Diastereoselective synthesis of syn-1,3-polyols and studies towards the C1-C31 and C32-C52 fragments of amphidinol 3

Grisin, Aleksandr Diastereoselective synthesis of syn-1,3-polyols and studies towards the C1-C31 and C32-C52 fragments of amphidinol 3. Doctor of Philosophy thesis, University of Liverpool.

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Abstract

Diastereoselective Synthesis of syn-1,3-Polyols The stereoselective construction of polyacetate 1,3-diols has attracted considerable attention due to the ubiquity of this motif in complex biologically active polyene macrolides (amphotericin B, RK-397, mycoticin, candidin). We have developed a highly stereoselective bismuth(III)-mediated two-component hemiacetal/oxa-conjugate addition reaction, which directly provides syn-1,3-diols in the form of cyclic acetals having an adjacent electron-withdrawing group in the form of aldehydes and ketones. The scope and limitations of this transformation were examined and culminated with the synthesis of the C18-C28 fragment of antibiotic RK-397. Studies towards the C1-C31 and C32-C52 Fragments of Amphidinol 3 Temporary-tethered reactions provide an important strategy for target- directed synthesis, since they circumvent the problems encountered with entropically unfavorable reactions. The temporary silicon-tethered ring-closing metathesis (TST- RCM) allows for the highly (Z)-selective coupling of mixed silaketals in the formation of the medium sized rings. The latter compounds can undergo a substrate controlled stereoselective electrophilic functionalisation, for example, hydroboration, dihydroxylation or epoxidation, and produce polyoxygenated motifs that are present in many biologically important natural products. In the course of these studies we have developed a highly convergent asymmetric synthesis of the C1-C31 polyol fragment of amphidinol 3, where the TST-RCM/hydroboration reaction is successfully employed for the efficient coupling ii of the C16-C23 and C24-C30 units of the natural product with concomitant introduction of the crucial propionate-type C23-C24 stereocentres. In the final part of thesis the investigation of the stereoselective dihydroxylation reaction of mixed syn and anti eight-membered cyclic silaketals was carried out. The resulting oxygenated products can be efficiently transformed via an intramolecular cyclisation of δ-hydroxy epoxides into the highly substituted syn- and anti-tetrahydropyrans (THPs), a strategy that could also have application in related natural products, for example, ladder polyether polyketides. The merit of the developed methodology was highlighted in the asymmetric synthesis of the common C31(52)-C39(44) THP fragment of amphidinol 3, which could be ultimately used in the bidirectional route towards the bis-THP segment of the natural product.

Item Type:	Thesis (Doctor of Philosophy)
Additional Information:	Date: 2012-09-12 (completed)
Uncontrolled Keywords:	Total synthesis, bismuth, catalysis, polyketides, TST-RCM, hydroboration
Subjects:	?? QD ??
Divisions:	Faculty of Science and Engineering > School of Physical Sciences
Depositing User:	Symplectic Admin
Date Deposited:	08 Aug 2013 10:58
Last Modified:	16 Dec 2022 04:38
DOI:	10.17638/00010373
Supervisors:	Evans, P Andrew
URI:	https://livrepository.liverpool.ac.uk/id/eprint/10373