JACS: synthesis of highly selective enantiomer bromoalcohol by divergent reaction of racemic intermediate

Asymmetric halide functionalization of olefins is an effective method for the synthesis of chiral halides, which has potential application value In the synthesis process, the process of olefin to olefin transfer and β - halocarbon cation mediated pathway are the main factors affecting the stereoselectivity Therefore, researchers focus on the intramolecular asymmetric halogenation Recently, Professor Mathias christmann's research group of Berlin Free University, Germany, proposed that the synthesis method of cyclic semiortho ester intermediate was prepared by using chiral phosphoric acid as catalyst, oxygen atom of ester compounds attacking halium ion, and water as nucleophilic reagent attacking ester carbonyl, and the target product enantiomer bromine alcohol (Figure 1a) was obtained by meso decomposition Relevant articles were published in J am Chem SOC (DOI: 10.1021 / JACS 8b06432) under the title of "synthesis of enriched bromhydrins via divergent reactions of racemic intermediates from angelic oxygen borrowing" (source: J am Chem SOC.) at the beginning of the experiment, N-bromosuccinimide (NBS) was used as the cation source of bromine to test the substrate 1t In the reaction, 10 mol% of chiral phosphoric acid C1 (CPA) was used as catalyst, and only 2.0 equivalent water was added The mixture of 2T and 3T was obtained with good EE value Interestingly, the author treated 3T with ET 3N to make it undergo intramolecular acyl transfer, and got ent - 2T (Figure 1b) The relationship between the yield and EE indicates that the racemic mixture (RRM) has a regional divergent reaction In order to screen good ester auxiliary groups, the author uses C1 as catalyst and aromatic group as research site to explore the influence of space and electron change (Table 1) The results showed that the activity of the reaction increased when the aryl group was substituted by the electron methoxy group, but decreased significantly when the 2,6-disubstituted group was substituted (entries 5,9) These results are consistent with the existence of cyclic semiortho ester intermediates and suggest that they are involved in the rate determining step of the reaction Most importantly, the increase of steric hindrance of 3-and 5-substituents has a positive effect on EE value (t Bu > pH > I pr > OME), and the target product EE value of di-tert-butyl substituent is the highest (entry 13) Finally, with 3,5-di-tert-butyl-4-methoxybenzoyl ester as the auxiliary group, CPA C5 as the catalyst, ch 2Cl 2 as the solvent, with excellent yield and high EE value, the author obtained 2 and 3 (entry 14) (source: J am Chem SOC.) next, the author examined the substrate range of the reaction (Table 2) Cinnamate containing various substituents in the para or meta position of benzene ring can make the reaction go on smoothly, and the target product (entries 1-8) with high yield and high EE value can be obtained It is worth noting that the electronic properties of the substituents affect the reaction rate, similar to the substituent effect in the auxiliary group It is proved that the formation of alkene halogenation and semiorthoester is related in kinetics Ortho substituted phenyl and 1-naphthyl derivatives are also suitable for this reaction (entries 9 − 11) After that, the high allyl ester substrates were investigated, and it was found that these compounds can be transformed smoothly (entries 13-18) (source: J am Chem SOC.) finally, the author proposes the basic principle of reaction (Figure 2) The whole process of the reaction can be divided into two catalytic stages In the first stage (non enantioselective bromination), CPA catalyzes bromination by activating NBS, and water is used as nucleophile to attack carbonyl carbon, so as to obtain corresponding cyclic semiesters (int and ENT int) with excellent non enantioselectivity In the second stage, the enantiomers of semiorthoesters can be folded into different isomers under the catalysis of chiral protonic acid It is suggested that the selectivity of the target product is due to the activation of different oxygen atoms in each enantiomer Some ints may split through path C to produce a small amount of ENT - 3 (source: J am Chem SOC.) Summary: the author proposed that chiral phosphoric acid catalyzes the bromination / regional divergence reaction of racemic intermediates In this method, olefins, NBS and water, which are easy to synthesize, are used as reactants to realize asymmetric halogen functionalization of olefins, and are suitable for different types of olefins.