Target preparation intermediates

Owing to their frequent occurrence in natural products and their synthetic utility, 2(5//)-furanones are important synthetic targets and intermediates. In considering the methods for the preparation of these compounds, we will emphasize the recent developments in this area. 

Finally, compound (iv) is condensed with either trimethyl(6-methyl-3-pyridyl)tin or the boronate ester by means of Pd(PPh3)4 to afford etoricoxib. The metallated pyridine (vii) is obtained by esterification of 3-hydroxy-2-methylpyridine with triflic anhydride to give the corresponding triflate, which is treated with a tin reagent to yield the target tin intermediate. The boron lithium salt (viii) is prepared by treatment of 5-bromo-2-methylpyridine with butyllithium followed by addition of triisopropyl borate. 

The only targeted preparation of a lA3,2A3-diphosphete complex is based on a thermal-induced chloride abstraction by a transition metal and rearrangement of the isolable intermediate (/ra t-l,2-dichloro-lA3,2A3-diphosphete)Fe2(CO)8 cr-complex lg which leads to the (lA3,2A3-diphosphete)Fe(CO)3 Jt-complex 112 <1999OM2021>. Bis-trimethylsilyl-l,3-diphosphetane-2,4-diyl 6e <1999AGE3028> may be reduced by K or Li to form aromatic 1,3-diphosphetediide salts, for example, 20 (Scheme 36) <2004AGE637, 2004PS779>. 

If one of these bonds is to be disconnected, a reaction (or sequence of reactions) must be available that will chemically form that bond in the synthesis. Subsequent simplifications (disconnections) lead ultimately to a molecule that can be recognized as commercially available, available by simple chemical techniques, or already prepared by others. This process of structural simplification via disconnection leads to a series of molecular fragments that serve as key intermediates, and each is a synthetic target. Such intermediates allow the synthetic chemist to mentally bridge the starting material with the final target in a logical and sequential manner. This process therefore constitutes a synthetic tree for which chemical reactions must be provided to accomplish the planned transformations. 

The application of forward chemical genetics to studies of translation provides an opportunity to identify small molecules that inhibit or stimulate this process without any underlying assumptions as to which step is most amenable to targeting by the chemical libraries under consideration. The opportunity exists to identify novel factors involved in translation, unravel new activities of known translation initiation factors, or characterize shortlived intermediates that are frozen by the small molecule inhibitor. We have undertaken a forward chemical genetic approach to identify small molecules that inhibit or stimulate translation in extracts prepared from Krebs-2 ascites cells (Novae et al., 2004). These screens have led to the identification of several novel inhibitors of translation initiation and elongation (Bordeleau et al., 2005, 2006 Robert et al., 2006a,b). 

Figure 1.7 Derivatives of carboxylic acids can be prepared through the use of active intermediates that react with target functional groups to give acylated products.

A method for the preparation of 1,3,2-diazaphospholidine heterocydes has been described by Deng and Chen (Scheme 6.225) [402], The authors found that treating hindered 1,2-diamino substrates such as a-amino acid amides with tris(diethylami-no)phosphine as reagent/solvent under open-vessel microwave conditions at 250 °C for 1 min furnished a trivalent phosphorus intermediate. Subsequent thiation of this intermediate with elemental sulfur in refluxing benzene provided the target l,3,2-diazaphospholidin-4-ones in good overall yields. The yields were much improved compared to those achieved by standard thermal methods. 

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