Rupak Dasgupta

Synthetic studies towards complex diterpenoids—VI : New synthetic routes to tetracyclic bridged-bicyclo[3.2.1]octane intermediates by intramolecular alkylation reactions through α-diazomethyl ketones of hydroaromatic γ,δ-unsaturated acids

Abstract Two new synthetic routes to a number of tetracyclic intermediates, for the total synthesis of some diterpenoids incorporating the bicyclo[3.2.1]octane moiety, are described. The syntheses of the bicyclo[3,2,1]octane derivatives begin with preparation of the hydroaromatic γ,δ-unsaturated acids 6, 15 and 17, and proceed via the α-diazomethyl ketones to the corresponding pentacyclic ketones 20, 24 and 26 by an intramolecular carbenoid insertion reaction, followed by a regiospecific acid-catalysed cleavage of the aromatic conjugated cyclopropane bond to the respective unsaturated ketones 27, 29 and 30. The second route to these unsaturated ketones involves a single step boron trifluoride etherate catalysed intramolecular alkylation in the corresponding α-diazomethyl ketones. The tetracyclic ketones 31, 34 and 35 were obtained in quantitative yields by a regiostereospecific hydrogenolytic cleavage of the aromatic conjugated cyclopropane bond in the respective pentacyclic precursors with PdC in ethanol. Under the same conditions, reduction of the styrenoid bond in the ketones 29 and 30 proceeds stereospecifically leading to 34 and 35 respectively, whereas the unsaturated ketone 27 gave a mixture of epimeric ketones 31 and 32 in a ratio of 69:31.

Condensed cyclic and bridged-ring systems. Part III. Regioselectivity and stereoselectivity in the acid-catalysed cyclisations of substituted benzylcyclohexanols. Stereocontrolled synthesis of some gem-carboxy–methyl-substituted hexahydrofluorene and hexahydro-5,9-methanobenzocyclo-octene derivatives

Treatment of ethyl 2-benzyl-2-hydroxy-1,3-dimethylcyclohexanecarboxylate (8) with polyphosphoric acid produced either (±)-c-2-benzyl-1,3-dimethylcyclohexane-r-1,c-3-carbolactone (6) or a mixture from which (1RS,4aRS,9aRS)2,3,4,4a,9,9a-hexahydro-1,4a-dimethyl-1H-fluorene-1-carboxylic acid (5a) was isolated in a moderate yield, depending upon the reaction temperature. Whereas aluminium chloride-catalysed cyclisation of the lactone (6) resulted in the stereospecific formation of (5SR,8RS,9SR,11RS)-5,6,7,8,9,10-hexahydro-8,11-dimethyl-5,9-methanobenzocyclo-octene-8-carboxylic acid (9), the epimeric t-2-benzyl lactone (7) produced a mixture of the hexahydrofluorene acid (5a) and the epimeric (8SR)-hexahydromethanobenzocyclo-octene acid (12), in high yields. By a similar process (±)-methyl t-2-benzyl-t-3-hydroxy-1,3-dimethylcyclohexane-r-1-carboxylate (4) gave the acid (9) and a mixture of hexahydrofluorene ester (5b) and (8SR)-hexahydromethanobenzocyclo-octene (13). Structures and configurations of the bridged-ring compounds were determined from chemical and n.m.r. spectral studies. Ready alkaline hydrolysis of the tertiary ester group in (5SR,8RS,9SR,11SR)-methyl 5,6,7,8,9,10-hexahydro-8,11-dimethyl-10-oxo-5,9-methanobenzocyclo-octene-8-carboxylate (11), through intramolecular oxo-group participation, revealed the stereochemistry of the ester group. The observed differences in the nature of products in polyphosphoric acid-catalysed cyclisation of (8) and the behavioural differences shown by the diastereoisomeric lactones (6) and (7) and the hydroxy-ester (4) in aluminium chloride-induced cyclisations are rationalised on the basis of steric and stereoelectronic factors in the intermediate cations as well as the thermodynamic stability of the products under reversible reaction conditions.

