Boron-catalyzed direct aldol reactions of pyruvic acids

Article abstract of DOI:10.1021/ol902322r

"Chemical Equation Presented" Interactions between pyruvic acids and diphenylborinic acid form the basis of an efficient, direct, boron-catalyzed aldol reaction that takes place in water at room temperature with low catalyst loadings. Both boronic and bor

Full text of DOI:10.1021/ol902322r

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5486-5489
Boron-Catalyzed Direct Aldol Reactions
of Pyruvic Acids
Doris Lee, Stephen G. Newman, and Mark S. Taylor*
Department of Chemistry, Lash Miller Laboratories, UniVersity of Toronto 80 St.
George Street, Toronto ON M5S 3H6, Canada
mtaylor@chem.utoronto.ca
Received October 7, 2009
ABSTRACT
Interactions between pyruvic acids and diphenylborinic acid form the basis of an efficient, direct, boron-catalyzed aldol reaction that takes
place in water at room temperature with low catalyst loadings. Both boronic and borinic acids function as catalysts, with the latter demonstrating
particularly high activity. A wide range of aldehydes, including enolizable species, may be employed, delivering useful isotetronic acid derivatives
in high yields.
The unique opportunities and challenges presented by water
as a reaction medium have motivated intensive research
efforts aimed at exploring chemistry in and “on” water.1
While the extent to which water constitutes a “green” solvent
for organic chemistry is dependent on numerous factors,2 it
is clear that mechanisms for rate acceleration3 and stereo-
selectivity4 in water may differ dramatically from those
operative in organic solvents. The development of catalytic,
carbon-carbon bond-forming reactions in water is an area
of particular interest,5 and progress has been achieved
through the use of metal-based species and organocatalysts.
In this paper, we demonstrate that borinic acids are
remarkably efficient catalysts for the direct aldol reaction of
pyruvic acids and aldehydes in aqueous suspension at 23
°C. Near-equimolar quantities of aldol donor and acceptor
are employed, with low catalyst loadings (as low as 0.5 mol
%); highly enolizable aldehydes such as acetaldehyde and
unbranched aliphatic aldehydes are tolerated. Underlying this
process is the stabilization of the enol tautomer of pyruvic
acids by organoboron species, a well-precedented interaction
in molecular recognition and chemical sensing that has not
previously been exploited in synthesis.
The development of “direct” aldol reactions, in which
enolates or enolate equivalents are generated in catalytic
amounts, is a major ongoing area of research. Success has
been realized through two strategies: amine-catalyzed reac-
tions proceeding through enamine intermediates;6 and pro-
cesses based on “soft” enolization with complexes of
nickel(II),7 copper(II),8 magnesium(II),9 and zinc(II).10
Although protocols based on the use of stoichiometric
quantities of boron reagents remain methods of choice for
aldol reactions used in complex molecule synthesis,11 boron-
catalyzed aldol reactions have been an elusive goal, despite
(6) Mukherjee, S.; Wang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007,
107, 5471–5569.
(1) Grieco, P. A., Ed. Organic Synthesis in Water; Blackie: London,
1998.
(7) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003,
125, 8706–8707.
(2) Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew.
Chem., Int. Ed. 2007, 46, 3798–3800.
(8) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Commun. 2000,
2211–2212.
(3) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159–164. (b) Narayan,
S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275–3279.
(9) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392–393.
(4) Lindstro¨m, U. M. Chem. ReV. 2002, 102, 2751–2772.
(5) (a) Li, C. J. Chem. ReV. 2005, 105, 3095–3165. (b) Hayashi, Y.
Angew. Chem., Int. Ed. 2006, 45, 8103–8104.
(10) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003–12004.
(11) Mahrwald, R., Ed. Modern Aldol Reactions; Wiley-VCH: Wein-
heim, Germany, 2004; Vols. 1 and 2.
