Asymmetric aldol reaction via memory of chirality

Article abstract of DOI:10.1039/c2cc31447a

Asymmetric aldol reactions of α-amino acid derivatives via memory of chirality were developed. Chiral oxazolidones with contiguous tetra- and trisubstituted chiral centers were obtained in 78-94% ee by the asymmetric aldol reaction followed by intramolecular acylation.

Full text of DOI:10.1039/c2cc31447a

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COMMUNICATION
Asymmetric aldol reaction via memory of chiralitywz
Hidetoshi Watanabe, Tomoyuki Yoshimura, Shimpei Kawakami, Takahiro Sasamori,
Norihiro Tokitoh and Takeo Kawabata*
Received 27th February 2012, Accepted 3rd April 2012
DOI: 10.1039/c2cc31447a
Asymmetric aldol reactions of a-amino acid derivatives via
memory of chirality were developed. Chiral oxazolidones with
contiguous tetra- and trisubstituted chiral centers were obtained
in 78–94% ee by the asymmetric aldol reaction followed by
intramolecular acylation.
We have studied asymmetric induction via memory of chirality.1,2
This strategy enables a direct construction of a-amino acid
derivatives with chiral tetrasubstituted carbon from readily
available a-amino acids without the aid of external chiral
Scheme 1 A reaction path of asymmetric methylation via axially
sources such as chiral catalysts or chiral auxiliaries. We have
reported several asymmetric intramolecular transformations
via memory of chirality such as alkylation,3 conjugate addition,4
and Dieckmann condensation.5 On the other hand, intermolecular
transformation via memory of chirality has been limited only
to simple alkylation and allylation.6 The relative difficulties in
developing intermolecular asymmetric transformation by this
strategy originate in the nature of intermediary enolates. Since the
intermediary chiral enolates are prone to undergo time-dependent
racemization, relatively slow intermolecular processes appear to
be more difficult than the corresponding intramolecular ones.
Here, we report the first example of asymmetric intermolecular
aldol reactions between a-amino acid derivatives and aromatic
aldehydes via memory of chirality through careful investigation of
the balance between the racemization behaviour of intermediary
chiral enolates and their reactivity toward aldehydes.7
chiral enolate A.
solvent mixture (toluene : THF = 4 : 1) is the key for the high
yield and asymmetric induction. Use of the major volume of
toluene is effective for slowing the racemization of enolate A,8
probably due to the formation of higher-order aggregates of
the enolate. On the other hand, use of the minor volume of
THF seems to be effective for increasing the reactivity of the
enolate to promote smooth alkylation.9 Based on the backgrounds
of the nature of the intermediary chiral enolates, we envisaged to
develop asymmetric aldol reactions through careful consideration
of the balance between kreaction of the aldol reaction and kracemization
of the chiral enolate intermediate.
We chose N-tert-butoxycarbonyl (Boc)-N-methoxymethyl
(MOM)-amino acid derivative 1 as the substrate for the
development of asymmetric aldol reactions, because the race-
mization behaviour of chiral enolate A generated from 1 has
been well studied.6a,8 Asymmetric aldol reaction of 1 was first
examined according to the protocol for asymmetric a-methylation
shown in Scheme 1. Treatment of 1 with 1.1 equivalents of
potassium hexamethyldisilazide (KHMDS) in toluene–THF
(4 : 1) for 30 min to generate axially chiral enolate A,6a followed
by addition of 3.0 equivalents of benzaldehyde (procedure I in
Table 1) gave oxazolidone derivative 2 in 85% yield and only
32% ee after intramolecular acylation of the resulting potassium
aldolate with the Boc moiety (entry 1). In order to avoid partial
racemization of the chiral enolate during the aldol reaction and to
gain insights into the asymmetric induction at the early stage of
the aldol reaction, another reaction procedure was employed.
