Synthesis of enantiopure substituted piperidines via an aziridinium ring expansion

Article abstract of DOI:10.1021/ol201349k

Herein we report a novel methodology for the asymmetric synthesis of 3-substituted piperidines from readily available chiral building blocks. This method, which features a novel irreversible dihydropyrole-tetrahydropyridine ring expansion, allows the intr

Full text of DOI:10.1021/ol201349k

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3830–3833
Synthesis of Enantiopure Substituted
Piperidines via an Aziridinium Ring
Expansion
Scott B. D. Jarvis and Andre B. Charette*
ꢀ
Department of Chemistry, Universite de Montreal, P.O. Box 6128, Station Downtown,
Montreal, Quebec, Canada, H3C 3J7
ꢀ
andre.charette@umontreal.ca
Received May 18, 2011
ABSTRACT
Herein we report a novel methodology for the asymmetric synthesis of 3-substituted piperidines from readily available chiral building blocks. This
method, which features a novel irreversible dihydropyrole-tetrahydropyridine ring expansion, allows the introduction of a large variety of
substituents at the 3-position and permits substitution at the 2- and 6-position giving mono-, di-, or trisubstituted piperidines with high
diastereocontrol.
Substituted piperidines are widespread subunits in natural
products and pharmaceuticals. Twenty-three of the “Top
200 Brand-Name Drugs by RetailDollars in 2009” contain
piperidine fragments.1 Consequently, their synthesis has
garnered much attention;2 however, the construction of
enantiopure 3-substituted piperidines still remains a sig-
nificant synthetic challenge (Scheme 1). The most common
ways to access these molecules are (a) hydrogenation of
pyridines followed by a resolution of the enantiomers by
diastereomeric salt separation;3 (b) alkylation and reduction
of oxazolopiperidones;4 and (c) ring expansion under ther-
modynamic control via an aziridinium salt from prolinol to
yield 3-halo and 3-O-acylated piperidines.5 Another ap-
proach involving an iridium-catalyzed enantioselective hy-
drogenation was recently developed by Andersson (d).6
Scheme 1. Methods To Prepare Chiral 3-Substituted Piperidines
(1) “Pharmaceutical Sales 2009. “Drug information online, Drugs.
com. April 5, 2011: http://www.drugs.com/top200_units.html.
(2) (a) Beng, T. K.; Gawley, R. E. J. Am. Chem. Soc. 2010, 132, 12216.
(b) Lovick, H. M.; Michael, F. E. J. Am. Chem. Soc. 2010, 132, 1249. (c)
Lemonnier, G. R.; Charette, A. B. J. Org. Chem. 2010, 75, 7465. (d)
Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234. (e) Barbe, G.;
St-Onge, M.; Charette, A. B. Org. Lett. 2008, 10, 5497. (f) Legault, C. Y.;
Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966. (g) Pattenden, L. C.;
Wybrow, R. A. J.; Smith, S. A.; Harrity, J. P. A. Org. Lett. 2006, 8, 3089.
(h) Kobayashi, T.; Hasegawa, F.; Tanaka, K.; Katsumura, S. Org. Lett.
2006, 8, 3813. (i) Goodenough, K. M.; Moran, W. J.; Raubo, P.; Harrity,
J. P. A. J. Org. Chem. 2005, 70, 207. (j) Poupon, E.; Francois, D.;
Kunesch, N.; Husson, H. P. J. Org. Chem. 2004, 69, 3836. (k) Good-
enough, K. M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A. J. Org. Chem.
2004, 70, 207. For reviews, see:(l) Buffat, M. G. P. Tetrahedron 2004, 60,
1701. (m) Escolano, C.; Amat, M.; Bosch, J. Chem.;Eur. J. 2006, 12,
8198. (n) Cossy, J. Chem. Rec. 2005, 5, 70.
