| Julia olefination | |
|---|---|
| Named after | Marc Julia |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | julia-olefination |
| RSC ontology ID | RXNO:0000117 |
TheJulia olefination (also known as theJulia–Lythgoe olefination) is thechemical reaction used inorganic chemistry ofphenylsulfones (1) withaldehydes (orketones) to givealkenes (olefins)(3) after alcohol functionalization and reductive elimination usingsodium amalgam[1][2] orSmI2.[3] The reaction is named after the French chemistMarc Julia.
The utility of this connective olefination reaction arises from its versatility, its wide functional group tolerance, and the mild reaction conditions under which the reaction proceeds.
All four steps can be carried out in a single reaction vessel, and use of R3X is optional. However, purification of the sulfone intermediate 2 leads to higher yield and purity. Most often R3 isacetyl orbenzoyl, withacetic anhydride orbenzoyl chloride used in the preparation of 2.
In 1973, Marc Julia and Jean-Marc Paris reported a novel olefin synthesis in which β-acyloxysulfones were reductively eliminated to the corresponding di-, tri-, or tetrasubstituted alkenes.[4] Basil Lythgoe andPhilip J. Kocienski explored the scope and limitation of the reaction, and today this olefination is formally known as the Julia-Lythgoe olefination.[5] The reaction involves the addition of a sulfonyl-stabilized carbanion to a carbonyl compound, followed by elimination to form an alkene. In the initial versions of the reactions, the elimination was done under reductive conditions. More recently, a modified version that avoids this step was developed by Sylvestre Julia (no relation to Marc).[1] 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 assodium amalgam[6][7] orSmI2.[8] Several reviews of these reactions have been published.[9][10]
The initial steps are straightforward. The phenyl sulfoneanion (2) reacts with an aldehyde to form thealkoxide (3). The alkoxide is functionalized with R3-X to give the stable intermediate (4). The exact mechanism of the sodium amalgam reduction is unknown but has been shown to proceed through a vinylic radical species (5)[11]. Protonation of the vinylic radical gives the desired product (6).
The stereochemistry of the alkene (6) is independent of the stereochemistry of the sulfone intermediate 4. It is thought that the radical intermediates are able to equilibrate so that the more thermodynamically stable trans-olefin is produced most often. This transformation highly favors formation of theE-alkene.[12]
The modified Julia olefination, also known as the one-pot Julia olefination is a modification of the classical Julia olefination. The replacement of the phenyl sulfones with heteroaryl sulfones greatly alters the reaction pathway.[13] The most popular example is thebenzothiazole sulfone.[14] The reaction of the benzothiazole sulfone (1) withlithium diisopropylamide (LDA) gives a metallated benzothiazolyl sulfone, which reacts quickly with aldehydes (or ketones) to give an alkoxide intermediate (2). Unlike the phenyl sulfones, this alkoxide intermediate (2) is more reactive and will undergo aSmiles rearrangement[15] to give the sulfinate salt (4). The sulfinate salt (4) will spontaneously eliminatesulfur dioxide andlithium benzothiazolone (5) producing the desired alkene (6).
Since the benzothiazole variation of the Julia olefination does not involve equilibrating intermediates, the stereochemical outcome is a result of the stereochemistry of the initial carbonyl addition. As a result, this reaction often generates a mixture of alkene stereoisomers.
| Julia–Kocienski olefination | |
|---|---|
| Named after | Marc Julia Philip Joseph Kocienski |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | modified-julia-kocienski-olefination |
| RSC ontology ID | RXNO:0000304 |
The Julia–Kocienski Olefination, a further refinement of the Modified Julia olefination, offers very goodE-selectivity. In the Julia–Kocienski olefination[16] thealkylating agent is atetrazole. It proceeds with the same mechanism as the benzothiazole sulfone above. The highE-selectivity of the Julia–Kocienski olefination is the result of kinetically controlled diastereoselective addition of metalated 1-phenyl-1H-tetrazol-5-yl (PT) sulfones to nonconjugated aldehydes. This yields anti-β-alkoxysulfones which stereospecifically decompose to theE-alkenes.[17] In one adaptation,[18] witht-butyltetrazoylmethyl sulfone the reaction conditions are eithersodium bis(trimethylsilyl)amide at −70 °C intetrahydrofuran orcaesium carbonate at +70 °C. This reaction is named after Philip J. Kocienski for his modification to the Julia olefination.
The Julia or modified Julia olefination reaction is a powerful and versatile synthetic transformation, widely utilized in the construction of complex natural products with excellent control of geometrical isomerism.
Pterostilbene is a stilbenoid chemically related to resveratrol. It belongs to the group of phytoalexins, agents produced by plants to fight infections.[19] Pterostilbene is a naturally occurring dimethyl ether analog of resveratrol. It is believed that the compound also hasanti-diabetic properties, but so far very little has been studied on this issue.
Compared to theWittig, Wittig-Horner,Perkin, or transition-metal-catalyzed reactions to synthesize pterostilebene, the Julia olefination offers a simple, economical alternative method for preparation of pterostilbene.[20][21]
One adaptation of the Julia-Kocienski olefination gives the synthesis of thestilbenoidresveratrol, a natural compound found in common foods like grapes, wines and nuts. Resveratrol is a biologically important stilbenoid which has been suggested to have many health benefits. The Julia-Kocienski olefination serves as a powerful reaction in the synthesis of resveratrol analogues with 3,5-bis(trifluoromethyl)phenyl sulfones. The following schematic displays the general scheme for synthesizing resveratrol analogues, where R2 is an aryl group.[22]
In the asymmetric total synthesis of (−)-callystatin A byAmos Smith, two separate Julia olefinations were used to append twoE-alkene moieties.[23] (−)-callystatin A is a member of the leptomycin family of antibiotics. The following schematic displays the Julia-Kocienski olefination used to achieve the precursor to the natural product, as indicated by use of the PT-sulfone.
