Highly regio- and enantioselective organocatalytic conjugate addition of alkyl methyl ketones TO A β-silylmethylene malonate

Article abstract of DOI:10.1021/ol900803n

(S)-N-(2-Pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid (3:1) combination catalyzed the direct addition of alkyl methyl ketones to β-dimethyl(phenyl)silylmethylene malonate at the methyl terminal with high yield and excellent regio- and enantioselectivity. The silyl group played crucial roles in regioselection and substrate reactivity.

Full text of DOI:10.1021/ol900803n

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3270-3273
Highly Regio- and Enantioselective
Organocatalytic Conjugate Addition of
Alkyl Methyl Ketones to a
ꢀ-Silylmethylene Malonate
Raghunath Chowdhury and Sunil K. Ghosh*
Bio-Organic DiVision, Bhabha Atomic Research Centre, Mumbai 400085, India
ghsunil@barc.goV.in
Received April 13, 2009
ABSTRACT
(S)-N-(2-Pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid (3:1) combination catalyzed the direct addition of alkyl methyl ketones to
ꢀ-dimethyl(phenyl)silylmethylene malonate at the methyl terminal with high yield and excellent regio- and enantioselectivity. The silyl group
played crucial roles in regioselection and substrate reactivity.
Chiral ꢀ-silyl carbonyl compounds1 are popular targets
because of their versatile nature. We are concerned for the
asymmetric synthesis of intermediates of type 1 or 2 (Figure
1) containing a silicon group2 positioned at ꢀ to both a ketone
and an ester functionality because they could be synthons3
for priVileged structures containing chiral N- and O-hetero-
cycles. Synthesis of silylated keto-ester 1 has been achieved
by asymmetric desymmetrization4 of 3-[dimethyl(phenyl)si-
lyl]glutaric anhydride followed by selective alkylation of one
of the carboxyl functionalities. Although high selectivity5 was
achieved in the desymmetrization process, it required specially
designed SuperQuat6 oxazolidinones. The desymmetrization of
anhydrides with a limited type of carbon nucleophiles7,8 has
been reported recently to produce keto esters. Enantio-/
diastereoselective conjugative silylation of unsaturated car-
bonyl compounds is also well-known.9 However, the most
suited chemical transformation that avoids additional reagents
and waste production would be an atom-economic regio- and
enantioselective conjugate addition of an alkyl methyl ketone
to the ꢀ-silyl acrylate 3 or ꢀ-silylmethylene malonate 4.10
Among the asymmetric Michael reactions developed in
the field of organocatalysis,11 direct addition of ketones or
aldehydes to R,ꢀ-unsaturated aldehydes,12 ketones,13 sul-
fones,14 and nitrostyrenes15 provided satisfactory results.
(1) Fleming, I. In Science of Synthesis; Fleming, I., Ed.; Thieme:
Stuttgart, 2002; Vol. 4, p 927.
(2) For a review on silicon-controlled stereoselective reactions, see:
Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063.
(3) For applications, see:(a) Verma, R.; Ghosh, S. K. J. Chem. Soc.,
Perkin Trans. 1 1999, 265. (b) Verma, R.; Ghosh, S. K. Chem. Commun
1997, 1601. (c) Singh, R.; Ghosh, S. K. Tetrahedron Lett. 2002, 43, 7711.
(4) Verma, R.; Mithran, S.; Ghosh, S. K. J. Chem. Soc., Perkin Trans.
1 1999, 257.
(6) Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry 1995, 6,
671.
(7) Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1057.
(8) Johnson, J. B.; Bercot, E. A.; Williams, C. M.; Rovis, T. Angew.
Chem., Int. Ed. 2007, 46, 4514, and references cited therein.
(9) For recent methodologies, see: Walter, C.; Oestreich, M. Angew.
Chem., Int. Ed. 2008, 47, 3818, and references cited therein.
(10) Date, S. M.; Singh, R.; Ghosh, S. K. Org. Biomol. Chem. 2005, 3,
3369.
(5) Chaubey, N.; Date, S. M.; Ghosh, S. K. Tetrahedron: Asymmetry
2008, 19, 2721.
10.1021/ol900803n CCC: $40.75
Published on Web 07/06/2009
 2009 American Chemical Society

lectivities, acyclic ketones gave poor results.17,20 Despite
some success of these methodologies, reaction with acyclic
nonsymmetrical ketones, especially the methyl ketones,
remains very challenging. Besides yield and enantioselec-
tivity, the regioselectivity of the addition is also an important
issue.21
Herein, we report an efficient, highly regio- and enanti-
oselective organocatalytic conjugate addition of acyclic
methyl ketones to the ꢀ-silylmethylene malonate 4 providing
the silylated keto-esters 2. The potential of this new strategy
has also been exemplified by synthesizing a known inter-
mediate for the synthesis of (+)-preussin 5,22 a pyrrolidine
natural product with interesting biological activities.
