Open Collections

Lithium-iodine exchange initiated intramolecular additions : application of a novel annulation protocol to the total synthesis of (±)-mangicol F

University of British Columbia

This dissertation is divided into two sections: methodological work and application of one of the developed methods to the total synthesis of the racemic version of naturally occurring mangicol F. In the first section, the possibility of effecting intramolecular conjugate addition reactions initiated by lithium-iodine exchanges was explored. The required substrates for the initial study were cyclic α,β-unsaturated ketones (Michael acceptors) bearing alkenyl iodide functionalized sidechains. The preparation of such substrates began with the facile hydriodination of acetylenic esters, supplying alkyl Z-iodoalkenoates such as 66, which were subsequently converted (in two steps) into their corresponding allylic bromides. Alkylation of cyclic vinylogous esters such as 45 with allylic bromides 44 afforded compounds such as 46 which were converted into the required enone substrates, 47. Stereoselective intramolecular conjugate additions of the anions of these substrates, generated by lithium-iodine exchange reactions, were cleanly effected at -78 °C in the presence of the additives TMSC1 and HMPA, furnishing czs-fused bicyclic ketones of general structure 48 in very good yields. In addition, this methodology was extended to the formation of tricyclic ketones (ie. 59 and 61) via the use of cyclic alkenyl iodides (58) and aryl iodides (60), respectively. The substrates required for the second methodology project were the vinylogous ester intermediates (46). Intramolecular addition of alkenyl anions, generated by lithium-iodine exchange, to the carbonyl function of the vinylogous esters furnished, after an acid-promoted hydrolysis-dehydration protocol, bicyclic dienones of general structure 50 in excellent yields. This methodology was extended to the formation of tricyclic compounds such as aryl enone (172) and furyl enone (177) via the use of aryl iodide (143) and furyl iodide (162) substrates, respectively. To commence the work described in the second part of this dissertation, the second method described above was employed to prepare approximately 30 g of bicyclic dienone 164. This latter material was the starting material for the total synthesis of the tetracyclic sesterterpene diol, (±)-mangicol F (52). Stereoselective hydrogenation of 164 with Lindlar's catalyst supplied enone 198. The third ring in the tetracyclic core of (±)-mangicol F was installed via an annulation sequence that involved the stereoselective conjugate addition of cuprate 208 to the enone function of 198. After conversion of the tributylgermanium function in 210 to the iodide in 211, a palladium-catalyzed coupling between the alkenyl iodide and the enolate anion of the ketone was effected to complete the annulation sequence, by producing enone 212. Stereoselective hydrogenation of the alkene function in tricyclic enone 212 followed by IBX-promoted dehydrogenation of the resulting ketone furnished enone 239. The fourth ring in the core of (±)-mangicol F was installed via an annulation protocol that began with the conjugate addition of organocopper species 249 to enone 239, furnishing 240. Base-promoted ring closure followed by stereoselective methylation of the resulting tetracyclic ketone afforded compound 236. Dehydration of the alcohol resulting from the reduction of the carbonyl function in 236 furnished diene 194. The final quaternary chirality centre in the core of (±)-mangicol F was introduced via a chemoselective cyclopropanation reaction, using ethyl diazoacetate. After conversion of the ester function in 291 into its corresponding aldehyde, selective cleavage of the cyclopropyl C - C bond distal to the spiro-junction was achieved via hydrogenolysis, supplying 193. Addition of the alkenyllithium 347 to aldehyde 193 afforded a diastereomeric mixture of alcohols 348 and 349. Reaction of the hydroxyl function of 348 with acetic anhydride and ketohydroxylation of the alkene function on the sidechain of the resulting acetate supplied the mono-acetate of mangicol F. Hydrolysis of the acetate function afforded (±)-mangicol F (52). The total synthesis of mangicol F was effected in 21 steps and in 0.94% overall yield from known materials. Further, due to X-ray crystallographical data obtained at a late stage of the synthesis, the relative configuration at the hydroxyl bearing carbon chirality centre in the sidechain was assigned, information that had not been determined in the original isolation report due to lack of material. [Chemical Diagrams]

Thesis/Dissertation

application/pdf

2009-11-27

For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.

http://hdl.handle.net/2429/15931

Chemistry

University of British Columbia

UBCV

DSpace