Highly enantioselective synthesis of α,α-dialkylmalonates by phase-transfer catalytic desymmetrization

Article abstract of DOI:10.1021/ja110349a

A novel enantioselective synthetic method for the construction of a quaternary carbon center from malonates via phase-transfer catalytic (PTC) alkylation has been developed. The asymmetric α-alkylation of diphenylmethyl tert-butyl α-alkylmalonates with alkylating agents under phase-transfer catalysis conditions (aq 50% KOH, toluene, 0°C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (8) as PTC catalyst afforded the corresponding α,α-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 97% ee) which could be readily converted to versatile chiral intermediates. Notably, the direct double α-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding α,α-dialkylmalonates without loss of enantioselectivity. The synthetic potential of this method has been demonstrated by the preparation of α,α-dialkylamino acid and oxindole systems.

Full text of DOI:10.1021/ja110349a

ARTICLE
pubs.acs.org/JACS
Highly Enantioselective Synthesis of r,r-Dialkylmalonates by
Phase-Transfer Catalytic Desymmetrization
Suckchang Hong,† Jihye Lee,† Minsik Kim,† Yohan Park,‡ Cheonhyoung Park,† Mi-hyun Kim,†
Sang-sup Jew,† and Hyeung-geun Park†,*
†Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea
‡College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea
S Supporting Information
b
ABSTRACT: A novel enantioselective synthetic method for
the construction of a quaternary carbon center from malonates
via phase-transfer catalytic (PTC) alkylation has been devel-
oped. The asymmetric R-alkylation of diphenylmethyl tert-
butyl R-alkylmalonates with alkylating agents under phase-
transfer catalysis conditions (aq 50% KOH, toluene, 0°C) in
the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (8)
as PTC catalyst afforded the corresponding R,R-dialkylmalo-
nates in high chemical (up to 99%) and optical yields (up to
97% ee) which could be readily converted to versatile chiral intermediates. Notably, the direct double R-alkylations of
diphenylmethyl tert-butyl malonate also provided the corresponding R,R-dialkylmalonates without loss of enantioselectivity.
The synthetic potential of this method has been demonstrated by the preparation of R,R-dialkylamino acid and oxindole systems.
’ INTRODUCTION
and poor enantioselectivities (up to 42%ee) due to the low
acidity of the second R-proton by A1,3-strain between the
N-substitutents and R-substuents (Scheme 2).8 In addition,
there are some limitations in the derivatization of the chiral
malonamide esters to various valuable chiral building blocks due
to their relatively low chemical reactivity with respect to amide
functionality and the limited chemoselectivity between amide
and ester functional groups. In this article, we report a novel
enantioselective synthesis of R,R-dialkylmalonates, one of the
most fundamental chiral building blocks, via direct R-alkylation
of malonates under phase-transfer catalytic conditions.9
Malonates are one of the most fundamental synthetic starting
materials in organic synthesis for C-C bond forma-
tion.1 Notably, chiral R,R-dialkylmalonates (1) have been quite
often employed for the construction of chiral quaternary carbon
centers of biologically active natural products and pharmaceu-
ticals. To date, chiral malonates could only be obtained by
desymmetrization of (()-R,R-dialkylmalonates or (()-R,
R-dialkylmalonic acids by enzymatic resolution via selective
hydrolysis or selective esterification, respectively.2 Although
construction of chiral quaternary carbon centers by asymmetric
R-alkylation of carbonyl systems,3 β-ketoester systems,4 and
chiral induction of the β-position to malonate by asymmetric
conjugate addition or palladium-catalyzed allylation of malonates5
have been extensively studied, the enantioselective direct
R-alkylation of malonates has not yet been reported.6
’ RESULTS AND DISCUSSION
First, we needed to design enantiotopic unsymmetrical
R-alkylmalonates as substrates for PTC R-alkylation. Since the
