An exceptionally mild catalytic thioester aldol reaction inspired by polyketide biosynthesis

Article abstract of DOI:10.1021/ja029452x

This report details our discovery of a new catalytic ester aldol reaction using malonic acid half thioesters (MAHTs) that directly affords β-hydroxythioesters. The reaction is catalyzed by combination of a Cu(II) salt and an amine base, and it can be perf

Full text of DOI:10.1021/ja029452x

Published on Web 02/14/2003
An Exceptionally Mild Catalytic Thioester Aldol Reaction Inspired by
Polyketide Biosynthesis
Gojko Lalic, Allen D. Aloise, and Matthew D. Shair*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received November 22, 2002 ; E-mail: shair@chemistry.harvard.edu
Table 1. Catalytic Thioester Aldol Reaction
The primary carbon-carbon bond-forming reaction in the
biosynthesis of polyketides and fatty acids is a decarboxylative
Claisen condensation with malonic acid half thioesters (1) (MAHTs)
as ester enolate equivalents (Scheme 1, eq 1).1 Nature uses
enzymatic activation of a MAHT to selectively generate a thioester
enolate, or its equivalent, in the presence of another thioester,
achieving a selective cross-Claisen condensation. The mild and
selective activation of MAHTs in nature has inspired us to explore
their use in metal-catalyzed decarboxylative aldol reactions (Scheme
1, eq 2).2 This report details our discovery of a catalytic ester aldol
reaction using MAHTs that directly affords â-hydroxythioesters.
The reaction does not require in situ aldolate functionalization or
excess nucleophile, common strategies in catalytic aldol reactions.3-5
The reaction is catalyzed by combination of a Cu(II) salt and an
amine base, and can be performed under exceptionally mild
conditions (23 °C, open to the air, wet solvent6).
Scheme 1. Claisen Condensation Step of Polyketide Biosynthesis
(eq 1) Inspired a Catalytic Ester Aldol Reaction (eq 2)a
a Conditions: 2 (1 equiv), aldehyde (1 equiv), Cu(2-ethylhexanoate)2
a ACP ) acyl carrier protein; KS ) ketosynthase.
(0.2 equiv), 5-methoxybenzimidazole (0.22 equiv), wet THF, 23 °C, open
reaction vessel. b Aldehyde used as 50% w/w mixture in H2O. c 1:1 ratio
of diastereoisomers. d From entry 1 aldol product, as a demonstration of
two iterations. 1.3:1 ratio of diastereoisomers.
Our first attempts to catalyze a decarboxylative aldol reaction
(Scheme 1, eq 2), based on the conditions developed for Claisen
condensations using either preformed Mg(II) salts7 of MAHTs or
MAHTs and Mg(OAc)2/imidazole,8 were unsuccessful. These
results prompted us to screen other metal salts including Ni(II),
Zn(II), Cu(II), and Cu(I) in combination with amine bases. The
first successful decarboxylative aldol reaction, albeit stoichiometric,
was observed with a combination of Cu(OAc)2 and imidazole.
Catalyst turnover was achieved by replacing imidazole with
benzimidazole bases. The best results were obtained using Cu(2-
ethylhexanoate)2 as the copper source and 5-methoxybenzimidazole
as the amine base. When a 1:1 mixture of 29 and dihydrocinna-
maldehyde in wet THF was treated with 20 mol % Cu(2-
ethylhexanoate)2 and 22 mol % 5-methoxybenzimidazole, the aldol
adduct was obtained in 82% yield (Table 1, entry 1). Catalyst
loading can be lowered to 5 mol % Cu(2-ethylhexanoate)2 and 5.5
mol % 5-methoxybenzimidazole affording a 75% yield of the aldol
adduct. However, with lower catalyst loadings, 3 equiv of aldehyde
must be used to maintain acceptable yields. All other metals tested
were significantly less efficient than Cu(II) in catalyzing this
reaction.
