resulting 4:1 diastereomeric mixture of lactams 2 and 3
(Scheme 1). Interestingly, when the above crude mixture was
Scheme 2. Enantioselective Synthesis of cis- and
trans-3,5-Disubstituted Piperidinesa
Scheme 1. Stereocontrolled Generation of Enantiopure
Bicyclic γ-Substituted δ-Lactamsa
a Reagents and conditions: (a) Et2O, anhyd Na2SO4, 0 °C, 1 h,
then 70 °C, 10-15 mmHg, 79% (2/3 ratio 89:11); (b) 3 N MeOH-
HCl, 25 °C, 24 h, quantitative (2/3 ratio 3:7).
a Reagents and conditions: (a) LiHMDS, -78 °C, 1 h, then MeI
or BrCH2CO2tBu, -78 °C, 2 h, 66% (4a, 70% 4b), 80% (7a), 60%
(7b); (b) 1 M BH3-THF, -78 °C, rt, 53% (trans-5a), 77% (trans-
5b), 47% (cis-5a), 57% (cis-5b); (c) MeOH-HCl, then H2/Pd(OH)2,
75% (trans-6a), 86% (trans-6c), 78% (cis-6).
treated under acidic conditions a reversal in the ratio of
isomeric lactams 2 and 3 was observed, and lactam 3 could
be easily isolated in 60% overall yield after chromatographic
purification.
To gain access to 3,5-disubstituted piperidines we explored
the stereochemical outcome of the alkylation of the enolates
derived from the above lactams 2 and 3. Although the
alkylation at the carbonyl R-position of bicyclic γ- and
δ-lactams derived from amino alcohols has received con-
siderable attention from both the synthetic and theoretical
standpoint,3 the observed stereoselectivities are difficult to
rationalize and, to our knowledge, there are no precedents
of such alkylations from δ-lactams with the substitution
pattern present in 2 or 3.
Generation of the enolate of 2 with lithium hexamethyl-
disilazide followed by alkylation with methyl iodide took
place with moderate facial diastereoselectivity to give a 7:3
mixture of the endo alkylation product 4a, in which the
piperidine â and â′ substituents are trans, and the exo epimer
in 94% overall yield (Scheme 2). A much better result from
the stereochemical standpoint was obtained from lactam 3,
which underwent exo alkylation with excellent yield (84%)
and high stereoselectivity to give lactam 7a, bearing cis
substituents at the piperidine â and â′ positions. Only very
minor amounts (<5%) of the corresponding endo epimer
were detected. The alkylated product 4a was converted to
piperidine trans-6a by borane reduction followed by catalytic
debenzylation of the resulting 3,5-dialkylpiperidine trans-
5a. A similar borane reduction from lactam 7a gave 3,5-
dialkylpiperidine cis-5a.
respective cis epimers, as a consequence of γ-gauche effects.
The same criterion was used in the b series (see below).
In this manner, as a consequence of the different facial
stereoselectivity in the above alkylations, it is possible to
prepare either trans or cis enantiopure 3,5-dialkylpiperidines.
It is simply a matter of using either the kinetic lactam 2,
formed through a dynamic kinetic resolution during the
cyclocondensation process, or the most stable isomer 3,
formed by a subsequent equilibration.
The above results prompted us to study similar alkylations
using a bromoacetate ester to prepare 5-ethyl-3-piperidine-
acetate derivatives, which were envisaged as synthetic
precursors of 20R- and 20S-dihydrocleavamine. These tet-
racyclic indole alkaloids,4 embodying a 3,5-disubstituted
piperidine moiety, differ in the configuration of the piperidine
carbon bearing the ethyl substituent.
As could be expected from the above results, alkylation
of the lithium enolates derived from lactams 2 and 3 with
tert-butyl bromoacetate also took place with opposite di-
astereofacial selectivity to give the respective lactams 4b
(endo alkylation) and 7b (exo alkylation) as the major
products. Both the chemical yields and stereoselectivities
were excellent (84%, 5:1 endo/exo ratio from 2; 75%, 1:4
endo/exo ratio from 3).
Treatment of lactams 4b and 7b with borane brought about
both the reductive opening of the oxazolidine ring and the
reduction of the lactam carbonyl to give the corresponding
piperidines, trans-5b and cis-5b, which were converted to
the 5-ethyl-3-piperidineacetic derivatives trans-6c and cis-6
by catalytic debenzylation in methanol solution in the
presence of HCl.
The cis-trans relationship between the substituents at the
â and â′ positions of the piperidine ring in lactams 4a and
7a, as well as in piperidines 5a, was deduced by 13C NMR
from the upfield chemical shift of the piperidine â and â′
carbons observed in the trans isomers as compared with the
(2) Amat, M.; Llor, N.; Hidalgo, J.; Bosch, J. Tetrahedron: Asymmetry
1997, 8, 2237-2240.
The synthesis of dihydrocleavamines from the above
5-ethyl-3-piperidineacetate derivatives required the introduc-
tion of the 2-(3-indolyl)ethyl chain on the piperidine nitrogen,
(3) (a) For reviews, see: Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503-9569 and ref 1b. See also: (b) Meyers, A. I.; Seefeld, M. A.;
Lefker, B. A.; Blake, J. F.; Williard, P. G. J. Am. Chem. Soc. 1998, 120,
7429-7438. (c) Ando, K.; Green, N. S.; Li, Y.; Houk, K. N. J. Am. Chem.
Soc. 1999, 121, 5334-5335. (d) Bailey, J. H.; Byfield, A. T. J.; Davis, P.
J.; Foster, A. C.; Leech, M.; Moloney, M. G.; Mu¨ller, M.; Prout, C. K. J.
Chem. Soc., Perkin Trans. 1 2000, 1977-1982. (e) Hughes, R. C.; Dvorak,
C. A.; Meyers, A. I. J. Org. Chem. 2001, 66, 5545-5551. See also ref 1e.
(4) (a) Quirin, F.; Debray, M.-M.; Sigaut, C.; Thepenier, P.; Le Men-
Olivier, L.; Le Men, J. Phytochemistry 1975, 14, 812-813. (b) van Beek,
T. A.; Verpoorte, R.; Svendsen, A. B. Tetrahedron 1984, 40, 737-748.
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