tert-butyl ester group has historically been essential for high
enantioselectivity in the previous enantioselective PTC R-alkyla-
tions, one of ester groups in the malonate substrate was employed
with a tert-butyl group (Scheme 3).10 For the preliminary study,
benzyl tert-butyl R-methylmalonate (10) was prepared and ex-
amined by R-benzylation under typical PTC conditions based on
previous reports. The enantioselective PTC benzylation of 10
was performed by the representative chiral phase-transfer cata-
lysts (4-9, 5-10 mol %),11 along with benzyl bromide (5.0
equiv) and 50% KOH (aq, 5.0 equiv) at 0 °C in toluene (entries
1-6 in Table 1). We thought at the beginning that the genera-
Recently, we reported a new synthetic method for chiral
R-monoalkylmalonamide esters by phase-transfer catalytic
(PTC) mono-R-alkylation of N,N-diarylmalonamide esters and
successfully proved its usefulness by applications to the synthesis
of various chiral building blocks (Scheme 1).7
Although PTC alkylation of N,N-diarylmalonamide esters
provided the corresponding monoalkylated products with high
enantioselectivity, the dialkylation for the construction of the qua-
ternary carbon center provided both low chemical yields (up to 65%)
Received: November 18, 2010
Published: March 09, 2011
r
2011 American Chemical Society
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Scheme 1. Enantioselective Phase-Transfer Catalytic Mono-R-alkylation of Malonamide Esters and Their Applications
ARTICLE
Scheme 2. Enantioselective Phase-Transfer Catalytic
R,R-Dialkylation of Malonamide Esters
Scheme 3. Phase-Transfer Catalytic R-Alkylation of
Malonates (2)
tion of chirality via the direct R-alkylation of R-methylmalonate
would be quite challenging due to the variable conformations of
the two ester groups. However, contrary to our expectation,
catalyst 8 surprisingly afforded the R-benzylated product (10c)
with 70% ee and 90% chemical yield (entry 5). Lower enantios-
electivity was observed with 9 (entry 6, 61%, 49% ee), which
previously showed excellent enantioselective efficiency com-
pared with 8 in the PTC alkylation of glycinimine esters.11f All
of the cinchona-derived catalysts (4-7) unfortunately afforded
quite lower enantioselectivities with similar chemical yields
compared to those of catalyst 8.
The unexpected promising results prompted us to optimize
the structure of malonate substrates to increase enantioselectivity.
Five additional alkyl tert-butyl R-methylmalonates (11-15) were
prepared by varying the ester alkyl groups, and their substrate
efficiencies were evaluated by PTC benzylation in the presence of
catalyst 8 (5 mol%).
As shown in Table 1 (entries 7-11), enantioselectivity values
were dramatically dependent on the alkyl ester group. 2-Biphenyl
groups (entry 7, 11, 80% ee) gave slightly higher enantioselec-
tivity compared to the benzyl group (entry 5, 70% ee), but com-
parable enantioselectivity was observed in nonaromatic cyclo-
hexyl group (entry 8, 12, 73% ee). The 9-anthracenylmethyl group
(entry 9, 13, 24% ee) exhibited quite low enantioselectivity. The
best enantioselectivity was accomplished by the diphenylmethyl
group (entry 10, 14, 95% ee). It was notable that thefluorenyl group
(entry 11, 15, 10% ee), the cyclized form of the diphenyl-
methyl group (14), showed a loss of enantioselectivity. Its planar
geometry might not be suitable for favorable binding to the PTC
catalyst 8. The variation of reaction temperature and solvent could
not significantly increase both enantioselectivity and chemical yield,
but a lower amount of catalyst 8 decreased the enantioselevtivity.
The substrate 14 was chosen for further investigation into the
scope and limitations of enantioselective PTC alkylation with
various electrophiles. The very high enantioselectivities (up to
97% ee) shown in Table 2 indicate that this reaction system is a very
efficient enantioselective synthetic method for R,R-dialkylmalonates.
Furthermore, R-phenyl- and R-fluoromalonate substrates (entry 7,
16; entry 8, 17) afforded very high enantioselectivities as well.
