Africanol synthesis

In another attempt to mimic the in vivo cyclization of humulene, Mlotkiewicz et have shown that treatment of humulene 4,5-epoxide (272) with boron trifluoride etherate leads to the formation of the two tricyclic alcohols (273) and (274) in 70% yield. The carbon skeleton of these two compounds is exactly that found in africanol (276) and the more recently isolated keto-angelate (275). Further elaboration of the alcohol (273) has in fact resulted in a biomimetic synthesis of the keto-alcohol corresponding to (275). This work constitutes the first example of the direct conversion of a humulene derivative into a naturally occurring compound. 

Paquette s synthesis of africanol advanced through the a,3-unsaturated acid (41). Addition of 2.2 equiv of methyllithium followed by standard work-up gave a 71% yield of the methyl ketone (42 equation 31). ... 

The last step in the synthesis of sesquiterpenoids africanol (44) and isoafricanol (45) employed the Simmons-Smith cyclopropanation with diethylzinc/diiodomethane. The addition occurred from the less hindered convex face bearing a hydroxy group to give the sesquiterpenes in good yield. ... 

A second example of the Nozaki ring expansion can be seen at the very beginning of the synthesis of africanol, followed by classical transformations to product (Scheme 54) [91]. 

The orthoester Johnson-Claisen rearrangement has been extended with great success for many applications in natural product synthesis. Paquette utilized the efficient 1,3-chirality transfer of the rearrangement in studies of africanol. 

Hoveyda et al. reported the enantioselective synthesis of (+)-africanol through asymmetric olefin metathesis followed by one-carbon contraction via decarbonylation (Scheme 8.16) [65]. When symmetrical norbornene 84 was treated with a chiral molybdenum catalyst, desymmetrization took place to afford the chiral bicycle 85 in an enantioselective fashion. The resulting vinyl terminus was subsequently transformed into a methyl group via hydroboration, oxidation to aldehydes, and decarbonylation. Further manipulations of the functional groups gave (+)-africanol. 

Hoveyda and Schrock s laboratories have pioneered in this field and developed a number of effective chiral Mo-based catalysts for enantioselective alkene metathesis [28]. A recent apphcation of catalytic enantioselective alkene ROM/RCM in the total synthesis of (+)-africanol (135) was reported by Hoveyda et al. (Fig. 36) [87]. Treatment of meso tertiary TBS ether (136) with 3 mol% chiral alkylidene [Mo] catalyst (137) smoothly afforded the desired bicycle (138) in 97% yield and 87% ee. 

The transannular cationic cyclization was used by Shira-hama and co-workers for synthesis of bicyclohumule-none and africanol. Interestingly, different modes of... 

Shirahama H, Hayano K, Kanemoto Y, Misumi S, Ohtsuka T, Hashiba N, Furusaki A, Murata S, Noyori R, Matsumoto T. Conformationally selective transannular cyclizations of humulene 9,10-epoxide. Synthesis of the two skeletally different cyclohumulanoids dl-bicyclohumulenone and dl-africanol. Tetrahedron Lett. 1980 21 4835-4838. 

SCHEME 24.41. Total synthesis of the africanol using AROM/RCM. 

Weatherhead GS, Cortez GA, Schrock RR, Hoveyda AH. Mo-catalyzed asymmetric olefin metathesis in target-oriented synthesis enantioselective synthesis of (—)-africanol. Proc. Natl. Acad. Sci. U.S.A. 2004 101 5805-5809. 

Paquette, L.A. and Ham, W.H. (1987) Total synthesis of the marine sesquiterpenes dactylol and africanol de novo construction of a cydooctanoid natural product from cycloheptane precursors. J. Am. Chem. Soc., 109, 3025-3036. 

Scheme 12.2 Synthesis of Africanol through an enantios-elective ring-opening/ring-closing metathesis (ROM/RCM) reaction. Ar = 2,4,5-Me3C6H2.

Enantioselective Synthesis of Africanol by a Ring-opening/Ring-closing Metathesis Reaction... 

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