Phosphine-catalyzed asymmetric synthesis of β-lactones from arylketoketenes and aromatic aldehydes

Article abstract of DOI:10.1021/ol100075m

In this paper, the development of a chiral phosphine-catalyzed formal [2 + 2] cycloaddition of aldehydes and ketoketenes that provides access to a variety of highly substituted β-lactones (14 examples) is reported. The BINAPHANE catalytic system displays excellent enantioselectivity (seven examples with ee ≥90%) and high diastereoselectivity favoring formation of the trans-diastereomer (nine examples with dr ≥90:10).

Full text of DOI:10.1021/ol100075m

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1664-1667
Phosphine-Catalyzed Asymmetric
Synthesis of ꢀ-Lactones from
Arylketoketenes and Aromatic
Aldehydes
Mukulesh Mondal,† Ahmad A. Ibrahim,† Kraig A. Wheeler,‡ and
Nessan J. Kerrigan*,†
Department of Chemistry, Oakland UniVersity, 2200 North Squirrel Road, Rochester,
Michigan 48309-4477, and Department of Chemistry, Eastern Illinois UniVersity,
600 Lincoln AVenue, Charleston, Illinois 61920-3099
kerrigan@oakland.edu
Received January 12, 2010
ABSTRACT
In this paper, the development of a chiral phosphine-catalyzed formal [2 + 2] cycloaddition of aldehydes and ketoketenes that provides
access to a variety of highly substituted ꢀ-lactones (14 examples) is reported. The BINAPHANE catalytic system displays excellent
enantioselectivity (seven examples with ee g90%) and high diastereoselectivity favoring formation of the trans-diastereomer (nine examples
with dr g90:10).
ꢀ-Lactones are important molecules which are found as
integral structural features of many pharmacologically active
molecules and, in addition, have been extensively used as
intermediates in complex molecule synthesis.1,2 Both chiral
Lewis acid and chiral nucleophile catalyzed approaches to
enantioenriched ꢀ-lactones have been investigated.3 The most
versatile methodologies providing access to enantioenriched
ꢀ-lactones rely on the use of alkaloid nucleophiles to catalyze
the formal [2 + 2] cycloaddition of ketenes and aldehydes.3
The seminal work of Wynberg’s group in the early 1980s
showed that cinchona alkaloid catalysts (quinine and quini-
dine) could catalyze the formal [2 + 2] cycloaddition of
ketene with chloral to afford a ꢀ-lactone in highly enanti-
oselective fashion.4 Subsequent advances were made by the
groups of Romo, Nelson, and Calter to extend the substrate
(2) (a) Taunton, J.; Collins, J. L.; Schreiber, S. L. J. Am. Chem. Soc.
1996, 118, 10412–10422. (b) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc.
2000, 122, 10470–10471. (c) Nelson, S. G.; Cheung, W. S.; Kassick, A. J.;
Hilfiker, M. A. J. Am. Chem. Soc. 2002, 124, 13654–13655. (d) Shen, X.;
Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. J. Am. Chem. Soc. 2006,
128, 7438–7439. (e) Wang, Y.; Tennyson, R.; Romo, D. Heterocycles 2004,
64, 605–658.
† Oakland University.
‡ Eastern Illinois University.
(1) (a) Pommier, A.; Pons, J.-M. Synthesis 1995, 729–744. (b) Yang,
H. W.; Romo, D. J. Org. Chem. 1997, 62, 4–5. (c) Dymock, B. W.;
Kocienski, P. J.; Pons, J.-M. Synthesis 1998, 1655–1661. (d) Reddy, L. R.;
Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230–6231
.
10.1021/ol100075m  2010 American Chemical Society
Published on Web 03/25/2010

