Morris, Michael Paul; (1999) The asymmetric synthesis of decalin synthons for use in flavour and fragrance compounds. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In the pursuit of synthons for the preparation of the secondary metabolites geosmin and dehydrogeosmin, four synthetic strategies were evaluated. To support this study, the preparation of a chiral auxiliary and new surfactant media were also investigated: Techniques for the production of laboratory scale quantities of the enantiomeric forms of butan-2,3-diol were identified: The bacterial fermentation of sugars by Bacillus subtilis strains to access optically pure D-(-)-(2R,3R)-butandiol and the kinetic enzymatic resolution of a commercially available isomeric mixture of the diol to recover the L-(+)-(2S,3S)-isomer in optically pure form. Two optically pure amino acid derived surfactants were synthesised, characterised and a measurement of their critical micellar concentration undertaken. A novel strategy to construct the dehydrogeosmin skeleton was designed, employing a 'biomimetic' intramolecular polyene cyclisation as the key step. The preparation of the trans olefinic cyclisation precursor was investigated and metal facilitated carbonylation was used to generate a requisite aldehydic intermediate. The biomimetic cyclisation was tested and generated the predicted bicyclic octalin ether in a chemical yield and an enantiomeric excess of 22% and >99% respectively. The novel Diels-Alder disconnection of geosmin was investigated, through the preparation of several diene systems and testing their reactivity in the [4π+2π] cycloaddition reaction. A similar disconnection was applied to the dehydrogeosmin system and optically pure ketals of butan-2,3-diol used in lithium perchlorate solution to generate a precursor in 70% enantiomeric excess. A study of the Hajos-Parrish reaction - an amino acid catalysed intramolecular cyclisation - was undertaken to evaluate the effects of solvent and amino acid choice on enantioselectivity. Conditions were identified to form the target bicyclic ketone intermediate in a chemical yield of 72% and an enantiomeric excess of 74%. The formation of the cyclisation precursor, from the Michael addition of 2- methylcyclohexane-1,3-dione to ethyl vinyl ketone, was found to be greatly enhanced by performing the reaction in micellar media with a yield of >99% in surfactant solution compared to 55% in water. The use of surfactant solutions in studies of Robinson annelations was also undertaken. The enantioselective dehydration of a decalol, using an optically pure amino acid as a catalytic dehydrator, was carried out to prepare a key geosmin precursor in a chemical yield and an enantiomeric excess of >99% and 54% respectively. As part of the study into the effect of solvent and amino acid choice on selectivity, new insights into the mechanism of action of the Hajos-Parrish reaction were gained.

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