A solution of 1 was added to a pre-cooled solution of benzaldehyde
(3.0 equiv.) and KHMDS (1.1 equiv.) (procedure II) in toluene–
THF (4 : 1) at ꢀ78 1C, and the resulting solution was stirred for
only 10 min to give 2 in 2% yield and 99% ee (entry 2). Treatment
of 1 under the identical conditions to those in entry 2 except for the
We have reported a-methylation of an amino acid derivative
via memory of chirality (Scheme 1).6a The asymmetric trans-
formation was proposed to proceed via axially chiral enolate A.
The half-life of racemization of A was measured to be 22 h at the
reaction temperature (ꢀ78 1C), which corresponds to the racemi-
zation barrier of the chiral enolate of 16.0 kcal molꢀ1. Since the
reaction rate of enolate A (kreaction(A)) with electrophiles is the same
as that of enolate ent-A (kreaction(ent-A)), the ratio between A
and ent-A directly correlates with the ee of the product. The
ratio between kreaction(A) and kracemization critically affects overall
efficiency of the asymmetric transformation. The choice of a
Institute for Chemical Research, Kyoto University,
Uji, Kyoto 611-0011, Japan. E-mail: kawabata@scl.kyoto-u.ac.jp;
Fax: +81 774 38 3197; Tel: +81 774 38 3190
w This article is part of the ChemComm ’Chirality’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, copies of 1H NMR and 13C NMR.
CCDC 867310 (10). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc31447a
c
5346 Chem. Commun., 2012, 48, 5346–5348
This journal is The Royal Society of Chemistry 2012

Table 1 Optimization of asymmetric aldol reactions via memory of
chirality
Table 2 Asymmetric aldol reactions of 1 with aromatic aldehydesa
Entry Ar
Temp/1C Time/h Productb,c Yield (%) ee (%)
Temp/
1C
Yieldb,c eed
Entry Procedurea Solvent
Time (%)
(%)
1
2
3
4
5
ꢀ60
ꢀ60
ꢀ60
ꢀ50
ꢀ50
6
12
6
2d
3e
4e
5e
6e
69
67
66
64
95
92
88
88
78
80
1
2
3
4
I
II
II
II
Tol : THF = 4 : 1
Tol : THF = 4 : 1
Tol : THF = 4 : 1
Tol : THF = 4 : 1
Tol
ꢀ78 2.5 h 85
ꢀ78 10 min 2
ꢀ30 10 min 7
32
99
96
71
80
83
87
78
84
ꢀ30 4 h
ꢀ30 6 h
ꢀ30 6 h
96
57
86
5
II
6
7
8
9
III
III
III
III
III
III
III
III
Tol
Tol
6
ꢀ50 10 h 65
ꢀ50 12 h 86
ꢀ50 12 h 95
Tol : THF = 2 : 1
Tol : t-Pr2O = 2 : 1
12
10
11
12
13e
Tol : t-BuOMe = 2 : 1 ꢀ50 12 h Quant. 81
Tol : i-Pr2O = 2 : 1
Tol : t-BuOMe = 2 : 1 ꢀ60 12 h 69
Tol : t-BuOMe = 2 : 1 ꢀ50 12 h 31f
ꢀ60 12 h 70
86
92
89
6
ꢀ50
ꢀ60
12
6
7e
8e
67
44
89
89
14g III
Tol : t-BuOMe = 2 : 1 ꢀ50 12 h Quant.h 82
7
a
I: 1 was treated with KHMDS (1.1 equiv.) for 30 min, then with
benzaldehyde (3.0 equiv.) for 2 h. II: A solution of 1 was added to a
solution of benzaldehyde (3.0 equiv.) and KHMDS (1.1 equiv.).
III: KHMDS (3.0 equiv.) was added to a solution of benzaldehyde
a
KHMDS (3.0 equiv.) was added to a solution of an aldehyde
b
(5.0 equiv.) and 1. A single diastereomer was obtained in each run.
c
Relative configuration of 2–6 and 8 was determined by NOE studies,
see ESI. Relative configuration of
b
7 was tentatively assigned
(5.0 equiv.) and 1. A single diastereomer was obtained in each run.
c
d
e
by analogy. (4S,5S). The absolute configuration was tentatively
assigned by analogy to 2.