These methods, although efficient, suffer from several
drawbacks including a dearth of substrate scope, lack of
(3) For an example, see: Grayson, N. A.; Bowen, W. D.; Rice, K. C.
Heterocycles 1992, 34, 2281.
r
10.1021/ol201349k
Published on Web 06/28/2011
2011 American Chemical Society

general conditions, the required separation of diastereo-
meric mixtures, limited substitution at other points on the
piperidine, and/or inability to yield enantiopure products.
Therefore, a new method giving access to enantiopure
3-substituted piperidines would be highly desirable.
Herein we report the highly efficient and versatile synth-
esis of enantiopure 3-substituted piperidines from easily
accessible chiral building blocks. The key step involves an
unprecedented irreversible regioselective nucleophilic ring
opening of an aziridinium salt leading to a ring expansion
process.
R,β-unsaturated aziridinium that would be produced from
a substituted dihydropyrole, as shown in Figure 1B. This
intermediate would then be reacted with nucleophiles in a
regioselective manner to yield the desired tetrahydropy-
ridine. We theorized that the SN20 product should be
precluded due to the lack of significant orbital overlap
between the π electrons of the alkene and the σ* of the
bridged CꢀN bond of the aziridinium due to the confor-
mational constraint of the bicyclic system. However, the
unsaturation should still be capable of activating the allylic
position and of reducing the undesired attack at the least
hindered position (d).
Cossy described an elegant and related prolinol/piperidine
ring expansion process involving halides and trifluoro-
acetate as nucleophiles (Figure 1A, b).5 This ring expan-
sion process succeeds only if the nucleophile is also a good
leaving group. The piperidine, the major product, derives
from the thermodynamic equilibrium between the two
constitutional isomers (piperidine vs pyrrolidine) through
an aziridinium intermediate.5,7 When such an aziridinium
salt is produced from either an N-alkyl-2-halomethyl-
pyrrolidine or an N-alkyl-3-halopiperidine and treated with
a nucleophile that is a poor leaving group such as an aryl-
cuprate, carbanion, amine, or acetate, then the 2-substituted
pyrrolidine is obtained selectively (Figure 1A, a).8 We
envisioned that achieving such a transformation with
nonlabile nucleophiles to form a piperidine as the kinetic
product selectively would require two important modifica-
tions: the use of a leaving group leading to an aziridinium
salt irreversibly and the use of a directing group favoring
nucleophilic attack at the more hindered electrophilic
center (c vsd). Directing groups, such as a carbonyl, enone,
or aryl, have been reported to override the steric demands
of aziridinium salts so that nucleophiles attack at the more
hindered carbon.9 We envisioned testing the opening of an
Figure 1. Ring expansion to piperidines via an aziridinium.
To accomplish this ring expansion and to avoid un-
desired reactive pathways the aziridinium was formed
cleanly and irreversibly by treating a hydroxymethylpyrro-
line with triflic anhydride in the presence of base atꢀ15 °C.
The choice of base was vital with the proton sponge
furnishing superior results. Temperature was also critical
with the aziridinium being unstable above ꢀ10 °C.10 The
aziridinium salt was then reacted with sodium dimethyl
malonate to produce the desired 3-substituted tetrahydro-
pyridine with a >99:1 ratio of tetrahydropyridine to
pyrroline, thus validating our hypothesis.
Withthe optimizedconditions in hand, wesubmitted the
aziridinium intermediate to a variety of nucleophiles and
were pleased to find the ring expansion proceeds smoothly
to substituted tetrahydropyridines (Table 1). Sodium bor-
odeuteride was an effective nucleophile to afford the
isotopically labeled tetrahydropyridine in a 77% yield
(entry 1). Carbon nucleophiles such as cyanide (entry 2),
malonate (entry 3), an ethyl cuprate (entry 6), and the first
reported example of an enamine reacting with an aziridi-
nium (entry 8) all produced the ring expansion product
in excellent yields. Variable substitution patterns at the
2-position of the piperidine were well tolerated for the ring
expansion (entries 3ꢀ5, and product 4). Nitrogen nucleo-
philes were well accepted with amide, carbamate, phthali-
mide, azide, amine, and anilines, giving good to excellent
(4) (a) Amat, M.; Lozano, O.; Escolano, C.; Molins, E.; Bosch, J. J.