10.1021/ol902322r CCC: $xxxx
Published on Web 11/11/2009
 2009 American Chemical Society

the low cost, low toxicity, and functional-group tolerance
of organoboron compounds. Kobayashi and co-workers
developed the first strategy for catalytic generation of boron
enolates, employing diphenylborinic acid to accelerate reac-
tions of silyl enol ethers.12 Recently, Whiting and co-workers
achieved the first direct, boron-catalyzed aldol reactions using
the “ate” complex of a bifunctional benzimidazolylphenyl-
boronic acid to promote aldol reactions of acetone and
hydroxyacetone with aldehydes.13 While the latter report
represents a conceptually fascinating mode of reactivity and
a significant step toward efficient boron-based catalysis of
the aldol reaction, practical limitations include the require-
ment for a large excess of aldol donor and the high catalyst
loadings used (20 mol %).
also been studied and characterized by X-ray crystallography
(Scheme 1, eq 2).16
We thus sought to determine whether catalytically generated
dioxoborolanones could engage in aldol reactions with alde-
hydes (Scheme 1, eq 3). Given that enzyme-catalyzed additions
of pyruvic acids and their derivatives to aldehydes are key steps
in carbohydrate biosynthesis and metabolism,17 acceleration of
this reaction by synthetic catalysts is worthy of study.18 Whereas
boron-carboxylate interactions have been exploited extensively
in the context of boron-catalyzed acyl transfer reactions,19 their
application in catalysis of carbon-carbon bond-forming reac-
tions is restricted to the boron-catalyzed Diels-Alder reactions
of R,ꢀ-unsaturated carboxylic acids reported recently by Hall
and co-workers.20
Screening experiments established that organoboron com-
pounds are indeed able to catalyze aldol reactions of pyruvic
acids: a variety of boronic and borinic acid derivatives
promoted the addition of phenylpyruvic acid to benzalde-
hyde, yielding isotetronic acid derivative 3a by aldol addition
and in situ lactonization (Table 1). Arylborinic acids proved
to be more efficient catalysts than arylboronic acids. Triph-
enylborane was also a competent promoter of the reaction:
we ascribe this behavior to rapid protonolysis of a C-B bond
by pyruvic acid under the reaction conditions, yielding a
borinic acid derivative.21 Brønsted acids and Lewis acidic
metal salts did not efficiently catalyze the reaction under these
conditions.22
Our strategy for the development of a boron-catalyzed
aldol reaction is based on the known reactivity of organobo-
ron compounds with pyruvic acids to furnish dioxoborol-
anones (Scheme 1). Such reactions were first observed almost
Scheme 1
.
Boron-Pyruvate Interactions as the Basis for a
Direct, Catalytic Aldol Reaction
Several electronically distinct arylborinic acids were tested
using anisaldehyde as the electrophile (entries 7-10): its
attenuated reactivity provided a more challenging testing
ground for these active catalysts. No trend in their reactivity
is evident; given the heterogeneous nature of the reaction
mixture (see below), the factors underlying catalyst activity
may be more complex than might be expected based on
simple electronic effects. Diphenylborinic acid is the optimal
catalyst, both in terms of its activity and its availability from
inexpensive 2b.
(16) Kliegel, W.; Pokriefke, J. O.; Rettig, S. J.; Trotter, J. Can. J. Chem.
2000, 78, 546–552.
a century ago and form the basis of methods for the
quantitative analysis of pyruvic acids.14 We were particularly
intrigued by the observations of Anslyn and co-workers, who
found that dioxoborolanones are rapidly generated from
amine-substituted boronic acids and pyruvic acids in aqueous
buffer at room temperature (Scheme 1, eq 1).15 The facile
formation of a stable, well-defined boron enolate in water
seemed ideally suited as the basis for a catalytic reaction.
Analogous dioxoborolanones derived from borinic acids have
(17) For a review, see: (a) Machajewski, T. D.; Wong, C.-H. Angew.
Chem. Int. Ed 2000, 39, 1352–1374. For examples, see: (b) Allen, S. T.;
Heintzelman, G. R.; Toone, E. J. J. Org. Chem. 1992, 57, 426–427. (c)
Woodhall, T.; Williams, G.; Berry, A.; Nelson, A. Angew. Chem., Int. Ed.
2005, 44, 2109–2112. (d) Serafimov, J. M.; Gillingham, D.; Kuster, A.;
Hilvert, D. J. Am. Chem. Soc. 2008, 130, 7798–7799.
