Diastereoselective synthesis of 4-hydroxypiperidin-2-ones via Cu(I)-catalyzed reductive aldol cyclization

Article abstract of DOI:10.1021/ol052599j

(Chemical Equation Presented) 4-Hydroxypiperidin-2-ones may be prepared in highly diastereoselective fashion using a Cu(I)-catalyzed reductive aldol cyclization of αβ-unsaturated amides with ketones. Used in combination with proline-catalyzed asymmetric M

Full text of DOI:10.1021/ol052599j

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5743-5746
Diastereoselective Synthesis of
4-Hydroxypiperidin-2-ones via
Cu(I)-Catalyzed Reductive Aldol
Cyclization†
Hon Wai Lam,* Gordon J. Murray, and James D. Firth
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings,
West Mains Road, Edinburgh EH9 3JJ, United Kingdom
h.lam@ed.ac.uk
Received October 27, 2005
ABSTRACT
4-Hydroxypiperidin-2-ones may be prepared in highly diastereoselective fashion using a Cu(I)-catalyzed reductive aldol cyclization of
r,â-
unsaturated amides with ketones. Used in combination with proline-catalyzed asymmetric Mannich reactions, this methodology enables the
enantioselective synthesis of more highly functionalized piperidin-2-ones and hydroxylated piperidines.
Metal-mediated cyclization reactions provide the basis for
many powerful methods of carbocyclic and heterocyclic ring
construction.1 Within this field, intramolecular reductive
aldol2 and Michael2c,h,3 reactions have proven to be of high
utility. These processes are initiated by the hydrometalation
of an R,â-unsaturated carbonyl compound, allowing the
regioselective generation of a metal enolate under mild
reaction conditions. Subsequent intramolecular trapping of
the enolate with an appropriate electrophile leads to the cyclic
product, often with high levels of diastereoselectivity. The
majority of such processes reported thus far have been
concerned with the preparation of carbocycles; however, we
recently reported a copper(I)-bisphosphine catalyzed reduc-
tive aldol cyclization (eq 1) that affords a variety of five-
† Dedicated to Prof. David A. Evans on the occasion of his 65th birthday.
(1) For representative examples, see: (a) Montgomery, J. Angew. Chem.,
Int. Ed. 2004, 43, 3890-3908. (b) Dounay, A. B.; Overman, L. E. Chem.
ReV. 2003, 103, 2945-2964. (c) Negishi, E.; Cope´ret, C.; Ma, S.; Liou,
S.-Y.; Liu, F. Chem. ReV. 1996, 96, 365-393. (d) Ojima, I.; Tzamarioudaki,
M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996, 96, 635-662.
(2) (a) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691-694. (b)
Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143-1146. (c) Wang,
L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.; Schultz, A. J.; Wang, X.; Krische,
M. J. J. Am. Chem. Soc. 2002, 124, 9448-9453. (d) Jang, H.-Y.;
Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 15156-
15157. (e) Chiu, P.; Leung, S. K. Chem. Commun. 2004, 2308-2309. (f)
Chiu, P.; Szeto, C.-P.; Geng, Z.; Cheng, K.-F. Org. Lett. 2001, 3, 1901-
1903. (g) Freir´ıa, M.; Whitehead, A. J.; Tocher, D. A.; Motherwell, W. B.
Tetrahedron 2004, 60, 2673-2692. (h) Miura, K.; Yamada, Y.; Tomita,
M.; Hosomi, A. Synlett 2004, 1985-1989.
(3) (a) Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.; Nomura, K.; Yoshii,
E. J. Org. Chem. 1992, 57, 2888-2902. (b) Hori, K.; Kazumo, H.; Nomura,
K.; Yoshii, E. Tetrahedron Lett. 1993, 34, 2183-2186. (c) Yoshii, E.; Hori,
K.; Nomura, K.; Yamaguchi, K. Synlett 1995, 568-570. (d) Yoshizaki,
H.; Tanaka, T.; Yoshii, E.; Koizumi, T.; Takeda, K. Tetrahedron Lett. 1998,
39, 47-50. (e) Takeda, K.; Ohkawa, N.; Hori, K.; Koizumi, T.; Yoshii, E.
Heterocycles 1998, 47, 277-282. (f) Suwa, T.; Nishino, K.; Miyatake, M.;
Shibata, I.; Baba, A. Tetrahedron Lett. 2000, 41, 3403-3406. (g) Kame-
necka, T. M.; Overman, L. E.; Ly Sykata, S. K. Org. Lett. 2002, 4, 79-82.
and six-membered â-hydroxylactones in moderate to good
yields and with moderate enantioselectivites when suitable
chiral bisphosphines are employed.4 Herein we describe the
extension of this process to the synthesis of 4-hydroxy-
piperidin-2-ones through the use of the corresponding
substrates containing an amide linkage in place of an ester.
(4) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225-4228.
10.1021/ol052599j CCC: $30.25
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Published on Web 11/15/2005

