Diastereoselective cobalt-catalyzed Aldol and Michael cycloreductions

Full text of DOI:10.1021/ja0040971

5112
J. Am. Chem. Soc. 2001, 123, 5112-5113
we report the first examples of catalytic aldol and Michael
cycloreductions (eqs 1 and 2). These reactions exhibit high levels
of syn- and anti-diastereoselectivity, respectively, and are viable
for both five- and six-membered ring formations.
Diastereoselective Cobalt-Catalyzed Aldol and
Michael Cycloreductions
Tae-Gon Baik, Ana Liza Luis, Long-Cheng Wang, and
Michael J. Krische*
UniVersity of Texas at Austin
Department of Chemistry and Biochemistry
Austin, Texas 78712
ReceiVed NoVember 28, 2000
Many classes of chemical transformations exist for which
catalytic variants have not been devised or require further
development. The aldol and Michael reactions represent classical
methods of carbon-carbon bond formation that have found
extensive use in synthesis, yet the selectivity issues posed by these
transformations have been answered only in part. In the case of
the aldol reaction, the vast majority of catalytic asymmetric
variants1 involve the utilization of latent enolates, which must be
preformed. More recently, direct catalytic asymmetric aldol
condensations of unmodified aldehyde and ketone partners have
been described.2 Although a tremendous advance, current catalytic
systems for the direct aldol reaction exhibit suboptimal diastereo-
selectivity and are restricted to symmetric ketone partners or those
possessing a single set of acidic hydrogens. Methodologies for
catalytic asymmetric Michael reaction are similarly restricted to
the use of preformed enol derivatives or â-dicarbonyl nucleo-
philes.3,4
Catalytic enone hydrometallation represents a promising strat-
egy for enolate generation, circumventing the utilization of
preformed enol or enolate derivatives. Indeed, the metal-catalyzed
reductive condensation of R,â-unsaturated carbonyl compounds
with aldehydes in the presence of a hydride donor, that is, a
“reductive aldol” reaction, has been described.5 There are,
however, no accounts of analogous catalytic reductive Michael
reactions. Additionally, despite a wealth of research on catalytic
aldol and Michael processes, intramolecular transition metal-
catalyzed variants have not been forthcoming.6,7 In this account,
Catalytic aldol cycloreductions were first examined. The
intermolecular reductive aldol reaction catalyzed by Co(dpm)2
(dpm ) dipivaloylmethane), which utilizes phenylsilane as the
terminal reductant, exhibits poor diastereoselectivity.5d In the case
of an intramolecular process, the geometrical requirements for
bond formation would be more stringent, and hence, enhanced
diastereoselectivities would be anticipated. Initial attempts at aldol
cycloreduction bore out this notion. Addition of 2a to a preformed
solution containing 5 mol% Co(dpm)2 and 120 mol% of phenyl-
silane in dichloroethane at 25 °C yielded the cyclization product
2b in 87% yield with a syn:anti ratio of >99:1 as determined by
HPLC analysis (Table 1, entry 2). These conditions proved quite
general for five-, six- and seven-membered ring formation, albeit
the latter in reduced yield (Table 1, entries 1-5). The heteroaro-
matic enones 6a and 7a also underwent cycloreduction in good
yield (Table 1, entry 4). Aliphatic enone partners, however, gave
diminished yields of the corresponding cyclized products (Table
1, entry 3). In all cases, irrespective of yield, only the syn-
diastereomers of products 1b-8b were observed. The capability
of both five- and six-membered ring formations is significant, as
related Ti-catalyzed cycloreductions of enals and enones only are
viable for five-membered ring formation.8
Analogous Michael cycloreductions serve to illustrate the scope
of this process with respect to variability of the electrophilic
partner. Symmetrical bis-enones were initially examined. Upon
exposure of bis-enone 10a to similar conditions employed for
the catalytic reductive aldol cyclization process, formation of the
anticipated reductive Michael cyclization product 10b was
observed (Table 1, entry 7). Whereas products obtained from the
reductive aldol cyclization exhibited syn-stereochemistry, anti-
stereochemistry was observed exclusively for products obtained
via reductive Michael cyclization. The formation of five- and six-
membered rings occurs in good yield under these conditions
(Table 1, entries 6-12). As evidenced by ether-linked substrate
11a, heteroatoms are tolerated in the tether-connecting enones
(Table 1, entry 8). Heteroaromatic enones, including 3-indolyl
substituted bis-enone 15a and 2-furyl substituted bis-enone 14a,
underwent cycloreduction in moderate yield. Michael cyclo-
reductions of unsymmetrical bis-enones 12a and 13a reveal the
capability of the catalyst to distinguish electronic differences
between enones in the hydrometallation event. Thus, mixed bis-
enone 12a, containing phenyl- and methyl-substituents, exhibits
a preference for hydrometalation of the phenyl-substituted enone
over the methyl-substituted enone. The isomeric products 12b
and 12c are obtained in a 3:1 ratio. In contrast, mixed enone 13a,
which contains phenyl- and 2-furyl-substituted enone moieties,
yields a 1:1 mixture of isomeric products 13b and 13c. These
results suggest that higher levels of chemoselectivity may be
(1) For reviews, see: (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2000, 39, 1353. (b) Denmark, S. E.; Stavenger, R. A. Acc. Chem.
Res. 2000, 33, 432. (c) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357.
(d) Carreira, E. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. III, p 1. (e)
Braun, M. In StereoselectiVe Synthesis, Methods of Organic Chemistry
(Houben-Weyl), ed. E21; Helmchen, G., Hoffman, R., Mulzer, J., Schaumann,
E., Eds.; Thieme: Stuttgart, 1996; Vol. 3, p 1730.