The relative configuration was determined by NOE studies (see ESI)
as well as an X-ray analysis of the derivative of 2 (see the text).
d
(4S,5S)-Isomer was obtained in each run. For determination of the
e
absolute configuration, see the text. The corresponding tert-butyl
the ee to 86–92% (entries 11 and 12). Based on these results,
we chose the conditions employed in entries 10 and 12,
procedure III in toluene–t-BuOMe (2 : 1), as the optimum ones.
The corresponding tert-butyl and benzyl esters of 1 treated under
the reaction conditions employed for entry 10 gave the corres-
ponding tert-butyl and benzyl esters of 2 in 89% ee (31% yield)
and 82% ee (quant.), respectively (entries 13 and 14).
f
ester was employed as a substrate. The yield of the corresponding
g
tert-butyl ester. The corresponding benzyl ester was employed as a
h
substrate. The yield of the corresponding benzyl ester.
temperature (ꢀ30 1C) gave 2 in a slightly increased yield (7%)
and a slightly decreased ee (96%) (entry 3). The reaction with
the prolonged reaction time (4 h) at the same temperature
(ꢀ30 1C) gave 2 in 96% yield in a decreased ee (71% ee) (entry 4).
Comparison of the results between entries 3 and 4 indicates
partial racemization of the intermediary chiral enolate during its
reaction with benzaldehyde. According to our observation on
racemization behaviour of the enolate,8,9 pure toluene was
employed as a solvent in order to minimize racemization of the
chiral enolate. Product 2 was obtained in an increased ee (80%
ee) by the reaction of 1 in toluene even after the longer reaction
time (6 h) than that employed for the corresponding reaction in
toluene–THF (4 : 1) (71% ee after 4 h) (entry 4 vs. 5). In order to
further increase both the yield and the ee of the reaction, another
procedure was examined. Three equivalents of KHMDS were
added to a pre-cooled solution of benzaldehyde (5.0 equiv.) and 1
(procedure III) in toluene at ꢀ30 1C, and the resulting solution
was stirred for 6 h to give 2 in 86% yield and 83% ee (entry 6).
While decrease in the reaction temperature to ꢀ50 1C increased
the ee of the aldol reaction to 87% ee that diminished the yield
to 65% (entry 6 vs. 7). Ethereal solvents were employed in
combination with toluene in order to improve the yield by
increasing the reactivity of the enolate (entries 8–10 vs. 7).
While the addition of either THF, i-Pr2O, or t-BuOMe is
effective in increasing the yield of the reaction (86% B quant.),
that slightly decreased the enantioselectivity of the aldol process
(78–84% ee). The corresponding reactions at ꢀ60 1C increased
The optimized conditions were applied to asymmetric aldol
reactions of 1 with various aromatic aldehydes (Table 2).
A mixture of 1 and an aldehyde in toluene–t-BuOMe (2 : 1)
was treated with KHMDS at ꢀ60 1C or ꢀ50 1C to give a chiral
oxazolidone with contiguous tetra- and trisubstituted chiral
centers in diastereomerically pure form through the asymmetric
aldol reaction followed by intramolecular acylation of the resulting
potassium aldolate. para-Substituted benzaldehydes gave oxazoli-
dones 3–6 by the reactions with 1 in 64–95% yield and 78–88% ee
(entries 2–5). ortho-Methoxybenzaldehyde underwent the
aldol-acylation reaction to give oxazolidone 7 in 67% yield
and 89% ee (entry 6). Reaction of 1 with 2-naphthaldehyde
gave oxazolidone 8 in high enantioselectivity (89% ee) and a
Fig. 1 Transformation of 2 into 10 and an X-ray structure of 10.
Chem. Commun., 2012, 48, 5346–5348 5347
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This journal is The Royal Society of Chemistry 2012

diastereoselective and enantioselective manner. Chiral oxazoli-
dones have been known to be useful chiral auxiliaries,11 and
recently disclosed to be a novel class of antibiotics.13 Oxazo-
lidones obtained by the present method are structural equiva-
lents to b-hydroxy-a-amino acids with a tetrasubstituted carbon
center,14 which are the frequently observed structural subunits
in biologically active natural products.15
Scheme 2 Asymmetric aldol-acylation reactions of 11 and 13.
