SQ 26,180, a novel monobactam. II. Isolation, structure determination and synthesis.

Abstract

A novel monocyclic i-lactam antibiotic SQ 26,180 has been isolated from bacteria and the structure, (R)-3-acetylamino-3-methoxy-2-oxo-l-azetidinesulfonic acid was deduced from its spectroscopic properties. Structural confirmation and assignment of absolute configuration were made by synthesis from 6-aminopenicillanic acid.Beta-lactam antibiotics comprise one of the major chemotherapeutic means for the control of bacterial infections. This group of antibiotics has been the subject of intensive research in recent years, leading to the discovery of several new classes of naturally occurring ;S-lactams, namely the cephamycins, nocardicins, clavulanic acids and a burgeoning family of carbapenems. We now wish to report the isolation and characterization of a strongly acidic monocyclic ~-lactam antibiotic, SQ 26,180, a member of a new class of ji-lactam antibiotics, discovered independently by workers at both Takeda" and Squibb2) for which we have suggested the generic term "monobactam".SQ 26,180, produced by fermentations of Chromobacterium violaceum SC 11,378, was shown to have structure 1, (R)-3-acetylamino-3-methoxy-2-oxo-l-azetidinesulfonic acid. Isolation of SQ 26,180 was monitored using sensitive strains of Bacillus licheniformis and Pseudomonas aeruginosa. The characterization of the producing organism and the fermentation are described in the accompanying paper.3) SQ 26,180 was isolated from fermentation broths as outlined in Fig. 1.The antibiotic was extracted into dichloromethane containing a tetraalkylammonium salt, cetyldimethylbenzylammonium chloride being effective for this purpose. Back extraction of SQ 26,180

Naturally Occurring β-Lactams

“…CO,Rl WASSERMANN has reported (19)(20)(21) the synthesis of (±)-3-ANA by way of the ~-lactam (25). Various methods were used to prepare (25), such as cyclopropane ring expansion of (24), cyclisation of (26) or acylation of the azetidine carboxylate (27). In another approach (22) the C(-methylene ~ lactam (28) has also been elaborated to 3-ANA via the use of (29).…”

“…Naturally Occurring ~-Lactams The structure of the simplest member of the series SQ 26,180 was deduced fairly readily from its spectroscopic properties (27), Confirmation and assignment of configuration were made by synthesis from the methoxylated cephalosporin (31) of known configuration, using the sequence (31)~(32)~(33)~ (34). In the case of SQ 26,445 (sulfazecin) the side-chain was identified by acid hydrolysis which gave D-glutamic acid and D-alanine; milder hydrolysis gave y-D-glutamyl-D-alanyl amide and 2-oxo-3-sulphoaminopropionic acid.…”

“…Generically called the monobactams, the known structural types are shown in Table 2. Me Me K OMe (26,27) References, pp.…”

“…In another approach (22) the C(-methylene ~ lactam (28) has also been elaborated to 3-ANA via the use of (29). CO,Et EtO,C CO,Et (27) (±) 3-ANA Reagents: (i) AgN03; (ii) NaH; (iii) (COCl),-HCI04 ; (iv) ArC03H + Pyridine; (v) Base-p-toluenesulphonyl azide. …”

EM5400, a family of monobactam antibiotics produced by Agrobacterium radiobacter. II. Isolation and structure determination.

“…[3][4][5] This class consists of monocyclic B-lactam antibiotics that are N-acyl derivatives of (S)-3-aminomonobactamic acid (1) or (R)-3-amino-3-methoxymonobactamic acid (2). All monobactams discovered to date are produced by bacteria.…”