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Total synthesis of (+-) neoverrucosan-5B-ol, (+-)-homoverrucosan-5B-ol, (+-)-verrucosan-2B-ol, and (+-)-(3R,4R,5R,6S,9R)-cyatha-12,18-diene : a new cyclohexenone annulation sequence

University of British Columbia

The total syntheses of four structurally related, naturally occurring compounds, (±)­verrucosan-2β-ol (61), (±)-neoverrucosan-5β-ol (62), (±)-homoverrucosan-5β,-ol (63), and (±)-(3R, 4R, 5R, 6S, 9#)-cyatha-12,18-diene (64) are discussed in the first part of this thesis. In connection with the total syntheses of the natural products 61-64, a new bifunctional reagent mediated cyclohexenone annulation sequence was developed, but attempted application of this sequence to the natural product syntheses was not successful. The generality, scope and synthetic utility of this new annulation method are described in the second part of this thesis. The syntheses of the natural products 61-64 started with the conversion of 3 ­methylcyclohex-2-en-l-one (140) into the known bicyclic enone 179. Recently developed methodology from our laboratory was used as a key step and involved the stereoselective conjugate addition reaction of the cuprate reagent 192 to the enone 179 with control of the 5,6 ring-juncture stereochemistry to afford the ketone 60. A double alkylation of 60, first with the bifunctional reagent 281, and then with methyl iodide, provided the ketone 287. Functional group manipulations were used to convert 287 into 273, which underwent an aldol cyclization-dehydration sequence to provide the corresponding enone 72. Dissolving metal reduction of the latter material afforded the tricyclic ketone 171. From compound 171, diverging synthetic routes gave the cyathane natural product 64 and the three verrucosane­type natural products 61-63. Ring expansion of 171 and functional group manipulations led to 64. Conversion of 171 into the tricyclic enone 174 involved a series of functional group transformations. Separate synthetic routes from compound 174 led to (±)-neoverrucosan-5β­ol (62) or (±)-verrucosan-2β-ol (61), both of which reacted with acid to produce (±)­ homoverrucosan-5 (5β-ol (63). The four racemic natural products were tested against the P388 murine leukemia cell line and possessed cytotoxicity with ED₅₀'s in the range of 1.7­ 21 µg/mL. The newly developed cyclohexenone annulation sequence involved alkylation of N,N­dimethylhydrazones of general structure 32 with the Afunctional reagent 253 to provide 354. Conversion of 354 into the keto alkenyl iodide 356, followed by n-BuLi-mediated cyclization of 356 and oxidative rearrangement of the resultant allylic alcohol 358 provided the cyclohexenone 359. Each step is experimentally simple, tolerates a variety of ring sizes and functionality, and proceeds in very good yield. [Formula]

Thesis/Dissertation

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2009-06-18

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http://hdl.handle.net/2429/9454

Chemistry

University of British Columbia

UBCV

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