This thesis focuses on methodology development using N-sulfinyl metallodienamines and metalloenamines derived from Davis-Ellman N-sulfinyl imines. The application of these methodologies toward the total syntheses of (+)-epiibogamine and (+)-chimonanthine is described. The vinylogous aldol reaction of N-sulfinyl metallodienamines was first reported in 2017 in the total synthesis of (−)-albocycline. However, the diastereoselectivity of this reaction was found to be incorrectly reported. Mosher ester analysis and HPLC analysis with a chiral column were employed to determine the dr. The vinylogous aldol reaction was optimized. Studies on the mechanisms affecting stereoselectivity revealed that stereochemical erosion occurred using SnCl4 combined with LiHMDS, but not with NaHMDS or KHMDS. A (Z)-metallodienamine with metal chelated transition state was proposed and supported by DFT calculations to rationalize the stereochemical course of the reaction. Iboga alkaloids have been historically used for anti-addictive properties and recently brought more attention as potential drug candidates for neurological disorders. However, the complex isoquinuclidine fused azapine scaffold of Iboga alkaloids are challenging to synthesize. To construct the key chiral 2-aminocyclohexene intermediate and isoquinuclidine ring more efficiently, three new methods were explored. These included the domino-Michael/Mannich annulation of N-sulfinyl metallodienamines, the Diels-Alder reaction of N-sulfinyl imines, and the three-component domino-Michael/Michael/Mannich (DM3) annulation of N-sulfinyl metalloenamines. The DM3 reaction provided the 1-amino-2,4-diester scaffold to access isoquinuclidine in high yield (84−94%) and excellent diastereoselectivity (up to >95:5 dr). Chiral N-sulfinyl silylenamines, were introduced to serve as a surrogate for poorly reacting N-sulfinyl aldimines in the DM3 reaction. This silyl-modified DM3 reaction enabled the shortest asymmetric total synthesis of (+)-epiibogamine in 7 steps. This isoquinuclidine intermediate would also provide access to (+)-dihydrocatharanthine and other Iboga alkaloids in future studies. Oxidative enolate coupling, via radical intermediates, was used to construct 1,4-dicarbonyl scaffold from the reaction between two enolate nucleophiles. An oxidative coupling of N-sulfinyl metalloenamines was discovered having the ability to construct vicinal quaternary stereocenters in high diastereoselectivity (16:1 dr). To showcase this new methodology, the synthesis of dimeric indole alkaloids, (+)-chimonanthine, was investigated. A new class of compounds, bis N-sulfinyl amidines, were prepared as the potential oxidative coupling monomers for the synthesis of (+)-chimonanthine in future studies.

The objective of this research was to development new methodologies for the asymmetric syntheses of amine and natural products from enantiopure sulfinimines (N-sulfinyl imines). In this context, new methods was devised for the asymmetric synthesis of 2,5-cis and trans-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates, prepared by an intramolecular metal carbenoid N-H insertion from a sulfinimine derived delta-amino-alpha-diazo- beta-ketophosphonate. Horner-Wadsworth-Emmos reaction of the 3-oxo pyrrolidine 2-phosphonates and aldehydes provided pyrrolidine enones. Hydrogenation (Pd/H2) of the pyrrolidine enones gave cis-2,5-disubstituted pyrrolidines. Luche reduction the pyrrolidine enones followed by a TFA-NaBH3CN mediated hydroxy directed reduction provided the 2,5-trans products. (+)-Preussin, a potent antiviral and antitumor agent was prepared in 9 steps in 28% overall yield from the sulfinimine. An acid catalyzed intramolecular Mannich cyclization of a sulfinimine-derived N-sulfinyl syn-alpha-methyl-beta-amino ketones was employed for the asymmetric synthesis of 2,3,5,6-tetrasubstituted piperidinones. The beta-amino ketones were prepare by treatment of prochiral lithium Weinreb amide enolates with enantiopure (E)-N-(4-(benzyloxy)butylidene)-2,4,6-triisopropylbenzenesulfinamide. This new methodology was highlighted in the first asymmetric synthesis of the poison frog alkaloid (-)-indolizidine 221T. By manipulation of water concentration in tetrahydrofuran, syn- and anti-2,3-diamino esters were prepared by treatment of the lithium enolate of N-(diphenylmethylene) glycine ethyl ester with sulfinimines. Anhydrous THF afforded enantiopure syn-2,3-diamino esters with a syn/anti selectivity of better than 25:1. In a THF-H2O the anti-2,3-diamino esters were formed. The mechanism involves the generation of H2O-LDA species in the formation of enolate which inhibited the retro-Mannich fragmentation in the diamino ester species. (SR,2S,3R)-(-)-Ethyl-2-(N,N-dibenzylamino)-3-N-(p-toluenesulfinyl)amino-pent-4-enoate was employed in an improved total synthesis of the anti-tumor antibiotic (-)-agelastatin A. A series of N-sulfinyl aza-Morita-Baylis-Hillman products were prepared by addition of vinylaluminum and N-methylmorpholine-N-oxide reagents to enantiopure N-(p-toluenesufinyl)- and N-(2-methypropanesulfinyl)-derived sulfinimines from the least hindered direction via a non-chelation control mechanism. Hydrogenation of the these acrylates with a rhodium(I) catalyst afforded anti-alpha-substituted-beta-amino esters with a anti/syn selectivity of better than 17:1. This new methodology is useful for the asymmetric synthesis of anti-alpha-alkyl-beta-amino esters, which are valuable chiral building blocks for the preparation of biologically active nitrogen-containing natural products.

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