A tripeptide-like prolinamide-thiourea as an aldol reaction catalyst

A tripeptide-like prolinamide-thiourea catalyst with (S)-proline, (1S,2S)-diphenylethylenediamine and (S)-di-tert-butyl aspartate as building blocks provides the products of the reaction between ketones and aromatic aldehydes in high to quantitative yields and high stereoselectivities (up to 99 : 1 dr and 99% ee). Both the chiral centers of the diamine unit are essential, while the thiourea hydrogen originating from the amine and the amide hydrogen play a predominant role for the catalyst efficiency

Prolinamides carrying a thiourea group as new catalysts for the asymmetric aldol reaction

At the beginning of the 21st century, organocatalysis has emerged as a new powerful methodology for the synthesis of enantiopure organic compounds. The breakthrough of proline-catalyzed asymmetric direct aldol reaction together with the pioneering work on catalytic thioureas and imidazolidinones opened new directions in asymmetric catalysis. The five-membered secondary amine structure of proline is considered as a“privileged” structure able to activate carbonyl compounds through the formation of enamine intermediates. In an attempt to develop new organocatalysts, we thought of combining a thiourea group with prolinamide or an α-amino acid amide unit. Thiourea group is a well known double hydrogen bond donor and recently we have shown that chiral thioureas based on tert-butyl esters of α- amino acids are excellent catalysts for the asymmetric Michael reaction.1 In the present work, we describe the synthesis of various α-amino acid amides based on a chiral diamine carrying a thiourea group (general structure 1). The catalytic efficiency of the new organocatalysts was evaluated in the aldol reaction between acetone and 4-nitrobenzaldehyde. Prolinamide derivative was more efficient than the valinamide and the threonine amide derivatives. The catalyst based on (S)-proline and (1S,2S)-diphenylethylenediamine proved to be an excellent catalyst providing the products between ketones and aromatic aldehydes in high to quantitative yield and high stereoselectivitie

Polymer-supported thiourea catalysts for enantioselective Michael reaction

Among the large number of reactions involving the formation of carbon-carbon bond, the addition of ketones to nitroolefins is a powerful tool for the synthesis of γ-nitro-carbonyl compounds, useful intermediates for pharmaceutical industry. Our recently reported primary amine-thioureas based on tert-butyl esters of natural amino acids exhibit excellent performance for the Michael reaction of ketones with nitroolefins providing the products quantitatively and almost stereospecifically (>99% ee).1,2 Using this methodology, enantiopure baclofen and phenibut (analogs of GABA) have been synthesized.2 Polymer-supported organocatalysts constitute a great challenge for the Michael reaction. In the current study, we report the immobilization of amine-thiourea catalysts containing (1S,2S)- or (1R,2R)-diphenylethylenediamine and tert-butyl aspartate, on various polymer supports, either directly or through spacer units. The solidsupported catalysts evaluated in the reaction between acetone and β- nitrostyrene and highlighted the importance of the choice of the polymer as well as the presence of the spacer or not. The direct attachment of the primary amine-thiourea-aspartate to a crosslinked polystyrene-divinyl benzene resin containing a uniform distribution of aminomethyl groups provides a supported catalyst that affords the product of the reaction between acetone and β-nitrostyrene quantitatively and in high enantioselectivity (91% ee)