(18) For aldol reactions of chiral hydrazones based on pyruvic acid,
see: (a) Enders, D.; Jegelka, U.; Du¨cker, B. Angew. Chem., Int. Ed. 1993,
32, 421–423. (b) Enders, D.; Narine, A. A. J. Org. Chem. 2008, 73, 7857–
7870. For organocatalytic aldol reactions of pyruvic acids and esters, see:
(c) Vincent, J.-M.; Margottin, C.; Berlande, M.; Cavagnat, D.; Buffeteau,
T.; Landais, Y. Chem. Commun. 2007, 4782–4784. (d) Dambruoso, P.;
Massi, A.; Dondoni, A. Org. Lett. 2005, 7, 4657–4660. For metal-catalyzed
aldol dimerization of pyruvate esters, see ref 8 and: (e) Gathergood, N.;
Juhl, K.; Poulsen, T. B.; Thordrup, K.; Jørgensen, K. A. Org. Biomol. Chem.
2004, 2, 1077–1085.
(12) (a) Mori, Y.; Manabe, K.; Kobayashi, S. Angew. Chem., Int. Ed.
2001, 40, 2815–2818. For asymmetric Mukaiyama aldol reactions using
chiral boron Lewis acids, see: (b) Furuta, K.; Maruyama, T.; Yamamoto,
H. J. Am. Chem. Soc. 1991, 113, 1041–1042. (c) Parmee, E. R.; Tempkin,
O.; Masamune, S. J. Am. Chem. Soc. 1991, 113, 9365–9366. (d) Kiyooka,
S.; Kaneko, Y.; Kume, K. Tetrahedron Lett. 1992, 33, 4927–4930.
(13) Aelvoet, K.; Batsanov, A. S.; Blatch, A. J.; Grosjean, C.; Patrick,
L. G. F.; Smethurst, C. A.; Whiting, A. Angew. Chem., Int. Ed. 2008, 47,
768–770.
(19) For a review, see: Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahe-
dron 2007, 63, 8645–8657.
(20) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed.
2008, 47, 2876–2879.
(21) NMR experiments provided support for this hypothesis. See the
Supporting Information for details. Such reactions are well-precedented:
Domaille, P. J.; Druliner, J. D.; Gosser, L. W.; Read, J. M.; Schmelzer,
E. R.; Stevens, W. R. J. Org. Chem. 1985, 50, 189–194.
(14) (a) Bo¨eseken, J.; Niks, A. Recl. TraV. Chim. Pays-Bas 1940, 59,
1062. (b) Knox, W. E.; Pitt, B. M. J. Biol. Chem. 1957, 225, 675–688.
(15) Zhu, L.; Zhong, Z.; Anslyn, E. V. J. Am. Chem. Soc. 2005, 127,
4260–4269.
(22) Catalysts tested include p-toluenesulfonic acid, benzoic acid,
magnesium(II) triflate, zinc(II) triflate, and copper(II) triflate.
Org. Lett., Vol. 11, No. 23, 2009
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Table 1. Evaluation of Organoboron Catalysts for Aldol
Reaction of Phenylpyruvic Acid and Benzaldehyde
Table 2. Scope of Diphenylborinic Acid-catalyzed Aldol
Reaction of Pyruvic Acids
catalyst
product (mol %)
yielda
(%)
entry
R
R′
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
0.5
20
5
5
5
1
5
10
5
5
5
90
70
81
82
4-MeOC6H4
4-F3CC6H4
2-thienyl
2-furyl
n-C5H11
cyclohexyl
CH3
entry
Ar
catalyst
yielda (%)
89
90b
84
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
1a
1b
1c
2a
2b
2c
2a
2d
2e
2f
19
40
8
90
83
55b, c
81 (68)d
80
9
CH(Me)Ph
10
11
12
13
4-HOC6H4 n-C5H11
2-O2NC6H4 n-C5H11
CH3
3j
3k
3l
87
89
71c, e
56c, e
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
68b
42b
22b
66b
Ph
n-C5H11
5
5
CH3
3m
a Isolated yield of pure product by recrystallization. b Isolated yield of
O-silylated isotetronic acid, purified by column chromatography. c 5 equiv
of acetaldehyde was used. d Diastereoselectivity was 4.8:1 in favor of the
syn adduct: the relative stereochemistry was elucidated by X-ray crystal-
lography. Yield in parentheses represents the isolated yield of diastereo-
merically enriched material (>20:1 dr) after recrystallization. e 3.0 equiv of
ketobutyric acid was used.