Figure 1. Structures of substrates, targets, and organocatalysts.
Initially, we chose acetone to obviate the regioselectivity
issue and concentrated our effort to optimize the yield and
enantioselectivity of the addition product 2a (Figure 1, R )
Me). The direct addition of acetone to malonate 4 using a
catalytic amount of racemic amino acids for the synthesis
of silylated ketodiester rac-2a has already been demonstrated
by us,23 as a part of our goal to develop silicon-based linkers
for solid-phase organic synthesis.24 Unfortunately, the asym-
metric version of this reaction with a few natural amino acid
catalysts in N-methylpyrrolidone (NMP) at room temperature
resulted in very poor enantioselectivity (Table 1, entries
1-3). Reaction with simple pyrrolidines derived from
proline, viz., diphenylprolinol 6a25 and its silyl ether 6b,26
was not effective for this addition (Table 1, entries 4 and
5). Pyrrolidine-based diamines derived from natural proline
such as N-(2-pyrrolidinylmethyl)pyrrolidine 6c and N-(2-
pyrrolidinylmethyl)piperidine 6d (Figure 1) are popular
organocatalysts for aldol,27 Michael,17,28 and Mannich reac-
tions.29 Moreover, they can be easily made,30 and also,
Barbas III has used such catalysts for asymmetric addition
of ketones to alkylidene malonates.17 When pyrrolidine 6c
was used under the reported conditions,17 addition of acetone
to 4 was very slow, and the desired addition product 2a was
formed in poor yield but with moderate enantioselectivity
(Table 1, entry 6). The catalytic ability of pyrrolidine 6c was
increased substantially with slight erosion of enantioselec-
tivity by changing the solvent to NMP (Table 1, entry 7).
Similarly, pyrrolidine 6d also showed moderate yield and
selectivity in NMP (Table 1, entry 8).
However, the addition of the same donors16-20 to alkylidene
malonates is less successful. Barbas III and co-workers17 for
the first time demonstrated that acetone can add to various
aryl- and alkylidene malonates under organocatalysis with
moderate yields and enantioselectivities. List et al.18 have
shown the natural proline-catalyzed direct addition of acetone
to an arylidene malonate with good yield but poor enanti-
oselectivity. Extension of this methodology to the three-
component domino reaction19 between ketones, aldehydes,
and Meldrum’s acid leading to the formation of two new
C-C σ-bonds showed almost no enantioselectivity. Very
recently, Tang et al.20 reported that N-(pyrrolidin-2-ylmeth-
yl)trifluoromethanesulfonamide catalyst gives Michael ad-
ducts in moderate to good yields and good to high enanti-
oselectivities, depending upon the substituents present on the
ketones and the arylidene malonates. Alkylmethylene mal-
onates were not good acceptors for this reaction. Although
cyclic ketones reacted with good diastereo- and enantiose-
(11) Selected reviews:(a) Dalko, P. I.; Moisan, L. Angew. Chem., Int.
Ed. 2004, 43, 5138. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
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Org. Lett., Vol. 11, No. 15, 2009
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and toluene. Although the yield was comparable in these
solvents, the enantioselectivity dropped (Table 2, entries 9
and 10). The other catalyst 6d turned out to be poor, as
revealed from the results in Table 2 (entry 11).
Table 1. Catalyst Screening for Direct Acetone Addition on
Silylmethylene Malonate 4
Table 2. Optimization of Direct Acetone Addition on
Silylmethylene Malonate 4 Using Additives
entry
catalyst
temp (°C)/time
% yielda
% eeb
1
2
3
4
5
6
7
8
(S)-Pro
(S)-Trp
(S)-Arg
6a
6b
6c
28/1 day
28/1 day
75
56
<5
<5
12
28/5 days
28/7 days
28/7 days
28/6 days
28/3.5 days
28/3.5 days
42c
trace
trace
10e
61
ndd
ndd
66
catalyst/ additive
(mol %)
% eea
entry
solvent/temp/time
(% yield)b
6c
6d
55
55
40c
1
2
3
4
5
6
7
8
9
6c/AcOH (10)
6c/PNBA (10)
6c/nil
NMP/4 °C/5 days
NMP/4 °C/5 days
84 (72)
80 (79)
80 (<5)c
a Yield of chromatographically homogeneous product. b Determined by
HPLC. c Incomplete reaction. d nd ) not determined. e Reaction was
performed in THF as reported in ref 17b.
