Asymmetric protonation of lithium enolates of alpha-amino acid derivatives with alpha-amino acid-based chiral Bronsted acids.

Article abstract of DOI:10.1039/b211523a

The reaction of lithium enolates of alpha-amino acid derivatives with chiral amides, easily synthesized from L-tert-leucine, gives corresponding optically active unnatural alpha-amino acid derivatives with up to 87% ee.

Full text of DOI:10.1039/b211523a

Asymmetric protonation of lithium enolates of a-amino acid derivatives
with a-amino acid-based chiral Brønsted acids†
Kentaro Futatsugi‡,a Akira Yanagisawab and Hisashi Yamamoto‡*a
a Graduate School of Engineering, Nagoya University, SORST, Japan Science and Technology Corporation
(JST), Chikusa 464-8603, Japan
b Department of Chemistry, Faculty of Science, Chiba University, Inage, Chiba 263-8522, Japan.
E-mail: yamamoto@uchicago.edu
Received (in Corvallis, OR, USA) 18th November 2002, Accepted 7th January 2003
First published as an Advance Article on the web 30th January 2003
The reaction of lithium enolates of a-amino acid derivatives
with chiral amides, easily synthesized from -tert-leucine,
L
gives corresponding optically active unnatural a-amino acid
derivatives with up to 87% ee.
The establishment of an effective synthetic method to supply
optically active a-amino acids with desirable absolute config-
urations is one of the most important challenges for organic
chemists.1 The construction of an asymmetric a-carbon of an a-
amino acid by asymmetric protonation2,3 is a conceptually
simple but effective route to this target molecule, and is
Scheme 2
At the next stage, we performed further optimization of the
amide part of 1a using a variety of primary amines (Table 1).
Use of chiral amides having a secondary carbon adjacent to the
nitrogen atom of the amide group gave better results than chiral
amides with a primary or tertiary carbon (entries 4–7 and 9 vs.
entries 1–3 and 12). Bulky chiral amides, such as 1ah in entry
8, could hardly discriminate the enantioface of lithium enolate
3 in spite of having a secondary carbon. This result may be
attributable to their sterically hindered structure, which pre-
cludes the formation of the preferable transition state. As a
particularly useful for the conversion from natural
L-amino
acids to unnatural -amino acids. There are few reports
D
however, on the protonation of prochiral metal enolates of a-
amino acid derivatives that give high enantioselectivity.4 Here
we wish to report on new types of chiral Brønsted acids based
on optically active a-amino acids and their application to the
asymmetric protonation of the lithium enolates of a-amino acid
derivatives.
The design of the asymmetric protonation approach depends
on the structure and acidity of the chiral proton source. We
envisaged that the use of combinatorial and related strategies5
would make the design and optimization of effective chiral
Brønsted acids more facile. From this point of view, we
prepared a new chiral amide, an a-amino acid derivative
possessing an acidic amide proton as a chiral proton source,
which is readily optimized by changing the acid anhydride part,
the a-amino acid part, and/or the primary amine part (Scheme
1).
Table 1 Structural optimization of the amide part of chiral amide 1aa
To optimize the structure of a-amino acid-based chiral
amide, lithium enolate of 2,2,6-trimethylcyclohexanone 3 was
chosen as a model substrate for the asymmetric protonation.6
Initially, the structure of the imide part was optimized based on
the chiral amide 1 by an iterative positional optimization
approach.7 Several derivatives possessing a phthalimide or
related units, which have a relatively planar structure, were
examined but they gave 4 ( < 9% ee). In contrast, the use of
chiral amide 1a, possessing a unique bicyclic structure derived
from a synthetic intermediate of biotin,8 led to a dramatic
increase in the enantioselectivity with excellent yield (59% ee,
98% yield, Scheme 2).
Entry
Chiral amide
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
1aa
1ab
1ac
1ad
1ae
1af
1ag
1ah
1a
89
> 99
> 99
98
> 99
88
62
26
98
56
26
15
42
69
71
53
78
3
59
13
< 1
17
10
11
12
1ai
1aj
1ak
64
31
a Unless otherwise specified, the lithium enolate 3 was generated from the
corresponding silyl enol ether 2 (1 equiv.) and a solution of nBuLi–hexane
(1.1 equiv.) in THF at 0 °C for 1.5 h. The following protonation was carried
out using a chiral amide (1.1 equiv.) in THF at 220 °C for 1 h. The reaction
was quenched by TMSCl at 278 °C to exclude the unreacted enolate 3.
b Isolated yield. c Determined by GC analysis with chiral column (astec,
Chiraldex G-TA). See also ref. 6
Scheme 1 Design of new chiral proton source.
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b2/b211523a/
‡ Present address: Department of Chemistry, University of Chicago, 5735
South Ellis Avenue, Chicago, IL 60637, USA.
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CHEM. COMMUN., 2003, 566–567
This journal is © The Royal Society of Chemistry 2003

