Catalytic asymmetric heterodimerization of ketenes

Article abstract of DOI:10.1021/ja211678m

In this Communication we describe an unprecedented catalytic asymmetric heterodimerization of ketenes of wide substrate scope. The alkaloid-catalyzed method provides access to ketene heterodimer β-lactones and allows even two different monosubstituted ketenes to be cross-dimerized, with excellent enantioselectivity (17 examples with ≥90% ee) and excellent heterodimer regioselectivity observed in all cases.

Full text of DOI:10.1021/ja211678m

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Heterodimerization of Ketenes
Ahmad A. Ibrahim, Divya Nalla, Maxwell Van Raaphorst, and Nessan J. Kerrigan*
Department of Chemistry, Oakland University, 2200 North Squirrel Road, Rochester, Michigan 48309-4477, United States
S
* Supporting Information
dimerization reaction, it is not surprising, that no asymmetric
ABSTRACT: In this Communication we describe an
unprecedented catalytic asymmetric heterodimerization of
ketenes of wide substrate scope. The alkaloid-catalyzed
method provides access to ketene heterodimer β-lactones
and allows even two different monosubstituted ketenes to
be cross-dimerized, with excellent enantioselectivity (17
examples with ≥90% ee) and excellent heterodimer
regioselectivity observed in all cases.
heterodimerization reaction has ever been reported. Romo
recently demonstrated that racemic ketene heterodimers,
obtained using Sauer’s method, can be used as intermediates
in the synthesis of salinosporamide A and cinnabaramide A.2
However, this work is illustrative of the deficiencies of current
thermal heterodimerization methodologies. The desired heter-
odimers were obtained in poor yields (5−12%), with poor
regioselectivity and with homodimers being formed as major
products of the ketene dimerization. In this Communication,
we describe our successful efforts toward the goal of developing
a catalytic, regioselective, and enantioselective heterodimeriza-
tion of ketenes to access ketene heterodimer β-lactones.
During the course of our studies investigating phosphine-
catalyzed homodimerizations of ketoketenes (disubstituted
ketenes), we became intrigued by the idea of developing an
asymmetric entry to ketene heterodimer β-lactones, which
seemed to promise greater potential as synthons than the
related ketene homodimers.5 We anticipated that a stepwise
mechanism promoted by a nucleophilic catalytic system would
overcome some of the difficulties associated with Sauer’s
thermal ketene heterodimerization reaction. To that end we
began investigations using a variety of catalytic systems that had
previously shown success in promoting ketene homodimeriza-
tions.4,5
We quickly found that phosphine catalytic systems
(BINAPHANE and Josiphos) were too active to facilitate the
desired heterodimerization. We next turned our attention to
the alkaloid catalytic systems that Calter’s group and others had
utilized for reactions of monosubstituted ketenes.4,11,12 We
were encouraged by the observation that TMS-quinine was
unable to catalyze the homodimerization of methylphenylke-
tene or dimethylketene.13 These results suggested to us a
strategy for enabling ketene heterodimerization. The alkaloid
catalyst would be mixed with a relatively unreactive ketene (a
disubstituted ketene or TMS-ketene, the acceptor ketene) and
β-Lactones are interesting targets in synthesis as they are
versatile intermediates and are integral structural features of a
number of biologically active molecules, such as (−)-panclicin
D, orlistat, 1233A, salinosporamide A, and cinnabaramide A.1,2
An important route to β-lactones can be achieved via
dimerization of ketenes.3−5 In 1996 Calter showed that a
nucleophilic catalyst system (TMS-quinine or TMS-quinidine)
could catalyze the homodimerization of monosubstituted
ketenes (aldoketenes) with high enantioselectivity.4 In addition,
Calter and co-workers have demonstrated that asymmetric
alkylketene homodimerization can be applied to the synthesis of
polypropionate natural products (siphonarienal, siphonariene-
dione, and siphonarienolone).6 However, the potential of this
methodology is compromised due to the requirement for a
repeating subunit in the target molecule (i.e., polypropionate)
to which the method is applied. On the other hand, ketene
heterodimerization (cross-dimerization of two different ketenes)
to access ketene heterodimer β-lactones has received little
attention, with only a handful of reports dealing with this topic
over the last 60 years.7−10 A catalytic asymmetric ketene
heterodimerization methodology would be expected to provide
greater synthetic potential than ketene homodimerization due
to the variety of substitution patterns possible within the ketene
heterodimer β-lactone structure, and hence there would be
opportunities for many applications, beyond polypropionates,
in natural product and drug molecule synthesis.
