Mechanisms of Nucleophilic Organocopper(I) Reactions

Alkyl and aryl phosphites and phosphines react with compounds having weak heteroatom–heteroatom bonds, such as SS, OO, etc., and with azo compounds to form reactive phosphonium salts. These phosphonium salts in turn promote “redox” condensation reactions with compounds having active hydrogens. The condensation reaction of alcohols using the redox couple of a triaryl- or trialkylphosphine and a dialkyl azodicarboxylate has become known as the Mitsunobu reaction, based on his pioneering work in the late 1960s. The overall reaction is summarized, wherein the alcohol (R1OH) and acidic compound (H–Nu) are condensed to form product (R1–Nu), while triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate is reduced to the hydrazine. Although the typical redox combination is diethyl azodicarboxylate (DEAD) and triphenylphosphine, many other combinations have found selected use. The reaction is generally limited to primary and secondary alcohols, although tertiary alcohols react in a few intramolecular and intermolecular reactions. For secondary alcohols the reaction usually proceeds with clean inversion of stereochemistry. The acidic component of the reaction generally has an aqueous pKa < 15, with intramolecular reactions providing the exceptions. Examples of H–Nu include oxygen nucleophiles such as carboxylic acids and phenols; nitrogen nucleophiles such as imides, hydroxamates, and heterocycles; sulfur nucleophiles such as thiols and thioamides; and carbon nucleophiles such as β-ketoesters.



Major reviews of the Mitsunobu reaction were published in 1981 by Mitsunobu and in 1983 by Castro. The former review concentrated on reactions using DEAD/triphenylphosphine, while the latter review focused on reactions in which halogens replaced the hydroxy group using reagents such as triphenylphosphine/carbon tetrachloride, triphenyl phosphite/iodomethane, and triphenylphosphine/N-halosuccinimide. Reactions involving the DEAD/triphenylphosphine redox system are the principal subject of this chapter, with emphasis on the literature between 1981 and 1988.


Keywords:

Mitsunobu reaction;
adduct formation;
alcohol activation;
SN2 reaction;
mechanisms;
carbon–oxygen bond;
carbon–nitrogen bond;
carbon–sulfur bond;
carbon–halogen bond;
carbon–carbon bond;
ambident nucleophiles;
dehydration;
alkenes;
method comparison;
ester formation;
lactone formation;
akyl aryl ether;
epoxides;
dialkyl ethers;
enol ethers;
dialkyl ethers;
imides;
azides;
experimental procedures;
scope;
limitations

The Mitsunobu Reaction

The aryl C-glycoside structure is, among the plenty of biologically active natural products, one of the distinct motifs embedded. Because of the potential bioactivity as well as the synthetic challenges, these structures have attracted considerable interest, and extensive research toward the total synthesis has been performed. This Review focuses on the synthetic strategies and tactics employed in the total synthesis of this class of natural products. The Introduction describes the historical background, structural features, and synthetic problems associated with aryl C-glycoside natural products. Next the Review summarizes the methods for constructing the aryl C-glycoside bonds. Completed total syntheses—and, in some cases, selected examples of incomplete syntheses—of natural aryl C-glycosides are also summarized. Finally described are the strategies for constructing polycyclic structures, which were utilized in the total syntheses.

Total Synthesis of Aryl C-Glycoside Natural Products: Strategies and Tactics

Recent Developments in the Ferrier Rearrangement

This chapter reviews the methods available for the synthesis of C-glycosides that involve the use of carbohydrate units expressing nucleophilic reactivity at C(1) (the anomeric site). A wide variety of “anionic” (organometallic derivatives) and neutral (free radical) C(1) nucleophiles are known and examples of all structural types are presented. Coverage includes methods for generating effective C(1)-nucleophiles, their reactivity and utility in C-glycoside synthesis and, where appropriate, any associated limitations.

Nucleophilic C-glycosyl donors for C-glycoside synthesis

Regio- and stereochemistry of cross coupling of organocopper reagents with allyl ethers: effect of the leaving group

Alkylation and acylation of phenylthio 2,3-dideoxy-α-D-erythro-hex-2-enopyranoside derivatives at the anomeric centre by polarity inversion give C-1 alkylated or acylated phenylthio 2,3-dideoxy-α-D-erythro-hex-2-enopyranosides.

Alkylation and acylation of phenylthio 2,3-dideoxyhex-2-enopyranosides at the anomeric centre by polarity inversion

Practical synthesis of an enantiomerically pure intermediate of the lactone moiety of mevinic acids

A new synthesis of 2,3-dideoxy-L-threo-hex-2-enono-1,5-lactones, starting from D-glucose, is described.

A straightforward synthesis of L-lactones from D-glucose. A simple entry into L-sugars

Stereocontrolled Synthesis of Methyl (Methyl-5-Acetamido-4-O-Benzoyl-7-O-Benzyl-3,5-Dideoxy-α-D-Arabino-2-Heptulopyranosid)Onate, a Model Compound for Sialic Acids

Silvestre Garcia-Ochoa

Papers

Regio- and stereochemistry of cross coupling of organocopper reagents with allyl ethers: effect of the leaving group

Alkylation and acylation of phenylthio 2,3-dideoxyhex-2-enopyranosides at the anomeric centre by polarity inversion

Practical synthesis of an enantiomerically pure intermediate of the lactone moiety of mevinic acids

A straightforward synthesis of L-lactones from D-glucose. A simple entry into L-sugars

Stereocontrolled Synthesis of Methyl (Methyl-5-Acetamido-4-O-Benzoyl-7-O-Benzyl-3,5-Dideoxy-α-D-Arabino-2-Heptulopyranosid)Onate, a Model Compound for Sialic Acids