Catalytic asymmetric couplings of ketenes with aldehydes to generate enol esters

Article abstract of DOI:10.1002/anie.200501434

(Chemical Equation Presented) With a little help from the ferrocenyl catalyst ((-)-1), a wide array of α-arylalkanoic acid derivatives can be produced from the catalytic asymmetric coupling of ketenes with aldehydes (see scheme). The enol esters are readily transformed into other useful families of compounds such as carboxylic acids and alcohols.

Full text of DOI:10.1002/anie.200501434

Communications
arylalkanoic acids).[2–5] Herein, we report a new method for
the enantioselective synthesis of esters: the catalytic asym-
metric coupling of a ketene with an aldehyde [Eq. (1)].
In the presence of planar-chiral dimethylaminopyridine
(DMAP) derivative 1,[6] we observed no reaction between
phenyl ethyl ketene and n-decanal (Table 1, entry 1). In
Table 1: Survey of carbonyl compounds: Catalytic asymmetric couplings
with ketenes.[a]
Entry
1
Carbonyl compound
ee [%]
Yield [%][b]
0
–
2
3
92
55
Asymmetric Catalysis
Catalytic Asymmetric Couplings of Ketenes with
Aldehydes To Generate Enol Esters**
9184
4
–
0
Carsten Schaefer and Gregory C. Fu*
[a] All data are the average of two experiments. [b] Isolated product.
The synthesis of enantiopure a-arylalkanoic acids is an
objective of significant interest, due in part to the bioactivity
and commercial importance of this family of compounds.[1]
One approach that has been pursued in industry is the
asymmetric addition of alcohols to aryl alkyl ketenes to
generate chiral esters (which can then be hydrolyzed to a-
contrast, phenylacetaldehyde coupled with the ketene to
furnish an enol ester in modest yield and with very good
enantioselectivity (entry 2). Diphenylacetaldehyde was an
excellent reaction partner (entry 3: 91% ee, 84% yield),
whereas a related ketone was not (entry 4).[7,8]
As illustrated in Table 2, we achieved the catalytic
asymmetric synthesis of a wide array of enol esters of a-
arylalkanoic acids through couplings of ketenes with diphe-
nylacetaldehyde.[9–11] Thus, reactions of phenyl alkyl ketenes,
in which the alkyl group ranges in size from methyl to tert-
butyl, proceeded with moderate to excellent enantioselectiv-
ity (Table 2, entries 1–6). Furthermore, the addition occurred
with very good stereoselectivity regardless of whether the
aromatic group of the ketene was bulky (Table 2, entries 7
and 8), electron-rich (entries 8 and 9), or electron-poor
(entry 10).
[*] Dr. C. Schaefer, Prof. Dr. G. C. Fu
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
[**] Support was provided by the NIH (NIGMS, GM57034), the
Deutsche Forschungsgemeinschaft (postdoctoral fellowship to
C.S.), Merck Research Laboratories, and Novartis. Funding for the
MIT Department of Chemistry Instrumentation Facility was fur-
nished in part by the National Science Foundation (CHE-9808061
and DBI-9729592).
Enol esters are attractive targets in synthetic organic
chemistry, in part as a result of the ease with which they can be
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200501434
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Chemie
Table 2: Catalytic asymmetric couplings of aldehydes with ketenes to
generate enol esters.[a]
Entry
Ar
R
ee [%]
Yield [%][b]
1Ph
2
3
Me
78
74
91
77
Ph
Ph
Ph
Et
iBu
iPr
84
81
95
99
96
99
95
89
96
4
98
5
6
7
8
9
10
Ph
Ph
o-tolyl
o-anisyl
p-anisyl
cyclopentyl
tBu
Et
Me
Et
Et
97
88
98
97
92
88
4-chlorophenyl
[a] All data are the average of two experiments. [b] Isolated product.
converted into other useful families of compounds. We have
established that our diphenyl-substituted enol esters can be
hydrolyzed and reduced under mild conditions without
racemization [Eqs. (2) and (3)].[12]
Scheme 1. Two of the possible mechanisms for the coupling of ketenes
with aldehydes to form enol esters: a) nucleophilic catalysis and
b) Brønsted acid/base catalysis.
