Asymmetric synthesis of 6-alkyl- And 6-arylpiperidin-2-ones. Enantioselective synthesis of (S)-(+)-coniine

Article abstract of DOI:10.1021/ol070757w

A variety of diolefinic hydrazides (1) have been assembled in a highly diastereoselective manner by addition of allyllithium to chiral SAMP hydrazones followed by N-acylation with acryloyl chloride. Substrates 1 undergo ring-closing metathesis to give the cyclic enehydrazides (5) which can be easily converted into virtually enantlopure 6-alkyl- or 6-arylpiperidin-2-ones (7). The versatility of this hydrazone addition-RCM protocol has been further exemplified by the conversion of the unsaturated heterocycle 5b into the piperidine alkaloid (S)-(+)-coniine.

Full text of DOI:10.1021/ol070757w

ORGANIC
LETTERS
2007
Vol. 9, No. 13
2473-2476
Asymmetric Synthesis of 6-Alkyl- and
6-Arylpiperidin-2-ones. Enantioselective
Synthesis of (S)-(+)-Coniine
Ste´phane Lebrun, Axel Couture,* Eric Deniau, and Pierre Grandclaudon
UMR 8009 “Chimie Organique et Macromole´culaire”, Laboratoire de Chimie
Organique Physique, Baˆtiment C3(2), UniVersite´ des Sciences et Technologies de Lille,
59655 VilleneuVe d’Ascq Cedex, France
axel.couture@uniV-lille1.fr
Received March 28, 2007
ABSTRACT
A variety of diolefinic hydrazides (1) have been assembled in a highly diastereoselective manner by addition of allyllithium to chiral SAMP
hydrazones followed by N-acylation with acryloyl chloride. Substrates 1 undergo ring-closing metathesis to give the cyclic enehydrazides (5)
which can be easily converted into virtually enantiopure 6-alkyl- or 6-arylpiperidin-2-ones (7). The versatility of this hydrazone addition
−RCM
protocol has been further exemplified by the conversion of the unsaturated heterocycle 5b into the piperidine alkaloid (S)-( )-coniine.
+
The piperidine ring is a ubiquitous structural feature of
numerous naturally occurring alkaloids and can be frequently
recognized in the structure of drug candidates.1 The interest
in piperidine alkaloids is well displayed by the wealth of
published material detailing their sources and biological
activities and their structural diversity makes them interesting
proving grounds for organic chemists. As a consequence
numerous methods have been developed for the synthesis
of substituted piperidines in a stereo- and enantioselective
manner2 and interest in their chemistry continues unabated.3
Piperidinones are somewhat less prominent but very often
they serve a role as advanced intermediates prior to their
conversion to piperidines.2c,4 In this context the corresponding
saturated or unsaturated δ-lactams have emerged as powerful
tools as they possess the requisite structure and functional
group locations for further elaboration to synthetic targets,
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P. D.; Millwood, P. A.; Smith, P. D. J. Chem. Soc., Chem. Commun. 1998,
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R. Tetrahedron 2003, 59, 2953-2989. (d) Felpin, F.-X.; Lebreton, J. Eur.
J. Org. Chem. 2003, 3693-3712. (e) Couty, F. Amino Acids 1999, 16, 297-
320.
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Heterocycl. Chem. 1999, 36, 1491-1500. (c) Husson, H. P.; Royer, J. J.
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D.; Silvani, A. Curr. Org. Chem. 2000, 4, 231-261. (e) Guilloteau-Bertin,
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(1) (a) Jones, T. H.; Blum, M. S. Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1983; Vol. 1, Chapter
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sterdam, The Netherlands, 1995; Vol. 16, pp 453-502.
