Stereoselective synthesis of 2,6-disubstituted 3-piperidinols: Application to the expedient synthesis of (+)-julifloridine

Article abstract of DOI:10.1021/ol051022z

(Chemical Equation Presented) The asymmetric synthesis of 2,6-disubstituted 3-piperidinols having a 2,3-cis and 2,6-trans relative stereochemistry was accomplished in three steps using the following sequence: stereocontrolled nucleophilic addition of an o

Full text of DOI:10.1021/ol051022z

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2747-2750
Stereoselective Synthesis of
2,6-Disubstituted 3-Piperidinols:
Application to the Expedient Synthesis
of (+)-Julifloridine
Alexandre Lemire and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec H3C 3J7, Canada
andre.charette@umontreal.ca
Received May 4, 2005
ABSTRACT
The asymmetric synthesis of 2,6-disubstituted 3-piperidinols having a 2,3-cis and 2,6-trans relative stereochemistry was accomplished in three
steps using the following sequence: stereocontrolled nucleophilic addition of an organomagnesium reagent to a chiral pyridinium salt;
monohydrogenation of the resulting 2-substituted 1,2-dihydropyridine; and a one-pot, highly diastereoselective epoxidation−nucleophilic addition
with a heteroatom nucleophile or an organometallic reagent. This methodology was applied to the expedient asymmetric synthesis of (
+)-
julifloridine in four steps.
The piperidine subunit is among the most important phar-
macophores found in biologically active molecules and
natural products. The stereoselective synthesis of polysub-
stituted piperidines remains a substantial challenge in organic
chemistry.1,2 Among this class of products, 2,6-disubstituted
3-piperidinol alkaloids such as 1-7 are frequently encoun-
tered in biologically active natural products (Figure 1).3,4 Our
(1) For recent reviews on the stereoselective synthesis of piperidines,
see: (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729. (b) Felpin,
F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712. (c) Weintraub,
P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953-2989.
(2) For recent examples: (a) Wang, X.; Dong, Y.; Sun, J.; Xu, X.; Li,
Figure 1. 2,6-Disubstituted 3-piperidinols natural products.
R.; Hu, Y. J. Org. Chem. 2005, 70, 1897-1900. (b) Toure, B. B.; Hall, D.
G. Angew. Chem., Int. Ed. 2004, 43, 2001-2004. (c) Ichikawa, E.; Suzuki,
M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
research program directed toward the expedient synthesis of
polysubstituted piperidines from cheap and readily available
starting materials5 prompted us to develop a general approach
for the stereocontrolled synthesis of substituted piperidinols.
2004, 126, 11808-11809. (d) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi,
T. J. Am. Chem. Soc. 2004, 126, 6240-6241. See also: (e) Comins, D. L.;
Goehring, R. R.; Joseph, S. P.; O’Connor, S. J. Org. Chem. 1990, 55, 2574-
2576. (f) Ge´nisson, Y.; Marazano, C.; Das, B. C. J. Org. Chem. 1993, 58,
2052-2057.
10.1021/ol051022z CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/28/2005

The realization of this goal and an application to the
expedient synthesis of julifloridine (1) is presented herein.
The approach is based on our ability to chemoselectively
functionalize various positions of the chiral dihydropyridine
8 obtained by diastereoselective nucleophilic 1,2-addition of
organometallic reagents to chiral pyridinium salts (Scheme
1).5a,d A chemoselective hydrogenation of the dihydropyridine
opposite to R1 (Scheme 1). The resulting labile epoxide 9
should undergo ring opening upon nucleophilic attack,
leading to 2,6-disubstituted 3-piperidinols 10. One potential
issue was the stereoselectivity of the nucleophilic attack on
the epoxide, which could afford 10 as a mixture of epimers.
