Synthetic Approaches to Clovene

Murray, Robert D. H (1960) Synthetic Approaches to Clovene. PhD thesis, University of Glasgow.

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The total synthesis of clovene, a tricyclic rearrangement product of caryophyllene has been undertaken. PART ONE. Methyl 3-methylcyclohexanone-3-acetate was prepared from 3-methylcyclohex-2-enone by treatment with diethyl malonate and sodium ethoxide, followed by hydrolysis, decarboxylation and re-esterification. Treatment of the keto-ester with malononitrile afforded 3-carbo-methoxymethyl-3-methylcyclonexylidenemalononitrlle, which was converted to 3-carbomethoxyrnethyl-3-methyl- l-cyano-l-dlcyanomethyleyclohexene as a mixture of stereoisomers. Hydrolysis, decarboxylation, reesterification and high-dilution, intra-molecular Dieckmann cyclisation furnished a separable mixture of 5-methylbicyclo [3:3:1] nonan-3-one-l-carboxylic acid and 5-methylbicycIo[3:2:1] octan-7-one-I-acetic acid. 5-methyl-l-(isopropenylaceto)-bicyclo [3:3:1] nonan-3-one was then prepared from the 5-methylbicyclo [3:3:1] nonan-3-one-l-carboxylic acid chloride, but it was found to be impossible to cyclise the enedione to clovan-2:6-dione. Further modifications of 5-methyibicyclo [3:3:1] nonan-3-one-l-carboxylic acid and several alternative unsuccessful cyclisations to the clovene skeleton are described# PART TWO. 2-Carbethoxy-6-methylcyclohexanone, on treatment with acrolein, gave 3-(l-carbethoxy-2-keto-3-methyl-cyclohexylJ-proptonaldehyde which cyclised in concentrated sulphuric acid to ethyl 5-methylbicyclo[3:3:1] non-3-ene-9-one-l-carboxylate. Clemmensen reduction of the corresponding keto-acid furnished 5-methyIbicyclo[3:3:1]-non-3-ene-l-carboxylic acid, which by direct allylic oxidation followed by catalytic reduction afforded 5-motnyl-bicyclo[3:3:1] nonan-2-nonan-2-one-1-carboxylic acid. A stepwise allylic oxidation of the olefinic-ester has been devised. Treatment with t-butyl perbenzoate, followed by trans-esterlfication with sodium methoxide and oxidation with manganese dioxide afforded methyl 5-methylbicyclo[3:3:1]-non-3-ene-2-cne-l-earboxylate in good overall yield In a high state of purity. Hydrogenation and saponification furnished 5-methylbieyclo {3:3:1] nonan-2-one-1-carboxylic acid. Various synthetic pathways from this system to the clovene skeleton have been pursued. 5-Methylbicyclo [3:3:1] nonane-l-carboxylic acid has been synthesised by Molff-Kishner reduction of 5-methylbicyclo-[3:3:1] nonan-3-one-1-carboxyilc acid and by catalytic hydrogenation of 5-methyIbicyclo [3:3:1] non-3-ene-l-carboxylic acid. The structure of the parent bicyclo[3:3:1] nonane system is thus authenticated by its synthesis from two totally independent synthetic pathways.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1960
Depositing User: Enlighten Team
Unique ID: glathesis:1960-79395
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 31 Mar 2020 09:09
Last Modified: 31 Mar 2020 09:09

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