Total synthesis

About: Total synthesis is a research topic. Over the lifetime, 25578 publications have been published within this topic receiving 489319 citations.

Stereoselective Halogenation in Natural Product Synthesis

Abstract: At last count, nearly 5000 halogenated natural products have been discovered. In approximately half of these compounds, the carbon atom to which the halogen is bound is sp(3) -hybridized; therefore, there are an enormous number of natural products for which stereocontrolled halogenation must be a critical component of any synthesis strategy. In this Review, we critically discuss the methods and strategies used for stereoselective introduction of halogen atoms in the context of natural product synthesis. Using the successes of the past, we also attempt to identify gaps in our synthesis technology that would aid the synthesis of halogenated natural products, as well as existing methods that have not yet seen application in complex molecule synthesis. The chemistry described herein demonstrates yet again how natural products continue to provide the inspiration for critical advances in chemical synthesis.

Simple Reagents for Direct Halonium-Induced Polyene Cyclizations

Abstract: Although there are many reagent combinations that can initiate polyene cyclizations, simple electrophilic halogen sources have not yet proven broadly effective as promoters of such processes. Herein is described a readily prepared and stable class of reagents capable of effecting such transformations for a wide range of electron-rich and -deficient terpenes derived from geraniol, farnesol, and nerol, thereby enabling the effective synthesis of a diverse array of complex chlorine-, bromine-, and iodine-containing polycyclic frameworks. Efforts to date have led to the first racemic laboratory total synthesis and structural revision of the anti-HIV natural product peyssonol A as well as an efficient and concise inaugural total synthesis of peyssonoic acid A. They have also permitted formal racemic total syntheses of aplysin-20, loliolide, K-76, and stemodin to be achieved through routes that are typically shorter, higher-yielding, and more environmentally conscious than previous efforts. Preliminary attempts to use chiral forms of the reagent class for enantioselective alkene halogenation are also described.

Total syntheses of the phytotoxic lactones herbarumin I and II and a synthesis-based solution of the pinolidoxin puzzle.

Abstract: A concise approach to a family of potent herbicidal 10-membered lactones is described on the basis of ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. This includes the first total syntheses of herbarumin I (1) and II (2) as well as the synthesis of several possible macrolides of the pinolidoxin series. A comparison of their spectral and analytical data with those of the natural product allowed us to establish the stereostructure of pinolidoxin, a potent inhibitor of induced phenylalanine ammonia lyase (PAL) activity, as shown in 46. This finding, however, makes clear that a previous study dealing with the relative and absolute stereochemistry of this phytotoxic agent cannot be correct. An important aspect from the preparative point of view is the fact that the stereochemical outcome of the RCM reaction can be controlled by the choice of the catalyst. Thus, use of the ruthenium indenylidene complex 16 always leads to the corresponding (E)-alkenes, whereas the secon...

Total synthesis of brasoside and littoralisone.

Abstract: The first total syntheses of littoralisone (1) and brasoside (2) have been achieved in 13 overall steps. Both natural products are forged from a common intermediate which is rapidly assembled using organocatalytic technology, including a proline-catalyzed α-aminoxylation and a contra-thermodynamic intramolecular Michael addition. Application of the two-step carbohydrate synthesis technology has enabled to access a selectively substituted glucose derivative for use as an intramolecular cycloaddition tether. This synthesis culminates with an intramolecular [2+2] photocycloaddition that serves to support the proposed biosynthetic origins of 1 from 2.

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

Abstract: N-Arylated aliphatic and aromatic amines are important substituents in many biologically active compounds. In the last few years, transition-metal-mediated N-aryl bond formation has become a standard procedure for the introduction of amines into aromatic systems. While N-arylation of simple aromatic halides by simple amines works with many of the described methods in high yield, the reactions may require detailed optimization if applied to the synthesis of complex molecules with additional functional groups, such as natural products or drugs. We discuss and compare in this review the three main N-arylation methods in their application to the synthesis of biologically active compounds: Palladium-catalysed Buchwald–Hartwig-type reactions, copper-mediated Ullmann-type and Chan–Lam-type N-arylation reactions. The discussed examples show that palladium-catalysed reactions are favoured for large-scale applications and tolerate sterically demanding substituents on the coupling partners better than Chan–Lam reactions. Chan–Lam N-arylations are particularly mild and do not require additional ligands, which facilitates the work-up. However, reaction times can be very long. Ullmann- and Buchwald–Hartwig-type methods have been used in intramolecular reactions, giving access to complex ring structures. All three N-arylation methods have specific advantages and disadvantages that should be considered when selecting the reaction conditions for a desired C–N bond formation in the course of a total synthesis or drug synthesis.