10.1021/ol070757w CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/23/2007

Scheme 1. Asymmetric Synthesis of 6-Alkyl- and 6-Arylpiperidin-2-ones 7a-e
particularly piperidine alkaloids. The subsequent introduction
but varying degrees of success have been claimed with regard
to their enantioselectivities. Except for some catalyst based
synthesis of these lactams10 most convenient strategies
involve the intramolecular cyclization of enantioenriched
â-keto,11 saturated,9,12 or unsaturated13 δ-aminoesters and
some of the corresponding azido derivatives.14 These highly
functionalized precursors are usually equipped with chiral
auxiliaries derived from the natural chiral pool or with tailor-
made stereocontrolling agents. They also have been obtained
by reductive opening of diastereochemically pure oxazolo-
piperidones15 or via an asymmetric amidoalkylation involving
interception of variously generated chiral iminium salts with
silyl derivatives16 or cyanocuprates.5c,17 On the other hand,
studies on the corresponding R,â- or γ,δ-unsaturated δ-lac-
tams are scarce and most of the chiral 6-substituted models
have been assembled from the corresponding saturated
lactams18 by a multistep sequence involving metalation/
electrophilic capture with phenylselenyl bromide/oxidation
reactions followed by an ultimate elimination reaction.
We now report combinations of a highly diastereoselective
nucleophilic 1,2-addition on chiral aliphatic and aromatic
of substituents on the carbon atoms of the piperidine ring
may indeed be achieved by R-amidoalkylation, enolate or
homoenolate alkylations, manipulation of the amide carbonyl
group, and functionalization of the olefinic moiety including
but not limited to epoxydation or dihydroxylation.5 The
substituted piperidin-2-ones are also substructural units of
barbiturates and glutarimides6 and are key intermediates for
the synthesis of aminopentanoic acids.7 Thus the development
of chiral nonracemic piperidinone building blocks with the
final aim of synthesizing enantiopure piperidine derivatives
still constitutes an area of current interest and alternative
methods are currently the object of intensive synthetic
endeavors.
Herein we wish to report the use of chiral cyclic ene-
hydrazides as substrates for catalytic hydrogenation, which
provides a new efficient and general route to optically active
6-alkyl- and 6-arylpiperidin-2-ones. The utility of this method
has been emphasized by the synthesis of the poisonous
hemlock alkaloid (S)-(+)-coniine.8 Organic chemists have
at their disposal a variety of synthetic strategies for the
asymmetric synthesis of 6-substituted piperidin-2-ones9-17
(13) (a) Davies, S. B.; McKervey, M. A. Tetrahedron Lett. 1999, 40,
1229-1232. (b) Kawecki, R. Tetrahedron 2001, 57, 8385-8390. (c) Burke,
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1387-1394.
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J. Org. Lett. 2001, 3, 3257-3260. (b) Senda, T.; Ogasawara, M.; Hayashi,
T. J. Org. Chem. 2001, 66, 6852-6856. (c) Amat, M.; Llor, N.; Hidalgo,
J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919-1928. (d)
Elworthy, T. R.; Brill, E. R.; Caires, C. C.; Kim, W.; Lach, L. K.; Tracy,
J. L.; Chiou, S.-S. Bioorg. Med. Chem. Lett. 2005, 15, 2523-2526.
(6) Laycock, G. M.; Shulman, A. Nature 1963, 200, 849-851.
(7) Meyers, C. Y.; Miller, L. E. Org. Synth. 1963, 32, 13-17.
(8) For a recent review on coniine and hemlock alkaloids, see: Reynolds,
T. Phytochemistry 2005, 66, 1399-1406.
(14) (a) Masaki, Y.; Imaeda, T.; Nagata, K.; Oda, H.; Ito, A. Tetrahedron
Lett. 1989, 30, 6395-6396. (b) Hodgkinson, T. J.; Shipman, M. Synthesis
1998, 1141-1144.
(15) (a) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7084-
7085. (b) Freville, S.; Celerier, J.-P.; Thuy, V. M.; Lhommet, G.
Tetrahedron: Asymmetry 1995, 6, 2651-2654.
(9) Enders, D.; Bartzen, D. Liebigs Ann. Chem. 1997, 1115-1123.
(10) (a) Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1998, 63, 6344-
6347. (b) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155-
158.
(11) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000,
2, 1041-1043.
