Stereoselective synthesis of 2,5,6-trisubstituted piperidines.

Article abstract of DOI:10.1021/ol025859v

[reaction: see text] A short and efficient synthesis of 2,5,6-trisubstituted piperidines was achieved by a combination of an aza-Achmatowicz oxidation of a furyl benzenesulfonamide, conjugate addition to the resulting 2H-pyridinone, and subsequent additio

Full text of DOI:10.1021/ol025859v

ORGANIC
LETTERS
2
002
Vol. 4, No. 12
029-2031
Stereoselective Synthesis of
,5,6-Trisubstituted Piperidines
2
2
†
Joel M. Harris and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received March 12, 2002
ABSTRACT
A short and efficient synthesis of 2,5,6-trisubstituted piperidines was achieved by a combination of an aza-Achmatowicz oxidation of a furyl
benzenesulfonamide, conjugate addition to the resulting 2H-pyridinone, and subsequent addition of various nucleophiles to a transient
N-sulfonyliminium ion. The steric bulk of the tosyl group directs attack of the nucleophile from its opposite side, thereby leading to the
formation of cis-substituted products.
6
Piperidine ring systems exhibit a variety of biological
activities and are found in numerous therapeutic agents. The
of imines, Lewis acid or electrophile induced cyclizations
1
7
of imines or iminium ions, and reactions of bicyclo cyano
piperidines and lactams have been employed for this
purpose. Most of the known indolizidine alkaloids are either
3,5- or 5,8-substituted.
8
related indolizidine structure forms the skeleton of many
2
naturally occurring alkaloids and presents a worthy target
3
9
for new synthetic methodology. Accordingly, novel strate-
gies for the stereoselective synthesis of six-membered aza-
heterocycles continue to receive attention from the synthetic
A critical problem in the total synthesis of various
indolizidine alkaloids involves setting the stereocenters in
the piperidine ring. We envisioned an approach to systems
4
community. In the past, addition of organometallic reagents
5
to N-acyl pyridinium salts, hetero Diels-Alder reactions
(5) Comins, D. L.; Killpack, M. O. J. Am. Chem. Soc. 1992, 114, 10973.
Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994,
116, 4719.
(6) Grieco, P. A.; Larsen, S. D. J. Am. Chem. Soc. 1985, 107, 1768.
Waldmann, H.; Braun, M. J. Org. Chem. 1992, 57, 4444. Ishihara, K.;
Miyata, M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc. 1994,
116, 10520.
(7) Flann, C.; Malone, T. C.; Overman, L. E. J. Am. Chem. Soc. 1987,
109, 6097. Tietze, L. F.; Bratz, M. Chem. Ber. 1989, 122, 997. Overman,
L. E.; Sarkar, A. K. Tetrahedron Lett. 1992, 33, 4103. Laschat, S.; Fr o¨ hlich,
R.; Wibbeling, B. J. Org. Chem. 1996, 61, 2829.
(8) Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H.-P. J. Am. Chem.
Soc. 1983, 105, 7754. Amat, M.; Llor, N.; Bosch, J. Tetrahedron Lett. 1994,
35, 2223. Munchhof, M. J.; Meyers, A. I. J. Am. Chem. Soc. 1995, 117,
5399. Francois, D.; Lallemand, M. C.; Selkti, M.; Tomas, A.; Kunesch,
N.; Husson, H.-P. Angew Chem., Int. Ed. 1998, 37, 104.
(9) Michael, J. P. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, 2001; Vol. 55, pp 91-258. Michael, J. P. Nat. Prod.
Rep. 2000, 17, 579. Daly, J. W. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 1998; Vol. 50, pp 141-171. Daly, J. W.;
Garraffo, H. M.; Spande, T. F. In The Alkaloids; Cordell, G. A., Ed.;
Academic Press: San Diego, 1993; Vol. 43, pp 185-288.
†
NIH postdoctoral fellow; grant GM 64027-0.
(1) Roth, H. J.; Kleeman, A. Pharmaceutical Chemistry; John Wiley and
Sons: New York, 1988. Elbein, A. D.; Molyneux, R. In Alkaloids, Chemical
and Biological PerspectiVes; Pelletier, W., Ed.; John Wiley and Sons: New
York, 1987; Vol. 57, p 1. Gogfraid, T.; Miller, R.; Wibo, M. Pharmacol.
ReV. 1986, 38, 321.
(2) Bosch, J.; Bonjoch, J. Studies in Natural Product Chemistry; Rahman,
A. U., Ed.; Elsevier: New York, 1988; Vol. 1, p 31. O’Hagan, D. Nat.
Prod. Rep. 2000, 17, 435-446. Bailey, P. D.; Millwood, P. A.; Smith, P.
D. Chem. Commun. 1998, 6, 633.
(
3) For recent reviews, see: Sardina, F. J.; Rapoport, H. Chem. ReV.
996, 96, 1825. Lekevits, E. Chem. Heterocycl. Compd. 1995, 31, 639.
4) For representative examples, see: Chutian, S.; Alcudia, A.; Yin, J.;
1
(
Liebeskind, L. S. J. Am. Chem. Soc. 2001, 123, 12477. Enders, D.; Thiebes,
C. Pure Appl. Chem. 2001, 73, 573. Comins, D. L.; Joseph, S. P. In
AdVances in Nitrogen Heterocycles; Moody, E. J., Ed.; JAI Press:
Greenwich, 1996; Vol. 2, p 251. Laschat, S.; Dickner, T. Synthesis 2000,
781. Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001,
23, 1004. Amat, M.; Perez, M.; Nuria, L.; Bosch, J.; Lago, E.; Molins, E.
1
1
Org. Lett. 2001, 3, 611.
1
0.1021/ol025859v CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/11/2002

