Diastereoselective synthesis of (2Ss,5R)-5-hydroxypipecolic acid and 6-substituted derivatives

Article abstract of DOI:10.1021/ol047774v

(Chemical Equation Presented) Herein, we report a diastereoselective synthesis of the natural product (2S,5R)-5-hydroxypipecolic acid and 6-substituted derivatives thereof. The key step in the synthetic sequence is a novel highly diastereoselective epoxidation reaction of an enantiomerically pure cyclic enamide intermediate.

Full text of DOI:10.1021/ol047774v

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4941-4944
Diastereoselective Synthesis of
(2S,5R)-5-Hydroxypipecolic Acid and
6-Substituted Derivatives
Peter N. M. Botman,† F. Jan Dommerholt,‡ Rene´ de Gelder,‡
Quirinus B. Broxterman,§ Hans E. Schoemaker,§ Floris P. J. T. Rutjes,‡ and
Richard H. Blaauw*,†
Chiralix B.V., P.O. Box 31070, 6503 CB Nijmegen, The Netherlands, Radboud
UniVersity Nijmegen, IMM, ToernooiVeld 1, 6525 ED Nijmegen, The Netherlands, and
DSM Research, Life SciencessAdVanced Synthesis, Catalysis and DeVelopment,
P.O. Box 18, 6160 MD Geleen, The Netherlands
richard.blaauw@chiralix.com
Received October 29, 2004
ABSTRACT
Herein, we report a diastereoselective synthesis of the natural product (2S,5R)-5-hydroxypipecolic acid and 6-substituted derivatives thereof.
The key step in the synthetic sequence is a novel highly diastereoselective epoxidation reaction of an enantiomerically pure cyclic enamide
intermediate.
The amino acid 5-hydroxypipecolic acid (1) is a natural
product that has been found in various plants and micro-
organisms.1 Furthermore, the 5-hydroxypiperidine skeleton
constitutes the core of numerous naturally occurring alkaloids
(Figure 1) such as febrifugine (2) and pseudoconhydrin (3).
As part of a larger research program, we investigated the
conversion of L-allysine ethylene acetal 4 into (2S,5R)-5-
hydroxypipecolic acid (trans-1).2 We now report a diastereo-
selective route that was developed leading to this natural
product.3 Additionally, one of the intermediates in the
synthetic sequence allowed facile introduction of substituents
at the 6-position involving N-acyliminium ion chemistry.4
† Chiralix B.V.
‡ Radboud University Nijmegen.
§ DSM Research.
(1) (a) Witkop, B.; Foltz, C. M. J. Am. Chem. Soc. 1957, 79, 192. (b)
Kondo, Y. J. Sericult. Sci. Japan 1957, 26, 345. (c) Goas, G.; Larher, F.;
Goas, M. C. R. Acad. Sci. Paris 1970, 271, 1368. (d) Fowden, L. In Progress
in Phytochemistry; Reinhold, L., Liwischitz, Y., Eds.; Wiley: London, 1970;
2, 203. (e) Hatanaka, I. Sci. Pap. Coll. Gen. Educ. UniV. Tokyo 1972, 22,
117. (f) Despontin, J.; Marlier, M.; Dardenne, G. Phytochemistry 1977,
16, 387.
(2) (a) Rumbero, A.; Mart´ın, F. C.; Lumbreras, M. A.; Liras, P.; Esmahan,
C. Bioorg. Med. Chem. 1995, 3, 1237. (b) Boesten, W. H. J.; Broxterman,
Q. B.; Plaum, M. J. M. EP0905257, 1999; Chem. Abstr. 1999, 130, 251283.
Figure 1.
10.1021/ol047774v CCC: $27.50
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The sequence to trans-1 started with N-carbonylation of
4 with Cbz-OSu, followed by methylation of the carboxylic
acid with MeI to obtain the protected amino acid 5 (Scheme
1).
Since N,O-acetal 7 constitutes a suitable N-acyliminium
ion precursor, we next turned our attention to its application
in the synthesis of 6-substituted 5-hydroxypipecolic acid
derivatives.9 Indeed, in situ formation of the N-acyliminium
ion intermediate by treatment of 7 with a catalytic amount
of Sn(OTf)2 in the presence of allyltrimethylsilane afforded
the 6-allylated product. However, the isolation and purifica-
tion of the desired compound was seriously hampered by
the formation of significant amounts of the corresponding
O-silylated product. To circumvent this undesired silyl
transfer reaction, the hydroxyl function was converted into
the corresponding acetate (8). This precursor could be reacted
smoothly with various suitable π-nucleophiles (Table 1).
Scheme 1. Synthesis of (2S,5R)-5-Hydroxypipecolic Acid
