Total Syntheses of Thiostrepton Macrocyclic Antibiotics Constructing of Unusual Amino Acid Residues and Heterocyclic Ring Moieties

一些大环硫链霉素类抗生素ge2270a、berinamycin a和B、thiocillines、nosiheptide和cyclothiazomycin的合成研究已经广泛进行。例如，通过将2,3,6-三噻唑基取代吡啶骨架[片段A- c ']与噻唑基噻唑段[片段B]偶联，合成了ge2270a的受保护的线性前体[片段A-B- c ']。片段B由合适的硫酰胺和β-溴-α-氧烷酸酯合成，后者首先通过连续的β-溴化和水解去除α-脱氢氨基酸酯中的α-(N-Boc)氨基得到。在环噻唑霉素的合成中，首先将受保护的丝氨酸硫胺衍生物与溴丙酮酸盐连续两次噻唑化，然后将序列的c端丝氨酸残基进行噻唑化，合成了连接在主吡啶骨架6取代基上的2-[2-（2-噻唑-4-基）噻唑-4-基]噻唑-4-羧酸盐[片段A]。其次，通过对2-（1-氨基）乙基-6-甲酰基吡啶衍生物的甲酰基进行噻唑化，再进行噻唑化，合成了中心(1'R)-2-{2-[2-(1-氨基乙基吡啶-6-基]噻唑-4-基}噻唑啉-4-羧酸盐[片段B]。第三，通过逐步延长适当的α-氨基酸和β-消除该序列的苏氨酸残基，合成了与吡啶骨架的2取代基结合的受保护的脱氢四肽[片段C]。最后，对三个片段进行缩合，得到受保护的片段A-B-C。

The synthetic studies of a few macrocyclic thiostrepton antibiotics, GE 2270 A, berinamycins A and B, thiocillines, nosiheptide, and cyclothiazomycin have proceeded extensively. For examples, synthesis of the protected linear precursor [Fragment A-B-C'] of GE 2270 A was achieved by coupling of a 2,3,6-tristhiazolyl-substituted pyridine skeleton [Fragment A-C'] with a thiazolylthiazole segment [Fragment B]. The Fragment B was synthesized from an appropriate thioamide and β-bromo-α-oxoalkanoate, the latter of which was first derived by consecutive β-bromonation and hydrolytic removal of the α-(N-Boc)amino group of α-dehydroamino acid ester. Furthermore, with regard to the synthesis of cyclothiazomycin, first, the 2-[2-(2-thiazol-4-yl)thiazol-4-yl]thiazoline-4-carboxylate [Fragment A], attached to the 6-substituent of the main pyridine skeleton, was synthesized by two consecutive thiazolations of the protected Ser thioamide derivative with bromopyruvate and then thiazolination of the C-terminal Ser residue of the sequence. Secondly, a synthesis of the central (1'R)-2-{2-[2-(1-aminoethylpyridin-6-yl]thiazol-4-yl}thiazoline-4-carboxylate [Fragment B] was also achieved by thiazolation of the formyl group of the 2-(1-amino)ethyl-6-formylpyridine derivative and then thiazolation. Thirdly, a synthesis of the protected dehydrotetrapeptide [Fragment C], which is bound to the 2-substituent of the pyridine skeleton, was attained by the stepwise elongation of the appropriate α-amino acids and β-elimination of a Thr residue of the sequence. Finally, the fragment condensation of the three Fragments gave the protected Fragment A-B-C.