A R T I C L E S
Abraham et al.
use of chiral auxiliaries,12 but the need for stoichiometric
amounts of chiral materials, in addition to the limitations
associated with integration, removal, and recovery of these
groups, has led to more practical routes. These include catalytic,
asymmetric epoxidation of R,ꢀ-unsaturated amides and ketones
followed by regioselective epoxide opening,13 asymmetric
reductive coupling of alkynes and aldehydes with subsequent
oxidation,14 phase transfer catalysis,15 chiral Lewis acid cataly-
sis,16 kinetic resolution,17 and enzymatic methods.18 Other
notable examples include a recent enantioselective R-addition
of isocyanides to aldehydes19 and a rhodium carbenoid-initiated
Claisen rearrangement.20 A mild and practical catalytic, asym-
metric approach to their design is necessitated by the increasing
number of optically active intermediates and pharmaceuticals
containing R-hydroxylated carbonyl fragments.
Scheme 1. Bifunctional Approach to R-Hydroxylated Carbonyl
Derivatives
While o-benzoquinones have received much attention for their
roles in redox chemistry,21 their application in asymmetric
synthesis has been largely ignored, though recent work in our
laboratory has demonstrated that o-quinones can serve as
attractive precursors to R-hydroxy carbonyl derivatives (Scheme
1).3 In this preliminary work, we reported the first catalytic
asymmetric synthesis of R-oxygenated carbonyl derivatives
through a [4 + 2] cycloaddition intermediate using chiral ketene
enolates and o-quinones. For instance, 10 mol% BQd (2a)
catalyzed the reaction of o-chloranil (4) and isovaleryl chloride
in the presence of Hu¨nig’s base to form cycloadduct 5a (R1 )
i-Pr). Methanol was then added, and the aryl group was cleaved
with ceric ammonium nitrate (CAN) forming R-hydroxy ester
7a in 55% yield and 93% ee. While this method affords
R-hydroxy esters with excellent enantioselectivity, greater efforts
were needed to improve the yield.
A Bifunctional System. Our catalytic, asymmetric bifunctional
system for the alkylation of o-benzoquinone diimides by ketene
enolates forms products in high yield and in virtual
enantiospecificity.2a The reaction combines cinchona alkaloid
derivatives and Zn(OTf)2 as cooperative cocatalysts; preliminary
evidence is consistent with the most obvious mechanism,
namely, catalytic enolate formation by the nucleophilic cinchona
alkaloid and simultaneous Lewis acid activation of the metal-
chelating diimides (8, Figure 1). This putative metal binding
was again seen with quinone imides (9).2b
of this reaction is illustrated in the synthesis of several
pharmaceutically and optically active, R-hydroxylated targets.
Results and Discussion
In medicinal, biological, and synthetic chemistry alike, chiral
R-hydroxylated carbonyl derivatives play a ubiquitous role; they
are found in a diverse array of pharmaceuticals of which recent
examples include selective M3 type muscarinic receptor an-
tagonists for the treatment of pulmonary disorders,4 inhibitors
of amyloid-ꢀ protein,5 γ-secretase inhibitors for the treatment
of Alzheimer’s disease,6 bradykinin B1 antagonists,7 and a
number of antibiotics and anticancer agents.8 In particular,
R-hydroxyesters, ketones, and amides are present in an astonish-
ing array of natural products9 and serve as chiral building blocks
for the synthesis of complex molecules.10 They have found use
as chiral auxiliaries for enantioselective reactions as well.11
The efficient, stereocontrolled production of R-hydroxycar-
bonyl compounds has presented an enticing challenge in the
field of asymmetric synthesis. Initial methods focused on the
We began our investigation into a bifunctional system for
o-quinone alkylation by employing much the same strategys
namely by screening metal cocatalysts that we believed would
(12) (a) Enders, D.; Bhushan, V. Tetrahedron Lett. 1988, 29, 2437–2440.
(b) Davis, F.; Weismiller, M. C. J. Org. Chem. 1990, 55, 3715–3717.
(c) Yu, H. C.; Ballard, E.; Boyle, P. D.; Wang, B. Tetrahedron 2002,
58, 7663–7679.
(4) Mase, T.; et al. J. Org. Chem. 2001, 66, 6775–6786.
(5) Wallace, O. B.; Smith, D. W.; Deshpande, M. S.; Polson, C.;
Felsenstein, K. M. Bioorg. Med. Chem. Lett. 2003, 13, 1203–1206.
(6) Prasad, C. V. C.; et al.; Bioorg. Med. Chem. Lett. 2007, 17, 4006–
4011.
(13) (a) Kakei, H.; Nemoto, T.; Ohshima, T.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2004, 43, 317–320. (b) Nemoto, T.; Kakei, H.; Gnanadesikan,
V.; Tosaki, S.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2002,
124, 14544–14545.
(7) Wood, M. R.; et al.; Bioorg. Med. Chem. Lett. 2008, 18, 716–720.
(8) Guenard, D.; Gueritte-Voegelein, F.; Poiter, P. Acc. Chem. Res. 1993,
26, 160–167.
(14) (a) Cho, C.; Krische, M. J. Org. Lett. 2006, 8, 891–894. (b) Miller,
K. M.; Huang, W.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442–
3443.
(9) Recent examples include: (a) Wen, T.; Ding, Y.; Deng, Z.; Ofwegen,
L.; Proksch, P.; Lin, W. J. Nat. Prod. 2008, 71, 1133–1140. (b) Wang,
N.; Song, J.; Jang, K. H.; Lee, H.; Li, X.; Oh, K.; Shin, J. J. Nat.
Prod. 2008, 71, 551–557. (c) Ding, G.; Liu, S.; Guo, L.; Zhou, Y.;
Che, Y. J. Nat. Prod. 2008, 71, 615–618. (d) Ishiyama, H.; Okubo,
T.; Yasuda, T.; Takahashi, Y.; Iguchi, K.; Kobayashi, J. J. Nat. Prod.
2008, 71, 633–636. (e) Taori, K.; Matthew, S.; Rocca, J. R.; Paul,
V. J.; Leusch, H. J. Nat. Prod. 2007, 70, 1593–1600.
(15) Ooi, T.; Fukumoto, K.; Maruoka, K. Angew. Chem., Int. Ed. 2006,
45, 3839–3842.
(16) Christensen, C.; Juhl, K.; Hazell, R.; Jorgensen, K. A. J. Org. Chem.
2002, 67, 4875–4881.
(17) Huerta, F. F.; Santosh Laxmi, Y. R.; Backvall, J. Org. Lett. 2000, 2,
1037–1040.
(10) (a) Coppola, G. M.; Schuster, H. F. R-Hydroxy Acids in Enantiose-
lectiVe Synthesis; Wiley-VCH: Weinheim, 1997. (b) Hanessian, S.
Total Synthesis of Natural Products: The Chiron Approach; Pergamon:
New York, 1983.
(11) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R.; Olive, J. L. J. Am.
Chem. Soc. 1993, 115, 9468–9479.
(18) Zhang, W.; Wang, P. G. J. Org. Chem. 2000, 65, 4732–4735.
(19) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, 9667–9676.
(20) Wood, J. L.; Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec,
A. A.; Dietrich, H. J. Am. Chem. Soc. 1999, 121, 1748–1749.
(21) Kharisov, B. I.; Me´ndez-Rojas, M. A.; Garnovskii, A. D.; Ivakhnenko,
E. P.; Ortiz-Me´ndez, U. J. Coord. Chem. 2002, 55, 745–770.
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17086 J. AM. CHEM. SOC. VOL. 130, NO. 50, 2008