A Diels-Alder approach to the stereoselective synthesis of 2,3,5,6-tetra- and 2,3,4,5,6-pentasubstituted piperidines

Article abstract of DOI:10.1021/ol052436v

(Chemical Equation Presented) A stereoselective synthesis of 2,3,5,6-tetra- and 2,3,4,5,6-pentasubstituted piperidines was achieved from oxidative cleavage of 2-aza-bicyclo[2.2.2]octene Diels-Alder adducts derived from N-protected 2-methyl-1,2-dihydropyri

Full text of DOI:10.1021/ol052436v

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5773-5776
A Diels−Alder Approach to the
Stereoselective Synthesis of
2,3,5,6-Tetra- and
2,3,4,5,6-Pentasubstituted Piperidines
Marcelo Sales and Andre´ B. Charette*
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received October 7, 2005
ABSTRACT
A stereoselective synthesis of 2,3,5,6-tetra- and 2,3,4,5,6-pentasubstituted piperidines was achieved from oxidative cleavage of 2-aza-bicyclo-
[2.2.2]octene Diels Alder adducts derived from N-protected 2-methyl-1,2-dihydropyridine. A chiral auxiliary mediated asymmetric synthesis of
−
the pentasubstituted piperidine is also demonstrated. This methodology incorporates orthogonal protecting groups, thus providing a piperidine
scaffold with easily modified points of diversity.
The pharmacological activity of natural products containing
polysubstituted piperidine subunits has generated much
interest toward their stereoselective synthesis.1 The Diels-
Alder reaction’s ability to produce six-membered rings and
potentially generate up to four contiguous stereogenic centers
in a stereocontrolled fashion has made it a useful reaction
in the synthesis of polysubstituted piperidines. In particular,
aza-Diels-Alder reactions of imines2 with dienes or dieno-
philes with azadienes3 generate the piperidine backbone in
one step. An alternate route is the Diels-Alder reactions of
cyclic dienes such as N-carbamoyl-1,2-dihydropyridines with
appropriate dienophiles to give azabicyclo[2.2.2]octene ad-
ducts, which are subsequently oxidatively cleaved to afford
the piperidine backbone.4 The readily available 1,2-dihydro-
Barluenga, J.; Aznar, F.; Ribas, C.; Valdes, C. J. Org. Chem. 1999, 64,
3736-3740. (e) Heintzelman, G. R.; Weinreb, S. M.; Parvez, M. J. Org.
Chem. 1996, 61, 4594-4599. (f) Waldmann, H. Synthesis 1994, 535-551.
(3) (a) Toure, B. B.; Hall, D. G. J. Org. Chem. 2004, 69, 8429-8436.
(b) Tietze, L. F.; Schuffenhauer, A. Eur. J. Org. Chem. 1998, 1629-1637.
(c) Boger, D. L.; Hueter, O.; Mbiya, K.; Zhang, M. J. Am. Chem. Soc.
1995, 117, 11839-11849. (d) Trione, C.; Toledo, L. M.; Kuduk, S. D.;
Fowler, F. W.; Grierson, D. S. J. Org. Chem. 1993, 58, 2075-2080. (e)
Boger, D. L.; Corbett, W. L.; Wiggins, J. M. J. Org. Chem. 1990, 55, 2999-
3000. (f) Overman, L. E.; Taylor, G. F.; Houk, K. N.; Domelsmith, L. N.
J. Am. Chem. Soc. 1978, 100, 3182-3189.
(1) For recent reviews: (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-
1729. (b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953-2989. (c) Felpin, F.-X.; Lebreton, J. Eur. J.
Org. Chem. 2003, 3693-3712.
(2) (a) Barluenga, J.; Mateos, C.; Aznar, F.; Valdes, C. J. Org. Chem.
2004, 69, 7114-7122. (b) Barluenga, J.; Mateos, C.; Aznar, F.; Valdes, C.
Org. Lett. 2002, 4, 1971-1974. (c) Badorrey, R.; Cativiela, C.; Diaz-De-
Villegas, M. D.; Galvez, J. A. Tetrahedron 1999, 55, 7601-7612. (d)
10.1021/ol052436v CCC: $30.25
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pyridines (()-1 and (-)-2 from cheap starting materials5 and
the possibility of rapid access to tetra- and pentasubstituted
piperidines from mono- and disubstituted dienophiles prompted
us to explore this route (Figure 1).
