Biomimetic Asymmetric Total Synthesis of (-)-Laurefucin via an Organoselenium-Mediated Intramolecular Hydroxyetherification Byungsook Kim, † Miseon Lee, † Mi Jung Kim, † Hyunjoo Lee, † Sanghee Kim, † Deukjoon Kim,* ,† Minseob Koh, ‡ Seung Bum Park, ‡ and Kye Jung Shin § The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea, Department of Chemistry, Seoul National UniVersity, Seoul 151-747, Korea, and Life Sciences Research DiVision, Center for Chemoinformatics Research, Korea Institute of Science and Technology, Seoul 130-650, Korea Received August 9, 2008; E-mail: deukjoon@snu.ac.kr Abstract: The first asymmetric total synthesis of (-)-laurefucin (1), a unique C-15 acetogenin with a 2,8- dioxabicyclo[5.2.1]decane skeleton, has been accomplished in nine steps in 31% overall yield from known oxocene 10. Highlights of the highly stereoselective synthesis include a novel organoselenium-mediated biomimetic hydroxyetherification. Introduction (-)-Laurefucin (1), the first C-15 acetogenin with a unique 2,8-dioxabicyclo[5.2.1]decane skeleton, was isolated by Irie and co-workers in 1972 from the red alga Laurencia nipponica. 1 Since then, a considerable number of congeners have been isolated from various marine sources. 2 The structure and absolute configuration of the R,R′-cis disubstituted medium ring marine natural product 1 were firmly established by X-ray crystallography. 3 Laurefucin (1) is reported to possess an interesting inhibitory activity for drug metabolism. 4 On the basis of enzymatic and chemical considerations, it was proposed that (-)-laurefucin (1) might be biogenetically derived from deacetyllaurencin (2) through the intermediacy of bromoether 3, which is designated as prelaurefucin. 2b,5 Dis- placement of the C-10 bromide functionality in 3 by transannular participation of the ring oxygen and subsequent nucleophilic attack by H 2 O at the C-10 position in the resultant oxonium ion 4 with retention of configuration would lead to laurefucin as depicted in Scheme 1. It has been demonstrated that deacetyllaurencin (2) is transformed to laurefucin (1) by action of lactoperoxidase 5a or bromoperoxidase. 5b In addition, the possible involvement of prelaurefucin (3) in the biosynthetic pathway was supported by a facile conversion of hexahydro- prelaurefucin, synthesized from natural laurefucin by a catalytic hydrogenation-bromination sequence, to hexahydrolaurefucin in aqueous solvents. 5a We have been involved in development of an efficient synthetic method for generation of the pivotal dioxatricyclic oxonium core in 4 in view of its possible involvement in the biosynthesis of other natural products such as notoryne (5) 2b,5a and ocellenyne (6) 6 as well as laurefucin. As shown in Scheme 2, nucleophilic attack at C-7 in dioxatricyclic oxonium ion 4 by chloride would lead to notoryne, an adjacent bis-tetrahydro- furanoid marine natural product. Likewise, attack of bromide ion at C-13 would produce ocellenyne with a 2,5- dioxabicyclo[2.2.1]heptane skeleton. Described herein is a highly stereoselective, substrate-controlled asymmetric total synthesis of (-)-laurefucin (1), featuring a novel highly efficient † The Research Institute of Pharmaceutical Sciences, College of Pharmacy. ‡ Department of Chemistry, Seoul National University. § Center for Chemoinformatics Research, Korea Institute of Science and Technology. (1) Fukuzawa, A.; Kurosawa, E.; Irie, T. Tetrahedron Lett. 1972, 13,3. (2) (a) Wratten, S. J.; Faulkner, D. J. J. Org. Chem. 1977, 42, 3343. (b) Kikuchi, H.; Suzuki, T.; Kurosawa, E.; Suzuki, M. Bull. Chem. Soc. Jpn. 1991, 64, 1763. (c) Ko ¨nig, G. M.; Wright, A. D. J. Nat. Prod. 1994, 57, 477. (3) Furusaki, A.; Kurosawa, E.; Fukuzawa, A.; Irie, T. Tetrahedron Lett. 1973, 14, 4579. (4) Kaul, P. N.; Kulkarni, S. K.; Kurosawa, E. J. Pharm. Pharmacol. 1978, 30, 589. (5) (a) Fukuzawa, A.; Aye, M.; Nakamura, N.; Tamura, M.; Murai, A. Tetrahedron Lett. 1990, 31, 4895. (b) Fukuzawa, A.; Aye, M.; Takasugi, Y.; Nakamura, M.; Tamura, M.; Murai, A. Chem. Lett. 1994, 2307. (6) (a) Schulte, G. R.; Chung, M. C. H.; Scheuer, P. J. J. Org. Chem. 1981, 46, 3870. (b) The stereochemistry of the 12,13-dibromo moiety and of the side chains of the bicyclic system was not firmly established. Scheme 1. Proposed Biogenetic Pathway of (-)-Laurefucin (1) Published on Web 11/17/2008 10.1021/ja806304s CCC: $40.75  2008 American Chemical Society J. AM. CHEM. SOC. 2008, 130, 16807–16811 9 16807