Talaromycin synthesis

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). ... 

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

In the total synthesis of talaromycin A, silylmethyl radical cyclization serves as a method for the stereoselective introduction of the 1,3-diol unit64. Starting from the corresponding alcohol, silylation, radical cyclization of the (bromomeihyl)dimethylsilyl eLher 4 and subsequent oxidative cleavage gives the desired product in 78% overall yield. 

Finally, a radical cyclization/oxidation protocol was utilized as the final step in the Crimmins synthesis of the natural product (-)-talaromycin A.41 Silylation of allylic alcohol 42 produced 43, which cyclized upon treatment with BusSnH and AIBN to provide 44. Oxidation of the crude residue resulting from the cyclization reaction resulted in the formation of (-)-talaromycin A (45). 

Temporary tethering of radical precursors has found other applications in natural product synthesis. Crimmins and O Mahony utilized a silyl ether temporary eonnection to direct a hydro-hydroxymethylation of enol ether 139 in their synthesis of talaromycin A, 140 [54]. Since talaromycin A is susceptible to acid-catalyzed isomerization to the thermodynamically more stable talaromycin B in which the hydroxymethyl substituent is equatorial, the use of the essentially neutral conditions of a radical cyclization to install the requisite axial hydroxymethyl group would avoid any potential isomerization problems. Formation of enol ether 139 was achieved in five steps from (4R)-4-ethylvalerolac-tone 141. Exposure of 139 to Bu3SnH in benzene at reflux in the presence of AIBN as initiator effected radical cyclization with delivery of the radical to the same face to whieh the ether tether was attached. Tamao oxidation proceeded uneventfully, furnishing the desired natural product (Scheme 10-47). 

Scheme 10-47 Crimmins and O Mahony used a silicon-tethered radical cyclization in a synthesis of talaromycin A.

Use of the (Bromomethyl)dimethylsilyl Ether Group in a Radical Cyclization in the Synthesis of Talaromycin A, 140 [54]... 

The hypoiodite method was also applied in a key step in the synthesis of antibiotic talaromycin 22 from 22a [16]. 

---