Catalytic asymmetric synthesis of esters from ketenes

Article abstract of DOI:10.1021/ja0506152

By building on elementary principles of Bronsted acid-base chemistry, a nucleophile-catalyzed method for the asymmetric synthesis of esters from ketenes has been transformed into a much more versatile and effective Bronsted acid-catalyzed process. The product aryl esters can be converted into useful derivatives, such as enantioenriched alcohols and carboxylic acids. Copyright

Full text of DOI:10.1021/ja0506152

Published on Web 04/05/2005
Catalytic Asymmetric Synthesis of Esters from Ketenes
Sheryl L. Wiskur and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received January 30, 2005; E-mail: gcf@mit.edu
During the past several years, we have established that planar-
chiral heterocycles, such as 1-5, serve as enantioselective catalysts
for an array of processes, including kinetic resolutions of alcohols
and amines, C-acylations that generate all-carbon quaternary
1
stereocenters, and coupling reactions of ketenes. As part of these
studies, in 1999, we reported that azaferrocene 1 catalyzes the
2
addition of MeOH to aryl alkyl ketenes (eq 1). Although the
enantioselectivity is only moderate (up to 80% ee), this is the most
effective catalytic asymmetric method for the synthesis of esters
from ketenes that has been described to date.3
-5
Figure 1. Two of the possible pathways for enantioselective additions to
ketenes: nucleophilic catalysis (top); Brønsted acid catalysis (bottom).
basicity of the catalyst should encourage the desired deprotonation.
Indeed, we have determined that phenol reacts with PPY derivative
In our 1999 investigation, we suggested that the addition of MeOH
to ketenes catalyzed by 1 might proceed through the nucleophile-
catalyzed pathway illustrated in Figure 1 (top). In contrast, in 2002,
on the basis of stereochemical, spectroscopic, and kinetic data, we
concluded that the enantioselective addition of 2-cyanopyrrole to
ketenes catalyzed by 3 (eq 2) likely involves a Brønsted acid-
catalyzed mechanism (Figure 1, bottom; X-H ) 2-cyanopyrrole).6
3
to quantitatively produce an ion pair (eq 5).
To the best of our knowledge, the process illustrated in eq 2
represents the first example of a planar-chiral heterocycle serving
as a chiral Brønsted acid catalyst. Naturally, we were interested in
determining if this mode of reactivity can be exploited in other
contexts. In view of the modest progress that has been described
toward the development of an effective catalyst for the enantiose-
lective synthesis of esters from ketenes (eq 1; e80% ee), we decided
to explore the possibility that Brønsted acid catalysis by planar-
chiral heterocycles could furnish a solution to this challenge.
An elementary analysis suggests that, to favor a mechanism in
which the catalyst serves as a Brønsted acid, rather than a
nucleophile, it might be desirable to drive the equilibrium depicted
in eq 3 toward the right. When MeOH and azaferrocene 1 are mixed,
Furthermore, if a ketene is added to a mixture of a phenol and
(-)-3, an addition reaction occurs to furnish nonracemic aryl esters.
The structure of the nucleophile has a substantial influence on the
enantiomeric excess of the product. Thus, phenol reacts with phenyl
ethyl ketene to afford the desired ester with modest enantioselec-
tivity (47% ee; Table 1, entry 1). The presence of an electron-
withdrawing para substituent leads to a decrease in enantiomeric
excess (entry 2), whereas an electron-donating group provides
higher enantioselectivity (entry 3). The incorporation of an ortho
1
there is no evidence by H NMR for formation of an ion pair (eq
4; cf. eq 1). Clearly, increasing the acidity of ROH and/or the
6176
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J. AM. CHEM. SOC. 2005, 127, 6176-6177
10.1021/ja0506152 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Catalytic Enantioselective Synthesis of Esters from
Ketenes: Dependence of Enantiomeric Excess on the Structure of
the Phenola
entry
ArOH
ee (%)
1
2
3
4
5
6
7
8
PhOH
47
35
72
80
81
80
88
91
4-(trifluoromethyl)phenol
4-methoxyphenol
2-methoxyphenol
2-methylphenol
2-isopropylphenol
2-phenylphenol
hypothesis that planar-chiral heterocycles can serve as chiral
Brønsted acid catalysts for an array of interesting processes.
Acknowledgment. Support has been provided by the NIH
(National Institute of General Medical Sciences: R01-GM57034),
Merck Research Laboratories, and Novartis.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
2-tert-butylphenol
a
All data are the average of two experiments.
Table 2. Catalytic Enantioselective Synthesis of Esters from
Ketenesa
References
(
1) For leading references, see: (a) Fu, G. C. Acc. Chem. Res. 2004, 37, 542-
5
47. (b) Fu, G. C. Acc. Chem. Res. 2000, 33, 412-420. (c) For more
recent work, see: Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2004,
4
2
3, 6358-6360; Mermerian, A. H.; Fu, G. C. Angew. Chem., Int. Ed.
005, 44, 949-952.
(
2) Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121,
2
637-2638.
entry
Ar
R
ee (%)
isolated yield (%)
(3) For pioneering studies of the catalytic enantioselective addition of alcohols
to ketenes, see: (a) Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634,
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
o-tol
o-anisyl
p-Cl
Me
Et
i-Bu
cyclopentyl
i-Pr
Et
Me
i-Pr
i-Pr
79
91
84
87
91
92
94
89
79
87
89
79
88
66
84
78
97
94
9
-22. (b) Pracejus, H.; M a¨ tje, H. J. Prakt. Chem. 1964, 24, 195-205
and references therein.
(4) For reviews of enantioselective protonations of enols/enolates, see: (a)
