Convenient Synthesis of the Central 3,6-Di(2-thiazolyl)-2-(4-thiazolyl)pyridine Skeleton of a Macrocyclic Antibiotic, GE 2270 A

Abstract

It was shown that 6-dimethoxymethyl-1,2-dihydro-2-oxo-3-pyridinecarbonitrile (5) is easily convertible into the titled ring system by a stepwise method. Both the 3-cyano and 6-dimethoxymethyl groups of 5 were converted into 2-thiazolyl groups via the thioamide and carbaldehyde groups by Hantzsch and Shioiri methods, respectively. The 2-pyridone function was changed to a bromoacetyl group via the coupling reaction between the corresponding triflate and ethyl vinyl ether, and then converted into the 4-thiazolyl group. Thus, the useful 3,6-di(2-thiazolyl)-2-(4-thiazolyl)pyridine derivative for the total synthesis of GE 2270 A was obtained. In fact, the method was recently applied to the total synthesis of an antibiotic, micrococcin P, which has a similar central skeleton.

From Amino Acids to Heteroaromatics—Thiopeptide Antibiotics, Nature's Heterocyclic Peptides

“…Examples include the thiazole building blocks of promothiocin A (3), [44] amythiamicin D (4), [24] GE2270A (5), [48][49][50] nosiheptide (6), [51,52] A10255G, [39] thiocilline, [53] and cyclothiazomycin. [54] By analogy with the use of serine derivatives in the synthesis of oxazolines, and hence oxazoles, the biomimetic cyclodehydration of the corresponding cysteine derivatives 26 would be expected to give thiazolines 27 and hence thiazoles 28.…”

“…This could subsequently be converted into thiazole 35 under classical Hantzsch conditions, and hence afford berninamycinic acid (36, Scheme 10). [59] Shin and co-workers have published the results of extensive research relating to the synthesis of the central pyridine cores of many different thiopeptide antibiotics, for example A10255, [60] berninamycin, [61] cyclothiazomycin, [54,62,63] GE2270A, [49,64,65] micrococcin P, [66] nosiheptide, [67,68] and thiocilline I. [69] There are a number of common strategies applied in these syntheses as illustrated in the routes to the substituted pyridines of nosiheptide (6, Scheme 11) and GE2270A (5, Scheme 12).…”

“…In the synthesis of the trisubstituted pyridine fragment 47 of GE2270A, [49,64,65] both nitrile/thioamide/thiazole and 2-pyridone to 4-thiazolyl sequences were employed successfully starting from 3-cyano-6-dimethoxymethyl-2-pyridone. The bisthiazole unit was installed by treating the 2-bromoacetylpyridine 44 with the thiazole-4-thiocarboxamide 45, prepared from a threo-phenylserine derivative.…”

Von Aminosäuren zu Heteroarenen – Thiopeptid‐Antibiotika als heterocyclische Peptide aus der Natur

“…synthetisierten die Pyridinkerne vieler unterschiedlicher Thiopeptid‐Antibiotika. Beispiele sind die Synthesen von A10255,60 Berninamycin,61 Cyclothiazomycin,54, 62, 63 GE2270A,49, 64, 65 Micrococcin P,66 Nosiheptid67, 68 und Thiocillin I 69. Die Synthesen erfolgten nach gängigen Methoden, die in den Schemata und am Beispiel der substituierten Pyridineinheiten von Nosiheptid ( 6 ) bzw.…”

Total Syntheses of the Thiopeptides Amythiamicin C and D

“…The formation of the macrocylic ring was in both synthetic approaches to the amythiamicins achieved by macrolactamization, either at the amide bond connecting the glycine to thiazolecarboxylic acid D [6] or at the amide bond connecting the thiazole fragments E and F. [7] Other strategies and total syntheses of thiopeptide antibiotics have been reviewed extensively. [2,10,11] The most notable recent achievement has been the synthesis and stereochemical assignment of micrococcin P1 by Ciufolini and Lefranc, in which the central pyridine ring was constructed by a Hantzsch synthesis. [12] Our own synthetic work in the area of thiopeptides was triggered by methodology studies concerning the regioselectivity of cross-coupling reactions [13] on certain heterocycles, specifically on pyridines and thiazoles.…”