Notes and references
low yield (44%) (entry 7). Although a single diastereomer was
obtained in each run after purification by column chromato-
graphy, the involvement of the minor diastereomer in the crude
mixture cannot be excluded, especially when the yield was low.
The attempted reactions of 1 with aliphatic aldehydes did not
afford the significant amounts of aldolates or the corresponding
oxazolidones.
1 For reviews on asymmetric synthesis via memory of chirality:
(a) T. Kawabata and K. Fuji, Top. Stereochem., 2003, 23, 175;
(b) H. Zhao, D. C. Hsu and P. R. Carlier, Synthesis, 2005, 1;
(c) T. Kawabata, Asymmetric Synthesis and Application of a-Amino
Acids, ACS Symp. Ser., 2009, 1009, 31–56.
2 For recent examples of asymmetric synthesis based on memory of
chirality: (a) P. R. Carlier, H. Zhao, S. L. MacQuarrie-Hunter, J. C.
DeGuzman and D. C. Hsu, J. Am. Chem. Soc., 2006, 128, 15215;
(b) L. Klolaczkowski and D. M. Barnes, Org. Lett., 2007, 9, 3029;
(c) M. Branca, D. Gori, R. Guillot, V. Alezra and C. Koulovsky, J. Am.
Chem. Soc., 2008, 130, 5864; (d) G. N. Wanyoike, Y. Matsumura,
M. Kuriyama and O. Onomura, Heterocycles, 2010, 80, 1177;
(e) M. Sasaki, T. Takegawa, H. Ikemoto, M. Kawahara,
K. Yamaguchi and K. Takeda, Chem. Commun., 2012, 48, 2897.
3 (a) T. Kawabata, S. Kawakami and S. Majumdar, J. Am. Chem.
Soc., 2003, 125, 13012; (b) T. Kawabata, S. Matsuda,
S. Kawakami, D. Monguchi and K. Moriyama, J. Am. Chem.
Soc., 2006, 128, 15394; (c) T. Kawabata, K. Moriyama,
S. Kawakami and K. Tsubaki, J. Am. Chem. Soc., 2008, 130, 4153.
4 T. Kawabata, S. Majumdar, K. Tsubaki and D. Monguchi, Org.
Biomol. Chem., 2005, 3, 1609.
5 T. Watanabe and T. Kawabata, Heterocycles, 2008, 76, 1593.
6 (a) T. Kawabata, H. Suzuki, N. Nagae and K. Fuji, Angew. Chem.,
Int. Ed., 2000, 39, 2155; (b) T. Kawabata, J. Chen, H. Suzuki,
Y. Nagae, T. Kinoshita, S. Chancharunee and K. Fuji, Org. Lett.,
2000, 2, 3883; (c) T. Kawabata, S. Kawakami, S. Shimada and
K. Fuji, Tetrahedron, 2003, 59, 965.
7 An intramolecular aldol reaction with memory of chirality has
previously been reported, see: A. G. Brewster, C. F. Frampton,
J. Jayatissa, M. B. Mitchell, R. J. Stoodley and S. Vohra, Chem.
Commun., 1998, 299.
The absolute configuration of 2 was determined by an X-ray
analysis of its derivative 10 (Fig. 1). Hydrolysis of 2 (85% ee)
obtained by the reactions in Table 1 followed by condensation
of the resulting acid with (S)-1-(1-naphthyl)ethylamine gave 9
in 86% yield in a diastereomerically pure form after column
chromatography. Treatment of 9 with trifluoroacetic acid gave
10 in 85% yield via Pictet–Spengler cyclization, in which the
MOM group serves as a formaldehyde equivalent.10 An X-ray
structure of a single crystal of 10 is shown in Fig. 1. This
indicates that asymmetric aldol reaction of 1 took place in
inversion of configuration at the newly generated tetrasubstituted
carbon center. Asymmetric aldol reactions of tyrosine derivative 11
and leucine derivative 13 with benzaldehyde that took place by the
treatment according to the protocol in Table 2 gave oxazolidones
12 and 14 in 85% ee (95% yield) and 94% ee (83% yield),
respectively (Scheme 2).
