Enantioselective syntheses of 2-alkyl- and 2,6-dialkylpiperidine alkaloids: preparations of the hydrochlorides of (-)-coniine, (-)-solenopsin A, and (-)-dihydropinidine.

Article abstract of DOI:10.1021/ol9912534

[reaction: see text] Sequences of lithiation-substitution, enantioselective hydrogenation, and diastereoselective lithiation-substitution provide efficient highly enantioselective syntheses of 2-substituted and cis and trans 2,6-disubstituted piperidines.

Full text of DOI:10.1021/ol9912534

ORGANIC
LETTERS
2000
Vol. 2, No. 2
155-158
Enantioselective Syntheses of 2-Alkyl-
and 2,6-Dialkylpiperidine Alkaloids:
Preparations of the Hydrochlorides of
(−)-Coniine, (−)-Solenopsin A, and
(−)-Dihydropinidine
Timothy J. Wilkinson, Nathan W. Stehle, and Peter Beak*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
beak@scs.uiuc.edu
Received November 17, 1999
ABSTRACT
Sequences of lithiation−substitution, enantioselective hydrogenation, and diastereoselective lithiation−substitution provide efficient highly
enantioselective syntheses of 2-substituted and cis and trans 2,6-disubstituted piperidines. The methodology is demonstrated by syntheses
of (−)-coniine, (−)-solenopsin A, and (−)-dihydropinidine as their hydrochlorides.
Direct elaborations of N-Boc amines by lithiation-substitu-
tion reactions offer opportunities for convenient and efficient
syntheses of alkaloid ring systems. The piperidine family,
which includes many compounds with useful pharmacologi-
cal properties, has been a target of particular interest.1
Enantioselective syntheses of members of this family, (-)-
coniine2 (1), (-)-solenopsin A2ab,3 (2) and (-)-dihydro-
pinidine2cd,4 (3) have been the focus of many studies.
We wish to report that lithiation-substitution and asym-
metric hydrogenation can be used as key steps in convenient
and efficient syntheses of highly enantioenriched 2-substi-
tuted and cis and trans 2,6-disubstituted piperidines from
commercially available materials. This methodology is
demonstrated for preparations of the hydrochlorides of the
(1) For a review, see Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem.
Comm. 1998, 633 and references therein.
(o) Nazabadioko, S.; Perez, R.; Brieva, R.; Gotor, V. Tetrahedron:
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10.1021/ol9912534 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/18/1999

