SCHEME 1. Syn th esis of Ra cem ic
4-Hyd r oxyp ip er id on ea
A Ster eod iver gen t Ap p r oa ch to Su bstitu ted
4-Hyd r oxyp ip er id in es
Mandy K. S. Vink, Christien A. Schortinghuis,†
J ordy Luten, J an H. van Maarseveen,
Hans E. Schoemaker,‡ Henk Hiemstra, and
Floris P. J . T. Rutjes*,†
Institute of Molecular Chemistry, University of Amsterdam,
Nieuwe Achtergracht 129,
a
Reagents and conditions: (a) Oxone, H2O, pH 6; (b) NaCN,
1018 WS Amsterdam, The Netherlands
MgSO4, H2O; (c) SOCl2, MeOH (51% from 5); (d) 50 psi H2, PtO2,
MeOH (81%).
rutjes@sci.kun.nl
is selectively converted into the acid or the amide.6 This
method is particularly useful in the case of prochiral
glutaronitriles, where desymmetrization enables a yield
of 100%.7 Once at the lactam stage, N-acyliminium ion
chemistry can be applied to functionalize the piperidones
in a regioselective way.8
In this paper, we will detail the synthesis of both
diastereomeric forms of substituted 4-hydroxypiperidines
following two complementary routes, both involving
functionalization of the key lactam 7 via N-acyliminium
ion chemistry. Starting from commercially available
vinylacetic acid (5), racemic 4-hydroxypiperidin-2-one (7)
was efficiently prepared in four steps (Scheme 1). Oxone-
mediated epoxidation of the double bond,9 followed by
ring opening with sodium cyanide and subsequent es-
terification, yielded cyano ester 6 in 51% overall yield.
Upon platinum-catalyzed hydrogenation of the nitrile,6b
spontaneous cyclization occurred to afford the desired
lactam 7.
Received May 17, 2002
Abstr a ct: A stereodivergent route toward both diastereo-
meric forms of functionalized 4-hydroxypiperidines has been
successfully developed. This route involves biocatalytic
generation of the enantiopure starting materials followed
by functionalization via N-acyliminium ion-mediated CC-
bond formation.
Functionalized piperidines are common substructures
in natural compounds (e.g., pipecolic acid, coniine, and
thalidomide)1 and often exhibit interesting biological
activity. Various methods have been developed in order
to arrive at piperidines in an enantiomerically pure
fashion.1,2 In most cases, the enantiopurity originates
from either chiral auxiliaries or enantiopure precursors
such as amino acid derivatives. A group of piperidines
that have not received much attention so far are ones
containing a 4-hydroxypiperidine unit, such as the natu-
rally occurring cis- and trans-4-hydroxypipecolic acids 1
and 2,3 the alkaloid SS20846A (3),4 and palinavir (4), a
highly potent inhibitor of the immunodeficiency virus
(HIV).5
Following a classical pathway to convert lactam 7 into
a suitable N-acyliminium ion precursor, the amide func-
tionality was methoxycarbonylated (8, Scheme 2). The
use of Mander’s reagent10 resulted in higher yields than
the corresponding chloroformate. Furthermore, n-butyl-
(2) For a review, see: (a) Laschat, S.; Dickner, T. Synthesis 2000,
13, 1781-1813.
(3) For an entry into the synthesis of these compounds, see, e.g.:
Rutjes, F. P. J . T.; Veerman, J . J . N.; Meester, W. J . N.; Hiemstra, H.;
Schoemaker, H. E. Eur. J . Org. Chem. 1999, 1127-1135.
(4) (a) Komoto, T.; Yano, K.; Ono, J .; Okawa, J .; Nakajima, T. J P
Patent 61035788, 1986. (b) Takemoto, Y.; Ueda, S.; Takeuchi, J .;
Nakmoto, T.; Iwata, C. Tetrahedron Lett. 1994, 35, 8821-8824.
(5) (a) Lamarre, D.; Croteau, G.; Bourgon, L.; Thibeault, D.; War-
drop, E.; Clouette, C.; Vaillancourt, M.; Cohen, E.; Pargellis, C.;
Yoakim, C.; Anderson, P. Antimicrob. Agents Chemother. 1997, 965-
971. (b) Gorys, V.; Soucy, F.; Yoakim, C.; Beaulieu, P. L. Eur. Patent
560 269, 1993. (c) Anderson, P. C.; Soucy, F.; Yoakim, C.; Lavalle´e, P.;
Beaulieu, P. L. US Patent 5 614 533, 1997; Chem. Abstr. 1997,
2131185.
(6) (a) Faber, K. Biotransformations in Organic Chemistry, 4th ed.;
Springer-Verlag: Heidelberg, 2000. (b) Cooling, F. B.; Fager, S. K.;
Fallon, R. D.; Folsom, P. W.; Gallagher, F. G.; Gavagan, J . E.; Hann,
E. C.; Herkes, F. E.; Phillips, R. L.; Sigmund, A.; Wagner, L. W.; Wu,
W.; DiCosimo, R. J . Mol. Catal. B: Enzymol. 2001, 11, 295-306. (c)
Wieser, M.; Nagasawa, T. In Stereoselective Biocatalysis; Patel, R. N.,
Ed.; Marcel Dekker: New York, 2000; Chapter 17, pp 461-486. (d)
Bunch, A. W. Antonie van Leeuwenhoek 1998, 74, 89-97.
(7) (a) Wang, M.-X.; Liu, C.-S.; Li, J .-S.; Meth-Cohn, O. Tetrahedron
Lett. 2000, 41, 8549-8552. (b) Beard, T.; Cohen, M. A.; Parratt, J . S.;
Turner, N. J .; Crosby, J .; Moilliet, N. J . Tetrahedron: Asymmetry 1993,
4, 1085-1104. (c) Kayeka, H.; Saikai, N.; Sano, A.; Yokoyama, M.;
Sugai, T.; Ohta, H. Chem. Lett. 1991, 1823-1824.
We developed a novel entry into the latter class of
compounds involving the cyclization of δ-amino esters
that are obtained via an enantioselective biocatalytic
hydrolysis of substituted glutaronitriles. In such enzy-
matic conversions, generally, one of the two cyano groups
† Department of Organic Chemistry, University of Nijmegen, Toer-
nooiveld 1, 6525 ED Nijmegen, The Netherlands.
‡ DSM Research, Life Science Products, PO Box 18, 6160 MD Geleen,
The Netherlands.
(1) Bailey, P. D.; Millwood, P. A.; Smith P. D. Chem. Commun. 1998,
633-640.
(8) For a recent review, see, e.g.: Speckamp, W. N.; Moolenaar, M.
J . Tetrahedron 2000, 56, 3817-3856 and references therein.
(9) Bloch, R.; Abecassis, J .; Hassan, D. J . Org. Chem. 1985, 50,
1544-1545.
10.1021/jo025943o CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/17/2002
J . Org. Chem. 2002, 67, 7869-7871
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