Enantioselective formal hydration of α,β-unsaturated imides by Al-catalyzed conjugate addition of oxime nucleophiles

Article abstract of DOI:10.1021/ja045563f

The (salen)Al-catalyzed asymmetric conjugate addition of salicylaldoxime to α,β-unsaturated imides is the key step in an efficient and highly enantioselective two-step formal hydration of these electron-deficient olefins. This reaction constitutes the first example of an enantioselective conjugate addition of an oxygen-centered nucleophile to α,β-unsaturated carboxylic acid derivatives. Application of this method to chiral, nonracemic substrates revealed a high level of catalyst-induced diastereoselectivity, underscoring its potential utility for polyketide natural product synthesis. Copyright

Full text of DOI:10.1021/ja045563f

Published on Web 10/26/2004
Enantioselective Formal Hydration of r,â-Unsaturated Imides by Al-Catalyzed
Conjugate Addition of Oxime Nucleophiles
Christopher D. Vanderwal† and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received July 23, 2004; E-mail: jacobsen@chemistry.harvard.edu
The conjugate addition of oxygen-centered nucleophiles to
electron-deficient olefins has proven a challenging problem in
organic synthesis. The relative weakness of O-nucleophiles, coupled
with problems associated with reaction reversibility, has hampered
the development of general methods for this transformation.1 As a
result, stereoselective variants of this reaction have been limited to
diastereoselective O-conjugate addition reactions of chiral alkoxides
to highly activated acceptors,2 intramolecular hemiacetal alkoxide
conjugate additions,3 and a single example of a catalytic asymmetric
ring-closure process involving a phenol.4 In this communication,
we describe the development of the catalytic asymmetric oxygen-
centered addition of salicylaldoxime to R,â-unsaturated imides, a
process that enables the synthesis of â-hydroxy carboxylic acid
Figure 1. (salen)Al-Catalyzed asymmetric conjugate additions to R,â-
unsaturated imides.
derivatives with high levels of enantioselectivity.5
Over the past several years, our laboratory has demonstrated the
utility of (salen)aluminum complexes (1a-c, Figure 1) as catalysts
for the highly enantioselective conjugate addition of a variety of
weakly acidic6 nucleophiles (HN3,7a HCN,7b malononitrile and
substituted cyanoacetates7c). In the hopes of using this catalyst
system to induce the conjugate addition of oxygen-centered nucleo-
philes, we sought reagents with increased acidity and nucleophilicity
relative to typical alcohols. Oximes fit both of these criteria,8 and
the oxime ethers that would result from such conjugate additions
contain a potentially labile N-O bond, enabling a reductive
cleavage to afford formal hydration products (Scheme 1).
Many readily available oximes were screened with catalysts 1b
and 1c in a variety of solvents,9 and inexpensive salicylaldoxime
(3)10 emerged as the O-centered nucleophile of choice. Under
optimized conditions, µ-oxo dimer catalyst [(R,R)-(salen)Al]2O
(1c)7c effected the addition of salicylaldoxime to a variety of R,â-
unsaturated imides (2a-f) in cyclohexane (Table 1). These additions
proceeded efficiently (g90% conversion) with excellent enantio-
selectivities (g97% ee) using 5 mol % of the dimeric catalyst.
Hydrogenolysis of the crude oxime ethers afforded the formal
hydration products 4a-f in high overall yields without erosion of
optical purity.
As highlighted in Table 1 (products 4d-f), the method is tolerant
of ester, acetal, and silyl ether functionality, allowing its potential
application as an acetate aldol alternative in polyketide natural
product synthesis (see below). Practical limitations include pro-
hibitively slow rates with substrates bearing aromatic or highly
hindered â-substituents, an apparent necessity for partial solubility
of the substrate in the alkane-based reaction media, and incompat-
ibility of functional groups reducible under the hydrogenolysis
conditions.11
Scheme 1. Approach to the Enantioselective Hydration of
R,â-Unsaturated Imides by an Asymmetric Conjugate Oxime
Addition/Hydrogenolysis Sequence
selectivity. Substrates 5, 7, and 9 were prepared in enantioenriched
form and subjected to the two-step formal hydration sequence (see
Scheme 2).
High conversions were attained in the oxime additions, with
nearly complete catalyst control. Thus, reaction of ethyl (R)-3-
hydroxybutyrate-derived 5 in the presence of (R,R)-1c led to highly
selective formation of the 1,3-anti addition product 6a, and (S,S)-
1c delivered the 1,3-syn product 6b. Analogous results were
obtained with malic acid-derived substrate 7 and Roche ester-
derived imide 9.12 All products were isolated in good yields after
hydrogenolysis of the crude oxime ethers.13 The utility of this
approach is envisioned to be greatest in complex settings when
substrate-controlled aldol reactions fail to provide acceptable levels
of stereochemical control.
The imide functionality required for achieving high enantio-
selectivity in these (salen)Al-catalyzed conjugate addition reactions7a
is converted readily into a variety of other carboxylic acid
derivatives. For example, ethanolysis of the â-hydroxy imides was
catalyzed by Er(OTf)3 with excellent regioselectivity and in high
yields;7c,14 the mild conditions were compatible with ester and acetal
functionalities such as those in the imide products derived from
4d and 4e.15 This process enabled the verification of the absolute
stereochemistry of the formal hydration products, as the ester
To assess the potential applicability of this method to the
synthesis of polyproprionate or polyacetate natural products, we
evaluated the ability of catalyst 1c to deliver stereochemically
complex products with high levels of catalyst-induced diastereo-
† Fellow of The Jane Coffin Childs Memorial Fund for Medical Research.