alkaloids 1-3 from N-Boc-3-methoxy piperidine and N-Boc-
δ-valerolactam via (S)-N-Boc-pipecolic acid.
tetrahydropyridine with (R)-BINAP-RuCl2, as reported by
Foti and Commins, gives an (S)-configured product in 52%
yield with an er of 90:10.7 It is interesting that their ester,
which differs from the methyl ester of 4 only by a tert-butyl
group vs a phenyl group on the N-carboxy function, gives a
product that has the same configuration as we observe,
although they use the catalyst of the opposite configuration.7,8
Changes in the facial selectivity in reductions with chiral
Ru(II) complexes at different pressures are known, although
changes to this degree are unusual.5b
Asymmetry is introduced into the piperidine ring by the
enantioselective hydrogenation of 2-carboxy-N-Boc-1,4,5,6-
tetrahydropyridine (4) with the Noyori catalyst5 (S)-BINAP-
RuCl2 to yield (S)-N-Boc-pipecolic acid (5) in high enan-
tioenrichment after one recrystallization as shown in Scheme
1. Prior to recrystallization, 5 is obtained in 95% yield with
The precursor to (S)-N-Boc-pipecolic acid (5), 2-carboxy-
N-Boc-1,4,5,6- tetrahydropyridine (4), was prepared by either
of two methods as shown in Scheme 2. Following our
Scheme 2
Scheme 1
an er of 98:2 as shown in Table 1. The table also shows that
reductions of the N-tert-butyl amide, the N-(3,5-dimethyl)
phenyl amide, the N, N-diethyl amide, and the methyl ester
corresponding to 4 with (S)-BINAP-RuCl2 provided the
Table 1. Reduction of 4 and Derivatives with
(S)-BINAP-RuCl2
previous report, 3-hydroxypiperidine hydrochloride (6) was
reacted with (Boc)2O to afford 7 in 83% yield.9 Treatment
of 7 with sodium hydride and iodomethane gave 8 in 89%
yield. The reaction of 8 with 2 equiv of s-BuLi/TMEDA
(-78 °C, 5 h), followed by the addition of carbon dioxide,
afforded 4 in 80% yield.9 In an alternative sequence,
δ-valerolactam (9) was reacted with (Boc)2O and DMAP in
acetonitrile to afford 10 in 79% yield. Reduction with
DIBALH gave lactamol 11, which was dehydrated without
purification with p-TsOH in toluene to provide the enecar-
bamate 12 in 86% yield from 10 following the procedure of
Dieter.10 When 12 was reacted with s-BuLi/TMEDA, under
conditions similar to those used for the conversion of 8 to
4, low yields of 4 were obtained. A yield of 52% of 4 was
Y
yield (%)
er
OH
95
99
78
83
66
98:2
98:2
96:4
87:13
73:27
NH-t-Bu
NH-3,5-Me2C6H3
N(C2H5)2
OCH3
expected enantioenriched reduction products in 99%, 78%,
83%, and 66% yields with ers of 98:2, 96:4, 87:13, and 73:
27, respectively. Reductions of 4 with (S)-BINAP-Rh(I),
(R, R)-DIPAMP-Rh(I) gave the racemic acid, while (R, R)-
Me-DuPhos-Rh(I) afforded the product with an er of 71:
29.6 Reduction of 2-carboxymethyl-N-phenoxycarbonyl 1,4,5,6-
(5) (a) Noyori, R.; Ohkuma, T.; Kitamura, M. J. Am. Chem. Soc. 1987,
109, 5856. See also (b) Noyori, R. Asymmertic Catalysis In Organic
Synthesis; Wiley-Interscience: New York, 1994; Chapter 2. (c) Saburi, M.;
Shao, L.; Sakaurai, T.; Uchida, Y. Tetrahedron Lett. 1992, 33, 7877.
(6) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souichi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Miyahsita,
A.; Takaya, H.; Souichi, T.; Noyori, R. Tetrahedron 1984, 40, 1245. (c)
Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. J. Org. Chem.
1987, 52, 3174. (d) Mashima, K.; Kusano, K.; Ohta, T.; Noyori, R.; Takay,
H. J. Chem. Soc., Chem. Commun. 1989, 1209. (e) Kawano, H.; Ikariya,
T.; Ishii, X.; Saburi, M.; Uchida, Y.; Kumobayashi, H. J. Chem. Soc., Perkin
Trans 1 1989, 1571. (f) Saburi, M.; Shao, L.; Sakurai, T.; Uchida, Y.
Tetrahedron Lett. 1992, 33, 7877. (g) Vineyard, B. D.; Knowles, W. J.;
Sabacky, M. J.; Bachman, G. L.; Weinkauff, D. J. J. Am. Chem. Soc. 1977,
99, 5946-5952. (h) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106. (i)
Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem.
Soc. 1993, 115, 10125-10138. (j) Burk, M. J.; Wang, X. M.; Lee, J. R. J.
Am. Chem. Soc. 1996, 118, 5142-5143. (k) Ojima, I.; Kogure, T.; Yoda,
N. J. Org. Chem. 1980, 45, 4728-4739.
(7) Foti, C. J.; Comins, D. L. J. Org. Chem. 1995, 60, 2656-2657.
(8) For mechanistic analysis of related reactions, see (a) Chan, A. S. C.;
Pluth, J. J.; Halpern, J. J. Am. Chem. Soc. 1980, 102, 5952. (b) Chua, P. S.;
Roberts, N. K.; Bosnich, B.; Okrasinski, S. J.; Halpern, J. J. Chem. Soc.,
Chem. Commun. 1981, 1278. (c) Landis, C. L.; Halpern, J. J. Am. Chem.
Soc. 1987, 109, 1746-1754. (d) Ashby, M. T.; Halpern, J. J. Am. Chem.
Soc. 1991, 113, 589-594.
(9) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109.
(10) Dieter, R. K.; Sharma, R. R. J. Org. Chem. 1996, 61, 4180.
156
Org. Lett., Vol. 2, No. 2, 2000

