Multi-step total syntheses

Despite their low cost and abundant availability, the applications of monoterpenes as chiral synthons or building blocks for synthesis of chiral fine chemicals on an industrial scale have lagged far behind amino acids and carbohydrates. Most of the work in this area is related to multi-step total synthesis of complex natural products in laboratory scale. With the structures of new drug candidates in the research and development pipeline of pharmaceutical companies getting bigger and more complicated, the application of more sophisticated chiral building blocks such as the terpenes will... 

The Corey-Kim protocol was successfully applied late in the multi-step total synthesis of ingenol (51) to convert diol 49 to a-ketol 50 where it was the less hindered hydroxyl group that was selectively oxidized.14 The newly formed ketone was then used to construct the allylic alcohol moiety of ingenol after several steps. 

In the multi-step total synthesis of Herboxidiene methyl ester, one step involved an Arhuzov reaction of an allyl bromide with the ethyl ester of diphenylphosphinous acid (Scheme 6)7... 

The relative contribution of any flow in this life cycle to the total global-warming score of the production of a unit mass of product 6 is shown. The highest shares in the impact score are exhibited by the two substrates, because their production is taken into account, comprising multi-step synthesis routes starting from crude oil. All other input mass flows show relatively small contributions (maximum of 4% for solvent 2). This is due to relatively high... 

Storer RI, Takemoto T, Jackson PS, Brown DS, Baxendale IR, Ley SV (2004) Multi-step application of immobilized reagents and scavengers a total synthesis of epothilone C. Chem Eur J 10 2529-2547... 

An impressive example of a multi-step biomi-metic domino process is the synthesis of codaphni-phyllin by Heathcock et al. (see scheme 14). Another example is the highly efficient biomimetic synthesis of (+)-hirsutine by my group (see scheme 13). In addition several other total syntheses of natural products have been developed using domino processes these are described in the different sections of this chapter. 

Hiemstra and co-workers reported the first example of an iodine-promoted allenyl N-acyliminium ion cyclization for the total synthesis of (+)-gelsedine, the enantiomer of the naturally occurring (-)-gelsedine [72], Compound 341 was prepared from (S)-malic acid. When 341 was dissolved in formic acid with a large excess of Nal and heated at 85 °C for 18 h, 343 was found to be the major product isolated in 42% yield. The latter was then successfully converted to (+)-gelsedine in a multi-step manner. Other routes without the allene moiety failed to provide the desired stereoisomer. The successful one-step transformation of 341 to 343 was key to the success of this synthesis. 

The feasibility of multi-step natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first achieved by Nicolaou and co-workers in epothilone synthesis and in the synthesis... 

It is dear from the variety of natural products described in this chapter that multi-component reaction strategies encompass a very broad scope of synthetic transformations. The development of new MCRs constantly generates new opportunities, and it is likely that the application of these powerful processes in natural product synthesis is still in its infancy. Appealing characteristics of MCR strategies such as convergence and step-economy are expected to draw more and more synthetic chemists to design and implement MCRs in the total synthesis of complex natural products. 

The total synthesis proceeds in >10 steps on solid phase and includes various transformations, including an asymmetric Diels-Alder reaction, oxidation with singlet oxygen, and olefin metathesis. This synthesis sequence is among the most advanced and demanding solid-phase syntheses developed so far for chemical genomics experiments. It demonstrates that the total synthesis of complex natural products in multi-step sequences on solid phase is feasible. 

A more advanced, direct route to the core structure of CP-263,114 (me-1) has recently been published by Wood et al., who used carbon-based fragmentation after a phenolic oxidation/ intramolecular Diels-Alder sequence [10], In addition, various cycloadditions for the synthesis of the central bicyclic skeleton have been established [11], Further methods to construct the bicyclic backbone by means of a Diels-Alder reaction [12] and by an exciting multi-step domino reaction [13] are introduced in the next sections, in the context of the total syntheses of the phomoidrides by Nicolaou and Shair, respectively [14]. 

Paramount to the success of this approach is that efficient and reliable methods and multi-step sequences for the total synthesis of natural products and analogues thereof on polymeric supports are available. The corresponding transformations must proceed with a degree of selectivity and robustness typical of related classical solution phase transformations, irrespective of the stringencies and differing demands imposed by the anchoring to the polymeric support. 

The transition-metal catalyzed cross-coupling reaction of (hetero)aryl hahdes and triflates with primary and secondary amines or (hetero)aryl amines is know as the Buchwald-Hartwig reaction [144]. Mechanistically, this reaction is related to the crosscoupling reactions outlined thus far (Fig. 4.6). The modification arises at the point of transmetalation. This step in the process is substituted with the coordination of the amine reactant. Deprotonation of the amine nitrogen now precedes the reductive elimination step to generate the aryl amine product. This reaction has foimd utility in the academic setting, for use in natural product total synthesis, and in industry, for the preparation of materials up to the multi-hundred kilogram scale. 

The significant antitumour and cytotoxic properties of vernolepin (436) and, to a lesser extent, vernomenin (437) have stimulated general interest in the natural occurrence and total synthesis of 2,3-secoeudesmanolides or elemanolides cf. Vol. 8, p. 111). Two new alternative multi-step syntheses of vernolepin (436) have recently been accomplished by independent research groups using the reaction sequences outlined in Schemes 41 and 42. 

Use a biological total synthesis by fermentation or multi step biotransformation (with growing cells, resting cells, multi-enzyme systems, genetically or metabolically engineered biocatalysts, etc). 

As a consequence, arene-Cr(CO)3 complexes offer new and unique opportunities for the stereoselective multi-step synthesis of complex molecules. By focusing on applications in the enantioselective total synthesis of natural products (and relevant analogs), this review intends to highlight the state of the art of synthetic arene chromium chemistry. It will be shown that highly original and competitive overall syntheses can be achieved especially in those cases, where the whole strategy is based on arene chromium chemistry and the chemical and stereochemical effects of the Cr(CO)3 unit can be exploited in several subse-... 

Cosford and coworkers presented a simple microreador setup for enabling multi-step synthesis of bis-substituted 1,2,4-oxadiazoles that required differential and controlled thermal treatments (between 0 and 200 °C) (Scheme 5.24) [34]. A base-assisted reaction between arylnitrile and hydroxylamine hydrochloride at 150°C in the first reactor produced amidoxime, which was quickly cooled to 0 °C before it was mixed with the add chloride. This mixture was then warmed and maintained at room temperature for 2 min in the connected tube before it entered a superheated chip-microreador where the high temperature (200 °C) and pressure (7.5-9.0 bar) accelerated the reaction leading to 40-63% of differently functionalized oxadiazoles within 30 min of total process time. Relativdy inferior yields were obtained from over three-day-long reaction in a sealed tube for the same products. 

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