Lythgoe aldehyde

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... 

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 alkenation, also known as the Julia-Lythgoe alkenation is a reaction of phenyl sulfones 4.54 with aldehydes or ketones followed by reductive elimination with sodium amalgam to give alkenes. 

The Julia-Lythgoe alkenation procedure gives predominantly E-aUcene, depending on the reaction conditions. For example, oxidation of sulfide 4.55 with m-CPBA gave sul-fone 4.56, which on treatment with a base and aldehyde 4.57 followed by reduction with sodium-mercury (Na-Hg) and disodium hydrogen phosphate in MeOH afforded the E-alkene 4.58 in 68% yield. ... 

The modified Julia-Lythgoe alkenation known as Julia-Kocienski alkenation is one-step synthesis of alkenes from benzothiazol-2-yl sulfones (RCH2SO2BT) 4.59 and aldehydes, which is an alternative procedure that leads to the alkene in one step and offers very good -selectivity. 

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. 

Marko, I. E., Murphy, F., Kumps, L., Ates, A., Touillaux, R., Craig, D., Carballares, S., Dolan, S. Efficient preparation of trisubstituted alkenes using the Sml2 modification of the Julia-Lythgoe olefination of ketones and aldehydes. Tetrahedron 2001,57, 2609-2619. 

The easiest approach to aldehydes and ketones via this disconnection is by oxidation of the corresponding alcohols. Lythgoe chose this route when he needed ketone (16) to demonstrate a new alkyne synthesis. Returning to the alcohol (17) by FGI followed by disconnection of the side chain gives the aldehyde (18) which can be made in the same way. 

This aldehyde is a key intermediate in the synthesis of the Inhoffen-Lythgoe diol, which is one possible precursor to vitamin D and its derivatives [21], The aldehyde could not be formed by pyrolysis of the corresponding ester in decalin at 95 C. Other procedures that accomplished the rearrangement required heating in excess of 220°C [22]. 

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

The tri-substituted olefin was also prepared by sulfoxide version of the Julia-Lythgoe olefination. The a-branched sulfoxide, cyclohexyl p-tolyl sulfoxide 54 was treated with LDA at -55 °C, then added to the aldehyde in THF to give the adduct 55 in 78% yield, which was a mixture of two diastereomers (L P = 66 34 L is less polar isomer and P is the more polar isomer on silica gel TLC). The mixture of 55 was separated by silica gel column chromatography. The isomers were acetylated separately to give 56 in almost quantitative yield. The 56 was treated with n-BuLi to provide final product 57. The P-isomer gave better yields (90%) than the L-isomer (43%). 

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. 

The synthesis of , Z-dienes, 79 and 80, was developed by Charette and co-workers from a,y9-unsaturated aldehydes, 77, and heteroarylsulfones, 78, using the Julia-Lythgoe olefination reaction. The selectivity of the olefination reaction under optimal conditions is better than 88 12 when a pyridylsuofone was used as the precursor. 

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. 

The macrolactins are a structurally diverse class of secondary metabolites isolated from a deep-sea bacterium. Macrolactin A exhibits a broad spectrum of activity with significant antiviral and cancer cell cytotoxic properties including inhibition of B16-F10 murine melanoma cell replication with in vitro IC50 values of 3.5 pg/mL. It also has implications for controlling human HIV replication and is a potent inhibitor of Herpes simplex types I and II. Marino and co-workers reported a stereocontrolled total synthesis of (-)-macrolactin A 107. Julia-Lythgoe olefmation was employed in the formation of C18-C19 double bond. ° The intermediate 105 was obtained in 78% yield by addition of sulfone 103 to aldehyde 102, benzolation of the adduct intermediate, and treatment with KOt-Bu. The alkene 106 was obtained in 56% yield with E/Z ratio of 8 2 by reduction of 105 using Sml2 in the presence of DMPU. 

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. 

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