Kinetic resolution of racemic lactones by conjugate additions of allylic organolithium species: Direct formation of three contiguous centers with high diastereo- and enantioselectivities

Article abstract of DOI:10.1021/ol0263898

(Matrix presented) Kinetic resolution of racemic α,β-unsaturated lactones by the organolithium species produced from asymmetric lithiation of N-Boc-N-(p-methoxyphenyl)cinnamylamine provides conjugate addition products with three contiguous stereogenic centers in yields of 62-77% with diastereomeric ratios from 75:25 to >99:1 and enantiomeric ratios for the major diastereomers from 94:6 to 98:2.

Full text of DOI:10.1021/ol0263898

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2657-2660
Kinetic Resolution of Racemic Lactones
by Conjugate Additions of Allylic
Organolithium Species: Direct
Formation of Three Contiguous Centers
with High Diastereo- and
Enantioselectivities
Sung H. Lim and Peter Beak*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
beak@scs.uiuc.edu
Received June 19, 2002
ABSTRACT
Kinetic resolution of racemic r,â-unsaturated lactones by the organolithium species produced from asymmetric lithiation of N-Boc-N-(p-
methoxyphenyl)cinnamylamine provides conjugate addition products with three contiguous stereogenic centers in yields of 62−77% with
diastereomeric ratios from 75:25 to >99:1 and enantiomeric ratios for the major diastereomers from 94:6 to 98:2.
Conjugate carbon-carbon bond formations that generate a
single asymmetric center via enantioselective 1,4-additions
have been developed with organozincate, metalloenolate,
organocuprate, and organolithium nucleophiles.1,2 Stereo-
selective conjugate additions that provide control of two
stereogenic carbons usually employ enol silanes or metal-
loenolates as nucleophiles.3 Feringa has developed kinetic
resolution of cyclohexenones via copper-phosphoramidite-
catalyzed conjugate addition.4 Buchwald has reported the
kinetic resolution and dynamic kinetic resolution of racemic
3,5-dialkylcyclopentenones via asymmetric conjugate reduc-
tion.5 We have reported organolithium-based (-)-sparteine-
mediated conjugate addition reactions of configurationally
stable allylic organolithium species to provide 1,4-addition
products with high diastereomeric and enantiomeric ratios.6
The products obtained from the conjugate addition reactions
(1) For reviews on conjugate addition reactions, see: (a) Perlmutter, P.
Conjugate Addition Reactions in Organic Synthesis; Pergamon Press:
Oxford, 1992. (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171.
(c) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (d) Sibi, M. P.; Manyem,
S. Tetrahedron 2000, 56, 8033 and references therein.
(2) For recent examples of asymmetric conjugate additions, see: (a)
Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. (b)
Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc. 2002, 124, 984. (c) Barbas,
C. F., III; Betancort, J. M. Org. Lett. 2001, 3, 3737. (d) Reetz, M. T.; Moulin,
D.; Gosberg, A. Org. Lett. 2001, 3, 4083. (e) Senda, T.; Ogasawara, M.;
Hayashi, T. J. Org. Chem. 2001, 66, 6852. (f) Totani, K.; Nagatsuka, T.;
Yamaguchi, S.; Takao, K.; Ohba, S.; Tadano, K. J. Org. Chem. 2001, 66,
5965.
(3) For leading references on asymmetric conjugate reactions with control
of the two new stereogenic centers, see: (a) Juaristi, E.; Beck, A. K.; Hansen,
J.; Matt, T.; Mukhopadhyay, M.; Simson, M.; Seebach, D. Synthesis 1993,
1271. (b) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996,
37, 8921. (c) Yasuda, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1997,
38, 3531. (d) Evans, D. A.; Scheidt, K. A.; Johnson, J. S.; Willis, M. C. J.
Am. Chem. Soc. 2001, 123, 4480 and references therein.
(4) Naasz, R.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Angew.
Chem., Int. Ed. Engl. 2001, 40, 927.
(5) Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 2892.
10.1021/ol0263898 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002

