Homer-Emmons, intramolecular

The remaining section highlights various other methods of generating piperidine cores. The scheme below depicts a simple route to piperidines heterocycles, such as 196, via an intramolecular Homer-Emmons cyclization of phosphonate 197 <06JA12743>. 

Paulsen, H, Vonde3m, W, Cyclitol reactions 13. S3mthesis of pseudosugars from D-glucose by intramolecular Homer-Emmons olefination, Liebigs Ann. Chem., 2, 125-131, 1987. 

The esterihcation of a 1,3-ketoaldehyde enol with a diethoxyphosphinyl-alkanoic acid, forming the ester linkage of the final molecule first, allows ring closure involving C-3-C-4 bond formation via an intramolecular Homer-Emmons reaction. ... 

Paulsen H, Deyn W (1987) Cyclitol reactions. Xni. Synthesis of pseudosugars from D-glucose by intramolecular Homer-Emmons olelinatirai. Liebigs Atm Chem 125-131... 

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... 

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Step 2 Intramolecular Homer-Wads worth-Emmons (HWE) reaction furnishes the cyclic enone G. 

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). ... 

An elegant route to pyrazoles, involves forming a ring closure precursor by Homer-Emmons condensation of a tosylhydrazone-phosphonate with an aldehyde, which becomes the 5-substituent intramolecular Michael addition and then loss of toluenesulfinate as the final aromatising step, completes the sequence. ... 

A novel approach has been developed towards the total synthesis of (+ )-allopumiliotoxin 339A (112), a minor consituent of skin extracts from the family of Panamanian poison frogs Dendrobates auratus, based on an intramolecular chromium(II)-mediated cyclization. Ketone 107, after a Homer—Emmons condensation, DIBAL reduction, and conversion to the bromide 109, is homologated based on Evans alkylation procedure [45] and transformed through a series of efficient reactions into the iodoolefin 110. 

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. ... 

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