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Design and stereoselective syntheses of Phe-Phe dipeptidomimetics
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several stereochemically well characterized Phe-Phe dipeptidomimetics have been designed and synthesized. The Phe-Phe vinyl isostere was used as a key intermediate. The synthesized series of mimetics includes two isomeric epoxides, four 1,2-dihydroxyethylene isomers, two isomeric allylic alcohols and two isomeric allylic fluorides.

Phe-Phe and Phe-Gly vinyl isosteres were epoxidized using three different peracids and VO(acac)2/TBHP. The stereoselectivities observed in the peracid epoxidation reactions may be rationalized by assuming a cooperative coordination of the incoming peracid by allylic carbamate and allylic hydroxymethyl, methyl ester or acyloxymethyl groups. The peracids were differently directed by different functional groups. The more acidic trifluoroperacetic acid was favourably directed by the methyl ester or acyl groups viahydrogen bond donation from the peracid to the substrate. The less acidic m-CPBA was directed by functional groups being able to donate a hydrogen bond such as the allylic carbamate and the hydroxymethyl functions. Hence, the face selectivity in the epoxidation of the double bond of the Phe-Phe vinyl isostere could be controlled by appropriate choice of directing group and epoxidation reagent. In m-CPBA epoxidation of the homoallylic silyl ether the threo epoxide isomer was formed in high yield whereas trifluoroperacetic acid mediated epoxidations of acylated homoallylic alcohol derivatives mainly produced the erythro isomers. The stereoselectivities observed in the VO(acac)2/TBHP reactions wererationalized by assuming a boat conformation in the transition state. The transition state for formation of the minor epoxide isomer is destabilized as a consequence of 1,3A interactions.

Syn dihydroxylation reactions on the Phe-Phe vinyl isostere could be controlled to some extent by appropriate choice of chiral ligand. The two isomeric anti dihydroxyethylene mimetics were obtained via an intramolecular regioselective epoxide ring opening reaction giving two isomeric oxazolidinone products which were hydrolyzed to aminotriols and thereafter Boc-protected. The allylic alcohols were obtained from the isomeric epoxides by a regio- and stereospecific epoxide ring opening reaction. The alcohols could be stereospecifically converted into aziridines which on treatment with diethylaminosulfur trifluoride produced the allylic fluoride derivatives.

Selected Phe-Phe vinyl isosteres were evaluated as inhibitors of substance P endopeptidase. Strong inhibition of the enzyme activity was obtained.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1998. , 66 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 181
Keyword [en]
Pharmaceutical biosciences
Keyword [sv]
Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
Research subject
Organic Pharmaceutical Chemistry
URN: urn:nbn:se:uu:diva-879ISBN: 91-554-4213-7OAI: oai:DiVA.org:uu-879DiVA: diva2:172089
Public defence
1998-05-15, sal B42, Uppsala Biomedicinska Centrum, Uppsala, 10:15
Available from: 1998-04-24 Created: 1998-04-24Bibliographically approved

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