Wadsworth-Emmons phosphonate

If a chiral cobalt complex, instead of Co(salen)2, is used, enantioselectivity during the ring-opening process is induced (at —20°C the optimal ee was 76%) <2002CC28>. The application of stabilized Horner-Wadsworth-Emmons phosphonates represents a viable alternative to ylides in the cyclopropanation reaction <2002JOC3142>. 

Important and widely used variants of the Wittig reaction are based on carbanionic organophosphorus reagents, and are known as the Wadsworth-Emmons reaction, Wittig-Horner reaction or Horner-Wadsworth-Emmons reaction. As first reported by Horner, carbanionic phosphine oxides can be used today carbanions from alkyl phosphonates 13 are most often used. The latter are easily prepared by application of the Arbuzov reaction. The reactive carbanionic species—e.g. 14 —is generated by treatment of the appropriate phosphonate with base, e.g. with sodium hydride ... 

Carboximide 160, the C35-C42 fragment, can be traced retro-synthetically to phosphonate 169 and aldehyde 170. In the synthetic direction, the C35-C36 bond in 160 could be constructed by an intermolecular Horner-Wadsworth-Emmons (HWE)70 coupling of intermediates 169 and 170. Reduction of the unsaturated coupling product and exchange of silyl protecting groups would then furnish compound 160. 

Aldehyde 170 is to serve as the electrophile in an intermolecular Homer-Wadsworth-Emmons (HWE) reaction70 with enantiomeri-cally pure phosphonate 169. Compounds 169 and 170 can in fact be joined efficiently under the mild reaction conditions shown in Scheme 50 to give a,/ -unsaturated imide 206 (96 % yield). The use... 

Intramolecular phosphonate-ketone condensation (Homer-Wadsworth-Emmons)... 

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... 

An efficient one-pot synthesis of mikanecic acid derivatives was accomplished from allylic phosphonates, ClC02Et, and aqueous HCHO (Eq. 12.38).100 The overall process involves a cascade sequence linking together metalation-alkoxycarbonylation, Homer-Wadsworth-Emmons,... 

There do not appear to be any simple phosphines that bear a CH2F group. However, fluorine NMR spectra of phosphonates, phosphane oxides, and phosphonium compounds with CH2F and —CHF- bound to phosphorous have been reported. Examples are given in Scheme 3.26, including spectral data for the useful Horner-Wadsworth-Emmons reagent, triethyl 2-fluoro-2-phosphonoacetate. 

Application of the Horner-Wadsworth-Emmons reaction to the functionalization of dendrimers allows one to prepare amino acid terminated macromolecules. Such a reaction conducted with dendrimers 10-[G ], 10-[G 3], lO-fG ] and phosphonates unsubstituted at the carbon a to the phosphoryl group affords in moderate yield dendrimers bearing various a, / unsaturated functional groups on the surface [18]. (Schemes 17 and 18). 

In 2000, the Merlic research group reported concise total syntheses of calphostins A and D and the first total syntheses of calphostins B and C [33]. This original approach to the naphthalene fragment relied on a chromium carbene intermediate to obtain the required regioselection. The synthesis began with phosphonate 39 (three steps), followed by a Homer-Wadsworth-Emmons olefination of 39 with... 

Although not widely exploited, the use of the phosphonate 148 in Wadsworth-Emmons reactions represents a process of great potential that has been used to access the 3-alkenyl-l,2,4-oxadiazole 149 (Equation 21) <1989J(P1)2047>. 

As shown in Equation (23), the 3-chloromethyl-l,2,4-oxadiazole 159 (X = H) undergoes Arbuzov reaction to give the phosphonate 148 which has been used in Wadsworth-Emmons reactions as shown previously in Equation (21) <1989J(P1)2047>. 

An asymmetric synthesis of phosphonylated thiazolines has been described. The phosphonodithioacetate 46 was aminated with a chiral amino alcohol 47 to give the phosphonylated thioamide 48 in good yield. This was then cyclised using a Mitsunobu procedure to give the chiral thiazoline phosphonate 49 in good yields under mild conditions. Homer-Wadsworth-Emmons reaction of these phosphonylated thiazolines gave chiral vinylic thiazolines 50 <00S1143>. 

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). 

An asymmetric Horner-Wadsworth-Emmons reaction has been developed which uses an external chiral ligand to avoid the need to prepare chiral phosphonate derivatives. ... 

Applicable to base-sensitive aldehydes and phosphonates for the Horner-Wadsworth-Emmons reaction... 