(12) (a) Huang, S. B.; Nelson, J. S.; Weller, D. D. Synth. Commun. 1989,
19, 3485-3496. (b) McIntosh, J. M.; Acquaah, S. O. Can. J. Chem. 1988,
66, 1752-1756. (c) Davis, F. A.; Szewczyk, J. M. Tetrahedron Lett. 1998,
39, 5951-5954. (d) Josephshon, N. S.; Snapper, M. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2004, 126, 3734-3735. (e) Bates, R. W.; Boonsombat, J.
Org. Biomol. Chem. 2005, 3, 520-523. (f) Enders, D.; Tiebes, J. Liebigs
Ann. Chem. 1993, 173-177.
(16) (a) Polniaszek, R. P.; Belmont, S. E.; Alvarez, R. J. Org. Chem.
1990, 55, 215-223. (b) Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett.
1994, 35, 2223-2226. (c) Suzuki, H.; Aoyagi, S.; Kibayashi, C. J. Org.
Chem. 1995, 60, 6114-6122.
(17) (a) Amat, M.; Llor, N.; Hidalgo, J.; Hernandez, A.; Bosch, J.
Tetrahedron: Asymmetry 1996, 7, 977-980. (b) Teran, J. L.; Gnecco, D.;
Galindo, A.; Juarez, J.; Berne`s, S.; Enriquez, R. G. Tetrahedron: Asymmetry
2001, 12, 357-360.
(18) (a) Varea, T.; Dufour, M.; Micouin, L.; Riche, C.; Chiaroni, A.;
Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett. 1995, 36, 1035-1038. (b)
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Chem. Soc., Perkin Trans. 1 2002, 2459-2472.
2474
Org. Lett., Vol. 9, No. 13, 2007

Table 1. Compounds 3, 1, 5, 6, and 7 Prepareda
yield, %
R
hydrazone
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
dienehydrazide
enehydrazide
hydrazide
(S,S)-6a
(S,S)-6b
(S,S)-6c
(S,R)-6d
(S,R)-6e
δ-lactam
(S)-7a
(S)-7b
(S)-7c
(R)-7d
(R)-7e
Et
Pr
Bu
Ph
85
90
87
80
83
(S,S)-1a
(S,S)-1b
(S,S)-1c
(S,R)-1d
(S,R)-1e
50
(S,S)-5a
(S,S)-5b
(S,S)-5c
(S,R)-5d
(S,R)-5e
73
95
97
95
93
98
80
78
83
85
80
52
45
49
54
68
65
70
75
p-MeOC6H4
1
a The diastereomeric excess de g98% was determined by H NMR and 13C NMR spectroscopy after flash chromatography. For all compounds the de
values were about the same before and after purification by chromatography.
SAMP hydrazones and subsequent acylation with acryloyl
chloride with a ring-closing metathesis (RCM) for the
synthesis of diastereochemically pure cyclic enehydrazides,
suitable candidates for the asymmetric synthesis of 6-alkyl-
or 6-arylpiperidin-2-ones.
commercially available Grubb’s ruthenium catalysts, which
is the less expensive first generation benzylidenebis(tri-
cyclohexylphosphine)dichloro-ruthenium I and the recent
second generation benzylidene[1,3-bis(2,4,6-trimethylphen-
yl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)-
ruthenium II in CH2Cl2 at rt or at reflux. The diolefinic
hydrazide 1a was chosen as the starting material for our
study. In all cases ring closure proceeded smoothly with
yields ranging from 32% to 75% but Grubb’s catalyst II
performed significantly better than its analogue I. The best
results were obtained by employing 5% of catalyst II at rt
in CH2Cl2 for 24 h and these optimal conditions were then
used to perform the annulation reactions of diolefinic
substrates 1b-e. Results are presented in Table 1 where it
can be seen that this simple procedure afforded very
satisfactory yields of the virtually diastereochemically pure
cyclic enehydrazides (S,S)-5a-c and (S,R)-5d,e. At this stage
it should be a priori possible to effect both the RCM reaction
and the subsequent reduction of the double bond as a single
operation by using the same ruthenium catalyst.21 However,
this possibility was not investigated since the double bond
of 5, still equipped with the chiral auxiliary, provides a useful
chemical handle for alternative functionalization chemistries.
