C O M M U N I C A T I O N S
Table 3. Catalytic Asymmetric Synthesis of Piperidines: Scope
Acknowledgment. Support has been provided by NSERC of
Canada (postdoctoral fellowship to R.P.W.), Merck, and Novartis.
We thank Luke Firmansjah and Dr. Peter Mueller for assistance
with X-ray crystallography and Degussa for a gift of chiral
phosphines for our preliminary studies.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). X-ray crystallographic file
(CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
with Respect to the Iminea
entry
R
ee (%)b
cis:trans
isolated yield (%)
1
Ph
98
98
96
98
96
99
68
60
99
97
97
91:9
93:7
93
98
86
42
99
98
98
75
96
98
76
2
3-MeC6H4
3,4,5-(MeO)3C6H2
4-(MeO)C6H4
4-ClC6H4
3
96:4
4
93:7
91:9
89:11
96:4
79:21
93:7
5
References
6
3-BrC6H4
2-(NO2)C6H4
2-ClC6H4
2-naphthyl
2-furyl
3-pyridyl
7
(1) For leading references, see: Fu, G. C. Acc. Chem. Res. 2004, 37, 542-547.
(2) For leading references, see: (a) Spivey, A. C.; Arseniyadis, S. Angew.
Chem., Int. Ed. 2004, 43, 5436-5441. (b) Murugan, R.; Scriven, E. F. V.
Aldrichimica Acta 2003, 36, 21-27.
(3) For a review, see: Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004,
346, 1035-1050.
(4) For some key pioneering examples, see: (a) Vedejs, E.; Daugulis, O.;
Diver, S. T. J. Org. Chem. 1996, 61, 430-431; Vedejs, E.; Daugulis, O.
J. Am. Chem. Soc. 1999, 121, 5813-5814; Shaw, S. A.; Aleman, P.;
Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368-13369. (b) Zhu, G.; Chen,
Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem. Soc. 1997, 119,
3836-3837; Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X.
J. Org. Chem. 1998, 63, 5631-5635. (c) Shi, M.; Chen, L.-H.; Li, C.-Q.
J. Am. Chem. Soc. 2005, 127, 3790-3800.
8
9
10
11
87:13
91:9
a All data are the average of two experiments. b The ee value is for the
cis diastereomer.
Scheme 1
(5) For leading references, see: (a) Naturally occurring alkaloids: Michael,
J. P. Nat. Prod. Rep. 2004, 21, 625-649; O’Hagan, D. Nat. Prod. Rep.
2000, 17, 435-446; Plunkett, O.; Sainsbury, M. In Rodd’s Chemistry of
Carbon Compounds; Sainsbury, M., Ed.; Elsevier: Amsterdam; 1998; Vol.
4, pp 365-421. (b) Pipecolic acid derivatives: Maison, W. In Highlights
in Bioorganic Chemistry; Schmuck, C., Wennemers, H., Eds.; Wiley-
VCH: New York, 2004; pp 18-29.
(6) For leading references, see: (a) Buffat, M. G. P. Tetrahedron 2004, 60,
1701-1729. (b) Felpin, F.-X.; Lebreton, J. Curr. Org. Synth. 2004, 1,
83-109. (c) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D.
R. Tetrahedron 2003, 59, 2953-2989. (d) Laschat, S.; Dickner, T.
Synthesis 2000, 1781-1813. (e) Rubiralta, M.; Giralt, E.; Diez, A.
Piperidine: Structure, Preparation, ReactiVity, and Synthetic Applications
of Piperidine and Its DeriVatiVes; Elsevier: New York, 1991.
(7) For two very recent reports, see: (a) Ichikawa, E.; Suzuki, M.; Yabu, K.;
Albert, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126,
11808-11809. (b) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.;
Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313-1317.
(8) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716-4717.
(9) For reviews of the chemistry of allenes, see: Krause, N., Hashmi, A. S.
K., Eds. Modern Allene Chemistry; Wiley-VCH: New York, 2004; Vol.
