the reaction (Table 3, entry 12), the endo-selectivity and
facial diastereoselectivity were relatively lower in the case of
CF2Cl (Table 3, entry 11). Cinnamaldehyde (1m) without an
electron-withdrawing group gave no DA adducts due to the
low reactivity of the imine intermediate formed in the reaction
(Table 3, entry 13). Although the endo/exo diastereoselectivity
of the DA adduct of acrylonitrile (1n) was quite good, the
facial diastereoselectivity was only 2.6 : 1, similar to that of the
p-tolyl substituent counterpart (Table 3, entry 14).11 It is worth
mentioning that the two endo products could be easily separated
by column chromatography or recrystallization and obtained in
pure form respectively.
To further demonstrate the utility of PFSAs as chiral auxiliaries
in the asymmetric IEDDA reaction, sulfinamide (SS)-2a was
successfully prepared in enantiopure form (>99% ee) by ammonia
hydrolysis of 2-chlorotetrafluoroethanesulfinyl-oxazolidione (5)14
with LiHMDS (Scheme 1). The enantioselective three-component
IEDDA reaction was then conducted with (SS)-2a and no
racemization was observed with product (SS,2S,4R)-6 as shown
by chiral HPLC analysis (>99.9% ee). The DA adduct (SS,2S,4R)-
6 could be smoothly converted into a number of valuable
compounds (Fig. 1). Limited attempts at direct desulfination of
(SS, 2S,4R)-6 led only to decomposition.11 Upon heating in THF,
however, disubstituted pyridine 7 was produced efficiently.10 The
transformation of (SS,2S,4R)-6 into its 2-hydroxy derivative 8 was
readily achieved in 58% yield with complete stereoselectivity15
by treatment with BCl3 in CH2Cl2, whereas the RO group was
removed chemoselectively to give compound 9 by nucleophilic
replacement with Et3SiH/BCl3 at ambient temperature. Depro-
tection of compound 9 was achieved conveniently with HCl/Et2O
in MeOH. Without purification, intermediate imine 1016 was
reduced with NaBH3CN directly to give a single diastereomer
of trifluoromethylated piperidine 11,1a,17 a fluorinated common
subunit found in compounds of varied pharmacological activities,
in 71% total yield with 98% ee.
Fig. 1 Synthetic potential of the cycloadducts.
of these PFSAs in the asymmetric synthesis are in progress in our
laboratory.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (No. 20872166) is gratefully acknowledged.
Notes and references
1 For reviews on the importance of piperidine derivatives, see: (a) P. D.
Bailey, P. A. Millwood and P. D. Smith, Chem. Commun., 1998, 633;
(b) M. Rubiralta, E. Giralt, A. Diez, Piperidine: Structure, Preparation,
Reactivity, and Synthetic Applications of Piperidine and Its Derivatives,
Elsevier, Amsterdam, 1991.
2 For recent reviews on stereoselective aza-Diels–Alder reactions, see:
(a) For a review on catalytic asymmetric aza-Diels–Alder reactions, see:
G. B. Rowland, E. B. Rowland, Q. Zhang and J. C. Antilla, Curr. Org.
Chem., 2006, 10, 981; (b) G. R. Heintzelman, I. R. Meigh, Y. Mahajan
and S. M. Weinreb, Org. React., 2005, 65, 141; (c) S. Kobayashi, in
Cycloaddition Reactions in Organic Synthesis (ed.: S. Kobayashi, K. A.
Jørgensen), Wiley-VCH: Weinheim, 2002, Chap. 5, 187–209.
3 (a) D. L. Boger and A. M. Kasper, J. Am. Chem. Soc., 1989, 111, 1517;
(b) D. L. Boger, W. L. Corbett and J. M. Wiggins, J. Org. Chem., 1990,
55, 2999; (c) D. L. Boger and T. T. Curran, J. Org. Chem., 1990, 55,
5439; (d) D. L. Boger, W. L. Corbett, T. T. Curran and A. M. Kasper,
J. Am. Chem. Soc., 1991, 113, 1713; (e) D. L. Boger, K. C. Cassidy and
S. Nakahara, J. Am. Chem. Soc., 1993, 115, 10733; (f) J. Hong and D.
L. Boger, J. Am. Chem. Soc., 1998, 120, 1218; (g) M. J. Schnermann
and D. L. Boger, J. Am. Chem. Soc., 2005, 127, 15704; (h) for a review
on the ADAR of 1-azadienes, see: M. Behforouz and M. Ahmadian,
Tetrahedron, 2000, 56, 5259.
4 For selected examples on diastereoselective ADARs of 1-azadienes, see:
(a) M. C. Aversa, A. Barattucci, M. C. Bilardo, P. Bonaccorsi and P.
Giannetto, Synthesis, 2003, 2241; (b) C. R. Berry and R. P. Hsung,
Tetrahedron, 2004, 60, 7629; (c) J. E. Tarver, Jr., K. M. Terranova and
M. M. Joullie´, Tetrahedron, 2004, 60, 10277.
5 R. C. Clark, S. S. Pfeiffer and D. L. Boger, J. Am. Chem. Soc., 2006,
128, 2587.
Scheme 1 Preparation of sulfinamide (SS)-2a.
In conclusion, we have developed a highly stereoselective
three-component IEDDA reaction assisted by PFSAs, providing
an efficient method for the synthesis of highly functionalized
piperidine derivatives (especially trifluoromethylated ones18) with
excellent endo/exo selectivities and facial diastereoselectivities.
Initial experiments that highlight the synthetic potential of
these piperidine derivatives and the convenient removal of the
per(poly)fluoroalkanesulfinyl groups were also presented. It is
noteworthy that the use of these PFSA auxiliaries made it
possible to monitor the process and stereoselectivities of the
reaction conveniently by 19F NMR spectroscopy. Moreover, the
one-pot three-component reaction avoided the manipulation of
the unstable imine intermediates, extending the scope of IEDDA
reaction to specific substrates. Further studies on the applications
76 | Org. Biomol. Chem., 2011, 9, 74–77
This journal is
The Royal Society of Chemistry 2011
©