Asymmetric Carbon-Carbon Bond Formation in Michael Reactions: Conjugate Addition Reactions of Configurationally Stable Benzylic and Allylic Organolithium Species

Full text of DOI:10.1021/jo990383n

2996
J . Org. Chem. 1999, 64, 2996-2997
Sch em e 1
Asym m etr ic Ca r bon -Ca r bon Bon d F or m a tion
in Mich a el Rea ction s: Con ju ga te Ad d ition
Rea ction s of Con figu r a tion a lly Sta ble
Ben zylic a n d Allylic Or ga n olith iu m Sp ecies
M. D. Curtis and P. Beak*
Department of Chemistry, University of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
Received March 3, 1999
Asymmetric carbon-carbon bond formation under the
control of a chiral ligand provides a direct strategic approach
for efficient asymmetric syntheses. Enantioselective conju-
gate additions have been developed using a variety of chiral
ligands with organozincates, metalloenolates, and most
commonly mixed organocuprates.1-4 Organolithium-based
chiral ligand mediated conjugate additions, although uncom-
mon, have been reported.5-13 To the best of our knowledge
only three laboratories have reported enantioselective Michael
additions of organolithium species which provide products
with two new contiguous stereogenic centers and good
enantiomeric ratios.8-13 Koga and co-workers reported ste-
reoselective Michael additions of organolithium reagents to
cyclic R,â-unsaturated aldimines in 1989.8 More recently,
Koga reported conjugate additions of lithioenolates to alkyl-
idene diesters in the presence of a complex chiral tetraamine
ligand which affords products in high yields, with high
diastereo- and enatioselectivties.9 Seebach reported stereo-
selective conjugate additions of lithioenolates to nitro olefins
in the presence of various TADDOL chiral additives.10 We
recently reported conjugate addition reactions of configura-
tionally stable benzylic and allylic organolithium species
under the influence of (-)-sparteine to cyclic unsaturated
ketones and esters which provide 1,4-addition products with
generally high diastereomeric and enantiomeric ratios.11-13
We are interested in developing a convenient, general
methodology for conjugate additions of organolithium species
to acyclic activated olefins with control of the new stereo-
genic centers at each carbon of the newly formed bond.
We now wish to report that â-substituted doubly activated
acyclic olefins and â-substituted nitro olefins afford conjugate
addition products on reaction with enantioenriched benzylic
and allylic organolithium species in good yields, with good
diastereoselectivities and high enantioselectivities. Repre-
sentative reactions are shown for 1 and 2. Treatment of
N-Boc-N-(p-methoxyphenyl)cinnamylamine (1) with 1.1 equiv
each of n-BuLi and (-)-sparteine (5) in toluene for 1 h
provides (R)-3‚5. Addition of benzylideneacetylacetone (6),
in the presence of TMSCl, to (R)-3‚5 affords the cis enecar-
bamate (S,S)-7 in 78% yield as a single diastereomer with
an enantiomeric ratio (er) of 96:4. Employing the same
reaction protocol with N-Boc-N-(p-methoxyphenyl)benzyl-
amine (2) provides configurationally stable (R)-4‚5 which
reacts with 6 to provide diastereomerically pure (S,R)-8 in
90% yield with an er of 95:5 (Scheme 1).
(1) For reviews on conjugate addition reactions, see: Perlmutter, P.
Conjugate Addition Reactions in Organic Synthesis; Pergamon Press:
Oxford, 1992. Lee, V. J . In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, Chapter 1.2.
Leonard, J .; Diez-Barra, E. Merino, S. Eur. J . Org. Chem. 1998, 2051.
(2) For examples of stereoselective conjugate additions with organozin-
cates, see: Alexakis, A.; Vastra, J .; Manganey, P. Tetrahedron Lett. 1997,
38, 7745. Alexakis, A.; Vastra, J .; Burton, J .; Manganey, P. Tetrahedron:
Asymmetry 1997, 8, 3193. de Vries, A.; Hof, R. P.; Staal, D.; Kellogg, R. M.;
Feringa, B. L. Tetrahedron: Asymmetry 1997, 8, 1539. Feringa, B. L.;
Pineschi, M.; Arnold, L. K.; Yokoyama, H.; Hayasaka, T.; Ebihara, K. J .
Org. Chem. 1988, 53, 4149.
