A robust platform for the synthesis of new tetracycline antibiotics.
A robust platform for the synthesis of new tetracycline antibiotics.
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用于合成新型四环素抗生素的强大平台。
DOI：
10.1021/ja806629e
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发表时间：
2008-12-31
影响因子：
15
通讯作者：
Myers AG
中科院分区：
文献类型：
--
作者：
Sun C;Wang Q;Brubaker JD;Wright PM;Lerner CD;Noson K;Charest M;Siegel DR;Wang YM;Myers AG
Tetracyclines and tetracycline analogs are prepared by a convergent, single-step Michael–Claisen condensation of the AB precursors 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at −78 °C, while Claisen cyclization of the enolate produced is rate-determining, typically occurring upon warming to 0 °C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semi-synthetic methods (presently the only means of tetracycline production), and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.
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影响因子：
5.2
作者：
Brubaker, Jason D.;Myers, Andrew G.
通讯作者：
Myers, Andrew G.
DOI：
10.1039/p19840001043
发表时间：
1984-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
影响因子：
--
作者：
CARPENTER, TA;EVANS, GE;WILKINSON, MR
通讯作者：
WILKINSON, MR
影响因子：
15
作者：
HOCHSTEIN, FA;STEPHENS, CR;WOODWARD, RB
通讯作者：
WOODWARD, RB
影响因子：
64.5
作者：
Brodersen, DE;Clemons, WM;Ramakrishnan, V
通讯作者：
Ramakrishnan, V
影响因子：
1.8
作者：
BELLAMY, FD;OU, K
通讯作者：
OU, K