A Highly Step‐Economical Synthesis of Dictyostatin

Abstract

In 1994 Petit reported the isolation and anti-cancer activity of the marine sponge-derived macrolide dictyostatin. [1] Wright subsequently isolated a sample that allowed initial biological characterization of dictyostatin as a potent inducer of tubulin polymerization, [2] and that was used by Wright and Paterson to make a full structural assignment in 2004. [3] This assignment was confirmed soon thereafter by total syntheses by Paterson [4] and Curran, [5] and the material thus obtained facilitated more detailed characterization of dictyostatin's mechanism of action. [6,7] Total syntheses by Phillips [8] and Ramachandran, [9] formal syntheses by Micalizio [10] and Cossy, [11] a synthesis of C(9)-epi-dictyostatin by Gennari, [12] second generation syntheses by Paterson [13] and Curran, [14] and several fragment syntheses [15] followed these initial reports. In addition, the Paterson/Wright [16] and Curran/Day [17] teams have reported extensive SAR studies, while the Paterson/Díaz/ Jiménez-Barbero [18] and Curran/Snyder [19] teams have advanced models for the interaction of dictyostatin with the taxane binding site on -tubulin. Because dictyostatin and some of the prepared analogs are among the most potent microtubule-stabilizing agents characterized to date, there has been and continues to be intense interest in the possibility of advancing dictyostatin or an analog thereof into the clinic, a goal which might be facilitated by the development of a significantly more efficient and step-economical synthesis. As part of a larger program devoted to the development of new strategies and methods for the synthesis of complex and precious marine macrolides with high levels of step-economy, efficiency, and scalability, [20] we have developed and report herein a synthesis of dictyostatin that comprises just 14 steps in the longest linear sequence.Similarly to the previous syntheses of dictyostatin, our retrosynthesis disconnected the target into three roughly equally complex fragments, 1, 2, and 3 (Fig. 1A). It was in the synthesis of the fragments, and especially the C(12)-C(14) and C(20)-C(22) stereotriad-containing fragments 1 and 2 that we saw an opportunity for a streamlining of the synthesis. Ever since its introduction by Roush more than 20 years ago, what might be called the "Roche ester strategy" has reigned supreme for the synthesis of such stereotriads, [21] and indeed was employed in the Paterson, Curran, and Ramachandran syntheses, in most of the approaches reported by others, and in most of the syntheses of the related natural product discodermolide. [22] In this approach, the requisite enantiomer of the Roche ester is protected, reduced, and oxidized to the corresponding aldehyde, which is then subjected to diastereoselective crotylation, followed by several additional functional group manipulations (Fig. 1B). Thus, these stereotriad syntheses typically comprise at least 6-7 steps of which all Correspondence to: James L. Leighton, leighton@chem.columbia.edu. Supporting information for this article is ava...

Recent advances in microtubule-stabilizing agents

“…role for the further synthesis researches [91][92]. In 2013, Stephen et al accomplished the total synthesis of dictyostatin via three fragment syntheses, and the most advantage of their strategy is that they used an unrivalled step-economy route with one-pot procedures at several points, and each of the three fragments was prepared by commercial reagents just in 4 or 5 steps, which further promoted the synthesis efficiency of dictyostatin [93].…”

Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

“…Due to the development of powerful and uniquely enabling new methodologies and strategies including the direct diaminophenol-activated complex fragment coupling crotylsilylation and n -Bu 4 NBr-catalyzed alkallylsilylation reactions, the synthesis described here proceeds in 22 steps in the longest linear sequence (1.4% overall yield) and 68 total steps. This is important not only in advancing the frontiers of step economy and efficiency in the synthesis of non-aromatic polyketide natural products 59 – 62 , but also in facilitating the compound development efforts necessary to begin evaluating whether the spongistatins, properly configured for use in ADCs and other conjugates, can serve as effective payloads. In the present case, this step economy and efficiency have allowed us to validate the D-ring redesign and rendered the synthesis and evaluation of linker functional group-equipped analogs 5b and 5c a far less laborious and time- and resource-intensive effort and have allowed us to secure a crucial proof-of-concept result in the form of 5c , a highly potent linker-equipped analog of the spongistatins.…”

Synthesis of (+)‐Discodermolide by Catalytic Stereoselective Borylation Reactions

“…Hydroformylation of this substrate class has been addressed by Landis et al. using the bisdiazaphos ligand,19 and similar reactions have been employed by the groups of Burke20 and Leighton21 for the construction of polypropionate arrays. Unfortunately, the bisdiazaphos ligands are not readily available.…”