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Title: Approaches towards the synthesis of the 20-deoxybryostatins and their 20,20-difluorinated analogues
Author: Mears, Paul
ISNI:       0000 0004 5353 3089
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2015
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This thesis describes approaches towards the synthesis of 20-deoxybryostatins and 20,20-difluorobryostatins. Towards the 20-deoxybryostatins, a route previously developed within the group was followed with a protecting group change designed to prevent problems encountered with a late-stage deprotection. To this end, (R)-pantolactone was transformed through to dimethyl (4S,6R,8R)-[4-(para-methoxybenzyloxy)-10-hydroxy-6,8-O-isopropylidine-3,3-dimethyl-2-one] phosphonate which was subsequently subjected to a Horner-Wadworth-Emmons condensation with (5R,E)-6-(4-methoxybenzyloxy)-5-triethylsilyloxy-3-(2’-triisopropylsilyloxyethylidene)hexanal. The reactions of the resulting enone through to the advanced intermediate allyl [(4R,6R)-6-((S)-2’-(4-methoxybenzyl)oxy-5-{(2’’S,6’’R)-6’’-(4-methoxybenzyloxymethyl)-4’’-[2-triisopropylsilyloxyeth-(Z)-ylidene]-tetrahydropyran-2’’-yl}-3,3-dimethyl-4’-oxopentyl)-2,2-dimethyl-1,3-dioxan-4-yl]-acetate are described, and this compound corresponds to a C1-C16 northern bryostatin fragment. A synthetic route to 20,20-difluorobryostatins was begun by the synthesis of three 3,3-difluoro-2-hydroxytetrahydro-4H-pyrans which started from an indium-mediated coupling of 3-bromo-3,3-difluoro-1-propene with an aldehyde. A strategy was employed which culminated in the preparation of 3,3-difluoro-2-hydroxy-2-(3-methylbut-1-en-3-yl)-4-(E)-methoxycarbonylmethylenetetrahydro-4H-pyran which corresponds to a C16-C23 20,20-difluorobryostatin southern fragment. Of particular interest is the selectivity observed in the reaction of α,α-difluoroketones with a stabilised Wittig reagent. The indium-mediated coupling was extended to include the first example of the coupling of a 2-alkyl substituted bromide.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: organic chemistry ; organofluorine chemistry ; natural products ; fluorinated natural products ; bryostatin