is formed by selective activation of the primary alcohol as a
leaving group with p-toluenesulfonyl chloride and triethyl-
amine at room temperature followed by cyclization of the
primary tosylate upon reflux.12 Cleavage of the Cbz group
under standard reductive conditions13 followed by derivati-
zation of the resulting primary amine with methanesulfonyl
chloride yields catalyst 1a. Catalysts of this type have been
prepared in multiple gram quantities.
Using this sequence, an initial series of catalysts was
synthesized in which the nature of the relative configuration
and the nitrogen substituent could be assessed (Figure 2).
Figure 1. Catalyst design and initial catalyst discovery.
proposed ligand scaffold prompted us to evaluate their
potential use as catalysts for hydrogen bond promoted
reactions. Herein, we report the successful identification and
optimization of a new class of hydrogen bond catalysts for
an enantioselective hetero Diels-Alder reaction.
Inspired by the recent success of Rawal and co-workers
in the development of hydrogen bond promoted catalytic
enantioselective hetero Diels-Alder reactions,8 we elected
to assess our new catalyst design for this important reaction
class. Therefore, we evaluated catalyst 1a for the hetero
Diels-Alder (HDA) reaction between benzaldehyde and
diene 2 (Figure 1).9 Decomposition of the Diels-Alder
adduct with acetyl chloride yielded the corresponding pyra-
none with a moderate enantiomeric excess of 44% and in
poor yield (25%). This proved to be an ideal starting point
for demonstrating the utility of our catalyst design.
Facile access to catalyst analogues can be accomplished
using the process outlined in Scheme 1. Aminodiol 5 is
Scheme 1
Figure 2. Catalyst optimization.
Evaluation of the initial set of catalysts for the HDA reaction
(eq 1) produced the following observations: (1) the relative
(7) (a) Lee, J.-Y.; Miller, J. J.; Hamilton, S. S.; Sigman, M. S. Org.
Lett. 2005, 7, 1837-1839. (b) Rajaram, S.; Sigman, M. S. Org. Lett. 2002,
4, 3399-3401.
(8) (a) See refs 2a, 2c, and 2d. (b) For the uncatalyzed reaction at room
temperature, see: Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321-3323.
(c) For an example of activation of ketone via hydrogen bonds, see: Huang,
Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662-9663.
(9) For preparation of diene 2, see: (a) Kozmin, S. A.; He, S.; Rawal,
V. H. Org. Synth. 2002, 78, 152-159. (b) Kozmin, S. A.; Janey, J. M.;
Rawal, V. H. J. Org. Chem. 1999, 64, 3039-3052.
synthesized readily by the addition of phenylmagnesium
bromide to serine methyl ester.10 â-Hydroxyamide 6 is
prepared in high yield by coupling 5 to Cbz-protected
phenylalanine using isobutyl chloroformate.11 Oxazoline 1g
(10) Sibi, M. P.; Chen, J.-X.; Cook, G. R. Tetrahedron Lett. 1999, 40,
3301-3304.
(6) For reviews on oxazolines in catalysis, see: (a) McManus, H.; Guiry,
P. J. Chem. ReV. 2004, 104, 4151-4202. (b) Braunstein, P.; Naud, F. Angew.
Chem., Int. Ed. 2001, 40, 680-699. (c) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325-335. (d) Ghosh, A. K.; Mathivanan, P.;
Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1-45.
(11) Wipf, P.; Fritch, P. C. J. Am. Chem. Soc. 1996, 118, 12358-12367.
(12) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos,
K. A.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541-4544.
(13) Downing, S. V.; Aguilar, E.; Meyers, A. I. J. Org. Chem. 1999,
64, 826-831.
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