Makrocyclische Lactame als Modelle für das Ansamycin Geldanamycin

Abstract

Als Modelle für das Antibiotikum Geldanamycin werden die offenkettigen und cyclischen 1,4‐Benzochinon‐Derivate 7 und 17 aus den entsprechenden Hydrochinonäthern 5 und 15 hergestellt. Die Umsetzung der Hydrochinonether 5 und 15 mit Salpetersäure ergibt die 1,2‐Benzochinon‐Derivate 8 und 18.

Synthesis of a para-quinone macrolactam related to geldanamycin by ring closing metathesis

“…8 This result was corroborated in recent studies by Andrus et al 10,23 Upon oxidation of an immediate geldanamycin precursor with 70% nitric acid they obtained in 55% yield a 10:1 mixture of the undesired ortho-and the desired para-geldanamycin. Oxidation with other reagents (Ag 2 O or MnO 2 impregnated with nitric acid) led to the formation of a para-azaquinone.…”

“…After cooling to 0 8C, the corresponding alkyl halide was added. Although Schill et al had used bromoalkanes in their alkylation experiments 8 we found the iodides superior allowing a smoother and cleaner conversion than the corresponding bromides and-more importantly-avoiding the use of an excess of the halide. The u-alkenyliodides 7 employed as electrophiles in the alkylation step are literature known and were prepared according to reported procedures.…”

“…The product was purified by chromatography (P/EA). (15), 166 (28), 151 (10), 137 (7), 55 (7) (CH 2 ), 29.9 (CH 2 ), 29.8 (CH 2 ), 29.6 (CH 2 ), 29.5 (CH 2 ), 29.5 (CH 2 ), 29.3 (CH 2 ), 29.1 (CH 2 ), 28.9 (CH 2 ), 24.7 (CH 2 (20), 359 (15), 348 (8), 226 (21), 196 (10), 181 (14), 166 (8), 151 (8), 123 (6), 95 (5), 69 (5), 55 (14), 41 (8). Anal.…”

“…); MS (EI, 70 eV), m/z (%): 401 (100) [M C ], 386(8), 370 (10), 153(7), 95 (66), 67(20); HRMS: m/z calcd for C24 H 35 NO 4 : 401.2566; found 401.2566. 5.1.17.…”

Synthesis of Ansa-Bridged Macrocyclic Lactams Related to the Antitumor Antibiotic Geldanamycin by Ring Closing Metathesis

“…6 The biological importance of geldanamycin makes itself and simpler analogs thereof interesting target compounds for de novo synthesis. 7,8 Structurally, geldanamycin is related to the ansamycin antibiotics macbecin I 9 and herbimycin A 10 syntheses of which have been previously reported. The macrolactam ring of these compounds has been formed by conventional macrolactamization.…”