Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS:The six-membered heterocycles containing oxygen and nitrogen (tetrahydropyrans, pyrans, piperidines) are among the most common heterocyclic structures ubiquitously present in bioactive molecules such as carbohydrates, smallmolecule drugs, and natural products. Chemical synthesis of fully functionalized pyrans and piperidines is a research theme of practical importance and scientific significance and, thus, has attracted continuous interest from synthetic chemists. Among the numerous synthetic approaches, Achmatowicz rearrangement (AchR) represents a general and unique strategy that uses biomass-derived furfuryl alcohols as the renewable starting material to obtain fully functionalized six-membered oxygen/nitrogen heterocycles, which provides golden opportunities for organic chemists to address various synthetic challenges. This Account summarizes our 10 years of work on exploiting AchR to address some challenges in organic synthesis ranging from green chemistry and organic methodology to the total synthesis of natural products. We enabled the sustainable and safe use of AchR in a small (academia) or large (industrial) scale by developing two generations of green approaches for AchR (oxone-halide and Fenton-halide), which largely eliminate the use of the most popular, but more toxic and expansive, NBS and m-CPBA. This triggered our intensive interest in developing new green chemistry for important organic reactions, in particular, halogenation/oxidation reactions involving reactive halogenating species with the aim of eliminating the use of commonly used toxic halogen agents such as elemental bromine, chlorine gas, and various N-haloamide reagents (NBS, NCS, and NIS). We successfully employed oxone-halide and Fenton-halide as green alternatives to several mechanistically related organic reactions including arene/alkene halogenation, oxidation or oxidative rearrangement of indoles, oxidation of alcohols/thioacetals, and oxidative halogenation of aldoximes for the in situ generation of nitrile oxide. These green reactions are expected to have a solid impact on the future of organic synthesis in academia and industries. We expanded the synthetic utility of AchR by exploring several new transformations of AchR products and developed a cascade reductive ring expansion, reductive deoxygenation/Heck−Matsuda arylation, palladium-catalyzed C-arylation, and regiodivergent [3 + 2] cycloaddition with 1,3-dicarbonyls. These methodologies offer a new avenue to fully functionalized six-membered heterocycles.The synthetic utility of AchR was demonstrated in our total synthesis of 28 natural products with a pyran/piperidine moiety. The AchR-based strategy endows the total synthesis with scalability, sustainability, and flexibility. The green and scalable approaches developed in our lab for AchR allow us to easily obtain decagrams of synthetically valuable pyrans and/or piperidines with low risk and low cost from biomass-derived furfuryl alcohol/aldehyde.

The Untold Journey of Total Synthesis of Natural Products

“…Achmatowicz rearrangement was one of the key reactions used in the early stage of our uprolide synthesis and identified as a pluripotent reaction for our characteristic development in total synthesis, synthetic methodology, medicinal chemistry, and green chemistry. 23 In fact, before the completion of the uprolide synthesis, the PhD student (L. Zhu) was also attracted by Achmatowicz rearrangement and had developed the reductive ring expansion of spiroketals derived from Achmatowicz rearrangement through cascade acetal reduction (TiCl4/Et3SiH) and intramolecular oxa-Michael cyclization, which delivered my first independent publication 24 at HKUST (Scheme 9). As a principal investigator, I would like to extend its synthetic utility in total synthesis of natural products and therefore searched for natural products that could be potentially synthesized via Achmatowicz rearrangement.…”

“…Achmatowicz rearrangement was one of the key reactions used in the early stage of our uprolide synthesis and it was identified as a pluripotent reaction for our characteristic development in total synthesis, synthetic methodology, medicinal chemistry, and green chemistry. 23 In fact, before the completion of the uprolide synthesis, the PhD student (L. Zhu) was also attracted by Achmatowicz rearrangement and had developed the reductive ring expansion of spiroke-Scheme 5 Claisen rearrangement-induced formation of O-quinone methide and its applications to the synthesis of 2H-chromenes and benzofurans (L.…”

De novoasymmetric Achmatowicz approach to oligosaccharide natural products

“…, 1 and 2 ). 21 While we have explored many asymmetric approaches to furan alcohols, two preferred methods are the Noyori hydrogen transfer reduction of acylfurans ( 1 to 3 ) and the Sharpless dihydroxylation of vinylfurans ( 2 to 3 ) (Scheme 1). 6,22 Application of the Sharpless asymmetric aminohydroxylation (AA) 23 of vinylfurans provides access to azasugars 24 via the aza-Achmatowicz reaction.…”

Ru-Catalyzed Isomerization of Achmatowicz Derivatives: A Sustainable Route to Biorenewables and Bioactive Lactones

“…The exploitation of the densely functionalized Achmatowicz dihydropyranones in organic synthesis has been reported in many instances. , The hemiacetal and ketone groups received particular attention as numerous oxidations of the hemiacetal − and reductions of the ketone group − have been reported. To a lesser extent, the reduction of the olefin has also been described. ,, …”