1,6-Addition of
â
-Ketoesters and Glycine Imine
A R T I C L E S
issues arising during the attack of a nucleophile.4 However, a
few methods based on stoichiometric, as well as catalytic,
transition metals have been developed, allowing the regiose-
lective,7 and in some cases enantioselective,8 addition of
organometallic reagents in a 1,6-fashion. Besides the coordina-
tion of a transition metal to the doubly unsaturated π-system
directing the attack to a certain position in the molecule, the
regioselectivity of the addition can also be governed by steric
factors, as it is known that δ-unsubstituted dienes tend to react
with stabilized carbanions, such as metal enolates, at their
terminal double bond.4,a,b,9
(Scheme 2), offering opportunities for further synthetic elabora-
tions leading to, e.g., carbocycles or substituted pyrrolidines.
Chart 1. Structures of Catalysts 6 Derived from
Dihydrocinchonine and 6′ Derived from Dihydrocinchonidine
Scheme 2. Organocatalytic Asymmetric 1,6-Additions
Results and Discussion
â-Ketoesters as Nucleophiles. We recently disclosed the new
phase-transfer catalysts 6 and 6′, derived from dihydrocincho-
nine and dihydrocinchonidine (Chart 1), bearing a 9-anthrace-
nylmethyl substituent at the quinuclidine nitrogen atom14 and a
1-adamantoyl group at the oxygen atom, enabling different
asymmetric transformations using cyclic tert-butyl â-ketoesters.12g,h
Their easy preparation (two steps without chromatography), their
high catalytic efficiency under mild reaction conditions, and
the synthetic versatility of the â-ketoester moiety render this
system a promising tool for the development of new routes
leading to optically active structures of use for further synthetic
elaborations.
The development of new asymmetric transformations giving
rapid access to chiral building blocks for synthetic applications
is undoubtedly of great importance in modern organic chemistry.
In this context, asymmetric organocatalysis10 and in particular
phase-transfer catalysis (PTC)11 play a fundamental role, due
to the typical operational simplicity of their procedures and the
relatively easy scalability. On these grounds, we thought it would
be of interest to investigate the possibility of an organocatalytic,
asymmetric 1,6-addition of stabilized enolates to activated
dienes. Herein, we present our efforts toward this goal which
culminated in the development of an enantioselective, phase-
transfer-catalyzed 1,6-addition of cyclic â-ketoesters 112 and the
benzophenone imine 213 derived from glycine to electron-poor
δ-unsubstituted dienes 3 (Scheme 2). This reaction, besides
expanding the applications of the principle of vinylogy in
asymmetric catalytic synthesis, gives an easy access to optically
active â-ketoesters 4 and R-amino acid derivatives 5 bearing a
double bond and an electron-withdrawing group in the side chain
Scheme 3. Representative Results for the Reaction between the
tert-Butyl â-Ketoester 1a and Diene 3a
Accordingly, to test the feasibility of an asymmetric 1,6-
addition of â-ketoesters, we tried the reaction between 1-in-
danone-derived tert-butyl â-ketoester 1a and the activated diene
3a as a single E-isomer,15 using 6 as the catalyst (Scheme 3).
At first instance, we tried the reaction under liquid-liquid phase-
transfer conditions at a temperature between +4 and -20 °C,
using different mild aqueous inorganic bases.12g,h Under these
conditions the reaction proceeded with complete regioselectivity,
(7) (a) Ganem, B. Tetrahedron Lett. 1974, 15, 4467. (b) Corey, E. J.; Kim, C.
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Canisius, J.; Mobley, T. A.; Berger, S.; Krause, N. Chem.sEur. J. 2001,
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Nishimura, T.; Yasuhara, Y.; Hayashi, T. Angew. Chem., Int. Ed. 2006,
45, 5164. (f) de la Herra´n, G.; Murcia, C.; Csa´ky¨, A. G. Org. Lett. 2005,
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references therein.
(8) (a) Hayashi, T.; Yamamoto, S.; Tokunaga, N. Angew. Chem., Int. Ed. 2005,
44, 4224. (b) Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6,
305. (c) Fillon, E.; Wilsily, A.; Liao, E.-T. Tetrahedron: Asymmetry 2006,
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(9) See, for example: (a) Kohler, E. P.; Butler, F. R. J. Am. Chem. Soc. 1926,
48, 1036. (b) Danishefsky, S.; Koppel, G.; Levine, R. Tetrahedron Lett.
1968, 9, 2257. (c) Danishefsky, S.; Hatch, W. E.; Sax, M.; Abola, E.;
Pletcher, J. J. Am. Chem. Soc. 1973, 95, 2410. (d) Pettig, D.; Scho¨llkopf,
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(10) See, e.g.: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40,
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(11) (a) O’Donnell, M. J. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: Weinheim, Germany, 2000; p 727. (b) Shioiri, T.;
Arai, S. In Stimulating Concepts in Chemistry; Vogtle, F., Stoddard, J. F.,
Shibasaki, M., Eds.; Wiley-VCH: Weinheim, Germany, 2000; p 123.
(12) For asymmetric PTC transformations of â-ketoesters, see: (a) Manabe, K.
Tetrahedron Lett. 1998, 39, 5807. (b) Manabe, K. Tetrahedron 1988, 54,
14465. (c) Dehmlov, E. V.; Du¨ttmann, S.; Neumann, B.; Stammler, H.-G.
Eur. J. Org. Chem. 2002, 2087. (d) Ooi, T.; Miki, T.; Taniguchi, M.;
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(15) Compound 3a was prepared in 39% yield by the aldol reaction between
acetone and acrolein, followed by Ac2O-promoted dehydration (see the
Supporting Information).
9
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