The objective of this research was the development of new methods for the asymmetric synthesis of nitrogen containing compounds. As one part of this goal, 3,4-dihydroxyprolines and their derivatives were prepared from sulfinimines (N-sulfinyl imines). During this project new methods were developed for asymmetric hydroxylation and decarboxylation of 3-oxo-2-carboxylate pyrroldines. The application of this new methodology was realized by the total synthesis of the α- and β-glycosidases inhibitor (+)-lentginosine. It was also found that electrophiles regioselectively add to the 4-position of 3-oxo-2-carboxylate-5-substituted pyrrolidines. The addition is accomplished through lithium diisopropyl amide generation of the pyrrolidine dianion. This addition was also compatible with 3-oxo-2-phosophono-5-substituted pyrroldines. Furthermore air oxidation of these pyrrolidines give the corresponding pyrroles. This procedure represents the first general preparation procedure for 2-phonopyrroles, which have been examined as HIV protease inhibitors. A range of β-amino carbonyl compounds were prepared from N-sulfinyl β-amino Weinreb amides in a concise and efficient procedure. A general method for the preparation of a variety of β-amino carbonyl compounds arose from the addition of an assortment of organometallic reagents to the Weinreb amides. The N-sulfinl β-amino Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy-N-methylacetamide with sulfinimines or lithium N,O-dimethylhydroxylamine with N-sulfinyl β-amino esters. / Chemistry

The development of new methodologies for the asymmetric synthesis of homotropinone and tropane alkaloids using enantiopure sulfinimines [RS(O)N=CR1R²] is the primary objective of this thesis. In one study a four-step intramolecular Mannich cyclization cascade reaction was devised for the asymmetric synthesis of substituted homotropinone alkaloids from enantiopure sulfinimine-derived N-sulfinyl ß-amino ketone ketals. These amino ketone ketal chiral building blocks were prepared in 67-71% yields and high dr (25-14:1) by addition of the Weinreb amide enolate of N-methoxy-Nmethylacetamide to masked oxo sulfinimines (N-sulfinyl imines). Treatment of these Weinreb amides with Grignard reagents gave the N-sulfinyl ß-amino ketone ketals in 93- 95% yields without epimerization. Heating the acyclic ß-amino ketone ketals with the buffer solution NH4OAc:HOAc resulted in a one-pot 4 step intramolecular Mannich cyclization cascade reaction to give substituted homotropinones including (–)- euphococcinine and (–)-adaline in 82-90% yields. In another study a sulfinimine-derived α,ß-unsaturated pyrrolidine nitrone was utilized in the development of a Lewis acid catalyzed [3+2] nitrone cycloaddition reaction for the asymmetric synthesis of the tropane alkaloid (+)-cocaine. The masked oxo sulfinimine was treated with an excess of the sodium enolate of methyl acetate to give N-sulfinyl ß-amino ester in 87% yield and high dr (97:3). Reduction of the ester to aldehyde followed by a Horner-Wadsworth-Emmons olefination reaction afforded the α,ß-unsaturated N-sulfinyl amino acetal. Hydrolysis of the unsaturated amino acetal gave a pyrrolidine, which was selectively oxidized to the pyrrolidine nitrone. The nitrone on heating with the Lewis acid Al(O-t-Bu)3 for 96 h underwent an intramolecular [3+2] cycloaddition to give a tricyclic isoxazolidine, which was transformed into (+)-cocaine