result, among a variety of primary amines tested, the highest
enantioselectivity (78% ee) was obtained when cyclododecyl
amine-derived chiral amide 1ag was used (entry 7).
low (entry 7). However, use of phenylglycine derivative 10,
which has a phenyl ring at the a position, gave an unsatisfactory
result (entry 8). From this result, it is assumed that the basicity
of the corresponding enolate would be critical to the enantioface
discrimination.
In summary, we developed a new chiral proton source that is
effective for deracemization of a-amino acid derivatives. This
type of chiral proton source, which consists of an acid anhydride
part, an amino acid part, and an amine part, has the great
advantage of optimizing its structure easily for the strict face
discrimination of prochiral enolates. Further study on asym-
metric protonation with this type of chiral amide and its precise
reaction mechanism is currently underway.
With the chiral amide optimized in a model system (1ag), we
focused on the asymmetric protonation of lithium enolate of a-
amino acid derivatives, which was generated from the corre-
sponding racemic amino acid derivatives and mesityllithium in
ether (Table 2). To evaluate precisely the capacity for the
asymmetric induction of 1ag, ‘corrected ee’ was applied to our
system, which is a corrected value based on the actual rate of
the protonated product by 1ag.9 The rate of protonated product
was determined by quenching both the deprotonation stage
(operation B) and the protonation stage (operation A) with D2O
at 278 °C. Optimization of the reaction conditions with a
racemic alanine derivative 5 as a starting substrate showed that
the unnatural alanine derivative 5 was obtained with the highest
enatioselectivity (87% ee, entry 2) when the reaction was
performed at 220 °C. This high level of asymmetric induction
clearly shows that this a-amino acid derived chiral amide 1ag
could be an effective chiral proton source for the asymmetric
protonation of the lithium enolate of a-amino acid derivatives,
i.e., “deracemization” of a-amino acid derivatives.
We gratefully acknowledge Sumitomo Chemical Co., Ltd.
for a gift of biotin precursor, and helpful advice on its
preparation.
Notes and references
1 Preparation of optically active a-amino acids: R. M. Williams, in
Synthesis of Optically Active a-Amino Acids, ed. J. E. Baldwin, Organic
Chemistry Series, Pergamon Press, Oxford, 1989; R. O. Duthaler,
Tetrahedron, 1994, 50, 1539; M. J. OADonnell, Aldrichimica Acta, 2001,
34, 3.
2 Reviews for asymmetric protonations: L. Duhamel, P. Duhamel, J.-C.
Launay and J.-C. Plaquevent, Bull. Soc. Chim. Fr., 1984, II, 421; C. Fehr,
Chimia, 1991, 45, 253; H. Waldmann, Nachr. Chem., Tech. Lab., 1991,
39, 413; S. Hünig, in Houben-Weyl: Methods of Organic Chemistry, ed.
G. Helmchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Georg
Thieme Verlag, Stuttgart, 1995, vol. E 21, p. 3851; C. Fehr, Angew.
Chem., Int. Ed. Engl., 1996, 35, 2566; A. Yanagisawa and H. Yamamoto,
in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz
and H. Yamamoto, Springer, Berlin, 1999, vol. III, 1295; J. Eames and N.
Weerasooriya, Tetrahedron: Asymmetry, 2001, 12, 1.
3 Recent asymmetric protonations: Y. Nakamura, S. Takeuchi, Y. Ohgo
and D. P. Curran, Tetrahedron, 2000, 56, 351; E. Vedejs, A. W. Kruger,
N. Lee, S. T. Sakata, M. Stec and E. Suna, J. Am . Chem. Soc., 2000, 122,
4602; S. Nakamura, M. Kaneeda, K. Ishihara and H. Yamamoto, J. Am.
Chem. Soc., 2000, 122, 8120; O. Roy, M. Diekmann, A. Riahi, F. Hénin
and J. Muzart, Chem. Commun., 2001, 533; M.-H. Xu, W. Wang, L.- J.
Xia and G.-Q. Lin, J. Org. Chem., 2001, 66, 3953; K. Flinois, Yi. Yuan,
C. Bastide, A. H. Marchand and J. Maddaluno, Tetrahedron, 2002, 58,
4707.
These successful results encouraged us to apply the chiral
proton source 1ag to a variety of lithium enolates of a-amino
