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Stereoselective Synthesis of 3-Aminoindan-1-ones and Subsequent Incorporation into HIV-1 Protease Inhibitors
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
2006 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 71, nr 3, s. 1265-1268Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A new method for the stereoselective synthesis of 3-aminoindan-1-ones from triflates of salicylic sulfinyl imines and ethylene glycol vinyl ether has been developed. The reaction sequence starts with a regioselective Heck reaction followed by stereoselective Lewis acid mediated annulation. Acidic cleavage of the sulfinamides produced pure (R)- and (S)-3-aminoindan-1-ones, which were successfully isolated and incorporated into active HIV-1 protease inhibitors.

Ort, förlag, år, upplaga, sidor
2006. Vol. 71, nr 3, s. 1265-1268
Nyckelord [en]
HIV Protease Inhibitors/*chemical synthesis/chemistry/*pharmacology, Imines/chemistry, Indans/chemical synthesis/*chemistry/*pharmacology, Molecular Structure, Stereoisomerism, Sulfones/chemistry
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-93600PubMedID: 16438552OAI: oai:DiVA.org:uu-93600DiVA, id: diva2:167127
Tillgänglig från: 2005-10-20 Skapad: 2005-10-20 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
Ingår i avhandling
1. New Methods for the Synthesis of 3-Substituted 1-Indanones: A Palladium-Catalyzed Approach
Öppna denna publikation i ny flik eller fönster >>New Methods for the Synthesis of 3-Substituted 1-Indanones: A Palladium-Catalyzed Approach
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

In medicinal chemistry, there is a constant need for new preparative methods, both to make the synthesis process more effective, and to increase the accessibility to a wide variety of compounds. A number of different approaches can be used to attain these goals. Transition metal catalysis is generally performed under mild conditions, providing both regio- and chemoselective reactions. Thus, it offers an attractive means of preparation of complex drug candidates. Two additional methodologies used to increase the preparative efficiency are one-pot protocols and controlled microwave heating. One-pot and multi-component reactions are less time consuming than step-by-step reactions, and microwave heating has been used to considerably shorten the reaction times.

This thesis describes a new palladium-catalyzed, one-pot reaction producing racemic acetal-protected 3-hydroxy-1-indanones from ethylene glycol vinyl ether and triflates of salicylic aldehydes. The triflates were prepared using controlled microwave heating. The reaction sequence starts with a regioselective internal Heck coupling, followed by an annulation cascade. By including secondary amines in the reaction mixture, the reaction was further developed into a three-component reaction delivering racemic acetal-protected 3-amino-1-indanones. This new method was utilized for the synthesis of primary, secondary and tertiary aminoindanones. Finally, by using enantiopure t-butyl sulfinyl imines, derived from salicylic aldehyde triflates and ethylene glycol vinyl ether as starting materials in a closely related type of palladium coupling–annulation sequence, a stereoselective protocol providing enantiomerically pure 3-amino-1-indanones was developed. To demonstrate an application in medicinal chemistry, the enantiopure 3-amino-1-indanones were incorporated as P2 and/or P2´ substituents into active HIV-1 protease inhibitors.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2005. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 18
Nyckelord
Organic chemistry, Heck, palladium, indanone, annulation, microwave heating, triflate, sulfinyl imine, HIV-1 protease inhibitor, Organisk kemi
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-6015 (URN)91-554-6366-5 (ISBN)
Disputation
2005-11-11, B22, BMC, Husargatan 5, Uppsala, 09:15
Opponent
Handledare
Tillgänglig från: 2005-10-20 Skapad: 2005-10-20Bibliografiskt granskad

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Wannberg, JohanLarhed, MatsHallberg, Anders

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