pubs.acs.org/joc
TABLE 1. Catalyst Screening for Catalytic Asymmetric Homodimer-
ization of Ketoketenes
Josiphos-Catalyzed Asymmetric Homodimerization
of Ketoketenes
Ahmad A. Ibrahim, Pei-Hsun Wei, Gero D. Harzmann, and
Nessan J. Kerrigan*
Department of Chemistry, Oakland University, 2200 North
Squirrel Road, Rochester, Michigan 48309-4477,
United States
concn
(M)
dimer:
trimera
convn
(% yield)b,c % eed
entry
phosphine
1e
2
3
4
5
6
3
0.5
0.5
0.5
0.5
0.5
0.5
0.125
0.125
nd
(78)
>99
>99
>99
0
>99
>99
>99 (74)
33
80
78
2
4a
4b
4c
4d
4e
4e
4e
69:31
70:30
64:36
Received September 21, 2010
70:30
97:3
97:3
82
80
90
7
8f
aDimer:trimer ratio determined by 1H NMR or GC-MS analysis of
c
crude product. bPercent yield is isolated yield for 2a. Z:E > 97:3 as
determined by GC-MS analysis, and a comparison of spectroscopic data
with that of ref 8. dPercent ee of dimer determined by chiral HPLC
analysis. eReaction conducted at -78 °C for 48 h. fCatalyst solution was
cooled to -25 °C.
route to β-lactones can be achieved via dimerization of
ketenes.3-5 Some time ago, Elam and, shortly after, Bentrude
showed that dimethylketene could be homodimerized using
trialkylphosphites as nucleophilic catalysts.4c,d More recently,
Calter showed that a nucleophilic catalyst (TMS-quinine or
TMS-quinidine) could catalyze the homodimerization of
alkyl-substituted aldoketenes with high enantioselectivity.6
While aldoketene dimer β-lactones have been used exten-
sively in the synthesis of polyketides (polypropionates) by
Calter and co-workers, ketoketene dimers have received less
attention due to the paucity of general methods for their pre-
paration.5,7-9 In 2008 our group reported a versatile trialkyl-
phosphine catalytic system that provided a general method
for ketoketene (disubstituted ketene) homodimerization.5
Around the same time Ye’s group also published their work
on the asymmetric N-heterocyclic carbene-catalyzed homo-
dimerization reaction.8 However, the latter method was found
to be unsuitable for the dimerization of ortho-substituted
arylketoketenes and dialkylketenes.8 In this communication
we report that Josiphos, a chiral diphosphine possessing
In this paper the development of a chiral phosphine-cata-
lyzed homodimerization of ketoketenes that provides access
to a variety of highly substituted ketoketene dimer
β-lactones (11 examples) is reported. The Josiphos cata-
lytic system displays good to excellent enantioselectivity
(up to 96% ee). Ring-opening reactions of the enantioen-
riched ketoketene dimers were also carried out to access
1,3-diketones, enol esters, and β-hydroxyketones with
good diastereoselectivity.
β-Lactones are important molecules which have been used
by many groups as intermediates for the synthesis of complex
molecules, and indeed often function as integral structural
features of biologically active molecules.1,2 An important
(1) (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.
(2) (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.
(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.
(4) (a) Sauer, J. C. J. Am. Chem. Soc. 1947, 69, 2444–2448. (b) Hasek,
R. H.; Clark, R. D.; Elam, E. U.; Martin, J. C. J. Org. Chem. 1962, 27, 60–64.
(c) Elam, E. U. J. Org. Chem. 1967, 32, 215–216. (d) Bentrude, W. G.;
Johnson, W. D. J. Am. Chem. Soc. 1968, 90, 5924–5926. (e) Aronov, Y. E.;
Cheburkov, Y. A.; Knunyants, I. L. Izv. Akad. Nauk SSSR, Ser. Khim. 1967,
8, 1758–1768. (f) Moore, H. W.; Duncan, W. G. J. Org. Chem. 1973, 38,
156–158.
(5) (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.
(6) (a) Calter, M. A. J. Org. Chem. 1996, 61, 8006–8007. (b) Calter, M. A.;
Orr, R. K. Org. Lett. 2003, 5, 4745–4748. (c) Purohit, V. C.; Richardson,
R. D.; Smith, J. W.; Romo, D. J. Org. Chem. 2006, 71, 4549–4558.
(7) (a) Calter, M. A.; Song, W.; Zhou, J. J. Org. Chem. 2004, 69, 1270–
1275. (b) Calter, M. A.; Liao, W. J. Am. Chem. Soc. 2002, 124, 13127–13129.
(8) Lv, H.; Zhang, Y.- R.; Huang, X.-L.; Ye, S. Adv. Synth. Catal. 2008,
350, 2715–2718.
(9) Lewis base-catalyzed enantioselective approaches to β-lactones from
ketoketenes and aldehydes: (a) Wilson, J. E.; Fu, G. C. Angew. Chem., Int.
Ed. 2004, 43, 6358–6360. (b) He, L.; Lv, H.; Zhang, Y.-R.; Ye, S. J. Org.
Chem. 2008, 73, 8101–8103. (c) Mondal, M.; Ibrahim, A. A.; Wheeler, K. A.;
Kerrigan, N. J. Org. Lett. 2010, 12, 1664–1667.
DOI: 10.1021/jo101867m
r
Published on Web 10/29/2010
J. Org. Chem. 2010, 75, 7901–7904 7901
2010 American Chemical Society