Spongipyran synthetic studies. Evolution of a scalable total synthesis of (+)-spongistatin 1

Abstract

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.

Organocatalysis in Total Synthesis

“…It is easy to find in the literature, many examples of application in total synthesis of this catalysis through different reactions (Fig XII.2). One of the most extensively explored has been aldol reaction, key step in the syntheses of callipeltoside C [7], convolutamydine A, B, E [8], (+)-przewalskin B [9], ()-salinosporamide A [10], (+)-spongistatin 1 [11], (S)-()-3-butylphthalide [12], and ()-anominine [13] among many other examples. The Mannich reaction, a classical method for the creation of new C-C bonds, can be found in the synthesis of natural products, such as (2S,3R,4S)-4-hidroxyisoleucine [14].…”

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…Smith and coworkers have used a Ca(II)-mediated equilibration strategy to access the singly anomeric CD spiroacetal of spongistatin-1, 15 [26] (Scheme 5). Oxidative removal of the dithiane 11 and subsequent spirocyclization afforded spiroacetals 12a and 12b in excellent yield, favoring the undesired doubly anomeric isomer.…”

“…However, transformation to the triol species 13b (doubly anomeric isomer not shown) allowed selective equilibration to the mono-anomeric spiroacetal 14b due to favorable chelation of the calcium ion. [26] A recent attempt to selectively control the dehydrative spirocyclization of a dihydroxyketone using a chiral-directing element has been reported by Paley et al [51]. Incorporation of an iron(0)-tricarbonyl diene complex into the dihydroxyketone skeleton was used to direct spirocyclization (Scheme 6).…”

Ether Transfer Methodology: Application to the Synthesis of Polyketide Natural Products

“…Among them, the spongistatins highlighted the method in a scalable total synthesis. 13,14 The spongistatins, isolated by Pettit in 1993, belong to a family of marine natural products that represents one of the most potent antimiotic and growth inhibitory substances discovered with the potential to become a new lead for cancer chemotherapy. [15][16][17] To overcome the low abundance of this natural product, seven total syntheses have been developed to date.…”