Tripeptide-Like prolinamide catalysts for the aldol reaction

Enzymes are the foundation upon which the majority of organocatalysts bearing more than one catalytic functionalities and act either by covalent or non-covalent interactions, has been developed. The proline and its derivatives containing bio-isosteric groups as replacements of the carboxylic group, constitute a good example of catalysts that bring out transformations as the aldol and Michael reaction succesfully, via bifunctional catalysis.1 Important improvement has been the development of catalysts combining a proline or proline derivative unit with additional functionalities able to act as hydrogen bond donors. Amide catalysts based on (S)-proline and (1S,2S)-1,2-diphenylethylenediamine or (1S,2S)-1,2-diphenyl-2-aminoethanol are representative examples featuring amine or hydroxyl group respectively, as the terminal donor group.2 These analogues provide the opportunity of introducing chiral substituents between donor groups and/or to the terminal heteroatom, thus enhancing the efficacy of the resulting catalyst. Furthemore, combination of additional chiral units, together with even more hydrogen bond donors, would mimic much better a “miniature active site”, providing therefore multifunctional organocatalysts. We have shown that prolinamide catalyst based on (1S,2S)- 1,2 diphenylethylenediamine and bears a double hydrogen bond donor thiourea group linked to a substituted aromatic ring, efficiently catalyze the aldol reaction between ketones and aromatic aldehydes in high to quantitative yields and with high stereoselectivities.3 Herein, we report a structure activity relationship study undertaken to identify the functional groups of the catalyst responsible for the activity resembling structure activity relationship studies to identify the pharmacophores of a lead bioactive compound. A tripeptide-like prolinamide-thiourea catalyst having as building blocks (S)-proline (1S,2S)-1,2-diphenylenediamine and (S)-di-tertbutyl aspartate provides the products of the aldol reaction in high to quantitative yields and in high stereoselectivities (up to 99:1 dr and 99% ee)

The importance of hydrogen bonding for the catalysis of the enantioselective aldol reaction by Tripeptide-Like prolinamide thioureas

The majority of the organocatalysts developed up to now for asymmetric organic transformations employ more than one functionalities in the catalytic mechanism that act through either covalent or non-covalent interactions. For example, proline employs the pyrrolidine nitrogen and the carboxylic acid group, while chiral thioureas combine the thiourea functionality with a tertiary or a primary amino group. We have recently shown that an amide of proline with a diamine carrying a thiourea group is a very good catalyst for the enantioselective aldol reaction.1 Trying to improve the activity, we have found that a tripeptide-like thiourea having as building blocks (S)-proline, (1S,2S)-diphenylethylenediamine and (S)- di-tert-butyl aspartate provides the products of the reaction between ketones and aromatic aldehydes in high to quantitative yields and high stereoselectivities (up to 99:1 dr and 99% ee). A number of structural modifications of the catalyst were undertaken in order to understand the role of the hydrogen bond donors of the catalyst, i.e. the prolinamide hydrogen and the two hydrogen atoms of the thiourea group. We have come to the conclusion that the importance of the hydrogen bond donors of the catalyst follows the order: thiourea hydrogen originated from aspartate › amide hydrogen › thiourea hydrogen originated from diphenylethylenediamine

Synthesis of new chiral organocatalysts (immobilized or not) and study of their catalytic activity in asymmetric organic transformations

