Total synthesis of amaminols

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Aalto-yliopiston teknillinen korkeakoulu | Doctoral thesis (monograph)
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Date

2010

Department

Kemian laitos
Department of Chemistry

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Mcode

Degree programme

Language

en

Pages

Verkkokirja (2911 KB, 149 s.)

Series

TKK dissertations, 219

Abstract

Amaminols A and B are cytotoxic bicyclic aminoalcohols isolated in 1999 from an unidentified tunicate of the family Polyclinidae, with an IC50 value of 2.1 µg/mL against P388 murine leukaemia cells. These cytotoxic properties could have potential importance in the development of new therapeutical agents for cancer treatment. Since the source of amaminols is practically unknown, the development of a practical synthesis route is probably the only way to obtain material for further evaluation of biological activities of these compounds. This thesis describes the total synthesis of amaminol A using an enantioselective organocalalytic intramolecular Diels-Alder reaction as one of the key steps. The full carbon skeleton of amaminol A is constructed using the Horner-Wadsworth-Emmons reaction of a phosphonate derived from natural amino acid L-alanine. Strategic reduction with copper hydride proved to be highly important and led to further development of this technology. Final reduction followed by removal of protections gave synthetic amaminol A, which was found to be identical with the isolated natural product. Our synthetic amaminol A was tested against various cancer cell lines at the National Cancer Institute. The second part of this thesis focuses on copper hydrides. The literature part presents an extensive review of achiral phosphine stabilized copper hydrides used in conjugate reductions of various α,β-unsaturated systems. Further development by us led to a highly selective method for reduction of α-chiral enones. This was also the first phosphite stabilized copper hydride methodology used in synthesis. Applicability of this new method was demonstrated in the synthesis of amaminol A. The third part of the thesis describes mechanistic studies of aerobic oxidations of alcohols catalyzed by copper-TEMPO system. Detailed evaluation of different catalyst components revealed second order kinetic correlation for copper and first order correlation for TEMPO. This information was used to generate a new mechanistic proposal which was in agreement with the obtained kinetic data. Oxidation of allylic primary alcohols with CuBr2-TEMPO system was found to be highly efficient. Oxidation of aliphatic alcohols proved to be more challenging and required the use of copper triflate.

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Supervising professor

Koskinen, Ari, Prof.

Thesis advisor

Koskinen, Ari, Prof.

Keywords

amaminol, total synthesis, biological activity, copper hydride, oxidation

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https://urn.fi/URN:ISBN:978-952-60-3093-7

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[diss] Kemian tekniikan korkeakoulu / CHEM