Hunig’s base, and a more reactive ketene (generated in situ
̈
from an acyl chloride precursor, the donor ketene) would be
slowly added to the reaction solution (Scheme 1). Addition of
the catalyst to the acceptor ketene is expected to be highly
reversible, if it occurs at all. Therefore, only one reactive
ammonium enolate (derived from the donor ketene) would be
favorably formed and regioselectivity in ketene heterodimeriza-
tion would be assured. Moreover, under these reaction
conditions, the likelihood of ketene homodimerization
occurring would be diminished. Finally, given the strong
precedent of asymmetric induction imparted by alkaloid
In 1947, Sauer reported that ketene heterodimers could be
formed through thermal ketene heterodimerization following
an amine-mediated dehydrohalogenation of a mixture of acyl
chlorides.7 However, the reaction was plagued by very poor
yields, low heterodimer regioselectivity, and competing
homodimer formation. In the 64 years since then, there have
been only three isolated reports of regioselective ketene
heterodimerizations, and only two of these described access
to β-lactones (rather than to 1,3-cyclobutanediones).8−10 These
examples involved structurally unusual ketenes such as tert-
butylcyanoketene or bistrifluoromethylketene and hence their
synthetic utility was severely compromised. In view of the
complications that have historically beset the ketene hetero-
Received: December 14, 2011
Published: January 27, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
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catalysts provided good to excellent enantioselectivity in ketene
heterodimerization, with TMS-quinine (TMSQ) providing
access to the (R)-enantiomer, and the pseudoenantiomeric
Me-quinidine (MeQd) providing access to the (S)-enantiomer.
Occasionally Me-quinine (MeQ) was used instead of TMS-
quinine, if modest conversion in heterodimerization was
observed with the latter catalyst (entries 3 and 9, Table 2).
Significantly, alkylarylketenes, a dialkylketene, and even
diphenylketene were tolerated as the acceptor ketene. In the
case of ethylphenylketene (entries 3 and 4, Table 2), lower
stereoselectivity for the Z-isomer of the olefin was obtained
presumably due to the closer steric size of the ethyl and phenyl
substituents. Alternatively reversible protonation−deprotona-
Scheme 1. Proposed Mechanism for Alkaloid-Catalyzed
Ketene Heterodimerization
tion, by ammonium salt of Hunig’s base, of intermediate II may
̈
be responsible for the partial isomerization (Scheme 1). For the
synthesis of heterodimers 3d from dimethylketene (entries 7
and 8, Table 2), it was necessary to add 2 equiv of LiClO4 to
limit competing homodimerization of methylketene. Only one
heterodimer regioisomer was observed in all cases as
1
determined by GC-MS and H NMR analysis of the crudes.
catalysis, as observed in Calter’s work on ketene homodime-
rization, we expected that the desired ketene heterodimeriza-
tion would proceed in a highly enantioselective fashion.4a
We began our optimization of the proposed methodology
with methylphenylketene as the less reactive ketene (acceptor
ketene), and with methylketene (generated from propionyl
chloride) as the more reactive ketene (donor ketene). All
alkaloid catalysts used in this study were easily prepared
through one step literature procedures described by the groups
of Calter and Gaunt.4,14 We found that it was necessary to add
propionyl chloride via syringe pump over 8 h to a CH2Cl2
solution of methylphenylketene, alkaloid catalyst (Me-quinidine
The number of equivalents of acyl chloride used for the
synthesis of all examples reported in Table 2 ranged from 0.5
equiv (entry 7 and 8) to 2.0 equiv (entries 1−6). The amount
of homodimer formed from the donor ketene ranged from 20
to 40% (of crude mixture) for those cases that required an
excess of acyl chloride (entries 1−6) to achieve complete
conversion to the desired heterodimer. Those examples that
required only 0.5−1.0 equiv of acyl chloride for full conversion
to the desired heterodimer afforded <1% donor ketene
homodimer (entries 7−10), as determined by GC-MS analysis
of the crude products.
