Methodology for the Enantioselective Synthesis of Isochromanes and their Dimers
Date
2006-11-14T13:02:28Z
Authors
Govender, Sameshnee
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Abstract
Pyranonaphthoquinones are biologically important molecules found in a wide variety of
bacteria, microbial fungi and plant species. Their biological activity is proposed to be a
consequence of their ability to function as bioreductive alkylating agents. This class of
compounds, which include monomeric and dimeric examples, contain the basic
naphtho[2,3-c]pyran-5,10-dione skeleton, usually with substituents at the C-1 and C-3
positions of the pyran ring. The aim of the first part of the project was to develop a novel
method for the synthesis of enantiomerically pure 5,8-dimethoxy-isochroman-4-ol, which
will provide a handle for stereoselectively adding substituents to the C-1 and C-3
positions of the pyran nucleus. In the second part of the project we wished to attempt to
synthesize the naturally occurring compound, cardinalin 3, the dimer of ventiloquinone L
previously synthesized in the Wits laboratories. The synthesis of the enantiomerically
pure isochromanol began with 2,5-dihydroxybenzoic acid, which was subjected to a
diallylation followed by a Claisen rearrangement. The phenols were protected by a
methylation reaction and the ester moiety was reduced to give (2-allyl-3,6-
dimethoxyphenyl)methanol. It was then allylated to produce a suitable precursor for a one
pot/two step ruthenium mediated isomerisation/ring closing metathesis reaction to
produce 5,8-dimethoxy-1H-isochromene in an overall yield of 47%. It was converted to
racemic 5,8-dimethoxy-isochroman-4-ol through a hydroboration-oxidation reaction in a
yield of 84%. The separation of the enantiomers was achieved by acetylating the alcohol
to form 5,8-dimethoxy-3,4-dihydro-1H-isochromen-4-yl acetate and then a lipase enzyme
was used to stereospecifically deacetylate one enantiomer, while leaving the other
enantiomer untouched. The second part of the dissertation discusses the progress towards
the synthesis of cardinalin 3. This project began with the formation of the C-C biaryl axis
starting from 1,3-dimethoxybenzene. The synthesis then continued with the diformylation
of the biphenyl to give 2,2’,6,6’-tetramethoxy[1,1′-biphenyl]-3,3′-dicarbaldehyde. This
was subjected to a Stobbe condensation and a Friedel-Crafts acylative cyclisation to
produce diethyl [4,4′-diacetoxy-6,6′,8,8′-tetramethoxy-7,7′-binaphthalene]-2,2′-
dicarboxylate. The synthesis will be continued in the PhD, using methodology previously
developed for the formation of the monomer, as well as methodology developed here.
Description
Faculty of Science
School of Chemistry
9800165e
govendor@aurum.wits.ac.za
Keywords
Aromatic, Compounds, Isochromanols, Isochromenes, Enzymatic Resolution