Asymmetric carbon-carbon bond formations by conjugate additions of lithiated N-Boc allylic amines to nitroalkenes: Enantioselective synthesis of functionalized cyclopentanoids

Article abstract of DOI:10.1021/ol026277g

(Matrix presented) Allylic organolithiums generated by enantioselective deprotonation of N-Boc-N-(p-methoxyphenyl) allylic amines undergo conjugate additions with nitroalkenes to provide enecarbamates containing two contiguous stereogenic centers in good

Full text of DOI:10.1021/ol026277g

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2747-2749
Asymmetric Carbon−Carbon Bond
Formations by Conjugate Additions of
Lithiated N-Boc Allylic Amines to
Nitroalkenes: Enantioselective
Synthesis of Functionalized
Cyclopentanoids
Timothy A. Johnson, Michael D. Curtis,† and Peter Beak*
Department of Chemistry, Roger Adams Laboratory, UniVersity of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
beak@scs.uiuc.edu
Received June 1, 2002
ABSTRACT
Allylic organolithiums generated by enantioselective deprotonation of N-Boc-N-(p-methoxyphenyl) allylic amines undergo conjugate additions
with nitroalkenes to provide enecarbamates containing two contiguous stereogenic centers in good yields with high diastereoselectivities and
enantioselectivities. Further elaboration of these adducts to enantioenriched substituted cyclopentanones and aminocyclopentanes is reported.
There are a number of strategies for the asymmetric synthesis
of cyclopentanoids.1,2 Often these are stimulated by the
occurrence of the cyclopentane ring in biologically active
compounds. For example, the trans-2,3-disubstituted cyclo-
pentanone structure is found in the E series of 11-deox-
yprostaglandins,3 and aminocyclopentanoids have been re-
ported to be potent glycosidase inhibitors.2a
subsequent conjugate additions to nitroalkenes provides
enecarbamate products that contain two contiguous stereo-
genic centers in good yields with high diastereoselectivity
and enantioselectivity. We have demonstrated that these
adducts serve as useful precursors to highly substituted
piperidines and pyrrolidines.4,5 We now report that these
asymmetric conjugate additions can be key steps in the
syntheses of 2,3-disubstituted cyclopentanones and cyclo-
pentylamines with high enantioenrichments.
We have recently reported the (-)-sparteine-mediated
lithiations of N-Boc-N-(p-methoxyphenyl) allylic amines, and
Treatment of N-Boc-N-(p-methoxyphenyl) allylic amines
1 and 2 with n-BuLi and (-)-sparteine at -78 °C provides
configurationally stable organolithiums 3 and 4, which on
conjugate additions to nitroalkenes 5 and 6 provide enecar-
† Present address: Procter and Gamble Pharmaceuticals, PO Box 191,
Norwich, NY 13825.
(1) For general approaches to cyclopentanoids, see: Hudlicky, T.; Price,
J. D.; Chem. ReV. 1989, 89, 1467.
(2) For recent asymmetric syntheses of cyclopentanoids, see: (a)
Denmark, S. E.; Dixon, J. A. J. Org. Chem. 1998, 63, 6178. (b) Barluenga,
J.; Tomas, M.; Ballesteros, A.; Santamaria, J.; Brillet, C.; Garcia-Granda,
S.; Pinera-Nicolas, A.; Vazquez, J. T. J. Am. Chem. Soc. 1999, 121, 4516.
(c) Trost, B. M.; Pinkerton, A. B. J. Org. Chem. 2001, 66, 7714. (d) La, D.
S.; Sattely, E. S.; Ford, J. G.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2001, 123, 7767.
(4) (a) Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001,
123, 1004. (b) Johnson, T. A.; Jang, D. O.; Slafer, B. W.; Curtis, M. D.;
Beak, P. J. Am. Chem. Soc., submitted for publication.
(5) For conjugate additions of lithiated allylic amines to other activated
olefins, see: (a) Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem.
Soc. 1997, 119, 10537. (b) Curtis, M. D.; Beak, P. J. Org. Chem. 1999, 64,
2996. (c) Lim, S. H.; Curtis, M. D.; Beak, P. Org. Lett. 2001, 3, 711. (d)
Lim, S. H.; Beak, P. J. Am. Chem. Soc., submitted for publication.
(3) Posner, G. H.; Sterling, J. J.; Whitten, C. E.; Lentz, C. M.; Brunelle,
D. J. J. Am. Chem. Soc. 1975, 97, 107.
10.1021/ol026277g CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/29/2002

