Talaromycins

Talaromycin A (a toxic substance produced by a fungus that grows on poultry house litter)... 

Cross-cyclization of epoxides with homoallylic amines is an easy way to access tetrahydropyran moieties, which form the core structure of many biologically important natural products such as avermectins, aplysiatoxin, oscillatoxins, latrunculins, talaromycins, acutiphycins, and apicularens. Even though many methods are available for the synthesis of this moiety [14—24], its importance and wide applicability demands further methods. 

Talaromycin B is a spiro-acetal produced by the fungus Talaromyces stipitatus, the toxicity of which may be due to its ability to block outward potassium fluxes. In an elegant synthesis, the requisite open-chain polyol with hydroxy groups in the y-and y -positions was assembled from nitrile oxide and olefin building blocks 50 and 51, both of which carry a f>w(hydroxyethyl) moiety protected as a cyclohexanone acetal (284). Hydrogenolysis of the N O bond of isoxazoline 52 using Raney nickel, followed by treatment with aqueous acid, gave the spiroketal 53, which was further transformed into racemic talaromycin B (54) (Scheme 6.54) (284). 

A versatile approach to spiro-oxacycles is the use of cyclic a-methylene enol ethers employed by us in an efficient and short enantioselective total synthesis of the mycotoxin talaromycin B (see Sect. 7.1). Later Pale and Vogel [148] employed the same protocol for the preparation of spiroacetals 2-145 using e.g. acrolein 2-78, methyl vinyl ketone and 2-pentenal, respectively with the enol ether 2-143 (Fig. 2-39). In most cases the yields were only modest, however, reaction of 2-143 and 2-78 in benzene in the presence of the mild Lewis acid ZnCl2 gave 2-145 in 70% yield as a single adduct. 

Spiroketals are not only important building blocks of polyethers but also may represent themselves highly active natural products. The suitability of oxa Diels-Alder reactions to efficiently generate this structure will be demonstrated by two impressive examples. Thus, our group prepared the mycotoxine (-)-talaromycin B 7-17 by a nine-step synthesis in 5% overall yield in enantiopure form. The... 

Spiroketalization, The synthesis of talaromycin B (3) with four chiral centers by cyclization of an acyclic precursor presents stereochemical problems. A solution involves cyclization of a protected (3-hydroxy ketone with only one chiral center.1 Because of thermodynamic considerations (i.e., all substituents being equatorial and the anomeric effect), cyclization of 1 with HgCl2 in CH3CN followed by acetonation results in the desired product (2, 65% yield) with a stereoselectivity of —10 1. Final steps involve conversion of the hydroxymethyl group to ethyl by tosylation and displacement with lithium dimethylcuprate (80% yield) and hydrolysis of the acetonide group. 

Finally, oxidative cyclization (HgO, I2, hiA of tqjpropriately substituted alcoholic ethers formed the basis of Kay s stereoselective syntheses of both 4-hydroxy-l,7-dioxaspiro[S.S]undecane, an olive fly pheromone component, and ( )-talaromycin B (equations 4 and 5). More recently, Danishefsky et at have further extended the scope of this spiroketal-forming reactitm in their elegant total synthesis of avermectin Ai (equation 6). ... 

CSA has also been used to catalyze spiroacetalizations. - In Schreiber s approach to the talaromycins, he utilized a CSA-catalyzed spiroacetalization (eq 10) and found that the use of different solvents led to varying percentages of isomeric products. Other approaches to the talaromycins also utilize CSA for the required spiroacetalization. ... 

This rearrangement proviided a starting material for the synthesis of the antibiotic talaromycin B (A. P. Kozikowski and J. G. Scripko,... 

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