pubs.acs.org/joc
molecular structure (Figure 1). Therefore, these natural
Stereoselective Synthesis of Cyclohexanones via
Phase Transfer Catalyzed Double Addition of
Nucleophiles to Divinyl Ketones.
products offer themselves as challenging synthetic targets
and have attracted considerable attention.5
Andrew C. Silvanus,† Benjamin J. Groombridge,†
‡
Benjamin I. Andrews, Gabriele Kociok-Kohn, and
†
€
David R. Carbery†,*
†Department of Chemistry, University of Bath, Bath BA2 7AY,
U.K, and ‡GlaxoSmithKline Medicines Research Centre,
Stevenage, Hertfordshire SG1 2NY, U.K.
FIGURE 1. Jiadifenolide 1 and jiadifenin 2.
A number of synthetic routes to functionalized cyclo-
hexanones have been be reported in recent years, underlining
the continued importance of this framework to the synthetic
community. Most notably [4 þ 2] cycloadditions,2a,6 organo-
catalyzed domino annulations,7 Rh(I)-catalyzed Pauson-
Khand,8 Pd-catalyzed intramolecular hydroalkylation,9 and
reductive tandem double Michael cascades.10
Received August 31, 2010
Divinyl ketones (DVKs) are predominantly associated
with the Nazarov reaction.11 However, they also act as com-
petent double electrophiles reacting with a variety of double
nucleophiles.12 The double addition of a methylene pro-
nucleophile is well-known (Scheme 1).13
SCHEME 1. Reaction of a Malonate with a Divinyl Ketone13
Functionalized cyclohexanones are formed in excellent
yield and diastereoselectivity from a phase transfer catalyzed
double addition of active methylene pronucleophiles to non-
symmetrical divinyl ketones.
For example, Kohler reported in 1924 that dibenzylidene
acetone 3a formed meso-cyclohexanone 5a when exposed to
dimethylmalonate and NaOH. The reaction is syn-selective,
with all subsequent reports involving the use of symmetrical
diaryl DVKs, or similar pseudosymmetrical diaryl sub-
stituted ketones, forming syn-diaryl cyclohexanones.14 The
The development of single-pot reactions which allow the
rapid construction of several bonds and stereocenters remains a
considerable challenge in modern organic chemistry.1 In many
instances this strategy can offer a simple and versatile synthesis
of valuable building blocks from inexpensive starting materials.
Highly substituted cyclohexanones and the related cyclo-
hexanols, provide key skeletal components of many natural
products with significant biological and pharmaceutical
importance.2 In particular, a number of important cyclo-
hexanol natural products exist which have a quaternary
center at C-4 (Figure 1). Jiadifenolide 13 and jiadifenin 24
are highly active neurotrophins which possess such a cyclo-
hexanol motif embedded within their compact and complex
(5) For total synthesis of 2, see: (a) Cho, Y. S.; Carcache, D. A.; Tian, Y.;
Li, Y-M; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 14358.
(b) Carcache, D. A.; Cho, Y. S.; Hua, Z.; Tian, Y.; Li, Y-M; Danishefsky,
S. J. J. Am. Chem. Soc. 2006, 128, 1016.
(6) (a) Kim, W. H.; Lee, J. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2009,
131, 12576. (b) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626.
(7) (a) Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jørgensen, K. A. Adv.
Synth. Catal. 2004, 346, 1077. (b) Gryko, D. Tetrahedron: Asymmetry 2005,
16, 1377. (c) Wang, J.; Ma, A.; Ma, D. Org. Lett. 2008, 10, 5425. (d) Hayashi,
Y.; Toyoshima, M.; Gotoh, H.; Ishikawa, H. Org. Lett. 2009, 11, 45.
(e) Enders, D.; Erdmann, N.; Raabe, G. Synthesis 2010, 2271.
(8) Jiao, L.; Lin, M.; Zhuo, L.-G.; Yu, Z.-X. Org. Lett. 2010, 12, 2528.
(9) Wang, X.; Pei, T.; Han, X.; Widenhoefer, R. A. Org. Lett. 2003, 5,
2699.
(10) Kamenecka, T. M.; Overman, L. E.; Ly Sakata, S. K. Org. Lett.
2002, 4, 79.
(11) (a) Pellissier, H. Tetrahedron 2005, 61, 6479. (b) Tius, M. A. Eur. J.
Org. Chem. 2005, 2193.
(12) For selected heteroatom double additions to divinyl ketones, see:
(a) Rosiak, A.; Hoenke, C.; Christoffers, J. Eur. J. Org. Chem. 2007, 4376.
(b) Radha Krishna, P.; Sreeshailam, A. Tetrahedron Lett. 2007, 48, 6924.
(c) Rosiak, A.; Frey, W.; Christoffers, J. Eur. J. Org. Chem. 2006, 4044.
(d) Rosiak, A.; Christoffers, J. Synlett 2006, 1434. (e) Reddy, D. B.; Reddy,
A. S.; Padmavathi, V. Synth. Commun. 2001, 31, 3429. (f) Brenstrum, T.;
Clattenburg, J.; Britten, J.; Zavorine, S.; Dyck, J.; Robertson, A. J.;
McNulty, J.; Capretta, A. Org. Lett. 2006, 8, 103.
(1) (a) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1. (b) Nicolaou, K. C.;
Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993. (c) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (d) Little, R. D.;
Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. Org. React. 1995, 47,
315. (e) Ho, T. L. Tandem Organic Reactions; John Wiley: New York, 1992.
(f) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(2) (a) Jiang, J.; Bunda, J. L.; Doss, G. A.; Chicchi, G. G.; Kurtz, M. M.;
Tsao, K.-L. C.; Tong, X.; Zheng, S.; Upthagrove, A.; K.; Samuel, K.;
Tschirret-Guth, R.; Kumar, S.; Wheeldon, A.; Carlson, E. J.; Hargreaves,
R.; Burns, D.; Hamill, T.; Ryan, C.; Krause, S. M.; Eng, W.; DeVita, R. J.;
Mills, S. G. J. Med. Chem. 2009, 52, 3039. (b) Bui, T.; Barbas, C. F.
Tetrahedron Lett. 2000, 41, 6951.
(3) Kubo, M.; Okada, C.; Huang, J.-M.; Harada, K.; Hioki, H.; Fukuyama,
Y. Org. Lett. 2009, 11, 5190.
(4) Yokoyama, R.; Huang, J.-M.; Yang, C.-S.; Fukuyama, Y. J. Nat.
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(13) Kohler, E. P.; Helmkamp, R. W. J. Am. Chem. Soc. 1924, 46, 1267.
DOI: 10.1021/jo101713d
r
Published on Web 10/13/2010
J. Org. Chem. 2010, 75, 7491–7493 7491
2010 American Chemical Society