The highly enantioselective phase-transfer catalytic mono-alkylation of malonamic esters

Article abstract of DOI:10.1039/b821468a

The phase-transfer catalytic alkylation of N,N-dialkylmalonamic tert-butyl esters in the presence of 1 mol% of (S,S)-3,4,5-trifluorophenyl-NAS bromide afforded highly enantioselective (S)-mono-α-alkylated products (up to 96% ee), which could be readily converted into versatile chiral building blocks without loss of chirality. The Royal Society of Chemistry.

Full text of DOI:10.1039/b821468a

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
The highly enantioselective phase-transfer catalytic mono-alkylation
of malonamic estersw
Mi-hyun Kim,a Sea-hoon Choi,a Yeon-Ju Lee,a Jihye Lee,a Keepyung Nahm,b
Byeong-Seon Jeong,c Hyeung-geun Park*a and Sang-sup Jew*a
Received (in College Park, MD, USA) 1st December 2008, Accepted 17th December 2008
First published as an Advance Article on the web 14th January 2009
DOI: 10.1039/b821468a
The phase-transfer catalytic alkylation of N,N-dialkylmalo-
namic tert-butyl esters in the presence of 1 mol% of (S,S)-
3,4,5-trifluorophenyl-NAS bromide afforded highly enantioselective
(S)-mono-a-alkylated products (up to 96% ee), which could be
readily converted into versatile chiral building blocks without
loss of chirality.
enantioselective PTC benzylation of 2A was performed by
the representative chiral phase-transfer catalyst (4,7a 5,6a 6,7b
or (S,S)-3,4,5-trifluorophenyl-NAS bromide (7)7c), along with
benzyl bromide (1.2 equiv.) and 50% KOH (aq., 13.0 equiv.)
at 0 1C in toluene (entries 1–4 in Table 1).
While all of the cinchona catalysts, 4–6, afforded almost
racemic mono-a-benzylated product 3A-c with low chemical
yields, catalyst 7 showed only moderate enantioselectivity
(Table 1, entry 4), without any trace of dibenzylated product.
A steady increase in both chemical yield and enantioselectivity
was observed by gradually decreasing the reaction tempera-
ture to ꢀ40 1C (Table 1, entries 5 and 6), but ꢀ60 1C gave a
significant decreased chemical yield with a longer reaction
time, in spite of a comparable enantioselectivity (Table 1,
entry 7). To confirm that there was no partial racemization
of the benzylated product, the isolated 3A-c (62% ee) was
stirred under the same PTC conditions, except for benzyl
bromide, for a further 2 h at ꢀ40 1C. No decrease in
enantioselectivity and partial hydrolysis of the methyl ester
was observed, which is strong evidence that there was no
racemization process under PTC alkali base conditions.8
Although the construction of chiral tertiary or quaternary
carbon centers by the asymmetric a-alkylation of carbonyl
systems has been extensively studied,1 enantioselective
catalytic alkylation at the 2-position of 1,3-dicarbonyl systems
is quite challenging, and few synthetic methods have been
disclosed for the sole construction of quaternary carbon
centers.2 In particular, the enantioselective catalytic direct
mono-alkylation of 1,3-dicarbonyl systems has not been
reported to date, mainly due to their ease of racemization
under basic or acidic conditions. Chiral mono-a-alkyl malonyl
derivatives could be quite attractive targets for valuable chiral
synthetic intermediates via successful chemoselective reduc-
tions.3 In this Communication, we report the first highly
efficient enantioselective direct mono-a-alkylation of malonyl
systems using asymmetric phase-transfer catalysis (Scheme 1).
Phase-transfer catalytic (PTC) reactions are regarded as
some of the most efficient synthetic methods from the view-
point of both economical and environmental concerns.4 Since
alkaline bases under PTC conditions can readily racemize the
mono-a-alkylated products of malonic esters 1, we first needed
to design racemization-resistant malonyl substrates under such
basic conditions. To reduce the acidity of the a-hydrogens of
malonic esters 1, one of the two ester groups was converted to
an amide (i.e., malonamic esters 2).5 In addition, enolization
of mono-alkylated products 3 might be inhibited by A1,3-strain
between the N- and a-substituents, as proposed by the Evans
group.3 First of all, as a simple and representative malonamic
ester, N,N-dimethylmalonamic methyl ester (2A) was prepared
and applied to enantioselective PTC benzylation. The PTC
conditions were adopted from the previous reports.6 The
a Research Institute of Pharmaceutical Sciences and College of
Pharmacy, Seoul National University, Seoul 151-742, Korea.
