described3 and treated with 5-6 equiv of TFA in MeOH to
remove the N-sulfinyl auxiliary (Scheme 2). The reaction
J2,3 was 3.3-3.7 Hz, which is consistent with the cis
orientation of the 2,6-substituents7 and which implies that
the major isomers have the trans orientation of the H(2) and
H(3) protons (vide infra). The assignment was further
confirmed by NOE experiments. Piperidine 3c, derived from
acetone, was isolated as a 1:1 mixture of products.
Scheme 2
Decarboxylation of 3 to the 4-oxo-2,6-piperidines was
accomplished by refluxing isomerically pure 3a or the 95:5
mixture with 3 equiv of LiOH/MeOH for 9 h.8 2-Methyl-
6-phenyl-4-oxopiperidine (4a)6c was obtained as a 9:1
mixture of cis:trans isomers (Table 1, entry 1). Acid-cata-
lyzed decarboxylation gave a similar mixture of isomers
(Table 1, entries 2 and 3), and purification by flash chromato-
graphy afforded (2R,6R)-(+)-4a.6c Best results were obtained
using 48% HBr/MeOH, affording (+)-4a in 76% isolated
yield (Table 1, entry 3). While all attempts to decarboxylate
3b under alkaline conditions failed, acidic hydrolysis with
6 N HCl gave (2S,6R)-2,6-diphenyl-4-oxopiperidine (4b)9
as a single isomer in 50% yield (Table 1, entry 5). Decar-
boxylation with 48% HBr/MeOH resulted in an improved
yield of 4b (62 vs 50%), but isomerization was noted (Table
1, entries 5 and 6). A base-induced retro-Mannich reaction
furnished (R)-(+)-6-phenylpiperidine-2,4-dione (5)3 in 70%
yield on refluxing (+)-3c with LiOH/MeOH (entry 7), and
its success suggests that the epimerization of 3a,b observed
under the acid and base conditions occurs by a similar
reaction mechanism. Decarboxylation of 3c with 48% HBr
gave the desired (R)-(+)-2,2-dimethyl-6-phenylpiperidin-4-
one (4c)10 in 70% yield (entry 8). The nearly exclusive
formation of the 2,6-cis-disubstituted piperidines 3 is con-
sistent with transition state TS-1 because A1,3 strain disfavors
TS-2 leading to the minor 2,6-trans isomer (Scheme 3).
mixture was loaded on a short pad of silica gel and eluted
with 30% EtOAc/hexanes to remove the sulfinyl byproducts
and then with MeOH to give the crude triflate salt 2. The
salt 2, in DCM, was treated with the appropriate aldehyde
or ketone at room temperature. After 2-3 h, aqueous
NaHCO3 was added. The resulting polysubstituted pip-
eridines 3 were isolated in 70-84% yield as mixtures of
isomers (Table 1). With acetaldehyde and benzaldehyde, 2
Scheme 3
Table 1. Syntheses of Piperidines 4 and 5
3: % yielda
4: % yield (cis:trans)
entry
R1, R2
(cis/trans)
method
1
2
3
4
5
6
7
8
(3a ) Me, H
80 (95:5)
84 (98:2)
70 (1:1)
61 (9:1), LiOH/MeOH
50 (85:15), 6 N HCl/MeOH
66 (94:6), 48% HBr/MeOH
no reaction, LiOH/MeOH
50 (99:1), 6 N HCl/MeOH
62 (94:6), 48% HBr/MeOH
70, (R)-(+)-5, LiOH/MeOH
70, 48% HBr/CHCl3
(3b) Ph, H
(3c) Me, Me
a Isolated yield of pure isomer.
To illustrate the efficacy of our intramolecular Mannich
protocol for the construction of substituted piperidines, the
asymmetric synthesis of the dendrobate alkaloid (+)-241D
and its C-4 epimer was undertaken.11 Alkaloid (+)-241D was
isolated from the skin extracts of dendrobate frogs and was
shown to exhibit potent biological activity.12 For example,
its racemate inhibits binding of [3H]perhydrohistrionicotoxin
gave piperidines 3a and 3b in 80 and 84% yields, respec-
tively. The J2,3 and J5,6 coupling constants for the major
isomer were 10.3 and 12.1 Hz, respectively, suggesting a
diaxial orientation for these protons. In the minor isomer
(5) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
(6) For recent applications of the Mannich reaction in the synthesis of
piperidines, see: (a) Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem.
Soc.,, Perkin Trans. 1 2000, 353. (b) Glasson, S. R.; Canet, J.-L.; Troin, Y.
Tetrahedron Lett. 2000, 41, 9797. (c) Ciblat, S.; Besse, P.; Canet, J.-L.;
Troin, Y.; Veschambre, H.; Gelas, J. Tetrahedron: Asymmetry 1999, 10,
2225. (d) Edwards, M. W.; Garraffo, H. M.; Daly, J. W. Synthesis 1994,
1167.
(7) Rubiralta, M. Giralt, E.; Diez, A. Piperidine; Elsevier: New York,
1991; Chapter 3.
(8) For a review on decarboxylation, see: Krapcho, A. P. Synthesis 1982,
893.
(9) Ravindran, T.; Jeyaraman, R. J. Org. Chem. 1991, 56, 4833.
(10) Balasubramanian, M.; Padma, N. Tetrahedron 1963, 19, 2135.
3170
Org. Lett., Vol. 3, No. 20, 2001