Catalytic hydrogenation proceeded uneventfully to provide
excellent yields of the corresponding hydrazides (S,S)-6a-c
and (S,R)-6d,e. The subsequent removal of the chiral
auxiliary was readily achieved by cleavage of the N-N bond
upon treatment of 6a-e with magnesium monoperoxy-
phthalate (MMPP) in MeOH and this operation delivered
the virtually enantiopure (S)-6-alkyl- and (R)-6-arylpiperidin-
2-one, (S)-7a-c and (R)-7d,e, respectively, with excellent
yields (Table 1). The absolute configuration as well as the
enantiopurity of these δ-lactams were determined by com-
paring the optical rotation values with that of authentic
samples assembled by conceptually different synthetic routes,
thus confirming the stereochemistry of the original addition
The first facet of the synthesis was the elaboration of the
diolefinic hydrazides 1a-e. These highly conjugated precur-
sors were easily obtained by the three-step sequence depicted
in Scheme 1. Initially the appropriate aliphatic and aromatic
carboxaldehydes 2a-e were converted into the corresponding
chiral hydrazones (S)-3a-e by simply mixing the enantio-
merically pure hydrazine (S)-(-)-1-amino-2-(methoxymeth-
yl)pyrrolidine (SAMP) with the commercially available
aldehydes 2a-e. Owing to the sensitivity of hydrazones to
nucleophilic attacks and to the high degree of stereoselec-
tivity observed upon reaction of SAMP hydrazones with
organometallic reagents, a property aptly exploited by
Enders,19 the subsequent installation of the mandatory olefinic
entities was performed as a single one-pot reaction. Chiral
hydrazones (S)-3a-e were allowed to react with allyllithium
and the transient lithium hydrazide salt 4 was intercepted
with acryloyl chloride in the sequel. Gratifyingly, conducting
this operation under this procedure afforded excellent yields
of the requisite opened dienehydrazides (S,S)-1a-c and
(S,R)-1d,e (Table 1). These olefinic precursors were obtained
essentially as single diastereomers detectable by NMR (de
g98% after chromatographic treatment) making evident the
high selectivity of the initial diastereofacial 1,2-addition
process19 allowing introduction of the absolute stereochem-
istry early in the sequence. With the properly substituted
dienehydrazides 1 in hand we next examined ring-closing
metathesis conditions to achieve the chiral R,â-unsaturated
piperidones 5. The olefin metathesis reaction has been widely
used in the recent past as a result of the development of
highly stable and active ruthenium alkylidene catalysts.2d,20
To ensure the optimal formation of the annulated compounds,
RCM reactions were carried out with variable amounts of
reaction, e.g., 7b {[R]20D +17.9 (c 0.5, CHCl3); lit.13c [R]22
D
+18.1 (c 0.6, CHCl3)} and 7d {[R]20D +58.5 (c 1.0, CHCl3);
lit.13c [R]25 +58.2 (c 1.0, CHCl3)}.
(19) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253-2329.
D
To illustrate further the utility of this methodology in
natural product synthesis the procedure was applied to the
asymmetric synthesis of the naturally occurring (S)-2-
propylpiperidine alkaloid (S)-(+)-coniine (8), a popular target
(20) (a) Phillips, A. J.; Abell, A. D. Aldrichim. Acta 1999, 32, 75-89.
(b) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. Synlett 2000, 1461-
1463. (c) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J. Org. Chem.
2002, 67, 1982-1992. (d) Schultz-Fademrecht, C.; Deshmukh, P. H.;
Malagu, K.; Procopiou, P. A.; Barrett, A. G. M. Tetrahedron 2004, 60,
7515-7524. (e) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-
2238. (f) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Synthesis
2006, 3490-3494.
(21) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 11312-11313.
Org. Lett., Vol. 9, No. 13, 2007
2475

for the demonstration of chiral methodology in the piperidine
field.22,23 (S)-Coniine is a poisonous hemlock alkaloid
extracted from the plant Conium maculatum and from many
tropical subspecies.8 The choice of the 2-C substituted
pyrrolidine as the chiral auxiliary was rewarded here.