in three steps 25% overall yield. This 9 step, 25% overall yield synthesis of (S)-(+)-cocaine from the masked oxo sulfinimine is the most efficient enantioselective route to cocaine from acyclic starting materials. This new methodology is adaptable to the preparation of various cocaine analogs including the first cocaine C-1 analogs. In other studies conformationally constrained novel pyrrolidine analogs (methanopyrrolidines) were synthesized stereoselectively to study the substituent (H, OH, or F) effect on amide conformational preferences. A nucleophilic displacement synthetic route was devised to prepare highly functionalized 5(6)-anti-substituted-methanopyrrolidines from N-benzyl-2-azabicyclo[2.1.1]hexylbromide(s) intermediates with the aid of neighboring group participation. These methanopyrrolidines were then transformed to constrained proline analogs (methanoprolines) to evaluate the impact of proline ring pucker on amide conformations. An α-methoxycarbonyl group was introduced in methanopyrrolidines by treating tert-butoxycarbonyl protected methanopyrrolidines with s-BuLi and quenching with various electrophiles such as CO2, DMF or ClCO2Me. Amide trans-cis conformational preferences (Ktrans/cis) of N-acetyl-methanopyrrolidines and N-acetyl-methanoprolines were determined in various solvents such as CDCl3 and D2O using NMR techniques, including NOE. The small trans amide preference for substituted fluoro- and hydroxy-methanopyrrolidines shows that it is the interaction of the !-methyl ester group and the amide moiety of the methanoprolines that plays a major role in determining amide conformational preferences. The gamma-substituent effect is primarily related to ring pucker and a resultant enhancement of the interaction between the amide carbonyl oxygen and ester carbonyl carbon. The results are relevant to the conformational stability of collagen and protein engineering. / Chemistry

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. / Chemistry

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

Η Ecteinascidin 743 είναι ένα σπουδαίο αντικαρκινικό φάρμακο, που καταστρέφει μέσω αλκυλίωσης τα καρκινικά κυττάρα και είναι εμπορικά διαθέσιμο με το όνομα Yondelis. Χρησιμοποιείται στην Ευρώπη, τη Ρωσία και τη Νότια Κορέα για τη θεραπεία του σαρκώματος του μαλακού ιστού, δηλαδή καρκίνου των ιστών που υποστηρίζουν το σώμα, όπως οι μύες, τα αιμοφόρα αγγεία και άλλα είδη ιστών που υποστηρίζουν και προστατεύουν τα όργανα του σώματος. Η Ecteinascidin 743 βρίσκεται υπό κλινικές δοκιμές για τη θεραπεία και άλλων μορφών καρκίνου, όπως του καρκίνου του μαστού, του προστάτη, των ωοθηκών, των νεφρών, των πνευμόνων και του μελανώματος. Απομονώθηκε από το μικρό θαλάσσιο οργανισμό, Ecteinascidia turbinate, που ζει στις θάλασσες της Καραϊβικής και ανακαλύφθηκε ότι έχει αντικαρκινική δράση το 1969. Αυτό το φυσικό προϊόν αποτέλεσε πηγή έμπνευσης για την παρούσα ερευνητική εργασία, όπου στην ρετροσυνθετική του πορεία (Εικόνα 3) περιλαμβάνεται η σύνθεση ενός μορίου πιπεραζίνης, καθώς και ενός β-λακταμικού δακτυλίου. Οι β-λακτάμες χρησιμοποιούνται σήμερα ως βακτηριοκτόνα, αντιβιοτικά, αναστολείς των πρωτεασών σερίνης και αναστολείς της ακυλομεταφεράσης της χοληστερολης (acyl-CoA: cholesterol acyltransferase, ACAT), η οποία είναι υπεύθυνη κυρίως για την αθηροσκληρωτική στεφανιαία καρδιακή νόσο. Η ασθένεια αυτή αποτελεί ήδη την πιο κοινή μορφή ασθένειας που προσβάλλει την καρδιά και