Synthetic studies towards complex diterpenoids—VII : Stereoselective synthesis and conformational analysis of all four possible racemates of 1,2,3,4,4a,9a-hexadydro-1-methylfluorene-1-carboxylic acids

Abstract Synthesis of the unsaturated acid 3 through H2SO4− catalysed cyclodehydration of the keto-ester 1 and its conversion to lactone 4 are described. The PPA induced cyclization of the keto-acid 9, on the other hand resulted in a stereoisomeric mixture of the octahydroanthracene derivatives 10a and 10b. The four possible racemates of the hydrofluorene derivatives 5, 6, 7, and 8 have been synthesized by chemical and catalytic reduction of 3 and 4. Li-liquid ammonia induced reductive cleavage of the lactone 4 proceeds with 65% retention and 35% inversion of configuration at the benzylic C-4a asymmetric centre to afford the trans and cis acids 5 and 8 respectively, while catalytic hydrogenolysis of 4 proceeds with inversion to give the cis acid 8. Li-liquid ammonia reduction of 3 gives trans acid 6 and cis 7 in 23% and 53% yields respectively, whereas catalytic hydrogenation of 3 affords 81% of cis acid 8 and 13% of cis acid 7. Some conformational properties of the methyl esters 17, 18, 19, and 20 have been deduced from chemical and NMR spectral data.

Condensed cyclic and bridged-ring systems. Part 13. Synthesis of the insect attractant hydrocarbon, 9a-carbamorphinan, and X-ray structural analyses of 9a-carbamorphinan-10-one and 9a-carba-14α-morphinan-10-one

The insect attractant bridged hydrocarbon, (±)-9a-carbamorphinan (1) and its inactive epimer, (±)-9a-carba-14α-morphinan (2), have been synthesized through (±)-9a-carbamorphinan-10-one (3), and (±)-9a-carba-14α-morphinan-10-one (4), prepared by polyphosphoric acid-catalysed cyclization of the double-bond isomeric benzyloctalins (7), derived from Huang-Minlon reduction of 1-benzyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (6), followed by the benzylic oxidation with chromic acid. The reduction of the easily accessible (±)-9a-carbamorphinan-16-one (10), the orthophosphoric acid-induced cyclization product of (6), provides an efficient alternative route to (1). The structures of the epimeric ketones (3) and (4) have been established by X-ray analysis.

Synthetic studies towards complex diterpenoids. Part 11. Stereochemically defined synthesis of the racemates of 1,2,3,4,4a,9a-hexahydro-7-methoxy-1-methylfluorene-1-carboxylic acid

Two simple synthetic routes to 1,2,3,4-tetrahydro-7-methoxy-1 -methylfluorene-1 -carboxylic acid (1b), a potential intermediate towards gibberellins, and its stereochemically defined transformations to three racemates of 1,2,3,4,4a,9a- hexahydro-7-methoxy-1 -methylfluorene-1 -carboxylic acid (4b)–(6b) are described. Catalytic hydrogenation of (1 b) yields a mixture of (5b) and (6b) in a ratio of ca. 95 : 5, whereas, lithium-liquid ammonia reduction of (1b) gives (4b) and (6b) in a ratio of ca. 23 : 77. A mechanism is proposed to explain the stereochemical results in the lithium–ammonia reduction of (1b) and related systems.

Condensed cyclic and bridged-ring systems. VII. Acid-catalysed cyclisation of methyl substituted benzylcyclohexanols. Factors influencing the nature of cyclisation products

The gross structures of the cyclised products from the acid-catalysed cyclisations of 2-benzyl-1, 3-dimethylcyclohexanol (6) and 1-benzyl-3, 5-dimethylcyclohexanol (11) revealing the influence of the structure of the benzylcyclohexanol derivative, and of the cyclisation reagent, have been evaluated. Polyphosphoric acid and aluminium chloride catalysed cyclisations of (6) result in the formation of predominantly 1, 4a-dimethyl-1, 2, 3, 4, 4a, 9a-hexahydrofluorene (7) and 4, 9-dimethyl-7, 8-benzobicyclo [3.3.1] non-7-ene (9) respectively. Under the same conditions, (11) produced cyclised products consisting mostly the benzobicyclo [3.3.1] non-7-ene derivative (12), characterised through 1,3-dimethyl-7,8-benzobicyclo [3.3.1] non-6-oxo-7-ene (14) by oxidation with chromium trioxide. Phosphorus pentoxide induced cyclisation of (6), followed by oxidation gave a mixture of the bridged-ring ketone (10) and the 9-oxohydrofluorene (8) in a ratio ofca. 3 : 2, whereas 2-benzyl-5-methylcyclohexanol (19) resulted in mostly 2-methyl-7,8-benzobicyclo [3.3.1] non-6-oxo-7-ene (19).