Solid natural products synthesis

Triazenes are disguised diazonium ions which can be released under very mild acidic conditions. Inspired by the use of triazenes in natural product synthesis by Nicolaou et al. [127] and the pioneering work of Moore et al. [128, 129] and Tour et al. [130] in the synthesis of triazenes on a solid support and the final detachment to give iodoarenes, a whole set of triazene-based linkers has been developed (Tab. 3.10) [131]. The arene diazonium salts generated from the triazene linkers offer diverse opportunities for multifunctional cleavage. Two linkers based on tria-... 

Mat Robinson was born in Malvern he graduated from the University of Wales Swansea with a first class M.Chem. degree in 2004. He is also currently studying there for his Ph.D. under the supervision of Dr. Andy Graham. His research interests include the development of novel solid Lewis and Bronsted acids, nanomaterials, and rearrangement reactions in natural product synthesis. 

CONTENTS Preface, Brian Hatton. Applications of Ring Strain in Natural Product Synthesis, James D. White and Nadine Chauyi Lee. Uses of the Vacuum Gas-Solid Reaction Procedure in Synthesis, W. E. Billups and Benny E. Amey, Jr. Polysubstituted Cubanes Towards Complete Systematic Substitution of the Cubane Nucleus, John Tsanaktsidis. A Personal Perspective on Norbomenes, Cyclobutenes, and Other Ring-Strained Dienophiles in Organic Synthesis, Ron N. Warrener. Synthetic Studies Related to Fullerenes and Fullerene Fragments, Goverdhan Mehta and H. Surya Prakash Rao. Index. 

Deshpande [74], has carried out carbon-carbon bond formation on a solid support using a polymer-supported aryl iodide and vinyl (or aryl) tins. In the area of natural-product synthesis. Overman and co-workers have carried out total syntheses of (—) and (+)-strychnine which include an aryltin/CO/alkenyltin coupling step [75] (a technique introduced earlier by Stille [1]). Very recently, Heathcock and co-workers have reported total syntheses of (—)-papuamine and (—)-haliclonadiamine which include a key step in which a 1,3-diene unit is constructed by coupling two alkenyltin moieties thus reaction (Scheme 4-27) only proceeds in the presence of copper (I) iodide [76]. 

The last examples demonstrated that the solid-to-solid photoinduced decarbonylation of crystalline ketones can have an important role in natural product synthesis and in green chemistry due to the high yield, the fewer steps involved and the easy scale-up of such reactions. 

Abstract Benzimidazole is a biologically important scaffold which displays important biological activities. Recent progress in the synthesis and bioactivity of benzimidazoles is reviewed. New synthetic procedures, including microwave-assisted synthesis, solid phase synthesis, natural product synthesis, and synthesis of bisbenzimidazoles are briefly described. Functionalization and cyclization reactions of benzimidazoles lead to a wide variety of novel benzimidazole structures. Selected bioactivity, such as anti-infective, anti-inflammatory, antitumor and receptor agonist/antagonist activities are presented. 

The modern renaissance of solid-phase synthesis offers vast new opportunities for synthetic chemists. Perhaps 10% of all known solution reaction types have been demonstrated on a support. How will different supports affect the rates of these reactions, i.e., is a solid support like a solvent Any known natural product synthesis is a candidate for at least partial combi-torialization by developing a new solid-phase method. In addition, the ability to synthesize our own molecular diversity brings with it the opportunity of making libraries in a way that makes their screening easier. How many assays will work when a library member is still attached to the support How will the structure of the support affect this What creative ways exist to release compounds prior to screening How small can we get All these questions and more await our discovery. 

The repetitive process in peptide chemistry makes it possible to prepare -30-residue sequences in high yield. Although the two-step process (deprotection and coupling) is extremely efficient, the chemistry unfortunately is still not fully effective for the ready preparation of small proteins (—70 residues or more). An alternative approach, referred to as convergent solid-phase peptide synthesis (CSPPS), relies on the same principles as those for natural product synthesis (see Chapter 9). In CSPPS, fragments of a desired sequence are synthesized and may be further purified and then attached to each other. 

The asymmetric epoxidation of functionalized alkenes still attracts considerable attention. Synthetic chemists continue to be in search of new and improved routes to epoxides, since they provide versatile intermediates for natural product synthesis. The topic of preparative techniques for chiral epoxides is seldom broached without the mention of the Sharpless epoxidation. Indeed, the impact of this protocol cannot be overestimated, as new applications continue to be reported. For example, linear poly(tartrate ester) ligands have been used this past year to generate a solid-supported Sharpless-type catalyst <97CC123>. 

SOLID-SUPPORTED REAGENTS AS TOOLS IN NATURAL PRODUCT SYNTHESIS... 

Scheme 18.9 First orchestrated and successive application of solid-supported reagents in the synthesis of natural products synthesis of epimaritidine and oxomaritidine.

The Kolbe-Schmitt reaction has been used as a key step in natural product synthesis. The early syntheses of isotubaic acid (Rotenic acid) used a Kolbe-Schmitt reaction in the final step. " Shriner and co-workers converted isotubanol (22) to its sodium salt under anhydrous conditions, then heated the phenoxide with solid carbon dioxide at 180 °C in a sealed reaction vessel to give an 86% yield of the natural product. Sheehan and co-workers also used the Kolbe-Schmitt reaction to prepare an early intermediate in the synthesis of gossypol where thymol is efficiently converted to o-thymotic acid in 65% yield. ... 

The coumarins, including the bronchodilator and vasodilator furanecoumarins, are a class of natural products that are found in many plants. They are structurally similar to lactones derived from o-cinamic acid, and 1,2-benzopyrone is the most simple example. Coumarins have been found to have a range of biological activities including anti-HIV, anticancer, vasodilator (anti-hypertension), anti-arrhythmia, anti-osteoporosis, bronchodilator (for treatment of asthma), and antisepsis properties. The solid-phase synthesis of coumarins (and the related isocoumarins) was reviewed by Correa and colleagues in their review of solid-phase natural product synthesis, and both the solid-phase synthesis of coumarins, and derivatization of supported coumarin... 

Flash chromatography is widely employed for the purification of crude products obtained by synthesis at a research laboratory scale (several grams) or isolated as extracts from natural products or fermentations. The solid support is based on silica gel, and the mobile phase is usually a mixture of a hydrocarbon, such as hexane or heptane, with an organic modifier, e.g. ethyl acetate, driven by low pressure air. (Recently the comparison of flash chromatography with countercurrent chromatography (CCC), a technique particularly adapted to preparative purposes, has been studied for the separation of nonchiral compounds [90].)... 

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

P. A. Keifer 1998, (New methods for obtaining high resolution NMR spectra of solid-phase-synthesis resins, natural products, and solution-state combinatorial chemistry libraries), Drugs Future 23, 301-307. 

Sequential pyrrolidine and hydantoin ring-forming reactions via intramolecular [2+3] cycloaddition have been applied to the stereoselective solid-phase synthesis of conformationally constrained tricyclic triazacyclopenta [C]pentalene scaffold 43 < 1999JOC8342>. These novel compounds 43 share the structural complexity characteristic of certain alkaloid natural products, angular triquinanes. The retrosynthetic analysis is shown in Scheme 87. 

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