期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 141, 期 11, 页码 4573-4578出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b01513
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资金
- EPSRC [EP/I038071/1]
- H2020 ERC [670668]
- Commonwealth Scholarship Commission UK
- BBSRC [BB/F011539/1] Funding Source: UKRI
- EPSRC [EP/I038071/1, EP/L011999/1] Funding Source: UKRI
Azetidines are important motifs in medicinal chemistry, but there are a limited number of methods for their synthesis. Herein, we present a new method for their modular construction by exploiting the high ring strain associated with azabicyclo[1.1.0]butane. Generation of azabicyclo[1.1.0]butyl lithium followed by its trapping with a boronic ester gives an intermediate boronate complex which, upon N-protonation with acetic acid, undergoes 1,2-migration with cleavage of the central C-N bond to relieve ring strain. The methodology is applicable to primary, secondary, tertiary, aryl, and alkenyl boronic esters and occurs with complete stereospecificity. The homologated azetidinyl boronic esters can be further functionalized through reaction of the N-H azetidine, and through transformation of the boronic ester. The methodology was applied to a short, stereoselective synthesis of the azetidine-containing pharmaceutical, cobimetinib.
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