(3) For some examples of stereoselective conjugate additions of metal-
loenolates, see: Yamada, K.; Arai, T.; Sasai, H.; Shibasaki, M. J . Org. Chem.
1998, 63, 3666. Manickam, G.; Sandararajan, G. Tetrahedron: Asymmetry
1997, 8, 2271. Bako, P.; Kiss, T.; Take, L. Tetrahedron Lett. 1997, 38, 7259.
Arai, T.; Sasai, H.; Yamaguchi, K.; Shibasaki, M. J . Am. Chem. Soc. 1998,
120, 441. Yamaguchi, M.; Shiraishi, T.; Igarashi, Y.; Hirama, M. Tetrahedron
Lett. 1994, 35, 8223. Inagaki, K.; Noazaki, K.; Takaya, H. Synlett 1997,
119. Kumamoto, T.; Aoki, S.; Nakajima, M.; Koga, K. Tetrahedron: Asym-
metry 1994, 5, 1431.
(4) For a review on conjugate additions of organocuprates, see: Rossiter,
B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. Lipshutz, B. H.; Sengupta,
S. Org. React. 1992, 41, 135.
(5) Ooi, T.; Kondo, Y.; Maruoka, K. Angew. Chem., Int. Ed. Engl. 1997,
36, 1183.
(6) Asano, Y.; Tomioka, K. Tetrahedron Lett. 1997, 38, 8973.
(7) Fu, F.; Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J . J .; Reider, P.
J .; Tetrahedron: Asymmetry 1998, 9, 1651.
(8) Tomioka, K.; Shindo, M.; Koga, K. J . Am. Chem. Soc. 1989, 111, 8266.
(9) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1997, 38, 3531.
(10) J uaristi, E.; Beck, A. K.; Hansen, J .; Matt, T.; Mukhopadhyay, T.;
Simson, M.; Seebach, D. Synthesis 1993, 1271.
Reaction of the η3-organolithium species (R)-3‚5 with other
activated olefins provides the enecarbamates 9-13 in good
yields, with good diastereoselectivities and high enantiose-
lectivities as shown in Table 1. Addition of diethyl ethylidene-
malonate to (R)-3‚5 provides product (S,S)-9 in 93%, with a
dr of 80:20 and er’s of 98:2 and 93:7 for the major and minor
diastereomers, respectively (entry 1). A diester-activated
olefin with a phenyl ring at the â position provides (S,S)-10
with a dr of 94:6 and an er of 98:2 on reaction with (R)-3‚5
(entry 2). This methodology is also applicable to dicyano-
activated olefins (entries 3 and 4). Reaction of (R)-3‚5 with
a dinitrile trisubstituted olefin affords (S,S)-11 in 80% yield
with a dr of 66:34 and high er’s of 94:6 and 95:5 for the major
and minor diastereomers. The diastereomers can be sepa-
rated by flash chromatography, providing highly enantioen-
riched products. Contiguous enantioenriched centers, one of
which is a quaternary center, can be formed by this
methodology as shown by the formation of (S,S)-12 in 95%
yield with a dr of 80:20 and er’s of 93:7 and 88:12 for reaction
of (R)-3‚5 with the tetrasubstituted dicyano olefin. Reaction
of (R)-3‚5 with trans â-nitrostyrene gives (S,R)-13 in 71%
yield with a dr of 94:6 and an er of 96:4 (entry 5). The
reaction conditions are also compatible with an aryl bromide
as shown by reaction of (R)-3‚5 with trans-â-p-bromoni-
(11) Park, Y.-S.; Beak, P. J . Org. Chem. 1997, 62, 1574.
(12) Park, Y.-S.; Weisenburger, G. A.; Beak, P. J . Am. Chem. Soc. 1997,
119, 10537.
(13) Pippel, D. J .; Weisenburger, G. A.; Beak, P. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2522.
10.1021/jo990383n CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/03/1999

Communications
J . Org. Chem., Vol. 64, No. 9, 1999 2997
Ta ble 1. Rea ction of (R)-3‚5 w ith Activa ted Olefin s
Ta ble 2. Rea ction of (R)-4‚5 w ith Activa ted Olefin s
a
Diastereomeric ratios determined by integration of the 1H
b
NMR spectrum. Enantiomeric ratios determined by CSP HPLC.
c Enantiomeric ratio determined by CSP HPLC following hydroly-
sis and decarboxylation of 19 (see text).
a
Diastereomeric ratios determined by integration of the 1H
b
NMR spectrum. Enantiomeric ratios determined by CSP HPLC.
