Formation of disubstituted β-lactones using bifunctional catalysis

Article abstract of DOI:10.1021/ol050411q

(Chemical Equation Presented) Acid chlorides and aromatic aldehydes react in the presence of a stoichiometric amount of a tertiary amine and catalytic amounts of a cinchona alkaloid derivative and a Lewis acid to produce β-lactones in high diastereo- and

Full text of DOI:10.1021/ol050411q

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1809-1812
Formation of Disubstituted
Using Bifunctional Catalysis
â-Lactones
Michael A. Calter,*,† Olexandr A. Tretyak,† and Christine Flaschenriem‡
Department of Chemistry, Wesleyan UniVersity, Middletown, Connecticut 06459-0180,
and Department of Chemistry, UniVersity of Rochester,
Rochester, New York 14627-0216
mcalter@wesleyan.edu
Received February 24, 2005
ABSTRACT
Acid chlorides and aromatic aldehydes react in the presence of a stoichiometric amount of a tertiary amine and catalytic amounts of a
cinchona alkaloid derivative and a Lewis acid to produce -lactones in high diastereo- and enantioselectivity. The sense of the diastereoselectivity
â
depends on the substitution of the acid chloride, with the reactions of aliphatic acid chlorides giving predominantly the trans-isomer and
those of alkoxyacetyl chlorides favoring formation of the cis-isomer.
Wynberg and Staring reported in 1982 that cinchona
alkaloids function as very effective asymmetric catalysts for
the addition of ketene to di- and trichloroaldehydes and
ketones (Scheme 1).1 This report offered the first evidence
Numerous reports have described the ability of the alkaloids
to also determine nucleophile facial selectivity;2 however,
the development of a version of the Wynberg reaction
employing substituted ketenes has been hampered by the
tendency of these ketenes to dimerize under nucleophilic
catalysis. Furthermore, the extension of the Wynberg reaction
to less highly activated carbonyl electrophiles has also been
complicated by rapid ketene dimerization. However, Lectka
et al. discovered that a number of Lewis acids are compatible
with the generation and cinchona alkaloid-catalyzed reactions
of ketenes with imine electrophiles.3 Furthermore, Nelson
and co-workers have recently reported that the combination
of a cinchona alkaloid with a Lewis acid, lithium perchlorate,
catalyzes the reaction of substituted ketenes with unactivated
aldehydes to give the cis-â-lactones.4 We report here that
lanthanide and pseudolanthanide triflates also co-catalyze the
addition of substituted ketenes to unactivated arylaldehydes
but in some cases afford the trans-isomer in high diastereo-
Scheme 1
(2) (a) Pracejus, H.; Ma¨tje, H. J. Prakt. Chem. 1964, 24, 195-205. (b)
Calter, M. A.; Orr, R. K.; Song, W. Org. Lett. 2003, 5, 4745-4748. (c)
Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 122,
7831-7832.
that the alkaloids could control the electrophile facial
selectivity in the reaction of acylammonium enolates.
(3) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka,
T. J. Am. Chem. Soc. 2002, 124, 6626-6635.
† Wesleyan University.
‡ University of Rochester.
(4) Nelson, S. G.; Zhu, C.; Shen, X. J. Am. Chem. Soc. 2004, 126, 14-
15. For a noncinchona alkaloid-based method for the synthesis of disub-
stituted â-lactones, see: Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed.
2004, 43, 6358-6360.
(1) (a) Wynberg, H.; Staring, E. G. J. Am. Chem. Soc. 1982, 104, 166-
168. (b) Wynberg, H.; Staring, E. G. J. J. Org. Chem. 1985, 50, 1977-
1979. (c) Wynberg, H. Top. Stereochem. 1986, 16, 87-129.
10.1021/ol050411q CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/26/2005

