Using a continuous flow reactor, the dehydration of Dfructose and other carbohydrates to 5-(chloromethyl)-furfural (1) is achieved in reaction times as short as 60 s. The biphasic flow process allows for high-yielding multigram scale production of CMF (1) which is obtained with excellent purity after a simple extractive work-up. Efficient conversion of D-fructose into 5-(hydroxymethyl)furfural (2) and levulinic acid (6) is also demonstrated using flow reactor techniques.
Controlled radical polymerization using the reversible addition-fragmentation chain transfer approach (RAFT) was successfully conducted under continuous flow processing conditions, provided that steel tubing was used to prevent quenching of the radical process by oxygen. A series of different monomers, including acrylamides, acrylates, and vinyl acetate, were polymerized to high conversions (between 80 and 100%) at temperatures between 70 and 100 °C using various initiators, solvents, and RAFT agents. Low dispersities, typically between 1.15-1.20, and average molecular weights similar to those of batch RAFT polymerizations were obtained. The methodology provides a facile, alternative scale-up route to conventional batch polymerization, which can be challenging because of the oxygen-sensitive nature of the RAFT process.
Although known for more than 50 years the rubromycin family still constitutes a fascinating class of antitumour antibiotics. They are characterized by a challenging molecular architecture with the central spiroketal unit as the key feature and possess highly attractive biological properties. After a short treatment of the history of their isolation, structural elucidation and biosynthesis, their biological activities will briefly be summarized. This review strongly emphasizes the synthetic efforts aimed at these complex hexacyclic spiroketals. Reactions leading to simple spiroketal model compounds are described, followed by the synthetic approaches to the fully functionalized naphthalene and isocoumarin “wings”. The coupling of these units and their transformations into more advanced spiroketals demonstrate “the state of the art” in this research field. Only Danishefsky and co‐workers have so far completed the total synthesis of a fully functionalized rubromycin derivative; however, their product heliquinomycinone (103) is still only the aglycon of the natural product heliquinomycin (7), and it was prepared as the racemic compound. All these achievements and pitfalls reveal that increased engagement of synthetic organic chemists is required to develop new methods to make rubromycins and their analogues available by a modular approach and with reasonable efficacy. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
As master craftsmen, modern synthetic chemists are challenged to achieve remarkable feats of efficiency and elegance toward molecular targets. The nature of this pursuit necessitates the collection of synthetic repertoires that are tried and true. With methodologies and pathways increasingly scrutinized, the adept chemist must seek out propitious tools to incorporate into the arsenal. With this in mind, this Account highlights the versatility of alkoxyallenes as precursors to valuable heterocyclic building blocks for such efforts as natural product synthesis. Accessed by the etherification of either propargyl alcohols or propargylic halides, alkoxyallenes are obtained after base-catalyzed isomerizations of the propargylic ethers. A host of umpolung synthons are available through this scheme after metalation, generating C(3) nucleophiles synthetically equivalent to vital anionic and zwitterionic synthons. Reactions with a diverse set of heteroatomic electrophiles yield carbohydrates, spiroketals, alkaloids, and heteroaromatics via [3 + 2] or [3 + 3] cyclizations. By employing lithiated alkoxyallenes into transformation routes, the natural product chemist can utilize this methodology as a viable resource in stereoselective synthesis. A survey of our own utilization of alkoxyallenes along synthetic pathways toward natural product targets reveals their suitability for generating advantageous precursors. A set of four stereoisomeric 2,6-dideoxyhexoses were stereoselectively obtained after an initial lithiated alkoxyallene and lactaldehyde cyclization, followed by the oxidative ring opening of the dihydrofurans. Through the addition of a lithiated alkoxyallene to a functionalized benzaldehyde, an essential spiroketal diastereomer was rapidly achieved in a few steps. We greatly benefitted from alkoxyallenes in the construction of complex nitrogen-containing synthetic targets, whether pyrrolidine alkaloids, substituted imidazole derivatives, or functionalized pyridines. A pinnacle example of their utility came from the coupling of alkoxyallenes to nitrones affording 1,2-oxazines, which served as a gateway to an array of novel polyfunctionalized compounds such as aminopolyols, hydroxylated pyrrolidines, or carbohydrate mimetics. Alkoxyallenes have proven themselves to be powerful C(3) building blocks toward complex molecular targets, revealing novel pathways to a variety of desirable highly functionalized heterocycles. In our view, the full extent of their synthetic utility has yet to be truly realized.
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