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

  • Author(s): Barcan, Gregg
  • Advisor(s): Kwon, Ohyun
  • et al.
Abstract

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 6π 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

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