Published: July 25, 2011 r2011 American Chemical Society 7287 dx.doi.org/10.1021/jo2013077 | J. Org. Chem. 2011, 76, 7287–7293 NOTE pubs.acs.org/joc Tandem CyclizationMichael Reaction by Combination of Metal- and Organocatalysis Jos  e Alem an,* ,† Virginia del Solar, ‡ Cecilia Martín-Santos, ‡ Leticia Cubo, ‡ and Carmen Navarro Ranninger ‡ † Departamento de Química Org  anica (C-1) and ‡ Departamento de Química Inorg  anica (C-7), Facultad de Ciencias, Universidad Aut onoma de Madrid, Cantoblanco 28049-Madrid, Spain b S Supporting Information L actones are present in a large number of natural products. Recently, a variety of lactones with quaternary centers at C-3 and substitution at C-5 have been isolated. 1 Examples of complex structures which incorporate this moiety include spir- ovibsanin (A), 1a,b trans-dehydrocrotonin (B), 1c and biologically active tetranoditerpenoids (C) 1d (Figure 1), along with teucrin A, 1e neoclerodane diterpenes, 1f and sesquiterpenes of Collybia macu- late (not shown). 1g Less complex examples include some β3- adrenergic receptor agonists (D) 2a and serine protease inhib- itors (E). 2b Various methodologies have been developed for the synthesis of furanones with this substitution pattern (F). 2c,d In the past decade, organocatalysis 3 has opened a new window for carrying out organic transformations. One of its primary advantages is the avoidance of expensive metal reagents or catalysts. However, more recent attention has been focused on the combina- tion of metal 4 and organocatalysis 3 to provide a complementary method for obtaining new complex structures or for enhancing the reactivity of the metal. 5 Dixon, 6a Jørgensen, 6b and C ordova 6c have each reported catalytic systems involving initial activation using a Lewis base followed by π-alkyne trapping with a metal catalyst (eq 1, Scheme 1). In this context, one of the most useful starting materials in organocatalysis is a methylene activated by two electron-with- drawing groups (EWG-CHR-EWG). However, a large difference in reactivity is observed between acyclic and cyclic substrates, 7 with better reactivities generally observed in the latter case due to increased acidity (see the Bordwell pK a table). 8 Given our group's experience working with π-acid activated alkynes using platinum catalysis 9 and organocatalysis 10 although in the oppo- site mode as described above (i.e., first platinum catalysis, then the Lewis base), we hypothesized that propargyl malonate derivatives 1 could be cyclized using platinum to afford intermediate 3. Subsequently, lactone 3, with its highly acidic R-proton, would be a prime target for an organocatalytic addition to activated alkenes (eq 2, Scheme 1) to afford compounds 4. In this work, we present our efforts toward developing this tandem procedure for the synthesis of γ-lactones with a C-3 quaternary center. We began by screening platinum catalysts (5af) 9 in toluene at room temperature while using 20 mol % of DABCO as the organocatalyst to deprotonate the acidic position. As shown in Table 1, the best catalyst was 5c, 11 which gave compound 4a with a conversion of 96% (entry 3, Table 1). Other similar catalysts, Figure 1. Lactones present in different natural products. Received: June 27, 2011 ABSTRACT: The use of a catalytic amount of platinum complexes (1 mol %) was found to be compatible with different organocatalysts (DABCO or the JørgensenHayashi catalyst) that were used in the functionalization of various activated methylenes. By this method, a series of lactones with C-3 quaternary centers and substitution at C-5 were prepared.