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10.1021/ja045563f CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Two-Step Enantioselective Synthesis of â-Hydroxy
Imides
hydrogenolysis, this (salen)aluminum-catalyzed reaction enables the
net enantioselective hydration of electron-deficient olefins with no
need for purification of the intermediate oxime ethers.
Acknowledgment. This investigation was supported by the NIH
(GM-43214) and aided by a grant from The Jane Coffin Childs
Memorial Fund for Medical Research.
Supporting Information Available: Complete experimental pro-
cedures and chiral chromatographic analyses of racemic and enantio-
merically enriched products. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For a phosphine-catalyzed addition of water and alcohols to a variety of
conjugate acceptors, see: (a) Stewart, I. C.; Bergman, R. G.; Toste, F. D.
J. Am. Chem. Soc. 2003, 125, 8696-8697. For a base-mediated addition
of alcohols to enones, see: (b) Kisanga, P. B.; Ilankumaran, P.; Fetterly,
B. M.; Verkade, J. G. J. Org. Chem. 2002, 67, 3555-3560.
(2) (a) Buchanan, D. J.; Dixon, D. J.; Hernandez-Juan, F. A. Org. Lett. 2004,
6, 1357-1360. (b) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´,
D. I. Angew. Chem., Int. Ed. 2003, 42, 4241-4244. (c) Enders, D.;
Haertwig, A.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 1998, 1771-
1792.
a
1
Conversion determined by H NMR, ee determined by chiral HPLC
(Chiralpak AD column) of the intermediate oxime ether adduct. b Isolated
yield over two steps, after chromatography, from reactions carried out on
0.5 mmol scale. c A yield of 80% was obtained for the two-step sequence
carried out on 1.08 g (3.0 mmol) scale.
(3) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446-2453.
(4) Sekino, E.; Kumamoto, T.; Tanaka, T.; Ikeda, T.; Ishikawa, T. J. Org.
Chem. 2004, 69, 2760-2767.
(5) For selected examples of an alternative two-step method for this
transformation involving asymmetric epoxidation of conjugate acceptors
followed by reduction of the R-C-O bond, see: (a) Kakei, H.; Nemoto,
T.; Ohshima, T.; Shibasaki, M. Angew. Chem., Int. Ed. 2004, 43, 317-
320 and references therein. (b) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999,
1, 1287-1290.
Scheme 2. Diastereoselective, Catalyst-Controlled, Two-Step
Hydration of Chiral, Nonracemic R,â-Unsaturated Imidesa
(6) The pKa range for nucleophiles that have demonstrated utility in these
conjugate additions is approximately 4-12.
(7) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-
8960. (b) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
4442-4443. (c) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003,
125, 11204-11205.
(8) For synthetic applications of the highly nucleophilic benzaldoximate anion,
see: (a) Leung-Toung, R.; Liu, Y.; Muchowski, J. M.; Wu, Y.-L. J. Org.
Chem. 1998, 63, 3235-3250. (b) Go´mez, V.; Pe´rez-Medrano, A,;
Muchowski, J. M. J. Org. Chem. 1994, 59, 1219-1221.
(9) Many typical organic solvents were tested, and alkane solvents proved
vastly superior with respect to reaction rate. The results with cyclohexane
and hexanes were comparable, while aromatic solvents led to much slower
reactions. Chlorinated and ethereal solvents were poor media for the oxime
addition reaction.
(10) Salicylaldoxime (o-hydroxybenzaldehyde oxime) is the least expensive
commercially available benzaldoxime derivative (Aldrich 2003-2004
catalogue: U.S. $36.10/100 g). For the results of a broad screen of oximes
for this reaction, see the Supporting Information.
(11) Substrates in which the â-substituent is aromatic, or aliphatic but much
bulkier than i-Pr, suffer from competitive 1,2-addition of the oxime to
both imide carbonyls. Highly insoluble substrates, such as those containing
carbamate- or phthalimide-protected primary amines, also proved unre-
active.
(12) To assess the intrinsic diastereofacial selectivities of these substrates, we
performed the addition reactions using an achiral variant of the (salen)Al
catalyst derived from ethylenediamine; however, this catalyst preferentially
promoted the 1,2-addition of the oxime nucleophile to the imide carbonyls.
Analysis of the crude reaction mixtures indicated that a small amount of
the desired conjugate addition products were formed in roughly equimolar
quantities with substrates 5, 7, and 9. An important feature of these
catalyst-controlled diastereoselective applications is the lack of intrinsic
facial bias of the substrates. The preparation of analogous products by
diastereoselective acetate aldol chemistry would likely be subject to
relatively high intrinsic facial selectivities that might be difficult to
override. Substrates 5, 7, and 9 were chosen to be representative of the
most typically encountered motifs in polyketide chemistry, the area for
which this method is most likely best suited.
a Reaction conditions for the two-step sequence were identical to those
outlined in Table 1. Diastereomeric ratios were determined by 1H NMR.
(13) The isolated yields of products 6, 8, and 10 correlate directly with
conversions in the oxime addition reactions (determined by 1H NMR):
6a (84%), 6b (81%), 8a (92%), 8b (92%), 10a (75%), 10b (83%).
(14) See Supporting Information for details.
derived from 4a is ethyl (S)-3-hydroxybutyrate, a commercially
available substance.14
We have developed the first catalytic asymmetric conjugate
addition of an oxygen-centered nucleophile to unsaturated carboxy-
lic acid derivatives. When combined with efficient N-O bond
(15) Attempted ethanolysis of product 4f was complicated by partial competitive
desilylation. This product could be converted to the corresponding Weinreb
amide in 88% yield. See Supporting Information for details. This useful
transformation should be applicable to the other â-hydroxy imide products.
JA045563F
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