Construction of enantiomerically enriched tertiary α- hydroxycarboxylic acid derivatives by phase-transfer-catalyzed asymmetric alkylation of diaryloxazolidin-2,4-diones

Article abstract of DOI:10.1002/anie.200600470

(Chemical Equation Presented) Center of attention: The chiral ammonium bromide 1 has been used as a catalyst for the highly enantioselective alkylation of diaryloxazolidindiones 2 under mild phase-transfer conditions (TBME = tert-butyl methyl ether). This

Full text of DOI:10.1002/anie.200600470

Angewandte
Chemie
Asymmetric Synthesis
DOI: 10.1002/anie.200600470
Construction of Enantiomerically Enriched
Tertiary a-Hydroxycarboxylic Acid Derivatives by
Phase-Transfer-Catalyzed Asymmetric Alkylation
of Diaryloxazolidin-2,4-diones**
Takashi Ooi, Kazuhiro Fukumoto, and Keiji Maruoka*
The direct alkylation of enolates is an important method for
the formation of carbon–carbon bonds in synthetic organic
chemistry. The concept of diastereoselective alkylation by
using chiral auxiliaries has played a dominant role over the
past three decades for rigorously controling the stereochem-
istry. The establishment of systems useful for a broad range of
substrates has resulted in chiral auxillaries attaining a
preeminent position in the field.[1] On the other hand,
complementary catalytic variants have been much less
developed despite their practical and fundamental impor-
tance.[2] In contrast to the recent emergence of highly efficient
transition-metal-catalyzed processes for asymmetric allyla-
tions,[2,3] arylations,[2] and vinylations[4] of enolates, reliable
protocols for catalytic enantioselective alkylation involving
sp3-hybridized electrophiles, such as alkyl halides, are still
restricted.[2,5,6] Although chiral phase-transfer catalysis has
made a significant contribution to this area,[2,6] the major
drawback of this strategy is that it is only effective for a
limited pool of substrates. In particular it has limited
applicability in accessing enantioenriched carbonyl com-
pounds of high value which possess quaternary a-carbon
stereocenters.[7] Our approach toward this largely unsolved
problem utilizes 3,5-diaryloxazolidin-2,4-diones 2 as novel
oxygen-containing substrates that undergo highly enantiose-
lective alkylation under mild phase-transfer conditions in the
presence of the N-spiro chiral quaternary ammonium bro-
mide 1e as catalyst (Scheme 1).[8] This substrate–catalyst
combination provides a new and practical entry to a wide
range of tertiary a-hydroxy-a-aryl carboxylic acid deriva-
tives.[9,10]
The requisite 3,5-diaryloxazolidin-2,4-diones 2 can be
readily prepared from racemic a-hydroxy esters by sequential
treatment with 1,1’-carbonyldiimidazole (CDI) and an appro-
[*] Dr. T. Ooi, K. Fukumoto, Prof. K. Maruoka
Department of Chemistry
Graduate School of Science
Kyoto University
Sakyo, Kyoto, 606-8502 (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by the Mitsubishi Chemical
Corporation Fund and 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.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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enantioselectivity (entry 2). To our surprise, however, a
dramatic improvement in the selectivity was attained in the
reaction with 1c (which has radially disposed 3,5-bis[3,5-
bis(trifluoromethyl)phenyl]phenyl moieties) as a catalyst,[12d,e]
and furnished 3a (Ar2 = Ph) in 85% yield and with 91% ee
(entry 3).
We then focused on modifying the catalyst further by
introducing an electron-withdrawing trifluoromethyl group at
the 6,6’-positions of each binaphthyl subunit. Evaluation of
the performance of the new chiral ammonium bromides 1d
and 1e revealed the superiority of 1e (entries 4 and 5); the
phase-transfer-catalyzed benzylation of 2a (Ar2 = Ph) in the
presence of 1e gave the desired 3a (Ar2 = Ph) with 96% ee.
