Entwicklung von Methoden zur Direkten Asymmetrischen Reduktiven Aminierung von Ketonen und 'Aktivitätsorientierte' Synthese der anti-HIV aktiven Naturstoffe Papuamide A und B
Zusammenfassung der Projektergebnisse
Chiral amines are key structural elements in bioactive natural products and pharmaceuticals rendering their synthesis an objective of high priority from the perspective of natural product chemistry and drug discovery. This project has been directed towards the development of novel - in comparison to known procedures more direct and effective - methods to synthesize chiral amines in only one chemical, stereoselective transformation from ketones as readily available building blocks ('direct asymmetric reductive amination') and applications of these procedures to the rapid assembly of structurally novel bioactive amines Based on an innovative biomimetic approach, we have developed a novel strategy for the direct reductive amination (2) of carbonlys (1), which utilizes the Hantzsch ester (3) for transfer hydrogenation and proceeds in the presence of catalytic amounts of thiourea (4) and molecular sieves.[1,2] The mild and nonacidic conditions together with the high chemoselectivity of this protocol enabled applications to a wide variety of substrates (5).[1-4] Furthermore, it could be adopted to a modular one-pot synthesis of polysubstituted amines (6) and the biological potential of these nitrogen-centred structures was demonstrated.[3,4] Furthermore, studies towards asymmetric variants by use of chiral thioureas were initiated. In addition, we have devised efficient procedures for the highly diastereoselective, directed reductive amination (8) of b-hydroxy-amines (7) for the preparation of 1,3-amino alcohols as key synthons in bioactive structures,[5] such as the tubulysins.[6] The operationally simple protocol uses Ti(iOPr)4 for coordination of the intermediate imino-alcohol and PMHS as reducing agent to access the 1,3-syn products (10). The method which proceeds via 9, was expanded to an asymmetric aldol-reductive amination sequence to allow a highly convergent synthesis of the hydroxy-amine core of the HIV-protease inhibitor ritonavir (11).[5]
Projektbezogene Publikationen (Auswahl)
- D. Menche, F. Arikan Thiourea-catalyzed Direct Reductive Amination of Aldehydes Synlett 2006, 841-844.
- D. Menche, F. Arikan, J. Li, S. Rudolph Directed Reductive Amination of ¿-Hydroxy-Ketones: Convergent Assembly of the Ritonavir/Lopinavir Core Org. Lett. 2007, 9, 267-270.
- D. Menche, F. Arikan, J. Li, S. Rudolph, F. Sasse An Efficient Procedure for the One-Pot Synthesis of Polysubstituted Amines: Modular Access to Novel Bioactive Agents Bioorg. Med. Chem. 2007, 15, 7311-7317.
- D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter, S. Rudolph Hydrogen Bond Catalyzed Direct Reductive Amination of Ketones Org. Lett. 2006, 8, 741-744.
- D. Menche, S. Böhm, J. Li, S. Rudolph, W. Zander Synthesis of hindered tertiary amines by a mild reductive amination procedure Tetrahedron Lett. 2007, 48, 365-369.
- F. Sasse, D. Menche Success in tubulysin D synthesis Nature Chem. Biol. 2007, 3, 87-89.