The present thesis refers to the synthesis of new chiral organocatalysts (immobilized ornot) and the study of the catalytic activity in asymmetric organic transformations. Τhedesign, synthesis and study of amide-thioureas in the asymmetric aldol reaction derivedfrom α-amino acids and 1,2-diphenylethylenediamine bearing also a terminal bulkybis(trifluoromethyl)-substituted aromatic ring, are described. The prolinamide-derivativeassociated with the group of thiourea via a (1S,2S)-1,2-diphenylethylenediaminespacer, subjected then to a systematic structure-activity relationship study in order toachieve optimal catalytic efficacy. The prolinamide-thiourea based on (1S,2S)-1,2-diphenylethylenediamine and (S)-di-tert-butyl-aspartate, has emerged as the bestcatalyst for asymmetric aldol reaction to afford the product in up to quantitative yield andexcellent stereoselectivity (99:1 dr and 99% ee).The synthesis and study of organocatalysts in solution is followed by the design,synthesis and study of supported-thiourea organocatalysts in organic polymericsubstrates (resins). Firstly was investigated the effect of immobilized analogues of theprolinamide-thiourea derived from (1S,2S)-1,2-diphenylethylenediamine and (S)-tertbutyl-phenylglycinatein the optimum conditions of the asymmetric aldol reaction. Thestudy of a directly- or via spacer-attached thiourea derived from (1S,2S)-1,2-diphenylethylenediamine and (S)-di-tert-butyl-aspartate in the Michael reaction betweenacetone and trans-β–nitrostyrene, follows a well-systematic investigation of thestructure-activity relationship of the polystyrene-1%-divinylbenzene directly-connectedanalogue, so as to achieve optimal catalytic activity. The organocatalyst based on(1R,2R)-1,2-diphenylethylenediamine and (S)-phenylglycine provides the product of theMichael reaction in very high yield (96%) and selectivity (99% ee), which is maintainedafter 4 recycles.Η παρούσα διατριβή αναφέρεται στη σύνθεση νέων χειρόμορφων οργανοκαταλυτών(ακινητοποιημένων ή μη) και τη μελέτη της καταλυτικής τους δράσης σε ασύμμετρουςοργανικούς μετασχηματισμούς. Αρχικά περιγράφεται ο σχεδιασμός, η σύνθεση και ημελέτη αμιδίων-θειουριών που προέρχονται από α-αμινοξέα, 1,2-διφαινυλοαιθυλενοδιαμίνη και φέρουν ακραίο ογκώδη δις(τριφθορομεθυλο)-υποκατεστημένο αρωματικό δακτύλιο, στην ασύμμετρη αλδολική αντίδραση. Τοπρολιναμιδικό παράγωγο που συνδέεται με την ομάδα της θειουρίας μέσω συνδέσμου(1S,2S)-1,2-διφαινυλοαιθυλενοδιαμίνης, υποβάλλεται στη συνέχεια σε μία συστηματικήμελέτη της σχέσης δομής-δράσης με σκοπό την επίτευξη βέλτιστης καταλυτικήςδραστικότητας. Το προλιναμίδιο-θειουρία που βασίζεται στη (1S,2S)-1,2-διφαινυλοαιθυλενοδιαμίνη και στον (S)-ασπαρτικό δι-tert-βουτυλεστέρα, αναδείχθηκε ωςο βέλτιστος καταλύτης της ασύμμετρης αλδολικής αντίδρασης παρέχοντας το προϊόνέως και ποσοτικά με 99:1 dr και 99% ee.Τη σύνθεση και μελέτη των οργανοκαταλυτών σε διάλυμα, διαδέχεται ο σχεδιασμός, ησύνθεση και μελέτη ακινητοποιημένων oργανοκαταλυτών θειουρίας σε οργανικάπολυμερικά υποστρώματα (ρητίνες). Μελετάται αρχικά η δράση ακινητοποιημένωναναλόγων του προλιναμιδίου-θειουρίας που προέρχεται από τη (1S,2S)-1,2-διφαινυλοαιθυλενοδιαμίνη και τον tert-βουτυλεστέρα της (S)-φαινυλογλυκίνης στιςβέλτιστες συνθήκες της ασύμμετρης αλδολικής αντίδρασης. Τη μελέτη ενός απευθείας-ή μέσω συνδέσμου-προσαρτημένου παραγώγου θειουρίας που προέρχεται από(1S,2S)-1,2-διφαινυλοαιθυλενοδιαμίνη και (S)-ασπαρτικό δι-tert-βουτυλεστέρα στηναντίδραση Michael μεταξύ της ακετόνης και του trans-β-νιτροστυρενίου, ακολουθεί μιαεπίσης συστηματική διερεύνηση της σχέσης δομής-δράσης του απευθείας-ακινητοποιημένου αναλόγου σε ρητίνη πολυστυρενίου-1%-διβινυλοβενζολίου, ώστε ναεπιτευχθεί η βέλτιστη καταλυτική δραστικότητα. Ο οργανοκαταλύτης που βασίζεται στη(1R,2R)-1,2-διφαινυλοαιθυλενοδιαμίνη και στη (S)-φαινυλογλυκίνη παρέχει το προϊόντης αντίδρασης Michael σε πολύ υψηλή απόδοση (96%) και εκλεκτικότητα (99% ee), ηοποία διατηρείται και μετά από 4 ανακυκλώσεις