Spongipyran Synthetic Studies. Evolution of a Scalable Total Synthesis of (+)-Spongistatin 1.

Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)-C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)-C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third- generation syntheses, designed with the goal of accessing one gram of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mgs of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.

Synthetic studies toward (-)-FR901483 using a conjugate allylation to install the C-1 quaternary carbon.

Two approaches to the aza-tricyclo dodecane skeleton of (-)-FR901483 are reported. Both routes utilized a Grignard addition to an N-acylpyridinium salt to establish the absolute stereochemistry at C-6 and a highly diastereoselective conjugate allylation reaction to form the quaternary center at C-1 of the natural product in an excellent yield. Although the desired polysubstituted piperidine intermediates were prepared regio- and stereoselectively, the construction of the C-8/C-9 bond connectivity could not be achieved. All attempts at a pinacol cyclization or an intramolecular 6-exo-tet epoxide opening were unsuccessful because of an unfavorable A(1,3) strain inherent in the molecule.

Spongistatin synthetic studies. evolution of a scalable synthesis for the EF fragment of (+)-Spongistatin 1 exploiting a Petasis-Ferrier union/rearrangement tactic.

[structure: see text] An efficient, stereocontrolled, and scalable second-generation synthesis of (+)-3, an advanced EF subtarget for the total synthesis of (+)-spongistatin 1, has been achieved. Highlights of the strategy include preparation of the F-ring pyran via a Petasis-Ferrier union/rearrangement sequence and installation of the chlorodiene side chain employing a cyanohydrin alkylation. The longest linear sequence, 26 steps, proceeds in 8.3% overall yield.