Scheme 1. Diels-Alder Reaction of 1 with Various
Dienophiles
Figure 1. Retrosynthesis for pentasubstituted piperidines.
To the best of our knowledge, the Diels-Alder reactions
of 1-N-amidine-1,3-dienes, whether acyclic or cyclic such
as 1, have not been reported. We herein communicate our
progress in this area as well as methods employed to remove
the amidine and oxidatively cleave the 2-aza-bicyclo[2.2.2]-
octene adducts to afford tetra- and pentasubstituted piperi-
dines.
The cycloaddition reaction of 1 with maleic anhydride in
CH2Cl2 gave an adduct that was directly converted to the
diester to afford 3a (dr >95:5) (Scheme 1). The cycloaddi-
tions with other doubly activated dienophiles such as
maleimide and phenyl maleimide proceeded with similar
reactivity and selectivity to give 4 (dr >95:5) and 5 (dr >95:
5), respectively. All three cycloadditions were facile, requir-
ing 1 equiv of dienophile at room temperature for >95%
conversion. The thermal cycloaddition reaction of 1 with
methyl acrylate at 50 °C in toluene gave <30% conversion
to 3b. Fortunately, the corresponding Lewis acid promoted
Diels-Alder reaction in the presence of BF3‚OEt3 at 50 °C
afforded BF3‚3b in 75% yield.6 The free amidine 3b could
be obtained in 95% yield by treatment of BF3‚3b with
aqueous NaOH (Scheme 1).7
Reactions of 3b with alane8 or Birch conditions9 both led to
complex mixtures. We envisioned an alternate strategy that
entailed changing the reactivity of the amidine moiety by
reaction with MeI to form a dimethylated iminium salt, which
could then undergo base hydrolysis to the corresponding
amide.10 Prior to alkylation with MeI, the esters 3a and 3b
were reduced with LiAlH4 to give 6a and 6b (Scheme 2).11
Scheme 2. Functional Group Interconversion of Amidine 6 to
Benzamide 7
Our results show that these cycloaddition reactions are
highly stereoselective, affording one diastereomer in each
case (i.e., highly endo-selective and high diastereofacial
selectivity of addition to diene).
With the Diels-Alder adducts in hand, the focus was
directed toward the reductive removal of the amidine moiety.
Indeed, treatment of the iminium salts derived from 6a and
6b with aqueous NaOH afforded complete conversion to
benzamides 7a and 7b, respectively (Scheme 2).
(4) (a) Maison, W.; Grohs, D. C.; Prenzel, A. H. G. P. Eur. J. Org. Chem.
2004, 1527-1543. (b) Arakawa, Y.; Murakami, T.; Ozawa, F.; Arakawa,
Y.; Yoshifuji, S. Tetrahedron 2003, 59, 7555-7563. (c) Maison, W.;
Adiwidjaja, G. Tetrahedron Lett. 2002, 43, 5957-5960. (d) Maison, W.;
Kuntzer, D.; Grohs, D. Synlett 2002, 1795-1798.
(5) Prepared from diastereoselective 1,2-nucleophilic additions of orga-
nometallic reagents to triflic anhydride activated pyridinium salts: Charette,
A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem.
Soc. 2001, 123, 11829-11830.
(6) For a recent example of an isolation of a BF3-imine complex, see:
Ma, Y.; Lobkovsky, E.; Collum, D. B. J. Org. Chem. 2005, 70, 2335-
2337
(8) Lemire, A.; Beaudoin, D.; Grenon, M.; Charette, A. B. J. Org. Chem.
2005, 70, 2368-2371.
(9) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747-2750.
(10) For hydrolysis of dimethyliminium salts, see: (a) Manh, G. T.;
Purseigle, F.; Dubreuil, D.; Pradere, J. P.; Guingant, A.; Danion-Bougot,
R.; Danion, D.; Toupet, L. J. Chem. Soc., Perkin Trans. 1 1999, 2821-
2828. (b) Nakayama, J.; Otani, T.; Sugihara, Y.; Ishii, A. Tetrahedron Lett.