scope of this reaction to include unactivated aldehydes.5-7
The expeditious use of mild Lewis acids, such as LiClO4 or
Sc(OTf)3, in combination with nucleophilic catalysis was
particularly noteworthy.6,7 However, all of these systems
have been limited with respect to the ketene substrate
tolerated; only ketene or simple monosubstituted ketenes can
be used as substrates with the alkaloid catalytic systems,
presumably due to their attenuated nucleophilicity. Fu’s
group showed that planar chiral ferrocenylamine catalysts
could catalyze the reaction of dialkylketenes with aromatic
aldehydes in high enantioselectivity, but with moderate
diastereoselectivity (dr up to 4.6:1). Moreover, their system
was not successful with aliphatic aldehydes or with alky-
larylketenes.8 Recently, Ye’s group showed that the reaction
of alkylarylketenes with highly electrophilic 2-oxoaldehydes
could be catalyzed by a chiral N-heterocyclic carbene
catalyst.9 However, they found that less reactive aldehydes
such as aromatic aldehydes were not tolerated as substrates
by their weakly nucleophilic catalytic system.
1 vs entry 2).11 Addition of a Lewis acid (LiI) led to much
lower diastereoselectivity, presumably due to competing
transition states, and was not investigated further (entry 3).6,7
With the aim of rendering the reaction asymmetric we then
examined a number of chiral catalysts, including those that
we had previously found promising in catalyzing enantiose-
lective ketoketene dimerization (BINAPHANE) and those
that had shown success in other organocatalytic settings.11,12
Axially chiral (R)-BINAPHANE was found to be the optimal
catalyst with respect to reactivity, diastereoselectivity, and
enantioselectivity (Table 1, entry 8).13
The scope of the BINAPHANE-catalyzed methodology
with respect to ketoketene and aldehyde structure was then
explored (Table 2). Reactions proceeded with 70-99%
Table 2. Scope of Phosphine-Catalyzed Formal [2 + 2]
Cycloaddition
With the broad goal of applying highly substituted
ꢀ-lactones, possessing vicinal quaternary and tertiary ste-
reogenic centers, to complex molecule synthesis, we inves-
tigated phosphines as nucleophilic catalysts for the formal
[2 + 2] cycloaddition of ketoketenes and aldehydes. We
envisaged that a phosphine catalytic system would supersede
these previously reported systems due to the enhanced
polarizability of the phosphorus atom relative to that of the
nitrogen atom in amines.10 The reaction of ethylphenylketene
with 4-chlorobenzaldehyde was used as the test reaction for
methodology optimization (Table 1).
entry
R1
R2
R3
% yielda
drb
% eec
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Me
Me
Ph
87
65
63
75
61
59
>99e
94e
51
99
72
72
55
62e
96:4
95:5
94:6
83:17 >99
>99:1 97
>99:1 93
75:25 n.d.
93:7
80:20 87
53:47 61/96
96:4
92:8
79
90
92
4-ClPh
4-NO2Ph
4-ClPh
CH2CH2Ph
(CH2)3CH3
2-ClPh
indolyld Et
indolyl
indolyl
Ph
Ph
Ph
Et
Et
Et
Et
Et
4-ClPh
4-NO2Ph
64
9
10
11
12
13
14
Ph
n-Bu 4-NO2Ph
Table 1. Catalyst Screening for the Formal [2 + 2]
Cycloaddition of Ketoketenes and Aldehydes
2-tolyl
4-tolyl
4-tolyl
Ph
Me
Me
Me
Ph
4-NO2Ph
4-ClPh
4-NO2Ph
4-NO2Ph
54
84
90:10 85
96
a Isolated yield (%) for ꢀ-hydroxy acid 4 derived from ꢀ-lactone 3 unless
stated otherwise. b Diastereomeric ratio (dr) determined by HPLC or 1H
NMR analysis. c % ee determined by chiral HPLC analysis for major
diastereomer. d Indolyl ) N-Me-3-indolyl. e Isolated yield (%) for ꢀ-lactone
3.
addition
time of 1a (h) (% yield)
% convna
entry
catalyst
drb
% eec
1
2
PBu3
direct
4
20
91
90:10
95:5
PBu3
PBu3 + LiI
(0.3 equiv)
Duanphos
Josiphos
(R,R)-4
(R)-5
BINAPHANE
3
4
5
6
7
8
direct
>99
0
(19)
6
(63)
(94)
60:40
4
4
4
4
4
56:44
71:29
92:8
n.d.
n.d.
32
93:7
64
a % convn ) % conversion to 3a; % yield is isolated yield for 3a.
b Diastereomeric ratio (dr) determined by HPLC or 1H NMR analysis. c
ee determined by chiral HPLC analysis.
%
conversion after 12-16 h, but crude products typically
contained 5-20% unreacted aldehyde. Therefore, most
isolated yields were determined following ring-opening of
crude ꢀ-lactones 3 with aqueous KOH to afford the corre-
sponding ꢀ-hydroxycarboxylic acids 4 as analytically pure
compounds (see the Supporting Information for procedures).
A variety of ketoketene aryl, including indolyl (entry
4-6) and alkyl substituents (entry 3 vs entry 9 vs entry
10), were tolerated, while even the sterically hindered
We carried out our initial optimization of the reaction with
PBu3 as the catalyst as we had found it to be a successful
achiral catalyst for the dimerization of a variety of ke-
toketenes.11 It was found necessary to add the ketoketene
solution via syringe pump over 4 h to the aldehyde/phosphine
solution in order to minimize ketoketene dimerization (entry
Org. Lett., Vol. 12, No. 8, 2010
1665

