As part of a program aimed at the total synthesis of
bioactive sesquiterpenoids of the Celastraceae,7 we required
an efficient synthesis of natural (-)-(1′S,2′S)-evoninic acid
(6s). Since the only literature synthesis provides (()-evoninic
acid (6s) in ∼1.8% overall yield (six steps) from noncom-
mercially available 3-amino-pent-2-enoic acid ethyl ester and
requires preparative GC separation of dimethylevoninate
from its anti diastereoisomer (dr ) 39:61, 5s/5a),8 we decided
to explore a de novo route via conjugate addition of a
2-pyridyl metal derivative to an enoate (Scheme 1).
to enones/enoates. In particular, tolerance of substitution at
C3 of the pyridine ring and at all positions on the alkene
moiety of the Michael acceptor was of interest. Addition
reactions of 2-pyridyl cuprates, as pioneered by Nilsson, were
investigated first (Table 1).
Table 1. Conjugate Addition of 2-Pyridyl Gilman
Homocuprates to R,â-Unsaturated Substrates
Scheme 1. Envisaged Approach to the Synthesis of Evoninic
Acid 6s: Retrosynthetic Analysis
We report herein the results of these studies in which the
scope of not only 2- but also the first 4-pyridyl cuprate
conjugate additions to enones/enoates has been delineated.
An expedient asymmetric synthesis of (-)-(1′S,2′S)-evoninic
acid using this methodology is then described.
Conjugate addition of aryls to unsaturated carbonyl-con-
taining compounds is generally achieved using Rh-catalyzed
aryl boronates/stannanes (and related species),9 Cu-catalyzed
aryl zinc/Grignard reagents,10 or stoichiometric aryl lithium
cuprates.11 Given the prevalence of pyridyl rings in phar-
macologically interesting structures, we were surprised to
find no reports of either Rh- or Cu-catalyzed pyridine addi-
tions and very few reports of the use of pyridyl cuprates
(none of which involved 4-pyridyl cuprates).11,12 Of note,
however, were three reports by Nilsson in the 1980s de-
scribing the conjugate addition of Gilman homo- and het-
erocuprates of 2-bromopyridine to (E)-1-phenyl-1-buten-3-
one, (E)-5-phenyl-2,2-dimethyl-4-penten-3-one, and (E)-ethyl
cinnamate in good yields.13-15 We therefore decided to
explore the scope of 2- and also 4-pyridyl cuprate additions
b
c
a Cf. Nilsson, 82% (ref 13). dr ) 20:80, syn/anti (9cs/9ca). dr ) 23:
77, syn/anti (9es/9ea). The (Z)-isomer, methyl angelate, gave dr ) 63:37
(9es/9ea) in 14% yield.
Using the 3-unsubstituted 2-pyridyl cuprate derived from
2-bromopyridine (7a), conjugate addition proceeded smoothly
with (E)-ethyl cinnamate (8a f 9a, 80% yield, Table 1, entry
1), (E)-methyl crotonate (8b f 9b, 79% yield, Table 1, entry
2), methyl tiglate (8c f 9c, 69% yield, Table 1, entry 3),
and (E)-3-penten-2-one (8d f 9f, 80% yield, Table 1, entry
9). By contrast, of the four 2-pyridyl cuprates containing
substituents at C3 that were investigated (i.e., derived from
2-bromopyridines 7b-e), only the one with a 3-methyl group
(i.e., derived from 2-bromo-3-methylpyridine, 7b) partici-
pated in conjugate addition reactions successfully (Table 1,
entries 4, 5, 10, and 11). Thus, reactions of this cuprate with
(E)-methyl crotonate (8b, Table 1, entry 4), methyl tiglate
(8c, Table 1, entry 5), methyl angelate (Table 1, entry 5,
footnote c), (E)-3-penten-2-one (8e, Table 1, entry 10), and
(E)-crotononitrile (8e, Table 1, entry 10) gave yields of 70%,
10%, 14%, 85%, and 81%, respectively. The low yields
obtained when using methyl tiglate and angelate probably
reflect the high steric demand of these substrates. The failure
of the reactions using 3-vinyl- (7c), 3-CH(OCH2CH2O)- (7d),
and 3-methoxymethyl- (7e) substituted 2-bromopyridine-
derived cuprates, despite extensive attempted optimization
of the conditions of the reactions, probably reflects either
coordinative stabilization of these cuprates by the appendages
or, again, steric hindrance.
(6) (a) Pailer, M.; Libiseller, R. Monatsh. Chem. 1962, 93, 403. (b) Pailer,
M.; Libiseller, R. Monatsh. Chem. 1962, 93, 511.
(7) Spivey, A. C.; Woodhead, S. J.; Weston, M.; Andrews, B. I. Angew.
Chem., Int. Ed. 2001, 40, 769.
(8) Pailer, M.; Pfleger, K. Monatsh. Chem. 1976, 107, 965.
(9) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
(10) (a) Ar2Zn: Pen˜a, D.; Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A.
J.; Feringa, B. L. Chem. Commun. 2004, 1836 and references therein. (b)
ArMgX: Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J.
Am. Chem. Soc. 2004, 126, 12784 and references therein.
(11) (a) Woodward, S. Chem. Soc. ReV. 2000, 29, 393. (b) Taylor, R. J.
K.; Casy, G. Organocopper Reagents: A Practical Approach; Oxford
University Press: Oxford, U.K., 1994. (c) Kozlowski, J. A. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 4, p 169.
(12) (a) Corey, E. J.; Pyne, S. G.; Schafer, A. I. Tetrahedron Lett.
1983, 24, 3291. (b) Caprio, V.; Mann, J. J. Chem. Soc., Perkin Trans. 1
1998, 3151. (c) Sa´nchez-Sancho, F.; Herrado´n, B. Heterocycles 2003, 60,
1843.
(13) Malmberg, H.; Nilsson, M. Tetrahedron 1982, 38, 1509.
(14) Malmberg, H.; Nilsson, M. J. Organomet. Chem. 1983, 243, 241.
(15) Lindstedt, E-L.; Nilsson, M. Acta Chem. Scand. 1986, B40, 466.
892
Org. Lett., Vol. 9, No. 5, 2007