E-mail: hgpk@snu.ac.kr; Fax: +82 2-872-9129;
Tel: +82 2-880-7871
b Department of Chemistry, Yeungnam University,
Gyeongsan 712-749, Korea
c College of Pharmacy, Yeungnam University, Gyeongsan 712-749,
Korea
w Electronic supplementary information (ESI) available: Experimental
procedures, full spectroscopic data for all new compounds, and copies
Scheme 1 The enantioselective catalytic mono-alkylation of malonyl
1
of H and 13C NMR spectra. See DOI: 10.1039/b821468a
derivatives under phase-transfer conditions.
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Table 1 The enantioselective PTC benzylation of malonamic esters:
screening and optimization of the substrate, catalyst and reaction
conditionsa
various alkyl halides under optimal reaction conditions
(Table 1, entry 15). The very high enantioselectivities (up to
96% ee) shown in Table 2 indicate that this reaction system is
a very efficient enantioselective synthetic method leading to
mono-a-alkylmalonamic tert-butyl esters. To the best of our
knowledge, this is the first report to accomplish the direct
mono-a-alkylation of a 1,3-dicarbonyl system under PTC
reaction conditions with very high enantioselectivities and
high chemical yields.
Entry
2
PTC (mol%) Temp./1C Time/h Yield (%)b ee (%)c
Based on the reported X-ray structure of catalyst 7,7c
a
1
2
3
4
5
6
7
8
2A 4 (10)
2A 5 (10)
2A 6 (10)
2A 7 (1)
2A 7 (1)
2A 7 (1)
2A 7 (1)
2B 7 (1)
2C 7 (1)
2D 7 (1)
2E 7 (1)
2F 7 (1)
2G 7 (1)
2H 7 (1)
2I 7 (1)
0
0
0
2
2
2
0.5
1
2
10
3
4
20
5
15
29
27
26
51
62
20
60
54
85
80
80
80
95
91
0
0
0
41
55
62
61
63
64
plausible energy-minimized complex between an E-enolate12
of 2H and catalyst 7, determined by quantum chemical
calculations,13 is shown in Fig. 1. The enolate carbonyl oxygen
of the ester is pointing at the quaternary ammonium ion of 7
and the amide moiety at the E-position is orientated outward
from the crowded pocket of 7. In the complex, the si-face of
the enolate is shielded by the 30,40,50-trifluorophenyl-substituted
naphthyl group of the catalyst, more specifically by one of the
naphthyl groups and one of the 30,40,50-trifluorophenyl groups
of the other naphthyl moiety. As a consequence, alkyl halides
approach the re-face of the enolate, affording S-isomer 3, in
accordance with the experimental results.
0
ꢀ20
ꢀ40
ꢀ60
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
9
10
11
12
13
14
15
90(S)d
75
78
87
96(S)d
95(S)d
15
24
10
12
a
Reactions were performed with 1.2 equiv. of benzyl bromide and
b
13.0 equiv. of 50% KOH(aq.) under the given conditions. Isolated
Optically active a-alkyl-N,N-diarylmalonamic tert-butyl
esters 3H and 3I could be readily converted into their corres-
ponding b-hydroxy acid, b-amino acid or b-amino alcohol
derivatives without any loss of chirality, as exemplified in
Scheme 2. Deprotection of tert-butyl ester 3H-c (96% ee) with
ZnBr2 gave the corresponding acid, 8.14 The selective amide
reduction of 8 with excess LiEt3BH, followed by methyl
esterification with excess diazomethane, provided b-hydroxy
ester 10 (96% ee).15 The reduction of 3I-c (95% ee) with
LiAlH4 also afforded N,N-bis(4-methoxyphenyl)amino alcohol
11. Removal of the two 4-methoxyphenyl (PMP) groups
with cerium(IV) ammonium nitrate (CAN),16 followed by
c
d
yields. Determined by chiral HPLC. Absolute configurations were
determined by comparison of the optical rotations of 2-benzyl-3-
hydroxypropanoic acid (9)11a or 3-N-Cbz-amino-2-benzylpropan-
1-ol (12),11b prepared from 3D-c, 3H-c or 3I-c, respectively, with
reported values. The other absolute configurations were tentatively
assigned as S from the absolute configurations of 3D-c, 3H-c or 3I-c.
