Stereoselective Total Synthesis of (+)‐Giganin and Its C10 Epimer by Using Late‐Stage Lithiation–Borylation Methodology

biological activities but in particular are highly active anticancer agents. These compounds are potent inhibitors of adenosine triphosphate (ATP) production and consequently deprive the cell of energy leading to cell death. As cancer cells have a high energy demand owing to rapid multiplication, this action renders the annonaceous acetogenins selective inhibitors of cancer cell growth. Of particular interest is that the annonaceous acetogenins show potential for the treatment of multidrug resistant cancer cells as these have an even higher requirement for ATP than the parental wild-type. Giganin, in particular, exhibits good cytotoxicity to human lung carcinoma, human breast carcinoma, and human colon adenocarcinoma in preliminary tests, thus making it an especially important target for total synthesis. Several members of the annonaceous acetogenins have previously been synthesized (of particular relevance are the syntheses of annonacin, pyranicin, and pyragonicin) but giganin itself has not. A common strategy towards this family of molecules has been to first add a functional group (an alkene) somewhere between the remote hydroxy groups and then to use it to aid disconnection. However, this is wasteful as the functional group has to be introduced and then removed at the end. An alternative approach would be to disconnect the molecule directly at a secondary alcohol as this would not only enable C C bond formation but also potentially control stereochemistry in the process. Herein, we report the application of our lithiation–borylation methodology to a highly convergent and stereoselective synthesis of giganin and demonstrate facile access to other stereoisomers. Recently, we reported the synthesis of enantioenriched secondary alcohols through a lithiation–borylation reaction. The method involved the reaction of an a-lithiated carbamate, generated by stereoselective deprotonation in the presence of ( )-sparteine, with a borane or boronic ester thus forming a boron ate complex with retention of stereochemistry. The boron ate complex then underwent a 1,2metallate rearrangement with migration of the R group and expulsion of the carbamate leaving group, resulting in a secondary boronic ester. Oxidation led to secondary alcohols in very high enantiomeric ratios (Scheme 2). Exchanging the diamine ligand for (+)-sparteine surrogate enables access to the opposite enantiomer of secondary alcohol from the same starting materials. The methodology is particularly good for generating secondary alcohols flanked by similar side chains, as present in giganin, which are difficult to synthesize by other methods (e.g. stereoselective reduction). Scheme 1. Annonaceous acetogenins.