*
In the presence of catalyst 1, the a proton of diphenyla-
cetaldehyde exchanges rapidly with D2O at 08C (in the
absence of 1, there is essentially no exchange after 3 days
at room temperature);
A number of mechanisms, two of which are illustrated in
Scheme 1, can be envisioned for this newcatalytic asymmetric
coupling of ketenes with aldehydes to generate enol esters. In
one possible pathway (Scheme 1a), catalyst 1 serves as a
nucleophile and adds to the ketene to afford chiral enolate
A,[13] which undergoes diastereoselective protonation by the
aldehyde to furnish the ion pair B. Acylation of the enolate by
the acylpyridinium ion then produces the enantioenriched
enol ester and regenerates the catalyst.
Alternatively, the role of catalyst 1 may be to serve as a
Brønsted base/acid (Scheme 1b). According to this hypoth-
esis, the catalyst deprotonates the aldehyde to furnish an
achiral enolate C. This nucleophilic enolate then adds to the
electrophilic ketene to produce a newachiral enolate D,[14]
which undergoes enantioselective protonation by its counter-
ion (protonated 1, a chiral Brønsted acid) to thereby generate
the enol ester.[15]
*
A small primary kinetic isotope effect is observed (kH/kD
ꢀ 2 for the reaction of diphenylacetaldehyde relative to
a-d-diphenylacetaldehyde).[18]
These data can be accommodated by either of the
pathways illustrated in Scheme 1, as well as by others. A
detailed mechanistic investigation will be required in order to
gain improved insight into this interesting process.
In summary, we have developed a new method for the
synthesis of enantioenriched esters: the catalytic asymmetric
coupling of ketenes with aldehydes. We have established that
this approach provides access to a wide array of a-arylalka-
noic acid derivatives. Future studies will build upon our
preliminary mechanistic observations to elucidate the reac-
tion pathway for this intriguing transformation.
To date, we have made the following observations with
respect to the reaction pathway:
Received: April 26, 2005
*
The ee value of the product correlates linearly with that of
the catalyst;[16]
*
When catalyst 1 is mixed with one equivalent of diphe-
nylacetaldehyde, there is no evidence for deprotonation of
the aldehyde to form an ion pair;[17]
Keywords: aldehydes · asymmetric catalysis · esters · ketenes
.
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[11] Notes: a) The reaction of phenyl ethyl ketene with diphenyla-
cetaldehyde proceeds in moderate to excellent enantioselectivity
in a variety of solvents (e.g., toluene, Et2O, EtOAc, 1,2-
dimethoxyethane, THF, and CH2Cl2; however, not N-methyl-
pyrrolidone); b) Slightly lower ee values were observed at room
temperature; c) Typically, ca. 85% of catalyst 1 can be recovered
at the end of the reaction.
[12] These enol esters are more reactive than the aryl esters produced
by the addition of 2-tert-butylphenol to ketenes (see ref. [4b]).
[13] For other processes catalyzed by 1 that are believed to proceed
through chiral enolate A, see: a) B. L. Hodous, G. C. Fu, J. Am.
Chem. Soc. 2002, 124, 1578 – 1579; b) Ref. [8].
[14] For a pioneering study of the O-acylation of enolates by ketenes,
see: K. Yoshida, Y. Yamashita, Tetrahedron Lett. 1966, 7, 693 –
696.
[15] For a process catalyzed by 1 that is believed to proceed through
an analogous chiral Brønsted base/acid pathway, see ref. [4b].
[16] For a reviewof nonlinear effects in asymmetric catalysis, see:
H. B. Kagan, T. O. Luukas in Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, NewYork, 1999, chapt. 4.1.
[1] For leading references to bioactive a-arylalkanoic acid deriva-
tives, see: a) “Fenvalerate”: The Merck Index, 13th ed., Merck,
Whitehouse Station, NJ, 2001, pp. 710 – 711; b) J. Robichaud, R.
Oballa, P. Prasit, J.-P. Falgueyret, M. D. Percival, G. Wesolowski,
S. B. Rodan, D. Kimmel, C. Johnson, C. Bryant, S. Venkatraman,
E. Setti, R. Mendonca, J. T. Palmer, J. Med. Chem. 2003, 46,
3709 – 3727; c) M. F. Landoni, A. Soraci, Curr. Drug Metab. 2001,
2, 37 – 51; d) C. D. W. Brooks, A. O. Stewart, T. Kolasa, A.
Basha, P. Bhatia, J. D. Ratajczyk, R. A. Craig, D. Gunn, R. R.
Harris, J. B. Bouska, P. E. Malo, R. L. Bell, G. W. Carter, Pure
Appl. Chem. 1998, 70, 271 – 274; e) K. Brune, G. Geisslinger, S.