Table 1. N-Acyliminium Ion Chemistry
Upon treatment of 5 with a catalytic amount of p-
toluenesulfonic acid in refluxing toluene, a smooth cycliza-
tion-elimination sequence occurred, providing tetrahydro-
pyridine 6 in an excellent yield.5,6
The key step in our strategy was the epoxidation of
enamide 6, which was performed in MeOH to invoke
immediate ring-opening of the unstable epoxide intermedi-
ate.7 The use of oxone gave the best results, leading to the
5-hydroxypipecolic acid derivative 7 with a 96:4 diastereo-
selectivity for the (2S,5R)-configured product. Subsequent
hydrogenation, followed by hydrolysis of the methyl ester
and precipitation from aqueous acetone provided the dia-
stereomerically pure target natural product trans-1 as the
corresponding HCl salt, with an overall yield of 87% starting
from 4.8
a Performed with 5 equiv. b Performed with 10 mol % Sn(OTf)2 or 2
equiv BF3‚OEt2. c Products isolated as a single diastereomer. d Isolated as
a (5R,6S):(5R,6R) ) 1.7:1 mixture. e Performed with 20 mol % Sn(OTf)2.
f Based on recovered starting material (10%) in hydrogenation.
The stereochemical assignment of the formed products by
1H NMR proved to be difficult due to the presence of
rotamers. Therefore, the obtained products were hydro-
genated with Pd/C under an atmosphere of H2, affording the
6-substituted 5-acetoxy pipecolic acid methyl esters 9a-c.
The preferred Lewis acid proved to be Sn(OTf)2, although
2 equiv of BF3‚OEt2 were required to reach full conversion
in the reaction with propargyltrimethylsilane (entry 2).
Products 9a and 9c (entries 1, 2, and 4) were isolated as
single diastereomers, which were shown to possess the
(2S,5R,6S)- configuration. The observed cis relationship
between the introduced alkyl group and the ester substituent
was expected, since it is known that in similarly substituted
piperidines, the incoming nucleophile preferably attacks the
N-acyliminium ion intermediate in a pseudoaxial fashion.10
(3) For previous synthetic approaches to enantiomerically pure trans-1,
see: (a) Herdeis, C.; Engel, W. Tetrahedron: Asymmetry 1991, 2, 945. (b)
Herdeis, C.; Heller, E. Tetrahedron: Asymmetry 1993, 4, 2085. (c) Bailey,
P. D.; Bryans, J. S. Tetrahedron Lett. 1988, 29, 2231. (d) Horeau, S.;
Fauche`re, J. L.; Pappalardo, L.; Roumestant, M. L.; Viallefont, P.
Tetrahedron: Asymmetry 1996, 7, 2585. (e) Shibasaki, T.; Sakurai, W.;
Hasegawa A.; Uosaki, Y.; Mori, H.; Yoshida, M.; Ozaki, A. Tetrahedron
Lett. 1999, 40, 5227.
(4) (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(b) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 1047-
1082.
(5) Although the exact role still remains unclear, the addition of DMF
(0.5 equiv) proved to be necessary to obtain a clean conversion of 5 to 6.
(6) (a) Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48, 5043. (b) Robl,
J. A. Tetrahedron Lett. 1994, 35, 393. (c) Mizutani, N.; Chiou, W.-H.;
Ojima, I. Org. Lett. 2002, 4, 4575. (d) Teoh, E.; Campi, E. M.; Jackson,
W. R.; Robinson, A. J. Chem. Commun. 2002, 978. (e) Clive, D. L. J.;
Coltart, D. M.; Zhou, Y. J. Org. Chem. 1999, 64, 1447. (f) Shono, T.;
Matsumura, Y.; Onomura, O.; Yamada, Y. Tetrahedron Lett. 1987, 28, 4073.
(7) For a related example, see: Rani, S.; Vankar, Y. D. Tetrahedron
Lett. 2003, 44, 907.
(9) For recent examples of N-acyliminium ion alkylations of piperidines,
see: (a) Vink, M. K. S.; Schortinghuis, C. A.; Luten, J.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem.
2002, 67, 7869. (b) Okitsu, O.; Suzuki, R.; Kobayashi, S. J. Org. Chem.
2001, 66, 809. (c) Mentink, G.; van Maarseveen, J. H.; Hiemstra, H.
Org. Lett. 2002, 4, 3497. (d) Santos, L. S.; Pilli, R. A. Synthesis 2002, 87.
(e) Tanaka, H.; Sakagami, H.; Ogasawara, K. Tetrahedron Lett. 2002,
43, 93.
(8) The whole sequence can be performed without any intermediate
purification steps (making it convenient for scale-up) in which case the
final product is obtained in 50% overall yield on multigram scale.
4942
Org. Lett., Vol. 6, No. 26, 2004

