Julia-Lythgoe olefination

Kocienski and Lythgoe found the reductive elimination could best be carried out with the acetoxy or benzoyloxy sulfones 2. If the lithio sulfone derivative is used for addition to the carbonyl, the reaction can be worked up with acetic anhydride or benzoyl chloride to obtain the alkene precursor. In the case where enolization of the carbonyl is a complication, the magnesium derivative can frequently be used successfully. Methanol, ethyl acetate/methanol or THF/methanol were the solvents of choice and a temperature of -20 °C was effective at suppressing the undesired elimination of the acetoxy group to produce the vinyl sulfone. 

The olefination of ketones to prepare trisubstituted alkenes employing Na-Hg affords moderate yields, unpredictable stereoselectivities and large amounts of retro-aldol products from the intermediate jS-alkoxy sulfones. High yields and moderate stereoselectivities of trisubstituted alkenes are obtained by a modification of the Julia-Lythgoe olefination reaction, involving the in situ capture of the intermediate y6-alkoxy sulfones with a 

Modified one-port Julia-Lythgoe olefination to give predominantly ( )-olefins from heteroarylsulfones 4 and aldehydes is called as Julia- 

The one-port olefination of Sylvestre Julia is operationally simpler and more amenable to scale up than the classical y4-step variant originally reported by Marc Julia. This reaction consists of the replacement of the phenyl sulfone moiety traditionally in the classical reaction, with different heteroaryl sulfones, such as benzothiazol-2-yl (BT, 5) sulfone. This allows the direct olefination process and eliminates the sulfone reduction step. The stereochemistry of the reaction in the synthesis of 1,2-disubstituted alkenes is dependent on the base and solvent. 

Kocienski and co-workers discovered that metallated 1-phenyl-1//-tetrazol-5-yl sulfones (PT, 6) gave much better yields compared to its BT-substituted counterpart suggesting that the PT sulfone anions are less prone to self-condensation. Other heterocyclic derivatives, such as pyridine-2-yl (PYR, 7), l-tert-butyl-l//-tetrazol-5-yl (TBT, 8), and 3,5-bis(trifluoro-methyl)phenyl (BTFP, 9) sulfones have also provided useful levels of stereoselectivity in the one-pot Julia-Kocienski olefination reaction. 

aryl R, R = H, alkyl, aryl, alkenyl R = alkyl, aryl X = Cl, Br, OCOR 

aryi R = aikyi, aryi.aikenyi Met = benzothiazoi-2-yi (BT), pyridin-2-yi (PYR), 1-phenyl-1 H-tetrazol-5-yl (PT) 

The exact mechanistic pathway of the classical J-L olefination is unknown. Deuterium-labeling studies showed that the nature of the reducing agent (sodium amalgam or Smb) determines what type of intermediate (vinyl radical or secondary alkyl radical) is involved. Both intermediates are able to equilibrate to the more stable isomer before conversion to the product. The high ( )-selectivity of the Kocienski-modified reaction is the result of kinetically controlled irreversible diastereoselective addition of metalated PT-sulfones to nonconjugated aldehydes to yield anti-P-alkoxysulfones which stereospecifically decompose to the ( )-alkenes. 

The first total synthesis of racemic indolizomycin was accomplished by S.J. Danishefsky et a. The natural product s trienyl side chain was elaborated using the classical J-L olefination. The macrocyclic a, 3-unsaturated aldehyde was treated with an ( )-allylic lithiated sulfone to give epimeric acetoxy sulfones upon acetylation. The mixture of epimers was exposed to excess sodium amalgam in methanol to afford the desired ( , , ) triene stereospecifically. 

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. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 136, Springer-Verlag Berlin Heidelberg 2009 

Julia—Lythgoe olefination. In Name Reactions for Homologations-Part 1 Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 447-473. (Review). 

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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... 

The reductive elimination of /i-hydroxysulfones is the final step in the Julia-Lythgoe olefin synthesis.218 The /Lhydroxysulfones are normally obtained by an aldol addition. 

The Julia-Lythgoe olefination operates by addition of alkyl sulfone anions to carbonyl compounds and subsequent reductive deoxysulfonation (P. Kocienski, 1985). In comparison with the Wittig reaction, it has several advantages sulfones are often more readily available than phosphorus ylides, and it was often successful when the Wittig olefination failed. The elimination step yields exclusively or predominantly the more stable trans olefin stereoisomer. 

Alkene-Forming Step of the Julia-Lythgoe Olefination... 

The last step of the Julia-Lythgoe olefination is an elimination, which is typically performed with sodium amalgam and starts with an Elcb elimination to give an alkenyl sulfone (mechanistic analysis Figure 4.40) with its reduction to the alkene following in situ. Both the related mechanism and an explanation of the resulting fraws-selectivity will be outlined later in Figure 17.85. 

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. 

Fig. 11.22. Julia-Lythgoe olefination of aldehydes to form trans-alkenes in two steps (1) addition of a lithium sulfone B <-> B1 to an aldehyde in-situ acetylation (2) reduction of the syir.cmti-diastereomeric mixture of the resulting sulfonylacetates C with sodium amalgam.

The Julia-Lythgoe olefination has already been addressed twice as an important C=C double bond-forming two- or three-step synthesis of trans-alkenes (trans-B in Figure 17.85). The step... 

Fig. 17.85. Mechanistic analysis of the second part of the reaction process where the treatment of the acetoxy sul-fones syn- and anti-A with sodium amalgam completes the Julia-Lythgoe olefination. Series of a first electron transfer (—> alkenyl phenylsulfone radical anion E), homolysis (—> alkenyl radical G + sodium benzene sulfinate), second electron transfer (—> alkenyl anion trans"-D) and in-situ protonation.

More recently, Marko has used Sml2 to reduce (5-benzoyloxy sulfones65 and sulfoxides66 in modified Julia Lythgoe olefinations. 

Although the Schlosser modification of the Wittig reaction provides access to trans-olefins from non-stabilized ylides, the Julia-Lythgoe olefination has proven to be the method of choice for solving this synthetic problem today, a) M. Schlosser, K.-F. Christmann, Justus Liebigs Ann. Chem. 1967, 708, 1-35 b) M. Schlosser, K.-F. Christmann, A, Piskala, Chem. Ber. 1970, 103, 2814-2820. 

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