We then investigated more challenging cross dimerizations
between two monosubstituted ketenes (Table 3). For these
heterodimerizations TMS-ketene was selected as the acceptor
ketene. We had previously determined that TMS-ketene was
unable to undergo homodimerization under alkaloid or even
phosphine catalysis conditions. We attributed the failure of
homodimerization under these conditions to the low reactivity
of onium enolate intermediate I (Scheme 1) derived from TMS
ketene, due to the well-known ability of silicon to stabilize α-
anions.15 However we anticipated that TMS-ketene would act
or Me-quinine/TMS-quinine) and Hunig’s base, in order to
̈
achieve optimal yields of the desired heterodimer (ca. 65%).
Complete regioselectivity for the desired heterodimer, as
1
determined by GC-MS and H NMR analysis of the crude
product, was observed (Table 1). In addition, the desired
heterodimer was obtained as a single olefin isomer (>97:3
favoring the Z-isomer).
Next we examined the substrate scope of the methodology
exploring a variety of disubstituted ketenes as acceptor ketenes
(entries 1−8, Table 2). Both TMS- and Me-protected alkaloid
a
Table 1. Optimization of Alkaloid-Catalyzed Heterodimerization of Ketenes
b
entry
catalyst
addition time of AcCl (h)
solvent
% yield (conv)
% ee
c
1
2
TMSQ
TMSQ
MeQ
1
1
1
1
8
8
8
THF
0
−
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
(40)
(50)
(65)
65
nd
nd
nd
d
3
e
4
MeQ
f
5
6
7
MeQ
83
f
MeQd
TMSQ
64
98
f
57
94
a
b
1
Only one heterodimer regioisomer observed in all cases by GC-MS and H NMR analysis of crude. Z:E ratio >97:3. ee determined by chiral
c
d
HPLC. TMSQ = TMS-quinine; MeQ = Me-quinine; MeQd = Me-quinidine. entries 1−3: 0.13 M concentration of acceptor ketene in solvent.
e
f
entries 4−7: 0.25 M concentration of acceptor ketene in solvent. MeQ and TMSQ afforded the (R)-enantiomer of 3a, while MeQd provided the
(S)-enantiomer of 3a.
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a
Table 2. Substrate Scope of Heterodimerization of Monosubstituted Ketenes with Disubstituted Ketenes
b
c
entry
catalyst
R1
R2
R3
% yield
% ee
Z:E
d
1
2
3
4
5
6
TMSQ
MeQd
MeQ
Me
Me
Me
Me
Me
Me
Me
Me
OAc
OAc
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Et
57
64
57
62
61
60
79
90
52
57
94 (+)
>97:3
>97:3
90:10
84:16
98 (−)
73 (+)
98 (−)
96 (−)
96 (+)
91 (+)
95 (−)
76 (+)
91 (−)
MeQd
TMSQ
MeQd
MeQ
Et
Ph
Ph
Me
Me
Me
Me
efg
, ,
7
8
9
efg
, ,
MeQd
MeQ
h
h
10
MeQd
a
b
c
Only one heterodimer regioisomer observed in all cases by GC-MS analysis of crudes and NMR analysis of 3. ee determined by chiral HPLC. Z:E
d
e
1
ratio determined by H NMR. Sign of specific rotation; (+)-enantiomer or (−)-enantiomer. In these cases 2 equiv of LiClO4 was used as an
additive. Isolated as Weinreb amide derivative due to volatility of heterodimer. 20 mol % of catalyst used. Isolated as Weinreb amide due to
susceptibility to decomposition on silica gel.
f
g
h
Table 3. Scope of Alkaloid-Catalyzed Heterodimerization of two Monosubstituted Ketenes
a
b
entry
catalyst
R1
Me
% yield
% ee
c
1
2
TMSQ
MeQd
TMSQ
MeQd
TMSQ
MeQd
67
75
44
49
53
55
95 (+)
98 (−)
97 (−)
98 (+)
97 (−)
95 (+)
Me
d
3
Cl-Et
Cl-Et
n-Hex
n-Hex
d
4
d
5
d
6
a
b
Only one heterodimer regioisomer observed in all cases by GC-MS analysis of crudes and NMR analysis of 3. Z:E ratio >97:3 in all cases. ee
c
d
determined by chiral HPLC or GC. Sign of specific rotation; (+)-enantiomer or (−)-enantiomer. 20 mol % of catalyst used.
as a suitable acceptor ketene for heterodimerization if it was
subjected to reaction with a more reactive ammonium enolate I.
