Highly diastereoselective and enantioselective carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylamines to nitroalkenes: Enantioselective synthesis of 3,4- and 3,4,5-substituted piperidines including (-)-paroxetine [15]

Full text of DOI:10.1021/ja005748w

1004
J. Am. Chem. Soc. 2001, 123, 1004-1005
Table 1. Conjugate Addition of N-Boc-N-(p-methoxphenyl)-
allylamines 1-3 to Nitroalkenes 4-8
Highly Diastereoselective and Enantioselective
Carbon-Carbon Bond Formations in Conjugate
Additions of Lithiated N-Boc Allylamines to
Nitroalkenes: Enantioselective Synthesis of 3,4- and
3,4,5-Substituted Piperidines Including
(-)-Paroxetine
Timothy A. Johnson, Michael D. Curtis, and Peter Beak*
nitro-
alkene
yield
entry substrate
R1
Ph
Ph
Ph
Ph
Ph
2-furyl
Me
R2
producta (%) drb
Department of Chemistry
UniVersity of Illinois at Urbana-Champaign
Urbana, Illinois 61801
1
2
3
4
5
6
7
1
1
1
1
1
2
3
4
5
6
7
8
4
4
Ph
(S,R)-10c 90 94:6
Cyd
i-Bu
(S,S)-11
(S,S)-12
83 95:5
73 98:2
ReceiVed NoVember 1, 2000
o-MeOPh (S,R)-13 82 93:7
2-furyl
Ph
(S,S)-14
82 94:6
(S,R)-15 90 93:7
(S,R)-16 74 90:10
Carbon-carbon bond-forming reactions that create two ste-
reogenic centers with high diastereo- and enantioselectivity in a
single step can open new strategic approaches to valued structures.
The piperidine ring is the central structure of many biologically
active alkaloid natural products and pharmaceuticals.1 General
strategies which have been developed for the synthesis of enantio-
enriched, substituted piperidines utilize amino acids, chiral cata-
lysts, and auxiliaries2 and focus on asymmetric carbon substitution
at the 2- and 6-positions.2,3 Methods providing substitution at the
3-, 4-, and 5-positions of the piperidine ring are quite limited.2,4
We now report the development of (-)-sparteine-mediated
lithiation and conjugate addition of N-Boc-N-(p-methoxyphenyl)-
allylamines to R,â-unsaturated nitro compounds. This addition
occurs with high enantio- and diastereoselectivity and serves as
the key step in the efficient synthesis of highly enantioenriched
piperidines with substitution at the 3-, 4-, and 5-positions. The
retrosynthetic analysis is shown below.
Ph
a Enantiomeric ratios were assessed to be at a minimum of 90:10
by CSP-HPLC.6 b Diastereomeric ratios were determined by 1H NMR
integration. c 96:4 er for major diastereomer.5 d Cy ) cyclohexyl.
Table 2. Conversion of Enecarbamates 10-13, 16 to Lactams
17-21
entry substrate R1
R2
lactam
yield (%)
dr
1
2
3
4
5
(S,R)-10 Ph Ph
(S,S)-11 Ph Cy
(S,S)-12 Ph i-Bu
(S,R)-13 Ph o-MeOPh (R,R)-20
(S,R)-16 Me Ph (R,R)-21
(R,R)-17
(R,S)-18
(R,S)-19
59
57
71
61
58
>99:1
>99:1
>99:1
>99:1
>99:1
Enecarbamates 10-13 and 16 were converted to the corre-
sponding 4,5-disubstituted lactams 17-21 in good yields as shown
in Table 2. Hydrolysis of the enecarbamates to the aldehydes,
followed by oxidation and esterification,7 provided nitroesters.
Reduction and concomitant cyclization provided the lactams in
good yield and as single diastereomers following recrystallization.
Lactams (R,R)-17 and (R,S)-19 were reduced with lithium
aluminum hydride and treated with Boc2O to provide 3,4-
disubstituted piperidines (R,R)-22 and (S,R)-23.
Treatment of N-Boc-N-(p-methoxyphenyl)allylamines 1-3 with
n-BuLi in the presence of (-)-sparteine at -78 °C in toluene for
1 h generated a lithiated intermediate that underwent conjugate
addition to nitroalkenes 4-8 and provided enecarbamates 10-
16 in good yield and with high diastereo- and enantioselectivities
as shown in Table 1.5 The utilization of a variety of N-Boc
allylamines and nitroalkenes allows for the incorporation of
aliphatic (entries 2-3 and 7), aromatic (entries 1-7), and
heterocyclic substituents (entries 5 and 6). After subsequent
transformations, the enantiomeric ratios (er’s) of diastereopure
derivatives were determined to be >97:3 (vide infra).
(1) (a) Elbein, A. D.; Molyneux, R. In Alkaloids; Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; John Wiley & Son: New York, 1987;
Vol. 57, p 1. (b) It has been noted by Watson (Watson, P. S.; Jiang, B.; Scott,
B. Org. Lett. 2000, 2, 3679) that over 12 000 piperidines were in preclinical
or clinical studies in a recent ten year period.
(2) For recent reviews, see: (a) Bailey, P. D.; Millwood, P. A.; Smith, P.
D. J. Chem. Soc., Chem. Commun. 1998, 633. (b) Nadin, A. J. Chem. Soc.,
Perkin Trans. 1 1998, 3493.
The enantiopurity of lactams 17-21 was assessed by deriva-
tization with enantiopure (-)-menthylchloroformate directly or
after reduction. In all cases, the enantiomeric ratio was assessed
(3) (a) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155.
