Iterative Synthesis of 1,3-Polyboronic Esters with High Stereocontrol: Applications to Bahamaolide A and Polyfunctionalised Hydrocarbons

Abstract

Polyketide natural products often contain common repeat motifs, e.g., propionate, acetate and deoxypropionate, and so can be synthesized by using iterative processes. We report a highly efficient iterative strategy for the synthesis of polyacetates based on boronic ester homologation that does not require functional group manipulation between iterations. This process involves sequential asymmetric diboration of a terminal alkene, forming a 1,2-bis(boronic ester), followed by regio- and stereoselective homologation of the primary boronic ester with a butenyl metallated carbenoid to generate a 1,3-bis(boronic ester). Each transformation independently controls stereochemical configuration, making the process highly versatile, and the sequence can be iterated prior to stereospecific oxidation of the 1,3-poly(boronic ester) to reveal the 1,3-polyol. The methodology was applied to a 14-step synthesis of the oxopolyene macrolide bahamaolide A, and the versatility of the 1,3-polyboronic esters was demonstrated in various stereospecific transformations, leading to poly-alkenes, -alkynes, -ketones, and -aromatics with full stereocontrol.

A Pyridine Dearomatization Approach for the Gram Scale Synthesis of (±)-Sparteine

“…4 The ability of sparteine to coordinate alkyl lithium reagents and generate configurationally stable anions was first developed in the 1990s and is still commonly leveraged in modern total syntheses. 5,6 Despite its broad use and ready extraction from Lupinus plants, periodic supply chain issues have motivated the development of synthetic approaches to access sparteine or sparteine surrogates. 7 Here we report a concise gram-scale synthesis of (±)-sparteine from the commodity chemicals pyridine and glutaryl chloride.To date, over 20 total syntheses of sparteine have been reported.…”

Stereocontrolled Total Synthesis of Bastimolide B Using Iterative Homologation of Boronic Esters

“…Indeed, by use of a comprehensive knowledge base of individual reactions, iterative methods can also now be recognized by computer algorithms in the construction of complex molecules . We recently reported the iterative synthesis of 1,3-polyols through a sequence of asymmetric alkene diboration and selective homologation of the resulting primary boronic ester with a metalated butenyl TIB ester A (Figure B, M = Li, MgCl, TIB = 2,4,6-triisopropyl­benzoyl) . We reasoned that performing anti-Markovnikov hydroboration, instead of diboration, followed by homologation with the same metalated butenyl TIB ester A could provide an iterative strategy for the construction of 1,5-polyols in just two steps per iteration rather than three (Figure C).…”

“…With fragments 4 and 5 in hand, we turned our attention to their union through a stereocontrolled lithiation–borylation reaction. , Before embarking on this key C–C bond forming reaction, we wanted to explore what level of substrate control might be imparted by the neighboring six-ring acetonide moiety in TIB ester 5 . Previously, Hoppe reported that the five-ring acetonide in carbamate 30 exerted strong control over stereoselectivity in the deprotonation with s BuLi in the absence of diamine ligands (Scheme A) .…”