The first step of the sequence involved a chemoselective
reduction of one of the two endocyclic alkenes of dihydro-
pyridine 115a to afford tetrahydropyridine 12. Hydrogenation
of the alkenes proceeded at significantly different rates, and
selective hydrogenation afforded good yields of 2-substituted
1,2,3,4-tetrahydropyridines (Table 1).7 To the best of our
Scheme 1. Strategy to Access 2,6-Disubstituted 3-Piperidinols
Table 1. Regioselective Hydrogenation of
1,2-Dihydropyridinesa
entry
R1
Ph
Me
Et
2-furyl
Ph
R2
yield (%)
product
followed by a diastereoselective epoxidation should generate
epoxide 9 that could be opened with a nucleophile to afford,
after deprotection, piperidinol 10. The versatility of this
approach should allow the rapid synthesis of substituted
piperidinols with four easily modified substituents (R1, R2,
OH, NH).
2-Substituted nitrogen heterocycles protected with an
electron-withdrawing group are known to place their sub-
stituents in axial positions to minimize the A1,3 strain.6 This
suggests that the epoxidizing reagent should react on the face
1
2
3
4
5
Bn
Me
Me
Me
Me
77
86
58
79
78
12a
12b
12c
12d
12e
a Substrate and catalyst were stirred in acetonitrile under a hydrogen
atmosphere (1 atm) for 2 h. See Supporting Information for details.
knowledge, this regioselective hydrogenation has no prece-
dent for monosubstituted 1,2-dihydropyridines.8,9
(3) (a) Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1985; Vol. 26, Chapter 3. (b) Astudillo S. L.;
Ju¨rgens, S. K.; Schmeda-Hirschmann, G.; Griffith, G. A.; Holt, D. J.;
Jenkins, P. R. Planta Med. 1999, 65, 161-162. (c) Melhaoui, A.; Belouali,
H. J. Ethnopharm. 1998, 62, 67-71. (d) Bolzani, V. S.; Gunatilaka, A. A.
L.; Kingston, D. G. I. Tetrahedron 1995, 51, 5929-5934. (e) Hootele´, C.;
Colau, B.; Halin, F. Tetrahedron Lett. 1980, 21, 5061-5062. (f) Baliah,
V.; Jeyaraman, R.; Chandrasekaran, L. Chem. ReV. 1983, 83, 379-423.
(4) For recent syntheses, see: (a) Cassidy, M. P.; Padwa, A. Org. Lett.
2004, 6, 4029-4031. (b) Randl, S.; Blechert, S. Tetrahedron Lett. 2004,
45, 1167-1169. (c) Chavan, S. P.; Praveen, C. Tetrahedron Lett. 2004,
45, 421-423. (d) Jourdant, A.; Zhu, J. Heterocycles 2004, 64, 249-259.
Liu, L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69,
6001-6009. (e) Wang, Q.; Sasaki, N. A. J. Org. Chem. 2004, 69, 4767-
4773. (f) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003, 5, 27-29.
(g) Sato, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3839-3842. (h)
Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron 2003, 59, 6445-6454. (i)
Ma, D.; Ma, N. Tetrahedron Lett. 2003, 44, 3963-3965. (j) Davis, F. A.;
Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855-3857. (k) Sengupta, S.;
Mondal, S. Tetrahedron 2002, 58, 7983-7986. (l) Singh, R.; Ghosh, S. K.
Tetrahedron Lett. 2002, 43, 7711-7715. (m) Toyooka, N.; Nemoto, H.
Drugs Future 2002, 27, 143-158. (n) Bailey, P. D.; Smith, P. D.; Morgan,
K. M.; Rosair, G. M. Tetrahedron, Lett. 2002, 43, 1071-1074. (o) Comins,
D. L.; Sandelier, M. J.; Grillo, T. A. J. Org. Chem. 2001, 66, 6829-6832.
(p) Enders, D.; Kirchhoff, J. H. Synthesis 2000, 2099-2105. (q) Agami,
C.; Couty, F.; Lam, H.; Mathieu, H. Tetrahedron 1998, 54, 8783-8796.
