Pyridyl thiols

The use of the acid chloride instead of the 2-pyridyl thiol ester also results in formation of the 2-keto-pyrrole functionality, but significant amounts of the 3-ketopyrrole isomer were also formed. Several rather complex substrates were used as acylating agents in s process with a high degree of success. Some examples of the 2-ketopyrroles that have been prepared are shown in Scheme 12. 

Attention should be drawn to the subtle differences between the reaction shown in Scheme 32 and the formation of the related erythronolide B intermediate (Scheme 11) by Corey and coworkers. As mentioned earlier (Section 1.13.2.2), the addition of the Grignard reagent derived from iodide (34) was carried out easily on the identical substrate, S-(pyridyl) thiol ester (36) used in the A series, providing erythronolide B intermediate (37). The reaction in the erythronolide A series appears to be sensitive to the presence of the MTM-protected alcohol. 

Kim has also studied the corresponding acylation of homocuprates by S-(2-pyridyl) thioates, discussed earlier in the context of total synthesis of monensin and erythronolide A (Sections 1.13.2.2 and 1.13.3.2). Under the standard anaerobic conditions necessary for cuprate formation, good yields of ketones could be derived from acylation of lithium dimethylcuprate (or lithium dibutylcuprate) by S-(2-pyridyl) thiobenzoate and other simple S-(pyridyl) thiol esters (equation 71). Interestingly, if the homocuprate is intentionally placed under an oxygen atmosphere before acylation and then reacted with the S-(2-pyridyl) thioate in oxygen at -78 C, one obtains good yields of the ctnresponding ester (equation 72). 

The construction of the naturally derived narbomycin and tylosin-aglycones by Masamune and coworkers employ identical methodology for seco-acid formation. In each case, Peterson alkenadon of a functionalized aldehyde (not shown) and the silyl ketones (96 R = SiMes Scheme 36) or (99 Scheme 37) efficiently introduced the required ( )-a,3-unsaturation. Silyl ketone formation is accomplished in each case through cuprate acylation by an activated carboxylic acid derivative. Formation of an acid chloride was not possible in the sensitive tylosin-aglycone intermediate however, selective acylation of the silylcuprate proceeded at the pyridyl thiol ester moiety of (98) and not with the r-butyl thiol ester. In a related investigation, (97), an advanced intermediate for 6-deoxyerythronolide B, was obtained from (95) via addition of lithium diethylcuprate to the acid chloride (84% yield). In all the above cases, no addition was observed at the f-butyl thiol ester. 

Carboxylic esters, especially lactones, are conveniently obtained via the pyridyl thioesters (18). Some examples are given in Scheme 1. The 2-pyridyl thiol ester method can be further improved if silver ions (AgC104) are used as activators. Corey and Brunelle have also introduced other heterocyclic disulfides, and (19) was found to be superior to other reagents tested for the formation of lactones from w-hydroxyalkanoic acids. 

The interesting antibiotics X-14S47A and A-23187 (calcimycin) contain a novel 2-ketopyrrole moiety, which is apparently important for biological activity. Nicolaou has developed a simple method for incorporation of this unit into the sensitive intennediates required for preparation of the natural products. Through use of the Mukaiyama protocol, formation of the 2-pyridyl thiol ester was effected with 2,2 -di-pyridyl disulfide and triphenylphosphine. The reaction mixture was then cooled to -78 C and was treated with a solution of pyrroylmagnesium chloride in THF (equation 21). 

Similarly, treatment of the 2-pyridyl thiol ester of 15-hydroxypentadecanoic acid in benzene with 1 eq. of silver perchlorate leads to rapid formation of the corresponding monomeric, dimeric, and trimeric lactones. 

K. Lloyd, G.T. Young, The use of acylamino acid-esters of 2-mercaptopyridine in peptide synthesis. J. Chem. Soc. Chem. Commun. 1968, 1400-1401 Amino acids and peptides. PartXXXrV. Anchimerically assisted coupling reactions the use of 2-pyridyl thiol esters. J. Chem. Soc. 1971,2890-2896 A.S. Dutta, J.S. Morley, Polypeptides. Part XII. The preparation of 2-pyridyl esters and their use in peptide synthesis. J. Chem. Soc. C. 1971, 2896-2900... 

Activation of Thiol Esters. Pyridyl thiol esters are converted into esters on treatment with AgBp4 and an alcohol. Acylation of alkynylsilanes can also be carried out using thiol esters in the presence of AgBp4. ... 

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