Leukotriene intermediates

The use of chiral precursors to prepare leukotriene intermediates -requently results in lengthy protection-deprotection sequences to remove unwanted groups. For this reason the use of chirally directed epoxidation of an achiral olefin represents a considerable advance in leukotriene synthesis. The hydroxy-ester (379) could not be epoxidised directly but two independent reports have described the preparation of 5S,6R-... 

The primary LOX metabolites, the hydroperoxy fatty acids, are further metabolized to an array of secondary products that may be classified into several groups according to their chemical structures (i) leukotrienes containing three conjugated double bonds, (ii) mono- and double-oxygenated polyenoic fatty acids that are not formed via a leukotriene intermediate and (iii) lipoxins and hepoxilins. 

Hydroxy-esters.—Ethyl 5-3-hydroxybutanoate is obtained in 87% optical purity by the reduction of ethyl acetoacetate with Bakers yeast. " Two independent chiral synthesis of the leukotriene intermediates (46), R = CHO and R = CH2OH, have appeared. An effective large-scale conversion of arachidonic acid into 5-hydroxy-6-fran5-8,ll,14-cis-eicosatetraenoicacid (5)HETE, including its resolution, is also reported by Corey and Hashimoto. ... 

A proposed biogenesis for neodidemnilactone (167) would involve formation of 8R-HPETE, conversion to an 8,9-leukotriene A4-like intermediate, and internal epoxide opening by the terminal carboxylate (Scheme 12). 

After protection, the a-hydroxy esters can be reduced by DIBAL-H into O-protected a-hydroxyaldehydes that are very useful synthetic intermediates (e.g., leukotrienes,7-9 ionophore antibiotics,10 insect pheremones,11 etc.). The secondary hydroxyl group of the a-hydroxy esters may also be substituted with inversion of configuration after activation as triflates of nosylates (p-nitrobenzenesulfonates) to give a-alkyl esters12 ora-amino esters.13... 

The successful application of this method was illustrated with a series of model dienes, and with the formal synthesis of leukotriene A4 methyl ester, a complex polyene monoepoxide, from the intermediate epoxyundecadienoate 17 prepared by selective epoxidation of trienyl ester 16 (equation 17). 

The structure of the leukotrienes receptor antagonist cinalukast (58-9) bears only the vaguest resemblance to its predecessor, or, for that matter, to a leukotriene. Reaction of the cyanomethylphosphonate (58-1) with hydrogen sulfide converts the nitrile to a thioamide (58-2). Treatment of that intermediate with the bromoketone... 

Preparation of a somewhat more complex leukotriene antagonist begins by aldol condensation of the methyl carbanion from quinoline (29-1) with meta-phthalalde-hyde (29-2) to give the stilbene-like derivative (29-3) dimer formation is presumably inhibited by the use of excess aldehyde. Reaction of that product with A,A-dimethyl-3-mercaptopropionamide in the presence of hexa-methylsilazane affords the silyl ether (29-4) of the hemimercaptal. Treatment of that intermediate with ethyl 3-mercaptopropionate leads to the replacement of the silyl ether by sulfur and the formation of the corresponding thioacetal (29-5). Saponification of the ester group leads to the carboxylic acid and thus to verlukast (29-6) [33]. 

The synthesis of a much more complex leukotriene antagonist starts with the intermediate (29-3) from the preceding synthesis. The aldehyde is extended by two-carbon atoms by first reacting the carbonyl with methylmagnesium bromide. 

Hydroxyhept-6-enoates have been key intermediates in the synthesis of a variety of natural products, especially of the arachidonic acid metabolic pathway, including prostaglandins, leukotrienes, and isoprostanes [105, 113-118]. The usage of two enantiocomplementary enzymes allowed convenient access to both enantiomers via an ADH-catalyzed reduction of 5-oxo-hept-6-enoate. Alcohol dehydrogenase from Lactobacillus brevis (ADH-LB) furnished the (S )-enantiomer, Thermoanaerobacter sp. ADH (ADH-T) the (7 )-enantiomer in excellent enantiomeric access respectively [119]. A cross-metathesis reaction followed by cyclopropanation led to the formal synthesis of constanolactones C and D (Fig. 16) [86, 120, 121]. 

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. 

The predecessor of Ultraflne was the Fine Chemicals Unit of Salford University Industrial Centre, which was set up partly to exploit a new route to prostaglandins.9 When the independent company was founded, it made sense to offer other eicosanoids. A key intermediate for the synthesis of leukotriene A4 (LTA4) (7), and thence LTC4, LTD4, and LTE4, was the epoxyalcohol (10), whose synthesis from 2-deoxy-D-ribose (8) (Scheme 29.2) had been reported.10... 

Figure 12.2. Alternate pathways of arachidonic acid release (a), and cellular locations of enzymes involved in eicosanoid formation (b). a Arachidonic acid may be directly released by phospholipase (PLA2), or alternatively by the successive action of phospholipase C (PLC) and diacylglycerol (DAG) lipase, b The major mechanism of release involves a cytosohc phospholipase A2 (CPLA2). An increase of Ca in response to an extrinsic signal causes binding of cPL A2 to the nuclear membrane. Cyclooxygenase (COX) and Lipoxygenase (LOX) form their respective intermediates, which are further processed by cytosolic enzymes to prostaglandins (PG), thromboxanes (TG), and leukotrienes (LT), respectively.

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