μία σημαντική αιτία πρόωρου θανάτου στην Ευρώπη, σε κράτη της Βαλτικής, τη Ρωσία, τη Βόρεια και Νότια Αμερική, την Αυστραλία και τη Νέα Ζηλανδία. Η αθηροσκλήρωση σχετίζεται με την στεφανιαία καρδιακή νόσο, η οποία αποδίδεται στην ανικανότητα της στεφανιαίας κυκλοφορίας να τροφοδοτεί με επαρκές αίμα το μυ της καρδιάς και τους περιβάλλοντες ιστούς. Οι παράγοντες που οδηγούν στην αθηροσκλήρωση είναι τα υψηλά επίπεδα χοληστερόλης, η υπέρταση, ο διαβήτης, το κάπνισμα, οι κακές διατροφικές συνήθειες, η παχυσαρκία και η έλλειψη σωματικής άσκησης. Οι παραπάνω δράσεις των β-λακταμών έχουν καταστήσει πολύ ενδιαφέρουσα τη στερεοεκλεκτική και εναντιοεκλεκτική σύνθεση αυτών. Ένας β-λακταμικός δακτύλιος είναι μία λακτάμη με δομή ετεροατομικού τετραμελούς δακτυλίου, που αποτελείται από τρία άτομα άνθρακα και ένα άτομο αζώτου. Ο β-λακταμικός δακτύλιος είναι μέρος της δομής μερικών κατηγοριών β- λακταμικών αντιβιοτικών, όπως οι πενικιλίνες, οι κεφαλοσπορίνες, οι κεφαμυκίνες, οι καρβαπενέμες, οι μονοβακτάμες, και οι τρινέμες. Οι ενώσεις των β-λακταμών παρασκευάστηκαν σύμφωνα με την Mannich αντίδραση μέσω σουλφινιμινών. Οι πιπεραζίνες χρησιμοποιούνται σήμερα ως μυκητοκτόνα, αγχολυτικά, αντιικά, και ανταγωνιστές του υποδοχέα της σεροτονίνης (5-HT). Η τελευταία θεραπευτική ικανότητα των πιπεραζινών είναι πλέον ένα θέμα εκτενούς επιστημονικής έρευνας και περιλαμβάνει υποδοχείς-στόχους που ανήκουν στην κατηγορία των υποδοχέων συζευγμένων με G-πρωτεΐνη (G-ptotein-coupled receptors, GPCRs). Η εκλεκτικότητα των πιπεραζινών για τις GPCRs εμφανίζεται εξαιτίας της βασικότητας. Αυξάνοντας το μέγεθος του όρθο υποκαταστάτη σε Ν-άρυλο πιπεραζίνες, αυξάνεται η ικανότητα πρόσδεσής τους και η λειτουργική τους δραστικότητα. Οι πιπεραζίνες είναι οργανικές ενώσεις, που αποτελούνται από έναν εξαμελή δακτύλιο, ο οποίος περιέχει δύο άτομα αζώτου, που βρίσκονται στις θέσεις 1 και 4 του δακτυλίου. Οι ενώσεις των πιπεραζινών παρασκευάστηκαν σύμφωνα με την Diels-Alder αντίδραση μέσω σουλφινιμινών. Οι σουλφινιμίνες αποτέλεσαν το μόριο-κλειδί για την σύνθεση όλων των τελικών επιθυμητών προϊόντων και είναι γνωστές ως πολύ καλοί πρόδρομοι αμινών, όταν αντιδράσουν με οργανομεταλλικές ενώσεις [RLi, RMgX (αντιδραστήρια οργανολιθίου, αντιδραστήρια Grignard)]. Οι οπτικώς καθαρές σουλφινιμίνες είναι σημαντικές δομικές μονάδες (building blocks) στην ασύμμετρη σύνθεση άμινο παραγώγων, και παρασκευάζονται σε πολύ καλές αποδόσεις μέσω ενός σταδίου από αρωματικές, ετεροαρωματικές και αλιφατικές αλδεΰδες. Στην παρούσα ερευνητική μελέτη συντέθηκαν νέες β-λακταμικές ενώσεις και υποκατεστημένες ενώσεις πιπεραζίνης, συμπληρώνοντας έτσι και ενισχύοντας τα ήδη υπάρχοντα δεδομένα για τις συγκεκριμένες κατηγορίες ενώσεων αφενός και, αφετέρου, παρέχοντας νέα δεδομένα για την ολική σύνθεση του φυσικού προϊόντος, Ecteinascidin 743 (σύνθεση των εξαμελών αζόξυ προϊόντων 18, 19 και 20). Η ρετροσυνθετική ανάλυση της Ecteinascidin 743, που περιγράφηκε αρχικά, δύναται να εφαρμοστεί, σύμφωνα με τα αποτελέσματα της παρούσας ερευνητικής εργασίας. / Ecteinascidin 743 is an important antitumor drug that can service a novel way of killing cancer cells, and it is sold under the brand name Yondelis. It has been approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma, cancers of the supporting tissues of the body, such as muscles, fat, blood vessels or in any other tissues that support, surround and protect the organs of the body. Ecteinascidin 743 is