The synthesis of enantiopure 1,3-dimethylisochroman and related racemic analogues using anacardic Acid as a bio-renewable starting material
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Date
2019
Authors
Lu, Tianqi
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Abstract
Isochromans are a class of oxygenated heterocycles with a
3,4-dihydro-1H-benzo[c]pyran scaffold that are found in a variety of natural
sources including bacteria, fungal, plants and insects. Isochroman-containing
compounds display a wide range of biological activities including anti-bacterial,
anti-tumour, anti-oxidation, anti-hypertension and herbicidal activities.
The dissertation involves research evaluating the use of lipase from Candida
rugosa for the enzymatic kinetic resolution of an advanced synthetic
intermediate rac-1-(2-allyl-3,6-dimethoxyphenyl)ethanol which eventually
resulted in the enantiopure synthesis of
(S)-5,8-dimethoxy-1,3-dimethylisochroman.
The synthesis of (S)-5,8-dimethoxy-1,3-dimethylisochroman commenced with
the diallylation of 2,5-dihydroxybenzoic acid. The allylated compound allyl
5-(allyloxy)-2-hydroxybenzoate was then subjected to a thermal
Claisen-rearrangement to afford allyl 2-allyl-3,6-dihydroxybenzoate which was
then protected using dimethylsulphate. The dimethoxy compound allyl
2-allyl-3,6-dimethoxybenzoate was reduced to form alcohol
(2-allyl-3,6-dimethoxyphenyl) methanol using lithium aluminium hydride
followed by a PCC oxidation yielding aldehyde
2-allyl-3,6-dimethoxybenzaldehyde. The aldehyde was then treated with
freshly made methylmagnesium iodide to yield the alcohol
1-(2-allyl-3,6-dimethoxyphenyl)ethanol as the racemate which was then
acetylated to form rac-1-(2-allyl-3,6-dimethoxyphenyl)ethyl acetate. Using
lipase hydrolysis of the acetate racemate, we were able to obtain enantiopure
(S)-1-(2-allyl-3,6-dimethoxyphenyl)ethanol which was then followed by
potassium tert-butoxide ring closure to afford
(S)-5,8-dimethoxy-1,3-dimethylisochroman with an overall yield of 1.31% starting from 2,5-dihydroxybenzoic acid.
In this dissertation, we also demonstrated the synthesis of hydroquinone
methyl 3-bromo-2,5-dihydroxy-6-pentadecylbenzoate using the bio-renewable
substrate anacardic acid as starting material. Starting with the selective
methylation of anacardic acid possessing a saturated side chain, methyl
2-hydroxy-6-pentadecyl benzoate was synthesized which was subjected to
N-bromosuccinimide bromination to afford methyl
3,5-dibromo-2-hydroxy-6-pentadecyl benzoate. A Ceric(IV) ammonium nitrate
oxidation followed by sodium dithionite reduction afforded methyl
3-bromo-2,5-dihydroxy-6-pentadecylbenzoate in an overall yield of 31% from
anacardic acid.
Using anacardic acid as starting material and potassium tert-butoxide as a key
step for the ring closure, we were able to synthesize another two isochroman;
rac-8-methoxy-1,3-dimethylisochroman was synthesized over 9 steps with an
overall yield of 13% and rac-8-methoxy-1-methyl-3-tridecylisochroman was
synthesized over 7 steps with an overall yield of 16%.
Description
A dissertation submitted to the Faculty of Science, University of the Witwatersrand,
Johannesburg In fulfilment of the requirements for the Degree of Master of Science
October 2019
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Citation
Lu, Tianqi. (2019). The synthesis of enantiopure 1,3-dimethylisochroman and related racemic analogues using anacardic acid as a bio-renewable starting material. University of the Witwatersrand, https://hdl.handle.net/10539/29638