Horner-Wadsworth-Emmons stereoselectivity

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 metallated phosphonic acid dialkyl esters other than those mentioned previously are also referred to as Horner-Wadsworth-Emmons reactions. Nevertheless, in these esters, too, the carbanionic center carries a substituent with a M effect, for example, an alkenyl group, a polyene or a C=N group. The Horner-Wadsworth-Emmons reactions of these reagents are also stereoselective and form the new C—C double bond fraus-selectively. 

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 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... 

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. 

A modified Horner-Wadsworth-Emmons reagent with high Z stereoselectivity using trifluoroethyl phosphonates in reaction with saturated, unsaturated or aromatic aldehydes. 

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. 

More recently, spirocyclizations utilizing (q -arene)RuCp+ complexes have been reported [102]. Treatment of Ru(II) complex 97 with NaH in the presence of an aldehyde initiates tandem stereoselective nucleophilic aromatic addition-Horner-Wadsworth-Emmons olefination to deliver stable cyclohexadienyl complex 98 (Scheme 15.33) [103]. Dearomatization was completed via formal oxidation of the cyclohexadienyl ligand accompanied by addition of an external nucleophile. The stereodirecting effects of the metal center and the preexisting stereocenter completely control diastereoselectivity, resulting in formation of optically pure 99 with recovery of the CpRu fragment. 

The highly stereoselective synthesis of ( )-a,P-unsaturated amides bearing (5)-a-methylbenzylamine has been achieved from readily available 2-phosphona-mides via Horner-Wadsworth-Emmons (H-W-E) reaction. " A broad range of substituted dihydropyrimidines (222) and thiazolines can be efficiently prepared using a four-component reaction involving phosphonates, nitriles, aldehydes and... 

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. 

Propose a mechanism for the Horner-Wadsworth-Emmons reaction. The reaction of aldehydes with 10 provides 1,2-disubstituted olefins with high E-selectivity. Provide (or look up) a rationale for this observation. Then explain why the reaction of 3 with 10 shows little stereoselectivity. (CJH-2)... 

In 2001 and 2002, the Smith group first disclosed the total synthesis of (+)-zampanolide [164] and (-n)-dactylolide [165], respectively. The synthetic strategy of (-i-)-zampanolide relied on the stereoselective construction of the 2,6-cjT-tetrahydropyran unit via the Petasis-Ferrier rearrangement and Horner-Wadsworth-Emmons macrocyclization at the C(2)-C(3) junction (Scheme 2.47). 

AB ABCE ABCDE - ABCDEF W-G aldehyde (-)-Strychnine] (27) After his racemic synthesis of strychnine (26), Kuehne also achieved an enantioselective synthesis of (—)-strychnine (Scheme 9). To avoid the low yield conversion of isostrychnine to strychnine, the second approach was directed to the W-G aldehyde. Starting from L-tryptophan methyl ester (86), the cyclization precursor 87 was prepared in seven steps in a similar way as in the previous racemic synthesis. The domino condensation-electrocyclization reaction of 87 with dienal 88 proceeded with quite high diastereoselectivity (>95% de) [AB ABCE, C7 quaternary center] (85). After conversion of the tetracyclic compound 89 to tosylate 92, removal of the benzyl group resulted in the clean formation of the D ring [ABCE ABCDE ]. Unlike in the first synthesis, introduction of the hydroxyethylidene side chain by a Horner-Wadsworth-Emmons reaction of ketone 93 proceeded with high stereoselectivity (E Z = 17 1). Einally, the E isomer 94E was converted to (-)-strychnine via the W-G aldehyde (50). 

The selective conversion of serine or threonine units of di- and tripeptides (392) into substituted, unsaturated aminoacids (394) has been reported by Hernandez et al. Thus, a-aminoacids esters (392) underwent a scission-phosphorylation process to give phosphonate derivatives (393). The Horner-Wadsworth-Emmons reaction of the latter with aldehydes or ketones afforded the final products (394) with excellent Z-stereoselectivity (Z E>98 2) (Scheme 138). ... 

Within the context of total synthesis, the application of CM to a one-pot sequential protocol has the potential to dramatically simplify the preparation of complex natural products. Trost and co-workers recently demonstrated an elegant example of this, wherein a one-pot CM-Takai olefination reaction was used for the preparation of the antitumor agent callipeltoside A and various analogs (Scheme 21). By using a three-step, two-pot sequence employing this protocol, the synthetic route toward these compounds was shortened by five steps and olefin stereoselectivity was increased (4 1 to >8 1 E/Z) relative to previous syntheses employing a classical Emmons-Wadsworth-Horner approach. 

A.iu. Phosphine Oxides and Phosphonate Esters. Many extensions of the Wittig reaction have been introduced that improve or modify the reactivity and/or stereoselectivity of the ylid. Horner et al. showed that a-lithiophosphine oxides such as that derived from 552 react with aldehydes or ketones to give a p-hydroxy phosphine oxide (553) as an isolable species. Subsequent treatment with base liberates the alkene, (554). Wadsworth and Emmons modified the Horner reaction to use phosphonate ester derivatives such as... 

---