selectivity. This diastereomer has not been previously
available from ketene/aldehyde additions, and we present
evidence that the lanthanide and pseudolanthanide triflate-cata-
lyzed reactions are mechanistically distinct from other Lewis
acid-catalyzed ketene/aldehyde additions. Furthermore, the
conditions reported here allow the formation of R-alkoxy-â-lac-
tones, the functional equivalent of glycolate aldol products.
The key observations came from exploring the reactions
of phenoxyacetyl chloride in the presence of Hu¨nig’s base
and the cinchona alkaloid derivative, TMSQD (Scheme 2,
aldehyde into the reaction failed to produce any lactone
product until a Lewis acid was also included in the reaction
mixture. Lanthanide and pseudolanthanide triflates afford the
highest reaction rates and conversions. The efficiency and
diastereoselectivity of the reaction depends highly on the size
of the Lewis acid. The use of triflates of the smaller
lanthanides, such as ytterbium and erbium, gives the highest
selectivity for the cis-isomer, while the use of either larger
or smaller metals, such as gadolinium or scandium, leads to
relatively larger proportions of the trans-isomer.
Table 2. Yields and Selectivities for the Formation of 3a-d
Scheme 2
products
3/4a
% yield of 3b (% ee)c
% yield of 4b (% ee)c
3a, 4a
3b, 4b
3c, 4c
3d, 4d
88:12
88:12
92:8
58 (>99)
55 (>99)
88 (>99)
68 (>99)e
nd
nd
5 (nd)
nd
87:13
1
a Determined by H NMR analysis of the unpurified reaction mixture.
b Yield of purified compound. c Determined by HPLC analysis of purified
1
isomer. d Determined by H NMR analysis of the purified product in the
presence of a chiral shift reagent. e Reaction performed with TMS-quinine
as catalyst; the enantiomer of 3d was the major product.
Table 1). These conditions likely result in the generation of
phenoxyketene, but we had previously observed that this
Other electron-withdrawing group-substituted benzalde-
hydes also yield the cis-â-lactones in high diastereo- and
enantioselectivities, as does benzaldehyde itself (Scheme 3,
Table 1. Yields and Selectivities for the Formation of 1 and 2
Lewis acid
1/2a
% yield of 1b (% ee)c % yield of 2b (% ee)c
Scheme 4
51:49
3 (ndd)
0
3 (nd)
0
BF3‚OEt2
Mg(OTf)2
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
Er(OTf)3
Y(OTf)3
38:63
87:13
71:29
91:9
2 (nd)
4 (70)
4 (74)
18 (93)
5 (92)
5 (92)
nd
24 (99)
52 (>99)
82 (>99)
89 (>99)
nd
92:8
50:50
83:17
93:7
Gd(OTf)3
Er(OTf)3
38 (92)
87 (>99)e
7 (38)
nd
Table 2). Lactones 3a and 3b partially decarboxylate to the
styrene derivatives under the reaction conditions, leading to
lower yields for these compounds.
1
a Determined by H NMR analysis of the unpurified reaction mixture.
b Yield of purified compound. c Determined by HPLC analysis of purified
isomer. d nd ) not determined. e Reaction performed with TMS-quinine as
catalyst; the enantiomer of 1 was the major product.
Table 3. Yields and Selectivities for the Formation of 5
ketene fails to dimerize under conditions that result in the
dimerization of alkylketenes.2b Inclusion of an aromatic
Lewis acid
5/6a
% yield of 5b
% ee of 5c
% ee of 6c
0
0
8
BF3‚OEt2
MgBr2
Zn(OTf)2
Sc(OTf)3
Yb(OTf)3
Nd(OTf)3
52:48
50:50
8:92
nd
nd
98
96
nd
nd
90
92
Scheme 3
7
85
76
0
20:80
a Determined by H1 NMR analysis of the unpurified reaction mixture.
b Yield of purified compound. c Determined by HPLC analysis of purified
isomer.
We next attempted the formation of â-lactones with alkyl
substituents in the R-position. We screened a number of
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Org. Lett., Vol. 7, No. 9, 2005

