A Simple and General Platform for Generating Stereochemically Complex Polyene Frameworks by Iterative Cross‐Coupling

Abstract

Aiming to maximally harness the inherent modularity of small molecules, we are pursuing the development of a synthesis strategy based on the iterative cross-coupling (ICC) of bifunctional building blocks representing the substructures that most commonly appear in natural products. [1, 2] In this vein, various combinations of trans-and cis-olefins are found in many small molecules derived from a wide range of biosynthetic pathways, including polyketides, hybrid peptide/ polyketides, polyterpines, and fatty acids (Scheme 1). [3,4] Enabling stereospecific access to these stereochemically complex polyene frameworks, we herein describe the development of a novel ICC platform that yields bifunctional iodopolyenyl N-methyliminodiacetic acid (MIDA) boronates in all possible stereoisomeric forms. The power of this approach has been realized in the first synthesis of the highly complex (E,E,E,Z,Z,E,E)-heptaene framework of the ion channel-forming polyene macrolide vacidin A.We recently reported three haloalkenyl MIDA boronates that enabled the preparation of a subset of polyene motifs by ICC.[2b] Albeit an important step forward, this collection only provided access to all-trans-polyene substructures and utilized polyenylchlorides. Accessing stereochemically complex polyene motifs is substantially more challenging because, in addition to the sensitivities observed with all polyenes to light, oxygen, and acid, frameworks containing cis double bonds can isomerize to the typically more thermodynamically stable all-trans structures. Moreover, poorly reactive polyenylchlorides proved to be minimally effective in complex applications.To overcome both of these limitations, we pursued a novel strategy for making iodopolyenyl MIDA boronates by ICC of iodide-masked [5] bifunctional building blocks. As shown in Scheme 2 A, the approach involves metal-selective crosscoupling of Sn/Ge bis-metalated olefins [6] to generate polyenylgermanium intermediates followed by stereospecific iododegermylations. [7] To the best of our knowledge, iododegermylations of polyenylgermanium species were unreported. However, the facility of halodegermylation [7] vs. halodesilylation [8] of simple olefins suggested that the former process had superior potential to be efficient and stereoretentive in the context of structurally and stereochemically complex polyene systems. Guided by this logic, we hypothesized that iterative cycles of metal-selective coupling/iododegermylation with core building blocks 1 and 2 (Scheme 2 B) could Scheme 1. Polyene natural products derived from a wide range of biosynthetic pathways. Scheme 2. A) A strategy for ICC of halogen-masked bifunctional building blocks. B) Core building blocks to enable general access to stereoisomeric iodopolyenyl MIDA boronates. C) New iodopolyenyl MIDA boronates for the synthesis of polyene natural products.

Amphotericin primarily kills yeast by simply binding ergosterol

“…These sensitivities can be magnified considerably when specific functional groups have been deleted from the polyene macrolide skeleton, which has previously precluded the synthesis of some targeted AmB derivatives, including C35deOAmB (29). To improve the efficiency and flexibility with which such complex small molecules can be prepared, we have recently developed a simple and modular synthesis strategy, analogous to iterative peptide coupling, in which building blocks having all of the required functional groups preinstalled in the correct oxidation states and with the desired stereochemical relationships are sequentially linked via iterative application of one mild reaction (30)(31)(32)(33)(34)(35)(36)(37)(38). Enabling this approach, we discovered that N-methyliminodiacetic acid (MIDA) is a highly effective ligand for reversibly attenuating the reactivity of a boronic acid and thereby permitting the controlled sequential assembly of bifunctional haloboronic acids (Fig.…”

Stereoselective Direct Chlorination of Alkenyl MIDA Boronates: Divergent Synthesis of E and Z α‐Chloroalkenyl Boronates

“…[10] Theu se of sp 3 -B MIDAb oronates, [11] which are typically bench-top and chromatographically stable solids, [12] circumvents potential C-to-O 1,3-boryl migration, and was the key to successful synthesis.T his result suggests the possibility of assembling a-haloalkenyl boronates through the direct halogenation of the corresponding alkenyl MIDA boronates.I ft his could be successfully conducted, the resulting a-haloalkenyl MIDAb oronates,w ith the boron presented in its protected form, might serve as ideal synthons for chemoselective iterative coupling reactions. [13] To realize such ap rocess,h owever,t he following potential challenges must be addressed. 1) Thewell-known deborylative halogenation reaction process may lead to an undesired alkenyl halide product.…”

The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

“…[95] This permits the iterative assembly of bifunctional halo MIDA-boronate building blocks through recursive cycles of boronic-acid-selective coupling followed by boron deprotection. [94,96,97] This method is also suitable for coupling highly unstable boronic acids because reactive boronic acid species can be slowly released during the reaction from the typically stable,c rystalline MIDA-boronate form. [98][99][100][101] To implement this modular approach, practical access to the corresponding MIDA-boronate building blocks is required.…”