| Abstract
| - The synthesis of the C18−C31 subunit of orevactaene (1) in an enantioselective and convergentmanner is reported. Four chiral centers in the structure (i.e., carbons 23, 25, 32, and 33) haveunknown configuration; thus, a modular approach has been devised to link the two stereocenter-containing ends of the structure together via a trisubstituted olefin template to ultimately produceall possible diastereomers of the target. Keys to the success of this approach include (i) an efficientsynthesis of four diastereomeric hydrophobic tails (C22−C29) of the molecule with two stereogeniccenters at C23 and C25; (ii) the synthesis of three stereodefined trisubstituted olefins 37, 38, and43 using palladium(0)-catalyzed hydrometalation and metallometalation; and (iii) the convergentassembly of the aforementioned sections by a ‘one-pot' lithium/halogen exchange, boron/lithiumexchange, borate ester saponification, and Suzuki cross-coupling followed by oxidative deprotection.The sequence provided the desired aldehydes 49 and 50 as single isomers in good yields. Compiledspectroscopic data from the literature and present work provides evidence that the relativeconfiguration of the methyl groups in the side chain of orevactaene may be 1,3-syn, which will beconfirmed when the total synthesis has been completed. These results have paved the way for aparallel synthesis approach to prepare all 16 possible stereoisomers of orevactaene so that therelative and absolute stereochemistry of this compound can be determined.
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