Julia-Lythgoe alkene synthesis

The reductive elimination of (3-hydroxysulfones is the final step in the Julia-Lythgoe alkene synthesis (see Section 2.4.3).301 The (3-hydroxysulfones are normally obtained by an aldol addition. 

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. 

The stereoselective synthesis of alkenyl halides is also possible via Julia-Lythgoe alkenation. The other two methods for the preparation of alkenyl halides - Wittig reaction (using... 

Fig. 4.40. Second step of the Julia-Lythgoe synthesis of trans-alkenes (first step cf. Figure 11.22) stereoconver-gent reduction of the sulfonyl-acetates syn- and anti-k to the uniformly configured alkene trans-C. The sequence starts with an E2 elimination yielding the alkenylsulfone f-B (mecha-nistical details as given), which is followed by the reduction to the final product (mechanistic analysis cf. Figure 17.85)...

The Julia-Lythgoe olefination has already been addressed twice as an important C=C double bond-forming two- or three-step synthesis of trans-alkenes (trans-B in Figure 17.85). The step... 

The strategy described here should find considerable use as a method for the stereoselective synthesis of alkenes. Although this olefination strategy involves one more step than the classic Wittig reaction, in many cases it may prove to be the more practical method. Finally, the scope, overall efficiency, and stereoselectivity of the 0-lactone route compares favorably to the Wittig, Julia-Lythgoe, and related established strategies for the synthesis of tri- and tetrasubstituted alkenes. 

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 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. 

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. 

A connective synthesis of alkynes inspired by the Julia alkenation was developed by Lythgoe and coworkers for the synthesis of la-hydroxy vitamin D3, as shown in Scheme 34. The P-keto sulfone (101) derived by condensation of the the metalated sulfone (99) with the ester (100) was converted to the enol phosphate (102), which on reductive elimination gave the enynene (103). 

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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