A short and enantioselective total synthesis of helioporins C and E, which are bioactive marine diterpenes containing a serrulatane or amphilectane skeleton, was elaborated. The chirogenic step, i.e. a Cu(I)-catalyzed allylic alkylation of a cinnamyl chloride with methylmagnesium bromide, proceeded with virtually complete enantioselectivity (99% ee) in the presence of a chiral phosphine-phosphite ligand. The other stereocenters were diastereoselectively established through Me(2)AlCl-mediated cationic cyclization and Ir-catalyzed hydrogenation.

Abstract:The copper(I)-catalysed S N 2'-type allylic substitution of E-3-aryl-allyl chlorides (cinnamyl chlorides) using Grignard reagents represents a powerful method for the synthesis of compounds carrying a benzylic stereocentre. By screening a small library of modular chiral phosphine-phosphite ligands a new copper(I)-based catalyst system was identified which allows the performance of such reactions with exceptional high degrees of regio-and enantioselectivity. Best results were obtained using TADDOLderived ligands (3 mol%), copper(I) bromide·di-methyl sulfide (CuBr·SMe 2 ) (2.5 mol%) and methyl tert-butyl ether (MTBE) as a solvent. Various (1-alkyl-allyl)benzene derivatives were prepared with up to 99% ee (GC) in isolated yields of up to 99%. In most cases the product contained less than 3% of the linear regioisomer (except for ortho-substituted substrates). Both electron-rich and electron-deficient cinnamyl chlorides were successfully employed. The absolute configuration of the products was assigned by comparison of experimental and calculated CD spectra. The substrates were prepared from the corresponding alcohols by reaction with thionyl chloride. Initially formed mixtures of regioisomeric allylic chlorides were homogenised by treatment with CuBr·SMe 2 (2.5 mol%) in the presence of triphenyl phosphine (PPh 3 ) (3 mol%) in MTBE at low temperature to give the pure linear isomers. In reactions with methylmagnesium bromide (MeMgBr) an ortho-diphenylphosphanyl-arylphosphite ligand with an additional phenyl substituent in ortho'-position at the aryl backbone proved to be superior. In contrast, best results were obtained in the case of higher alkyl Grignard reagents (such as ethyl-, n-butyl-, isopropyl-, and 3-butenylmagnesium bromides) with a related ligand carrying an isopropyl substituent in ortho'-position. The method was tested on a multimmol scale and is suited for application in natural product synthesis.

Copper(I) complexes of TADDOL‐based phosphane–phosphite ligands catalyze enantioselective conjugate additions of various Grignard reagents to cyclic enones. Through trapping of the resulting chiral magnesium enolates with N‐benzylidene‐4‐methylbenzenesulfonamide (as an imine) in one‐pot procedures, the corresponding Mannich products (i.e., β‐aminocarbonyl compounds) were obtained in good yields and high enantiomeric purities, although with only low diastereoselectivities.