(-)-Siccanin (1), a natural product possessing significant antifungal properties, was synthesized enantioselectively via a biomimetic route. This synthetic route features two sequential radical cyclizations: a Ti(III)-mediated radical cyclization of epoxyolefin 48 to construct the B-ring, and a Suarez reaction to establish the tetrahyrofuran ring. Chiral chroman moiety of siccanin was prepared based on our recent development of the Pd-catalyzed asymmetric allylic alkylation (AAA) of phenol trisubstituted allyl carbonates. Several other members of the siccanin family were also synthesized including siccanochromenes A (2), B (3), E (6), F (7), and the methyl ether of siccanochromene C (55). These studies may shed light on the biosynthesis of this novel family of compounds.

Biomimetic enantioselective total synthesis of (-)-siccanin via the Pd-catalyzed asymmetric allylic alkylation (AAA) and sequential radical cyclizations.

Limonoids are highly oxygenated C13α-triterpenes and common secondary metabolites. Several hundred congeners have been isolated to date. The first total synthesis of (±)-limonin, the flagship congener of the limonoids, is now reported and features 1) a tandem radical cyclization generating the BCD ring system with the C13α configuration that is essential to the limonoids and a Robinson annulation to construct the limonoid androstane framework, 2) a singlet-oxygen cycloaddition and a Baeyer–Villiger oxidation to synthesize the highly oxidized D ring, and 3) a Suarez reaction to construct the unique AA′ ring system.

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Total Synthesis of Limonin

On pd-catalyzed cycloisomerization versus cycloreduction. a general strategy for drimane synthesis and a short total synthesis of siccanin

The polycyclic ring system which forms the nucleus of a series of sesquiterpene-phenol natural products, including the antimalarial 15-oxopuupehenol, can be constructed in racemic form in four efficient steps, the last of these being a stereoselective manganese(III) acetate-mediated radical cyclisation reaction.

A conjugate addition–radical cyclisation approach to sesquiterpene-phenol natural products

The total synthesis of hongoquercin B was carried out in 9 steps from trans,trans-farnesyl acetate using a palladium catalyzed decarboxylative π-farnesyl rearrangement of a diketo-dioxinone ester, aromatization and cationic diene-epoxide cyclization as key steps. This cascade tetracyclization simplifies the synthesis of terpenoid resorcylate natural products.

Cascade polyketide and polyene cyclizations: biomimetic total synthesis of hongoquercin B.

Total synthesis of dl-siccanin and dl-siccanochromene E

Total synthesis of racemic siccanin

11-Acetoxy-12bα-methoxymethyl-4,4,6aα,9-tetramethyl-1,2,3,4,4aα,5,6,6a, 12aβ,12b-decahydro-12H-benzo[a]xanthene (34), which has been expected as a promising key intermediate for the synthesis of siccanin (1), was synthesized via acid-catalyzed cyclization of 1α-(2-hydroxy-6-methoxy-4-methylbenzyl)-8aα-methoxymethyl-2,5,5-trimethyl-1,4,4aα,5,6,7,8,8aα-octahydronaphthalene (13) and isomeric exo olefin 21. The phenol acetate 34, however, was so resistant to oxidation that no corresponding 12-oxo derivative, which was expected to provide 11-acetoxy-12bα-acetoxymethyl-12-oxo-4,4,6aα,9-tetramethyl-1,2,3,4,4aα,5,6,6a,12aα,12b-decahydro-12H-benzo[a]xanthene (4) on epimerization at its C(12a) position as well as hydrofuran ring formation at the C(12) position with its angular methoxymethyl substituent, was obtained.

A Search for New Synthetic Routes toward Siccanin

The stereoselective synthesis of dl -siccanin (1) and dl -siccano-chromene E (2) has been described. Acid isomerization of nonconjugated octalone 11a, derived from known octalone 5, stereoselectively provided cis-fused octalone 12, from which cis -drimane aldehyde 31 was obtained. After condensation of 31 with lithio-orcinol dimethyl ether, the product 32 was treated with pyridinium chloride to give tetrahydrofuran 33 whose complete stereostructure was unambiguously established by an X-ray crystal analysis. While cyclization of monophenol 34, obtained by partial demethylation of 33, with sulfuric acid afforded siccanochromene E methyl ether (35), reaction of 34 with Lewis acid gave siccanin methyl ether (36) along with 35. In the latter cyclization, the formation of 36 was demonstrated to occur from initially formed 35. Finally, demethylation of 35 and 36 provided 2 and 1, respectively. A novel tetrahydrofuran formation by a neighboring participation, which was observed in hydroxy ketone 24 and diol 32, are also discussed.

Yukio Matsumura

Papers

Total synthesis of dl-siccanin and dl-siccanochromene E

Total synthesis of racemic siccanin

A Search for New Synthetic Routes toward Siccanin

Total Synthesis of dl-Siccanin and dl-Siccanochromene E.

A Search for New Synthetic Routes Toward Siccanin.