Alkenes Julia olefinations

This section deals with reactions that correspond to Pathway C, defined earlier (p. 64), that lead to formation of alkenes. The reactions discussed include those of phosphorus-stabilized nucleophiles (Wittig and related reactions), a a-silyl (Peterson reaction) and a-sulfonyl (Julia olefination) with aldehydes and ketones. These important rections can be used to convert a carbonyl group to an alkene by reaction with a carbon nucleophile. In each case, the addition step is followed by an elimination. 

The Julia olefination involves the addition of a sulfonyl-stabilized carbanion to a carbonyl compound, followed by elimination to form an alkene.277 In the initial versions of the reaction, the elimination was done under reductive conditions. More recently, a modified version that avoids this step was developed. The former version is sometimes referred to as the Julia-Lythgoe olefination, whereas the latter is called the Julia-Kocienski olefination. In the reductive variant, the adduct is usually acylated and then treated with a reducing agent, such as sodium amalgam or samarium diiodide.278... 

C. Charrier, L. Ettouati, J. Paris, New application of the Julia olefination for the synthesis of Tyr-Gly -alkene and carba isostere pseudopeptides. Tetrahedron Lett. 40 (1999) 5705-5707. 

A disadvantage of the Julia Olefination is its low tolerance for reducible functional groups. The ( -selectivity is generally good to very good for alkenes with a low degree of substitution, while the selectivity improves as a function of increased branching in the substitutents. 

The Modified Julia Olefination (or Julia-Kocienski Olefmation) enables the preparation of alkenes from benzothiazol-2-yl sulfones and aldehydes in a single step ... 

P. R. Blakemore, The Modified Julia Olefination Alkene Synthesis via the Condensation of Metallated Heteroarylalkylsulfones with Carbonyl Compounds, J. Chem. Soc. Perkin Trans. 12002, 2563—2585. 

The fact that the Julia-Lythgoe olefination requires more than one step to prepare alkenes has generally been accepted as an inconvenient and inevitable part of the procedure developed by Marc Julia and Basil Lythgoe. This flaw kept nagging at Marc Julia s brother Sylvestre, who would not rest until he had found the one-step (Sylvestre) Julia olefination. The (Sylvestre) Julia-Kocienski olefination has become the state-of-the-art-variant of this olefination (Figure 11.23). It may be applied to any kind of aldehyde. 

The short sequence of steps (starting with sulfone plus aldehyde and leading through to alkene) is known as the Julia olefination. It is our first example of a connective double bond synthesis—in other words, the double bond is formed by joining two separate molecules together (the aldehyde... 

The Julia-Kocienski olefination of heterocyclic sulfones and aldehydes, which is an alternative to the modified Julia olefination, forms alkenes with good -selectivity. First, sulfone 54 is deprotonated in the a-position to the sulfur by sodium hexamethyldisilazide (NaHMDS) and the sulfur-stabilized anion 55 then adds to the alde-... 

Julia-Lythgoe olefmation is probably the most important method for synthesizing acceptor-free, -configured alkenes, starting from an aldehyde and a primary alkylphenyl sulfone. In this two-step procedure, first the sulfone reacts with the aldehyde to form an acetyl-protected alcoholate and second this species undergoes Elcb elimination to afford the desired alkene. (Sylvestre) Julia olefination is a one-step procedure. It also affords -configured olefins from an aldehyde and an alkylsulfone as substrates, but is limited to base-resistant aldehydes. The most advanced variant is (Sylvestre) Julia-Kocienski olefination, which is also a one-step procedure and is applicable to all kinds of aldehydes. The mechanism is shown below. 

The Julia olefination reaction is highly regioselective and ( )-stereoselective, providing a valuable alternative to the Schlosser reaction for making rrans -disubstituted olefins. The reaction involves condensation of a metalated alkyl phenyl sulfone with an aldehyde to yield a P-hydroxysulfone, which is then subjected to a reductive elimination to produce the alkene. There are limitations to the preparation of tri- and tetra-substituted alkenes via the sulfone route because the P-alkoxy sulfones derived from addition of the sulfone anion to ketones may be difficult to trap and isolate or they may revert back to their ketone and sulfone precursors. 

