Polycyclic ethers, stereoselective synthesis

Boron trifluoride etherate promotes the fWt/a-selcctivc oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The oxacyclization transformations may mimic ringforming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products <2002JOC2515>. 

Crimmins, M.T, McDougall, P.J., and Emmitte, K.A. (2005) A convergent coupling strategy for the formation of polycyclic ethers stereoselective synthesis of the BCDE flagment ofbrevetoxin A. Org. Lett., 7,4033- 36. 

Maemoto, M., Kimishima, A., and Nakata, T. (2009) Stereoselective synthesis of 2,6-syu-dimethyl-tetrahydropyran derivatives, important segments of marine polycyclic ethers, by unique insertion of the methyl group. Org. Lett., 11, 4814-4817. 

The stereoselectivity seen in the reduction of the seven-membered ketone above has proved to be general. This particular result, rationalized by the propensity for pseudoaxial hydride addition under Luche conditions, proved useful in the convergent total synthesis of Gymnocin-A, a polycyclic ether toxin isolated from the red tide dinoflagellate—Karenia mikimotoi.u The Luche reduction was used for the production of allylic alcohol 9 from ketone 8 in 84% yield. Luche conditions were similarly applied to the synthesis of the related polycyclic ether toxin gambierol.12... 

In the total synthesis of (-)-gambierol, a marine polycyclic ether toxin, by two groups [28,29], the sensitive terminal (Z, Z)-triene side chain in 53 was constructed as a crucial step by stereoselective coupling of (Z)-alkenyl iodide 51 with (Z)-l,4-pentadienylstannane 52 in DMSO to afford 53 in 72% yield without isomerization of the triene system. Pd2(dba)3 and Cul as catalysts and TFP (1-3) as a ligand were used [29]. Similar coupling using the less reactive alkenyl bromide provided 53 in 43 % yield [28]. 

A rhenium oxide-catalyzed methodology has been developed for stereoselective polycyclic ether synthesis (Scheme 41). For example, the epoxide (192) reacts to provide the spirocyclic product (193) as the only stereoisomer formed. It is suggested that the ketone acts as a stereochemical conduit to relay the chirality of the epoxide through the cascade reaction. The initial cyclization provides the carboxonium ion (194) and then ion (195) precedes spirocycle formation. 

In 2011, Corey s group found that Inij and InBr3 were effective catalysts for the it activation of C=C triple bonds to initiate the conversion of chiral propargylic alcohols or silyl ethers to polycyclic products in excellent yields with high stereoselectivity (Scheme 9.24) [35]. The method was applied to the synthesis of chiral fused hexacyclic ring systems with the creation of multiple new stereocenters. 

The product distribution depends on the nickel-phosphine ratio and the best yield of A (70% cis/trans = 19/1) is obtained when bisdiene is treated in toluene at 60 °C with llmol% Ni(COD)2 and 33mol% PhjP [124]. When a phosphite ligand is used, cyclohexene B or cyclopentane C derivatives are the major products. Functional groups such as esters, ketones, or ethers remain intact under the reaction conditions. The reaction is stereoselective and has been used for the synthesis of polycyclic natural products [125-128]. For example, the key intermediate for the enantioselective synthesis (-H)-asteriscanolide is obtained from a similar synthetic route [128]. The use of this strategy for the construction of a taxan skeleton has been briefly explored [129]. 

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