Stereoselective Syntheses of 3-Substituted Flavene Derivatives and Asymmetric Dehydration via Kinetic Resolution

Abstract

The 2-phenyl-2H-chromene structural core is a widespread element in natural flavonoids and has attracted intense attention since a wide range of biological activities associated with the scaffold have been identified. Accordingly, the development of facile synthetic strategies to access such heterocycles is of considerable interest and a few asymmetric synthetic methods have been reported recently. Although the asymmetric methods could provide enantioenriched flavene derivatives, their development for more functionalized flavene skeleton has proven to be a challenging synthetic task. In this communication, we wish to report diastereoselective Reformatsky reaction of flavene-3-carbaldehydes to provide β-(2H-3-flavenyl)-β-hydroxy esters and disclose a new enantioselective synthetic method for 3substituted flavene derivatives by asymmetric dehydration via kinetic resolution. We have initially investigated the substrate controlled diastereoselective addition of Reformatsky reagent to flavene-3-carbaldehydes 1, in which the chiral center at the C(2) position of 2H-chromene exerts control over the formation of new stereogenic center. In an initial experiment, to a solution of BrZnCH2CO2t-Bu (3 equiv) in THF was added a solution of flavene-3-carbaldehyde 1a in THF, and the resulting mixture was heated to reflux to afford the products 2a and 3a in 91% yield with a diastereomeric ratio (dr) of 71:29. (entry 1, Table 1) Different experimental conditions have been tested on flavene-3-carbaldehyde 1a to improve the diastereoselectivity of the addition. Since the diastereoselectivity could be enhanced by effecting the reaction at low temperature, different reaction temperatures have been tested on flavene-3-carbaldehyde 1a as summarized in Table 1. As the reaction temperature decreases, the dr is improved as shown in entries 1-5. The ratio of major 2a to minor product 3a was 79:21 at rt, whereas it was 90:10 at −15 °C. At −30 °C, much slower reaction gave products 2a and 3a with only 15% conversion after 5 h and a slightly improved dr of 92:8. (entry 5) Polar solvents were then screened in an attempt to increase the solubility of the reagent and to enhance the rate and the selectivity of the reaction. The use of THF-DMSO (1:1), THF-p-dioxane (1:1) and p-dioxane respectively as solvent (entries 6-9) did not increase the stereoselection and decreased the yield of the reaction. Under the optimized condition at −15 °C in THF, the reaction of o-methoxy substituted flavene aldehyde 1b gave slightly lower dr (entry 10) and p-methoxy substituted flavene aldehydes 1c-e reacted with Reformatsky reagent leading to 2c-e and 3c-e with drs ranging from 89:11 to 91:9, which are practically independent on the presence of the substituents on the aromatic rings and substitution pattern. While 4chloro substituent increase the selectivity up to 94:6 dr (entry 16), 2-methyl substituted chromenes 1f and 1g showed much lower selectivity (entries 14-15). Non-enzymatic kinetic resolution of racemic compounds using chiral catalyst is an area of great importance in contemporary organic synthesis. We recently reported the first example of the kinetic resolution in dehydration of alcohols using D-Phg-L-Pro-derived chiral ligand 5. Given