C O M M U N I C A T I O N S
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
References
(1) For reviews of routes to optically active arylpropionic acids, see: Stahly,
G. P.; Starrett, R. M. In Chirality in Industry II; Collins, A. N., Sheldrake,
G. N., Crosby, J., Eds.; Wiley: New York, 1997; Chapter 3 and references
therein.
(2) (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9-22. Pracejus,
H.; Ma¨tje, H. J. Prakt. Chem. 1964, 24, 195-205. (b) Hodous, B. L.;
Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.
(3) For pioneering examples of diastereoselective additions of chiral amines
to ketenes, see: (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634,
23-29. (b) Pracejus, H.; Tille, A. Chem. Ber. 1963, 96, 854-865. (c)
Winter, S.; Pracejus, H. Chem. Ber. 1966, 99, 151-159.
Figure 1. Transformations of the N-acylpyrroles.
(4) Catalog numbers from Strem Chemicals: (+)-1: 26-3700. (-)-1: 26-
3701.
(5) For previous applications of PPY derivative 1 in asymmetric catalysis,
see: (a) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532-
11533. (b) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew. Chem.,
Int. Ed. 2001, 40, 234-236. (c) Hodous, B. L.; Fu, G. C. J. Am. Chem.
Soc. 2002, 124, 1578-1579.
(6) Notes: (a) Approximately 80% of the catalyst can be recovered at the
end of the reaction. (b) In a gram-scale reaction, comparable ee and yield
were obtained.
(7) (a) For leading references, see: Evans, D. A.; Scheidt, K. A.; Johnston,
J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480-4491. (b) See
also: Arai, Y.; Masauda, T.; Masaki, Y. Chem. Lett. 1997, 145-146.
(8) A number of important nonsteroidal antiinflammatory drugs are arylpro-
pionic acids (e.g., ibuprofen and naproxen). For leading references, see
ref 1.
Figure 2. Possible mechanism for the enantioselective addition of pyrroles
to ketenes catalyzed by 1.
(9) This process resembles that employed for the synthesis of fenvalerate, a
commercial insecticide, which also involves the acylation of an alcohol
with an isopropyl-substituted arylacetic acid derivative. For an overview
of fenvalerate, see: Yoshioka, H. CHEMTECH 1985, 15, 482-486.
50 min), and we have made the following observations: (1)
Treatment of 2-cyanopyrrole with 1 leads to deprotonation of the
pyrrole and formation of an ion pair; this ion pair, not 1 itself, is
the resting state of the catalyst during the reaction. (2) The reaction
is first-order in phenyl tert-butyl ketene, first-order in 1, and zero-
order in 2-cyanopyrrole. (3) A primary kinetic isotope effect of
∼5 is observed (1-H-2-cyanopyrrole vs 1-D-2-cyanopyrrole). (4)
The ee of the N-acylpyrrole varies linearly with the ee of 1.13,14
On the basis of these data, we believe that enantioselective
additions of pyrroles to ketenes catalyzed by PPY derivative 1
proceed through the pathway illustrated in Figure 2. Deprotonation
of 2-cyanopyrrole by the catalyst furnishes ion pair 7. The
nucleophilic pyrrole anion then adds to the ketene, generating a
new ion pair (8), which consists of an achiral enolate and a chiral
Brønsted acid (protonated 1). In the turnover-limiting and stereo-
chemistry-determining step of the catalytic cycle, proton transfer
occurs to produce a chiral N-acylpyrrole and to liberate catalyst 1.
Deprotonation of 2-cyanopyrrole by 1 then regenerates ion pair 7,
completing the catalytic cycle.
In the pathway depicted in Figure 2, the role of catalyst 1 is to
serve, in protonated form, as a chiral Brønsted acid.15 This contrasts
with other applications of planar-chiral catalyst 1 and related
compounds, wherein they function as chiral nucleophiles (Lewis
bases).16
In summary, we have developed the first method for the catalytic
enantioselective addition of amines (specifically, pyrroles) to
ketenes, and we have demonstrated that the resulting acylpyrroles
can be transformed into a broad spectrum of useful derivatives.