(r) Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.; Naito, T.
Tetrahedron 1998, 54, 15589-15606 and references therein.
Initial attempts to epoxidize the enamine were conducted
with 2-phenyl-1,2,3,4-tetrahydropyridine 12a. However, only
decomposition products resulted when attempting to isolate
the epoxide if m-chloroperoxybenzoic acid (MCPBA) or
dimethyldioxirane (DMDO) was used as the epoxidizing
agent. Use of the Camps reagent (MCPBA-KF) did not lead
to either the desired epoxide or its epoxide opening product
(6) (a) Comins, D. L.; Joseph, S. P. AdVances in Nitrogen Heterocycles;
Moody, C. J., Ed.; JAI Press, Inc.: Greenwich, CT, 1996; Vol. 2, pp 251-
294. (b) Hoffmann, H. R. Chem. ReV. 1989, 89, 1841-1860. (c) Johnson,
F. Chem. Rev. 1968, 68, 375-413.
(7) For a review on stereocontrolled additions to di- and tetrahydro-
pyridines, see: (a) Kumar, R.; Chandra, R. AdV. Heterocycl. Chem. 2001,
78, 269-313. For a review on dihydropyridines, see: (b) Lavilla, R. J.
Chem. Soc., Perkin Trans. 1 2002, 1141-1156. For stereoselective synthesis
of 1,2,5,6-tetrahydropyridines, see: (c) Huang, H.; Spande, T. F.; Panek,
J. S. J. Am. Chem. Soc. 2003, 125, 626-627. (d) Felpin, F.-X.; Lebreton,
J. Curr. Org. Synth. 2004, 1, 83-109.
(8) For 2,6-disubstituted 1,2-dihydropyridines, see: (a) Comins, D. L.;
Weglarz, M. A. J. Org. Chem. 1991, 56, 2506-2512. (b) Yamaguchi, R.;
Nakazono, Y.; Matsuki, T.; Hata, E.-i.; Kawanisi, M. Bull. Chem. Soc. Jpn.
1987, 60, 215-222. For 3,5-disubstituted dihydropyridines, see: (c) Comins,
D. L.; Williams, A. L. Org. Lett. 2001, 3, 3217-3220.
(9) For disubstituted 1,2-dihydropyridines substituted with an electron-
withdrawing group, see: (a) Kita, Y.; Maekawa, H.; Yamasaki, Y.;
Nishiguchi, I. Tetrahedron 2001, 57, 2095-2102. (b) Lavilla, R.; Gotsens,
T.; Gullo´n, F.; Bosch, J. Tetrahedron 1994, 50, 5233-5244. (c) Naito, T.;
Lida, N.; Ninomiya, I. J. Chem. Soc., Perkin Trans. 1 1986, 99-104.
(5) (a) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel,
J. J. Am. Chem. Soc. 2001, 123, 11829-11830. (b) Legault, C.; Charette,
A. B. J. Am. Chem. Soc. 2003, 125, 6360-6361. (c) Lemire, A.; Grenon,
M.; Pourashraf, M.; Charette, A. B. Org. Lett. 2004, 6, 3517-3520. (d)
Lemire, A.; Beaudoin, D.; Grenon, M.; Charette, A. B. J. Org. Chem. 2005,
70, 2368-2371.
