Calyculins ester

During studies toward the synthesis of calyculin C, Karisalmi and Koskinen noted the particular stability of boronate ester 65, although details were not given <200481331 >. 

First, the (/f)-2-methylcysteine compound 5 is N- and S-protected and coupled with the threonine methyl ester to the hydroxyamide 57 with benzotriazole-1 -yloxy-tripyrrolidino-phos-phonium hexafluorophosphate (pyBOP) [16]. Burgess reagent [17] turns out to be the best choice for the conversion of 57 into 58. The use of Burgess reagent for the synthesis of oxazo-line was examined extensively by Wipf et al. [ 18]. For other methods of synthesizing oxazoles, which were developed in connection to the synthesis of calyculin A, see [19]. 

Introduction of a phosphate monoester and removal of its protecting groups was a serious impediment in a synthesis of the serine-threonine phosphatase inhibitor Calyculin A by Evans and co-workers [Scheme 7,22].38 The four phosphate protecting groups evaluated were 2-cyanoethyl and 2-(trimethylsi]y])ethyl (see below), benzyl and p-methoxybenzyl. Of these, the p-methoxybenzyl phosphate ester offered the best compromise between base stability (it survived a Wittig reaction in the presence of a metal amide base) and acid lability required for the final deprotection step in which three secondary terf-butyldimethylsiiyl... 

Protection of phosphates as 2-(trimethylsilyl)ethyl esters was first developed by the Masamune group as part of their efforts to synthesise Calyculin A with its highly hindered phosphate monoester.77 A diallyi phosphate was evaluated in a model compound, but it was rejected because of incomplete deprotection under Pd(0)-catalysis, The corresponding bis-[2-(trimethylsilyl)ethyl] ester 37 1, on the... 

Tautomycin was obtained from the terrestrial microorganism Streptomyces spiroverticillatus and is chemically characterised as an ester of a carboxylic acid derived fi om a dialkyl maleic anhydride, with a long chain (26-C) polyol containing two cyclic ethers. In a simultaneous study of the best-known natural inhibitory compounds of PP2A, in which the non-radioactive malachite green assay was applied, tautomycin was the least potent compound [144]. This is consistent with the findings reported by Honkanen et al. [129] and other authors. Its primary site of phosphatase inhibition is PPlc, as was reported in a comparative study with okadaic acid and calyculin A [131]. 

ElectophUic iodination using I2 has also been employed to effect net oxidation of oxazolines to 2-substituted 4-oxazolecarboxylic acid esters. Koskinen and co-workers" " ° prepared an intermediate oxazole fragment of calyculin using this method (Scheme 1.18). Here, the oxazoline 57 was first treated with LiHMDS and TMSCl to protect the carbamate as a sUyl amide followed by treatment with KHMDS and iodine to generate the oxazole 58. Interestingly, the authors also isolated diastereomeric spirocyclic ortho ester aminals 59 in 25 to 30% yield under these reaction conditions. 

Barrett and co-workers prepared a key intermediate oxazole 350 in their synthesis of calyculin A using Comforth methodology (Scheme 1.94). The benzyl ester of (/ )-2-methyl-4-pentenoic acid 347 was converted to (/ )-2-methyl-4-pentenenitrile 348 in two steps. Pinner reaction of 348, followed by amine exchange with glycine methyl ester, gave the imidate 349 in 73% yield. Base-catalyzed formylation of 349 with in situ cyclization produced the 2-alkyl-4-oxazolecarboxylic acid methyl ester 350 in good yield. This entire sequence... 

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