Table 1. Catalytic Reductive Aldol Cyclizations To Form 4-Hydroxypiperidin-2-onesa
a Reactions were conducted using 1.0 mmol of substrate, 5 mol % Cu, 5 mol % DPPF, and 1.0 mmol of TMDS in 5 mL of THF. b Isolated yield.
c Conducted using 0.2 mL of substrate, 5 mol % Cu, 5 mol % DPPF, and 0.2 mmol of TMDS in 2 mL of THF. d (EtO)2MeSiH (2.0 mmol) was employed
in place of TMDS. PMP ) p-methoxyphenyl, OMP ) o-methoxyphenyl.
To increase the synthetic versatility of the products, we
elected to examine the reactions of substrates 1 containing
a removal nitrogen substituent, and PMP (p-methoxyphenyl)
and OMP (o-methoxyphenyl) groups were chosen for this
study.5 N-Alkyl-N-arylamides such as 1 are known to exist
predominantly as the E-amide rotamer, with the aryl group
twisted such that the plane of the aromatic ring is ap-
proximately perpendicular to that of the amide group
(Scheme 1).6 At the outset of these investigations, it was
not clear whether this rotamer distribution would have any
impact on the ability of these substrates to undergo cycliza-
tion.
5 mol % 1,1′-bis(diphenylphosphino)-ferrocene (DPPF), and
1 equiv of 1,1,3,3-tetramethylhydrosiloxane (TMDS) in THF
at room temperature), a range of substrates 1a-k under-
went cyclization to form 4-hydroxypiperidin-2-ones 2a-k
(Table 1). The reaction proved to be tolerant to wide variation
in the ketone component, with alkyl (entries 1-3 and 7-10),
aromatic (entries 4, 5, and 11), and heteroaromatic (entry 6)
ketones reacting readily. However, the reaction was less
tolerant of substitution in the R,â-unsaturated carbonyl
component. Acryloyl amides were found to be the best
substrates, giving the desired piperidin-2-one products for
all cases examined (entries 1-6 and 9). Although crotonoyl
amides also underwent cyclization (entries 7, 8, 10, and 11),
reaction rates and conversions were generally lower.7 In
the case of substrate 1k, use of (EtO)2MeSiH in place of
TMDS proved to be beneficial (entry 11). The reactions
Scheme 1. Rotational Isomers of Cyclization Precursors 1
(5) PMP and OMP groups may be removed oxidatively, for example,
using ceric ammonium nitrate (CAN). See: (a) Kronenthal, D. R.; Han, C.
Y.; Taylor, M. K. J. Org. Chem. 1982, 47, 2765-2768. (b) Ishitani, H.;
Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 7153-7154. For
the removal of OMP groups using PhI(OAc)2, see: (c) Porter, J. R.;
Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001,
123, 10409-10410.
(6) (a) Pederson, B. F.; Pederson, B. Tetrahedron Lett. 1965, 6, 2995-
3001. (b) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.;
Shudo, K. Tetrahedron Lett. 1989, 30, 6177-6180. (c) Curran, D. P.; Hale,
G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandes, M.
Z.; Freitas, L. C. G. Tetrahedron: Asymmetry 1997, 8, 3955-3975.
(7) As the size of the substituent on the R,â-unsaturated amide is
increased further, the formation of uncyclized side products resulting
from both ketone reduction and conjugate reduction also becomes prob-
lematic.
In the event, using the conditions described previously for
the corresponding ester substrates4 (5 mol % Cu(OAc)2‚H2O,
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Org. Lett., Vol. 7, No. 25, 2005

