"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.

The stereoselective formation of C-C bonds is of great importance for the synthesis of enantiomerically pure natural products and pharmaceuticals. A broad repertoire of chiral auxiliaries, reagents, and catalysts can be utilized for the reliable generation of tertiary stereocenters. In contrast, the synthesis of organic compounds with quaternary stereocenters is a much more demanding and challenging task. Every enantioselective synthetic method can demonstrate its value through the generation of a fully substituted carbon center. In this Minireview examples of newer stoichiometric and catalytic methods are summarized which have proved their suitability for the enantioselective construction of quaternary stereocenters.

Enantioselective Construction of Quaternary Stereocenters

Role of Organolithium Aggregates and Mixed Aggregates in Organolithium Mechanisms

The direct decarboxylative arylation of α-oxo acids has been achieved by synergistic visible-light-mediated photoredox and nickel catalysis. This method offers rapid entry to aryl and alkyl ketone architectures from simple α-oxo acid precursors via an acyl radical intermediate. Significant substrate scope is observed with respect to both the oxo acid and arene coupling partners. This mild decarboxylative arylation can also be utilized to efficiently access medicinal agents, as demonstrated by the rapid synthesis of fenofibrate.

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Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of α-Oxo Acids

The nucleophilic addition of carbon nucleophiles to amides has traditionally been a difficult task, both due to reactivity and selectivity problems. When successful, these processes would represent straightforward routes towards carbonyl-type or amine compounds, depending on the fate of the generated tetrahedral intermediate. The direct addition of nucleophiles to amides for the preparation of ketones has been studied and applied to the syntheses of several natural products. On the other hand, the addition of nucleophiles to amides to obtain substituted amines represented a major challenge, and only scattered applications on particular substrates have appeared. Initial improvements were based on the activation of amides by introduction of particular substituents, such as in N-methoxy amides (Weinreb amides) or electron-withdrawing groups able to increase the carbon nucleophilicity. Although these strategies facilitate the introduction of nucleophiles, chemoselectivity issues arise when additional electrophilic moieties (i.e., carbonyls) are present, thus decreasing the versatility of the methods. In recent years, important advancements towards fully chemoselective methods have been realized. The capture of tetrahedral intermediates with acids generates highly electrophilic iminium species able to undergo chemoselective additions of various nucleophiles, thus accessing substituted amines. Alternatively, the in situ generation of an iminium triflate ion allows highly chemoselective additions of nucleophiles, yielding amines, ketones or ketimines. Also thioamides can be used as precursors of ketones or alpha-substituted amines. The success of the above methodologies is further showcased by the application in various syntheses of natural products or biologically active molecules.

Increasing the Reactivity of Amides towards Organometallic Reagents: An Overview

The preparation and the synthetic utility of the N-methoxy-N-methyl amides, also called as Weinreb amides, for the preparation of aldehydes and ketones has been discussed. Also the various reagents based on Weinreb′s amide has been compiled.

The Growing Synthetic Utility of Weinreb′s Amide

Synthesis and Application of N-Methoxy-N-methyl-2-phenylsulfonylacetamide as a Two-Carbon Homologating Agent

Two carbon chain homolgation of enantiopure four carbon erythro configured iodo derivative 5 with N-methoxy-N-methyl-2-phenylsulfonylacetamide 6 affords for the first time a stable and storable precursor 3 of D-amicetose in the acyclic form, wherein the sensitive aldehyde is masked as a Wcinreb amide. The differential protection in this acyclic derivative offers all the potential to exclusively arrive at the pyranose form of the target dideoxy-sugar.

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Synthesis of a stable, storable and differentially protected acyclic precursor of D-amicetose and its conversion to 4-O-benzyl-protected D-amicetose

Synthesis of a Stable, Storable and Differentially Protected Acyclic Precursor of D-Amicetose and Its Conversion to 4-O-Benzyl-Protected D-Amicetose (V).

N. Satyamurthi

Papers

The Growing Synthetic Utility of Weinreb′s Amide

Synthesis and Application of N-Methoxy-N-methyl-2-phenylsulfonylacetamide as a Two-Carbon Homologating Agent

Synthesis of a stable, storable and differentially protected acyclic precursor of D-amicetose and its conversion to 4-O-benzyl-protected D-amicetose

Synthesis of a Stable, Storable and Differentially Protected Acyclic Precursor of D-Amicetose and Its Conversion to 4-O-Benzyl-Protected D-Amicetose (V).

Synthesis and Application of N-Methoxy-N-methyl-2-phenylsulfonyl-acetamide as a Two-Carbon Homologating Agent.