Epoxidation Weitz-Scheffer reaction

The publication (70) in 1976 of the preparation of optically active epoxyketones via asymmetric catalysis marked the start of an increasingly popular field of study. When chalcones were treated with 30% hydrogen peroxide under (basic) phase-transfer conditions and the benzylammonium salt of quinine was used as the phase-transfer catalyst, the epoxyketones were produced with e.e. s up to 55%. Up to that time no optically active chalcone epoxides were known, while the importance of epoxides (arene oxides) in metabolic processes had just been discovered (71). The nonasymmetric reaction itself, known as the Weitz-Scheffer reaction under homogeneous conditions, has been reviewed by Berti (70). 

In the early 1980 s Julia and Colonna published a series of papers which, to some extent, filled the gap left by the natural biocatalysts. The Spanish and Italian collaborators showed that a, -unsaturated ketones of type 1 underwent asymmetric oxidation to give the epoxide 2 using a three-phase system, namely aqueous hydrogen peroxide containing sodium hydroxide, an organic solvent such as tetrachloromethane and insoluble poly-(l)-alanine, (Scheme 1) [12]. The reaction takes place via a Michael-type addition of peroxide anion (the Weitz-Scheffer reaction). 

Most of the methods for the epoxidation of electon-poor olefins are applications or variants of the Weitz-Scheffer reaction using alkaline H202. The requirement of a nucleophilic peroxy oxygen and the efficiency of the purely organic systems appear to be the main reasons why metal peroxides have been moderately used for this reaction. 

The Weitz-Scheffer reaction, the epoxidation of a,(3-unsaturated carbonyls, is valuable transformation in organic chemistry.75 The accepted two-step mechanism involves the addition of peroxy anion and formation of peroxyenolate, which undergoes a ring-closing intramolecular nucleophilic substitution of C2 carbon atom. 

Electrondeficient olefins can be epoxidized by hydrogen peroxide in the presence of bases. This method, known as the Weitz-Scheffer reaction, is used especially for the epoxidation of o,p-unsaturated ketones. Wynberg et al. [4] epoxidized a series of such ketones with hydrogen peroxide in the presence of quaternary ammonium salts of optically active alkaloids. Especially when phase-transfer conditions were used they yielded an e.e. of about 50% (Scheme 3). 

Compared to metal-catalyzed asymmetric epoxidation reactions, asymmetric versions of this reaction without the need of a catalyst (apart from a base) are rarely known. In 2000 Adam and coworkers reported a method for the asymmetric Weitz-Scheffer epoxidation of substituted enones 91 by the secondary, optically active hydroperoxide (5 )-(l-phenyl)ethyl hydroperoxide (equation 27, Table 10). ... 

One of the early examples for organocatalysis is the asymmetric Weitz-Scheffer epoxidation of electron-deficient olefins, which can be effected either by organic chiral phase transfer catalysts (PTC) under biphasic conditions or by polyamino acids. This reaction has gained considerable attention and is of great synthetic use. 

Initially, /-menthyl 2-cyano-3-methyI-2-pentenoate, and /-menthyl and r/-bornyl cy-clopentylidenecyanoacetateswere epoxidized with hydrogen peroxide in the presence of sodium tungstate. Some asymmetric induction was achieved, but the degree of diastereoselectivity was not estimated26. In the final step of the synthesis of the antibiotic phosphonomycin, (Z)-propenylphosphonic acid was epoxidized under Weitz-Scheffer conditions and 92% optically pure phosphonomycin (+ )-x-phenethylammonium-c -epoxypropylphosphonate crystallized from the reaction mixture. It is unclear whether an asymmetric induction occurs during the epoxidation step and to what extent27. 

The majority of this work is confined to the synthesis of the epoxy derivatives of natural terpenes bearing an exocyclic double bond (see table overleaf). The stereochemical course of the reaction is governed by the factors discussed in Section 4.5.1.3.1. Umbellulone 1 was smoothly converted under typical Weitz-Scheffer conditions to a single epoxyumbellulone 233. (+)-Pulegone 3 gave a mixture of cis- and /ram-epoxides in a ratio 64.5 35.5, while piperitenone oxide 6 yielded piperitenone dioxide 7 as the sole product34,35. Epoxidation of pinocarvone 8... 

The unusual nucleophilic epoxidation of /i-hydroxyenones under Sharpless conditions (see Section 4.5.1.3.2.1.) is also applicable to compounds 1 with endocyclic double bonds. The. sj H-epoxides are produced with complete selectivity. The stereochemical outcome of the reaction under Weitz-Scheffer conditions significantly differs from that observed for acyclic compounds. While the acyclic enones afforded preferentially the moderate ratio, cyclic ones gave predominantly s>7i-epoxides32. 

Another reaction where amino acids play a key role is the Julia-Golonna epoxidation of a,P-unsaturated ketones [52], which involves the use of a catalytic amount of polymeric amino acids, able to catalyze the Weitz-Scheffer epoxidation of chalcone using basic hydrogen peroxide, with high enantioselectivity (Scheme 8.17 Equation a). 

Initial failures by Weitz and Scheffer to obtain epoxides from i-jrioemaldehyde or crotonaldehyde were presumably caused by excessive alkalinity in the reaction medium, and may be rectifiable by suitable pH control. 

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