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Cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating
Personal Chemistry AB.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
2002 (Engelska)Ingår i: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 5, nr 7, s. 571-574Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A general procedure for the synthesis of a large variety of compounds comprising an alpha, beta-unsaturated carbonyl functionality was developed. The use of one-pot cascade synthesis with (triphenylphosphoranylidene)ethenone as a versatile reagent for various formations including heterocycles of different ring sizes and unsaturated amides in combination with microwave dielectric heating is described. The method was used to synthesize a small library of unsaturated amides.

Ort, förlag, år, upplaga, sidor
2002. Vol. 5, nr 7, s. 571-574
Nyckelord [en]
microwave heating, one-pot synthesis, cascade reaction, library synthesis, (triphenylphosphoranylidene)ethenone, organic-synthesis, cumulated ylides, chemistry
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-100964ISI: 000181710400008PubMedID: 12470270ISBN: 1386-2073 (tryckt)OAI: oai:DiVA.org:uu-100964DiVA, id: diva2:211425
Tillgänglig från: 2009-04-14 Skapad: 2009-04-14 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Ingår i avhandling
1. On the Versatility of Microwave-Assisted Chemistry: Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry
Öppna denna publikation i ny flik eller fönster >>On the Versatility of Microwave-Assisted Chemistry: Exemplified by Applications in Medicinal Chemistry, Heterocyclic Chemistry and Biochemistry
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Today, the demand for speed in drug discovery is constantly increasing, particularly in the iterative processes of hit validation and expansion and lead optimization. Irradiation with microwaves (MWs) has been applied in the area of organic synthesis to accelerate chemical reactions and to facilitate the generation of new chemical entities since 1986. In the work presented in this thesis, the use of MW-mediated heating has been expanded to address three fields of drug discovery, namely hit expansion, chemical library generation and genomics.

In the first project, potential inhibitors of malaria aspartic proteases were designed and synthesized, partly by MW-assisted organic chemistry, and evaluated with regard to their inhibitory efficacy on five malaria aspartic proteases and their selectivity over two human aspartic proteases. The synthetic work included the development of fast and convenient methods of MW-assisted formation of thiazolidines and epoxy esters. Some of the resulting structures proved to be efficacious inhibitors of the aspartic protease that degrades haemoglobin in all four malaria parasites infecting man. No inhibitor affected the human aspartic proteases.

Expedient, two-step, single-operation synthetic routes to heterocycles of medicinal interest were developed in the second and third projects. In the former, the use of a versatile synthon, Ph3PCCO, provided α,β-unsaturated lactones, lactams and amides within 5–10 minutes. In the latter project, saturated lactams were formed from amines and lactones in 35 minutes, in the absence of strong additives. These two MW-mediated protocols allowed the reduction of the reaction time from several hours or days to minutes.

In the fourth project, a fully automated MW-assisted protocol for the important enzyme-catalysed polymerase chain reaction (PCR) was established. In addition, the PCR reaction could be performed in unusually large volumes, 2.5 mL and 15 mL, with yields corresponding to those from conventional PCR. Good amplification rates suggested that the thermophilic enzyme, Taq polymerase, was not affected by the MW radiation.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2009. s. 109
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 100
Serie
Nyckelord
microwave-assisted chemistry, malaria, aspartic protease, plasmepsin, PfPM4, PmPM4, PoPM4, PvPM4, inhibitor, unsaturated lactone, unsaturated lactam, unsaturated amide, lactam, Bestmann's ylide, ionic liquid, polymerase chain reaction, thermophilic enzyme
Nationell ämneskategori
Läkemedelskemi Organisk kemi Biokemi och molekylärbiologi
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:uu:diva-101356 (URN)978-91-554-7535-2 (ISBN)
Disputation
2009-06-12, B22, Biomedical Centre (BMC), Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-05-20 Skapad: 2009-04-23 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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