1 and 2.
1-3). In contrast, for an unsubstituted allene (R ) H), moderate
enantioselectivity is observed (entries 4-5).12
A range of imines can be employed as substrates in this catalytic
enantioselective synthesis of piperidine derivatives (Table 3). Thus,
the imine can bear an electron-rich (entries 3-4), electron-poor
(entries 5-8), or ortho-substituted (entries 7-8) aromatic group,
although it is worth noting that the electron-rich 4-anisyl imine is
a reluctant coupling partner (entry 4) and that ortho-substituted,
electron-poor imines react with lower stereoselectivity (entries 7
and 8). Heteroaryl imines are suitable substrates for this annulation
process (entries 10 and 11).13-15
(10) Gladiali, S.; Dore, A.; Fabbri, D.; De Lucchi, O.; Manassero, M.
Tetrahedron: Asymmetry 1994, 5, 511-514.
(11) For leading references to the use of these phosphines as chiral ligands for
transition metal-catalyzed processes, see: Junge, K.; Hagemann, B.;
Enthaler, S.; Oehme, G.; Michalik, M.; Monsees, A.; Riermeier, T.;
Dingerdissen, U.; Beller, M. Angew. Chem., Int. Ed. 2004, 43, 5066-
5069.
(12) If R is an electron-rich aromatic group, the annulation proceeds sluggishly
(but with high stereoselectivity).
(13) Notes: (a) Kwon reported that, with PBu3 as the catalyst, enolizable imines
are not suitable substrates for the annulation reaction (ref 8). Under our
standard conditions, catalyst 1 is also ineffective for this family of
compounds. (b) The phosphine oxide of 1 does not catalyze the Kwon
annulation. (c) 1,2-Dichloroethane is also a suitable solvent. Reactions
conducted in toluene, acetone, and THF proceed very slowly. (d) If the
Ts group is replaced with P(dO)Ph2 or Ms, the annulation proceeds in
lower yield and ee.
The products of these [4 + 2] reactions can be transformed into
a variety of useful derivatives. For example, the olefin can be
dihydroxylated with excellent diastereoselectivity (eq 2).16 Alter-
(14) Like many trialkylphosphines, catalyst 1 is susceptible to oxidation. The
corresponding air-stable phosphonium salt can be prepared via protonation
with HBF4 (for a discussion of this general strategy, see: Netherton, M.
R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298), and, in the presence of
K2CO3, it furnishes stereoselectivity identical to that of 1 for the annulation
illustrated in entry 1 of Table 3 (74% yield).
(15) According to 31P NMR spectroscopy, the resting state of 1 during the
reaction is the free catalyst.
(16) For leading references to hydroxylated piperidines/azasugars, see: (a)
Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005, 16, 1239-1287.
(b) Depezay, J.-C. In Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley-
VCH: New York, 1998; pp 307-326.
(17) (a) For the isolation of 6-oxoalstophyllal and 6-oxoalstophylline, see: Kam,
T.-S.; Choo, Y.-M. J. Nat. Prod. 2004, 67, 547-552. (b) For leading
references, see: Hamaker, L. K.; Cook, J. M. In Alkaloids: Chemical
and Biological PerspectiVes; Elsevier: New York, 1995; Vol. 9, pp 23-
84.
natively, transannular cyclization affords ready access to a frame-
work common to an array of important natural products (Scheme
1).17,18
In summary, we have demonstrated that a chiral phosphepine
can catalyze the Kwon [4 + 2] annulation of imines with allenes,
providing six-membered nitrogen heterocycles with excellent di-
astereo- and enantioselectivity. Additional synthetic and mechanistic
investigations of asymmetric nucleophile-catalyzed processes are
underway.
(18) For a method for annulating the dihydropyran ring, see: Bi, Y.; Zhang,
L.-H.; Hamaker, L. K.; Cook, J. M. J. Am. Chem. Soc. 1994, 116,
9027-9041.
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