Sch em e 2
trostyrene to provide (S,R)-14 in 78% yield with a dr of 90:
10 and an er of 98:2 (entry 6). The absolute configurations
of 7,9-14 are assigned by analogy to that of (S,S)-10 which
was unambiguously established by X-ray crystallography of
an amide derivative.14
Reaction of (R)-4‚5 with several activated olefins provides
the conjugate addition products 15-19 in good yields, with
good to high diastereoselectivities and high enantioselec-
tivities as shown in Table 2. Addition of diethyl ethylidene-
malonate to (R)-4‚5 gives (S,R)-15 in 92% yield with a dr of
80:20 and er’s of 97:3 and 93:7 (entry 1). Reaction of diethyl
benzylidenemalonate with (R)-4‚5 provides (S,R)-16 in 72%
yield as a single diastereomer with an er of 96:4 (entry 2).
Reaction of (R)-4‚5 with the dicyano-tetrasubstituted olefin
(entry 3) provides (S,S)-17 with an enantiomerically en-
riched quaternary center in 91% yield with a dr of 92:8 and
an er of 95:5 (entry 3). Reaction of trans-â-nitrostyrene with
(R)-4‚5 gives (S,R)-18 in 90% yield with a dr of 90:10 and
an er of 97:3 (entry 4). Reaction with the mixed olefin,
R-cyanoethyl cinnamate, introduces three new contiguous
stereogenic centers on reaction with (R)-4‚5 (entry 5).
Addition to the mixed olefin by (R)-4‚5 affords (S,R)-19 in
85% yield as a 75:25 ratio of diastereomers epimeric at the
carbon bearing the nitrile and ester groups.
The er of (S,R)-19 was determined by CSP HPLC following
hydrolysis, decarboxylation, nitrogen deprotection, and cy-
clization to the stereochemically pure butyrolactam (3R,4S)-
20 in 79% yield (Scheme 2). The absolute configuration of
(3R,4S)-20 was assigned unambiguously by X-ray crystal-
lography of the brominated derivative (2R,3R,4S)-21.14 The
absolute configuration of (S,S)-17 was also determined using
the sequence described above while the absolute configura-
tions of 8, 15, 16, and 18 are assigned by analogy to (S,S)-
17 and (S,R)-19.14
The observation of inversion of configuration for the
reaction of (R)-3‚5 with diethyl benzylidenemalonate is
opposite to the conjugate addition of (R)-3‚5 to a cyclic
activated olefin.13 Inversion of configuration at (R)-4‚5 is
consistent with our previous working hypothesis.11,12
In summary, conjugate additions of the configurationally
stable organolithium species (R)-3‚5 and (R)-4‚5 to doubly
activated acyclic olefins, or nitro olefins, provide products
in good yields with high enantioselectivities at both termini
of the newly formed bond. The availability of both (R) and
(S) epimers of 3‚5 and 4‚5 through a stannylation/lithiation
sequence allows selection of the configuration on the donor
organolithium species and thus either enantiomer of the
product.15,16 Products with enantioenriched contiguous ter-
tiary/tertiary or tertiary/quaternary stereocenters can be
formed using activated tri- and tetrasubstituted olefins,
respectively. Useful transformations of these compounds can
be envisioned, with the conversion of (S,R)-19 into (2R,3R,4S)-
21 as an example. Extension of this methodology to other
substrates, complete elucidation of the stereochemical course
of the reactions, and evolution of a predictive model for the
transition structure are areas of future interest.17
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-18874) for the support of this
work.
(14) Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication numbers 115139-
115141. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB21EZ, U.K. (fax (+44)1223-336-033;
email deposit@ccdc.cam.ac.uk).
(15) Park, Y.-S.; Boys, M. L.; Beak, P. J . Am. Chem. Soc. 1996, 118, 3757.
(16) Weisenburger, G. A.; Beak, P. J . Am. Chem, Soc. 1996, 118, 12218.
(17) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y.-S.; Thayumanavan, S.
Acc. Chem. Res. 1996, 29, 552. Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986,
19, 356.
Su p p or tin g In for m a tion Ava ila ble: Details of experimental
procedures and spectroscopic and analytical data are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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