are precursors to a number of synthetically useful com-
pounds, including substituted piperidines6d and bicarbocyclic
compounds.7 We now report kinetic resolution8 of racemic
R,â-unsaturated lactones with the organolithium species
under the influence of (-)-sparteine to provide conjugate
addition products with three contiguous stereogenic centers
with high diastereo- and enantioselectivity in a single step.
Treatment of N-Boc-N-(p-methoxyphenyl)cinnamylamine
1 with 1.1 equiv of n-BuLi in the presence of (-)-sparteine
at -78 °C in toluene for 30 min generates the lithiated
intermediate 2.6b Addition of 2 to a premixed solution of
trimethylsilyl chloride (TMSCl) and 2.5 equiv of 5-substi-
tuted 5H-furan-2-ones in toluene provides the 1,4-addition
products 3-8 in good yields with high diastereo- and
enantioselectivities as shown in Table 1. In the absence of
The relative configuration of 5 has been determined by
X-ray crystallographic analysis.10 On the basis of the
configuration of the recovered electrophile, (S)-5-ethyl-5H-
furan-2-one, which was determined by comparing the opti-
cal rotation,11 the absolute configuration is assigned as
(3R,2′R,3′′S)-5. This result established that the reaction
proceeds with the retention of the configuration relative to
the organolithium, which is consistent with our previous
results in which 5,6-dihydro-pyran-2-one reacts with the
organolithium with retention to afford 13 (vide infra).6b The
absolute configurations of the other products are assigned
by analogy.
Two separate experiments were conducted to confirm that
(R)-alkyl 5H-furan-2-ones have matched selectivity with the
lithiated intermediate 2 (Scheme 1). With the (S)-5-(tert-
butyldimethyl-silanyloxymethyl)-5H-furan-2-one 9 as the
electrophile, the products 10 and 11 were obtained in 70 and
18% yields, respectively, with >95:5 dr.12 Both 10 and 11
can be easily deprotected with tetrabutylammonium fluoride,
TBAF, to afford the same isomer 12 in 98 and 91% yields,
respectively. With (R)-9 as the electrophile, only a trace of
the 1,4-addition product was obtained. This set of experi-
ments shows the (R)-alkyl 5H-furan-2-ones to have the
matched stereochemistry for these highly stereoselective
conjugate additions.
Table 1. Kinetic Resolution of 5-Alkyl-Substituted
5H-Furan-2-ones
Scheme 1
entry
R
product
% yield
dr
era
1
2
3
4
5
6
7
H
Me
Et
Pr
hex
3
4
5
6
7
8
na
71
77
62
62
69
75
na
97:3
97:3
97:3b
94:6c
95:5c
96:4
96:4
97:3
na
>99:1
>99:1
>99:1
>99:1
na
hex-3-enyl
Ph
a Enantioselectivities were determined by CSP-HPLC analysis by
comparison with authentic racemic material. b To 2 was added 1.3 equiv
of electrophile. c Electrophile (2.5 equiv) was used.
TMSCl, the yield of the reaction decreases significantly. In
all cases, the selectivity factors were >20.9 With a phenyl
at the 5-position, the 1,4-addition product was not obtained;
the organolithium acted as a base to afford the isomerized
electrophile.
The methodology can be extended to kinetic resolutions
of 5-alkyl-5,6-dihydro-pyran-2-ones. The results are sum-
marized in Table 2. The diastereoselectivities are lower than
those for the 5-alkyl-5H-furan-2-ones. The diastereomers of
13 were separated by preparatory HPLC to afford a single
diastereomer.6a The kinetic resolution products 14 and 15
were obtained as mixtures of diastereomers as shown in
(6) (a) Park, Y.-S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc.
1997, 119, 10537. (b) Pippel, D. J.; Weisenburger, G. A.; Beak, P. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2522. (c) Curtis, M. D.; Beak, P. J. Org.
Chem. 1999, 64, 2996. (d) Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am.
Chem. Soc. 2001, 123, 1004.
(7) Lim, S. H.; Curtis, M. D. Beak, P. Org. Lett. 2001, 3, 711.
(8) For leading references on kinetic resolution, see: (a) Kagan, H. B.;
Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330. (b) Hoveyda, A. H.;
Didiuk, M. T. Curr. Org. Chem. 1998, 2, 489-526. (c) Keith, J. M.; Larrow,
J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5. (d) Blackmond, D.
G. J. Am. Chem. Soc. 2001, 123, 545.
(9) The selectivity factor, s ) ln [1 - C(1 + ee)]/[1 - C(1 - ee)], was
calculated using the enantiomeric excess of the conjugate addition product.
For each substrate, s was greater than 20.
(10) Crystallographic data for structure of 5 has been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 18373. Copies of the data can be obtained free of charge upon
application to the CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax
(+44) 1223-336033; e-mail deposit@ccdc.cam.ac.uk).
(11) Tsuboi, S. J. Org. Chem. 1998, 63, 1102.
(12) The R and S designations of configuration change with 9 and 17
due to a change in priorities; the absolute configurations are as shown.
2658
Org. Lett., Vol. 4, No. 16, 2002

