Part A. Nickel-catalyzed asymmetric hydrovinylation and related reactions. Part B. Development of efficient cyclization methods

In part A, Ni(II)-catalyzed asymmetric hydrovinylation (HV) and related reactions are described. Hydrovinylation has been successfully developed to generate all-carbon chiral quaternary centers. Using this efficient method, neuro-active (-)-desoxyeseroline and related natural products such as non-substituted (-)-physostigmine and key intermediates for the synthesis of its derivatives have been synthesized. The first generation synthesis was initiated by applying linear beta-substituted styrenes with functional groups as hydrovinylation substrates. Substrates with a phthalimido functionality at the beta-position underwent hydrovinylation reactions successfully, but the enantioselectivities were only modest. The desired hydrovinylation product was converted into the known key intermediate for the target compounds. In order to improve the enantioselectivity and efficiency, cyclic vinylarenes were tested instead of initial linear derivatives. These compounds gave excellent enantioselectivities in the HV reaction. Using a ring expansion/contraction strategy, the formal synthesis of (-)-desoxyeseroline has been completed in excellent overall selectivities.;In a related objective in the development of the asymmetric HV reaction, the mechanism of Ni-phosphoramidite complex catalyzed reaction has been studied. The single crystals of (allyl)Ni(L1)Br (L 1 = phosphoramidite) complex were obtained, whose three-dimensional structure confirmed the square planar geometry of the Ni-complex and the binding mode of the phosphoramidite ligand. Moreover, induced atropisomerism of the racemic biaryl by the appended chiral amine was confirmed by the X-ray structure. 31P NMR studies using three (allyl)Ni(L)Br and corresponding BARF complexes provided the first evidence of the hemilabile coordination of a pendant phenyl-group in phosphoramidite ligands. In addition, matched/mismatched ligand effects for hydrovinylation to generate all-carbon chiral quaternary centers were studied.;Isomerization of terminal alkenes have been observed during hydrovinylation or cycloisomerization reactions of alpha,o-dienes. Based on this observation, a new Pd(II)- and Ni(II)-catalyzed isomerization of terminal alkenes has been developed. Modified conditions for the generation of metal-hydride complexes were applied for selective isomerizations of terminal alkenes. These conditions gave the desired isomerized products in excellent yields and selectivities. Compared with two representative methods reported recently using Ir- and Ru-catalysts, these reactions appear to be cleaner and more selective. The Pd(II)-catalysts can isomerize even geminal disubstituted alkenes in good yields. Such a reaction is currently not known.;In part B, new cyclization methods are described. Searching for a new method for the preparation of heterocyclic hydrovinylation substrates, seleniranium ion-triggered electrophilic cyclizations have been developed. Generated by AgSbF6 and PhSeBr, seleniranium ion-mediated cyclofunctionalizations give Friedel-Craft cyclization products in good to excellent yields even with substrates carrying non-activated aryl-groups. Detosylative and debenzylative cyclizations ensue when appropriate N-substituted derivatives are used.;In pursuit of a biomimetic total synthesis of 7-bromoindolactam V, a key intermediate for all-carbon quaternary center-containing lynbyatoxin A, an unexpected Cu-mediated tandem cyclization has been discovered. This procedure which uses CuI/CsOAc is quite mild compared to the more harsh Buchwald-Hartwig amination conditions for macrolactamizations. In a dipeptide substrate an unexpected tetracyclic 2,5-diketopiperazine was formed in a tandem reaction in good yields. Structure of the new compound was confirmed by X-ray crystallography. Mechanism of the tandem reaction was studied in simplified model compounds. The simplified compounds - acyclic benzolactam-V8 - were made by Rh-catalyzed asymmetric hydrogenation. These substrates were successfully applied to the Cu-mediated tandem cyclization to get tricyclic DKPs, rigid synthetic congeners of benzolactam-V8. Scholkopf reagent, which can be used to prepare unnatural aminoacids, was used as a chiral building-block for the synthesis of DKP-containing heterocycles.