Intramolecular reactions Homer-Wadsworth-Emmons reaction

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>. 

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 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. 

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. 

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

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). ... 

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. 

Methyl 3-C-allyl-4,6-0-benzylidene-3-deoxy-a-D-glucopyranoside has been used as a common starting material for preparing annulated sugars involving intramolecular Homer-Wadsworth-Emmons reactions. Thus successive reaction of the allyl derivative with osmium tetroxide, lithium dimethylmethylphosphonate, Dess-Martin periodane then potassium carbonate furnished 51. Whereas successive reaction of the allyl derivative with borane-THF, PCC oxidation, lithium dimethylmethylphosphonate, Dess-Martin periodane then potassium carbonate afforded 52. Analogous chemistry was also performed on methyl 2-C-allyl-4,6-0-benzylidene-2-deoxy-a-D-allopyranoside. ... 

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

In this case, the approach involved the construction of two bibenzyl and one biaryl units using Homer-Wadsworth-Emmons and an intramolecular Suzuki-Miyaura reaction. The overall yield for the 11 steps was 10.6%. 

The Homer-Wadsworth-Emmons (HWE) reaction involves the addition of a stabilized phosphonate anion to an aldehyde or ketone to afford an intermediate which undergoes an elimination reaction to form predominately the ( )-alkene. The HWE reaction has been applied inter- and intramolecularly to simple as well as highly functionalized systems. 

The pivotal step associated with our approach to compounds 31-34 was an organocatalysed, enantioselective and intramolecular Michael addition reaction of the nucleophilic C-2 carbon of a pyrrole to an iV-tethered a,p-unsaturated aldehyde residue and thereby estabhshing the required CD-ring system. Full details of the reaction sequence are shown in Scheme 4 and this involves initial reaction of the potassium salt, 35, of pyrrole with butyrolactone (36) to give, after acidic workup, compound 37 (60-90%). Conversion of this last species into the corresponding Weinreb amide 38 (87%) followed by its reaction with ethylmagnesium bromide then afforded the ethyl ketone 39 (95%) that was subjected to standard Homer-Wadsworth-Emmons (HWE) conditions and thereby generating the... 

Diphenyl phosphite-ester-aldehyde substrates (83) undergo a Z-selective intramolecular Homer-Wadsworth-Emmons (HWE) reaction to give macrocyclic ene-lactones (84). Terminal placement of the ester in the substrate gives a macrocyclic alkene with... 

Ddmling and coworkers adapted a four-component Ugi-type reaction sequence to the synthesis of highly substituted 3-pyrrolin-2-ones (Scheme 104 20040L39). The combination of aUyl isocyanide (395), primary amine 396, a-phosphonoacetic acid 397, and a-ketoaldehyde 398 gives the 5-carboxamido-3-pyrrolin-2-one 399. The two-step process involves an Ugi multicomponent reaction followed by an intramolecular Homer/ Wadsworth/Emmons cycHzation. 

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

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