In the asymmetric total synthesis of (-)-callystatin A by A.B. Smith and co-workers, two separate Julia olefinations were used to install two ( )-alkene moieties.The C6-C7 ( )-alkene was installed using the Kocienski-modified process in which the PT-sulfone was dissolved along with the a, 3-unsaturated aldehyde in DME and treated with NaHMDS in the presence of HMPA. The ( )-olefin was the only product but due to the relative instability of the starting PT-sulfone, the isolated yield of the product was only modest. 

Blakemore, P. R. The modified Julia olefination alkene synthesis via the condensation of metallated heteroarylalkylsulfones with carbonyl compounds. J. Chem. Soc., Perkin Trans. 1 2002, 2563-2585. 

The Julia olefin synthesis is rather like the Wittig reaction with a sulfone instead of a phosphonium salt but with one other important difference the elimination step is stereoselective and both dia-stereoisomers of the intermediate can give the same isomer of the alkene. Treatment of the sulfone 147 with a strong base gives the anion 148 (or a metal derivative) that combines with an aldehyde to give a diastereomeric mixture of adducts 149. Elimination by various methods gives, in open chain compounds, mostly -150 but, in cyclic compounds, mostly the Z-alkene.29... 

Support for this mechanism came from an unexpected quarter. In a synthesis of sterpuric acid 215, Paquette planned to put in the alkene at the end by a Julia olefination.35 Addition of MeLi to the ketone 216 and non-stereospecific elimination (chapter 15) looked a good strategy. The 1,2-relationship between OH and ketone in 216 is awkward and the decision was made to try a hydroxylation on the silyl enol ether of the parent ketone 217. 

Since its original publication,94 the Julia olefination has become a very important tool in organic synthesis for the site- and stereoselective synthesis of alkenes. The synthetic importance of the process is reflected by its numerous applications in the synthesis of a diverse range of functionalized alkenes such as allylic alcohols,198 allylic amines,199-201 homoallylic alcohols,202 homoallylic amines,203 and allylsilanes.204,129 The reaction has also been used as a key step in many... 

Z)-Alkenes. These sulfones are very stable and participate in the Julia olefination with improved yields. 

The removal of the sulfone group can be accomplished under a number of different reductive conditions. Most popular is the concomitant removal of both the sulfone and the derivatized (3-hydroxy group to give an alkene and this is commonly termed the Julia olefination reaction (see Section 2.8). 

Unlike the corresponding phosphonium salts, addition of sulfonium salts to aldehydes results, not in the alkene products, but in the formation of epoxides (see Section 1.1.5.2). However, sulfones can be used to prepare alkenes, by way of the a-metallo derivatives, in what is termed the Julia olefination (alkenylation). Addition of the organometallic species to an aldehyde or ketone gives a p-hydroxy sulfone which, in the form of its 0-acyl or 0-sulfonyl derivative, undergoes reductive cleavage with, for example, sodium amalgam in methanol to form the alkene. The reaction is regioselective and can be used to prepare mono-, di- and trisubstituted alkenes (2.91). 

Generation of Sulfur Ylides Julia Olefination and Related Processes. Recently, the modified Julia olefination, which employed certain heteroarylsulfones instead of the traditional phenyl-sulfones, has emerged as a powerful tool for alkene synthesis. Although the reaction was first reported with LDA, bases such as LHMDS, NaHMDS, and KHMDS are now commonly used. In addition, solvent as well as base counter-cation have been shown to markedly affect the stereochemical outcome of the olefination reaction. For instance, KHMDS was less selective than NaHMDS for the coupling between benzothiazoylsulfone (1) and cyclopropane carboxaldehyde (2) in toluene, furnishing a 3.7 1 ratio compared to a 10 1 ratio favoring the Z-isomer. However, both bases provided a 1 1 mixture of isomers when the reaction was run in DMF (eq 54). ... 

More recently, the modified Julia olefination, which employed certain heteroarylsulfones instead of the traditional phenylsul-fones, has emerged as a powerful tool for alkene synthesis. Although the reaction was first reported with LDA, bases such... 

The retrosynthetic analysis is outlined in Scheme 22. The amide was introduced by the Curtius rearrangement, and the macrolide 117 was formed by Horner-Emmons macrocyclization at the C2-C3 bond. The C17-C18 bond was constructed by the ring-opening of epoxide 118. 119 was formed via the Kocienski-Julia olefination at the C8-C9 bond. The cis-2,6-disubstituted tetrahydropyran in 120 was constructed by the Petasis-Ferrier rearrangement. The C4-C5 (Z)-trisubstituted alkene in 121 was formed by carbomet-allation to an alkyne. 

---