Synthesis of New Quinolone Antibiotics Utilizing Azetidine Derivatives Obtained from 1-Azabicyclo[1.1.0]butane

Abstract

Although 1-azabicyclo[1.1.0]butane (ABB, 3) proved to be the unique molecule bearing the highly strained bicyclic structure, little attention has been paid to the unusual ring system. [1][2][3][4][5][6][7][8][9][10] Specifically, the synthetic utility of ABB (3), which must be useful for the preparation of various 1,3-disubstituted and 3-monosubstituted azetidines, 1,9,10) has scarcely reported because of its synthetic difficulty due to the remarkably strained structure. These azetidine moieties have often been found in many natural products 11) and biologically active compounds such as carbapenems 1) and new quinolone antibiotics.12-15) 1,3,3-Trinitroazetidine (TNAZ), 16,17) an insensitive high explosive, was also synthesized by using ABB (3). In recent years, we established an efficient method for synthesis of ABB (3) starting from allylamine (1) via 2,3-dibromopropylamine hydrobromide (2), and reported its application to the synthesis of several azetidine derivatives, as shown in Chart 1. 9) We also reported a practical synthesis of 1-(1,3-thiazolin-2-yl)azetidine-3-thiol as the fascinating pendant moiety of a new oral 1b-methylcarbapenem antibiotic, L-084 by starting from ABB (3).1) This expeditious construction method for 3-monosubstituted azetidine derivatives employing ABB (3) seemed to be useful also for developing new quinolone antibiotics.Fluoroquinolones have been developed and are widely used clinically. This is because they have potent, a broad spectrum of antibacterial activities, and few side effects. [18][19][20][21][22] However, increasingly multidrug-resistant pathogens, especially methicillin-resistant Staphylococcus aureus (MRSA), have become a serious problem particularly during the last decade.23) The resistance levels to quinolones are as yet relatively low but are steadily increasing.24) Therefore new antibacterial agents have become increasingly urgent. This prompted us to develop new quinolones utilizing the azetidine derivatives, in which the C7 substituents of fluoroquinolone carboxylic acids play important antibacterial roles.18-22) Previously, we communicated synthesis and antibacterial activities of new quinolone derivatives utilizing ABB (3). 10)We now describe, in detail, a convenient method of synthesizing several 3-sulfenyl-and 3-aminoazetidine derivatives utilizing ABB (3), and we discuss the synthesis and antibacterial activities of new quinolone antibiotics incorporating these azetidine derivatives to the C7 position. Although several examples of 7-azetidinylquinolones have been reported, [12][13][14][15] there have been not many prominent quinolone antibiotics bearing the azetidinyl substituent groups thus far. We envisaged that the introduction of azetidine derivatives onto the C7 position of the quinolone nucleus might enhance their antibacterial activities against MRSA. Results and DiscussionA tetrahydrofuran (THF) solution of ABB (3), obtained by treatment of 2,3-dibromopropylamine hydrobromide (2) with n-BuLi at Ϫ78°C in THF followed by codistillation with THF, 1) was...

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

“…41 During the course of synthetic studies toward new quinolone antibiotics, Nagao demonstrated that aniline attacks ABB at C3 to afford azetidine 83 (Figure 5B). 42 The reaction requires superstoichiometric amounts of Lewis acids (e.g., Mg(ClO 4 ) 2 ) and also works with some thiols and dibenzylamine. Unfortunately, this approach failed to give 85 when ABB was instead treated with other alkyl amines such as piperidine.…”

Quinolone–Triazole Hybrids and their Biological Activities

“…A series of 3‐sulfenylazetidine quinolone hybrids were assessed for their in vitro antibacterial activities against representative clinically Gram‐positive and Gram‐negative pathogens by Nagao et al . Among them, the 1,2,4‐triazole conjugate 2 (MIC: 0.125–8 μg/mL) exhibited considerable potency in inhibiting the growth of Gram‐positive strains including methicillin‐sensitive S. aureus /MSSA and methicillin‐resistant S. aureus /MRSA, which was as potent as or more active than levofloxacin.…”

Coumarin–triazole Hybrids and Their Biological Activities

“…Many derivatives that showed promising antimycobacterial activity, that is, (+)‐Calanolide A and I‐A09 (Fig. ), have shown promising in vitro and in vivo activities against Mycobacterium tuberculosis (MTB) . Thus, coumarin–triazole hybrids may be promising antimycobacterial agents.…”