acid derivatives. Moderate to high asymmetric induction
occurred in the protonation of lithium enolates of a-amino acid
derivatives 5-8 with good yield (entries 2, 4–6), even in the
presence of a hetero atom in the alkyl side chain such as 8 (entry
6). The highest enantioselectivity (87% ee) was obtained with
the enolate of alanine derivative 5 (entry 2). Protonation with
the enolate of leucine derivative 7 also gave rise to significant
induction (85% ee, entry 5). The reaction with the enolate of
phenylalanine derivative 9 also afforded moderate optical
purity, though the chemical yield of the reaction was somewhat
Table 2 Enantioselective protonation of various lithium enolates of a-
amino acid derivatives 5–10 with chiral amide 1aga
4 For enantioselective protonations of metal enolates of a-amino acid
derivatives: L. Duhamel and J.-C. Plaquevent, J. Am. Chem. Soc., 1978,
100, 7415; L. Duhamel and J.-C. Plaquevent, Tetrahedron Lett., 1980, 21,
2521; L. Duhamel and J.-C. Plaquevent, Bull. Soc. Chim. Fr., 1982, II,
75; L. Duhamel, S. Fouquay and J.-C. Plaquevent, Tetrahedron Lett.,
1986, 27, 4975; L. Duhamel, P. Duhamel, S. Fouquay, J. J. Eddine, O.
Peschard, J.-C. Plaquevent, A. Ravard, R. Solliard, J.-Y. Valnot and H.
Vincens, Tetrahedron, 1988, 44, 5495; E. Vedejs and N. Lee, J. Am.
Chem. Soc., 1995, 117, 891; J. Martin, M.-C. Lasne, J.-C. Plaquevent and
L. Duhamel, Tetrahedron Lett., 1997, 38, 7181; E. Vedejs, A. W. Kruger
and E. Suna, J. Org. Chem., 1999, 64, 7863; M. Calmès, C. Glot and J.
Martinez, Tetrahedron: Asymmetry, 2001, 12, 49; A. Yanagisawa, Y.
Matsuzaki and H. Yamamoto, Synlett, 2001, 1855.
5 K. W. Kuntz, M. L. Snapper and A. H. Hoveyda, Curr. Opin. Chem. Biol.,
1999, 3, 313; K. D. Shimizu, M. L. Snapper and A. H. Hoveyda, in
Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and
H. Yamamoto, Springer, Berlin, 1999, vol. III, 1389.
6 A. Yanagisawa, T. Kikuchi, T. Watanabe and H. Yamamoto, Bull.Chem-
.Soc.Jpn., 1999, 72, 2337; A. Yanagisawa, T. Watanabe, T. Kikuchi and
H. Yamamoto, J. Org. Chem., 2000, 65, 2979.
7 Similar a-amino acid derivatives have already developed in our
laboratory: Y. Hoshino and H. Yamamoto, J. Am. Chem. Soc., 2000, 122,
10452.
8 Synthesis of a biotin precursor: S. Lavielle, S. Bory, B. Moreau, M. J.
Luche and A. Marquet, J. Am. Chem. Soc., 1978, 100, 1558; Sumitomo
Chemical Co. Ltd. Jpn. Kokai, Tokyo Koho JP 7608,270; F.-E. Chen, Y.-
D. Huang, H. Fu, Y. Cheng, D.-M. Zhang, Y.-Y. Li and Z.-Z. Peng,
Synthesis, 2000, 14, 2004.
Yield Ee
Entry Conditions
R
(%)b (%)c Configuration
1
2
3
4
5
6
7
8
278 °C, 3 h
Me
(5) 57
(5) 73
(5) 89
(6) 77
(7) 66
13d
87d
79d
64e
85f
78g
65g
23g
Sd
220 °C, 2.5 h Me
Rd
Rd
—
Rh
—
Rh
—
0 °C, 1.5 h Me
220 °C, 2.5 h Et
220 °C, 2.5 h Isobutyl
220 °C, 2.5 h (CH2)2SMe (8) 79
220 °C, 2.5 h Bn
220 °C, 2.5 h Ph
(9) 27
(10) 87
a For the details of the experimental procedure, see ESI.† b Isolated yield.
c Corrected value based on the actual rate of the protonated product. See also
note 9 and ESI.† d Ref. 4. e Determined by HPLC analysis (Chiralcel AD-H,
Daicel Chemical Industries, Ltd.). f Determined by HPLC analysis
(Chiralcel AS, Daicel Chemical Industries, Ltd.). g Determined by HPLC
analysis (Chiralcel OD-H, Daicel Chemical Industries, Ltd.). h Determined
by comparison of its retension time with that of the authentic sample
9 For example, 87% ee (entry 2, Table 2) was calculated using the
following data: 79% ee, > 99% enolization (from operation B), 10%
deuteration in quench (from operation A). Therefore the actual rate of the
protonated product should be 90%, and corrected ee should be obtained
by dividing the observed ee by the actual rate of the protonated product.
Further details about these operations are described in the ESI†.
synthesized from the corresponding -a-amino acid.
L
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