Org. Chem. 2007, 72, 4431. (b) Amat, M.; Llor, N.; Hidalgo, J.;
Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919. (c) Amat, M.;
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Brunaccini, E.; Checa, B. a.; Perez, M.; Llor, N. R.; Bosch, J. Org. Lett.
2009, 11, 4370. (d) Nakamura, Y.; Burke, A. M.; Kotani, S.; Ziller, J. W.;
Rychnovsky, S. D. Org. Lett. 2009, 12, 72. (e) Gnecco, D.; Lumbreras,
A. M.; Teran, J. L.; Galindo, A.; Juarez, J. R.; Orea, M. L.; Castro, A.;
Enriquez, R. G.; Reynolds, W. F. Heterocycles 2009, 78, 2589.
(5) (a) Metro, T. X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2007, 72,
6556. (b) Cossy, J.; Dumas, C.; Pardo, D. G. Eur. J. Org. Chem. 1999,
1693. (c) Cossy, J.; Mirguet, O.; Pardo, D. G. Synlett 2001, 1575.
(6) Verendel, J. J.; Zhou, T. G.; Li, J. Q.; Paptchikhine, A.; Lebedev,
O.; Andersson, P. G. J. Am. Chem. Soc. 2010, 132, 8880.
ꢀ
(7) (a) D’Hooghe, M.; Catak, S.; Stankovic, S.; Waroquier, M.; Kim,
Y.; Ha, H. J.; Van Speybroeck, V.; De Kimpe, N. Eur. J. Org. Chem.
2010, 2010, 4920. (b) A noteable exception is the reaction with DAST
ꢀ
where the nitrogen protecting group is bulky; see: Dechamps, I.; Gomez
Pardo, D.; Cossy, J. Eur. J. Org. Chem. 2007, 2007, 4224.
(8) (a) Davis, F. A.; Deng, J. Tetrahedron 2004, 60, 5111. (b)
ꢀ
Villeneuve, G.; Cecyre, D.; Lejeune, H.; Drouin, M.; Lan, R.; Quirion,
R. Bioorg. Med. Chem. Lett. 2003, 13, 3847. (c) Tchelitcheff, P. Bull. Soc.
Chim. Fr. 1958, 736. (d) Biel, J. H.; Hoya, W. K.; Leiser, H. A. J. Am.
€
Chem. Soc. 1959, 81, 2527. (e) Heindl, C.; Hubner, H.; Gmeiner, P.
Tetrahedron: Asymmetry 2003, 14, 3153. (f) Davies, S. G.; Nicholson,
R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Savory, E. D.; Smith,
A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758.
(9) (a) Kim, Y.; Ha, H. J.; Yun, S. Y.; Lee, W. K. Chem. Commun.
2008, 4363. (b) Couturier, C.; Blanchet, A.; Schlama, T.; Zhu, J. P. Org.
Lett. 2006, 8, 2183. (c) Chuang, T. H.; Sharpless, K. B. Org. Lett. 2000, 2,
3555. (d) Andrews, D. R.; Dahanukar, V. H.; Eckert, J. M.; Gala, D.;
Lucas, B. S.; Schumacher, D. P.; Zavialov, I. A. Tetrahedron Lett. 2002,
43, 6121. (e) For a review on aziridinium opening, see: Metro, T. X.;
Duthion, B.; Pardo, D. G.; Cossy, J. Chem. Soc. Rev. 2010, 39, 89.
(10) See Supporting Information for optimization data.
