| dc.description.abstract | Enantiospecific syntheses of (+)-valerane 2, (-)-valeranone 1, 5-epicyperanes 107 and 123, and cyperane 134 have been accomplished. To begin with, (R)-carvone 38 was converted into the allyl alcohol 40 in three steps. An ortho ester variant of the Claisen rearrangement of the allyl alcohol 40 furnished the ester 41 in a stereospecific manner. An Amdt-Eistert based homologation of the ester 41 generated the homologated ester 65, which was converted into the diazo ketone 60. Intramolecular cyclopropanation of the diazo ketone 60 with anhydrous copper sulfate and copper in refluxing cyclohexane furnished the tricyclic ketone 62. Regioselective cyclopropane ring cleavage followed by hydrogenation of the isopropenyl double bond transformed the tricyclic ketone 62 into (+)-valeran-3-one 63. Deoxygenation via the thioketal 71 converted (+)-valeran-3-one 63 into (+)-valerane 2.
For the synthesis of valeranone 1, the hydrindanone 53, obtained from the diazo ketone 42 in four steps, was transformed into the lactone 72 employing a regioselective Baeyer-Villiger oxidation. Two alternative strategies were developed for the conversion of the lactone 72 into (-)-valeranone 1. The first strategy was based on the regiospecific protection of the primary alcohol in the diol 73. Reduction of the lactone 72 using LAH generated the diol 73. Selective protection of the diol 73 furnished the hydroxy ether 76, which on oxidation generated the keto ether 77. The keto ether 77 on treatment with tetrabutylammonium fluoride furnished the hemiketal 79, which on oxidation with PCC furnished the keto aldehyde 57. The second strategy was based on the Wittig olefination of the lactol 80. Controlled reduction of the lactone 72 with DIBAL furnished the lactol 80, which on treatment with methylenetriphenylphosphorane generated the hydroxy olefin 81. Oxidation of the hydroxy olefin 81 with PCC gave the keto olefin 82, which on ozonolysis furnished the keto aldehyde 57. Intramolecular aldol condensation of the keto aldehyde 57 furnished the (+)-valerenone 59, whose conversion to (-)-valeranone 1 has already been reported.
In continuation of the synthesis of valeranes, an enantiospecific approach to cyperane 84 and its analogues employing a similar strategy was developed. 3-Ethylcarveol 108 was prepared from (-)-carvone 38 via alkylative 1,3-enone transposition followed by stereoselective reduction of the resultant ethylcarvone 109. Ethyl carveol 108 was transformed into ester 111 employing the Johnson's orthoester Claisen rearrangement. Intramolecular cyclopropanation of the diazo ketone 104, derived from the ester 111, furnished the tricyclic ketone 106. Regioselective cyclopropane ring cleavage transformed the tricyclic ketone 106 into 5-epicyperane 107.
Similarly, the sequence starting from benzyl carveol 115, obtained from (-)-carvone 38, generated the bicyclic ketone 121. Oxidative cleavage of the phenyl group transformed the bicyclic ketone 121 into epicyperane 123 containing a carboxyl group at the C-15 position of cyperane. Synthesis of the cyperane carbon framework 84 was achieved by a similar reaction sequence via the enol/alcohol 126, obtained by a Mitsunobu reaction of the syn-alcohol 108. Reaction of the allyl alcohol 108 with triphenylphosphine and diethyl azodicarboxylate in the presence of benzoic acid generated the benzoate 125, which on hydrolysis furnished the anti-alcohol 126. The ortho ester Claisen rearrangement of the allyl alcohol 126 furnished the ester 127, which was converted into diazo ketone 130. Intramolecular cyclopropanation of the diazo ketone 130 derived from the ester 127 furnished the tricyclic ketone 131. Regioselective ring cleavage followed by hydrogenation of the isopropenyl group transformed the tricyclic ketone 131 into bicyclic ketone 133. Oxidative degradation of the phenyl group transformed the bicyclic ketone into cyperane 134 containing a carboxyl group at the C-15 position.
A general and efficient enantiospecific strategy for the construction of optically active bicyclo[4.3.1]decanes and spiro[5.5]undecanes was developed employing an acid-catalyzed intramolecular type II carbonyl-ene reaction. Treatment of the aldehyde 78, obtained from carvone 73 via alkylative enone transposition, reduction, and Claisen rearrangement sequence, with boron trifluoride etherate furnished the bicyclo[4.3.1]decanols 84 and 85 in a highly regio- and stereoselective manner. The generality of the methodology was established using the aldehydes 106-108 and 138, containing competing sidechains, as substrates. Alkylative 1,3-enone transposition followed by stereoselective reduction transformed carvone 73 into the allyl alcohols 115-117 and 144. Claisen rearrangement of the allyl alcohols 115-117 and 144 furnished the aldehydes 106-108 and 138. Intramolecular ene reaction of the aldehydes 106-108 and 138 with boron trifluoride etherate furnished the bicyclo[4.3.1]decanols 120, 124, 125, and 139. However, when the reaction was carried out with the aldehydes 149 and 167, containing a methallyl group, spiro[5.5]undecanes 151 and 159 were obtained via participation of the methallyl group in the ene reaction. Based on these results, a general methodology for spirocyclohexannulation of cyclic ketones was developed. | |