Although the electronic nature of the aryl group (Ar2) on the
nitrogen atom of 2a subtly affected the enantioselectivity and
reaction efficiency (entries 6 and 7), we observed a beneficial
effect of using ethereal solvents such as cyclopentyl methyl
ether (CPME) and tert-butyl methyl ether (TBME). Sub-
stantial rate acceleration and virtually complete stereochem-
ical control were achieved by using TBME (entries 8 and 9). It
should be noted that the decreased chemical yield stems from
hydrolysis prior to the alkylation because of the increased
polarity of the solvent, which was overcome by reducing the
concentration of the base to an aqueous solution of 25%
KOH (entry 10).
With optimized conditions in hand, the scope of this new
asymmetric enolate alkylation protocol was thoroughly
investigated, and the representative results are summarized
in Table 2.[13] In general, 1 mol% of 1e with 1.2equivalents of
alkyl halide was sufficient for smooth alkylation, and in some
cases the reaction was performed at lower temperature to
enable the catalyst to achieve its full stereocontrol. A series of
benzylic bromides of different steric and electronic properties
were tolerated, thus allowing the preparation of structurally
diverse, enantioenriched a-alkyl mandelic acid derivatives
(entries 1–5). Construction of stereogenic quaternary carbon
centers bearing allylic and propargylic substituents on 2 can
also be achieved in a similar manner (entries 6–8). Both
Scheme 1. Enantioselective alkylation of 3,5-diaryloxazolidin-2,4-diones
2 by phase-transfer catalysis of (S,S)-1 to afford optically active tertiary
a-hydroxy amides 3.
priate aromatic amine (Ar2NH2) in CH2Cl2.[11] The feasibility
of the stereoselective alkylation of 2 was examined under
typical liquid–liquid phase-transfer conditions with 3,5-diphe-
nyloxazolidin-2,4-dione (2a, Ar2 = Ph) as a representative
substrate and chiral quaternary ammonium bromide (S,S)-
1a[12a,b] as the catalyst. The reaction of 2a (Ar2 = Ph) with
benzyl bromide (1.2equiv) in the presence of 1a (1 mol%) in
toluene/50% aqueous solution of KOH was found to proceed
at 08C, and TLC analysis confirmed the consumption of all
the substrate 2a after 18 h. Subsequent addition of dioxane
and continuous stirring of the reaction mixture at room
temperature for 1 h facilitated the one-pot partial hydrolysis
to directly afford the corresponding tertiary a-hydroxy amide
3a (Ar2 = Ph) in 79% yield, albeit with low enantiomeric
excess (19% ee; Table 1, entry 1). Switching the 3,3’-aromatic
substituent (Ar) to a 3,5-bis(trifluoromethyl)phenyl group
(1b)[12c] resulted in a diminished yield with a similar degree of
Table 1: Optimization of the phase-transfer-catalyzed asymmetric benzylation of 2a using (S,S)-1 as the catalyst.[a]
Entry
Catalyst
2a (Ar2)
Solvent
t [h]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
Ph
Ph
Ph
Ph
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CPME
TBME
TBME
18
20
19
20
19
18
17
3
79
65
85
83
87
84
81
69
75
82
19
19
91
92
96
87
94
92
99
99
Ph
p-F-C6H4
p-MeO-C6H4
Ph
Ph
Ph
9
5
7
10[d]
[a] Unless otherwise specified, the reaction was carried out with 1.2 equiv of benzyl bromide in the presence of (S,S)-1 (1 mol%) in a mixture of organic
solvent and a 50% aqueous solution of KOH at 08C for the given reaction time, after which dioxane was added and stirring was continued at room
temperature for 1 h. [b] Yield of isolated product. [c] The enantiopurity of a-hydroxy amide 3a was determined by HPLC analysis on a chiral stationary
phase (DAICEL Chiralpak AS-H) with hexane/2-propanol as the solvent. The absolute configuration was deduced from that of 3g. [d] Aqueous 25%
KOH solution was used as a base.
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Chemie
Table 2: Catalytic asymmetric alkylation of 3-phenyl-5-aryloxazolidin-2,4-dione (2) under phase-transfer
genic quaternary carbon centers,
conditions.[a]
and offers direct access to various
optically active tertiary a-hydroxy
acids and their derivatives. These
compounds are an important class
of chiral building blocks, in partic-
ular for the preparation of complex
biologically active substances.[15]
Further investigations on expand-
ing the scope of our approach in
terms of both the nucleophiles and
electrophiles are currently under-
way.