Org. Lett., Vol. 13, No. 15, 2011
3831

yields (entries 9ꢀ17). Also, oxygen nucleophiles, such as
anacetate, phenoxide, oralcohol, all gavegood toexcellent
yields (entries 18ꢀ21). Sulfur nucleophiles and fluoride
gave moderate yields (entries 22ꢀ24). Substituting the
5-position of the pyrroline was also compatible with the
ring expansion, which could yield the 2,3,6-trisubstituted
tetrahydropyridine as a single diastereomer enantiopure
with either diastereomer at the 6-position available
(entries 25ꢀ26).
Table 1. Pyrrolinol Ring Expansion to Piperidines
The limitation in the choice of nucleophile appears to be
directly related to its basicity, which has been alluded to in
literature.9b For example, the sodium enolate of acetophe-
none furnished poor yields (<40%) with significant de-
composition; however, the enamine of acetophenone gave
a good yield to obtain 2h. Likewise, sodium ethoxide
decomposed the aziridinium to unidentifiable products;
however, relatively unreactive ethanol afforded the ether
2s in a good yield.
The stereochemical outcome of the reaction was further
investigated by substituting the pyrrolinemethanol moiety
with a methyl group (Table 1: R1 = CH3). The diaster-
eomeric purity and enantiomeric excess of the pyrroline-
methanol was preserved during the ring expansion to the
tetrahydropyridine, with the regioselectivity and relative
stereochemistry confirmed by NMR. In all cases, only one
isomer was observed after the ring expansion except when
the nucleophile was an alkyl organocuprate (entries 6
and 7; entry 6: ꢀ15 °C, 1:3 anti SN2:syn SN20). However,
decreasing the temperature of the reaction significantly
improved the selectivity (ꢀ78 °C, 18:1 anti SN2:syn SN20).
When no methyl substituent was present (R1 = H), only
one regioisomer was obtained (entries 3, 10, 16, and 22)
except for the organocuprate example where a 20:1 ratio
was observed (entry 7).
For our approach to be efficient, an expedient synthesis
of enantio- and diastereoenriched pyrrolinol derivatives
had to be conceived from cheap and commercially available
starting materials. trans-4-Hydroxyproline is a common
precursor for 3,4-dehydroproline,11 but we found it to be
suboptimal due the length of the synthesis and due to
partial epimerization occurring during the synthesis which
has been noted by others.11b,12 An enantioselective Birch
reduction of a pyrrole to a pyrroline with good enantios-
electivity has been reported by Donohoe;13 however, we
sought enantiopure material with the flexibility of substi-
tuting other positions with high diastereocontrol. These
limitations led us to consider using the PetasisꢀMannich
(PM) condensation as the key step to assemble the basic
core of 2-hydroxymethyldihydropyrrole units.
a Enantiomeric excess was the same as that of a pyrrolinol precursor
prepared from 4-hydroxyproline, 94% ee. b Run at ꢀ78 °C; obtained a
ratio of 18:1 of anti-2,3- to syn-2,5-disubstituted tetrahydropyridine.
c Obtained a 20:1 ratio of six- to five-membered ring. d Enantiomeric
excess was the same as that of the pyrrolinemethanol precursor, >99%
ee. e Obtained by analysis of the crude mixture by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard.
The PM condensation would allow us to prepare 1,
2-amino-alcohols with high enantiomeric purity and
diastereocontrol.14 A previous drawback of this elegant
reaction was that it required R-hydroxyaldehydes, which
are nontrivial to prepare in enantiopure form even at a
moderate scale. In situ deprotection of an enantiopure
R-siloxyether aldehyde with TBAF in the presence of a
vinylboronic acid and an allylic amine led to the PM
condensation product with excellent diastereoselectivity
(>99%) and yield. More importantly, the enantiomeric
purity of the precursors was maintained (Table 2).15 This
(11) (a) Dormoy, J. R. Synthesis 1982, 753. (b) Arakawa, Y.; Ohnishi,
M.; Yoshimura, N.; Yoshifuji, S. Chem. Pharm. Bull. 2003, 51, 1015.