(2) (a) Yoshikawa, N.; Yamada., Y. M. A.; Das, J.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 4168. (b) List, B.; Lerner, R. A.; Barbas, C.
F., III. J. Am. Chem. Soc. 2000, 122, 2395. (c) Trost, B. M.; Ito, H. J. Am.
Chem. Soc. 2000, 122, 12003. (d) Yoshikawa, N.; Kumagai, N.; Matsunaga,
S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 2466.
(3) For a review, see: Yamaguchi, M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. III, p 1121.
(4) For selected examples, see: (a) Sasai, H.; Arai, T.; Satow, Y.; Houk,
K. N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194. (b) Evans, D. A.;
Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1, 865. (c) Evans, D. A.; Rovis,
T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc. 1999, 121, 1994. (d)
Zhang, F.-U.; Corey, E. J. Org. Lett. 2001, 3, 639.
(5) (a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809. (b)
Matsuda, I.; Takahashi, K.; Sata, S. Tetrahedron Lett. 1990, 31, 5331. (c)
Kiyooka, S.; Shimizu, A.; Torii, S. Tetrahedron Lett. 1998, 39, 5237. (d)
Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 2005. (e) Taylor, S. J.; Morken,
J. P. J. Am. Chem. Soc. 1999, 121, 12202. (f) Taylor, S. J.; Duffey, M. O.;
Morken, J. P. J. Am. Chem. Soc. 2000, 122, 4528.
(6) Asymmetric aldol cyclodehydrations have been catalyzed using antibod-
ies and chiral amines: (a) List, B.; Lerner, R. A.; Barbas, C. F., III. Org.
Lett. 1999, 1, 59. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int.
Ed. Engl. 1971, 10, 496. (c) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974,
39, 1615. (d) Agami, C.; Platzer, N.; Sevestre, H. Bull. Soc. Chim. Fr. 1987,
2, 358.
(7) A radical-mediated aldol/Michael cycloreduction has been described:
Suwa, T.; Nishino, K.; Miyatake, M.; Shibata, I.; Baba, A. Tetrahedron Lett.
2000, 41, 3403.
(8) (a) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
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10.1021/ja0040971 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/03/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 5113
Table 1. Cobalt-Catalyzed Aldol and Michael Cycloreductionsa
representing a “formal” σ-bond metathesis. Mechanisms involving
σ-bond metathesis have been proposed for the related titanium-
catalyzed cycloreductions of 1,5-enones and 1,5-enals conducted
in the presence of silane.8 Although we have not yet engaged in
detailed mechanistic studies, a plausible pathway for the catalytic
aldol cycloreduction is depicted in Scheme 1. Thus, exposure of
Co(dpm)2 to phenylsilane generates hydrido-cobalt species I
which, upon hydrometallation of the enone, yields cobalt enolate
II. Subsequent addition to the appendant aldehyde, results in the
formation of cobalt-alkoxide III. σ-Bond metathesis liberates the
product to regenerate the hydrido-cobalt species I and complete
the catalytic cycle (Scheme 1, top). An analogous catalytic cycle
is postulated for the related Michael cycloreduction (Scheme 1,
bottom). Notably, the use of catalytic Co(acac)2 under these
conditions gives a complex distribution of products, suggesting
that at least one dpm ligand remains bound to the metal throughout
the catalytic cycle.
Scheme 1. Top: Postulated Mechanism for the
Cobalt-Catalyzed Aldol Cycloreduction; Bottom: Postulated
Mechanism for the Cobalt-Catalyzed Michael Cycloreduction
In summary, we have developed highly diastereoselective aldol
and Michael cycloreductions. A remarkable aspect of this
hydrometallative approach to enolate generation lies in the ability
to selectively direct the formation of ketone enolates in the
presence of aliphatic aldehydes, which are more acidic, while at
the same time circumventing competitive alkene and aldehyde
hydrosilation processes. The parallel development of both catalytic
aldol and Michael cycloreductions serves to illustrate the broad
scope of this hydrometallative approach to enolate generation.
From a practical standpoint, the catalyst precursor, Co(dpm)2 may
prepared in large scale, is easily isolated in pure form via
sublimation, and may be handled in air. Further work is in
progress to utilize this and related systems for other functional
group interconversions including the development of enantio-
selective variants of the processes described herein.
a Procedure: Co(dpm)2 (5 mol %) was added to a solution of
phenylsilane in dichloroethane (0.45 M with respect to substrate) at
room temperature. After 30 min, the substrate was added as a 0.45 M
solution in dichloroethane, and the reaction was allowed to stir at the
indicated temperature until complete.
achieved in the Michael cycloreduction of unsymmetrical bis-
enones, provided a sufficient electronic bias.
The Chalk-Harrod process is the widely accepted mechanism
for olefin hydrosilation where, after oxidative addition of the silane
to the metal, hydride-olefin insertion occurs followed by alkyl-
silicon reductive elimination to afford the product.10 For metal
diketonate complexes, it is likely that any silyl-metal species
formed via oxidative addition of silane would reductively
eliminate to give the silyl enol ether of the diketonate ligand,
Acknowledgment is made to the Robert A. Welch Foundation, the
NSF-CAREER program and donors of the Petroleum Research Fund
administered by the ACS for partial support of this research. KOSEF is
acknowledged for generous postdoctoral support of Tae-Gon Baik.
Supporting Information Available: Spectral data for all new
compounds (1H NMR, 13C NMR, IR, HRMS). This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) (a) Chalk, A. J.; Harrod, J. F. J. Am. Chem. Soc. 1965, 87, 16. (b) This
mechanism is the subject of debate: Bosnich, B. Acc. Chem. Res. 1998, 31,
667.
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