Entry
2 (Ar1)
RBr
T [8C]
t [h]
Yield[b] [%]
ee[c,d] [%]
Product
1
2
3
Ph (2a)
Ph (2a)
Ph (2a)
R1 =M
R1 =F
e
À20
0
0
81
80
9
83
97
94
3b 94
3c
3d
23
8
R1 =Ph
Received: February 4, 2006
Published online: May 3, 2006
4
5
Ph (2a)
Ph (2a)
0
10
22
76
80
94
96
3e
3 f
Keywords: alkylation · asymmetric
.
synthesis · phase-transfer catalysis ·
synthetic methods
À20
=
6
7
8
Ph (2a)
Ph (2a)
Ph (2a)
p-F-C6H4
p-MeO-C6H4
2-furyl
CH2 CHCH2Br
0
À20
0
7
24
9
6
23
7
83
80
81
76
87
81
81
95
97
86
90
90
94
99
3g
3h
3i
3j
3k
3l
=
CH2 C(Me)CH2Br
ꢀ
CH CCH2Br
[1] For reviews, see: a) D. A. Evans in
Asymmetric Synthesis, Vol. 3 (Ed.:
J. D. Morrison), Academic Press,
New York, 1983, chap. 1, p. 83;
b) A. I. Meyers in Asymmetric Syn-
thesis, Vol. 3 (Ed.: J. D. Morrison),
Academic Press, New York, 1983,
chap. 3, p. 213; see also: c) W.
Oppolzer, R. Moretti, S. Thomi,
Tetrahedron Lett. 1989, 30, 5603;
d) A. G. Myers, B. H. Yang, H.
Chen, L. McKinstry, D. J. Kopecky,
J. L. Gleason, J. Am. Chem. Soc.
9
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
0
10
11
12
À20
0
2-thienyl
À20
24
3m
[a] The reaction was carried out with 1.2 equiv of alkyl halide and 1 mol% of 1e in a mixture of TBME and
an aqueous 25% KOH solution under the given reaction conditions. [b] Yield of isolated product. [c] The
enantiomeric excess of 3 was determined by HPLC analysis on a chiral stationary phase. [d] The absolute
configuration of 3g was assigned to be S by comparison of the optical rotation with the reported value
after amide hydrolysis[13] (see Scheme 2).
electron-withdrawing and electron-donating substituents on 2
were also tolerated (entries 9 and 10). Moreover, the catalytic
asymmetric quaternization of 2 possessing a heteroaromatic
group as Ar1 was feasible, and excellent enantioselectivity was
observed (entries 11 and 12).
1997, 119, 6496; e) A. Job, C. F. Janeck, W. Bettray, R. Peters, D.
Enders, Tetrahedron 2002, 58, 2253.
[2] For reviews, see: a) D. L. Hughes in Comprehensive Asymmetric
Catalysis, Vol. 3 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
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2005, 127, 10506.
The tertiary a-hydroxy amide 3 thus obtained can be
cleanly converted into the corresponding a-hydroxycarbox-
ylic acid by simple treatment with KOH in ethylene glycol at
1508C as shown in Scheme 2, and no loss in the enantiomeric
excess of 4 was confirmed by HPLC analysis after further
derivatization to its methyl ester 5. The absolute configura-
tion of 4 was assigned to be S by comparison of the optical
rotation with the literature value.[14]
In conclusion, we have successfully introduced a new
catalyst 1e for realizing catalytic, highly enantioselective
alkylation of substrates 2 under mild phase-transfer condi-
tions. This system represents the first example of the catalytic
asymmetric alkylation of glycolates that establishes stereo-
[6] For recent representative reviews on asymmetric
phase-transfer catalysis, see: a) T. Shioiri in Hand-
book of Phase-Transfer Catalysis (Eds.: Y. Sasson, R.
Neumann), Blackie Academic
&
Professional,
London, 1997, chap. 14, p. 462; b) M. J. OꢀDonnell in
Catalytic Asymmetric Syntheses, 2nd ed. (Ed.: I.
