Enantioselective addition of amines to ketenes catalyzed by a planar-chiral derivative of PPY: possible intervention of chiral Bronsted-acid catalysis.

Full text of DOI:10.1021/ja027466x

Published on Web 08/02/2002
Enantioselective Addition of Amines to Ketenes Catalyzed by a Planar-Chiral
Derivative of PPY: Possible Intervention of Chiral Brønsted-Acid Catalysis
Brian L. Hodous and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received June 26, 2002
Table 1. Dependence of Enantioselectivity on the Structure of the
Pyrrole
The catalytic asymmetric addition of nucleophiles to ketenes
represents an attractive strategy for the synthesis of enantioenriched
carbonyl derivatives, including biologically and industrially sig-
nificant classes of compounds such as arylpropionic acids.1 For
the catalyzed addition of alcohols to ketenes, enantiomeric excesses
as high as 75-80% have been obtained.2 In contrast, to the best of
our knowledge there are no examples of catalytic asymmetric
additions of achiral nitrogen nucleophiles to ketenes.3 In this
communication, we describe a method for achieving this objective
(eq 1).
a Average of two runs. b No N-acylpyrrole was produced.
Table 2. Catalytic Enantioselective Addition of 2-Cyanopyrrole to
a Range of Ketenes (eq 1)
entry
Ar
R
ee (%)a
yield (%)a
1
2
3
4b
5
6
7
Ph
Ph
Ph
Ph
Me
Et
i-Pr
t-Bu
Et
81
90
95
81
98
94
86
91
93
96
90
95
94
80
o-tol
o-anisyl
3-(N-methylindolyl)
Because simple amines can rapidly add to ketenes in the absence
of a catalyst, we focused our investigation on less-reactive nitrogen
nucleophiles. In early studies, we determined that pyrroles do not
react at room temperature with ketenes such as phenyl ethyl ketene.
In contrast, additions can proceed swiftly when commercially
available planar-chiral 4-(pyrrolidino)pyridine (PPY) derivative 14,5
is employed as a catalyst; significantly, in the presence of
enantiopure 1 and an appropriate pyrrole, the N-acylpyrrole can be
generated in high enantiomeric excess (Table 1).
With pyrrole itself as the nucleophile, the new stereocenter is
produced in moderate ee (Table 1, entry 1). Although incorporation
of an alkyl substituent into the 2-position leads to racemic product
(entry 2), the presence of an electron-withdrawing group provides
enantioenriched N-acylpyrroles (entries 3-5), with commercially
available 2-cyanopyrrole furnishing excellent stereoselection (91%
ee; entry 5). A pyrrole that bears electron-withdrawing groups in
the 3- and 4-positions affords fair ee (entry 6), as does indole (entry
7). 2,5-Disubstituted pyrroles do not appear to be suitable reaction
partners (entry 8).
Me
Bn
a Average of two runs. b 5% catalyst.
stereocenters that are relatively difficult to generate by other
methods (e.g., alkylation). An increase in the size of the aryl group
leads to an increase in enantiomeric excess (entries 5 vs 2 and
entries 6 vs 1), and heteroaryl substituents are tolerated in this
process (entry 7).
We anticipated that, in contrast to simple amides, we would be
able to derivatize our N-acylpyrroles under relatively mild condi-
tions, thereby enhancing the utility of this new catalytic asymmetric
addition reaction. Although a few transformations of N-acylpyrroles
have been described,7 none involve a 2-cyanopyrrole. We were
pleased to discover that these N-acylpyrroles can be converted into
a wide array of useful compounds with essentially no erosion in
enantiomeric excess (Figure 1; e2% racemization in all cases).
Thus, chiral acids (2),8 esters (3),9 and amides (4)10 can be generated
through reactions with water, alcohols, and amines, respectively.
In addition, by appropriate choice of reducing agent, an aldehyde
(5; LiAlH(Ot-Bu)3)11 or an alcohol (6; NaBH4)12 can be produced
selectively.
We next turned our attention to determining the range of ketenes
that are suitable substrates for this new catalytic enantioselective
process (Table 2).6 We have established that very good ee’s and
yields are obtained for reactions of a wide array of phenyl alkyl
ketenes (R ) Me f t-Bu; entries 1-4); particularly noteworthy
are the results for sterically demanding phenyl isopropyl ketene
and phenyl tert-butyl ketene (entries 3 and 4), which furnish R
We have pursued an investigation of the mechanism and origin
of stereoselection for the enantioselective addition of pyrroles to
ketenes catalyzed by 1. We chose to focus our attention on the
coupling of 2-cyanopyrrole with phenyl tert-butyl ketene, since this
* To whom correspondence should be addressed. E-mail: gcf@mit.edu.
reaction proceeds at a convenient rate at room temperature (t1/2
≈
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J. AM. CHEM. SOC. 2002, 124, 10006-10007
10.1021/ja027466x CCC: $22.00 © 2002 American Chemical Society

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
of charge via the Internet at http://pubs.acs.org.
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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