achieved in the reaction of 12 with n-BuLi/TMEDA (-65
to -30 °C, 30 min), followed by treatment with carbon
dioxide. The crude product from this reaction contained
approximately 25% 5-nonanone, based on its 1H NMR
spectrum, indicating that nucleophilic additions of n-BuLi
to carbonyl groups can be competitive with the lithiation of
12 by n-BuLi.
Pd/C then gave 18 in 95% yield. Lithiation of 18 with
s-BuLi/TMEDA followed by treatment with dimethyl sulfate
provided 19 in 80% yield as shown in Scheme 4.3a,f,5
Scheme 4
The formation of 4 from 12 is considered to occur by
metalation at the vinyl position, followed by reaction of the
vinyllithium intermediate with carbon dioxide. A reasonable
pathway for the conversion of 8 to 4 is initial lithiation
adjacent to nitrogen followed by elimination of methoxide
to afford 12.9 However, the lower yield of 4 from the direct
reaction of 12 with s-BuLi (vide supra) and the failure of
12 to give increased yields of 4 in the presence of lithium
methoxide suggests that these reactions have similar but
different pathways.
The enantioselective formation of 5 combined with our
previous studies of diastereoselectivities in lithiation-
substitutions of substituted N-Boc-piperidines provides a
basis for convenient syntheses of highly enantioenriched
2-substituted and 2,6-disubstituted piperidine alkaloids. The
following syntheses are based on previous syntheses.9
(-)-Coniine Hydrochloride (1‚HCl). Reduction of 5 with
BH3 ‚THF provided alcohol 13 in 97% yield. The alcohol
13 was oxidized by the Katzenellenbogen modification of
the Swern oxidation to provide aldehyde 14, which was
immediately reacted with the ylide of (ethyl)triphenylphos-
phonium bromide to afford 15 in 79% overall yield based
on 13.2no,5,11 Catalytic hydrogenation of 15 with 5% Pd/C
provided 16 in 93% yield as shown in Scheme 3. Treatment
Deprotection with HCl-MeOH gave (-)-solenopsin A
hydrochloride (2‚HCl) in 97% yield. The overall yield from
5 is 56%. Mp 148-149 °C (lit.3c 147-150 °C); [R]20D -8.2
(c 0.5, CHCl3) (lit.3c [R]20 -7.7 (c 0.51, CHCl3)).
D
(-)-Dihydropinidine Hydrochloride (3‚HCl). Treatment
of 16 with s-BuLi/TMEDA followed by DMF afforded a
10:90 cis-trans mixture of aldehydes, based on the 1H NMR
spectrum of the crude product. The aldehyde mixture was
isomerized with silica gel to provide an 83:17 cis-trans
mixture from which 20 was obtained in 74% yield by flash
chromatography.5,13 Reduction of 20 with sodium borohy-
dride gave 21 in 85% yield. Deoxygenation of 21 was
accomplished in two steps by a Barton deoxygenation.14
Alcohol 21 was converted to the thionocarbonate 22 in 88%
yield by the reaction with phenylchlorothionoformate/DMAP.
Reduction with tributyltin hydride/AIBN followed by reflux
with TBAF provided 23 in 48% yield. Deprotection of 23
with HCl-methanol afforded (-)-dihydropinidine hydro-
chloride (3‚HCl) in 90% yield as shown in Scheme 5. The
Scheme 3
Scheme 5
of 16 with HCl-methanol afforded (-)-coniine hydrochlo-
ride (1‚HCl) in 98% yield. The overall yield from 5 is 70%.
Mp 219-220 °C (lit.2c 218-221 °C); [R]20D -6.5° (c ) 1.0,
EtOH) (lit.2c [R]20 -7.3° (c 1.0, MeOH)).
D
(-)-Solenopsin A Hydrochloride (2‚HCl). Reaction of
aldehyde 14 with the ylide of (decyl)triphenylphosphonium
iodide afforded 17 in 79% yield.12 Hydrogenation with 10%
(11) Reed, P. E.; Katzenellenbogen, J. A., J. Org. Chem. 1991, 56, 2624.
(12) Chasin, D. G.; Perkins, E. G. Chem. Phys. Lipids 1971, 6, 8.
(13) A related isomerization was reported with K2CO3-methanol:
Kotsuki, H.; Kusumi, M. I.; Ushio, Y.; Ochi, M. Tetrahedron Lett. 1991,
32, 4159.
Org. Lett., Vol. 2, No. 2, 2000
157

as a result of A1,3 strain, provides 24 and 25 in which the
lithium is equatorial.9,15 Subsequent methylation of 24 occurs
with retention of configuration to afford 19. Similarly, 16
provides 26 via 25. In this case, however, A1,3 strain provides
a driving force for equilibration to afford 20.9,15 The reactions
are outlined in Scheme 6. The stereochemical outcomes of
the reactions leading to cis or trans 2,6-disubstituted pip-
eridines are consistent with principles that should be ap-
plicable to related systems.
Scheme 6
Because both enantiomers of the catalyst are commercially
available, both (S)-and (R)-N-Boc-pipecolic acid can be
prepared with high enantiointegrity.5 The diastereoselectivi-
ties of subsequent lithiation-substitution and equilibration
allows a high degree of stereochemical control. Although
the present syntheses afford alkyl-substituted piperidines, this
approach can provide highly enantioenriched 2-substituted
and cis and trans 2,6-disubstituted piperidine rings with many
functionalities and with any desired absolute configuration.
overall yield from 5 was 17%. Mp 242-243 °C (lit.4b 234
°C); [R]20 -13.3° (c 1.0, EtOH) (lit.4b [R]20 -12.74° (c
0.47 EtOH)).
The flexibility of this methodology, in accessing both cis
and trans 2,6-disubstituted piperidines, lies in the structure
and reactivity of the intermediate lithiated N-Boc piperidines.9
Lithiations of 16 and 18, in which the 2-substituent is axial
Acknowledgment. We are grateful to the National
Institutes of Health (GM-18874) and the National Science
Foundation (NSF-19422) for support of this work. Tim
Wilkinson is grateful to Wheaton College for sabbatical
support.
D
D
Supporting Information Available: Full experimental
details for the syntheses reported are provided. This material
is available free of charge via the Internet at http://pubs.acs.org
(14) Robins, M. J.; Wilson, J. S.; Hanssla, F. J. Am. Chem. Soc. 1983,
105, 4059.
(15) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
OL9912534
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