Publikationsserver der RWTH Aachen University
Organokatalytische Synthesen biologisch aktiver Naturstoffe : Totalsynthesen von Amaminol A und B und (+)-Mitsugashiwalacton sowie Synthesen 2,6-disubstituierter Tetrahydropyranen
Abstract
dc:descriptionAmaminol A and B are two diastereomeric 1,2-aminoalcohols of marine origin with a basic structure of a trans-fused bicyclononane. This work, for the first time, developed a complete synthesis of amaminol B, which, starting from 2E,4E-hepta-2,4-dien-1-ol and in a process of only eleven steps achieves a total yield of 21%. The overall concept of the complete synthesis of amaminol A and B is characterised by three key organocatalytic steps. The basic structure of amaminol A and B including the desired configuration of the four stereocenters was realized in one single organocatalytic step by an intramolecular Diels-Alder reaction of a synthesised tetraenal with an imidazolidinone-derivative as effective organocatalyst and TFA as co-catalyst. This reaction yielded the desired indane core with high selectivity, high endo/exo-selectivity and a surplus of enantiomers of 98% ee. As it turned out in the course of development of the total synthesis, not the initially explored organocatalytic transferhydration of a 1,2-unsaturated aldehyde in the presence of additional double bonds, but rather the reduction of an 1,2-unsaturated ester with magnesium successfully yielded the substrate for an organocatalyzed Henry reaction. The reaction also generated a new and interesting tricycle as a by-product, which occurs as a complex fragment in biologically active natural compounds. The preliminarily investigated selective nitroaldol reactions to generate the precursors of amaminol warrant further studies. In order to complete the synthesis by introducing the aminofunction, aminoacid derivatives from the chiral pool were used. Under optimised Masamune-Roush conditions a Horner-Wadsworth-Emmons reaction generated N-Boc-aminoketones. A Raney® nickel reduction of the conjugated double bond and, in the case of amaminol A, a syn-selective and, in the case of amaminol B, an anti-selective reduction resulted in N-Boc-amaminole A und B with very attractive yields and adequate selectivities. A comparison of the 1H-,13C-NMR-spectra of the synthesised N-Boc-amaminols and the naturally occurring amaminol derivatives confirmed the correct stereoconfiguration of the produced compounds. As a second project, the complete synthesis of the naturally occurring monoterpenoid (+)-Mitsugashiwalactone based on a biomimetic key step was realized. Starting out with succinalaldehyde, via only eight steps of reactions, the (+)-Mitsugashiwalactone could be synthesised with a total yield of 22%. It could be shown, that, similar to a Rauhut-Currier reaction, a symmetrical diendienal is transformed into a cyclopentene derivative in an organocatalytic 5-exo-trig-cyclization. In this reaction the required stereocenter is generated using diarylprolinolsilylethers as organocatalysts. In this set-up, under optimised conditions, enantioselectivities of up to 59% ee were achieved for the first time. The ample choices for expansion of the range of substrates and for additional optimisation of reactions that this dienamine-catalyzed cyclization provides, should be further explored in the future. Finally, preliminary investigations were undertaken of the feasibility of one-step proline-catalysed aldol reactions with subsequent palladium(II)-catalysed cyclization to form 2,6-disubstituted tetrahydropyranes. Direct aldol reactions of long-chain aldehydes as acceptors and cyclopentanons as donors result in 4,5-unsaturated syn- and anti-hydroxyketones with reasonable yields. Extensions of the aliphatic chains reduce the diastereoselectivities. For the first time, thus, 2,6-disubstituted tetrahydropyranes with a cyclization in the 2-position could be synthesised. These preliminary results of a palladium(II)-enabled cyclization of unsaturated hydroxyketones should facilitate further investigations, which could lead to selective syntheses of 2,6-cis-2,2´-syn- and 2,6-trans-2,2´-syn-tetrahydropyrane derivatives.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2009
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Jacobs, Wiebke Cordula
- Contributors dc:contributor
-
- Christmann, Mathias
Subjects
dc:subject × 12Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- ger