Wadsworth-Emmons reaction intramolecular

Scheme 2.18 gives some representative olefination reactions of phosphonate anions. Entry 1 represents a typical preparative procedure. Entry 2 involves formation of a 2,4-dienoate ester using an a, 3-unsaturated aldehyde. Diethyl benzylphosphonate can be used in the Wadsworth-Emmons reaction, as illustrated by Entry 3. Entries 4 to 6 show other anion-stabilizing groups. Intramolecular reactions can be used to prepare cycloalkenes.264... 

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution have been utilized in macrocycle syntheses. Entries 7 and 8 show macrocyclizations involving the Wadsworth-Emmons reaction. Entries 9 to 11 illustrate the construction of new double bonds in the course of a multistage synthesis. The LiCl/amine conditions are used in Entries 9 and 10. 

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

In a process starting with the stereospecific Homer-Wadsworth-Emmons reaction of phosphonoglycinates 99 with 2-iodobenzaldehydes to afford the corresponding (Z)-didehydro-phenylalanine derivatives 100, Brown similarly utilized an intramolecular palladium-catalyzed animation of 100 (Y = 2-chloro-3-pyridyl, Ph, OBn) to form the N-substituted indole carboxylates 101 <00TL1623>. 

Furo[3,4-f]pyranones are produced by an intramolecular hetero-Diels-Alder reaction of a,/3-unsaturated 7-keto esters, 81. The Horner-Wadsworth-Emmons reaction of phosphonates with a-diketones is used to assemble compounds 81 (Scheme 17) <2004TL4297>. 

B. M. Heron, Heterocycles from Intramolecular Wittig, Homer and Wadsworth-Emmons Reactions, Heterocycles 1995, 41, 2357. 

A different strategy has been adopted for the transformation of 21a into 335 and 336. In these cases, one carbon atom of the final benzene ring comes from an external phosphonate reagent by means of intramolecular Wadsworth-Emmons reactions. The overall transformations can be classified as C2/C/C6 [84JCS(PI)1035]. 

Tsai, H,-J, Thenappan, A., and Burton, D.J., A novel intramolecular Homer-Wadsworth-Emmons reaction, A simple and general route to a-fluoro-a,P-unsaturated diesters, J. Org. Chem., 59, 7085, 1994. 

Long-chain phosphonylated aldehydes aie generally prepared to achieve the formation of macro-cycles via an intramolecular Homer-Wadsworth-Emmons reaction. The phosphonate group is frequently incorporated at one extremity of the chain by a carbanionic approach. Thus, displacement of iodide of the alkyl chain containing epoxide by the sodium enolate of diethyl l-(ethoxycarbo-nyl)methylphosphonate at 50°C in DMF leads to diethyl l-(ethoxycarbonyl)-4,5-epoxyalkylphos-phonate in 78% yield (Scheme 4.21). 

The last 25 years have seen very signihcant progress in the chemistry of formylphosphonates. - This chapter describes their preparation, their use in intermolecular and intramolecular Horner-Wadsworth-Emmons reactions, and, given their discovery in nature, their importance as precursors for aminophosphonic acids. 

The same strategy has been used to prepare trans bicyclic enones. The protected C5 phosphonylated aldehyde is obtained in 84% yield by a CuBr SMe2-mediated Michael addition of the Grignard reagent derived from 4-chlorobutyraldehyde diethyl acetal to a 5-phosphonylated 2,3-dihydro-4-pyridone in THF. Subsequent room-temperature hydrolysis of the acetal using aqueous oxalic acid in THF affords a near-quantitative yield of the crude aldehyde, which undergoes an intramolecular Homer-Wadsworth-Emmons reaction under treatment with Et3N/LiCl in THF at room temperature (89%). ... 

To date long-chain phosphonylated aldehydes (n > 10) have been prepared exclusively as precursors for the synthesis of 11- to 17-membered macrocycles via intramolecular Homer-Wadsworth-Emmons reactions (Scheme 5.63). This widely used cyclization step provides the best method for preparing macrocycles. 