diphenylketene proved a successful substrate (entry 14).14
In general, aromatic aldehydes, particularly those pos-
sessing electron-withdrawing aromatic substituents (NO2
or Cl), gave very good levels of diastereoselectivity and
enantioselectivity (e.g., entries 2, 3, 12, and 13). Less
activated aromatic aldehydes such as benzaldehyde also
functioned well with good diastereoselectivity and with
slightly lower enantioselectivity being obtained (entry 1).
It was especially noteworthy that the method could be
extended to some unactivated aliphatic aldehydes (entries
5 and 6) with excellent levels of asymmetric induction
(>90%) being displayed.6,15 Poor diastereoselectivity was
observed in some cases (Table 2, entries 7 and 10), and this
is presumably due to competing reaction mechanisms (see
Scheme 2, mechanism A vs mechanism B).
Scheme 2. Postulated Mechanisms A and B for
Phosphine-Catalyzed Formal [2 + 2] Cycloaddition of
Ketoketenes and Aldehydes
The potential synthetic utility of highly substituted ꢀ-lac-
tones 3 can be estimated from the relative ease with which
they may be converted to useful synthons such as ꢀ-hydroxy
carboxylic acids 4 and ꢀ-azido carboxylic acids 5 (Scheme
1).16 Although 3b was obtained in lower ee than many
NAPHANE system, phosphonium alkoxide 6 would add to
another molecule of ketoketene 1 to generate enolate 7.
Intramolecular SN2 (4-exo-tet) would provide trans-3 as the
major product.
Although the more commonly encountered mechanism B
cannot be ruled out at this point, tentative support for
mechanism A was derived from a number of observations.
The sense of enantioselectivity in the (R)-BINAPHANE-
catalyzed dimerization of methylphenylketene (31% ee, (S)-
enantiomer ) major, see the Supporting Information for
procedure), a process that is presumed to involve phospho-
Scheme 1. Ring-Opening Reactions of ꢀ-Lactones 3
(4) (a) Wynberg, H.; Staring, E. G. J. 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, 87–130.
(5) (a) Tennyson, R.; Romo, D. J. Org. Chem. 2000, 65, 7248–7252.
(b) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001,
123, 7945–7946.
(6) Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352–
5353.
(7) Calter, M. A.; Tretyak, O. A.; Flaschenriem, C. Org. Lett. 2005, 7,
1809–1812.
(8) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 6358–
6360.
(9) He, L.; Lv, H.; Zhang, Y.-R.; Ye, S. J. Org. Chem. 2008, 73, 8101–
8103.
(10) (a) Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035–
1050. (b) Wei, Y.; Sastry, G. N.; Zipse, H. J. Am. Chem. Soc. 2008, 130,
3473–3477.
examples in Table 2, it served as an effective representative
example to evaluate retention of chirality during KOH-
promoted hydrolysis. Efficient transfer of chirality was noted
both for the conversion of 3b (79% ee) to ꢀ-hydroxy
carboxylic acid 4b (79% ee) and for the conversion of 3c
(90% ee) to ꢀ-azido carboxylic acid 5c (90% ee). No erosion
of diastereomeric purity was detected in either case.
We speculate that the mechanism for formation of trans-3
involves initial attack of BINAPHANE on aldehyde 2 to give
phosphonium alkoxide 6 (Scheme 2).17 Indeed, there is
precedence for such a mode of addition in the work of Fu’s
group on the synthesis of trans-ꢀ-lactams from ketoketenes
and N-triflyl imines. They provided both 1H NMR and X-ray
crystallographic evidence that the nucleophilic catalyst, a
chiral 4-(pyrrolidino)pyridine derivative, adds first to the
N-triflylimine rather than to the ketoketene.18 In the BI-
(11) (a) Kerrigan, N. J.; Ibrahim, A. A.; Harzmann, G. D. Abstracts of
Papers, 236th National Meeting of the American Chemical Society,
Philadelphia, PA; American Chemical Society: Washington, DC, 2008;
ORGN 531. (b) Ibrahim, A. A.; Harzmann, G. D.; Kerrigan, N. J. J. Org.
Chem. 2009, 74, 1777–1780. (c) Ibrahim, A. A.; Smith, S. M.; Henson, S.;
Kerrigan, N. J. Tetrahedron Lett. 2009, 50, 6919–6922.
(12) (a) Vedejs, E.; Daugulis, O.; MacKay, J. A.; Rozners, E. Synlett
2001, 1499–1505. (b) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
12234–12235. (c) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006,
45, 1426–1429.
(13) The relative stereochemistry of ꢀ-lactones 3 was determined to be
trans through X-ray crystallographic analysis of (()-3d. See the Supporting
Information for further details.
(14) The absolute configuration of 3n (entry 14, Table 2) was determined
to be (R) through X-ray crystallographic analysis (see the Supporting
Information for further details). The absolute configuration of ꢀ-lactones
3a-m was assigned to be (R,R) by analogy.
(15) Aliphatic aldehydes possessing R-branching, such as isobu-
tyraldehyde, were also investigated but gave lower yields (<40%).
(16) Nelson, S. G.; Spencer, K. L.; Cheung, W. S.; Mamie, S. J.
Tetrahedron 2002, 58, 7081–7091.
(3) (a) Paull, D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009, 65,
6771–6803. (b) Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545–
3565. (c) Schneider, C. Angew. Chem., Int. Ed. 2002, 41, 744–746. (d)
Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403–6434.
(17) Precedent for the addition of phosphines to aldehydes: Lee, S. W.;
Trogler, W. C. J. Org. Chem. 1990, 55, 2644–2648.
(18) Lee, E. C.; Hodous, B. L.; Bergin, E.; Shih, C.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 11586–11587.
1666
Org. Lett., Vol. 12, No. 8, 2010

