Horner-Emmons-Wadsworth procedur

Olefination. Although the conventional procedure for the Horner-Emmons-Wadsworth reaction calls for enolate generation with NaH in an aprotic solvent, more complex substrates tend to give unsatisfactory results due to elimination and/or epimerization. The Ba(OH)2/aqueous THE system is uniquely effective at room temperature in such cases. Usually 0.3 equivalent of activated (by heating 100-140°C for... 

The C(l)-C(5) fragment was thus synthesized in seven steps from (R)-methyl 3-hydroxy-2-methylpropanoate in 33% overall yield with excellent diastereoselectivity in the construction of the C(2) and C(3) stereocenters. Diastereo-selective hydrogenation of (R)-49 was accomplished with Ru(II)-catalyst prepared in situ from [Ru(COD)(r -2-methylallyl)2] and (5)-SYNPHOS as a chiral ligand. The product of hydrogenation (3/ ,4R)-50 was obtained in 94% yield and > 95% de. To achieve the Cl-Cl 3 fragment, both subunits C1-C5 and C6-C13 were coupled with the Horner-Wadsworth-Emmons reaction procedure to create the C5-C6 bond. 

The (Horner-)Wadsworth-Emmons reaction generally is superior to the Wittig reaction, and has found application in many cases for the synthesis of a ,/3-unsaturated esters, a ,/3-unsaturated ketones and other conjugated systems. Yields are often better then with the original Wittig procedure. However the Wadsworth-Emmons method is not suitable for the preparation of alkenes with simple, non-stabilizing alkyl substituents. 

Similarly, starting from 2,3 5,6-di-0-isopropylidene-D-mannofuranose 72, a one-pot procedure that implies the synthesis of glycosyl sulfones by Horner-Wadsworth-Emmons olefination with phosphonate 73, followed by subsequent Michael addition and Ramberg-Backlund reaction92 gives compound 74 in 78% yield93 (Scheme 24). 

The one-step Seyferth procedure offers an alternative to the Corey -Fuchs sequence. After a Horner-Wadsworth-Emmons olefmation of an aldehyde 37 to an unsaturated diazo compound 38. elimination of nitrogen and [1,2]-rearrangement of the resulting vinylcarbene 39 leads here as well to a Cy-extended terminal alkyne 40.19... 

Step 1 (3-keto phosphonates often are used for olefmation of ketones (Horner-Wadsworth-Emmons modification of the Wittig reaction). Steps 2 + 3 The cuprate-mediated 1,4-addition and subsequent Lemieux-Johnson oxidation of a vinyl group are excellent procedures for the introduction of the p-formyl group. 

Fig. 11.28. Aldehyde alkyne chain elongation via [1 -rearrangement of a vinyl carbene (Seyferth procedure). First, a Horner-Wadsworth-Emmons olefination of the aldehyde is carried out to prepare alkene A. Upon warming to room temperature, alkene A decomposes and gives the vinyl carbene B. From that, the alkyne is formed by way of a [1,2]-rearrangement.

A simple procedure for the preparation of trifluoromethylated vinyl- and dienyl-phosphonates with y-alkoxycarbonyl moiety of exclusively or predominantly (Z)-configuration (201) has been described. It involves acylation of ethyl-1,1-bisphosphonate (202) with trifluoroacetic anhydride, addition of selected Reformatsky reagents to the resulting 1-trifluoroacetyl-1,1-ethyl bisphos-phonates (203) and finally spontaneous Horner-Wadsworth-Emmons (HWE) olefination of the adducts (Scheme 55). " ... 

Horner-Wadsworth-Emmons procedures are also commonplace in synthetic materials chemistry, recent examples including donor-acceptor substituted molecules with bicyclo-spacers, which require napthalene-, anthracene-, and pyrene-substituted phosphonates, (112), (113) and (114) respectively, well-defined, electroactive PPE/PPV copolymers through the condensation of dialdehydes and bisphosphonate (115), ° and triphenylamine-substituted PPV. ° ... 

An important addition to the Wittig tran -olefination procedure is the introduction of phosphonate-stabilized carbanions as olefin-forming reagents, referred to as the Horner-Wadsworth-Emmons or HWE reaction. The HWE olefination offers several advantages over the Wittig reaction using stabilized ylides ... 

Parallel kinetic resolution is a developing area of asymmetric synthesis which facilitates the simultaneous conversion of both enantiomers of a racemic mixture into useful products. Pedersen and co-workers have recently reported the first Horner-Wadsworth-Emmons procedure that allows the parallel kinetic resolution of racemic aldehydes. 

Emmons reaction (Scheme 26). ° Horner-Wadsworth-Emmons reactions also feature in new routes to (diphenylphosphono)acetic acid esters and alkenes. The latter involve combining the Homer-Wadsworth-Emmons procedure with a Heck coupling reaction for the synthesis of tri-substituted alkenes. 

The Horner-Wadsworth-Emmons modification of the Wittig reaction continues to find wide application in contemporary organic synthesis. Two reviews, looking at different aspects of the stereoselectivity of this procedure, have been published. One considers approaches to improve the Z-selectivity of the Horner-Wadsworth-Emmons reaction, and the other the use of heteroatoms to improve the stereoselectivity of the Horner-Wadsworth-Emmons reaction. A combined experimental and computational study of the selectivity of the Horner-Wadsworth-Emmons reaction of a series of phosphonoacetates (172) has... 

Horner-Wadsworth-Emmons procedures have been used to prepare a variety of compounds including chiral tetrahydrofuran- and tetrahydropyran-deriva-tives/ novel organo-sulfur electron donors containing dithiole and azulene... 

Tandem reactions have emerged as promising procedures for the synthesis of highly functionalised compounds in a single step. Horner-Wadsworth-Emmons reactions have been coupled with 1,4-Michael additions to prepare 6-substituted a,p-unsaturated carboxylic acids derivatives, and with Diels-Alder reactions, which utilised sugar-derived phosphonate (176) to prepare enantiomerically pure bicyclo[4.3.0]nonanes. ... 

The synthesis of the Cl-Cl5 segment (116) [198] of streptovaricin D (109) has been carried out from the aldehyde (115) [199], an enantiomer of an intermediate used by the same authors in the synthesis of the rifamycin ansa chain. Compound (105) was submitted to the Evans aldol procedure to give an aldol, which was transformed into the corresponding acetonide. Ozonolysis to the expected aldehyde and crotylmetallation with chromium(II) chloride provided a 5 1 mixture of diastereoisomers. The major component was acylated, giving only one diastereoisomer after ozonolysis and crotylboration. Final introduction of the corresponding (2 ,4Z)-dienoate unit by two subsequent Horner-Wadsworth-Emmons olefinations afforded compound (116) (Scheme 51). 

Universal methods for coupling of the synthetic building blocks are the Wittig reaction, the Horner-Wadsworth-Emmons reaction, the sulfone coupling by Julia s procedure, the enol ether condensation (Miiller-Cunradi-Pieroh reaction), and the Saucy-Marbet rearrangement. Since in very many cases mixtures... 

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