Bicyclic- and Tricyclic--lactones via Organonucleophile-Promoted Bis-Cyclizations of Keto Acids: Enantioselective Synthesis of (+)-Dihydroplakevulin Huda Henry-Riyad, Changsuk Lee, Vikram C. Purohit, and Daniel Romo* Department of Chemistry, P.O. Box 30012, Texas A&M UniVersity, College Station, Texas 77842-3012 romo@mail.chem.tamu.edu Received July 23, 2006 ABSTRACT A highly diastereoselective, nucleophile-promoted bis-cyclization process, employing readily available and tractable keto acid substrates, is described. This methodology provides concise access to bicyclic- and tricyclic--lactones bearing tertiary carbinol centers and quaternary carbons, greatly extending the scope of previous routes to bicyclic--lactones from aldehyde acid substrates. The utility of the method was demonstrated by application to an enantioselective synthesis of (+)-dihydroplakevulin A. This and related processes may be revealing a subtle interplay between [2+2] cycloaddition and nucleophile-catalyzed aldol lactonization (NCAL) reaction manifolds. In recent years, the asymmetric synthesis of -lactones has become an area of active research 1 because these heterocycles are useful synthetic intermediates for natural product syn- thesis, 2 are found in a growing number of bioactive natural products, 3 and have continued potential as enzyme inhibitors 4 and as monomers for polymer synthesis. 5 The Wynberg catalytic, asymmetric -lactone synthesis, involving an alkaloid-promoted reaction of ketene with highly electrophilic aldehydes (e.g., R-chlorinated), stands as a benchmark for further developments in this area. 6 We recently developed an intramolecular version of this nucleophile-catalyzed aldol lactonization (NCAL) process building on the work of Wynberg, which provided the first strategy to circumvent the limitation of highly electrophilic substrates (Scheme 1). This process employed aldehyde acid substrates 1 (R 2 ) H), O-acetylquinidine (AcQUIN) as nucleophilic catalyst, and modified Mukaiyama’s reagents (2a, 2b), as carboxylic acid activators, and effectively merged catalytic, asymmetric -lactone synthesis with carbocycle synthesis. 7 Recent studies employing Lewis acid additives further extend the utility of the intermolecular Wynberg process. 1d,f The primary mecha- nistic pathway for this process with aldehyde acid substrates enables catalytic, asymmetric organocatalysis via ammonium (1) For reviews, see: (a) Pommier, A.; Pons, J.-M. Synthesis 1993, 441. (b) Yang, H. W.; Romo, D. Tetrahedron 1999, 55, 6403. For more recent advances, see: (c) Kramer, J. W.; Lobkovsky, E. B.; Coates, G. W. Org. Lett. 2006, 8, 3709 and references cited therein. (d) Zhu, C.; Shen, X.; Nelson, S. G. J. Am. Chem. Soc. 2004, 126, 5352. (e) Wilson, J. E.; Fu, G. Angew. Chem., Int. Ed. 2004, 43, 6358. (f) Calter, M. A.; Tretyak, O. A.; Flaschenriem, C. Org. Lett. 2005, 7, 1809. (2) Wang, Y.; Tennyson, R. L.; Romo, D. Heterocycles 2004, 64, 605. (3) Lowe, C.; Vederas, J. C. Org. Prep. Proced. Int. 1995, 27, 305. (4) (a) For lead references, see: Lall, M. S.; Ramtohul, Y. K.; James, M. N. G.; Vederas, J. C. J. Org. Chem. 2002, 67, 1536. (b) Purohit, V. C.; Richardson, R. D.; Smith, J. W.; Romo, D. J. Org. Chem. 2006, 71, 4549. (5) For a lead reference, see: Rieth, L. R.; Moore, D. R.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 15239. (6) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166. (7) (a) Cortez, G. S.; Tennyson, R.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945. (b) Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001, 11, 1731. (c) Oh, S. H.; Cortez, G. C.; Romo, D. J. Org. Chem. 2005, 70, 2835. ORGANIC LETTERS 2006 Vol. 8, No. 19 4363-4366 10.1021/ol061816t CCC: $33.50 © 2006 American Chemical Society Published on Web 08/23/2006