To optimize the structure of the malonamic ester to increase
reaction’s enantioselectivity, eight N,N-dialkylmalonamic
esters, 2B–2I, were prepared by varying the N,N-dialkyl or
ester alkyl groups, and their efficiencies were evaluated by PTC
benzylation in the presence of catalyst 7 (1 mol%). As shown
in Table 1, entries 8–15, both the enantioselectivity and
chemical yield were dramatically increased by the introduction
of a tert-butyl ester group (Table 1, entry 10; 85% yield, 90% ee),
which is consistent with the enantioselective PTC alkylation
of the benzophenone imines of glycine esters for the synthesis
of a-amino acids.9 This result might provide evidence that,
among the two possible enolates, the ester enolate anion of 2
participates in the formation of an ionic complex with the
quaternary ammonium cation of catalyst 7, rather than the
amide enolate of 2. Both the N,N-diethyl group (Table 1, entry
11; 75% ee) and the pyrrolidine moiety (Table 1, entry 12;
78% ee) gave slightly lower enantioselectivities compared to
the N,N-dimethyl group (Table 1, entry 10; 90% ee),
but a comparable enantioselectivity was observed for the
N,N-dibenzyl group (Table 1, entry 13, 87% ee). It is notable
that the N,N-diphenyl group provided the best results
(Table 1, entry 14; 95% yield, 96% ee) and that the high
enantioselectivity was conserved with 4-methoxy substitution
of the phenyl group (Table 1, entry 15; 95% ee). We speculate
that p–p stacking interactions of the aryl groups in these
substrates with catalyst 7 might play an integral role in the
high enantioselectivities.10
Table 2 Preliminary scope of the PTC mono-alkylation of 2Ia
Entry RX
Time/h Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
CH3Id
CH2QCHCH2Br
C6H5CH2Br
4-F–C6H5CH2Br
4-Me–C6H5CH2Br
4-MeO–C6H5CH2Br
4-NO2–C6H5CH2Br
24
42
22
6
17
20
19
70
82
91
92
90
90
90
85
80 (S)
90 (S)
95 (S)e
96 (S)
92 (S)
94 (S)
93 (S)
94 (S)
2-(Bromomethyl)naphthalene 24
a
The reaction conditions were the same as in Table 1, except for the
b
c
alkylating agents. Isolated yields. The enantiomeric purity was
determined by HPLC analysis of the corresponding alkylated malo-
namic esters 3I on chiral columns (column information is summarized
d
in the ESI) with hexanes/2-propanol as the eluent. 5.0 equiv. of
e
CsOH(s) were used. The absolute configuration was determined by
comparison of the optical rotation of 3-N-Cbz-amino-2-benzylpropa-
nol (12),11b prepared from 3I-c, with the reported value. The other
absolute configurations were tentatively assigned as S from the
absolute configurations of 3D-c, 3H-c and 3I-c.
Substrate 2I was chosen for further investigations of the
scope and limitations of enantioselective PTC alkylations with
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2 (a) K. Tomioka, K. Ando, Y. Takemasa and K. Koga, J. Am.
Chem. Soc., 1984, 106, 2718; (b) B. M. Trost, R. Radinov and
E. M. Grenzer, J. Am. Chem. Soc., 1997, 119, 7879; (c) T. Ooi,
T. Miki, M. Taniguchi, M. Shiraishi, M. Takeuchi and
K. Maruoka, Angew. Chem., Int. Ed., 2003, 42, 3796;
(d) Z.-L. Wu and Z.-Y. Li, J. Org. Chem., 2003, 68, 2479;
(e) T. B. Poulsen, L. Bernardi, J. Aleman, J. Overgaard and
K. A. Jørgensen, J. Am. Chem. Soc., 2007, 129, 441.
3 The synthesis of mono-a-alkyl 1,3-dicarbonyl synthons via the
acylation of a chiral oxazoline imide enolate was reported by the
Evans group: D. A. Evans, M. D. Ennis, T. Le, N. Mandel and
G. Mandel, J. Am. Chem. Soc., 1984, 106, 1154.
4 For recent reviews on phase-transfer catalysis, see: (a) T. Ooi and
K. Maruoka, Chem. Rev., 2003, 103, 3013; (b) M. J. O’Donnell,
Acc. Chem. Res., 2004, 37, 506; (c) B. Lygo, Acc. Chem. Res., 2004,
37, 518; (d) T. Ooi and K. Maruoka, Angew. Chem., Int. Ed., 2007,
46, 4222; (e) T. Hashimoto and K. Maruoka, Chem. Rev., 2007,
107, 5656.
Fig. 1 A quantum chemical calculation-based stereoscopic view of a
plausible complex between an E-enolate of 2H and catalyst 7 in an
asymmetric PTC alkylation reaction.
5 When ethyl acetoactetate (pKa = 14.2) is transformed into N,N-
dimethyl acetoacetamide (pKa = 18.2), the pKa of its methylene
protons increases by ca. 4: (a) F. G. Bordwell, Acc. Chem. Res.,
1988, 21, 456; (b) F. G. Bordwell and H. E. Fried, J. Org. Chem.,
1991, 56, 4218.