NMP/-10 °C/7 days
NMP/-10 °C/7 days
NMP/-10 °C/7 days
NMP/-10 °C/7 days
NMP/-10 °C/7 days
NMP/-10 °C/7 days
DMF/-10 °C/7 days
Tol/-10 °C/7 days
c
6c/AcOH (10)
6c/TFA (10)
6c/TFA (5)
6c/TFA (15)
6c/TFA (30)
6c/TFA (10)
6c/TFA (10)
6d/TFA (10)
88 (<5)
90 (76)
88 (56)
88 (57)
90 (44)
84 (78)
We next attempted to improve the yield and the enanti-
oselectivity using the catalysts 6c and 6d in combination with
different additives. Many research groups have used varying
amounts of Bronstead acids as additives to accelerate the
amine-catalyzed Michael addition of aldehydes and ketones
to nitroolefins28,31 resulting in good yields and stereoselec-
tivities. Barbas III17 has suggested that these reactions
proceed through enamine intermediates32 of the carbonyl
donors. While investigating the role of acid in the formation
of enamine from carbonyl compounds, Hine33 has shown
that the process was 15 times faster with the protonated
primary amines than the free base. Therefore, the Michael
reaction of acetone with silylidene malonate 4 was next
examined with the pyrrolidine catalysts 6c and 6d in the
presence of different organic acids in NMP.
We were delighted to see that the addition of 10 mol %
of AcOH or p-nitrobenzoic acid (PNBA) and 30 mol % of
catalyst 6c at 4 °C provided the desired product 2a in good
yield (Table 2, entries 1 and 2) with a significant improve-
ment of enantioselectivity. To see the effect of temperature,
the reactions using catalyst 6c and with or without 10 mol
% of AcOH were carried out at -10 °C for 7 days. Although
this improved the enantioselectivity, the conversion was
abysmally poor (Table 2, entries 3 and 4). Interestingly,
trifluoroacetic acid (TFA) appeared to be a better additive,
and using 10 mol % of it with 30 mol % of catalyst 6c at
-10 °C for 7 days gave a decent yield of the product 2a
with excellent enantioselectivity (Table 2, entry 5). Ad-
ditional experiments with varying amounts of TFA (5-30%)
(Table 2, entires 5-8) established 10 mol % of TFA to be
optimum for the reaction. We also tried the reaction in DMF
c
10
11
82 (88)
c
NMP/-10 °C/10 days 84 (44)
a Determined by HPLC. b Yield of chromatographically homogeneous
product. c Incomplete reaction.
Next we extended the optimized protocol for the Michael
addition between 4 and methyl alkyl ketones to address the
issue of regioselectivity. It is well established28a that in the
presence of acid the prototropy of the reactive enamine is
more favorable and the equilibration between the more and
the less substituted enamine could occur. This leads to the
formation of the more stable substituted enamine on ther-
modynamic grounds. But the regiocontrol of the reaction is
often governed by Curtin-Hammett kinetics. Therefore, the
balance between Curtin-Hammett kinetics and acidity
decides the regioselectivity. Many research groups have
addressed the issue of regioselectivity during aldol34 and
Michael35 addition involving unsymmetrical ketone donors,
by tuning the acidity of the R and R′ protons with suitable
functional groups. When methyl isopropyl ketone was reacted
with silylmethylene malonate 4 under the optimized condi-
tions as described in Table 2, we obtained only one
regioisomeric product, as revealed by 1H NMR spectrum of
the crude reaction product in very high yield and with
(34) (a) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. (b)
Pan, Q.; Zou, B.; Wang, Y.; Ma, D. Org. Lett. 2004, 6, 1009. (c) Co´rdova,
A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W. Chem.
Commun. 2005, 3586. (d) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.;
Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285.
(e) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8,
4417.
(31) (a) Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed. 2008, 47, 545.
(b) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624
.
(32) For asymmetric Michael addition of preformed enamines derived
from chiral amines to nitroalkenes and alkylidene malonates, see:(a) Blarer,
S. J.; Seebach, D. Chem. Ber. 1983, 116, 2250. (b) Blarer, S. J.; Schweizer,
W. B.; Seebach, D. HelV. Chim. Acta 1982, 65, 1637.
(35) (a) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5,
2559. (b) Terakado, D.; Takano, M.; Oriyama, T. Chem. Lett. 2005, 34,
962. (c) Cao, Y. J.; Lai, Y. Y.; Wang, X.; Li, Y. J.; Xiao, W. J. Tetrahedron
Lett. 2007, 48, 21. (d) Beloi, S.; Sulzer-Mosse, S.; Kehril, S.; Alexakis, A.