nium enolate intermediate E-8, differed from that of the (R)-
BINAPHANE-catalyzed reaction of methylphenylketene and
4-NO2PhCHO (92% ee, (R,R)-enantiomer ) major).11,14,17
While the large difference in the degree of enantioselectivity
could be interpreted in terms of different transition-state
energies for each electrophile (one having a later transition
state than the other), the different sense of enantioselectivity
is less easily explained by a mechanism involving enolate
E-8 in both reactions. Equilibration of enolate E-8 to the
Z-isomer would presumably be required to provide a different
configuration at the quaternary stereocenter of 3 to that of
methylphenylketene dimer 10. In nucleophile-catalyzed reac-
tions of ketenes, such a process has only been proposed to
occur under very specialized conditions (using an anionic
imidazoline catalyst at 0 °C) and is unlikely to occur under
the present reaction conditions (neutral catalyst at -78 °C).19
Furthermore, subjecting a stoichiometric amount of phos-
phonium enolate 8, derived from diphenylketene and PBu3,
to reaction with 4-NO2PhCHO resulted in no ꢀ-lactone (3n)
being formed. This was in contrast to the result of the
BINAPHANE-catalyzed reaction (Table 2, entry 14). Indeed,
if the reaction was to involve a phosphonium enolate
intermediate 8, one would expect a higher level of enanti-
oselectivity to be observed in reactions with electronically
less reactive aldehydes due to the involvement of a later
transition state (a trend that was observed in Fu’s studies).8
This is not the case with the BINAPHANE system as
4-NO2PhCHO gives superior enantioselectivity to 4-ClPhCHO
(Table 2, entries 8 vs 9) and PhCHO (Table 2, entries 1 vs
3). It is also interesting to note that the analogous ferroce-
nylamine system of Fu catalyzes the formal [2 + 2]
cycloaddition of dialkylketenes and aromatic aldehydes to
give cis-ꢀ-lactones, via a postulated ammonium enolate
intermediate.8 Mechanistic investigations will be carried out
to clarify which of the two mechanisms (A or B) is operative
in the BINAPHANE system.20
In summary, we have developed a versatile chiral phos-
phine-catalyzed formal [2 + 2] cycloaddition of aldehydes
and ketoketenes that provides access to highly substituted
ꢀ-lactones with excellent enantioselectivity (g90% ee for
seven examples) and good diastereoselectivity (g90:10 for
nine examples). Future studies will focus on elucidating the
mechanism, the substrate scope with respect to chiral
aldehydes, and the mode of enantioselectivity of this reaction.
Acknowledgment. Support has been provided by the
National Science Foundation (Grant Nos. CHE-0911483 to
N.J.K. and CHE-0722547 to K.A.W.) and by Oakland
University (N.J.K.). We thank Degussa for a gift of chiral
phosphepines.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal-
lographic files (CIF). This information is available free of
charge via the Internet at http://pubs.acs.org.
OL100075M
(20) 31P NMR monitoring of the PBu3-catalyzed reaction of
4-NO2PhCHO and diphenylketene was inconclusive, with signals observed
at 13.4, 28.2, and 34.2 ppm .
(19) Weatherwax, A.; Abraham, C. J.; Lectka, T. Org. Lett. 2005, 7,
3461–3463.
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