Yanagisawa, A. In ComprehensiVe Asymmetric Catalysis (Supplement 2)
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
2004; pp 125-132. (b) Yanagisawa, A.; Yamamoto, H. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1999; Chapter 34.2. (c) Eames, J.; Weerasooriya,
N. Tetrahedron: Asymmetry 2001, 12, 1-24. (d) Fehr, C. In Chirality in
Industry II; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; Wiley:
New York, 1997.
3-thienyl
a
(5) The asymmetric addition of alcohols to ketenes to generate arylpropionic
acid derivatives is of potential industrial interest: (a) Larsen, R. D.; Corley,
E. G.; Davis, P.; Reider, P. J.; Grabowski, E. J. J. J. Am. Chem. Soc.
All data are the average of two experiments.
substituent on the phenol results in enhanced enantiomeric excess
entries 4-8), with a large tert-butyl group producing the best
1
989, 111, 7650-7651. (b) Villa, C. G. M.; Panossian, S. P. In Chirality
(
in Industry; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; Wiley:
New York, 1992; Chapter 15. (c) 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.
selectivity among the phenols that we have examined to date.
This combination of 2-tert-butylphenol and 3 provides the most
effective and versatile method reported to date for the catalytic
asymmetric synthesis of esters from ketenes (Table 2);7 the reaction
predominantly affords the enantiomer that we had anticipated on
the basis of our mechanistic hypothesis (chiral Brønsted acid cataly-
sis w the same sense of stereoselection as in eq 2). Although we
obtain only moderate enantiomeric excess for the reaction of phenyl
methyl ketene (entry 1), we observe good enantiomeric excesses
for a range of other phenyl alkyl ketenes (entries 2-5). If the
aromatic substituent of the ketene is ortho-substituted, the ester is
generated with high enantioselectivity (entries 6 and 7). The process
tolerates both electron-rich and electron-poor aryl groups (entries
(
6) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10006-10007.
7) General Procedure: In the air, catalyst (-)-3 (0.011 mmol; 0.030 equiv)
was weighed into a flask, which was then purged with argon. Toluene
(
,8
(30 mL) and 2-tert-butylphenol (0.390 mmol; 1.04 equiv) were added. A
solution of ketene (0.375 mmol; 1.00 equiv) in toluene (1.0 mL) was added
by syringe over 30 min to the solution of catalyst and 2-tert-butylphenol.
The reaction mixture was stirred at room temperature for 2 h, and then
n-propylamine (0.05 mL) was added. The resulting solution was passed
through a plug of silica gel (a 1:1 mixture of Et
elute the ester, and then a 1:9 mixture of NEt :EtOAc was used to elute
2
O:hexanes was used to
3
catalyst 3). The ester was then purified by flash chromatography.
8) Notes: (a) Upon increasing the scale of the General Procedure, we have
obtained essentially identical enantiomeric excess and yield. (b) The
catalyst can typically be recovered in g80% yield. (c) In a preliminary
study, we have obtained 50% ee for the addition of a phenol to a
dialkylketene (cyclopentyl methyl ketene). (d) Price of 2-tert-butylphe-
nol: $55 for 2 L (Aldrich).
(
7
and 8), but it furnishes somewhat lower enantiomeric excess for
(
9) A wide variety of R-alkyl-R-arylacetic acid derivatives are bioactive. For
leading references, see: (a) Fenvalerate: The Merck Index, 13th ed.;
Merck: Whitehouse Station, NJ, 2001; pp 710-711. (b) Bodor, N.;
Woods, R.; Raper, C.; Kearney, P.; Kaminski, J. J. J. Med. Chem. 1980,
23, 474-480. (c) Brooks, C. D. W. et al. Pure Appl. Chem. 1988, 70,
a 3-thienyl-substituted ketene (entry 9). It is worth noting that none
of the methods that had been described earlier for the catalytic
enantioselective synthesis of esters from ketenes2 had been shown
to be effective for ketenes with an ortho-substituted aromatic
substituent or with an alkyl group larger than ethyl (maximum
,3
2
71-274. (d) Robichaud, J. et al. J. Med. Chem. 2003, 46, 3709-3727.
(
e) Sonawane, H. R.; Bellur, N. S.; Ahuja, J. R.; Kulkarni, D. G.
Tetrahedron: Asymmetry 1992, 3, 163-192. (f) Rieu, J.-P.; Boucherle,
A.; Cousse, H.; Mouzin, G. Tetrahedron 1986, 42, 4095-4131.
2
9,10
enantiomeric excess for an ethyl-substituted ketene: 68% ).
(
10) The fact that the ester is generated in high enantiomeric excess despite
the presence of an achiral proton donor (the phenol) that is more abundant
and more acidic than protonated 3 is readily accommodated within the
mechanism outlined in the bottom of Figure 1; the enolate of ion pair A
prefers to react with its chiral counterion, rather than participating in a
bimolecular reaction with the phenol. This would suggest that, at higher
concentration or in a more polar solvent, intermolecular protonation by
the phenol might become competitive, leading to an erosion in enantio-
meric excess; this is indeed observed.
Although phenyl esters are reactive toward a variety of nucleo-
philes, transformations of more hindered aryl esters (e.g., BHT
esters; BHT ) 2,6-di-tert-butyl-4-methylphenol) can be difficult.11
As illustrated in eq 6, we have established that 2-tert-butylphenyl
esters may be converted into useful derivatives in excellent yield
(without racemization).
(11) For example, see: Doyle, M. P.; Bagheri, V.; Wandless, T. J.; Harn, N.
K.; Brinker, D. A.; Eagle, C. T.; Loh, K.-L. J. Am. Chem. Soc. 1990,
Thus, we have designed and developed an effective catalytic
asymmetric method for synthesizing esters from ketenes. Ongoing
studies are directed at furnishing additional support for our
112, 1906-1912.
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