Table 2. Formation of C5- and C6-Substituted
4-Hydroxypiperidin-2-onesa
Figure 1. Possible reactive conformations for the cyclization of
substrates 3a-d.
moderate to excellent levels of 1,2- and 1,3-asymmetric
induction in these reactions may be rationalized by invoking
the chelated chairlike conformations A-D shown in Figure
1, with substituents in the tether linking the amide enolate
and the ketone preferring to adopt pseudoequatorial posi-
tions.11
The synthetic utility of the piperidinone products was
illustrated by a number of transformations. Reductive
removal of the carbonyl group allows entry to the piperidine
ring system, a ubiquitous structural feature of many natural
products and biologically important compounds.12 For ex-
ample, treatment of 1d with borane at reflux provided
piperidine 5 in good yield, which could be converted into 6
by oxidative removal of the PMP group5c followed by in
situ treatment of the resulting amine with Boc2O (Scheme
2). The amide reduction of piperidin-2-ones 4c and 4d with
a Reactions were conducted using 0.2 mmol of substrate, 5 mol % Cu,
5 mol % DPPF, and 0.2 mmol of TMDS in 2 mL of THF for 2-24 h.
b Determined by 1H NMR analysis of the unpurified reaction mixtures.
Minor diastereomers (not shown) are assumed to possess inverted configura-
tions at C3 and C4. c Isolated yield of major diastereomer.
Scheme 2. Conversion of Piperidinone Products into
Piperidines
1
proceeded with high diastereoselectivities (>95:5 by H
NMR analysis), and the relative configurations of the
products8 were found to match those of the lactone products
described previously.4
We next examined the effect of preexisting stereocenters
in the tether linking the amide and the ketone on the
diastereoselectivity of the process (Table 2). Acrylamide 3a,
containing a methyl substituent R to the ketone, cyclized to
give a mixture of two diastereomers in a ratio of 8:1, from
which piperidinone 4a was isolated in 78% yield (entry1).
By employing L-proline-catalyzed direct asymmetric Man-
nich reactions to prepare the requisite â-aminoketones,9 we
were able to access acrylamides 3b-3d in enantiomerically
enriched form, and these cyclized to give piperidinones 4b-
4d, respectively, as the major products (entries 2-4).10 The
borane was accompanied by reduction of the ethyl esters to
give piperidines 7 and 8, respectively. Polyhydroxylated
piperidines are of considerable biological interest due to their
potential to act as glycosidase inhibitors.13
(8) The relative configurations of the piperidinones 2a, 2d, and 2g were
confirmed by X-ray crystallography. See Supporting Information for details.
The stereochemistries of the remaining products were assigned by analogy.
(9) (a) Notz, W.; Watanabe, S.-I.; Chowdari, N. S.; Zhong, G.; Betancort,
J. M.; Tanaka, J.; Barbas, C. F., III. AdV. Synth. Catal. 2004, 346, 1131-
1140. See also: (b) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J.
Am. Chem. Soc. 2002, 124, 827-833. (c) List, B. J. Am. Chem. Soc. 2000,
122, 9336-9337.
(10) The stereochemistries of the piperidinones 4a, 4c, and 4d were
determined by X-ray crystallography. Analysis of 1H NMR coupling
constants was used to establish the stereochemistry of 4b. See Supporting
Information for details.
(11) For related cyclizations involving the SmI2-promoted intramolecular
Reformatsky reactions of â-haloacetoxyketones and an excellent discussion
of the factors determining the stereochemical outcomes, see: Molander,
G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.-J. J. Am. Chem. Soc. 1991,
113, 8036-8045.
(12) For reviews of piperidine synthesis, see: (a) Weintraub, P. M.; Sabol,
J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953-2989.
(b) Laschat, S.; Dickner, T. Synthesis 2000, 1781-1813.
Org. Lett., Vol. 7, No. 25, 2005
5745

In summary, we have applied copper(I)-catalyzed reductive
aldol cyclizations to the highly diastereoselective synthesis
of 4-hydroxypiperidin-2-ones. L-Proline-catalyzed Mannich
reactions may be used to prepare more highly substituted
cyclization precursors in enantiomerically enriched form,
enabling the enantioselective synthesis of piperidin-2-ones
and piperidines. Current work is focused on identifying
catalyst systems that allow a greater range of substituted R,â-
unsaturated amides to become viable substrates, developing
enantioselective variants of this process, and applying this
methodology to other substrate classes. The results from these
studies will be reported in due course.
Acknowledgment. This work was supported by the
University of Edinburgh, the Nuffield Foundation (NAL/
00827/G), and the Royal Society (2004/R1). AstraZeneca
and Merck Sharp & Dohme are gratefully acknowledged for
generous unrestricted research funding. The EPSRC National
Mass Spectrometry Service Centre at the University of
Wales, Swansea is thanked for their assistance.
Supporting Information Available: Experimental pro-
cedures, full spectroscopic data for all new compounds, and
crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) For a recent review, see: Pearson, M. S. W.; Mathe´-Allainmat, M.;
Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159-2191.
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