Scheme 2 Reagents and conditions: i, Red-Al, THF, reflux, 8 h, 60%; ii,
AlH3, THF, 278 °C, 90 min, then 25 °C, 2 h, 84%; iii, H2, Pd(OH)2/C,
(Boc)2O, AcOEt, 25 °C, 82%.
Scheme 4 Reagents and conditions: i, toluene, reflux, 24 h, 58%; ii, LiAlH4
(10 equiv.), rt, 15 h; iii, H2, Pd(OH)2, MeOH, rt, 81%.
treatment of 13 with Red-Al or BH3 afforded complex mixtures
resulting from partial reduction of the heteroaromatic ring, more
satisfactorily, reduction of 13 with 9-BBN in refluxing THF
provided (73%) a 37+63 mixture of isomers 14a and 14b,
respectively. The lower stereoselectivity of this reduction as
compared with the 9-BBN reduction of the related phenyl-
lactams 3 and 4 probably reflects the lesser ability of pyridine,
a p-deficient heterocycle, to stabilize the intermediate iminium
ion B in comparison with a phenyl group. In this series, the best
result regarding stereoselectivity was obtained when 13 was
treated with an excess of LiAlH4. The desired piperidine 14a
was obtained in 78% yield along with only minor amounts (6%)
of its epimer 14b. Hydrogenolysis of pure isomer 14a over
Pearlman’s catalyst afforded the alkaloid (2)-anabasine [15,
[a]22 274.7 (c 0.1, CHCl3); lit.8 [a]23 275.5 (c 0.1,
D
D
CHCl3)].
Scheme 3
This work was supported by the DGICYT, Spain (BQU2000-
0651), and the CUR, Generalitat de Catalunya (2001SGR-
0084). We also thank the Ministry of Education, Culture and
Sport for a fellowship to M. C.
genolysis of 10 over Pearlman’s catalyst in the presence of
(Boc)2O afforded cis-2-methyl-3-ethylpiperidine 11.
The remarkable difference in the stereoselectivity of the
above reactions can be explained in terms of the reactive
intermediates A and B as depicted in Scheme 3. Thus, the
stereoselectivity in the reduction of related 8a-alkyl substituted
Notes and references
1 S. R. Angle and J. G. Breitenbucher in Studies in Natural Products
Chemistry, ed. Atta-ur-Rahman, Elsevier, Amsterdam, 1995, vol. 16, pp.
453–502; P. D. Bailey, P. A. Millwood and P. D. Smith, Chem. Commun.,
1998, 633; S. Laschat and T. Dickner, Synthesis, 2000, 1781.
2 P. S. Watson, B. Jiang and B. Scott, Org. Lett., 2000, 2, 3679.
3 M. Amat, J. Bosch, J. Hidalgo, M. Cantó, M. Pérez, N. Llor, E. Molins,
C. Miravitlles, M. Orozco and J. Luque, J. Org. Chem., 2000, 65, 3074;
M. Amat, M. Pérez, N. Llor, J. Bosch, E. Lago and E. Molins, Org. Lett.,
2001, 3, 611; and previous papers in this series. For reviews on the
enantioselective synthesis of piperidines from chiral lactams, see: A. I.
Meyers and G. P. Brengel, Chem. Commun., 1997, 1; M. D. Groaning and
A. I. Meyers, Tetrahedron, 2000, 56, 9843.
lactams (X
= O, R1 = alkyl, R2 = H), leading to
2-alkylpiperidines with retention of configuration, has been
rationalized7 by considering that, after the reduction of the
carbonyl lactam, the reductive cleavage of the oxazolidine ring
takes place through complexation of the oxygen with the
reductant, followed by delivery of the hydride from the same
face of the C–O bond (A). The opposite stereochemical result
observed in the reduction of the 8a-aryl substituted lactams 3
and 4 with 9-BBN suggests that, using this reductant, the
reaction takes place through a different pathway involving the
formation of the ion paired intermediate B (R1 = C6H5). The
intramolecular delivery of the hydride under stereoelectronic
control from the preferred conformation BA accounts for the
stereoselective formation of isomers b of piperidines 5 and 6.
Due to steric interactions, the 9-BBN reduction of intermediate
4 M. Amat, M. Cantó, N. Llor, V. Ponzo, M. Pérez and J. Bosch, Angew.
Chem., Int. Ed. Engl., 2002, 41, 335.
5 H. Poerwono, K. Higashiyama, T. Yamauchi and H. Takahashi,
Heterocycles, 1997, 46, 385.
6 K. Hattori and H. Yamamoto, Tetrahedron, 1993, 49, 1749.
7 M. J. Munchhof and A. I. Meyers, J. Org. Chem., 1995, 60, 7084; S.
Fréville, J. P. Célérier, V. M. Thuy and G. Lhommet, Tetrahedron:
Asymmetry, 1995, 6, 2651; A. I. Meyers, C. J. Andres, J. E. Resek, C. C.
Woodall, M. A. McLauhlin, P. H. Lee and D. A. Price, Tetrahedron,
1999, 55, 8931. See also: L. Micouin, J. C. Quirion and H.-P. Husson,
Tetrahedron Lett., 1996, 37, 849; S. Fréville, M. Bonin, J.-P. Célérier, H.-
P. Husson, G. Lhommet, J.-C. Quirion and V. M. Thuy, Tetrahedron,
1997, 53, 8447.
8 For previous asymmetric syntheses, see: W. Pfrengle and H. Kunz, J.
Org. Chem., 1989, 54, 4261; F.-X. Felpin, G. Vo-Thanh, R. J. Robins, J.
Villiéras and J. Lebreton, Synlett, 2000, 1646; J.-M. Andrés, I. Herráiz-
Sierra, R. Pedrosa and A. Pérez-Encabo, Eur. J. Org. Chem., 2000, 1719;
A. Barco, S. Benetti, C. De Risi, P. Marchetti, G. P. Pollini and V.
Zanirato, Eur. J. Org. Chem., 2001, 975. See also ref. 6.
A is slower than the formation of the iminium salt B (R1
=
C6H5). Moreover, the presence of the 8a-phenyl group in
lactams 3 and 4 contributes to the stabilization of this
intermediate B, making the C–O bond here more prone to
undergo cleavage than in 8a-alkyl lactams. This is in agreement
with the different stereoselectivity in the 9-BBN reduction of 9,
where 10, resulting from a retention of configuration, was the
major stereoisomer.
To further illustrate the potential of the cyclodehydration-
stereocontrolled reduction sequence here developed, we under-
took the synthesis of the tobacco alkaloid (2)-anabasine.8 The
required bicyclic lactam 13 was obtained as a single stereoi-
somer by cyclocondensation of keto-acid 129 with (R)-
phenylglycinol in refluxing toluene (Scheme 4). Although
9 G. B. R. de Graaff, W. C. Melger, J. Van Bragt and S. Schukking, Recl.
Trav. Chim. Pays-Bas, 1964, 83, 910.
CHEM. COMMUN., 2002, 526–527
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