undergoing clinical trials for the treatment of breast, prostate, ovarian, renal, lung, and melanoma cancers. It is isolated from the Caribbean tunicate Ecteinascidia turbinate, and was found to have anticancer activity in 1969. We were inpired by this natural product and as we can observe from its retrosynthetic analysis (Scheme 3), the synthesis of a piperazine molecule and a β-lactam ring are involved. The extreme importance of β-lactams serving not only as bactericidal and as key structural units of several important antibiotics, but also as mechanism-based inhibitors of serine proteases and as inhibitors of acyl-CoA cholesterol acyltransferase (ACAT), which is mainly responsible for atherosclerotic coronary heart disease. Coronary heart disease is already the most common form of disease affecting the heart and is an important cause of premature death in Europe, the Baltic states, Russia, North and South America, Australia and New Zealand. Atherosclerosis is most commonly equated with atherosclerotic coronary artery disease, which is rendered in the failure of the artery circulation to supply with sufficient blood the heart muscle and the surrounding tissues. Risk factors for the coronary heart disease include high levels of cholesterol, hypertension, diabetes, smoking, bad diet habbits, obesity, and lack of excercise. The above activities of β-lactams have propelled strong resurgent interest toward their stereoselective and enantioselective synthesis. A β-lactam ring is a lactam with a heteroatomic four-membered ring structure, consisting of three carbon atoms and one nitrogen atom. Penicillins, cephalosporins, cephamycins, carbapenems, monobactams, and trinems are classified as b-lactam antibiotics. β-Lactams were prepared by the Mannich reaction using sulfinimines. Piperazines are used now-a-days as antifungals,antidepressants, antiviral, and serotonin receptor antagonists (5-HT). The latter therapeutic area of piperazines has been the subject of intense research and includes targets belonging to the G-Protein- Coupled Receptor (GPCR) superfamily. The selectivity of piperazines towards GPCRs has deen attributed to their basicity. Increasing the size of the ortho substituent in N-aryl piperazines resulted in an increase in binding affinity and functional potency. Piperazines are organic compounds that consists of a six-membered ring containing two opposing nitrogen atoms, at the 1 and 4 positions of the ring. Piperazines were prepared by the Diels-Alder reaction using sulfinimines. Sulfinimines are the key-compounds for the synthesis of the final desirable products described herein and excellent precursors of amines, when they react with organometallic compounds [RLi, RMgX (organolithium reagents, Grignard reagents)]. Enantiomerically pure sulfinimines representing, important building blocks in the asymmetric synthesis of amine derivatives, are prepared in high yields in one step from aromatic, heteroaromatic, and aliphatic aldehydes. In this project, novel β-lactam compounds and substituted piperazine compounds were synthesized, in order to complete and highlight the already existing data for these specific compounds classes and provide new data about the total synthesis of the natural product, Ecteinascidin 743 (synthesis of six-membered azoxy products 18, 19 and 20). The retrosynthetic analysis of Ecteinascidin 743 could be viable given the result described in Scheme 44.