Enantioselective addition of alcohols to ketenes catalyzed by a planar- chiral azaferrocene: Catalytic asymmetric synthesis of arylpropionic acids [21]

Full text of DOI:10.1021/ja984021t

J. Am. Chem. Soc. 1999, 121, 2637-2638
Enantioselective Addition of Alcohols to Ketenes
2637
Catalyzed by a Planar-Chiral Azaferrocene:
Catalytic Asymmetric Synthesis of Arylpropionic
Acids
Brian L. Hodous, J. Craig Ruble, and Gregory C. Fu*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed NoVember 23, 1998
Figure 1. A possible mechanism for the azaferrocene-catalyzed addition
of an alcohol to a ketene.
Due to their biological activity, arylpropionic acids constitute
an important family of targets for asymmetric synthesis. Although
1
5
6
tones, and the rearrangement of O-acylated enolates, the chiral
DMAP derivatives have consistently provided higher stereose-
lectivity than the chiral azaferrocenes. Recently, we turned our
attention to the catalytic enantioselective addition of alcohols to
ketenes, in the hope that our planar-chiral heterocycles might
improve upon the benchmark established by Pracejus. In this
report, we describe the achievement of this objective: With a
chiral azaferrocene as the catalyst, MeOH adds to an array of
arylalkylketenes with good levels of enantioselectivity and in
excellent yields (eq 2).
catalytic enantioselective reactions have the potential to provide
particularly efficient access to these compounds, a relatively
narrow range of such processes has been explored. Most of the
studies reported to date have focused on transition metal-catalyzed
additions to olefins (e.g., asymmetric hydrogenation and hydro-
formylation of substituted styrenes). Optically active arylpropionic
acid derivatives can also be synthesized through the stereoselective
addition of an alcohol to an arylmethylketene. Nearly all inves-
tigations of this process have relied upon the use of a stoichio-
metric quantity of a chiral alcohol to induce asymmetry (eq 1).2
Indeed, to the best of our knowledge the only publications that
describe effective enantioselective catalysis of this reaction are
those of Pracejus, who studied the alkaloid-catalyzed addition of
methanol to two ketenes, phenylmethylketene (maximum ee:
In early experiments, we established that planar-chiral azafer-
rocene 2c catalyzes the addition of MeOH to phenylmethylketene
with significant enantioselection (eq 3). One possible mechanism
for this transformation is the nucleophile-catalyzed pathway
illustrated in Figure 1.7 Taking this mechanism as our working
hypothesis, we speculated that for step 2, use of an alternate (to
ROH) proton source might affect the enantioselectivity of the
reaction. We therefore screened several acids, and we were
pleased to discover that addition of 2,6-di-tert-butylpyridinium
triflate (12 mol %) appreciably enhances asymmetric induction
6%) and phenyl-R-o-trimethyleneketene (maximum ee: 40%).3
7
A few years ago, we initiated a program directed at the
,8
development of planar-chiral heterocycles as enantioselective
nucleophilic catalysts, focusing our attention on chiral DMAP
derivatives (1) and chiral azaferrocenes (2). For the processes
(
eq 4; cf. eq 3).9
that we have studied to date, namely, the kinetic resolution of
4
secondary alcohols, the deracemization/ring-opening of azlac-
(1) For reviews of routes to optically active arylpropionic acids, see: (a)
Sonawane, H. R.; Bellur, N. S.; Ahuja, J. R.; Kulkarni, D. G. Tetrahedron:
Asymmetry 1992, 3, 163-192. (b) Rieu, J.-P.; Boucherle, A.; Cousse, H.;
Mouzin, G. Tetrahedron 1986, 42, 4095-4131.
(4) (a) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230-7231. (b)
Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492-
1493. (c) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794-
2795.
(
2) For example, see: (a) J a¨ hme, J.; R u¨ chardt, C. Angew. Chem., Int. Ed.
Engl. 1981, 20, 885-887. (b) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider,
P. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111, 7650-7651. (c) For
related work involving thiols, see: Fehr, C.; Stempf, I.; Galindo, J. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1044-1046. For an overview, see: Fehr, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2566-2587.
(5) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154-3155.
(6) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532-11533.
(7) For a report of the N-acetylation of 2,3,4,5-tetramethyl-1-azaferrocene
by acetyl chloride, see: Kuhn, N.; Schulten, M.; Zauder, E.; Augart, N.; Boese,
R. Chem. Ber. 1989, 122, 1891-1896.
(3) (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9-22. (b)
Pracejus, H.; Kohi, G. Justus Liebigs Ann. Chem. 1969, 722, 1-11. (c)
Pracejus, H.; Tille, A. Chem. Ber. 1963, 96, 854-865. (d) Pracejus, H.; M a¨ tje,
H. J. Prakt. Chem. 1964, 24, 195-205. (e) For polymer-bound variants of
the Pracejus catalyst, see: Yamashita, T.; Yasueda, H.; Nakamura, N. Bull.
Chem. Soc. Jpn. 1979, 52, 2165-2166.
(8) A pathway involving Brønsted-base catalysis is also possible. For a
discussion of the mechanism of addition reactions to ketenes, see: (a) Tidwell,
T. T. Ketenes; Wiley: New York, 1995; Chapter 5.5.1. (b) Andraos, J.; Kresge,
A. J. J. Am. Chem. Soc. 1992, 114, 5643-5646. (c) Seikaly, H. R.; Tidwell,
T. T. Tetrahedron 1986, 42, 2587-2613.
1
0.1021/ja984021t CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/05/1999