Menzel-Soglowek, J. Clin. Pharmacol. 1992, 32, 944 – 952;
f) H. R. Sonawane, N. S. Bellur, J. R. Ahuja, D. G. Kulkarni,
Tetrahedron: Asymmetry 1992, 3, 163 – 192; g) J.-P. Rieu, A.
Boucherle, H. Cousse, G. Mouzin, Tetrahedron 1986, 42, 4095 –
4131; h) N. Bodor, R. Woods, C. Raper, P. Kearney, J. J.
Kaminski, J. Med. Chem. 1980, 23, 474 – 480.
[2] For examples of industrial interest in using asymmetric additions
to ketenes to produce arylpropionic acid derivatives, see:
a) R. D. Larsen, E. G. Corley, P. Davis, P. J. Reider, E. J. J.
Grabowski, J. Am. Chem. Soc. 1989, 111, 7650 – 7651; b) C. G. M.
Villa, S. P. Panossian in Chirality in Industry (Eds.: A. N. Collins,
G. N. Sheldrake, J. Crosby), Wiley, NewYork, 1992, chapt. 15;
c) G. P. Stahly, R. M. Starrett in Chirality in Industry II (Eds.:
A. N. Collins, G. N. Sheldrake, J. Crosby), Wiley, NewYork,
1997, chapt. 3.
[17] This behavior contrasts with enantioselective additions of 2-tert-
butylphenol to ketenes catalyzed by 1 in which the catalyst
deprotonates the phenol; the mechanism is likely a chiral
Brønsted acid catalyzed pathway (see ref. [4b]).
[18] Owing to the rapidness of the reaction at 08C, this experiment
was conducted at À908C (t1/2 ꢀ 1 h).
[3] For pioneering studies of asymmetric catalysis of this process,
see: a) H. Pracejus, Justus Liebigs Ann. Chem. 1960, 634, 9 – 22;
b) H. Pracejus, H. Mätje, J. Prakt. Chem. 1964, 24, 195 – 205, and
references therein.
[4] For our studies of asymmetric catalysis of this process, see:
a) B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999,
121, 2637 – 2638; b) S. L. Wiskur, G. C. Fu, J. Am. Chem. Soc.
2005, 127, 6176 – 6177.
[5] For reviews of enantioselective protonations of enols/enolates,
see: a) A. Yanagisawa in Comprehensive Asymmetric Catalysis
(Supplement 2) (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, NewYork, 2004, pp. 125 – 132; A. Yanagisawa, H.
Yamamoto in Comprehensive Asymmetric Catalysis (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, NewYork, 1999,
chapt. 34.2; b) J. Eames, N. Weerasooriya, Tetrahedron: Asym-
metry 2001, 12, 1 – 24; c) C. Fehr in Chirality in Industry II (Eds.:
A. N. Collins, G. N. Sheldrake, J. Crosby), Wiley, NewYork,
1997, chapt. 16; C. Fehr, Angew. Chem. 1996, 108, 2726 – 2748;
Angew. Chem. Int. Ed. Engl. 1996, 35, 2567 – 2587.
[6] For leading references, see: G. C. Fu, Acc. Chem. Res. 2004, 37,
542 – 547.
[7] For a report of the O-acylation of b-ketoesters upon treatment
= =
with excess ketene (O C CH2) and pyridine, see: K. W. Rosen-
mund, G. Kositzke, H. Bach, Chem. Ber. 1959, 92, 494 – 501.
[8] In contrast, treatment of a ketene with catalyst 1 and a non-
enolizable aldehyde (e.g., PhCHO) leads to [2+2] cycloaddition
to generate a b-lactone with good stereoselectivity: J. E. Wilson,
G. C. Fu, Angew. Chem. 2004, 116, 6518 – 6520; Angew. Chem.
Int. Ed. 2004, 43, 6358 – 6360.
[9] Interestingly, under these conditions, catalyst
1 does not
rearrange the enol ester to a 1,3-dicarbonyl compound. For
example, see: I. D. Hills, G. C. Fu, Angew. Chem. 2003, 115,
4051 – 4054; Angew. Chem. Int. Ed. 2003, 42, 3921 – 3924.
[10] General procedure: Under argon, a solution of the ketene
(1.0 equiv) in CHCl3 was added by syringe over 7 min to a
solution of the catalyst (10%) and diphenylacetaldehyde
(1.1 equiv) in CHCl3 at 08C. The resulting solution was stirred
at 08C, and then the reaction was quenched by the addition of
MeOH (1 mL). The solvent was removed by rotary evaporation,
and the residue was purified by column chromatography.
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