Abstract:A practical synthesis of (-)-englerin A was accomplished in 17 steps and 11% global yield from commercially available achiral precursors. The key step consists of a Pt-catalyzed [4C+3C] allenediene cycloaddition that directly delivers the trans-fused guaiane skeleton with complete diastereoselectivity. The high enantioselectivity (99% ee) stems from an asymmetric Ru-catalyzed transfer hydrogenation of a readily assembled diene-ynone. The synthesis also features a highly stereoselective oxygenation, and a late-stage cuprate alkylation that enables the preparation of previously inaccessible structural analogues.Along the last years, the guaiane sesquiterpene (−)-englerin A (1, Figure 1) has attracted the attention of chemists, biologists and physicians because of its potent and highly selective activity as inhibitor of renal cancer growth. [1] Recent work carried out independently by Waldmann, Beech and Christmann, [2] as well as by a Novartis' team, [3] identified the transient receptor potential Ca 2+ channel TRPC4 as its main target. [4] TRPC channels are complex membrane proteins that are implicated in multiple biological functions, but they are unusual targets for antitumoral compounds. [5] The activation of this particular channel by 1 has been shown to induce cell death by elevated Ca 2+ influx, [2] however, the general mechanisms that govern TRPC4 activation remains elusive. [5] In this context, the development of efficient and versatile approaches to englerin A and related structural analogues is of major current interest.Since its isolation, [1] several synthesis of englerin have been accomplished, [6,7] some of which are asymmetric. [8] Most of the shortest (<20 steps) asymmetric synthesis rely on the use of prebuilt five-membered rings derived from the chiral pool, and already equipped with key stereocenters of the product. [8b] Although some of these approaches are efficient, the types of analogues that can be assembled are inherently restricted, in particular with respect to the substitution at the five membered ring. [9,10] The groups of Ma and Echavarren independently developed synthetic routes that allow the direct assembly of the bicarbocyclic scaffold of 1 by using a gold-catalyzed cycloisomerization of enantioenriched ketoenynes. [7d,e] The Ma route makes use of the chiral pool to prepare the ketoenyne, whereas Echavarren's approach relies on a Sharpless asymmetric epoxidation to generate the key stereocenter of the annulation precursor. While these approaches are very elegant, the cycloisomerization yields are moderate and the generation of the correct stereochemistry at the ring fusion requires the destruction and regeneration of stereocenters.Herein, we report an enantioselective synthesis of (−)-englerin A that allows to overcome many of the above limitations. The approach relies on a Pt-catalyzed [4C+3C] cycloaddition, and allows to build the bicyclic skeleton of 1 with the correct stereochemistry at the ring fusion, from a readily available allenediene precursor (Figure 1). ...

Aldehydes can be α-alkylated with allenamides by the combined action of an organocatalyst and a gold complex. The reaction requires the simultaneous generation of an enamine and a gold-activated allenamide. Importantly, by using a chiral amine as organocatalyst it is possible to obtain aldehyde products featuring all-carbon quaternary stereocenter at their α-position, with moderate to good levels of enantioselectivity.

A cycloaddition reaction at room temperature between aryl azides and 1,3-dicarbonyl compounds in the presence of potassium carbonate in dimethylsulphoxide yielded 10 4-ethoxycarbonyl-1-aryl-5-methyl-1 H-1,2,3-triazoles and seven other closely-related compounds. The 1,2,3-triazoles, nine of which are new, were obtained in good to high yields and only the 1,4-regioisomers were formed.