Synthesis of Naturally Occurring, Conformationally Restricted Oxazole‐ and Thiazole‐Containing Di‐ and Tripeptide Mimetics

Abstract

COMMUNICATIONS 4a: 1 (473 mg, 1.8 mmol), 3 (430 mg, 1.8 mmol), and bis(triphenylphosphane1-(ethene)platinum (83 mg, 0.12 mmol, 6.2 mol%) in toluene (15 mL) were heated under reflux for 24 h. Afterwards, the precipitate was isolated by filtration, washed several times with THF and CH,Cl,, and dried in vacuum. Yield: 455 mg (50.6%)) m.p.: >310"C, 'HNMR (ZOOMHz, [D,]MeOH): 6 =6.5-6.9 (m); I3C NMR (50 MHz, [DJMeOH): 6 = 146.3,120.9, 116.4(C6H.,), CBnot observed; "BNMR (64 MHz, [DJMeOH): 6 = 34 (Av,,~ = 524 Hz), 18 (AvIj, = 58 Hz, C,H,02BOCD,); HR-MS (EI): m/z 500.1209 ( M + , calcd '2C,,1H,,'oB,'60,: 500.1217); correct C, H analysis. 2b, 2c: A suspension of 2a (785 mg, 1 mmol) in toluene (15 mL) and methyllithium (8 mL of a 1.5 M solution in diethyl ether, 12 mmol) was first stirred for 1.5 h at -5 "C and then for 8 h at 25 "C. After removing the insoluble components, a yellow solution of 2b was obtained which contained minor amounts of boranates. I I B 29 Hz); GC-MS: m/z ("A) 317 (100) [M+], 302 (17.4) [ M + -Me], 41 (92.4) [BMe,+]. An excess of pyridine was added to the yellow solution. Crystalline 2c precipitated from the resulting orange-red solution at room temperature. Yield: 296 mg(33%), m.p.: >250°C (decomp), 'HNMR (200 MHz, CDCI,): 6 = -0.3 to 0.3 (m, BMe), 5.8 -6.9 (m, C,H,), 7.0 (m, Py), 7.5 (m, Py), 8.2 (m, Py); 13C NMR (50MHz, CDCI,): 6 =13.0 (BMe, br), 114.6, 116.5, 118.2, 120.0, 153.6, 160.0 (C6H,), 123.7, 136.6, 149.6 (Py), 168.0 (CB, br); I l B NMR (64 MHz, CDCI,): 6 = 0.3 ( A V , ,~ = 204 Ht); MS (FD): m/z 982 [ M + -Py -4Mel. NMR (64 MHz): 6 = 6 (AVlj2 = 466 Hz), -17.4 (Av,,, = 87 Hz), -20.6 (AVlj2 =

Synthesis of thiazole, imidazole and oxazole containing amino acids for peptide backbone modification

“…The intermediate imidazoline 7 was obtained in high yield (80%) by cyclization of the imino ether 6 with L-2,3-diaminopropionic acid methyl ester·HCl [27,28] according to Reference [26]. Oxidation of 7 gave the imidazole 8 (83%) using a mixture of DBU/CCl 4 /acetonitrile/pyridine [21]. The synthesis of Boc-2-(2-aminomethyloxazole-4-yl)-oxazole-4-carboxylic acid methyl ester was accomplished via a novel route (Figure 3).…”

“…DBU (0.6 ml, 6 mmol) was added to 7 (0.5 g, 2 mmol) in a mixture of CCl 4 (10 ml), pyridine (15 ml) and acetonitrile (15 ml) [21]. After 3 h at r.t. the solvent was removed in vacuo, the residue dissolved in EtOAc, the solution extracted with 0.5 N HCl and the aqueous phase reextracted with EtOAc (2 ×).…”

“…We discovered a novel procedure for the oxidative conversion of an imidazoline intermediate into the corresponding imidazoles using a mixture of 1,8-diazabicyclo [5.4.0. ]-undec-7-ene, CCl 4 , acetonitrile and pyridine [21]. Fmoc-Arg (Pbf)-OH (3.24 g, 5 mmol) (1), pyridine (0.25 ml) and (Boc) 2 O (1.5 g, 6.5 mmol) were dissolved in dioxane (15 ml), and then ammonium hydrogencarbonate (0.5 g, 6.3 mmol) was added and the mixture was stirred for 16 h [22].…”

Structure Elucidation and Chemical Synthesis of Microbial Metabolites

“…This continuous knowledge was decisive for the success of several projects, e. g. synthesis of heterocyclic backbone modifying amino acids as a part of the microcin B17 structure [7] and the total synthesis of microcin B17 in 1996 [8]. 320 …”

“…In subsequent work, synthesis of the novel oxazole and thiazole amino acids had to be achieved [7], which ended up in the total synthesis of microcin B17 in 1996 [8]. The total synthesis of microcin B17 was performed on solid support using fragment condensations in order to form the nonaglycine sequence, which was not accessible by stepwise successive standard solution phase chemistry.…”