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...
Ring-opening reactions of azabicyclobutane (II) with thiols or aromatic amines (I) provide access to sulfenylazetidines and aminoazetidines (III). Introducing azetidine derivatives into fluoroquinolonecarboxylic acid (IV) affords the corresponding fluoroquinolone antibiotics. Most of the fluoroquinolones reveal more potent activity profiles vs. Gram-positive bacteria than Gram-negative bacteria. Especially compounds (V) show fairly potent activity against methicillin-resistant S. aureus in comparison with that of levofloxacin. -(IKEE, Y.; HASHIMOTO, K.; KAMINO, M.; NAKASHIMA, M.; HAYASHI, K.; SANO*, S.; SHIRO, M.; NAGAO, Y.; Chem. Pharm. Bull. 56 (2008) 3, 346-356; Grad. Sch. Pharm. Sci., Univ. Tokushima, Sho, Tokushima 770, Japan; Eng.) -H. Hoennerscheid 34-222
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