1997, 38, 5013-5016. (c) Alonso, M. A.; Ubeda, J. I.; Avendano, C.;
Menendez, J. C.; Villacampa, M. Tetrahedron 1993, 49, 10997-11008.
(d) Kantlehner, W.; Greiner, U. Synthesis 1979, 339-342. (e) Janousek,
Z.; Collard, J.; Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1972, 11, 917-
918.
(7) The yield was calculated on the basis of mass recovery of 3b from
a 1:1 complex of BF3:3b.
(11) Compound 6a crystallized as monohydrate; see Supporting Informa-
tion for crystal structure.
5774
Org. Lett., Vol. 7, No. 26, 2005

The newly acquired benzoyl moeity served as N-protecting
group to be removed at a later stage. To prevent acetal
formation from aldehydes formed during an oxidative
cleavage of alkenes 7a and 7b, the hydroxyl groups were
benzylated to give 8a and 8b, respectively (Scheme 2).
Dihydroxylation of 8a using a modification of the racemic
Sharpless procedure, known to dihydroxylate sterically
hindered alkenes, gave poor conversions to 9a (<40%).12
We later found that the use of quinuclidine as an additive
gave reproducible and improved yields of 9a (63%, dr >95:
5) (Scheme 3). As expected, the sterically less hindered face
Scheme 3. Two-Step Oxidation-Reduction-Hydrolysis
Figure 2. Crystal structure of 11a.
The pharmacological importance of â-hydroxylamines and
the potential use of substrates such as 11a and 11b in natural
product synthesis provided the impetus to differentiate the
primary alcohols.17 The silylation of 11a and 11b was highly
regioselective for γ-hydroxyl (γ:â 15:1 for both) and afforded
12a (76%) and 12b (60%) (Scheme 5).18 The regioselectivity
was dihydroxylated.4a,12b,13 Diol 9a was cleaved using silica-
supported sodium periodate.14 A reductive workup with
NaBH4 was used to avoid epimerization of the dialdehyde.15
Upon NaOH quench, it was observed that the benzamide
moiety of 10a was prone to a neighboring hydroxyl facilitated
base hydrolysis and 9a gave 11a (75%) in one step (Scheme
3).
Scheme 5. Regioselective Silylation of Diols 11a and 11b and
Ensuing Carbamate Formation
Taking this facilitated hydrolysis into account, we per-
formed the ozonolysis of 8a and 8b followed by NaBH4
reduction and treatment with NaOH at 40 °C to afford 11a
(52%) and 11b (66%) in one pot (Scheme 4). NMR data
Scheme 4. One-Pot Oxidation-Reduction-Hydrolysis
supports the all-cis relative configuration of substituents for
11a and 11b.16 Crystal structure confirmed the all-cis
configuration of 11a (Figure 2).
may be explained due to the reduced nucleophilicity of the
â-hydroxyl group as a result of hydrogen bonding to the
neighboring amine. The derivatization to carbamates 14a and
14b provided confirmation of silylation at the γ-hydroxyl
(12) DABCO and MeSO2NH2 as additives: (a) Kinsman, A. C.; Kerr,
M. A. J. Am. Chem. Soc. 2003, 125, 14120-14125. (b) Kinsman, A. C.;
Kerr, M. A. Org. Lett. 2001, 3, 3189-3191. (c) Eames, J.; Mitchell, H. J.;
Nelson, A.; O’Brien, P.; Warren, S.; Wyatt, P. J. Chem. Soc., Perkin Trans.
1 1999, 1095-1104.
(17) For bioactive amino alcohols, see: (a) Wu, X.; Dubois, K.; Rogiers,
J.; Toppet, S.; Compernolle, F.; Hoornaert, G. J. Tetrahedron 2000, 56,
3043-3051. (b) Harrison, T.; Williams, B. J.; Swain, C. J. Bioorg. Med.
