Chiral piperidine and pyrrolidine containing pharmaceuticals have a range of biological functions including antihypertensives, HIV protease inhibitors, antidepressants, antihistamines, and anesthetics. The wide-ranging biological activity of N-heterocycles suggests that future drug targets will also feature these functional groups. The hydroamination reaction, the formal addition of an N-H bond across a C=C or C≡C bond, is an attractive method for the synthesis of these molecules as the reaction has 100% atom economy. However, the best current catalysts for asymmetric hydroamination of aminoallenes use precious metals such as gold or rhodium, and use highly engineered chiral ligands such as substituted BINAP derivatives. There has been a resurgence of interest in early metal catalysis, especially titanium, for carrying out asymmetric catalysis, though our group has been studying titanium and tantalum hydroamination for more than 15 years. We have recently revisited a project that uses chiral sulfonamide complexes for asymmetric hydroamination. Chiral, sterically bulky sulfonamide alcohols were prepared in a two- to three-step procedure from chiral pool amino acids. Their respective titanium and tantalum complexes were synthesized by protonolysis reactions starting from Ti(NMe2)4, TiCl(NMe2)3, or Ta(NMe2)5. The complexes were studied as catalysts for the asymmetric intramolecular hydroamination of aminoallenes. The regio- and stereoselectivity of the reactions were determined by 1H NMR spectroscopy and chiral GC-MS. The sulfonamide complexes give pyrrolidine products with enantioselectivities up to 25 %ee using titanium and 48 %ee using tantalum. These are the most selective titanium catalyzed aminoallene hydroamination reactions that have been reported to date.

Substituted sulfonamide alcohols as ligands for titanium and tantalum catalyzed asymmetric aminoallene hydroamination

2019 Spring National Meeting

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