2638 J. Am. Chem. Soc., Vol. 121, No. 11, 1999
Communications to the Editor
Table 1. Catalytic Asymmetric Addition of Alcohols to Ketenesa
Figure 2. Enantiomeric excess as a function of temperature for the
addition of MeOH to phenyl-R-o-trimethyleneketene.
a
All data are the average of two runs.
loading (77% ee with 10% catalyst; 64% ee with 0.5% catalyst).
Interestingly, we have found that the esters are produced with
the greatest enantiomeric excess when the reactions are run at
ca. -70 °C, and that the ee drops both at lower and at higher
temperatures (Figure 2).12
We have explored the use of a range of planar-chiral azafer-
rocenes and DMAP derivatives as catalysts for the enantioselective
addition of MeOH to phenylmethylketene (eq 5). In the case of
We have initiated studies directed at elucidating the origin of
enantioselection as well as the mechanism of this azaferrocene-
catalyzed addition process. In a preliminary investigation, we have
established that the ee of the product varies linearly with the ee
of the catalyst, an observation that provides no evidence for the
involvement of two or more catalyst molecules in the stereochem-
istry-determining step. Furthermore, we have determined that the
reaction exhibits a deuterium kinetic isotope effect of 3.2 (eq 6).
azaferrocenes, the stereoselection is a strong function of the steric
demand of the 2-substituent: we observe the highest ee in the
case of the CH OTBS group (catalyst 2c) and lower ee’s for both
2
smaller (2a and 2b) and larger (2d) substituents. In contrast to
the azaferrocenes, the planar-chiral DMAP derivatives (1a and
1b) are not effective at inducing asymmetry in this addition
In summary, we have demonstrated that planar-chiral hetero-
cycles can serve as effective catalysts for the enantioselective
addition of alcohols to ketenes. In contrast to our previous studies,
wherein DMAP derivatives had provided uniformly higher
stereoselection than azaferrocenes, for this process an azaferrocene
is the catalyst of choice. Compared to the alkaloid catalyst
developed by Pracejus, azaferrocene 2c appears to be both more
generally applicable and more enantioselective. We believe that
the new benchmark that we have established for the catalytic
asymmetric addition of alcohols to arylmethylketenes represents
a useful advance in the development of efficient approaches to
the synthesis of enantiopure arylpropionic acid derivatives. Studies
aimed at developing an improved mechanistic understanding and
at further optimizing the stereoselectivity of this reaction are
underway.
reaction (eq 5; <5% ee).
We have established that in the presence of azaferrocene
catalyst 2c, MeOH adds with good enantioselectivity to an array
10,11
of arylalkylketenes (Table 1).
For arylmethylketenes, the ee
is relatively insensitive to remote electronic effects, and the methyl
esters of ibuprofen, naproxen, and fenoprofen can be generated
in 74-77% enantiomeric excess (entries 2-4). On the other hand,
the ee is relatively sensitive to steric effects: the presence of a
larger alkyl substituent on the ketene leads to lower enantiose-
lection (entry 5; cf. entry 1). In the case of phenyl-R-o-
trimethyleneketene, one of the two substrates studied by Pracejus
(maximum ee: 40%), azaferrocene 2c, catalyzes formation of the
methyl ester in 80% ee (entry 6).
For the addition of MeOH to phenylmethylketene, we observe
somewhat lower enantioselectivity when we decrease the catalyst
Acknowledgment. We thank Wendy Jen, Dr. Hallie A. Latham, and
Dr. Yong Sun Park for preliminary experiments and the Buchwald group
(MIT) for generously sharing their GC and HPLC equipment. Support
has been provided by Bristol-Myers Squibb, Merck, the National Institutes
of Health (National Institute of General Medical Sciences, R01-
GM57034), the National Science Foundation (predoctoral fellowship to
J.C.R.), Pfizer, Pharmacia & Upjohn, and Procter & Gamble.
(
9) Interestingly, the enantioselectivity is a strong function of the counterion
triflate is the best of the several that we have screened).
10) Lower enantioselectivity is observed in solvents other than toluene
e.g., THF and CH Cl ).
(
(
(
2
2
(
2
11) Representative procedure (Table 1, entry 1): Under N , a solution of
phenylmethylketene (45.0 mg, 0.341 mmol) in toluene (2.8 mL) was added
by cannula to a -78 °C mixture of catalyst (+)-2c (13.7 mg, 0.034 mmol),
2
,6-di-tert-butylpyridinium triflate (14.0 mg, 0.041 mmol), and MeOH (20.7
µL, 0.511 mmol) in toluene (4.0 mL). The resulting homogeneous solution
was stirred at -78 °C for 24 h, and then the reaction was quenched by the
addition of n-propylamine (0.2 mL). The solvent was removed by rotary
evaporation, and the residue was immediately purified by flash chromatography
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.
(
5% f 10% EtOAc/hexanes), which afforded 49.1 mg (88%) of a colorless
JA984021T
liquid. For ee determination, the ester was reduced, trifluoroacetylated, and
analyzed by GC (Chiraldex G-TA), which revealed a 77% ee.
(12) We have observed analogous behavior with other arylalkylketenes.