Palladium-catalyzed synthesis of heterocycles and highly functionalized polycyclics

摘要

Palladium catalyzes the regio- and stereoselective annulation of allenes by vinylic halides bearing tertiary alcohol and p-toluenesulfonamide groups to produce a variety of 5- and 6-membered ring heterocycles containing a 1,3-diene moiety. In addition, the palladium-catalyzed reaction of N-(2-iodo-2-alkenyl)-p-toluenesulfonamides with diphenylacetylene or 4,4-dimethyl-2-pentyne affords pyrolidine derivatives containing a 1,3-diene moiety, or unexpected 2-alkenyl substituted [alpha],[beta]-unsaturated aldehydes. These synthetically useful intermediates are difficult to prepare or inaccessible by other existing methodology;A number of 3,4,6-tri- and 3,4,5,6-tetrasubstituted [alpha]-pyrones have been prepared in good yields by the reaction of vinylic iodides or triflates bearing ester functionality with internal alkynes in the presence of a palladium catalyst. The methodology provides an especially simple, convenient, and regioselective route to [alpha]-pyrones containing aryl, silyl, tert,-alkyl and other hindered groups. This methodology is important due to the fact that [alpha]-pyrones occur as structural subunits in numerous natural products that exhibit a wide range of biological activity, and very recently, low molecular weight [alpha]-pyrones have been shown to be potent HIV-1 protease inhibitors;2,5-Cyclohexadienyl-substituted aryl and vinylic iodides have been reacted with carbon nucleophiles (diethyl malonate, 2-methyl-1,3-cyclohexanedione), nitrogen nucleophiles (morpholine, potassium phthalimide, N-benzyl tosylamide, di-tert,-butyl iminodicarboxylate, lithium azide and anilines), a sulfur nucleophile (sodium benzenesulfinate), and oxygen nucleophiles (lithium acetate and phenols) in the presence of a palladium catalyst to afford products of cyclization and subsequent cross-coupling in good to excellent yields. In most cases, this process is highly diastereoselective and the products are formed as single diastereoisomers. The structures of the representative compounds have been determined by 1H NMR, 13C NMR, COSY, HMQC, and NOESY spectroscopy. This methodology has potential applications in natural product synthesis, and may provide quick access to a library of compounds with different skeletons and functionality.