In addition, the successive double R-alkylations of malonate,
18, also could afford the corresponding R,R-dialkylmalonates
without loss of enantioselectivity with a high chemical yield
(Scheme 4). To the best of our knowledge, this is the first report
to accomplish enantioselective catalytic direct R-alkylation of
malonates.
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Table 1. Enantioselective PTC Alkylation of r-Methylmalonatesa
a Reactions were performed with 5.0 equiv of benzyl bromide and 5.0 equiv of 50% KOH (aq) under the given conditions. b Isolated yields.
c Enantiopurity was determined by HPLC analysis using a chiral columns. d Enantiopurity was determined via 14c transformed from 12c.
Scheme 4. Double PTC R-Alkylations of Malonate 18
tives, respectively, as exemplified in Scheme 5. Catalytic hydrogena-
tion of 14c with Pd/C-H2 followed by acid activation and
ammonolysis gave tert-butyl malonamide ester (19). The Hof-
mann rearrangement of 1912 followed by acidic hydrolysis
provided (R)-R-methylphenylalanine (90%).13 PTC benzylations
of 20 with benzyl bromide and 4-chlorobonzyl bromide afforded the
corresponding R-benzylated product 21 (93%, 95% ee) and 23 (99%,
96% ee), respectively. The reduction of 21 and 23 by Raney Ni
hydrogenation provided R,R-dialkyloxindole 22 (78%) and 24
(76%), respectively. This method can be applied to the synthesis of
Optically active R,R-dialkylmalonates (14c, 21, 23) could be
readily converted to non-natural R-amino acids and indole deriva-
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Table 2. Enantioselective Synthesis of r,r-Dialkylmalonates via PTC Alkylationa
a Reactions were performed with 5.0 equiv of benzyl bromide and 5.0 equiv of 50% KOH(aq) under the given conditions. b Isolated yields.
c Enantiopurity was determined by HPLC analysis using a chiral column (DAICEL Chiralpak ADH). d Solid KOH(5.0 equiv) was used at -20 °C.
e Absolute configuration was determined by comparison of the optical rotations of (R)-R-methylphenylalanine13 prepared by acidic hydrolysis of the
benzylated product, 14c. f Absolute configuration was tentatively assigned R from the X-ray crystal structure of 24. g Solid CsOH was used at -78 °C.
h Absolute configuration was determined by comparison of the optical rotations of (S)-methyl tert-butyl R-fluoro-R-benzylmalonate6b prepared via the
hydrogenation of the benzylated product, 17c, followed by methyl esterification with excess of diazomethane.
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Scheme 5. Application of the Enantioselective PTC Alkylations of Malonates
’ AUTHOR INFORMATION
Corresponding Author
hgpk@snu.ac.kr
’ ACKNOWLEDGMENT
This work was supported by the Midcareer Researcher Sup-
port Programs of the National Research Foundation of Korea
(2009-0078814) and the National Research Foundation (NRF)
grant funded by the Korea government (MEST) (No.
201000017).
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Figure 1. X-ray crystallographic structure of (R)-24.
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’ CONCLUSIONS
A novel enantioselective synthetic method for R,R-dialkylma-
lonates via PTC alkylation has been developed. The asymmetric
PTC R-alkylation of diphenylmethyl-tert-butyl R-alkylmalonates
afforded the corresponding R,R-dialkylmalonates in high chemi-
cal (up to 99%) and optical yields (up to 97% ee). It is notable
that the direct double R-alkylations of diphenylmethyl tert-butyl
malonate (18) also provided the corresponding R,R-dialkylma-
lonates without loss of enantioselectivity. Ournewcatalyticsystem
provides an attractive synthetic method for universal chiral building
blocks that could be readily converted to versatile chiral target
molecules involving quaternary carbon centers. Further applica-
tions are now under investigation.
’ ASSOCIATED CONTENT
S
SupportingInformation. Representative experimental pro-
b
cedures and spectroscopic characterization of all new compounds as
well as an X-ray crystallographic analysis of (R)-24. This information
is available free of charge via the Internet at http://pubs.acs.org/.
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