Treatment with the borane-THF complex of (S,S)-6b
followed by aqueous alkaline workup effected reductive
N-N bond cleavage with the concomitant reduction of the
lactam carbonyl group and final treatment with HCl in Et2O
afforded the target natural product 8 as its hydrochloride salt
(Scheme 2). The absolute configuration of the stereogenic
the unprecedented ring-closing metathesis of diastereopure
diolefinic hydrazides. The utility of the chiral building blocks
was illustrated by a five-step asymmetric synthesis of
piperidine alkaloid (S)-(+)-coniine. The main advantages of
this synthesis method lie in the small number of synthetic
steps and the ready availability of the aliphatic and aromatic
aldehyde SAMP hydrazone precursors. We believe that this
work provides a strong incentive for the elaboration of larger
or structurally modified alkaloids as well as their biogeneti-
cally related congeners.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org..
Scheme 2. Asymmetric Synthesis of (S)-(+)-Coniine
OL070757W
(22) For recent enantioselective syntheses see: (a) Wilkinson, T. J.;
Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155-158. (b) Andre´s, J. M.;
Herra´iz-Sierra, I.; Pedrosa, R.; Pe´rez-Encabo, A. Eur. J. Org. Chem. 2000,
1719-1726. (c) Bois, F.; Gardette, D.; Gramain, J.-C. Tetrahedron Lett.
2000, 41, 8769-8772. (d) Hunt, J. C. A.; Laurent, P.; Moody, C. J. J. Chem.
Soc., Chem. Commun. 2000, 1771-1772. (e) Eskici, M.; Gallagher, T.
Synlett 2000, 1360-1362. (f) Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829-11830.
(g) Hayes, J. F.; Shipman, M.; Twin, H. J. Chem. Soc., Chem. Commun.
2001, 1784-1785. (h) Xu, X.; Lu, J.; Li, R.; Ge, Z.; Dong, Y.; Hu, Y.
Synthesis 2004, 122-124. (i) Gommermann, N.; Knochel, P. J. Chem. Soc.,
Chem. Commun. 2004, 2324-2325. (j) Passarella, D.; Barilli, A.; Belin-
ghieri, F.; Fassi, P.; Riva, S.; Sacchetti, A.; Silvani, A.; Danieli, B.
Tetrahedron: Asymmetry 2005, 16, 2225-2229. (k) Girard, N.; Pouchain,
L.; Hurvois, J.-P.; Moinet, C. Synlett 2006, 1679-1682. (l) Nagata, K.;
Nishimura, K.; Yokoya, M.; Itoh, T. Heterocycles 2006, 70, 335-344. (m)
Itoh, T.; Nishimura, K.; Nagata, K.; Yokoya, M. Synlett 2006, 2207-2210.
(23) For the synthesis of coniine with use of the ring-closing metathesis,
see: (a) Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.;
Rodriguez-Solla, H. Synlett 2002, 1146-1148. (b) Pachamuthu, K.; Vankar,
Y. D. J. Organomet. Chem. 2001, 624, 359-363. (c) Kumareswaran, R.;
Hassner, A. Tetrahedron: Asymmetry 2001, 12, 2269-2276. (d) Hunt, J.
C. A.; Laurent, P.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 2002, 2378-
2389.
center was confirmed to be (S) from the sign of the specific
rotation of the hydrochloride and the enantiopurity of our
synthetic (S)-(+)-coniine [(S)-8] was clearly established from
the optical rotation and spectroscopic data that matched those
reported for the natural product {(S)-8, HCl: mp 215-216
°C, [R]20D +7.8 (c 0.5, EtOH); (S)-(+)-coniine, HCl: lit.3c
mp 216-217 °C, lit.22g [R]25 +8.1 (c 0.6, EtOH)}.
D
In conclusion we have devised a new, convenient, general,
and flexible method for the highly diastereo- and enantio-
selective synthesis of N-substituted and free NH 6-substituted
piperidin-2-ones. The key steps are the highly diastereo-
selective nucleophilic 1,2-addition to SAMP hydrazones and
2476
Org. Lett., Vol. 9, No. 13, 2007