Total Synthesis, Absolute Configurational Determination, and Antifouling Activity Evaluation of Cretenyne B

The relative configuration of the tetrahydrofuran moiety in cretenyne B (2) has been previously determined. However, the stereochemistries at the C6 and C13 side-chain positions of 2 remain unresolved. Herein, we report the absolute configuration of 2 using nuclear magnetic resonance (NMR) analysis and total synthesis, and the antifouling activity of two candidate diastereomers for 2. To predict the C6 stereochemistry of 2, the natural NMR data were compared with those of the C6 stereoisomers of cretenyne A (1), which we had previously synthesized. This analysis suggested two candidate compounds from four possible diastereomers. We then conducted total synthesis of candidate compounds 2a and 2b. Enone 31 was synthesized using 5-exo-tet-cyclization, cis-selective olefinations, and stereoselective chlorination as key transformations. Luche reduction of 31 served as the branching step at the late-stage of synthesis to yield 2a and 2b. Comparison of their data with those of the natural product revealed natural (-)-cretenyne B as the enantiomer of 2a. We expect 2a and 2b and their synthetic intermediates to be used in the total synthesis of cretenynes C-E (3-5). We also found 2a and 2b to be antifouling-active and nontoxic toward the cypris larvae of the barnacle Amphibalanus amphitrite.