bamates 7-9 in good yields and with good diastereomeric
(dr) and enantiomeric ratios (er).4,5
aldehydes with basic alumina results in intramolecular
nitroaldol reaction and dehydration to provide the nitro-
alkenes 10-12.6 Reduction of nitroalkenes 10-12 with
NaBH47 using the conditions reported by Borchardt provides
crude nitroalkanes that can be converted to trans-2,3-
disubstituted cyclopentanones 13-15 in good yields by a
Nef reaction.8
Elaboration of the 2,3-disubstituted cyclopentanones to
2,3,5-trisubstituted cyclopentanones can be diastereoselective.
Treatment of 14 with LDA at -78 °C in THF/HMPA
followed by substitution with MeI provides the trisubstituted
cyclopentanone 16 in 78% yield and good diastereoselec-
tivity.
Both aryl- and alkyl-substituted allylic amines and ni-
troalkenes can be utilized in the conjugate addition to give
the conjugate addition products in good yields with high
selectivities. The absolute configurations of 7 and 8 have
been determined previously by X-ray crystallographic analy-
sis of derivatives.4a The absolute configuration of 9 is
assigned by analogy.
Table 1. Conjugate Addition of
N-Boc-N-(p-Methoxyphenyl)allylamines 1 and 2 to Nitroalkenes
5 and 6
An amine group can be introduced at the 2-position of a
3,4-disubstituted cyclopentanone from 7 by reduction of the
nitro functionality and subsequent transformations. The
approach is shown in Scheme 2. Hydrolysis of 7 followed
yield
entry amine R1 nitroalkene R2 product (%)
dra
erb
1
2
3
1
1
2
Ph
Ph
Me
5
6
6
Ph
i-Bu
i-Bu
7
8
9
90 94:6
73 98:2 >97:3
74 84:16 >97:3
96:4c
Scheme 2
a Diastereomeric ratios were determined by 1H NMR integration.
b Enantiomeric ratios of diastereopure derivatives. c Enantiomeric ratios were
determined by CSP-HPLC.
The enecarbamates 7-9 are readily converted to 2,3-
disubstituted cyclopentanones by the transformations shown
in Scheme 1. Acidic treatment of 7-9 provides the nitro-
Scheme 1
by treatment of the resulting nitroaldehyde with KOt-Bu
provides nitro alcohol 17 in 79% yield as a mixture of
diastereomers. Hydrogenation of the nitro group and treat-
ment of the resulting amine with Boc2O furnishes Boc-amino
alcohol 18 in 69% yield. Oxidation of the alcohol with TPAP/
NMO provides ketone 19 in 79% yield and 93:7 dr. Although
the diastereomeric ratio of crude 19 is 80:20, column
chromatography in the presence of Et3N allows equilibration
of 19 to a thermodynamic product ratio of 93:7.
The nitroalkene 10 can be an intermediate for synthesis
of a 2,3-disubstituted cyclopentylamine as demonstrated by
the conversion of 10 to 20. Reduction of the double bond
and nitro group, accomplished in a single step using
(6) Ballini, R.; Castagnani, R.; Petrini, M. J. Org. Chem. 1992, 57, 2160.
(7) Sinhababu, A. K.; Borchardt, R. T. Tetrahedron Lett. 1983, 24, 227.
(8) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122,
10716.
aldehydes with the necessary 1,5-relationship between the
functional groups for intramolecular cyclization to a cyclo-
pentane ring. Subsequent heating at reflux of the crude
2748
Org. Lett., Vol. 4, No. 16, 2002

BH3‚THF with a catalytic amount of NaBH4,9 followed by
Boc protection of the crude amine provided 20 in 69% yield,
albeit as a 58:42 mixture of diastereomers.
can readily be converted to a number of substituted cyclo-
pentanone and cyclopentylamine derivatives. Since either
epimer of the lithiated intermediates can be obtained, this
approach can be useful to provide both enantiomers of the
products.4b,10 Further development of this methodology is
anticipated.
Acknowledgment. We are grateful to the National
Institutes of Health (GM-18874) for support of this work.
Supporting Information Available: Experimental pro-
cedures for the preparation of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed a new approach for the
asymmetric synthesis of functionalized substituted cyclo-
pentanoids. The key carbon-carbon bond formation is a (-)-
sparteine-mediated lithiation of N-Boc-N-(p-methoxyphenyl)
allylic amines followed by conjugate addition to nitroalkenes.
The nitro enecarbamate products of the conjugate addition
OL026277G
(10) The epimers of 3 and 4 can be produced by a stannylation-lithiation
sequence, albeit with some loss of enantioselectivity.
(9) Kabalka, G. W.; Guindi, L. H. M. Tetrahedron 1990, 46, 7443.
Org. Lett., Vol. 4, No. 16, 2002
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