2748
Org. Lett., Vol. 7, No. 13, 2005

when 2-propanol was subsequently added.10 However, the
reaction with DMDO using methanol as a cosolvent led to
13a in 82% yield. Isolation of the product as its acetate (14a)
afforded an excellent yield of the product as a single
diastereomer (Table 2, entry 1). The stereochemical outcome
of equivalents could be lowered to 2 (entries 3 and 4). In all
the examples we tested, the 2,3-cis product was always
formed as the exclusive diastereomer.11
Having established that heteroatom nucleophiles could
efficiently react with the epoxide, we then examined methods
for the introduction of carbon-based nucleophiles. Spectro-
scopic studies have shown that the epoxide is moderately
stable at -78 °C in the absence of Lewis acids or nucleo-
philes. However, all our efforts to remove acetone upon
concentration under reduced pressure at low temperature led
to epoxide decomposition. Furthermore, our attempts to
induce a BF3‚OEt2- or TMSOTf-mediated epoxide opening
in the presence of allylstannanes or allylsilanes were unsuc-
cessful. This failure may be attributed to the presence of
acetone as a solvent in these reactions since the epoxide could
not be isolated. Since DMDO was used as a dilute solution
in acetone, our attention turned to nucleophiles that were
compatible with acetone at low temperature. Gratifyingly,
methylzinc bromide reacted with the in situ-generated
epoxide to afford 13e in good yield, again as a single
diastereomer (Table 2, entry 5). Interestingly, a cis relative
stereochemistry was observed, which is consistent with the
stereochemistry obtained using heteroatom nucleophiles. The
organozinc halide generated from methylmagnesium bromide
and zinc chloride reacted equally well, but the use of zinc
triflate proved to be less effective. Furthermore, generation
of the methylzinc bromide from organometallic reagents
other than Grignards led to lower yields. Addition of
magnesium bromide dimethylcuprate or magnesium bromide
methylcyanocuprate also led to 13e, albeit in a 1:1 mixture
of 2,3-cis and 2,3-trans isomers. Diorganozinc reagents added
nicely to the epoxides generated from 12a-e (Table 2, entries
6-12). Phenylzinc bromide and vinylzinc bromide gave
excellent yields of the piperidinols 13l and 13m (entries 13
and 14).
Table 2. Stereoselective Epoxidation/Opening Sequencea
entry substrate
nucleophile (R3)
yield (%)b product
1
2
3
12a
12a
12a
MeOH (MeO)
i-PrOH (i-PrO)
4-BrC6H4CH2OH
(4-BrC6H4CH2O)
phthalimide
MeZnBr (Me)
Me2Zn (Me)
Et2Zn (Et)
Et2Zn (Et)
Me2Zn (Me)
Et2Zn (Et)
89
92
60
14a
14b
14c
4
5
6
7
8
12a
12a
12a
12a
12b
12c
12c
12d
12e
12e
12e
77
67
91
75
57
75
60
65
92
91
89
14d
13e
13e
13f
13g
13h
13i
13j
13k
13l
9
10
11
12
13
14
Et2Zn (Et)
Me2Zn (Me)
PhZnBr (Ph)
CH2dCHZnBr (vinyl)
13m
a Entries 1 and 2: the substrate and nucleophile (used as a cosolvent)
were stirred at -78 °C, and then 1.1 equiv of DMDO (ca. 0.08 M in acetone)
was added. Entries 3 and 4: the substrate and nucleophile (2.0 equiv) were
stirred at 0-5 °C, and then 1.1 equiv of DMDO (ca. 0.08 M in acetone)
was added. Entries 5-14: the substrate was stirred at -78 °C, and 1.1
equiv of DMDO (ca. 0.08 M in acetone) was added. After 5 min, the
nucleophile (5-10 equiv) was added. b Entries 1-4: isolated yield of
acetylated product 14 (two steps). Entries 5-14: isolated yield of the free
alcohol 13. See Supporting Information for details.
Selected NOE correlations demonstrating the structures
of 14a and 13f are illustrated in Figure 2. As expected,
of the reaction was determined by NMR and was rather
surprising since the expected axial attack would have led to
the 2,3-trans isomer.
We then decided to explore the reactivity of various
heteroatom nucleophiles to examine the scope of this
oxidation/epoxide opening sequence as well as the generality
of the sense of induction of the stereochemical induction.
As shown in Table 2, various alcohols reacted equally well,
producing the ring-opened products as single diastereomers
(entries 2 and 3). Phthalimide was also found to react in a
similar fashion, producing the N-substituted adduct (entry
4). For more valuable or nonvolatile nucleophiles, the number
Figure 2. Selected NOEs for 14a and 13f.