Gijsen, H.J.M., and Wong, C.-H., Synthesis of a cyclilol via a tandem enzymatic aldol-intramolecular Horner-Wadsworth-Emmons reaction. Tetrahedron Lett., 36, 7057, 1995. 

Comins, D.L., and Olhnger, C.G., Inter- and intramolecular Homer-Wadsworth-Emmons reactions of 5-(diethoxyphosphoryl)-l-acyl-2-alkyl(aryl)-2,3-dihydro-4-pyridones, Tetrahedron Lett., 42, 4115, 2001. 

Oxygen and nitrogen nucleophiles add to diethyl l-(ethoxycarbonyl)vinylphosphonate to generate the formation of various fused heterocyclic compounds. Thus, A -carbapcncrns are readily prepared by the Michael addition of A-lithio-4-vinylazetidin-2-one to diethyl l-(ethoxycarbo-nyl)vinylphosphonate followed by ozonolysis of the adduct and subsequent treatment of the generated aldehyde by intramolecular Homer Wadsworth-Emmons reaction (Scheme 8.28). ... 

Burn at Hoffmann-La Roche chose to couple the two monomeric units via an intramolecular Wadsworth-Emmons reaction rather than lactonization (see Scheme 4.16). Thus dithiane 70, obtained by formylation of the anion derived from 69, underwent a regiospecific 1,3 dipolar cycloaddition with acetonitrile oxide to afford isoxazoline 71. Dibal reduction to the related amino alcohol followed by optical resolution with D-camphorsulfonic acid led to the isolation... 

K2CO3 and 18-crown-6 initiated an intramolecular Wadsworth-Emmons reaction... 

The Wadsworth-Emmons reaction of the aldehyde (190) with the complex phosphonate (191) has been used to construct the Cio-Cn double bond in a convergent synthesis of lacrimin A (192) (Scheme 27). Phosphonate-based olefination has been extensively used in the synthesis of cytohalasans (e.g. 193), a group of biologically active fungal metabolites. 12 The phosphonate (194) has been used to construct a triene function which ultimately forms the tricyclic structure through an intramolecular Diel s Alder reaction. 14,15-Dehydroforskolin (196) has been prepared by the base-induced reaction of the aldehyde (195) with dimethyl diazomethylphosphonate.l 13 Under certain conditions the phosphonate (197) can be isolated and this provides evidence for the involvement of the Wadsworth-Emmons intermediate (198) in the reaction. The phosphonate... 

With the alkene in place, the E-ring dihydrofuran was constructed by an intramolecular Wadsworth-Emmons reaction to yield ester 53 (Scheme 25). Adjustment of the oxidation state afforded aldehyde 54, and completion of the synthesis involved extension of the side-chain by addition of methallylstannane. Various conditions for this reaction were investigated, with the best results obtained with the use of 5 M lithium perchlorate31. This gave a 1.3 1 mixture of separable alcohols 55 and 56 in quantitative yield. The production of both diastereomers in nearly equal... 

A less direct strategy for indole synthesis (58) is the intramolecular Buchwald-Hartwig amination of an enamine 57 catalyzed by (DPPF)PdCl2.99 It is necessary to use the Z-enamine isomer 57 that was set by a Homer-Wadsworth-Emmons reaction. 

A one-pot synthesis of 4-hydroxycyclopent-2-en-l-ones (150), involving (Z)-stereoselective olefination of a-diketones to give (149) followed by intramolecular aldol condensation, has been reported. Wadsworth-Emmons reactions of bis(2,2,2-trifluoroethyl)phosphono sulfoxides (151) with aromatic aldehydes give predominantly (Z)-a,p-unsaturated sulfoxides while similar reactions with the corresponding sulfides (152) give ( )- or lower (Z)-selectivity. In olefinations using (5)-dimethyl phosphorylmethyl p-tolyl sulfoxide (153) substantial racemisation at sulfur occurs when -butyllithium is used as base. ... 

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