blocks for the enantioselective synthesis of diversely sub-
stituted piperidine derivatives has previously been demon-
strated.7
excellent yield by treatment of the corresponding saturated
lactams 3 with KH and methyl phenylsulfinate, followed by
heating of the resulting sulfoxides in toluene solution
(Scheme 1). As we have already reported,8a both cis- and
In this context, in recent work we have established that
unsaturated lactams A (X ) CO2Bn) and B (X ) CO2Bn, R
) H or Et), which differ in the configuration at the C-8a
stereocenter, undergo conjugate addition of cyanocuprates
with opposite facial selectivity.8 This result was explained
by considering that the conformation of the piperidine ring
differs in lactams A and B and that the attack of the
nucleophile takes place, under stereoelectronic control, axial
to the electrophilic carbon of the conjugated double bond
(Figure 2). This has led to the enantiodivergent synthesis of
Scheme 1. Conjugate Addition of Enolates to
Phenylglycinol-Derived R,â-Unsaturated δ-Lactamsa
Figure 2. Stereoelectronic control.
both enantiomers of the antidepressant drug paroxetine
starting from the epimeric lactams A and B (X ) CO2Me,
R ) H) derived from the same chiral inductor, (R)-
phenylglycinol.8a Interestingly, when R ) Et, the additions
to B stereoselectively lead to the C-7/C-8 cis isomers, thus
providing a synthetic entry to enantiopure cis-3-alkyl-4-
arylpiperidines.8b This stereochemical outcome contrasts with
the usual stereoselectivity of conjugate additions to γ-sub-
stituted R,â-unsaturated δ-lactams, in which the trans isomers
are formed.9
The conjugate addition of stabilized anions to R,â-
unsaturated carbonyl compounds differs from the cuprate
additions in that it is a reversible process. As a consequence,
thermodynamic control operates, which can have stereo-
chemical implications. For this reason, we decided to
investigate if the conjugate addition of stabilized anions to
the diastereomeric lactams trans-4 (A, X ) H) and cis-4
(B, X ) H, R ) H), lacking the ethyl substituent, takes place
with the same stereoselectivity as the addition of cuprates
to the related trans and cis lactams A (X ) CO2Bn) and B
(X ) CO2Bn, R ) H or Et) mentioned above. The required
nonactivated10 unsaturated lactams 4 were prepared in
a Reagents and conditions: (i) KH, C6H5SO2Me, THF, reflux,
then Na2CO3, toluene, reflux, 86%; (ii) ethyl 1,3-dithiolane-2-
carboxylate, LDA, THF, HMPA (from cis-4), 60% (5), 72% (7);
(iii) NiCl2‚6H2O, NaBH4, 1:3 THF-MeOH, 79% (6), 71% (8), 93%
(10); (iv) 1,3-dithiane, n-BuLi, THF, 71%.
trans-3 are easily accessible by cyclodehydration of methyl
5-oxopentanoate with (R)-phenylglycinol, the former being
the kinetic product and the latter the more stable isomer.
The introduction of an acetate chain at the piperidine
4-position of cis-4 was accomplished by conjugate addition
of the enolate derived from ethyl 1,3-dithiolane-2-carboxy-
late,11 followed by desulfurization of the resulting dithioacetal
5 with Ni boride. Piperidineacetate 6 was obtained as a single
stereoisomer detectable by spectroscopic methods. However,
all attempts to induce the conjugate addition of the sodium
salt of dimethyl malonate failed,12 the corresponding pyridone
being the only isolable product under forcing conditions. A
similar two-step sequence from lactam trans-4 led to ester
8, again as a single stereoisomer.13 It is worth mentioning
(7) For reviews, see: (a) Meyers, A. I.; Brengel, G. P. Chem. Commun.
1997, 1. (b) Meyers, A. I.; Andres, C. J.; Resek, J. E.; Woodall, C. C.;
Mclaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron 1999, 55, 8931.
(c) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843.
(8) (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.; Llor, N.;
Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65,
3074. (b) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J.; Lago, E.; Molins, E.
Org. Lett. 2001, 3, 611.
(10) Attempted conjugate addition of the enolates derived from CH2(CO2-
Me)2, MeCOCH2CO2Me, or CH3S(O)CH2CO2Me to the more activated
unsaturated lactam A (X ) CO2Bn) under a variety of conditions resulted
in failure, the only identifiable product being the 2-pyridone formed by the
opening of the oxazolidine ring promoted by the abstraction of an acidic
C-8 proton.
(9) For the addition of organocuprates, see: (a) Fleming, I.; Reddy, N.
L.; Takaki, K.; Ware, A. C. J. Chem. Soc., Chem. Commun. 1987, 1472.
(b) Herdeis, C.; Kaschinski, C.; Karla, R.; Lotter, H. Tetrahedron:
Asymmetry 1996, 7, 867. For the addition of stabilized anions, see: (c)
Battersby, A. R.; Turner, J. C. J. Chem. Soc. 1960, 717. (d) Takano, S.;
Sato, M.; Ogasawara, K. Heterocycles 1981, 16, 799. (e) Fujii, T.; Ohba,
M.; Sakaguchi, J. Chem. Pharm. Bull. 1987, 35, 3628.
(11) Hermann, J. L.; Richman, J. E.; Schlessinger, R. H. Tetrahedron
Lett. 1973, 2599.
(12) For a similar result, see: Mpango, G. B.; Mahalanabis, K. K.;
Mahdavi-Damghani, Z.; Sniekus, V. Tetrahedron Lett. 1980, 21, 4823.
(13) Ester 8 was also prepared, although in lower overall yield, by
conjugate addition of the enolate derived from MeSCH2CO2Et to trans-4
(32%) followed by desulfurization (93%).
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Org. Lett., Vol. 4, No. 16, 2002