DMDO reacts with the enamine on the opposite face of the
C-2 substituent. An interesting feature of this reaction is the
cis stereochemistry observed between the newly formed C-2
and C-3 asymmetric centers. To our knowledge, this
represents the first intermolecular cis stereoselective epoxi-
dation-ring opening and nucleophilic substitution of an
endocyclic amino-substituted epoxide.12-16 The 2,3-cis ster-
(10) Camps, F.; Coll, J.; Messeauer, A.; Pujol, F. J. Org. Chem. 1982,
47, 5402-5404. 2-Propanol was used as a nucleophile since methanol is
described to be incompatible with this epoxidation procedure. Furthermore,
both nucleophiles were shown to cleanly react with 12 (with DMDO, see
Table 2). This KF-MCPBA complex was shown to cleanly epoxidize
diverse glucals; see: Bellucci, G.; Catelani, G.; Chiappe, C.; D’Andrea, F.
Tetrahedron Lett. 1994, 35, 8433-8436.
(11) Cis product is the kinetic product since treatment of 13a with TFA
in EtOH for 76 h led to the 2,3-trans-ethanol adduct in 74% yield.
Org. Lett., Vol. 7, No. 13, 2005
2749

eochemistry would suggest that epoxide 9 opens before the
nucleophilic attack, generating an iminium-alkoxide.17,18
Having shown that we can efficiently epoxidize 12 and
open 9 with organozinc nucleophiles, we turned our attention
to a demonstration of the applicability of this methodology
in the context of total synthesis. (+)-Julifloridine (1, Scheme
2) is a 2,6-disubstituted 3-piperidinol alkaloid isolated from
Prosopis juliflora by Ahmad.19 The synthesis of julifloridine
is straightforward and has been realized in four steps from
pyridine as depicted in Scheme 2.20 The synthesis began with
the regio- and diastereoselective addition of Grignard reagent
16 on the chiral pyridinium salt generated from amide 15.
Dihydropyridine 17 was then monohydrogenated, affording
tetrahydropyridine 18. The epoxidation-methylation proce-
dure produced 19 in excellent yield given the complexity of
the product formed. Simultaneous removal of the amidine
chiral auxiliary and benzyl ether cleavage, leading to (+)-
julifloridine, was achieved upon treatment with lithium in
Scheme 2. Total Synthesis of (+)-Julifloridine
(12) Blaauw and co-workers reported an oxone-mediated epoxidation-
methanol opening of a related tetrahydropyridine, but the cis-trans ratio
was not specified. See: Botman, P. N. M.; Dommerholt, F. J.; de Gelder,
R.; Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R.
H. Org. Lett. 2004, 6, 4941-4944.
(13) Related cis stereoselective pyridinone epoxide intramolecular open-
ing with an alcohol, leading to an oxazolopiperidine, has been reported:
Amat, M.; Llor, N.; Huguet, M.; Molins, E.; Espinosa, E.; Bosch, J. Org.
Lett. 2001, 3, 3257-3260.
(14) Asymmetric epoxidation of unsubstituted N-tosyl-1,4,5,6-tetra-
hydropyridirines has been reported, but the yields or enantioselectivities
are modest; see: Sunose, M.; Anderson, K. M.; Orpen, A. G.; Gallagher,
T.; Macdonald, S. J. F. Tetrahedron Lett. 1998, 39, 8885-8888.
(15) DMDO and MCPBA epoxidation of unsubstituted N-ethylcarbam-
oyl-1,4,5,6-tetrahydropyridines has been reported, but the cis-trans selectiv-
ity of the nucleophilic substitution of the epoxide is low (1:1.5 to 1:1.8),
see: (a) Sugisaki, C. H.; Carroll, P. J.; Correia, C. R. D. Tetrahedron Lett.
