. J. Am. Chem. Soc. 2004, 126,
11790. (b) Ooi, T.; Fukumoto, K.; Maruoka, K. Angew. Chem., Int. Ed.
2006, 45, 3839.
(12) Shirakawa, S.; Yamamoto, K.; Kitamura, M.; Ooi, T.; Maruoka,
K. Angew. Chem., Int. Ed. 2005, 44, 625.
(13) For comparison of the nitrogen-protecting groups, see the Supporting
Information.
Org. Lett., Vol. 9, No. 20, 2007
3947

Scheme 2
Table 3. Stereoinversion of syn-5 to anti-5 through a
Deprotonation-Protonation Sequencea
proton yield
eed,e
5a in a ratio of 8:92 (90% isolated yield), and neither (2R,3R)
nor (2S,3R) isomers were detected (Scheme 2). This observa-
tion certainly confirms that the stereoinversion occurs
exclusively at the R-carbon of 5.
entry
R1 (5, syn/anti, %ee)
Ph (5a, 95:5, 95)
source (%)b syn/antic (%)
1
2
3
4
5
6
7
H2O
MeOH
t-BuOH
96
94
96
17:83
17:83
14:86
8:92
8:92
9:91
88
87
88
89
88
92
84
In conclusion, we have successfully demonstrated that the
phase-transfer catalysis of chiral quaternary ammonium
bromide 1d and 18-crown-6 creates a new opportunity for
the asymmetric alkylation of glycinate Schiff base, which
involves an efficient kinetic resolution of racemic secondary
alkyl halides, giving a straightforward entry to enantiomeri-
cally enriched syn-â-alkyl-R-amino acid esters. Moreover,
a simple deprotonation-protonation procedure has been
elaborated for the stereoinversion of the syn product to the
corresponding anti isomer. We believe the present study
paves the way to the practical chemical synthesis of all the
stereoisomers of a wide range of â-alkyl-R-amino acid
derivatives.
Ph3COH 93
p-F-C6H4 (5b, >95:5, 97)
p-Me-C6H4 (5c, >95:5, 99)
2-Naph (5d, >95:5, 86)
87
89
90
5:95
a
The reaction was performed by the treatment of syn-5 with 3 equiv of
LDA at -78 to -20 °C for 0.5 h and subsequent addition of an appropriate
proton source at -20 °C. b Isolated yield. c Determined by 1H NMR analysis.
d Enantiopurity of anti-5 was determined by HPLC using a chiral column.
e
For details, see the Supporting Information. The absolute configuration
of anti-5a was assigned to be (2S,3S) (see the Supporting Information),
and those for anti-5b-d were assumed in analogy.
With this information in hand, we examined the stereo-
inversion of various enantiomerically enriched syn-5, and
typical results included in Table 3 demonstrate the effective-
ness of the deprotonation-protonation procedure for the
preparation of anti-â-methyl-R-amino acid esters (anti-5)
with high levels of diastereo- and enantiomeric excesses
(entries 5-7). It is worth noting that the decrease in the
enantiomeric excess of anti-5 is not due to the intervention
of inversion at the â-stereogenic center and is primarily
dependent on the stereochemical purity of the starting syn-
5, i.e., stereoselectivity of the initial alkylation process.
Indeed, exposure of essentially pure (2R,3S)-5a to similar
conditions resulted in the formation of (2R,3S)- and (2S,3S)-
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research on Priority Areas
“Advanced Molecular Transformation of Carbon Resources”
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. K.O. is grateful to the Japan Society for
the Promotion of Science for Young Scientists for a Research
Fellowship.
Supporting Information Available: Detailed experi-
mental procedures including stereochemical assignment and
spectroscopic characterization of new compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) We demonstrated that 5a can be readily derivatized to the corre-
sponding amino acid without loss of stereochemical purity. For details, see
the Supporting Information.
OL701558E
3948
Org. Lett., Vol. 9, No. 20, 2007