A general strategy for the synthesis of cladiellin diterpenes: enantioselective total syntheses of 6-acetoxycladiell-7(16),11-dien-3-ol (deacetoxyalcyonin acetate), cladiell-11-ene-3,6,7-triol, sclerophytin A, and the initially purported structure of sclerophytin A.

Enantioselective total syntheses of the cladiellin diterpenes, 6-acetoxycladiell-7(16),11-dien-3-ol (deacetoxyalcyonin acetate, 6), cladiell-11-ene-3,6,7-triol (1), sclerophytin A (8), and tetracyclic diether 7, have been achieved by differential elaboration of tricyclic allylic alcohol 57. The central step in these syntheses is acid-promoted condensation of alpha,beta-unsaturated aldehydes 45, 69 or 87, and cyclohexadienyl diol 44 to form, with complete stereocontrol, the hexahydroisobenzofuran core and five stereocenters of these cladiellin diterpenes. These syntheses also feature stereospecific photolytic deformylation of beta,gamma-unsaturated aldehydes 46, 70, and 71 to remove the extraneous carbon introduced in the Prins-pinacol step; chemo- and stereoselective hydroxyl-directed epoxidation of 49, 72, and 90 followed by regioselective reductive opening with hydride to install the C3 tertiary hydroxyl group; and a diastereoselective Nozaki-Hiyama-Kishi cyclization of iodoaldehyde 56 to forge the oxacyclononane ring and the C6 hydroxyl stereocenter. Other key transformations include chemo- and stereoselective hydroxyl-directed epoxidation of tricyclic allylic alcohol 57 followed by regioselective reductive opening with hydride to install the C7 tertiary hydroxyl center of 1 and 8; chemo-, regio-, and stereoselective intramolecular oxymercuration-reductive demercuration of dienyl diol 62 to form the bridging tetrahydropyran ring of tetracyclic diether 7; and photochemical isomerization of the endocyclic double bond of 92 and 1 to give exocyclic congeners 7 and 8. The absolute stereochemistry of the synthetic products originates from two chiral nonracemic starting materials, (S)-(+)-carvone and (S)-(-)-glycidol. These syntheses define a versatile and concise strategy for the total synthesis of cladiellin diterpenes and provide additional illustrations of the uncommon utility of pinacol-terminated cationic cyclizations for the stereocontrolled synthesis of complex oxacyclic products.

Enantioselective syntheses of authentic sclerophytin A, sclerophytin B, and cladiell-11-ene-3,6,7-triol.

[figure: see text] Two distinctively different total syntheses of natural sclerophytin A in its revised structural formulation are reported. The first proceeds from (S)-carvone via a cladiellene triol and involves photoisomerization of the double bond. The second route makes use of (5S)-5-(d-menthyloxy)-2(5H)-furanone, which is subjected to cycloaddition, Claisen ring expansion, and regiocontrolled dihydroxylation tactics.

Stereoselection in the Prins-pinacol synthesis of acyltetrahydrofurans.

[reaction: see text]. Depending upon the nature of the alkene and allylic substituents, acid-promoted rearrangements of acetals derived from anti allylic diols give 12 or stereoisomeric acyltetrahydrofurans 13. Stereoelectronic effects of the allylic substituents and the extent of bonding in the Prins cyclization transition state are central features of a proposed new model for predicting stereoselection in the Prins-pinacol synthesis of acyltetrahydrofurans.

Stereoselection in the prins-pinacol synthesis of 2,2-disubstituted 4-acyltetrahydrofurans. Enantioselective synthesis of (-)-citreoviral.

[reaction: see text] The condensation of allylic diols with unsymmetrical ketones proceeds with high stereoselection to form 2,2-disubstituted 4-acyltetrahydrofurans when the alpha-substituents of the ketone differ substantially in size. A Prins-pinacol condensation of this type is the central strategic step in an enantioselective synthesis of (-)-citreoviral.