Ojima), Wiley-VCH, New York, 2000, chap. 10,
p. 727; c) T. Shioiri, S. Arai, In Stimulating Concepts
Scheme 2. Conversion of tertiary a-hydroxy amide 3g into the corresponding
a-hydroxy acid 4 and ester 5.
Angew. Chem. Int. Ed. 2006, 45, 3839 –3842
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3841

Communications
in Chemistry (Eds.: F. Vogtle, J. F. Stoddart, M. Shibasaki),
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[7] T. Ooi, K. Maruoka in Quaternary Stereocenters-Challenges and
Solutions for Organic Synthesis (Eds.: J. Christoffers, A. Baro),
Wiley-VCH, Weinheim, 2005, chap. 10, p. 265; for recent
excellent general reviews, see: a) C. J. Douglas, L. E. Overman,
Proc. Natl. Acad. Sci. USA 2004, 101, 5363; b) J. Christoffers, A.
Baro, Adv. Synth. Catal. 2005, 347, 1473.
[8] For
a recent impressive study on phase-transfer-catalyzed
asymmetric alkylation of a-alkoxyacetophenone derivatives,
see: a) M. B. Andrus, E. J. Hicken, J. S. Stephens, Org. Lett.
2004, 6, 2289; b) M. B. Andrus, E. J. Hicken, J. S. Stephens, D. K.
Bedke, J. Org. Chem. 2005, 70, 9470.
[9] For other powerful strategies for catalytic asymmetric synthesis
of tertiary a-hydroxycarboxylic acid derivatives, see, for exam-
ple: a) D. P. Curran, S.-B. Ko, J. Org. Chem. 1994, 59, 6139; b) Y.
Hamashima, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2000,
122, 7412; c) E. F. DiMauro, M. C. Kozlowski, J. Am. Chem. Soc.
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Shibasaki, Angew. Chem. 2003, 115, 5529; Angew. Chem. Int. Ed.
2003, 42, 5489; e) B. M. Trost, K. Dogra, M. Franzini, J. Am.
Chem. Soc. 2004, 126, 1944.
[10] For leading contributions utilizing stoichiometric amounts of
chiral sources, see: a) F. A. Davis, M. C. Weismiller, J. Org.
Chem. 1990, 55, 3715; b) S. V. Pansare, R. G. Ravi, Tetrahedron
1998, 54, 14549; c) A. Loupy, D. A. Monteux, Tetrahedron 2002,
58, 1541, and references therein.
[11] For a recent report on the preparation and synthetic utility of N-
substituted oxazolidin-2,4-diones, see: T. Kurz, K. Widyan,
Tetrahedron 2005, 61, 7247.
[12] a) T. Ooi, M. Takeuchi, M. Kameda, K. Maruoka, J. Am. Chem.
Soc. 2000, 122, 5228; b) T. Ooi, M. Kameda, K. Maruoka, J. Am.
Chem. Soc. 2003, 125, 5139; c) T. Ooi, T. Miki, M. Taniguchi, M.
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126, 9685; e) T. Ooi, S. Fujioka, K. Maruoka, J. Am. Chem. Soc.
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[13] Unfortunately, the present system was not effective for less
reactive electrophiles; for example, the attempted methylation
of 2a with methyl iodide (10 equiv) under otherwise similar
conditions afforded 3 (Ar1 = Ph, R = Me) in 45% yield with
36% ee. In addition, alkylation with alkyl halides such as ethyl
iodide and butyl iodide gave only O-alkylation product.
[14] H. Moorlag, R. M. Kellogg, M. Kloosterman, B. Kaptein, J.
Kamphuis, H. E. Schoemaker, J. Org. Chem. 1990, 55, 5878.
[15] a) S. Hanessian, Total Synthesis of Natural Products. The Chiron
Approach, Pergamon Press, New York, 1983, chap. 2; b) G. M.
Coppola, H. F. Schuster, a-Hydroxy Acids in Enantioselective
Syntheses, Wiley-VCH, Weinheim, 1997; see also Refs. [9a] and
[10c].
†
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