Alkenes Julia-Kocienski olefination

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 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. 11.23. Julia-Kocienski olefination to obtain tmns-alkenes from aldehydes in a single step their condensation reaction with the sulfonyl anion B, followed by an Ar-SN reaction (- E) and a fragmentation.

In the synthesis of novel antifimgal agent Ambruticin by Jacobsen and coworkers [114] the major building blocks were connected using the Julia-Kocienski olefination reaction (Scheme 87). It was found that high selectivity for either double bond isomer could be obtained NaHMDS in THF providing Z alkene (Table 24, entries 1 and 2) whereas LHMDS in polar solvents afforded the desired E isomer almost exclusively (entries 3 and 4). 

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 reaction between a carbanion derived from alkyl 3,5-bis(trifluoromethyl)phenyl sulfones and aldehydes affords, with good yields and stereoselectivities, the corresponding 1,2-disubstituted alkene through the Julia-Kocienski olefination reaction. This one-pot protocol can be performed using the phosphazene base at —78 °C and has been successfully used in a high yielding and stereoselective synthesis of various stilbenes such as resveratrol [47] (Scheme 5.28). 

The Julia-Kocienski olefination has inspired McGeary and coworkers to develop the transformation of epoxides 54 into the corresponding alkenes fScheme 19.28T In a first step, the nucleophilic addition of the BT-thiol 55 to the epoxide 54 afforded the p-hydroxy BT-thioether 56, which can fiirther evolve under prolonged reaction time to give the episulfide 57... 

Srhpiup iQ.2fi Conversion of epoxides to alkenes related to Julia-Kocienski olefination. 

The Julia-Kocienski olefination is more convenient in the synthesis of alkenes than the classical Julia olefination. A direct synthesis of olefins by reaction of carbonyl compounds with lithio derivatives of BT sulfones was... 

Zhu LG, Ni CF, Zhao YC, Hu JB. 1-tert-Butyl-lH-tetrazol-5-yl fluoromethyl sulfone (TBTSO2CH2F) a versatile fluo-romethylidene synthon and its use in the synthesis of mono-fluorinated alkenes via Julia-Kocienski olefination. reiraAefi roM2010 66(27-28) 5089-5100. 

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

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 19.2S General mechanistic pathway of the. Tnlia-Kocienski olefination. Scheme 19.26 Conversion of epoxides to alkenes related to Julia-Kociensld...

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. 

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. 

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. 

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... 

Spirotryprostatin A 142 and B 143 are two powerfully bioactive indole alkaloids. Both compounds inhibit the cell cycle in the G2/M phase, and 143 shows cytotoxic activity on the growth of human leukemia cell lines. Meyers and Carreira reported a total synthesis of 143. The Kocienski modified Julia olefmation was used in the formation of trisubstituted olefin without scrambling at Ci8. The alkene 146 was prepared in 78% yield by reacting sulfone 145 with aldehyde 144. The final product 143 was obtained by four-step reaction from the intermediate 146. 

---