An expeditious, bidirectional synthesis of furofuranones: a new application of Morita–Baylis–Hillman adducts Goverdhan Mehta * , Bilal Ahmad Bhat, T. H. Suresha Kumara Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India article info Article history: Received 23 June 2009 Revised 3 September 2009 Accepted 11 September 2009 Available online 13 September 2009 abstract A concise, flexible approach of general utility to the furo[3,2-b]furanones from readily available Morita– Baylis–Hillman adducts is delineated. In an expeditious variant of this approach, a four-step cascade pro- cess is executed in a one-pot operation to generate the furofuranoid framework containing two quater- nary centers. Ó 2009 Elsevier Ltd. All rights reserved. Natural products based on the furo[3,2-b]furanone framework such as goniofufurone 1 1 and plakortones A and B 2 2 have period- ically surfaced in the literature. However, the furofuranone motif has been widely encountered as a dominant sub-structure in a di- verse range of complex natural products of mixed biosynthesis including pallavicinin 3, 3 norrisolide 4, 4 dendrillolide A 5, 5 and more recently, micrandilactone A 6 6 and its siblings, Figure 1. Interestingly, not only goniofufurone 1 and plakortones A and B 2, based exclusively on the furo[3,2-b]furanone platform, but even others such as 3–6, containing this moiety as part of their struc- ture, exhibit a wide range of biological activities. For example, plant-derived 1 is known to be cytotoxic to several human cancer cell lines 1 and marine-derived 2 displayed activation of cardiac SR- Ca 2+ -pumping ATPase at micromolar concentrations. 2,7 Com- pounds 3–6 have also been found to exhibit a range of biological activities. 8 Thus, the furo[3,2-b]furanone core appears to be a promising pharmacophoric group and this attribute, along with the complex natural product architecture into which it is embed- ded, has generated considerable interest in assembling this moiety. However, synthetic efforts in this area have mainly focused on a particular natural product target bearing the furo[3,2-b]furanone moiety, 9,10 and generally applicable solutions to this system are lacking, barring an approach based on the Pd-mediated carbonyl- ation of 1,3-diols. 11 We report herein a simple, concise methodol- ogy for assembling diverse furo[3,2-b]furanones from readily available Morita–Baylis–Hillman (MBH) adducts. 12,13 An outline of the methodology is delineated in Scheme 1 involv- ing propargylation of the MBH adduct (7?8), elaboration to a c-butenolide (8?9) and an oxy-Michael addition (9?10), to generate the requisite furo[3,2-b]furanone moiety. 10 Bi-direction- ality can be imparted to this overall process by exploiting either of the two oxygen functionalities of the MBH adduct 7 for the ini- tial propargylation reaction and its manifestation provides access to either furo[3,2-b]furanone 10 or 12 with swapping of the R 1 and R 2 substituents. This protocol gives considerable latitude in terms of the placement of the substituents, particularly with qua- ternary centers on the furo[3,2-b]furanone framework. To test the viability of the methodology depicted in Scheme 1, the readily available TBS-protected MBH adduct 13, 13 from methyl vinyl ketone and formaldehyde, was smoothly propargylated to 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.09.059 * Corresponding author. E-mail address: gm@orgchem.iisc.ernet.in (G. Mehta). O O O HO Ph HO H H O O O H R O O O H O H H H H O O O H H AcO H H H O O O H H OH H O O O O H H O OH O H 2 1 Plakortone A (R = Et), Plakortone B (R = Me) 3 4 6 5 O O O H H AcO H H Figure 1. Structural diversity in furofuranone-containing natural products. Tetrahedron Letters 50 (2009) 6597–6600 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet