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.

Chiral amines are ubiquitous in natural products and are found in many drugs and drug candidates. Enantiopure sulfinimines [RS(O)N=CHR1] are useful chiral building blocks for the stereoselective synthesis of amines and amine derivatives. The aim of this thesis research is to develop new methods to access chiral amine building blocks for applications in the synthesis of nitrogen-heterocycles including ring-substituted tropinones, tropanes, cyclic cis-beta-amino acid derivatives, and amino-cyclopentitols.

Chemistry

After the overwhelming success of Asymmetric Synthesis - The Essentials, displaying a broad range of organic asymmetric syntheses, this is the second edition with latest subjects and authors. While the aim of the first edition was mainly to honor the achievements of the pioneers in asymmetric syntheses, the aim of this new edition was bringing the current developments, especially from younger colleagues, to the attention of students. The format of the book remained unchanged, i.e. short conceptual overviews by young leaders in their field including a short biography of the authors. The growing multidisciplinary research within chemistry is reflected in the selection of topics including metal catalysis, organocatalysis, physical organic chemistry, analytical chemistry, and its applications in total synthesis, materials research and industry. The prospective reader of this book is a graduate or undergraduate student of advanced organic chemistry as well as the industrial chemist who wants to get a brief update on the current developments in the field.