1998, 39, 3413-3416. (b) Burgess, L. E.; Gross, E. K. M.; Jurka, J.
Tetrahedron Lett. 1996, 37, 3255-3258.
(16) (a) Treatment of N-acetyl-1,4,5,6-tetrahydropyridines with peroxy-
benzoic acid gave N-acetyl-2-benzoyloxy-3-hydroxypiperidine, but the cis-
trans ratio was not specified; see: Masamune, T.; Hayashi, H.; Takasugi,
M.; Fukuoka, S. J. Org. Chem. 1972, 57, 2343-2345. (b) A related MCPBA
epoxidation of N-methylcarbamoyl-1,4-dihydropyridine has been shown to
give the corresponding addition products with trans relative stereochemistry.
However, use of DMDO afforded a dioxane dimer from dimerization of
the opened epoxide; see: Lavilla, R.; Baro´n, X.; Coll, O.; Gullo´n, F.;
Masdeu, C.; Bosch, J. J. Org. Chem. 1998, 63, 10001-10005.
(17) For a related cis stereoselective glycal epoxide opening using
organozinc triflate or organozinc chloride, see: Xue, S.; Han, K.-Z.; Guo,
Q.-X. Synlett 2003, 870-872. Use of organoaluminum and organoboron
reagents, see: Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W.
B.; Rainier, J. D. Tetrahedron 2002, 58, 1997-2009. Use of sodium
thiophenolate, see: Marzabadi, C. H.; Spilling, C. D. J. Org. Chem. 1993,
58, 3761-3766.
(18) For an interesting DMDO/TiCl4 semipinacol-type rearrangement of
2-cycloalkanol-substituted N-tosyl-1,4,5,6-tetrahydropyridines, see: Dake,
G. R.; Fenster, M. D. B.; Fleury, M.; Patrick, B. O. J. Org. Chem. 2004,
69, 5676-5683.
(19) Isolation: (a) Ahmad, V. U.; Basha, A.; Haque, W. Z. Naturforsch.,
B: Anorg. Chem., Org. Chem. 1978, 33B, 347-348. (b) Ahmad, V. U.;
Usmanghani, K.; Najmus-Saqib, Q. Sci. Pharm. 1979, 47, 333-334.
Absolute configuration determination: (c) Ahmad, V. U.; Qazi, S. Z.
Naturforsch., B: Anorg. Chem., Org. Chem. 1983, 38B, 347-348.
(20) For asymmetric synthesis of 1, see ref 4r. For racemic synthesis,
see: Paterne, M.; Brown, EÄ . C. R. Se´ances Acad. Sci., Ser. 2 1983, 296,
433-434.
ammonia. Expedient total synthesis of (+)-julifloridine was
realized in four steps and 33% overall yield, from pyridine.
In conclusion, the asymmetric synthesis of 2,6-disubsti-
tuted 3-piperidinols having a 2,3-cis-2,6-trans stereochemistry
was accomplished in three steps using the following se-
quence: stereocontrolled nucleophilic addition of an organo-
magnesium reagent to a chiral pyridinium salt; chemoselec-
tive monohydrogenation of a 2-substituted 1,2-dihydro-
pyridine; and a tandem, highly diastereoselective epoxida-
tion-nucleophilic addition with a heteroatom nucleophile
or an organometallic reagent. Highly substituted 3-piperidinol
derivatives can be prepared using this approach, which was
demonstrated by a rapid and stereoselective total synthesis
of (+)-julifloridine.
Acknowledgment. This work was supported by the
National Science and Engineering Research of Canada
(NSERC), Merck Frosst Canada & Co., Boehringer Ingel-
heim (Canada), Ltd., and the Universite´ de Montre´al. A.L.
thanks NSERC (Canada) and FQRNT (Que´bec) for a
postgraduate fellowship.
Supporting Information Available: Experimental pro-
cedures and data for each reaction. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL051022Z
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Org. Lett., Vol. 7, No. 13, 2005