(b) Dawei Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503. (c) Davis, F. A.; Chao,
B. Org. Lett. 2000, 2, 2623. (d) Guilloteau-Bertin, B.; Compere, D.; Gil, L.;
Marazano, C.; Das, B. C. Eur. J. Org. Chem. 2000, 1391 and references therein.
(4) For recent examples, see: (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto,
M.; Perez, M.; Llor, N.; Molins, E.; Miravitales, C.; Orozco, M.; Luque, J. J.
Org. Chem. 2000, 65, 3074. (b) Meyers, A. I.; Lamar, J. E.; Dwyer, M. P.
Tetrahedron Lett. 1999, 40, 8965. (c) Ghosez, L.; Jnoff, E. J. Am. Chem.
Soc. 1999, 121, 2617. (d) Schuffenhaur, A.; Borner, C.; Schneider, C. Eur. J.
Org. Chem. 1999, 3353.
1
to be >97:3 by H NMR, 13C NMR, and GC. The absolute
configurations of (R,R)-17 and (R,S)-19 were determined by X-ray
crystallographic analysis of the N-p-bromobenzyl derivative.8 All
other configurations are assigned by analogy.
(6) Precise enantiomeric ratios could not be assessed due to low E/Z and
disastereoselectivity in reactions utilizing achiral ligands. These reactions
afforded chromatographically inseparable mixtures that do not allow for reliable
analyses.
(5) For the first report of this addition, see: Curtis, M. D.; Beak, P. J.
Org. Chem. 1999, 64, 2996 and refernces therein.
(7) Whisler, M. C.; Soli, E. D.; Beak, P. Tetrahedron Lett. 2000, 41, 9527.
10.1021/ja005748w CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/11/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 5, 2001 1005
marketed as the hydrochloride, Paxil/Seroxat, a selective seratonin
reuptake inhibitor.10 Treatment of 33 with n-BuLi in the presence
of (-)-sparteine under standard conditions followed by conjugate
addition to nitroalkene 34 provided the desired enecarbamate
(S,S)-35 in 83% yield as a single diastereomer (Scheme 2).
Scheme 2
This methodology can be extended to 3,4,5-trisubstituted
piperidines by substitution of 4,5-disubstituted lactams. Treatment
of benzyl-protected lactam (R,R)-24 with t-BuLi or LDA followed
by substitution with electrophiles and subsequent lithium alumi-
num hydride reduction provided N-benzyl-3,4,5-trisubstituted
piperidines (R,R,R)-25 and (R,R,R)-26 as single diastereomers.
Because the 2-furyl substituent can be transformed to other
functionalities, its location at the 3- or 4-position would be
synthetically useful. The enecarbamates (S,S)-14 and (R,S)-15
were hydrolyzed and reduced to provide nitro alcohols (R,R)-27
and (R,S)-28 in good yields (Scheme 1). Further reduction9
Scheme 1
Hydrolysis and reduction of the resulting aldehyde provided nitro
alcohol (R,S)-36 in 88% yield. Reduction of the nitro functionality
by transfer hydrogenation and subsequent Boc-protection afforded
(R,S)-37 in 95% yield. Cyclization and deprotection afforded
(S,R)-38 in 83% yield. Mesylation followed by displacement with
sesamol and subsequent deprotection provided (S,R)-39 in 72%
yield and >97:3 er (11 steps, 41% from 33.).
In summary, lithiation of N-Boc-N-(p-methoxyphenyl)ally-
lamines in the presence of (-)-sparteine and subsequent conjugate
addition to nitroalkenes provides Z-enecarbamates in good yields
and with high enantio- and diastereoselectivity. These adducts
are useful precursors to enantioenriched 3,4- and 3,4,5-substituted
piperidines. In conjunction with our previous work,3a highly
diastereo- and enantioselective substitution at every position of
the piperidine ring can be achieved by lithiation/substitution
methodology. Further exploration of the synthetic utility of the
conjugate addition and determination of the origin of diastereo-
selectivity are areas of future interest.
followed by Boc protection provided the Boc-amino alcohols
(R,R)-29 and (R,S)-30. Cyclization was achieved by mesylation
and treatment with KOt-Bu to provide Boc-piperidines (R,R)-31
and (S,R)-32 in good yield and with high er’s.
Acknowledgment. We are grateful to the National Institutes of Health
We have demonstrated the synthetic utility of this methodology
by an efficient synthesis of (-)-paroxetine ((S,R)-39), which is
(GM-18874-29) for the support of this work.
Supporting Information Available: Detailed experimental proce-
dures including spectroscopic and analytical data (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(8) Crystallographic data for structures (R,R)-17 and (R,S)-19 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication nos. 145232 and 145233, respectively. Copies of the data can be
obtained free of charge on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ, U.K. (fax (+44) 1223-336033; e-mail deposit@
ccdc.cam.ac.uk).
(9) Chandler, M.; Conroy, R.; Cooper, A. W.; Lamont, R. B.; Scicinski, J.
J.; Smart, J. E.; Storer, R.; Weir, N. G.; Wilson, R. D.; Wyatt, P. G. J. Chem.
Soc., Perkin Trans. 1 1995, 1189.
JA005748W
(10) Previous syntheses have utilized resolution of enantiomers, chiral
auxiliaries, and most recently a porcine liver esterase catalyzed disymmetri-
zation, see: (a) Yu, M. S.; Lantos, I.; Peng, Z.; Yu, J.; Cacchio, T. Tetrahedron
Lett. 2000, 41, 5647. (b) Reference 4a and references therein.