The Development and Application of Phosphine-Catalyzed Annulation Reactions: Synthetic Studies on the Total Synthesis of (+/-)-Reserpine and Studies Concerning Torquoselectivity

A mixed double-Michael addition onto electron deficient acetylenes was developed. The reaction allows for the facile preparation of optically active oxazolidines, thiazolidines, and pyrrolidines from amino acid-derived pronucleophiles. Optimal reaction efficiencies were obtained by employing bis(diphenylphosphino)propane as catalyst which suggests a reaction mechanism involving anchimeric stabilization of the phosphonium intermediate.;Several highly functionalized scaffolds en route to the synthesis of (+/-)-reserpine were prepared. Synthesis of the D-ring was achieved by virtue of a phosphine-catalyzed [4+2] annulation setting the C3 stereocenter. The first generation route employed a torquoselective 6pi electrocyclization for the remote transfer of stereochemical information from C3 to C18. Elaboration of the remaining E-ring stereochemistry was carried out in a completely diastereoselective fashion. Other key features of the first generation synthesis includes the development and application of a low temperature dibromo ketene acetal Claisen rearrangement and a tandem cross-coupling/6pi electrocyclization cascade of 2,2-dimethyldioxole. A second generation approach involved the construction of the E-ring through a torquoselective 6pi electrocyclization of a different triene scaffold and the installation of the C15 and C16 stereocenters. A copper-mediated Stille reaction allowed for the preparation of four distinct second generation triene scaffolds which underwent thermal torquoselective 6pi electrocyclization reactions.;Inspired by the high levels of stereocontrol in the torquoselective 6pi electrocyclization reaction, an effort to assess the stereocontrolling elements in these reactions was undertaken. A series of tetrahydroisoquinoline-derived model triene scaffolds were prepared through the application of a carbopalladation/Suzuki cross-coupling cascade. By varying the substitution at the 3-position of the trienes, it has been demonstrated that allylic strain is a source of torquocontrol in the 6pi electrocyclization of all-carbon hexatrienes. These results are supported by computational data that correlates with the experimental results...