Scheme 1
Scheme 2a
such as 4 (Scheme 1) that is based on the aza-Achmatowicz
reaction, a process defined as the conversion of furylamides
such as 1 into 1,6-dihydro-2H-pyridin-3-ones (i.e., 2). This
10
istry of the Michael addition products were unambiguously
assigned on the basis of NMR spectroscopic analysis as well
as an X-ray crystal structure of compound 7a. The stereo-
chemistry of the conjugate addition product is the result of
axial attack from the face opposite the diaxial substituents
novel rearrangement has been used for the synthesis of
1
1
azasaccharides, izidine structures, â-lactam intermediates,
and unusual amino acids and, we believe, possesses signifi-
cant potential for the preparation of a variety of piperidine-
based alkaloids. The successful application of this approach
for the stereocontrolled synthesis of various 2,5,6-trisubsti-
tuted piperidines is the subject of this communication.
To test our strategy for the eventual synthesis of indoliz-
idines such as 4, we needed to evaluate the stereochemical
aspects of the 1,4-conjugate addition to the dihydro-2H-
pyridone intermediate. 6-Methoxy-2-methyl-1-(toluene-4-
sulfonyl)-1,6-dihydro-2H-pyridin-3-one (6) was prepared
from furyl sulfonamide 5 in two steps and in 72% overall
yield (Scheme 2). The stereochemical assignment of 6 as
the cis-isomer is based on NMR spectroscopic analysis (1D
NOE). The exclusive formation of 6 can be rationalized by
2 6
at C and C . This may be attributed to steric hindrance
between the pseudoaxially oriented 2,6-substituents and the
equatorially approaching nucleophile, thereby leading to the
exclusive formation of the kinetically favored axial 1,4-
1
5
adduct. It should be noted that related conjugate additions
in the literature using dihydropyranulosides as substrates
generally led to the formation of a mixture of diastereomers.16
More than likely, the absence of a tosyl group makes the
molecule more flexible, thereby permitting attack from both
1
7
sides of the π-bond.
Stereoselective functionalization of the pyridinone ring at
the 6-position was accomplished by treating the heterocyclic
1
,3
assuming that A -strain between the two substituents and
the tosyl group forces the methoxy and methyl groups to
adopt a pseudoaxial orientation. It should be noted that this
stereochemistry (vide infra) does not follow from previous
literature results with related systems.1 The earlier reports
either have suggested that the trans-dihydropyridinone isomer
system with allyl trimethylsilane under the influence of BF
OEt at 0 °C (Scheme 3). For example, the reaction of
compound 6 with CH dCHCH SiMe and BF ‚OEt af-
3
‚
2
2
2
3
3
2
forded 8 in 85% yield. Similarly, treating 7a and 7d with
allyl silane under comparable reaction conditions furnished
9 and 10 in 85% yield, respectively. Propenyl acetate reacted
2,13
12
results from the oxidative cyclization or have not unequivo-
cally elucidated the configuration of the product.1
Treatment of 2H-pyridinone 6 with various cuprate
reagents (entries 1-4) proved to be remarkably stereospe-
cific, providing the Michael adducts (7a-d) in pure diaster-
eomeric form and in high yield (Scheme 2).
with 7a in the presence of BF
3 2
‚OEt to give ketone 11 in
3
70% isolated yield. In all of the above examples, a single
diastereomer was isolated whose stereochemistry was as-
signed as the 2,6-cis-disubstituted isomer. This assignment
18
rests on literature analogy and also is consistent with a NOE
enhancement between the hydrogens on the C -methyl group
and the methylene hydrogens of the allyl side chain at C
2
Thiophenol and glycine methyl ester also furnished 1,4-
6
.
14
addition products 7e and 7f in high yield. The stereochem-
(
14) For some related additions, see: Koulocheri, S. D.; Magiatis, P.;
(
10) For an excellent review of the subject, see: Ciufolini, M. A.;
Hermann, C. Y. W.; Dong, Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett
998, 105.
Skaltsounis, A. L.; Hartoutounian, S. A. Tetrahedron 2000, 56, 6135.
(15) The 2-axial conformation of N-acylpiperidines is well established.
See: Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem. Soc. 1988,
110, 7445.
(16) For some recent results in this area, see: Liao, L. X.; Wang, Z. M.;
Zhang, Z. X.; Zhou, W. S. Tetrahedron: Asymmetry 1999, 10, 3649.
(17) Apostolopoulos, C. D.; Couladouros, E. A.; Georgiadis, M. P.
Liebigs Ann. Chem. 1994, 781. Couladouros, E. A.; Apostolopoulos, C.
D.; Georgiadis, M. P. Carbohydr. Res. 1993, 249, 399.
(18) Shono, T.; Matsumara, Y.; Tsubata, K.; Uchida, K. J. Org. Chem.
1986, 51, 2590.
1
(
(
11) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401.
12) Zhou, W. S.; Lu, Z. H.; Xu, Y. M.; Liao, L. X.; Wang, Z. M.
Tetrahedron 1999, 55, 11959. Zhou, W. S.; Xie, W. G.; Lu, Z. H.; Pan, X.
F. J. Chem. Soc., Perkin Trans. 1 1995, 2599. Altenbach, H. J.; Wischnat,
R. Tetrahedron Lett. 1995, 36, 4983.
(
13) Lu, Z. H.; Zhou, W. S. J. Chem. Soc., Perkin Trans. 1 1993, 593.
Zhou, W. S.; Xie, W. G.; Lu, Z. H.; Pan, X. F. Tetrahedron Lett. 1995, 36,
291.
1
2030
Org. Lett., Vol. 4, No. 12, 2002

