https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates

The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes.

The total synthesis of natural products and biologically active compounds, such as pharmaceuticals and agrochemicals, has reached an extraordinary level of sophistication. We are, however, still far away from the 'ideal synthesis' and the state of the art is still frequently hampered by lengthy protecting-group strategies and costly purification procedures derived from the step-by-step protocols. In recent years several new criteria have been brought forward to solve these problems and to improve total synthesis: atom, step and redox economy or protecting-group-free synthesis. Over the past decade the research area of organocatalysis has rapidly grown to become a third pillar of asymmetric catalysis standing next to metal and biocatalysis, thus paving the way for a new and powerful strategy that can help to address these issues - organocatalytic cascade reactions. In this Review we present the first applications of such asymmetric organocascade reactions to the total synthesis of natural products.

Organocatalytic cascade reactions as a new tool in total synthesis

Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask Flow equipment provides chemists with unique control over reaction parameters enhancing reactivity or in some cases enabling new reactions This relatively young technology has received a remarkable amount of attention in the past decade with many reports on what can be done in flow Until recently, however, the question, “Should we do this in flow?” has merely been an afterthought This review introduces readers to the basic principles and fundamentals of flow chemistry and critically discusses recent flow chemistry accounts

The Hitchhiker's Guide to Flow Chemistry

"Economy" is referred to as the thrifty and efficient use of material resources, as the principle of "minimum effort to reach a goal." More illuminating is: "the aim to portion one's forces in order to use as little as possible of them to reach a goal." Such statements certainly apply when the goal is to synthesize a complex target molecule. Redox economy then implies the use of as few redox steps as possible in the synthetic conquest of a target compound. While any sort of economy will help to streamline the effort of total synthesis, redox economy addresses a particularly weak area in present-day total synthesis. It is not enough to point out the present deficiencies, rather the purpose of this Review is to serve as a teaching tool for all practitioners of the field by giving and illustrating guidelines to increase redox economy in multistep organic synthesis.

Redox economy in organic synthesis.

Biological systems sense and respond to mechanical stimuli in a complex manner. In an effort to develop synthetic materials that transduce mechanical force into multifold changes in their intrinsic properties, we report on a mechanochemically responsive nonconjugated polymer that converts to a conjugated polymer via an extensive rearrangement of the macromolecular structure in response to force. Our design is based on the facile mechanochemical unzipping of polyladderene, a polymer inspired by a lipid natural product structure and prepared via direct metathesis polymerization. The resultant polyacetylene block copolymers exhibit long conjugation length and uniform trans-configuration and self-assemble into semiconducting nanowires. Calculations support a tandem unzipping mechanism of the ladderene units.

Mechanochemical unzipping of insulating polyladderene to semiconducting polyacetylene.

A new method for effecting catalytic enantioselective intramolecular [5 + 2] cycloadditions based on oxidopyrylium intermediates is reported. The dual catalyst system consists of a chiral primary aminothiourea and a second achiral thiourea. Experimental evidence points to a new type of cooperative catalysis with each species being necessary to generate a reactive pyrylium ion pair that undergoes subsequent cycloaddition with high enantioselectivity.

https://dash.harvard.edu/bitstream/handle/1/8737994/42924693.pdf?sequence=1

Dual Catalysis in Enantioselective Oxidopyrylium-Based [5+2] Cycloadditions

Anregungen fur die organische Synthese: Stufen- und Atomokonomie haben sich als nutzliche Kriterien erwiesen, an denen sich die Effizienz einer Synthese festmachen lasst. Dieser Aufsatz weist auf eine weitere Form der Okonomie hin, die bei der Planung und Bewertung einer mehrstufigen Synthese berucksichtigt werden sollte: die Redoxokonomie. Etliche Beispiele und Leitfaden werden vorgestellt, die das Konzept illustrieren und Anregungen fur die Syntheseplanung geben.

“Okonomie” bezeichnet den sparsamen und effizienten Umgang mit materiellen Ressourcen, das Prinzip, sein Ziel mit einem minimalen Aufwand zu erreichen. Vielleicht noch treffender: “Seine Krafte so einzuteilen, um moglichst wenig davon zur Erreichung eines Ziels zu verbrauchen”. Diese Aussagen treffen sicher auch zu, wenn es darum geht, ein komplexes Zielmolekul zu synthetisieren. Redoxokonomie bedeutet dann, so wenig wie moglich Redoxschritte in der Synthese eines Zielmolekuls einzusetzen. Wahrend jede Art von Okonomie hilft, den Aufwand einer Totalsynthese in Grenzen zu halten, betrifft Redoxokonomie einen besonderen Schwachpunkt heutiger Totalsynthesen. Es genugt nicht, auf dieses Defizit zu verweisen, vielmehr soll dieser Aufsatz allen mit Totalsynthese Befassten einen Leitfaden geben und Hinweise beisteuern, wie sich die Redoxokonomie in mehrstufigen Synthesefolgen der organischen Chemie verbessern lasst.

Redoxökonomie in der organischen Synthese

The first total synthesis of the highly complex and potent anticancer agent haouamine A is reported through an eight-step sequence. Brevity of the sequence and complete control of chemo-, position-, and stereoselectivity (both planar and axial chirality) were possible through the invention of chemistry specifically tailored for the problems at hand, namely a cascade annulation proceeding via a hitherto unknown chemical entity for the indeno-tetrahydropyridine ring system as well as a pyrone-assisted stitching of the daunting bent-aromatic ring.

/pdf/total-synthesis-of-haouamine-a-47hbh52i73.pdf

Noah Z. Burns

Papers

Redox economy in organic synthesis.

Mechanochemical unzipping of insulating polyladderene to semiconducting polyacetylene.

Dual Catalysis in Enantioselective Oxidopyrylium-Based [5+2] Cycloadditions

Redoxökonomie in der organischen Synthese

Total synthesis of (+/-)-haouamine A.