DARZENS Epoxide synthesis

DAKIN Oxidation 84 DAKIN WEST Acylation 84 DANHEISER Annutation 85 DANISHEFSKY Sitytoxydenes 66 DARAPSKI Ammoacid synthesis 87 DARZENS - NENITZESCU Acylation 67 DARZENS Epoxide synthesis 88 DAVIDSON Oxazola synthase 89 OELEPINE Aldehyde oxidation 89 DAVIS Oxidumg reagent 90 Decker 127... 

It will be recognized by the reader that the aldol reaction has been one of the most intensely studied reactions (see Volume 2, Chapters 1.5-1.7) in contemporary organic chemistry, in terms of mechanism, stereochemical outcome and practical application, and therefore this work is relevant in the context of the Darzens condensation. Very recently, this technology has been applied to the Darzens condensation, making available a new asymmetric stereocontrolled epoxide synthesis, and this work is discussed in Section 1.13.7.2. 

Of interest is a recent report of a rapid synthesis of efaroxin (51), a potent, selective O2 adrenoceptor antagonist, using Darzens Reaction. Accordingly, a-bromoester 48 was condensed with aldehyde 47. The glycidic ester (49) was then hydrogenated to reduce the more labile epoxide bond to give alcohol 50. Subsequent standard transformations subsequently lead to a completed 4-step synthesis of efaroxin. o... 

The aza-Darzens reaction is analogous to the Darzens synthesis of epoxides (see Section 1.2.3.2) but employs imines in the place of aldehydes (Scheme 1.27). 

A number of glycidates are important intermediates in the synthesis of fragrance materials. A few glycidates are fragrance materials in themselves. They are prepared either by epoxidation of the corresponding acrylates or by condensation of aldehydes or ketones with a-chloro substituted fatty acid esters (Darzens reaction). 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

In the past, Darzens methodology was primarily used for the synthesis of aldehydes and ketones, as a homologation reaction without any consideration of stereocontrol in the epoxide formation. For this sequence, saponification of the a,P-epoxy ester followed by decarboxylation gives the substituted carbonyl compound ... 

The basic route to the synthesis of epoxides and, in general, vicinal bifunctional derivatives is a non-isohypsic (oxidative) transformation of alkenes (to be discussed below), Epoxides can also be formed directly as a result of certain C-C bond-forming reactions such as the Darzens reaction (modification of a classical aldol-like reaction with a-chloro esters 130 as a methylene component)... 

Synthesis of Optically Active Epoxides. Alkaloids and alkaloid salts have been successfully used as catalysts for the asymmetric synthesis of epoxides. The use of chiral catalysts such as quinine or quinium benzylchloride (QUIBEC) have allowed access to optically active epoxides through a variety of reaction conditions, including oxidation using Hydrogen Peroxide (eq 5), Darzens condensations (eq 6), epoxidation of ketones by Sodium Hypochlorite (eq 7), halohydrin ring closure (eq 8), and cyanide addition to a-halo ketones (eq 9). Although the relative stereochemistry of most of the products has not been determined, enan-tiomerically enriched materials have been isolated. A more recent example has been published in which optically active 2,3-epoxycyclohexanone has been synthesized by oxidation with t-Butyl Hydroperoxide in the presence of QUIBEC and the absolute stereochemistry of the product established (eq 10). ... 

An asymmetric aziridine synthesis was reported through an aza-Darzens reaction of T-diphenylphosphinylimines with a chiral a-bromo enolate of 582 (R = GOGH2Br) <2006T3694>. Asymmetric /7-halomethoxylation catalyzed by silver(l) <2006TA210>, yy -dihydroxylation <2000TA1027>, and epoxidation with different oxidants <2004T6657> of unsaturated sultams 582 (R = GOGR =GR R ) were performed. 

The Darzens-type products from a-halo sulfoxides and carbonyl compounds undergo reductive desulfurization by the action of butyllithium. This is a useful synthetic route to various epoxides. Yamakawa and coworkers disclosed a novel asymmetric synthesis of epoxides (109) using optically active 1-chlo-roalkyl p-tolyl sulfoxide (107). This method is most effective when the starting ketones are symmetrical, because only one diastereomer is then formed in the Darzens-type condensation (equation 26). 

During the enantioselective total synthesis of (-)-coriolin, I. Kuwajima and co-workers used a Darzens-type reaction to construct the spiro epoxide moiety on the triquinane skeleton. Interestingly, the usual Darzens condensation where the a-bromoketone was condensed with paraformaldehyde yielded a bromohydrin in which the hydroxymethyl group was introduced from the concave face of the molecule. This bromohydrin upon treatment with DBU gave the undesired stereochemistry at C3 (found in 3-ep/-coriolin). To obtain the correct stereochemistry at C3, the substituents were introduced in a reverse manner. It was also necessary to enhance the reactivity of the enolate with potassium pinacolate by generating a labile potassium enolate in the presence of NIS. The in situ formed iodohydrin, then cyclized to the spiro epoxide having the desired stereochemistry at C3. 

In the laboratory of P.G. Steel, a five-step synthesis of ( )-epiasarinin from piperonal was developed. The key steps in the sequence involved the Darzens condensation, aikenyi epoxide-dihydrofuran rearrangement and a Lewis acid mediated cyclization. The desired vinyl epoxide intermediate was prepared by treating the solution of ( )-methyl-4-bromocrotonate and piperonal with LDA, then quenching the reaction mixture with mild acid (NH4CI). 

The Darzens reaction (tandem aldol-intramolecular cyclization sequence reaction) is a powerful complementary approach to epoxidation (see Chapter 5) that can be used for the synthesis of a,P-epoxy carbonyl and a,p-epoxysulfonyl compounds (Scheme 8.32). Currently, all catalytic asymmetric variants of the Darzens reactions are based on chiral phase-transfer catalysis using quaternary ammonium salts as catalysts. 

Martynov, V.E, and Timofeev, V.E., Compounds containing a three-membered epoxide ring. Part 35. Application of the Darzens reaction for the synthesis of epoxyalkylphosphonic esters. Zh. Obshch. Khim., 34, 3890, 1964 J. Gen. Chem. USSR (Engl. Transl.), 34, 3950, 1964. 

The Darzens glycidic ester condensation involves the condensation of an aldehyde or ketone with an a-halo ester, in the presence of a base, to afford an a,3 epoxy ester (a glycidic ester ). The first synthesis of a glycidic ester was reported by Erlenmeyer in 1892 and is illustrative of the general reaction, as shown in equation (1). The reaction was subsequently developed and generalized by Darzens. Glycidic esters, in addition to undergoing transformations normally associated with epoxides, afford upon hydro-... 

Piozzi et al. (219) have confirmed 317 as the structure of japonine by synthesis (Scheme 27). Application of Darzen s reaction to 2-nitro-5-methoxybenzaldehyde furnished epoxide 314. This was converted with hydrogen chloride and hydroquinone into 315, which was reduced to the 3-hydroxy-4-quinolone 316 methylation then afforded japonine as the major product. 

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