UVM Theses and Dissertations
Format:
Print
Author:
Ding, Hui
Title:
Dept./Program:
Chemistry
Year:
2005
Degree:
PhD
Abstract:
Chiral a-branched amines are ubiquitous components in numerous natural products, synthetic medicinal molecules, and chiral ligands for asymmetric synthesis. Developing effective protocols for asymmetric amine synthesis is an important area to investigate. Additions to C=N bond of imino compounds provide direct access to chiral a-branched amines. Our efforts have been focusing on asymmetric allylation, Strecker-type cyanation, and Cu(I)-mediated radical additions to N-acylhydrazones which are easy-to-form, air-stable, crystalline surrogates for imines. We first developed highly stereos elective allylsilane addition to enantiopure N-acylhydrazones derived from (S)-4-benzyl-2-oxazolindinone, with dual activation by fluoride and In(OTf)₃. Key design elements in this new acyclic stereocontrol mode include Lewis acid activation of the C=N bond of hydrazone and restriction of rotamer populations by two-point binding, which allows effective shielding of the Re face. Subsequent removal of the auxiliary generates enantiopure homoallylic amines protected by trifluoroacetyl (TFA). This has been achieved via TFA-activated nitrogen-nitrogen bond cleavage of hydrazines by samarium(II) iodide. Trifluoroacetyl derivatives of hydrazines undergo clean and efficient reductive cleavage of N-N bond with SmI2 in the presence of MeOH, with excellent yields for a wide range of hydrazines. These conditions accommodate alkene functionality, avoid racemization, and furnish chiral amines bearing a readily removable TFA protecting group.
Finally, application of the asymmetric allylsilane addition has been demonstrated in the study toward total synthesis of lasubine II. Two different routes starting from a homoallylic amine have been taken. The first one emphasizes the construction of the quinolizidine skeleton by Mannich cyclization and the second uses ring closing metathesis (RCM) as the key step. The formation of a stable enone seriously impedes the desired Mannich cyclization under various conditions. The second route was executed successfully to build the quinolizidine skeleton of lasubine II, by N-alkylation, intramolecular allylic amination and RCM reaction, in order. The final elaboration of the internal alkene group to a hydroxyl group in lasubine II was unsuccessful.
Finally, application of the asymmetric allylsilane addition has been demonstrated in the study toward total synthesis of lasubine II. Two different routes starting from a homoallylic amine have been taken. The first one emphasizes the construction of the quinolizidine skeleton by Mannich cyclization and the second uses ring closing metathesis (RCM) as the key step. The formation of a stable enone seriously impedes the desired Mannich cyclization under various conditions. The second route was executed successfully to build the quinolizidine skeleton of lasubine II, by N-alkylation, intramolecular allylic amination and RCM reaction, in order. The final elaboration of the internal alkene group to a hydroxyl group in lasubine II was unsuccessful.