| Several new aspects of the palladium catalyzed asymmetric allylic alkylation (AAA) were explored. A simple improvement to the palladium catalyzed desymmetrization of meso-biscarbamates using cyclohexanediamine-derived chiral ligand 1.1 was discovered. Addition of one equivalent of triethylamine improved the enantiomeric excess in all cases examined to greater than 94%. The desymmetrization of anthracene derived meso-biscarbamate 1.40 was used as the key step in an efficient asymmetric synthesis of the anticancer compound (-)-swainsonine. Following the desymmetrization, the final two chiral centers of swainsonine were set by a diastereoselective dihydroxylation. Protection of the diol and unmasking of the protected double bond afforded the useful chiral cyclohexene building block 1.44 which was taken on to aldehyde 1.52 in four steps. The natural product was synthesized in five steps from 1.52 involving a Homer-Wadsworth-Emmons two-carbon homologation followed by lactamization to close the piperidine ring. Overall, (-)-swainsonine was synthesized in 15 steps and 15% overall yield from achiral diol 1.22.; The AAA of conduritol B tetracarboxylates was also examined. A dynamic kinetic asymmetric transformation (DYKAT) of tetracarbonate 4.10 was developed for carbon, nitrogen and oxygen nucleophiles. In general, mono-addition was observed for carbon and most nitrogen nuclophiles, while di-addition was observed for oxygen nucleophiles. In most cases high (>90%) enantioselectivity was observed. The utility of this methodology for the synthesis of biologically relevant cyclitol natural products was illustrated in very efficient five-step asymmetric syntheses of D-myo-inositol 1,4,5-trisphosphate and (-)-cyclophellitol from racemic tetracarbonate 4.10.; Generation of a new chiral center at the nucleophile in the palladium catalyzed AAA reaction was also studied. Good selectivities were generally observed for a range of prochiral six-membered beta-ketoester nucleophiles, but moderate to low selectivities were seen when other ring sizes or non-beta-ketoester soft nucleophiles were used. Finally, conditions were developed to successfully monoallylate simple ketone enolates (i.e. alpha-tetralone) via the corresponding tin enolate, albeit with moderate levels of enantioselectivity (40--50%). |
