Enantioselective synthesis of 2-arylpiperidines from chiral lactams. A concise synthesis of (-)-anabasine

Article abstract of DOI:10.1039/b200020m

Cyclodehydration of achiral or racemic aryl-δ-oxoacids with (R)-phenylglycinol stereoselectively affords chiral non-racemic bicyclic lactams, from which the enantiodivergent synthesis of (R)- and (S)-2-phenylpiperidine, the diastereodivergent synthesis of cis- and trans-3-ethyl-2-phenylpiperidine, and the enantioselective synthesis of the piperidine alkaloid (-)-anabasine is reported.

Full text of DOI:10.1039/b200020m

Enantioselective synthesis of 2-arylpiperidines from chiral lactams.
A concise synthesis of (2)-anabasine
Mercedes Amat,* Margalida Cantó, Núria Llor and Joan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028- Barcelona, Spain.
E-mail: amat@farmacia.far.ub.es; Fax: +34 93 402 18 96; Tel: +34 93 402 45 40
Received (in Cambridge, UK) 2nd January 2002, Accepted 29th January 2002
First published as an Advance Article on the web 12th February 2002
Cyclodehydration of achiral or racemic aryl-d-oxoacids with
(R)-phenylglycinol stereoselectively affords chiral non-ra-
cemic bicyclic lactams, from which the enantiodivergent
synthesis of (R)- and (S)-2-phenylpiperidine, the diaster-
eodivergent synthesis of cis- and trans-3-ethyl-2-phenyl-
piperidine, and the enantioselective synthesis of the piper-
idine alkaloid (2)-anabasine is reported.
Next we turned our attention to the reduction of the 8-ethyl
substituted lactam 4, which was prepared (43%) by cyclo-
condensation of racemic 4-benzoylhexanoic acid (2) with (R)-
phenylglycinol, in a process involving a dynamic kinetic
resolution. The best stereoselectivities in the reduction of
lactam 4 were obtained again with Red-Al and 9-BBN, which
afforded the cis- and trans-piperidines 6a and 6b, respectively,
as single stereoisomers detectable by spectroscopic methods.
Reduction of 4 with AlH3 and BH3 showed the same level of
stereoselectivity we had observed in the reduction of 3, thus
revealing that the C-8 substituent has no influence on the
stereoselectivity of the reduction. Removal of the benzylic N-
substituent of the epimeric piperidines 6a and 6b by hydro-
genolysis over palladium afforded cis and trans piperidines 8,
respectively. In this way, starting from easily available racemic
g-substituted d-oxoacids, the above three-step sequence pro-
vides easy access to enantiopure cis- and trans-3-alkyl-
2-arylpiperidines.
The phenyl substituent at the angular 8a-position has a
dramatic influence on the stereoselectivity (inversion of
configuration) of the above reductions with 9-BBN because
9-BBN reduction of lactam 9,4 bearing a 8a-methyl substituent,
led to a 9+1 mixture (55%) of cis-piperidine 10 (retention of the
configuration at C-8a) and its C-2 epimer (Scheme 2). As
expected, reduction of 9 with Red-Al or AlH3 afforded cis-
piperidine 10 as a single stereoisomer, thus providing an
efficient entry to enantiopure cis-2,3-dialkylpiperidines. Hydro-
The search for new methods for the enantioselective synthesis
of piperidine derivatives1 constitutes an area of current interest
in pharmaceutical research2 because this heterocyclic ring is a
common moiety in many natural and synthetic biologically
active compounds with therapeutic applications.
In previous papers we have described the enantioselective
synthesis of diversely substituted piperidines3 from a chiral
bicyclic lactam derived from methyl 5-oxopentanoate and
phenylglycinol (Fig. 1, A, R1 = R2 = H) by successive
introduction of the ring substituents. More recently we have
reported4 that the cyclodehydration of racemic d-ketoacids with
(R)-phenylglycinol stereoselectively affords one of the four
possible chiral bicyclic lactams substituted at the 8 and 8a
positions (Fig. 1, A, R1 and R2 = alkyl or aryl). These lactams
can be envisaged as advanced precursors for the synthesis of
cis- or trans-2,3-disubstituted piperidines. The efficiency of this
transformation relies on the stereocontrol in the reductive
opening of the oxazolidine ring, which involves the 8a
stereocentre. In this paper we describe our findings in the
stereoselective reduction of 8a-aryl substituted lactams and its
application to the enantiodivergent synthesis of 2-arylpiper-
idines, the diastereodivergent synthesis of cis- and trans-2-aryl-
3-alkylpiperidines, and the enantioselective synthesis of the
piperidine alkaloid (2)-anabasine.
Fig. 1 Stereocontrolled reduction of the C8a-bond.
The 8a-phenyl substituted lactam 3 was readily obtained
(90%) as a single stereoisomer from 5-phenyl-5-oxopentanoic
acid (1) and (R)-phenylglycinol (Scheme 1). Treatment of
lactam 3 with Red-Al gave 2-phenylpiperidine 5a as the only
stereoisomer detectable by spectroscopic methods (Table 1).
However, reduction of 3 with AlH3 or BH3 showed poor
stereoselectivity, affording mixtures of 5a and 5b in which 5a
was the major stereoisomer. Interestingly, treatment of lactam 3
with an excess of 9-BBN provided 2-phenylpiperidine 5b,
resulting from an inversion of the configuration at C-8a, with
excellent stereoselectivity. Hydrogenolysis of the benzylic
Scheme 1 Reagents and conditions: i, (R)-phenylglycinol, toluene, reflux;
ii, H2, 10% Pd/C, MeOH, rt, ~ 70%.
Table 1 Reduction of lactams 3 and 4 to piperidines 5 and 6
Reductanta
(equiv.)
Temp./°C
(time/h)
Product (a+b Yield
Entry Lactam
ratio)
(%)
1
2
3
4
5
6
7
3
3
3
3
3
4
4
Red-Al (5)
AlH3 (4)
BH3 (3)
Reflux (8)
5 (98+2)
54
93
85
90
75
56
86
278 (1), 25 (2) 5 (67+33)
278 (2), 25 (2) 5 (60+40)
substituent of 5a and 5b gave (S)-2-phenylpiperidine [7, [a]22
D
BH3 (3)
Reflux (1)
5 (73+27)
5 (3+97)
6 (98+2)
6 (3+97)
226.9 (c 1.0, MeOH); lit5 [a]20D 227.0 (c 0.43, MeOH)] and
9-BBN (10) Reflux (16)
Red-Al (2.5) Reflux (8)
9-BBN (10) Reflux (8)
(R)-2-phenylpiperidine [ent-7, [a]22 +25.2 (c 0.4, MeOH;
D
lit6 [a]24D +27.6 (c 1.0, MeOH)], respectively. The above three-
step sequence opens a short enantiodivergent route to 2-ar-
ylpiperidines from easily available achiral d-oxoacids.
a In THF.
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CHEM. COMMUN., 2002, 526–527
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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.
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