Remarkably, the metal-catalyzed aldol reaction is performed open
to the air, at 23 °C, with reagents added in any order, and in wet
THF.10,11 Furthermore, the reaction can be run in an open vial, using
acetone or EtOAc from a laboratory wash bottle as solvent. The
mildness of the reaction is demonstrated by the use of aliphatic,
enolizable aldehydes (Table 1, entries 1, 6, and 9) which are
typically poor substrates in catalytic aldol reactions that do not use
pre-enolized nucleophiles (enolsilanes).12 The products of aldehyde
self-condensation have not been observed in any of the reactions,
demonstrating the mildness and selectivity of MAHTs activation
under the Cu(II)/benzimidazole conditions. The reaction can even
be performed with tetrahydrofuran-3-carboxaldehyde (entry 5) that
is supplied as a 50% w/w solution in water. While only a modest
yield of aldol product was obtained with benzaldehyde (entry 7),
activated 3-nitrobenzaldehyde afforded the aldol adduct in 82%
yield (entry 8). More reactive aldehydes, such as ethyl glyoxylate,
performed well, yielding the aldol product in 97% yield (entry 3).
Malonic acid half oxyesters, when used instead of MAHTs, do not
participate in the catalytic aldol reaction.
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J. AM. CHEM. SOC. 2003, 125, 2852-2853
10.1021/ja029452x CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
able, obviating the need for aldolate functionalization or excess
reagent to drive the reaction to completion.
Acknowledgment. We gratefully acknowledge Bristol-Myers
Squibb, Novartis, Eli Lilly, Merck, the Alfred P. Sloan Foundation,
Glaxo Smith Kline, and the Arthur C. Cope Fund for support and
Mr. Greg Korbel for his contributions.
Supporting Information Available: Experimental procedures and
product characterization (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
a Conditions: (a) 3 (1 equiv), 4 (2 equiv), Cu(2-ethylhexanoate)2 (0.2
equiv), 5-methoxybenzimidazole (0.2 equiv), wet THF, 23 °C, open reaction
vessel. (b) 3 (1.5 equiv), 6 (1 equiv), Cu(2-ethylhexanoate)2 (0.2 equiv),
5-methoxybenzimidazole (0.2 equiv), wet THF, 23 °C, open reaction vessel.
References
(1) Recent review: Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18,
380.
(2) (a) Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem.
2002, 67, 4615. (b) Nokami, J.; Mandai, T.; Watanabe, H.; Ohyama, H.;
Tsuji, J. J. Am. Chem. Soc. 1989, 111, 4126. (c) Tanaka, M.; Oota, O.;
Hiramatsu, H.; Fujiwara, K. Bull. Chem. Soc. Jpn. 1988, 61, 2473.
(3) General reviews on the catalytic aldol reaction: (a) Carreira, E. M. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; 1999; Vol. 3, p 997. (b) Nelson, S. G. Tetrahedron:
Asymmetry 1998, 9, 357.
(4) Catalytic enantioselective and diastereoselective non-Mukaiyama ester
aldol reactions: (a) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem.
Soc. 1986, 108, 6405. (b) Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am.
Chem. Soc. 1999, 121, 9742. (c) Taylor, S. J.; Duffey, M. O.; Morken, J.
P. J. Am. Chem. Soc. 2000, 122, 4528. (d) Evans, D. A.; Tedrow, J. S.;
Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392.
(5) Recent examples of â-hydroxyketones and â-hydroxyaldehydes as products
of direct aldol reactions: (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc.
2000, 122, 12003. (b) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am.
Chem. Soc. 2000, 122, 2395. (c) Yoshikawa, N.; Yamada, Y. M. A.; Das,
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Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
6798.
To evaluate the diastereoselectivity of this reaction, methylma-
lonic acid half thioester (3) and dihydrocinnamaldehyde (4) were
treated with our standard catalyst combination at 23 °C, in wet
THF, and open to the air. Aldol product 5 was isolated in 52%
yield and as a 7:1 syn/anti mixture of diastereoisomers (Scheme
2). The same thioester in a reaction with ethyl glyoxylate (6)
afforded aldol 7 in 82% yield and as a 8:1 syn/anti mixture of
diastereoisomers. A 3:1 anti/syn ratio of propionate aldol diaster-
eoisomers was not altered upon exposure to the reaction conditions,
indicating that the selectivity for the syn product is not the result
of equilibration of the aldol adducts.