Only the relatively small nucleophile TMS-CN gave rise
to a mixture of diastereomers (9b), which was determined
to be 1.7:1 in favor of the (2S,5R,6S)-isomer.11
Besides the intermolecular C-C bond formations, our
attention was drawn toward intramolecular N-acyliminium
ion reactions. To this end, the hydroxyl part of 7 was
alkylated with 3,5-dimethoxybenzyl bromide (Scheme 3).
For the hydrogenations, the choice of solvent proved to
be crucial for the outcome of the reactions. The use of Pd/C
in EtOAc effected a smooth reduction in the case of the allyl-
and cyanide-substituted intermediates (entries 1 and 3),
affording products 9a and 9b, respectively, in good yields
over two steps. However, for the hydrogenation of the
allenyl-substituted intermediate (entry 2), the solvent had to
be changed to methanol. The use of methanol in the case of
the cyanide (entry 3) caused reduction of the cyano group
to the primary amine. Finally, the Cbz deprotection of the
acetophenone-substituted intermediate (entry 4) in either
methanol or EtOAc was accompanied by the reduction of
the ketone function to the corresponding alcohol. This
problem of overreduction could be circumvented by per-
forming the hydrogenation in acetonitrile, affording the
desired product 9c in good yield.
Scheme 3. Intramolecular C-C Bond Formation
In addition to the TMS-nucleophiles, we investigated the
reaction of N-acyliminium ion precursors 7 and 8 with
electron-rich aromatic nucleophiles. However, the reaction
with 1,3-dimethoxybenzene in the presence of BF3‚OEt2
brought about an unexpected ring-opening of the intermediate
piperidine product (Scheme 2). Apparently, the highly
Treatment of cyclization precursor 12 with a catalytic amount
of Sn(OTf)2 provided 13 in a reasonable yield of 66% along
with 20% of starting material. Attempts to force the reaction
to completion by applying longer reaction times or higher
temperatures merely led to decomposition of 13. Most
probably, the origin of the instability of 13 resides in the
ring-opening of the piperidine ring as was observed for the
intermolecular coupling with 3,5-dimethoxybenzene (Scheme
2). After hydrogenation, amine 14 was obtained as a single
diastereomer. X-ray structure analysis of the corresponding
HCl salt unequivocally proved the product to possess the
expected (2S,5R,6R)- configuration (Figure 2).12
Scheme 2. Unexpected Opening of the Piperidine Ring
electron-rich aromate significantly weakens the C-N bond
and subsequently stabilizes the formed cation, which is
trapped by a second aromatic moiety producing diarylated
products. In addition, in case of precursor 7, the piperidine
ring opening was followed by spontaneous lactonization
affording product 10.
Figure 2. Chem3D representation of the crystal structure of
14‚HCl.
(10) (a) Bull, S. D.; Davies, S. G.; Epstein, S. W.; Leech, M. A.; Ouzman,
J. V. A. J. Chem. Soc., Perkin Trans. 1 1998, 2321. (b) Tjen, K. C. M. F.;
Kinderman, S. S.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T.
Chem. Commun. 2000, 699.
In conclusion, we have developed a straightforward,
diastereoselective synthesis of the natural product (2S,5R)-
5-hydroxypipecolic acid, involving a highly diastereoselective
epoxidation of an enantiomerically pure cyclic enamide. One
(11) Stereochemistry of products 9a and 9b was proven by 1H NMR
NOESY experiments. The assignment of 9c was made by comparison of
1
its H NMR spectrum with those of 9a and 9b.
Org. Lett., Vol. 6, No. 26, 2004
4943

of the intermediates in this synthesis proved to be a versatile
precursor to various 6-substituted derivatives by means of
N-acyliminium ion chemistry. Currently, we are aiming to
apply the developed methodology to the total synthesis
of the natural products febrifugine (2) and pseudoconhydrin
(3).
Acknowledgment. Senter (Ministry of Economic Affairs,
The Netherlands) is gratefully acknowledged for providing
financial support.
Supporting Information Available: Full experimental
procedures, characterization of all new products, X-ray data,
and references to known compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Crystal structure data can be obtained free from charge via the
Internet at www.ccdc.cam.ac.uk/conts/retreiving.html with the following
deposition number: CCDC 253396.
OL047774V
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Org. Lett., Vol. 6, No. 26, 2004