(12) See Supporting Information for synthesis from 4-hydroxyproline.
(13) (a) Donohoe, T. J.; Thomas, R. E. Chem. Rec. 2007, 7, 180. (b)
Donohoe, T. J.; Freestone, G. C.; Headley, C. E.; Rigby, C. L.; Cousins,
R. P. C.; Bhalay, G. Org. Lett. 2004, 6, 3055.
(14) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120,
11798. (b) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3635. (c) Ritthiwigrom, T.; Pyne, S. G. Org. Lett. 2008,
10, 2769. (d) For a review, see: Candeias, N. R.; Montalbano, F.; Cal, P.
M. S. D.; Gois, P. M. P. Chem. Rev. 2010, 110, 6169.
(15) The products in entries 1 and 3 of Table 2 were determined to be
>99% ee (SFC on chiral stationary phase). Entries 4 and 5 combined
two enantiopure precursors to obtain the intermediate as a single
diastereomer.
3832
Org. Lett., Vol. 13, No. 15, 2011

greatly simplified the synthesis of the precursors as these
enantiopure aldehydes are trivial to prepare in signifi-
cant amounts. Therefore, this procedure was used to
prepare the precursors necessary to access 2,3,6-substi-
tuted tetrahydropyridine with high diastereocontrol
(entries 4ꢀ5 in Table 2 and entries 25ꢀ26 in Table 1).
The RCM of the PM products proceeded well under
typical conditions using Grubb’s second generation
catalyst to yield the 2-hydroxymethyldihydropyrroles,
even when done on the reaction mixture resulting from
the PM condensation (entry 5).
Scheme 3. Preparing Both the 2- and 3-Substituents of a Piper-
idine from a Common Intermediate
Table 2. PetasisꢀMannich and Ring Closing Metathesis
Moreover, to further show the versatility of this method,
we prepared 1c in two steps from commercially available
materials (Table 2). 1c can be easily prepared in either
enantiomeric form with enantiopurity. It can be used to
prepare 1f in a one-pot procedure with >99% ee (Scheme 2),
or 1c can be used to synthesize the versatile intermediate 1g
(Scheme 3). From 1g, both the 2- and 3-substituents of the
piperidine can be changed in three steps via aziridinium
intermediates to compounds such as 5. Finally, access to the
fully reduced substituted piperidines can be accomplished
upon treating tetrahydropyridines with hydrogen gas and
PtO2, or Pd(OH)2 on carbon.2c,e
In conclusion, we have developed a concise and flexible
asymmetric method to prepare substituted piperidines from
easily available enantiopure precursors. This method affords
3-substituted tetrahydropyridines with a large variety of nu-
cleophiles and with excellent regio- and stereocontrol. Appli-
cation of this methodology to assemble complex piperidine
containing natural products will be reported in due course.
Sequence To Prepare Substituted Pyrrolinols
yield 3
yield 1
entry
R1
CH3
R2
R3
products
(%)
(%)
1
2
3
4
5
H
H
3a, 1a
3b, 1b
3c, 1c
3d, 1d
1e
83
61
77
76
nd
70
71
65
68
35b
CH(CH3)2
CH2OHa
CH3
H
H
H
H
Bn
H
H
CH3
Bn
a Unprotected hydroxyaldehyde was used, and the TBAF treatment
was omitted. b Combined yield for the two steps, with the RCM done on
the mixture from the PM.
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC), the Canada Research Chair Pro-
gram, the Canada Foundation for Innovation, and the
Scheme 2. Synthesis of Chiral N-Bn-3,4-Dehydroprolinol 1f
ꢀ
Universite de Montreal.
ꢀ
Supporting Information Available. Experimental pro-
cedures for the preparation and spectroscopic data.
This material is free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
3833