Chem. Lett. 1994, 4, 2733-2734. (c) Harrison, T.; Williams, B. J.; Swain,
C. J.; Ball, R. G. Bioorg. Med. Chem. Lett. 1994, 4, 2545-2550. For related
tetrasubstituted natural product 223A, see: (d) Toyooka, N.; Fukutome,
A.; Nemoto, H.; Daly, J. W.; Spande, T. F.; Garraffo, H. M.; Kaneko, T.
Org. Lett. 2002, 4, 1715-1717.
(13) Koenigsberger, K.; Faber, K.; Marschner, C.; Penn, G.; Baumgartner,
P.; Griengl, H. Tetrahedron 1989, 45, 673-680.
(14) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622-
2624.
(15) The dialdehyde readily epimerizes overnight at room temperature.
(16) See Supporting Information for NMR analysis (NOE and 3J) of
related 12a and 12b.
(18) The silylation of 11b gave an easily separable mixture of 12b (60%),
13b (7%) and recovered 11b (14%).
Org. Lett., Vol. 7, No. 26, 2005
5775

(Scheme 5). An analysis of NMR data showed that the
piperidine ring of 14a favors a chair conformation. However,
the piperidine ring of 14b adopted a twist-boat so as to avoid
unfavorable 1,3-diaxial interactions between the CH2OTBS
and CH2OBn substituents.19 This avoidance of 1,3-diaxial
interactions may explain the relatively facile formation of
14b at room temperature compared to 14a at 50 °C (Scheme
5).
To apply our methodology to the synthesis of enantio-
enriched piperidines, we investigated a chiral auxiliary
approach to 11a from (-)-2. The facile reaction of (-)-2
with maleic anhydride (1 equiv, rt) followed by diester
formation to 15 and LiAlH4 reduction gave 16 (71% over
three steps, dr >95:5) (Scheme 6). As was the case with
(+)-8a. This was a consequence of a slow rate of alkylation
of 17 with MeI at 40 °C. The rate of alkylation was
dramatically increased with µwave at 150 °C. The ensuing
hydrolysis of iminium salt gave varying mixtures of (+)-8a
and 18. The “free” amine 18 was conveniently converted in
situ to (+)-8a by addition of benzoyl chloride. Finally, (+)-
8a was isolated in 63% from 17 (Scheme 6). The enantiopu-
rity of (+)-8a (92% ee) was established by SFC on chiral
stationary phase.20 The one-pot oxidation-reduction-hy-
drolysis protocol was used to convert (+)-8a to (-)-11a in
54%.
In conclusion, we have developed an expedient and
stereoselective synthesis of tetra- and pentasubstituted pi-
peridines. In particular, starting from 1-N-amidine-1,3-dienes
1 or (-)-2, the polysubstituted piperidines (()-11a, (()-
11b, and (-)-11a were conveniently obtained in six steps
in 25%, 37%, and 20% overall yields. The key reactions of
this methodology were the diastereoselective [4 + 2]
cycloadditions of 1 and (-)-2, the facile functional group
conversion of amidines 6 to benzamides 7, and the one-pot
oxidation-reduction-hydrolysis of 8 to 11. In addition, it
was demonstrated that 11 could undergo regioselective
silylation to provide versatile building blocks 12.
Scheme 6. Chiral Auxiliary Approach to (-)-11a
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC), Merck Frosst Canada & Co., Boehringer
Ingelheim (Canada) Ltd., and the Universite´ de Montre´al.
We would like to thank Charles Banville for his preliminary
work on potential routes and Francine Be´langer-Garie´py for
X-ray analysis. M.S. would like to thank Alexandre Lemire
and Dr. Thilo Focken for useful conversations.
Supporting Information Available: General information,
experimental procedures, and characterization data for 3-9
and 11-17, crystal structures of 6a and 11a in CIF format,
1
and H and 13C NMR spectra of all new compounds. This
diene 1, the cycloaddition of (-)-2 with maleic anhydride
was highly diastereoselective. Dibenzylation of 16 gave 17
(81%). The alkylation-hydrolysis protocol previously used
to convert 6 to 7 was ineffective to convert 17 to benzamide
material is available free of charge via the Internet at
http://pubs.acs.org.
OL052436V
(19) See Supporting Information for NMR analysis of 14a and 14b.
(20) See Supporting Information for SFC traces.
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Org. Lett., Vol. 7, No. 26, 2005