Sulfones, Julia-Lythgoe olefination

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 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. 

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.

Among the different methods for the formation of C-C double bonds, the reductive elimination of (3-functionalized (mainly P-hydroxy or (3-carboxy) sulfones, is one of the most widely used ones in organic synthesis. The reductive elimination of (3-hydroxy sulfones and derivatives is the so-called Julia,94 or Julia-Lythgoe olefination reaction (Eq. 2). It usually involves a condensation between the anion of an alkyl sulfone and a carbonyl compound to afford a (3-hydroxy sulfone (Eq. 47). The metal alkoxide intermediate is typically transformed in situ into a carboxylic or sulfonic ester derivative, which is then reduced... 

A major drawback when reducing alkenyl sulfones with Na/Hg is that the configuration of the double bond is not necessarily preserved. Additionally, reduction of the double bond is occasionally observed as shown in Eq. 84, where a Julia-Lythgoe olefination process is also taking place.135... 

Julia-Lythgoe olefination with, 34 reduction to thioethers, 115 reductive desulfurization, 70 synth. by oxn. of thioethers, 80, 216-217 Sulfonic adds catalysts for cationic reactions acetal hydrolysis, 337 acetafixations and transacetalizations,... 

Desulfonylation. It is possible to complete the Julia-Lythgoe olefination by using the SmIj-HMPA/THF system to eliminate the 3-hydroxy sulfone unit.- " An alternative method consists of dehydration (via the acetates) and reduction of the alkenyl sulfones. (Previously, this step was performed by using Na-Hg). ... 

Samarium iodide can also be used as an alternative to sodium/ mercury amalgam for the reductive elimination of 1,2-acetoxy-sulfones in the Julia-Lythgoe olefination. The alkene is generated in a two-step process that first involves DBU or LDA treatment to generate a vinyl sulfone that is then reductively cleaved with samarium iodide (eq 44). The diastereoselectivity of both transformations is usually quite good and the method is compatible with the synthesis of monoalkenes as well as dienes and trienes. 

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... 

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. 

Modification of the Julia-Lythgoe olefination reaction between ketones and primary sulfones leads to trisubstituted alkenes in good overall yields reported by Marko and co-workers. Samarium diiodide/HMPA shown to play a crucial role in the reductive elimination step. Starting from sulfone 40, key intermediate 42 was produced in 93% yield, which was further converted to 43 in 73% yield with E/Z ratio of 2 1. More complicated intermediate 44 was similarly reduced by Smh to 45 in 68% yield. 

The use of the Julia-Lythgoe olefination with cyclopropylsulfones and cyclopropylsulfoxides for the synthesis of alkylidenecyclopropanes was reported by Bernard and co-workers. The adduct sulfide 60, prepared from sulfide 58, was oxidized to sulfone 61 and sulfoxide 64 by controlling oxidation temperature. Both intermediate 61 and 64 can be further converted to trisubstituted alkene 63 under different reductive condition. 

Marko and co-workers also made an efforts on the modification of the classical Julia-Lythgoe olefination using sulfoxides instead of sulfones. The modified reaction, after in situ benzoylation and Sml2/HMPA- or DMPU-mediated reductive elimination, provides 1,2-di-, tri-, and tetra-substituted olefins in moderate to excellent yields and E/Z selectivity. For example benzoated sulfoxide 67 was obtained by addition of sulfoxide 66 to aldehyde 33, which was subsequently reduced into alkene 68 in 67% yield with E/Z ratio of > 95 1. 

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. 

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... 

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. 

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... 

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. 

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