Development of metal-catalyzed asymmetric allylic alkylations for the total synthesis of alkaloids and other nitrogen containing biologically active targets [electronic resource]

This dissertation deals with the development of metal-catalyzed asymmetric allylic alklyations, and their use for the synthesis of alkaloids and other nitrogen-containing biologically active compounds. The synthesis of the drug (--)-ranirestat is disclosed, which relies on a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) as a key step. The development and application of pyrroles and indoles as nucleophiles in the Pd-AAA is described. A Pd-catalyzed decarboxylative asymmetric alkylation approach to constructing vicinal all-carbon quaternary stereocenters is disclosed, and this methodology is used to complete the formal synthesis of several cyclotryptamine alkaloids. Finally, a catalytic asymmetric total synthesis of the alkaloid (--)-perophoramidine and efforts towards the alkaloid communesin B are described. Both syntheses employ a molybdenum-catalyzed asymmetric allylic alkylation as a key asymmetric step. (--)-Ranirestat is a potent aldose reductase inhibitor currently in phase III clinical testing for its ability to treat diabetic neuropathy. We have developed a concise, catalytic asymmetric total synthesis of (--)-ranirestat, which was completed in 8 steps and 14% overall yield starting from inexpensive, commercially available 2-(trichloroacetyl)pyrrole. A palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) of an imidomalonate and an allylic carbonate serve as a key transformation to construct the tetrasubstituted stereocenter in the target with high yield and enantioselectivity. Protiodesilylation followed by oxidative cleavage of the allyl moiety and cyclization are used to access (--)-ranirestat. Nitrogen heterocycles are found in a variety of natural products and other biologically active compounds. We have demonstrated that pyrroles and indoles bearing electron-withdrawing groups are competent nucleophiles in the Pd-AAA with vinyl aziridines. The resulting alkylated products were obtained with high levels of regio-, chemo-, and enantioselectivity. Both substituted 1H-pyrroles and 1H-indoles were successfully employed to give exclusively the branched N-alkylated products. The synthetic utility of this asymmetric process was demonstrated through the elaboration of pyrrole products into bromopyrrole alkaloids longamide B, longamide B methyl ester, hanishin, agesamides A and B, and cyclooroidin. Likewise, the synthetic utility of the indole products was demonstrated by elaboration into several patented piperazinones and piperazine medicinal chemistry lead compounds. 1H-Pyrroles have also shown to serve as nucleophiles with meso electrophiles in the Pd-AAA. The products from this transformation were obtained as a single regio- and diastereomer in high yield and % ee. To demonstrate synthetic utility, a pyrrole-substituted nucleoside analogue was synthesized employing this methodology as the asymmetric step. Quaternary all-carbon stereocenters are present in many natural products and biologically active compounds. The presence of this structural element greatly complicates the asymmetric assembly of molecules due to steric congestion. The asymmetric assembly is complicated further when a second vicinal, quaternary center is present in a molecular target. We have discovered that a two-fold Pd-DAAA of an oxindole-derived dienol carbonate can be used to construct two vicinal all carbon quaternary stereocenters in a diastereo- and enantioselective fashion. To demonstrate the synthetic utility of this process, the product of this transformation was used to complete the formal syntheses of the cyclotryptamine alkaloids (--)-chimonanthine, (+)-calycanthine (--)-folicanthine, and ditryptophenaline. Mechanistic investigations have suggested that the two-fold Pd-catalyzed transformation proceeds through an unusual matched and mismatched allylation to deliver the desired product. Perophoramidine was isolated from the ascidian organism Perophora namei and displays cytotoxicity toward the HCT116 colon carcinoma cell line with an IC50 of 60 µM. The complex polycyclic cage-like core of this alkaloid makes it a challenging and interesting target for total synthesis. A catalytic asymmetric total synthesis of (--)-perophoramidine was developed employing a molybdenum-catalyzed asymmetric allylic alkylation between an allylic phosphate and an alkyl oxindole as an asymmetric step. This key transformation provides a chiral oxindole product in high yield and with high levels of regio-, diastereo-, and enantioselectivity. The chiral oxindole product, which contains the key quaternary stereocenter present in perophoramidine, was further elaborated to a pentacyclic imino ether using a reductive cyclization, oxidative cleavage and lactamization as key transformations. The imino ether was alkylated with allyl iodide to construct the second vicinal quaternary stereocenter providing an allyl imino ether as a single regio- and diastereomer. The allyl imino ether was converted to an aldehyde via ozonolysis, which was subjected to a reductive amination and cyclization sequence to complete (--)-perophoramidine.

Keywords: Chemistry.
Advisor: Trost Barry M. primary advisor. Thesis advisor
Du Bois Justin advisor. Thesis advisor
Wender Paul A. advisor. Thesis advisor