Chem. Commun. 2008, 4694.
(33) Hine, J.; Chou, Y. J. Org. Chem. 1981, 46, 649.
3272
Org. Lett., Vol. 11, No. 15, 2009

excellent enantioselectivity (Table 3, entry 2). Initially it was
envisaged that the high regioselectivity might be an outcome
of the steric crowding by the isopropyl group. However, this
was discounted from the results with several other ketones,
lacking any such steric congestion. In all the cases (Table 3,
entries 3-9), only the addition product at the methyl terminal
was obtained in excellent yields and enantioselectivities.
To establish the role played by the ꢀ-silyl group, other
ꢀ-substituted methylene malonates, viz., diethyl esters of
benzylidene, 4-fluorobenzylidene, and 3-phenylpropylidene
malonates, were reacted with methyl ethyl ketone in the
presence of catalyst 6c under the optimized conditions. No
reaction36 took place indicating that the silyl substitution is
crucial for the reactivity of the methylene malonate 4 as well
as regioselectivity of the addition.
configuration of 7 to be (S) and, thus, of its progenitor 2g
also as (S). The absolute configurations of other products
2a-f and 2h-i were tentatively assigned to be (S) in analogy
with 2g.
Scheme 1. Synthesis of (+)-Preusssin 5
Table 3. Regioselctive Addition of Alkyl Methyl Ketones to
Silylmethylene Malonate 4
Considering that the reaction goes via the enamine of the
ketone, the stereochemical outcome for the formation of 2e
can be explained by a transition state assembly13e,20 depicted
in Figure 2. The malonate 4 approaches the enamine from
the less hindered si face. The hydrogen bonding interaction
of tertiary nitrogen, one of the carbonyl groups of 4, and
TFA activated the substrates by bringing them to proximity,
demonstrating that a catalytic amount of TFA can speed up
the reaction.
In conclusion, we have developed an organocatalytic
asymmetric Michael addition of alkyl methyl ketones to a
silylalkylidene malonate with high regio- and enantioselec-
tivity. This is the first successful attempt to engage unsym-
metrical methyl ketones to add via terminal carbon in such
reactions, and the silyl group is the key to this success. The
products thus obtained can easily undergo deethoxycarbo-
nylation to give a variety of ꢀ-silylated keto esters with
excellent synthetic potential. Further studies to use these
silylated ketoesters for generation of skeletal and stereo-
chemical diverse products are currently under active inves-
tigation.
entry
ketone (equiv)
MeCOMe (12)
time product (% yield)a % eeb
1
2
3
4
5
6
7
8
9
7 days
7 days
2a (76)
2b (82)
2c (82)
2d (81)
2e (85)
2f (94)
2g (88)
2h (92)
2i (78)
90.0
99.5
96.7
92.8
91.2
99.6
91.1
91.3
85.4
MeCOCHMe2 (12)
MeCOCH2CHMe2 (5) 6 days
MeCOCH2Me (12) 7 days
MeCO (CH2)2Me (12) 7 days
MeCO(CH2)4Me (5)
MeCO(CH2)8Me (5)
3 days
3 days
MeCO(CH2)6-OBn (2) 6 days
MeCOCH(OMe)2 (6) 7 days
a Yield of chromatographically homogeneous product. b Determined by
HPLC; see the Supporting Information.
The absolute configuration of 2g was assigned by convert-
ing it to a known keto ester 7, an advanced precursor3a,b of
(+)-preussin 5. For this, the diester 2g was subjected to
Krapcho deethoxycarbonylation to give the monoester 8,37
which on hydrolysis38 followed by esterification with diaz-
omethane gave the methyl ester 7 (Scheme 1). Comparison
of its optical rotation with the reported3a values established
Figure 2. Potential transition state.
Supporting Information Available: Typical experimental
(36) Reaction of diethyl 4-fluorobenzylidene malonate with methyl ethyl
ketone in the presence of catalyst 6c and TFA in NMP at 28 °C gave a
∼3:2 mixture of regioisomers with Me end addition product as the major.
See the Supporting Information for details.
1
procedure, full characterization data, and copies of H and
13C NMR. This material is available free of charge via the
Internet at http://pubs.acs.org.
(37) Enantiomeric excess of 8 was found to be 90% by HPLC analysis.
(38) Hydrolysis of ꢀ-silyl esters do not epimerize the ꢀ-C center. See
ref 3.
OL900803N
Org. Lett., Vol. 11, No. 15, 2009
3273