The following phenomena appear to be intriguing from
mechanistic viewpoints and enolate chemistry. (1) While
methylation of 1 proceeds in retention of configuration, its
aldol reaction took place in inversion of configuration. These
reactions seem to proceed via a common chiral enolate intermediate
(at least for the reactions of entry 1 in Table 1 and Scheme 1). Thus,
the reacting enantioface of the axially chiral enolates is reverse to
each other depending on the electrophile (alkyl halide or aldehyde).
(2) While the enolate generated from 1 by the procedure I
(entry 1 in Table 1 and Scheme 1) has been known to be a 2 : 1
Z/E mixture,6a its aldol reaction with benzaldehyde gave a
diastereomerically pure product in 85% yield. Some of the
other related aldol reactions also gave diastereomerically pure
products in good yields. We are not ready to propose the
rationale for these phenomena, yet. Mechanistic investigations
are currently underway in our laboratory.
8 The half-life of racemization of enolate A in pure THF at ꢀ78 1C
was determined to be 0.5 h, which is B1/40 of that in toluene–THF
(4 : 1).
9 While the reaction in pure THF gave the a-methylated product in
93% yield and 35% ee (ref. 6c), the corresponding reaction in pure
toluene gave the a-methylated product in 47% yield and 75% ee.
This could be ascribed to higher reactivity of the enolate in THF
and resistance of the enolate against racemization in toluene.
10 T. Kawabata, O. Ozurk, H. Suzuki and K. Fuji, Synthesis, 2003, 505.
¨
11 For reviews on chiral auxiliary-based asymmetric synthesis including
asymmetric aldol reactions: (a) D. A. Evans, Aldrichimica Acta, 1982,
15, 23; (b) D. A. Evans, G. Helmchen, M. Ruping and J. Wolfgang,
Asymmetric Synthesis, 2007, p. 3.
12 For pioneering examples of catalytic asymmetric aldol reactions:
(a) S. Kobayashi, Y. Fujisawa and T. Mukaiyama, Chem. Lett.,
1990, 1455; (b) H. Sasai, T. Suzuki, S. Arai, T. Arai and M. Shibasaki,
J. Am. Chem. Soc., 1992, 114, 4418; (c) B. List, R. A. Lerner and
C. F. Barbas, III, J. Am. Chem. Soc., 2000, 122, 2395.
In conclusion, we have developed an intermolecular asymmetric
aldol reaction of a-amino acid derivatives via memory of chirality
for the first time.7 Although asymmetric aldol reactions have
been extensively developed,11,12 the present method has unique
characteristics in which asymmetric induction is controlled solely
by the enolate chirality in the absence of chiral catalysts or chiral
auxiliaries. Chiral oxazolidone derivatives with contiguous
tetra- and trisubstituted chiral centers can be obtained from
readily available a-amino acids by the present method in a highly
13 For selected reviews: (a) M. Barbachyn and C. W. Ford, Angew.
Chem., Int. Ed., 2003, 42, 2010; (b) T. A. Mukhtar and
G. D. Wright, Chem. Rev., 2005, 105, 529.
14 For selected recent examples of catalytic asymmetric synthesis of
b-hydroxy-a-amino acid derivatives with a tetrasubstituted carbon
center: (a) M. Terada, H. Tanaka and K. Sorimachi, J. Am. Chem.
Soc., 2009, 131, 3430; (b) T. Yoshino, H. Morimoto, G. Lu,
S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2009,
131, 3430.
15 For a review, see: S. H. Kang, S. Y. Kang, H.-S. Lee and
A. J. Buglass, Chem. Rev., 2005, 105, 17082.
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5348 Chem. Commun., 2012, 48, 5346–5348
This journal is The Royal Society of Chemistry 2012