Ketalization/ring-closing metathesis: Synthesis of didemniserinolipid B and thromboxane B2

Ketalization/ring-closing alkene metathesis (K/RCM) is a powerful strategy for the desymmetrization of C2-symmetric diene diols. Intermolecular ketalization is an efficient, and high yielding means to desymmetrize C2-symmetric diene diol subunits via formation of a pseudo-C2-symmetric ketal intermediate. RCM facilitates the differentiation of diastereotopic alkenes to produce a dissymmetric 6,8-dioxabicyclo[3.2.1]octene. These bicyclic ketals are rigid scaffolds that can be exploited for chemo- and stereoselective synthesis. This K/RCM strategy was applied to concise, stereoselective synthesis of natural products didemniserinolipid B and thromboxane B2.;Didemniserinolipid B is an unusual serinolipid isolated from a cytotoxic extract of the tunicate Didemnum sp. This molecule possesses a central 6,8-dioxabicyclo[3.2.1]octane ring system and is an ideal target for K/RCM. Use of this strategy resulted in a concise modular synthesis, wherein the central 6,8-dioxabicyclo[3.2.1]octane core was constructed without the need for protecting groups. The axial C10 alcohol was established via a selective epoxidation, followed by reductive trans-diaxial epoxide opening. Etherification introduced the serinol moiety of the natural product, and cross metathesis was used to orthogonally introduce the ester-containing side chain. Didemniserinolipid B was thus prepared in 12 steps from a diene diol and ketone in 2.6% overall yield.;Thromboxane B2 is the stable hydrolysis product of thromboxane A2, a signaling molecule responsible for the clotting of blood. The K/RCM synthesis of thromboxane B2 resulted in the first application of this methodology to molecules containing an embedded vinylogous 1,2-diol segment. After construction of a 6,8-dioxabicyclo[3.2.1]octene via K/RCM, a key Sharpless asymmetric epoxidation established an oxirane on the endo face of this bicyclic acetal. Treatment of this oxirane with lithioacetonitrile resulted in trans-diaxial epoxide opening, and formation of the C7-C8 bond. Following methanolysis of the bicyclic acetal, 1,3-allyl alcohol transposition established the stereochemistry at C15. Thromboxane B2 was completed in 16 steps from a C2-symmetric (S,S)-diene diol, comparing favorably to previous syntheses of this molecule.