This proved to be the case as TMS-ketene engaged in
asymmetric heterodimerizations with methylketene, n-hexylke-
tene and 2-chloroethylketene, with the desired heterodimer
being formed with excellent enantioselectivity and complete
regioselectivity in each case (Table 3, entries 1−6). The
asymmetric entry to heterodimers derived from 2-chloroethyl-
ketene (entries 3 and 4), and from n-hexylketene (entries 5 and
6) was particularly noteworthy as we anticipated that these
examples would function as intermediates for the asymmetric
synthesis of salinosporamide A and cinnabaramide A
respectively.2 Slightly lower yields (44−49%) were obtained
in some cases (entries 3 and 4) due to competing
homodimerization of the donor ketene. The amount of
donor ketene homodimer formed ranged from 20 to 40% for
entries 1−4 (0.5−2.0 equiv of acyl chloride used), while lower
levels of donor ketene homodimer (<10%) were observed for
entries 5 and 6 (0.5 equiv of acyl chloride used), presumably
due to the slower addition of the acyl chloride in the latter cases
(12 h for entries 5 and 6 compared to 4−8 h for entries 1−4).
In most cases volatile homodimer was removed under high
vacuum or the desired heterodimer was separated from the
homodimer by flash column chromatography through a plug of
neutral silica (see SI for full details).
We also noted that in certain cases that the olefin geometry
of the heterodimer could be switched from Z to E when LiClO4
(2 equiv) was added to the alkaloid catalytic system (example
3b in Scheme 2 compared with entries 3 and 4, Table 2).16 This
ability to switch between olefin isomers of a given heterodimer
could be potentially useful for synthetic applications involving
aldol reactions of heterodimer-derived enolates.6e
In our initial studies on reactions of the heterodimers, we
found that Weinreb amide 4d derived from heterodimer 3d
underwent diastereoselective reduction when exposed to
KEt3BH, to access the synthetically useful β-hydroxyamide 6
with excellent anti-diastereoselectivity, and in good yield
(Scheme 3).6a
Finally, in situ generation of the acceptor ketene as well as of
the donor ketene was investigated (Scheme 4). (−)-3a was
formed with comparable yield (61%) and with slightly lower
enantiomeric excess (91% ee) than when purified methyl-
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Scheme 2. Isomerization of Ketene Heterodimer Olefin
Geometry
ACKNOWLEDGMENTS
■
Support has been provided by the National Science
Foundation: Grant CHE-0911483 to N.J.K., CHE-0821487
for NMR facilities, and CHE-1048719 for LC-MS facilities at
Oakland University.
REFERENCES
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Scheme 3. Application of Enantioenriched Ketene
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Synthesis
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Scheme 4. In Situ Generation of Both Ketenes
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phenylketene was used (Table 2, entry 2). This result
demonstrates the utility of the method and suggests that the
scope of the method could be broadened in the future to
include less stable non-isolable acceptor ketenes.
In summary, we have developed a catalytic asymmetric
heterodimerization of ketenes of wide substrate scope that
allows even two different monosubstituted ketenes to be cross-
dimerized with excellent enantioselectivity (17 examples with
≥90% ee) and excellent regioselectivity (only one heterodimer
formed in all cases). Studies are currently underway to apply
the new methodology to the asymmetric synthesis of
biologically interesting molecules such as cinnabaramide A.
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(13) Me-quinine and Bz-quinine were also found to be ineffective at
catalyzing the homodimerization of dimethylketene.
ASSOCIATED CONTENT
■
(14) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2003, 42, 828−831.
S
* Supporting Information
(15) (a) Bassindale, A. R.; Taylor, P. G. In The chemistry of organic
silicon compounds; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons:
New York, 1989; pp 893−963. (b) Wetzl, D. M.; Brauman, J. I. J. Am.
Chem. Soc. 1988, 110, 8333−8336.
Experimental procedures, characterization data, and spectra for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Olefin geometry was assigned on the basis of NOE experiments.
See SI for further details.
AUTHOR INFORMATION
■
Corresponding Author
kerrigan@oakland.edu
Notes
The authors declare no competing financial interest.
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