- Ring Opening of Donor-Acceptor Cyclopropanes with the Azide Ion: A Tool for Construction of N-Heterocycles
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A general method for ring opening of various donor-acceptor cyclopropanes with the azide ion through an SN2-like reaction has been developed. This highly regioselective and stereospecific process proceeds through nucleophilic attack on the more-substituted C2 atom of a cyclopropane with complete inversion of configuration at this center. Results of DFT calculations support the SN2 mechanism and demonstrate good qualitative correlation between the relative experimental reactivity of cyclopropanes and the calculated energy barriers. The reaction provides a straightforward approach to a variety of polyfunctional azides in up to 91% yield. The high synthetic utility of these azides and the possibilities of their involvement in diversity-oriented synthesis were demonstrated by the developed multipath strategy of their transformations into five-, six-, and seven-membered N-heterocycles, as well as complex annulated compounds, including natural products and medicines such as (-)-nicotine and atorvastatin. A new world of opportunities: Stereospecific ring opening of donor-acceptor cyclopropanes with the azide ion gives rise to densely functionalized building blocks that are valuable for the assembly of a diverse range of N-heterocycles (see scheme; EDG=electron donating group; EWG=electron withdrawing group). These synthetic opportunities are provided by the simultaneous presence of the N3 group, which reacts as a latent amine or 1,3-dipole, easily modifiable donor and acceptor substituents, as well as the activated CH fragment.
- Ivanov, Konstantin L.,Villemson, Elena V.,Budynina, Ekaterina M.,Ivanova, Olga A.,Trushkov, Igor V.,Melnikov, Mikhail Ya.
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p. 4975 - 4987
(2015/03/18)
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- The biosynthesis of [5'-14C]cotinine and other radiolabeled nicotine metabolites
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The present study describes the biosynthesis and isolation of the major radiolabeled nicotine metabolites formed using phenobarbitone (PB)-induced rabbit hepatic homogenates (10,000 g fraction). The optimal incubation and extraction methods for cotinine formation from non-labeled nicotine were established. The biosynthesis and isolation of [5'-14C]cotinine and other radiolabeled metabolites such as [2'-14C]nornicotine and [4-14C]-(3-pyridyl)-4-oxobutyric acid, from commercially available [2'-14C]nicotine, were carried out using the developed methods. Cotinine was isolated using preparative silica gel TLC, whereas the other metabolites were obtained using a cation-exchange HPLC method. This study showed that in addition to the two major metabolites (i.e. cotinine and nornicotine), 4-(3-pyridyl)-4-oxo-butyric acid, 3-hydroxycotinine, norcotinine, nicotine-1'-N-oxide and cotinine-1-N-oxide were also formed when PB-induced rabbit hepatic homogenates were used. Two further metabolites of unknown structure were detected. However, the isolation and further purification were only carried out on cotinine, nornicotine and 4-(3-pyridyl)-4-oxo-butyric acid.
- Tsai, Mui-Chiung,Sai, Yang,Li, Yan,Aislaitner, George,Gorrod, John W.
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p. 387 - 407
(2007/10/03)
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