10
a Yield (0.2 mmol scale) as determined by NMR with 4,4′-di-tert-
butylbiphenyl as a quantitative internal standard. b 20 mol % of catalyst
used.
Solvent effects in the borinic acid-catalyzed aldol reaction
are dramatic. The reactions are most effective when carried
out in aqueous suspension or “on water”:3b lower reactivity
was observed when organic solvents (protic or nonprotic)
were employed.21 The addition of surfactants, or the use of
saturated sodium chloride instead of distilled water, did not
measurably accelerate the reaction. We note that the two
previously developed boron-catalyzed aldol reactions also
make use of aqueous conditions:12a,13 while a mechanistic
explanation for this feature is not apparent, it is clear that
boron catalysis offers considerable potential as a strategy
for carbon-carbon bond-forming reactions under aqueous
conditions.
and aromatic aldehydes react efficiently. While a catalyst
loading of 5 mol % was generally employed, in certain
instances as little as 0.5-1 mol % of diphenylborinic acid
was sufficient (entries 1 and 6).
The use of a chiral electrophile, 2-phenylpropionaldehyde,
resulted in moderate selectivity (4.8:1 dr) for the diastereomer
predicted by the Felkin-Anh model (entry 9). The yields
presented in Table 2 were obtained by recrystallization,with-
out resort to column chromatography: indeed, isotetronic
acids have been found to be unstable toward chroma-
tography.18a,d,e In cases where recrystallization was not
feasible, the isotetronic acids were O-silylated and isolated
by column chromatography.
Variation of both the aldehyde and pyruvic acid component
revealed that this method is useful for the preparation of a
broad range of isotetronic acid derivatives (Table 2). The
isotetronic acid motif is found in a number of bioactive
natural products, including compounds with antitumor23 and
aldose reductase inhibitory24 activities. Isotetronic acids are
also useful building blocks for the preparation of butenolide-
and polyketide-based natural products.25 Under the conditions
described here, sterically and electronically diverse aliphatic
A noteworthy aspect of the reactions described here is the
ability to use near-equimolar ratios of pyruvic acid and
aldehyde (generally 1.1 equiv of aldehyde is used), even
when the latter is prone to enolization. Selective, direct, cross-
aldol reactions of two enolizable species remains a challenge:
generally, an excess of one component (usually the ketone)
or slow addition protocols are used.26 The ability to achieve
a direct aldol reaction of acetaldehyde as an acceptor (Table
2, entry 8) illustrates the ability of the boron catalyst to
promote the selective enolization of pyruvic acids. This is a
remarkable result, given the high propensity of acetaldehyde
to serve as the aldol donor in conventional amine- or metal-
catalyzed direct aldol reactions.
(23) (a) Kiriyama, N.; Nitta, K.; Sakaguchi, Y.; Taguchi, Y.; Yamomoto,
Y. Chem. Pharm. Bull. 1977, 25, 2593–2601. (b) Suzuki, M.; Hosaka, Y.;
Matsushima, H.; Goto, T.; Kitamura, T.; Kawabe, K. Cancer Lett. 1999,
138, 121.
(24) Namiki, T.; Nishikawa, M.; Itoh, Y.; Uchida, I.; Hashimoto, M. J.
Antibiot. 1987, 40, 1400.
(25) Stork, G.; Rychnovsky, S. D. J. Am. Chem. Soc. 1987, 109, 1564–
1565.
(26) For example, see: Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 6798–6799.