Scheme 3
Scheme 4
hexahydro-1H-pyrindine and octahydro-quinoline ring sys-
tems 13 and 15 in 60% and 80% yield, respectively.
In conclusion, we have shown that 2-methyl-6-methoxy-
2,6-dihydro-2H-pyridin-3-one (6) readily undergoes conju-
gate addition with various nucleophiles to deliver cis-
substituted 2,5-piperidines. The resulting products can be
further utilized as precursors for N-sulfonyliminium ions by
reaction with various nucleophiles in the presence of a Lewis
acid. The stereochemistry associated with the conjugate
additions was established by X-ray analysis and is believed
As suggested by others,19 the preference for the 2,6-cis-
1
,3
disubstituted product can be rationalized by the A -strain
present between the tosyl and methyl groups that causes the
tosyl group to shield the opposite face of the molecule. The
steric bulk associated with the tosyl group directs the attack
of the nucleophile on the iminium ion to the side of the C -
2
methyl group, leading to the formation of the cis-product.
In the past few years, the use of the ring closing metathesis
2
0
21
reaction (RCM) for creating heterocyclic systems from
acyclic diolefins has increased enormously as a result of the
ruthenium alkylidene catalysts that have been developed by
1
,3
to arise from A -strain between the tosyl and adjacent
substituents. Further utilization of this method for the
stereoselective synthesis of several indolizidine alkaloids is
under current investigation and will be reported in due course.
20
Grubbs and co-workers. Prompted by the ease with which
pyridinones 12 and 14 can be prepared (Scheme 4), we
decided to investigate their ring closing olefin metathesis
chemistry. The key cyclization reaction of 12 and 14 was
performed with the Grubbs ruthenium benzylidene catalyst
Acknowledgment. This research was supported by the
National Institutes of Health (BM59384 and GM60003). We
thank our colleague, Dr. Kenneth Hardcastle, for his as-
sistance with the X-ray crystallographic studies together with
grants NSF CHE-9974864 and NIH S10-RR13673.
2 3 2 2 2
Cl (PCy ) RudCHPh (3 mol %) in CH Cl under an
atmosphere of nitrogen. Dienes 12 and 14 were completely
consumed within 3 h at room temperature furnishing the
Supporting Information Available: Complete descrip-
tion of the synthesis and characterization of all compounds
prepared in this study and an Ortep drawing for compound
(
19) Hopman, J. C. P.; van de Berg, E.; Ollero, L. O.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron Lett. 1995, 36, 4315.
(
20) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(21) For several examples of the synthesis of piperidines via olefin
7
a. This material is available free of charge via the Internet
metathesis, see: Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114,
324. Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 65. Rutjes, F.
P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38, 677. Jo, E.; Na,
Y.; Chang, S. Tetrahedron Lett. 1999, 40, 5581.
7
at http://pubs.acs.org.
OL025859V
Org. Lett., Vol. 4, No. 12, 2002
2031