Scheme 5
Scheme 6
Lewis acids for the reaction of propionyl chloride and
3-chlorobenzaldehyde (Scheme 4, Table 3). Several Lewis
acids favored the addition, and all of the reactions produced
a higher percentage of the trans-isomer than observed with
alkoxy-substituted acetyl chlorides. The optical activities of
both the cis- and trans-isomers were uniformly excellent.
Scandium triflate was selected as the optimal Lewis acid
catalyst for substrate screening based on its ability to furnish
synthetically useful diastereoselectivity for the trans-isomer.
The aliphatic acid chloride reactions proceeded effectively
with a set of aromatic aldehydes similar to those that were
effective substrates in the reaction of alkoxy acid chlorides
(Scheme 5, Table 4). The diastereo- and enantioselectivities
that the transition-state leading to this isomer includes two
molecules of Lewis acid. For example, the trans/cis ratio in
the formation of 7c changes from 56:44 with 7.5 mol % of
Sc(OTf)3 to 92:8 with 15 mol %. This result indicates that
the aldehyde and the ammonium enolate both bind to separate
molecules of Lewis acid in the transition state leading to
the trans-isomer.
The cis-isomer formed in the reactions of phenoxyacetyl
chloride could result from a closed transition-state aldol
reaction or an alternative open transition-state process
Table 4. Yields and Selectivities for the Formation of 7a-d
product
R
Ar
trans/cisa % yield of 7b % ee of 7c
7a
7b
7c
7d
Me phenyl
91:9
91:9
92:8
95:5
75
82
80
80
92
96
99
99
Me 4-nitrophenyl
Me 4-cyanophenyl
Et 4-cyanophenyl
1
a Determined by H NMR analysis of the unpurified reaction mixture.
b Yield of purified compound. c Determined by HPLC analysis of purified
isomer.
were relatively unaffected by changes in the electronic nature
of the aldehyde.
Scheme 7
An examination of the results suggests a rationale for
stereochemical induction realized with the aliphatic acid
chlorides and also a modification of the model proposed by
Wynberg. The Lewis acid apparently activates the aldehyde
and allows the ketene/aldehyde addition to predominate over
ketene dimerization. The stereochemistry of the reaction is
most likely set in the reaction of the Z-acylammonium enolate
intermediates (Scheme 6). Considerable precedence suggests
that the syn-aldol product, and therefore cis-â-lactone, results
from a closed transition-state aldol reaction of the Z-enolate.
Therefore, we believe that the trans-lactone forms through
an open transition-state process. An anti-periplanar arrange-
ment between the enolate and the carbonyl in such a
transition-state, and minimization of nonbonded interactions,
correctly predicts formation of the trans-isomer. The open
transition-state model also predicts the observed enantiomer
in Wynberg’s cases, where R1 ) H and the aldehyde is
sufficiently electrophilic to react without Lewis acid
activation.1c
Higher concentrations of Lewis acid favor formation of
the trans-isomer from the aliphatic acid chlorides, indicating
Org. Lett., Vol. 7, No. 9, 2005
1811

(Scheme 7). The phenoxy group most likely forms a chelate
with the Lewis acid bound to the acylammonium enolate.
The interaction between the R group and the metal ligands
would disfavor the antiperiplanar, open transition state, lead-
ing to a relative preference for a gauche, open transition state.
In conclusion, we have shown that the combination of a
chiral nucleophile and an achiral Lewis acid catalyzes the
asymmetric condensation of acid chlorides with aromatic
aldehydes, presumably by way of acylammonium enolate
intermediates. This catalyst system allows an expansion in
the scope of the Wynberg reaction and also the first direct
access to trans-â-lactones.
Acknowledgment. We acknowledge the Chemistry De-
partments of the University of Rochester and Wesleyan
University for support of this work.
Supporting Information Available: General experimen-
tal procedures and characterization data for compounds 1,
3a-d, 5, and 7a-d and details of stereochemical proofs,
including results of a single-crystal X-ray diffraction structure
of 3c. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL050411Q
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Org. Lett., Vol. 7, No. 9, 2005