5488
Org. Lett., Vol. 11, No. 23, 2009

While the catalyst system presented here mediates aldol
reactions of pyruvic acids that do not bear an aryl substituent
(Table 2, entries 12 and 13), these reactions are less broad
in scope than those involving arylpyruvic acids. This
limitation is due to efficient boron-catalyzed aldol dimer-
izations of sterically unhindered pyruvic acids (Scheme 2,
To investigate the feasibility of developing an enantiose-
lective variant of this reaction, we explored the chiral
amine-boronate receptors employed by Anslyn and co-
workers for recognition of R-hydroxy acids (Scheme 3).15
Scheme 3. Chiral Amine Boronate-Catalyzed Aldol Reaction
Scheme 2. Borinic Acid-Catalyzed Direct Homo- and
Cross-Aldol Reactions of Pyruvates
Receptor 5 alone did not catalyze the direct aldol reaction,
but its activity was restored upon adding Brønsted acids
(presumably protonation at nitrogen destabilizes a N-B bond
or an amine-stabilized B-O bond).28 While neither the yield
nor the enantioselectivity of this process are synthetically
useful, we note that receptor 5 was developed for a purpose
distinct from asymmetric catalysis, and it differs profoundly
from the diarylborinic acids that show optimal catalytic
activity for this aldol reaction.29
The ability of organoboron compounds to activate pyruvic
acids in a selective fashion under aqueous conditions has
thus enabled the development of highly efficient boron-
catalyzed direct aldol reactions. The use of water as reaction
medium, the isolation of the products by recrystallization,
and the low loadings of inexpensive catalyst all contribute
to the practicality of this method. Employing boron-based
receptors as an inspiration for new reactivity represents an
unconventional strategy for developing catalysts that operate
under aqueous conditions. Efforts to apply boron-pyruvate
and related interactions in the context of other useful
carbon-carbon bond-forming reactions, and to devise ef-
ficient chiral variants thereof, are the focus of our ongoing
research efforts.
eq 1). Pyruvic acid undergoes rapid homoaldol reaction under
these conditions, such that cross-aldol reactions with alde-
hydes do not occur in useful yields.27 The cross-aldol reaction
of phenylpyruvic acid and ethyl pyruvate is also possible
(Scheme 2, eq 2). The latter represents an interesting example
of a direct, catalytic cross-aldol reaction of two enolizable
ketone partners.
A detailed mechanistic study of this new reaction will
likely be challenging given the heterogeneous nature of the
reaction mixture. Nonetheless, 11B NMR experiments (see
the Supporting Information), as well as previously reported
results,14,15 are consistent with the facile formation of a
tetracoordinate boron species from boronic or borinic acids
and phenylpyruvic acid in a variety of solvents. This
observation suggests that dioxoborolanone intermediates
(Scheme 1) are indeed accessible under the reaction condi-
tions. Since these species are tetracoordinate at boron, closed
transition states involving activation of the aldehyde by Lewis
acidic boron, as are invoked in conventional boron-based
aldol reactions, seem unlikely. The aldol reactions shown in
Table 2 are inhibited by bases, including 2,6-di-tert-butyl-
4-methylpyridine and potassium carbonate, suggesting that
the aldehyde may be activated by acid catalysis. Computa-
tional studies aimed at addressing this issue are underway.
The lactonization step of the initially generated hydroxy
acid may be catalyzed by the borinic acid, given the extensive
precedent for borinic acid-catalyzed acyl transfer reactions
of carboxylic acids.19 Simple Brønsted acid catalysis of
related lactonizations has, however, been observed in previ-
ous studies.18c,d In any case, this lactonization step may play
a role in facilitating catalyst turnover, since the carboxylate
group is no longer available for binding to boron.
Acknowledgment. We acknowledge funding for this
research from NSERC (Discovery Grants Program, and a
graduate fellowship to D.L.), the Canadian Foundation for
Innovation, the Province of Ontario, Merck Research Labo-
ratories, and the University of Toronto.
Supporting Information Available: Complete experi-
mental procedures and characterization data; X-ray data for
3i (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL902322R
(28) Zhu, L.; Shabbir, S. H.; Gray, M.; Lynch, V. M.; Sorey, S.; Anslyn,
E. V. J. Am. Chem. Soc. 2006, 128, 1222–1232.
(27) Uncatalyzed homoaldol reaction of pyruvic acid in water is rapid,
yielding a mixture of dimer and other oligomers. Selective dimerization is
achieved by diphenylborinic acid catalysis in cyclohexane solvent.
(29) The decrease in enantiomeric excess over time may reflect changing
catalyst composition or a pathway for product racemization under these
conditions.
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