On the basis of mechanistic studies, we suggest that the planar-
chiral catalyst plays an unanticipated role in this process as a chiral
Brønsted acid.
(10) This acylated pyrrolidine represents the core of RPR 111905 and RPR
107880, non-peptide substance P antagonists: (a) Mutti, S.; Daubie´, C.;
Decalogne, F.; Fournier, R.; Rossi, P. Tetrahedron Lett. 1996, 37, 3125-
3128. (b) Mutti, S.; Daubie´, C.; Malpart, J.; Radisson, X. Tetrahedron
Lett. 1996, 37, 8743-8746.
(11) Aldehydes (and ketones) that bear an aryl-substituted R stereocenter are
unusually prone to racemization. For some examples, see: (a) Campbell,
J. B.; Dedinas, R. F.; Trumbower-Walsh, S. A. J. Org. Chem. 1996, 61,
6205-6211. (b) Oppolzer, W.; Darcel, C.; Rochet, P.; Rosset, S.; De
Brabander, J. HelV. Chim. Acta 1997, 80, 1319-1337. (c) Myers, A. G.;
Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J.
Am. Chem. Soc. 1997, 119, 6496-6511.
(12) This alcohol is the N-methyl derivative of an intermediate in the synthesis
of pemedolac, a nonsteroidal antiinflammatory drug: Katz, A. H.;
Demerson, C. A.; Shaw, C.-C.; Asselin, A. A.; Humber, L. G.; Conway,
K. M.; Gavin, G.; Guinosso, C.; Jensen, N. P.; Mobilio, D.; Noureldin,
R.; Schmid, J.; Shah, U.; Van Engen, D.; Chau, T. T.; Weichman, B. M.
J. Med. Chem. 1988, 31, 1244-1250.
(13) Additional observations: (a) By 1H NMR spectroscopy, we have
determined that the potassium salt of 2-cyanopyrrole reacts with phenyl
tert-butyl ketene to generate an enolate (see compound 8 in Figure 2),
which furnishes an N-acylpyrrole upon treatment with a suitable proton
source. (b) By 1H NMR spectroscopy, we detect no interaction upon
mixing phenyl tert-butyl ketene (or phenyl ethyl ketene) with 1 equiv of
1. (c) Although both processes involve transformations of ketenes, the
stereoselectivity and reactivity profile of catalyst 1 is very different for
Staudinger reactions (reference 5c) versus additions of 2-cyanopyrrole
(this work). For example, the same enantiomer of the catalyst provides
the opposite absolute stereochemistry at the carbon R to the carbonyl group
of the product. In addition, the reactivity pattern for Staudinger reactions
and pyrrole additions is significantly different: e.g., PPY derivative 1
effectively catalyzes pyrrole additions, but not Staudinger reactions, of
hindered ketenes. Collectively, these observations are consistent with the
idea that catalyst 1 may be performing distinct mechanistic roles in these
two processes.
(14) (a) For a discussion of a mechanism for the addition of an amine to a
ketene, see: Allen, A. D.; Tidwell, T. T. J. Org. Chem. 1999, 64, 266-
271, and references therein. (b) For a discussion of a mechanism for a
base-catalyzed addition of an alcohol to a ketene, see: Cannizzaro, C.
E.; Strassner, T.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 2668-2669
and references therein. See also: Buschmann, H.; Scharf, H.-D.; Hoff-
mann, N.; Esser, P. Angew. Chem., Int. Ed. Engl. 1991, 30, 477-515.
(15) For a review, see: Yanagisawa, A.; Yamamoto, H. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; Chapter 34.2.
Acknowledgment. Support has been provided by the National
Institutes of Health (NIGMS, R01-GM57034), Bristol-Myers
Squibb, and Novartis.
(16) For example, see refs 5a and 5c.
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J. AM. CHEM. SOC. VOL. 124, NO. 34, 2002 10007