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UBC Theses and Dissertations

Copper(I)-mediated intramolecular conjugate additions : total synthesis of (+/-)-1-desoxyhypnophilin and (+/-)-6,7-epoxy-4(15)-hirsuten-5-ol Skupinska, Krystyna A.


The use of Cu(I)-mediated intramolecular conjugate addition reactions of alkenyltrimethylstannane functions to α,β-unsaturated ketones to afford novel, functionalized tricyclic ketones 88-91, and 94 was investigated. Vinylogous esters of general structure 71 were prepared by alkylation of the vinylogous esters 76 (m=2) or 82 (m=l) with the allylic bromide 73 and Mel (for 71 where R¹=Me). Compounds 71 were readily transformed via either reduction or Grignard addition, followed by hydrolysis and dehydration of the resultant products, into enones of general structure 70. Treatment of compounds 70 with CuCN in DMSO provided tricyclic ketones 88-91 and 94. The analogous Cu(I)-mediated cyclization of aryltrimethylstannanes was also studied. Upon treatment with CuCN in DMSO, enones 112, 114, and 116 underwent cyclization to provide functionalized, tricyclic ketones 117-119, containing an aromatic ring. Further synthetic transformations involving olefinic ketones 88-91 and 54 were investigated. The oxidative cleavage of the tetrasubstituted double bond of 88-91 and 54 provided triones 142-146. Similar transformation of the olefinic ketals prepared from 88- 90 and 54 generated the ketal diones 135, 136, 137 and 141, respectively. Interestingly, treatment of the triones 142, 143 and 144 with a catalytic amount of p-toluenesulfonic acid in refluxing TFfF afforded products of the aldol condensation reaction (149, 148 and 147, respectively). Under similar reaction conditions triketone 146 generated compound 151. The Cu(I)-mediated intramolecular conjugate addition reaction of alkenyltrimethylstannane functions to enones was used in a key step of the total syntheses of the triquinane natural products, (±)-l-deoxyhypnophilin 61 and the related alcohol (±)- 62. Vinylogous ester 175 was obtained by alkylation of 82 with the allylic bromide 176. Compound 59 was prepared by treatment of the vinylogous ester 175 with methylmagnesium bromide, followed by treatment of the resultant material with ptoluenesulfonic acid. Conversion of 59 into the tricyclic ketone 60 was accomplished by treatment of the former substance with CuCN in DMSO in a sealed reaction vessel. The ketone function of 60 was reduced to the a alcohol, which was used in the hydroxydirected hydrogenation of the alkenic function to form the alcohol 196. The alcohol function of 196 was oxidized to provide ketone 174. Compound 174 was converted to the enone 197. Introduction of the a methylidene function gave the dienone 198. Monoepoxidation of the internal olefrnic function of 198 afforded the natural product (±)- 1-desoxyhypnophilin (61). Subsequent reduction of the ketone function of (±)-61 provided (±)-62.

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