Wadsworth-Emmons reaction stereoselectivity

Several other methodologies have been developed for control of the stereoselectivity of Wadsworth-Emmons reactions. For example, K2C03 in chlorobenzene with a catalytic amount of 18-crown-6 is reported to give excellent Z-selectivity.261 Another group found that use of excess Na+, added as Nal, improved Z-selectivity for 2-methylphenyl... 

The stereoselective Horner-Wadsworth-Emmons reaction of aldehydes with 2-fluoro-2-diethylphosphonoacetic acid utilizing isopropyl magnesium bromide afforded (Z)-a-fluoro-a,j8-unsaturated carboxylates (42) as the major products in 81-98% yield [58] (Scheme 14). 

Table 8 Comparison of the stereoselectivities obtained in batch and a microreactor for the Horner-Wadsworth-Emmons reaction...

Condensations between aldehydes and metalated phosphonic acid dialkyl esters other than those mentioned previously are also referred to as Homer-Wadsworth-Emmons reactions. Nevertheless, in these esters, too, the carbanionic center carries a substituent with a pi electron withdrawing group, for example, an alkenyl group, a polyene or a C=N group. The Homer-Wadsworth-Emmons reactions of these reagents are also stereoselective and form the new C=C double bond /ra/ ,v-selectively. 

However, although the Wittig reaction is regiospecific, i.e. the alkene is formed in a particular position in the molecule, it is stereoselective rather than stereospecific. Both cis and trans geometrical isomers can be formed. The ratio of geometrical isomers may be varied. The phospho-nate variant of the process (the Wadsworth-Emmons reaction) leads to trans alkenes. 

Sano, S., Takehisa, T., Ogawa, S., Yokoyama, K., Nagao, Y. Stereoselective synthesis of tetrasubstituted (Z)-alkenes from aryl alkyl ketones utilizing the Horner-Wadsworth-Emmons reaction. Chem. Pharm. Bull. 2002, 50, 1300-1302. 

The dimethyl 2-(zert-butyldimethylsilyl)-2-oxoethylphosphonate reacts smoothly with a variety of aldehydes under standard Homer-Wadsworth-Emmons reaction conditions (NaH, THF, room temperature) or mud nonbasic conditions (LiCl, DBU, MeCN, room temperature) to give the corresponding tran5 -a,P-unsaturated acylsilanes in excellent yields (54-97%) with high stereoselectivity (Scheme 2.37). However, this reaction is considerably slower under these mild conditions (24 h) compared to standard conditions (90 min). The efforts to extend the reaction to ketones were disappointing. ... 

Sodium amide, o LDA, l.illMI)S. " NaHMDS, KHMDS, ° sodium and magnesium methoxide or ethoxide, and DBU are less frequently used. The nature of the cation present in the Homer-Wadsworth-Emmons reaction depends on the chosen base and greatly influences the stereoselectivity of the reaction. The chiral lithium 2-aminoalkoxides (17 ,2S) have been used as chiral bases for the enantioselective reaction between diethyl cyanomethylphosphonate and 4-terz-butylcyclohexanone." ... 

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... 

A stereoselective synthesis of methyl (Z)-(4,4-difluoro-2,3,4,5-tetrahydro-l//-l-benzazepin-5-ylidene) acetate via a Homer-Wadsworth-Emmons reaction has been reported <05CPB589>. 

The enone 91 was made by a Horner-Wadsworth-Emmons reaction (chapter 15) and so has the E-configuration. The cyclisation to 90 in dilute methanolic acid in 92% yield occurs with remarkable selectivity. Only one of the two free OH groups reacts, only conjugate addition occurs, and the stereoselectivity is 97 3 in favour of the isomer shown. 

The Homer-Wadsworth-Emmons reaction is an important methodology used in the synthesis of natural products, but side reactions in many cases do not allow the application of this reaction in stereoselective synthesis. 

However, Nangia et al. ( ref 34 ) recently described, by using the Homer-Wadsworth-Emmons reaction in a controlled way, the stereoselective synthesis of boschnialactone as depicted in scheme 22. 

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. ... 

Laevoglucosenone provides short, stereoselective routes to chiral synthons leading to (-)-S-multistriatin and (+)-Prelog-Djerassi lactonic acid (84)(see also Vol.16, p.265). The allo-oxiran (85) (obtained from D-glucose) has been used as the chiral control in a synthesis of chrysanthemic acids (86)(Scheme 17), the cyclopropane ring being formed by Wadsworth-Emmons reaction. ... 

An important modification (often called the Horner-Wadsworth-Emmons reaction) of fhe Wiffig reaction makes use of phosphonate esters, RP0(0R )2- It is highly stereoselective for the formation of E-alkenes.The reaction and mechanism are depicted below for the preparation of (E)-stilbene. Instead of using a phosphorus cation to stabilize the negative charge, as in the phosphonium ylide above, a phosphonate ester group is used to stabilize an adjacent carbanion. 

Recent advances in the stereoselective olefination of phosphorus-stabilized carbon nucleophiles have been reviewed. Recent applications of the Horner-Wadsworth-Emmons reaction to the synthesis of natural products have been highlighted. ... 

Recent advances in the stereoselective olefination of phosphorus-stabilized carbon nucleophiles have been reviewed. Applications of the Horner-Wadsworth-Emmons reaction to the synthesis of natural products have been highligted. A highly Z-selective synthesis of a, -unsaturated nitriles using the Homer-Wadsworth-Emmons reaction has been reported this involves a new nitrile reagent, (o-t-BuC6H40)2P(0)CH2CN, which reacts with various types of aldehydes with 86 to >99% Z selectivity. 

In a synthesis of the C(2) - C(9) fragment (64) of the polyether ionomycin (Scheme 13), enone (63), produced by intramolecular Wadsworth-Emmons reaction, underwent stereoselective introduction of a methyl group by use of a higher-order cuprate.49... 

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