Still-Gennari olefination reaction

Also obtained were significant amounts of allyl alcohol 49 and its trans-isomer 53, resulting from the reduction of the aldehyde 54. The structures were confirmed by comparison with authentic samples that were prepared from the trans Still-Gennari olefin 51. The mechanism of this double bond isomerization is not clear. It occurs at -78 °C even before the aldol reaction takes place and may be the consequence of an addition/elimination process of chloride or triethylamine induced by boron coordination to the aldehyde oxygen atom, but this is speculative. However, I should note at this point that exposing aldehyde 8 separately to all the reagents used in the process produces no change apart from minimal reduction in the presence of (+)-DIP-Cl. 

The mechanism for the Still-Gennari HWE reaction is shown in above for an aldehyde condensation. The phosphoryl-stabilized carbanion 23 attacks the carbonyl to give oxyanion intermediate 24, which then decomposes via a transient four-centered intermediate 25 to yield olefin 26. The stereochemistry is in favour of erythro isomer, a kinetic adduct. 

Mickel and co-workers at Novartis Pharma was very successful in large-scale synthesis of (+)-discodermolide 92, Still-Gennari HWE reaction in the formation of Cs-Co (Z)-olefin especially. " The compound 91 was obtained in 76% yield (622 g) from 90 by two step reactions, and KHMDS was used as base in the olefination reaction. 

The stereostructure of the alkoxide intermediate of a Horner-Wadsworth-Emmons reaction which finally leads to the trans-o cim was recorded in Figure 9.14 (as formula A). The Still-Gennari variant of this reaction (Figure 9.15) must proceed via an alkoxide with the inverse stereostructure because an olefin with the opposite configuration is produced. According to Figure 9.16, this alkoxide is a 50 50 mixture of the enantiomers C and ent-C. Each of these enantiomers contributes equally to the formation of the finally obtained cw-configured acrylic ester D. 

Related reactions , Horner-Wadsworth-Emmons olefination - Still-Gennari modification, Julia-Lithgoe olefination, Peterson... 

Related reactions Horner-Wadsworth-Emmons olefination, Homer-Wadsworth-Emmons olefination - Still-Gennari modification, Julia-Lithgoe olefination, Takai-Utimoto olefination, Tebbe oiefination, Wittig reaction, Wittig reaction - Schiosser modification ... 

The practical applicability of the HWE reaction and Still-Gennari varianted HWE olefination reaction is evident from its employment in the total-synthesis of numerous complex natural products. Macrolactin A, 68, is a 24-membered polyene macrolide. It displays strong cytotoxic activity in vitro on... 

In the effort of total synthesis of discodemolide, the Still-Gennari type HWE reaction was also used by Paterson and Lyothier to form the Cg-C9 olefin. Phosphonate 94 was treated with NaH in THE at 0 °C for 30 min prior to the addition of aldehyde 93. The crude product showed a mixture of (Z)- and ( )-olefins, 95 and 96, in a 5 1 ratio. The desired (Z)-isomer 96 could be isolated by flash chromatography in 73% yield. The (Z)-enone 96 was further treated with K-Selectride at 25 C for 24 h. A single diastereomeric alcohol 97 was formed selectively and isolated in 59% yield. This alcohol processing (7/ )-configuration was leading to 1-epi-discodermolide 98 as final product by four additional reactions. 

This reaction has been modified to occur under mild conditions such as those of Masamune and Roush, Still, and Ando. In addition, chiral phosphonates (or phospho-namides) have been used for this reaction. In particular, the method developed by Still and Gennari using [bis(trifiuoroethyl)phosphono] esters, generally known as Gennari-Still phosphonates, is very useful in the preparation of Z-olefins. Illustrated is the HWE reaction using Gennari-Still phosphonates to give c/ -olefins, and its mechanism. 

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