Preliminary experiments have been performed to elucidate the
mechanism of this reaction. If all reagents are mixed together with
the exception of an aldehyde, decarboxylation13,14 is not observed,
suggesting that a Cu(II) thioacetate enolate is not generated. In
addition, gem-dimethylmalonic acid half thioesters do not participate
in the catalytic aldol reaction. Although by no means conclusive,
this result suggests that enolization of the MAHT may be required
for the reaction to proceed. Exposure of aldol product (Table 1,
entry 1) to Cu(2-ethylhexanoate)2, 5-methoxybenzimidazole, and
cyclohexane carboxaldehyde did not afford any detectable crossover
product, indicating that under the reaction conditions a retro-aldol
reaction is not operative.15
(6) Wet solvent refers to solvent that was handled without protection from
the air. In some examples, up to 20:1 THF/H2O is tolerated.
(7) (a) Ireland, R. E.; Marshall, J. A. J. Am. Chem. Soc. 1959, 81, 2907. (b)
Brooks, D. W.; Lu, L. D. L.; Masamune, S. Angew. Chem. Int. Ed. Engl.
1979, 18, 72. (c) Scott, A. I.; Wiesner, C. J.; Yoo, S.; Chung, S. K. J.
Am. Chem. Soc. 1975, 97, 6277.
(8) (a) Kobuke, Y.; Yoshida, J. Tetrahedron Lett. 1978, 19, 367. (b) Sakai,
N.; Sorde, N.; Matile, S. Molecules 2001, 6, 845.
(9) (2) was prepared in one step from malonic acid and benzyl mercaptan by
following the procedure in Imamoto, T.; Masahito, K.; Yokoyama, M.
Bull. Chem. Soc. Jpn. 1982, 55, 2303.
(10) The same results were obtained when the reactions were performed under
an atmosphere of argon with rigorous exclusion of water.
The use of substrates, such as ATP, that are thermodynamically
unstable (relatively high ∆Gf°) and kinetically stable (relatively
high ∆G°q) is often encountered in biochemistry.16 Another example
is MAHTs, used in the Claisen condensation step of polyketide
biosynthesis. The energy released upon loss of CO2, in part
responsible for the thermodynamic instability of MAHTs, provides
a driving force for the Claisen condensation. Their kinetic stability
makes enzymatic activation a necessity. In borrowing MAHTs from
nature for our Cu(II)/amine-catalyzed aldol reaction, we are
inheriting thermodynamic and kinetic properties that are useful in
laboratory reactions. The kinetic stability of MAHTs17 allows these
ester enolate equivalents to be compatible with water and air. Their
thermodynamic instability renders this reaction energetically favor-
(11) For a recent review on stereoselective reactions, including aldol, in the
presence of water, see: Lindstrom, U. M. Chem. ReV. 2002, 102, 2751.
(12) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573.
(13) For metal-catalyzed decarboxylation of malonic acids and malonic acid
half oxyesters, see: (a) Toussaint, O.; Capdevielle, P.; Maumy, M.
Synthesis 1986, 12, 1029. (b) Darensbourg, D. J.; Holtcamp, M. W.;
Khandelwal, B.; Reibenspies, J. H. Inorg. Chem. 1994, 33, 531.
(14) For an alternative role of metal salts in decarboxylation of malonic acids
and malonic acid half oxyesters, see: Brunner, H.; Muller, J.; Spitzer, J.
Monatsh. Chem. 1996, 127, 845.
(15) For
a detailed description of this experiment, see the Supporting
Information.
(16) For a discussion of thermodynamic and kinetic properties of ATP and its
role in biology, see: Westheimer, F. H. Science 1987, 235, 1173.
(17) MAHTs 2 and 3 can be stored in an open vial at room temperature for
months without decomposition.
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