In related studies, it has been shown that a-fluorobenzylphosphonates ArCHFPO(OEt)2 (38) will undergo Wadsworth-Emmons-type olefination reactions with aldehydes and ketones [57]. 39 was prepared from benzaldehydes and HP(0) (OEt)2, which was fluorinated using diethylaminosulfur tiifluoride for example, diethyl [(3,5-dimethylphenyl)(fluoro)methyl]phosphonate (38) was formed in 91%. An 82% yield of Me 2-[(fluoro)(4-fluorophenyl)methylene]butanoate (1 1 E Z) (40) was obtained from 38 and methyl 2-oxobutanoate (Scheme 13). 

Wadsworth-Emmons reaction of the phosphonate anion of a benzothiazine (compound 239, synthesis shown in Equation (23) has been reported <2004BML1477>. Compound 35 was formylated in a Vilsmeier reaction (Equation 20) <1972CPB1325>. 

Examples of nucleophilic attack at the saturated 2-carbon of dihydro-l,4-thiazines, which may be assisted by the neighboring sulfur atom, are shown below. The nucleophiles include water, which was used in the acid-catalyzed hydrolysis of the ketal in 236 (Equation 21) <1982S424>, methanol in the conversion of 214 into a monothioacetal (Equation 22) <1982JHC131>, ethanol and dimethylaniline, which both reacted with 237 (Scheme 29) <1982TL4963>, and triethyl phosphite that was used to convert 238 into the phosphonate 239 required for Wadsworth-Emmons reaction (Equation 23) <2004BML1477>. Compound 240 reacted with both methanol and methanethiol (Equation 24) <1990JME1898>. 

The asymmetric Horner-Wadsworth-Emmons (HWE) reaction of l,3-dioxan-5-ones with phosphonate 184 and a chiral diamine was reported. With the /i r/-butyl-substituted l,3-dioxan-5-one, the product possesses a chiral axis. It was obtained in good yield and with 80% ee (Scheme 53) <2002TL281>. The HWE reaction with similar heterocyclic substrates was used to provide conformationally restricted arachidonic acid derivatives <1999TA139>. 

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>. 

The resulting tetramic and tetronic acid phosphonate reagents undergo the Wadsworth-Emmons olefination with a variety of aldehydes to afford (E)-a.B-unsaturated and diene acyl tetramic and tetronic acids in good to excellent yields upon treatment with potassium tert-butoxide (2 equiv) in tetrahydrofuran. For readily enolizable substrates use of the N-protected systems is generally required. The following compounds have been prepared, in the indicated yields, in this manner... 

This method, sometimes called the Horner-Emmons, Wadsworth-Emmons, or Wittig-Hor-ner reaction,658 has several advantages over the use of phosphoranes.659 These ylides are more reactive than the corresponding phosphoranes, and when R is an electron-withdrawing group, these compounds often react with ketones that are inert to phosphoranes. In addition, the phosphorus product is a phosphate ester and hence soluble in water, unlike PhjPO, which makes it easy to separate it from the olefin product. Phosphonates are also cheaper than phosphonium salts and can easily be prepared by the Arbuzov reaction ... 

To connect the C2 and C3 atoms of the 1-hydroxyethylene moiety, Wuts et al.[341 and Poss and Reid 35 used the Wadsworth-Emmons reaction between a (3-amino-a-hydroxy-aldehyde and a phosphonate (two-carbon fragment) to give the desired isostere after reduction of the alkene. In the synthesis reported by Poss and Reid (Scheme 17) the stereochemistry of the hydroxyl group at C4 is established by a highly diastereoselective aldol addition to furan. A slight modification was employed by Chakravarty et all36 and Plata et al.[37 where 4-amino-3-oxo phosphonates were reacted with an aldehyde or ketone form of the two-carbon fragment. 

Statine was identified as a starting material that contains predetermined stereochemistry at the C4 and C5 atoms. Nakano and co-workers155 56 degraded statine to an aldehyde, (45,5R)-4-alkyl-3-benzyloxycarbonyl-5-formyl-2,2-dimethyloxazolidine, which is an intermediate of the method described in Scheme 17. Then, the elongation of this aldehyde was carried out by the Wadsworth-Emmons reaction with diethyl phosphonate. 

A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of ( )-lycoramine (299) (Scheme 30) (165). Thus, the O-allylated o-vanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl IV-methylcarbamate to the intermediate a,(3-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneami-no)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl-l,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 8-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. 

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