Leukotrienes Wittig reaction

An excellent application of the distinction between stabilised and unstabilised ylids is in the synthesis of leukotriene antagonists.10 The intermediate 39 (R is a saturated alkyl group of 6, 11 or 16 carbon atoms) was needed and disconnection of the Z-alkene with a normal Wittig reaction in mind followed by removal of the epoxide exposed a second alkene with the E configuration that could be made from the aldehyde 43 and the stabilised ylid 42. 

Because the geometry of the 9-double bond was not clear at that time, Corey et al. 75> tried to prepare the (Z)-9-isomer as well as the ( )-9-isomer of leukotriene-A (78 and 86). In the synthesis of the former isomer the tribenzoyl derivative of D-(—)-ribose (79) was converted in 8 stepy into the optically active epoxyaldehyde 71 and the latter to 72. 72 was olefmated with ylide 82, generated by treatment of the corresponding phosphonium mesylate with lithium diisopropylamide in THF/ HMPA75) (Scheme 15). In the first olefination step 72+82- 78, however, similar to the first method, a A9-isomer mixture was formed. The loss of (Z)-selectivity of the Wittig reaction is due to the use of conjugated unsaturated, i.e. moderate ylides of type 82, and had to be expected because of the mechanism of the Wittig reaction (see Sect. 2). 

The Wittig reaction and its numerous derivations have undoubtedly proven to be one of the most useful and efficient methods for forming carbon-carbon double bonds . The reaction of an organophosphorus reagent with an aldehyde or ketone has also been frequently employed to extend simple dienals and dienones into more elaborate polyene systems. A key step in the convergent synthesis of the TB DMS-protected leukotriene A4 methyl ester, 19/ ,5 -Z-butyldimethylsiloxy-5S, 6S -epoxyeicosa-7 ,9 , 1IZ, 14Z-tetraenoate (43), was accomplished using a Wittig reaction between homoallylic phosphorus ylide 44 and Cl—Cll chiral epoxy dienal 45, derived from (—)-2-deoxy-D-ribose, shown in equation 29. ... 

The olefination reaction leads to a mixture of alkenes (56) and (57) which on heating forms (58) and (59). Both the Wittig reaction and the Homer-Wittig have been used in the synthesis of leukotrienes and their metabolic products, for example 12-(S)-hydroxyeicosatetraenoic acid... 

The isomeric isoxazole-substituted phosphine oxides (61) and (63) have been synthesised and used in Horner-Wittig reactions to prepare isoxazoles of types (62) and (64) regiospecifically.32 An alternative approach to (62) and (64) involves reaction of the isoxazole aldehydes (e.g. 65) with alkyldiphenylphosphine oxide anions (Scheme 11). The routes described have been applied to the synthesis of isoxazoles containing leukotriene-like carbon chains. 

Leukotrienes. Prostaglandins and Related Compounds.- Examples of the use of the Wittig reaction in the synthesis of compounds related to arachidonic acid include an efficient synthesis of methyl arachidonate (148) by a three-carbon homologation sequence involving (3,3-diisopropoxy-propyl)triphenylphosphorane (149).91 Both diastereomers of trioxilin B3... 

Examples of the use of Wittig methods in leukotriene synthesis include the preparation of 13,13-difluoroleukotriene B4 (155)96 and the synthesis of ( + )-LTB4 (159) and homo-LTBa (160) by the reaction of the ylide (156) with the aldehydes (157) and (158), respectively.97 The dihydro-LTBa metabolite (161) and its C-12 epi-analogue have been prepared by a Wittig reaction of the ylide (162) (derived from L-glutamic acid) and the aldehyde... 

A short synthesis of the important leukotriene synthon (136) has been reported, Good, reliable methods of synthesis for leukotrienes and related compounds have now been developed, although the work still requires a high level of practical skill on the part of the chemist. The Wittig reaction has been... 

Ticolubant (310) is a leukotriene receptor antagonist that exhibits anti-inflammatory activities. The Wittig reaction with 3-hydroxy-6-methylpicolinaldehyde followed by a Mitsunobu reaction with 2-phenylethanol gave phenyl ether 308. Oxidation with wCPBA converted the pyridine ring into the corresponding A-oxide, which then underwent the Boekelheide reaction with TFAA to afford the methyl alcohol 309. Reaction with thionyl chloride and then 2,5-dichlorothiophenol followed by saponification gave 310. ° ... 

Good Z-selectivities were observed for the reaction of aldehydes with carboxy ylides prepared from the corresponding phosphonium salt and LHMDS. This strategy has been extensively used in the total synthesis of prostaglandins, monohydroxy-eicosatetraenoic acids (HETE), and leukotrienes. Eor instance, the Wittig condensation between aldehyde 5 and car-boxy phosphonium salt 6 in the presence of LHMDS provided 49% yield of the TBDPS-protected 10(5)-HETE methyl ester 7 (eq42). ... 

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