Table 2. Kinetic Resolution of
5-Alkyl-5,6-dihydro-pyran-2-one
entry
R
product
% yield
dr
er (minor)a
1
2
3
H
Me
Et
13
14
15
85
67
65
89:11b
75:25
80:20
96:4c
98:2 (93:7)
98:2 (93:7)
a Enantioselectivities were determined by CSP-HPLC analysis in com-
parison with an authentic sample. b Diastereomerics were separated by
HPLC. c To 2 was added 1.3 equiv of electrophile.
Table 2. For 14 and 15, enantiomeric ratios of 98:2 er and
93:7 er were observed for the major and minor diastereomers,
respectively.
Figure 1. SHELXTL Crystal Structure of plots showing 35%
probability circles for non-H atoms and circles of arbitrary size for
H atoms.
The kinetic resolution of N-Boc-5-methyl-dihydropyrrol-
2-one 17 was investigated (Scheme 2). First, treatment of
organolithium species prior to retentive substitution.14 Lac-
tones with the R substituent located away from the Ph group
on the allyllithium lead to the transition structure represented
as A to avoid the steric interaction between the groups
evident in B.
Scheme 2
the organolithium 2 with a premixed solution of 16 and
TMSCl afforded 18 in 58% yields with 87:13 dr and 83:17
er. The diastereomers were separated using preparative HPLC
to provide 18 as a single diastereomer. The kinetic resolution
of the N-Me lactam 17 with 2 afforded 19 in good yield,
but with a selectivity significantly lower than that observed
for lactones. Recovered 17 had the (S)-configuration, which
is consistent with the results with the 5-alkyl-5H-furan-2-
ones.12,13 With N,N,N′,N′-tetraethylethylenediamine, TEEDA,
as the ligand, rac-19 was obtained from 2 as a single
diastereomer; the er of the minor diastereomer could not be
determined.
Figure 2. Proposed transition structure for reaction of the
organolithium, (-)-sparteine, and the electrophile.
In summary, kinetic resolutions of racemic cyclic unsatur-
ated esters with the organolithium intermediates derived from
(13) Cuiper, A. D.; Brzostowska, M.; Gawronski, J. K.; Smeets, W. J.
J.; Spek, A. L.; Hiemstra, H.; Kellogg, R. M.; Feringa, B. L. J. Org. Chem.
1999, 64, 2567.
(14) Electrophiles such as alkyl halides and activated olefins6c,d react
with inversion of configuration, as either their rate of reaction with the
organolithium is faster than complexation or the molecule does not contain
functionality that precoordinates to Li in the productive transition structures.
The absolute configuration of the orgolithium has been established.6,15
(15) Pippel, D. J.; Weisenberger, G. A.; Fabish, N. C.; Beak, P. J. Am.
Chem. Soc. 2001, 123, 4919.
A reasonable transition structure for the substitution
reactions of the 5-alkyl-5H-furan-2-ones is depicted in Figure
2. Our working hypothesis is that the carbonyl group of R,â-
unsaturated lactones complexes to the lithium atom of the
Org. Lett., Vol. 4, No. 16, 2002
2659

lithiation of N-Boc-N-(p-methoxyphenyl)cinnamylamine with
n-BuLi/(-)-sparteine provides 1,4-conjugate addition prod-
ucts in good yields with high diastereo- and enantioselec-
tivity. The present methodology provides a conjugate addition
approach that generates three contiguous stereogenic centers
simultaneously with high stereoselectivities. Extension of this
methodology to other substrates and synthetic application
are areas of future interest.
Acknowledgment. This work was supported by a grant
from the National Institutes of Health (GM-18874). We are
grateful for this support.
Supporting Information Available: Detailed experi-
mental procedures, including spectroscopic and analytical
data for the preparation of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0263898
2660
Org. Lett., Vol. 4, No. 16, 2002