Julia-Lythgoe-Kocienski olefinations

The Julia-Lythgoe-Kocienski olefination reaction7 between 5 and 8 to obtain alkene 23... 

The first step in this multistage reaction is the nucleophilic addition of sulfone anion 28 to aldehyde 8 (Scheme 14.6). This produces a p-alkoxysulfone intermediate 29 which is trapped with acetic anhydride. The resulting P acetoxysulfone mixture 22 is then subjected to a reductive elimination with Na/Hg amalgam to obtain alkene 23. The tendency of Julia-Lythgoe-Kocienski olefinations to provide ( )-1,2-disubstituted alkenes can be rationalised if one assumes that an a-acyloxy anion is formed in the reduction step, and that this anion is sufficiently long-lived to allow the lowest energy conformation to be adopted. Clearly, this will... 

Scheme 14.6 The Julia-Lythgoe-Kocienski olefination method.

The sulfone is a versatile functional group comparable to the carbonyl functionality in its ability to activate molecules for further bond construction, the main difference between these two groups being that the sulfone is usually removed once the synthetic objective is achieved. The removal most commonly involves a reductive desulfonylation process with either replacement of the sulfone by hydrogen (Eq. 1), or a process that results in the formation of a carbon-carbon multiple bond when a P-functionalized sulfone, for example a (3-hydroxy or (3-alkoxy sulfone, is employed (Eq. 2). These types of reactions are the Julia-Lythgoe or Julia-Paris-Kocienski olefination processes. Alkylative desulfonylation (substitution of the sulfone by an alkyl group, Eq. 3), oxidative desulfonylation (Eq. 4), and substitution of the sulfone by a nucleophile (nucleophilic displacement, Eq. 5) are also known. Finally, p-eliminations (Eq. 6) or sulfur dioxide extrusion processes (Eqs. 7, 8 and 9) have become very popular for the... 

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 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. 

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. 

Marc) Julia-Lythgoe- and (Sylvestre) Julia-Kocienski Olefination... 

Lythgoe, Kocienski and their coworkers investigated the scope, stereochemistry and mechanism of the classical Julia olefination (also called the Juha-Lythgoe olefination) and paved the way for its broad application in target-oriented synthesis [87-90]. The bias towards fi-olefins, with the isomer ratio being typically in the range 7/3 to 9/1 for primary unhindered sulfones and aldehydes, marks a distinctive stereochemical feature of the reaction. 

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. 

Julia-Kocienski Olefination or Julia-Lythgoe Olefination)... 

Sylvestre Julia and co-workers discoveried in 1991 a direct synthesis of olefins by reaction of carbonyl compounds with lithio derivatives of 2-[alkyl- or (2 -alkenyl)- or benzyl-sulfonylj-benzothiazoles (BT, 5). Since the initial study of the reaction of metallated BT sulfone 5 with carbonyl compounds, the versatility of these derivatives has been fully demonstrated through their application in the total synthesis of a large number of nature products. Kocienski and co-workers found in 1998 that l-phenyl-17/-tetrazol-5-yl sulfone (PT, 6) is a better olefination partner comparing to BT sulfones. This allowed the one-port Julia-Lythgoe olefination to be employed more efficiently and broadly, especially in the synthesis of nature products. 

A stereoselective construction of the Z)-e/yr/tro-azidosphingosine characteristic trans double bond was accomplished by Panza and co-workers by condensation reaction between tetradecanol and a heterocyclic sulfone derived from diethyl Z)-tartrate, following the Kocienski modification of the Julia-Lythgoe olefination. Alcohol 71 was first converted into the 1-phenyl-l//-tetrazole-5-yl thioether under Mitsunobu conditions and then oxidized to 73 in 80% yields. A solution of sulfone 73 in DME at -55 "C was treated with KHMDS to give a stable anion of compound 73, which was then reacted with tetradecanal to give compound 74 in 53% yield. The compound 74 can be efficiently transformed into the target, 3-(9-(4-methoxybenzyl)-azidosphingosine, with reported procedure. 

The Julia-Lythgoe olefination and Kocienski modification have applied broadly in the synthesis of nature products. Isoprostane of A2 and h are isomeric of the cyclopentenone prostaglandins A2 and J2, respectively, which are reported to exert unique biological effects. Prostaglandins of A2 and J2 series have been reported to be active against a wide variety of DNA and RNA viruses, including HIV-1 and influenza virus. They also possess a potent anti-inflammatory activity due to the inhibition and modification of the subunit IKKP of the enzyme IA B kinase. Zanoni and co-workers reported the first total synthesis of A2 Isoprostane 101 employed a stereoselective Julia-Lythgoe olefination in the formation of C 13 14 double bond. The intermediate 99, obtained in 87% yield by addition of sulfone 97 to aldehyde 98, was reduced by Na(Hg) to alkene 100 in 81% yield. 

Hennoxazole A displays potency against Herpes Simplex virus type 1 and peripheral analgesic activity comparable to that of indomethacin. Williams and co-workers reported a total synthesis of (-)-hennoxazole A 141. The Kocienski modification of the Julia-Lythgoe olefination was very successfully employed in the formation of Cn-Cis alkene in 85% yield with excellent iJ-selectivity E/Z = 91 9) by reacting sulfone 140 with aldehyde 139. Hydrolysis of the C4 pivaloate ester (LiOH in aqueous THF/MeOH) provided synthetic hennoxazole A (141) in 72% yield. 

Julia, M. Paris, J. M. Syntheses a L aide de Sulfones. V. Methode de Syntheses Generale de Doubles Liasons Tetrahedron Lett. 1973, 15, 4833-4836. Kocienski, P. J. Lythgoe, B. Ruston, S. Scope and Stereochemistry of an Olefin Synthesis from -Hydroxy-Sulfones /. Chem. Soc., Perkin Trans. 1 1978, 829-834. 

Marc Julia and Paris invented this methodology for the preparation of E)-olefin in the synthesis of Liaisons in 1973. The Julia coupling was applied to the synthesis of mono-, di- and tetra-substituted alkenes in the original communication. Kocienski and Lythgoe first demonstrated the trans... 

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