6 (a) H.-g. Park, B.-S. Jeong, M.-S. Yoo, J.-H. Lee, M.-K. Park,
Y.-J. Lee, M.-J. Kim and S.-s. Jew, Angew. Chem., Int. Ed., 2002,
41, 3036; (b) S.-s. Jew, Y.-J. Lee, J. Lee, M. J. Kang, B.-S. Jeong,
J.-H. Lee, M.-S. Yoo, M.-J. Kim, S.-h. Choi, J.-M. Ku and
H.-g. Park, Angew. Chem., Int. Ed., 2004, 43, 2382.
7 (a) E. J. Corey, F. Xu and M. C. Noe, J. Am. Chem. Soc., 1997,
119, 12414; (b) S.-s. Jew, M.-S. Yoo, B.-S. Jeong and H.-g. Park,
Org. Lett., 2002, 4, 4245; (c) T. Ooi, M. Kameda and K. Maruoka,
J. Am. Chem. Soc., 2003, 125, 5139.
8 The lack of racemization was also confirmed by a deuterium
exchange experiment with alkylated product 3D-c, in which no
detectable H–D exchange with 50% KOD in D2O–toluene(ꢀ40 1C,
2 h) was observed.
Scheme 2 The conversion of a-alkyl-N,N-diarylmalonamic tert-butyl
esters 3H and 3I into versatile chiral building blocks.
protection of the resulting primary amine with benzyl chloro-
formate, gave N-Cbz-amino alcohol 1211b (95% ee), which
could be further transformed into the corresponding b-amino
acid by a previously reported oxidation method.17
9 M. J. O’Donnell, W. D. Bennett and S. Wu, J. Am. Chem. Soc.,
1989, 111, 2353.
10 (a) Y.-J. Lee, J. Lee, M.-J. Kim, T.-S. Kim, H.-g. Park and
S.-s. Jew, Org. Lett., 2005, 7, 1557; (b) Y.-J. Lee, J. Lee,
M.-J. Kim, B.-S. Jeong, J.-H. Lee, T.-S. Kim, J. Lee, J.-M. Ku,
S.-s. Jew and H.-g. Park, Org. Lett., 2005, 7, 3207.
11 (a) D. H. Kim, J.-i. Park, S. J. Chung, J. D. Park, N.-K. Park and
J. H. Han, Bioorg. Med. Chem., 2002, 10, 2553; (b) L. Banfi,
G. Guanti and R. Riva, Tetrahedron: Asymmetry, 1999, 10, 3571.
12 The structure of the E-enolate of 2H:
In summary, a highly efficient enantioselective catalytic
a-mono-alkylation of a malonamic ester system has been
developed. The asymmetric PTC alkylation of N,N-diaryl-
malonamic tert-butyl esters afforded the corresponding
a-mono-alkylated products in high chemical and optical
yields, which could then be readily converted to versatile chiral
intermediates, such as a-alkyl-b-hydroxy acids, a-alkyl-b-
amino alcohols and a-alkyl-b-amino acids. The high enantio-
selectivity and mild reaction conditions could make this
method very useful for the synthesis of valuable chiral building
blocks. Further investigations and applications are now under
investigation.
This work was supported by a grant (E00257) from the
Korea Research Foundation (2005).
13 Calculations were performed using GAUSSIAN03. The complex
of an E-enolate of 2H and catalyst 7 was energy-minimized at
RHF/3-21G and UFF, respectively, except selected atoms of the
enolate (ester COO, amide CON, a-carbon and a-hydrogen),
which were calculated at the B3LYP/6-31+G(d) level (ONIOM).
14 (a) G. A. Hall, J. Am. Chem. Soc., 1950, 72, 4709; (b) R. Kaul,
Y. Brouillette, Z. Sajjadi, K. A. Hansford and W. D. Lubell,
J. Org. Chem., 2004, 69, 6131.
15 Anhydrous conditions are critical for the conservation of chirality.
16 L. E. Overman, C. E. Owen, M. M. Pavan and C. J. Richards, Org.
Lett., 2003, 5, 1809.
17 (a) R. A. Barrow, T. Hemscheidt, J. Liang, S. Paik, R. E. Moore
and M. A. Tius, J. Am. Chem. Soc., 1995, 117, 2479; (b) Y. Chi and
S. H. Gellman, J. Am. Chem. Soc., 2006, 128, 6804.
Notes and references
1 For reviews, see: (a) D. A. Evans, in Asymmetric Synthesis, ed.
J. D. Morrison, Academic Press, New York, 1983, vol. 3, ch. 1,
pp. 83–110; (b) A. I. Meyers, in Asymmetric Synthesis, ed.
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pp. 213–274; (c) T. Hayashi, in Catalytic Asymmetric Synthesis, ed.
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127, 62.
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784 | Chem. Commun., 2009, 782–784