Enantioselective Dihalogenation of Allylic Alcohols

The development of a catalytic enantioselective reaction of bromination of alkenes can be at least as complicated as the corresponding dichlorination variant. The background reaction of bromine and other common dibrominating reagents capable of reacting rapidly with alkenes with no need of catalyst and the fact that bromonium ions can rapidly racemize in the presence of alkene do not make it any easier.

Recently in 2013 Burns and co-workers approached this challenge with a different strategy: to formally separate Br2 into electrophilic and nucleophilic components that are unreactive on their own. Diethyl dibromomalonate as the bromonium source and titanium bromide as the bromide anion source do the trick. To induce enantiocontrol a chiral TADDOL ligand is used as a chiral promoter and allylic alcohols capable to bind to the titanium metal centre are chosen as substrates. The TADDOL-type ligand used in the reaction has been found to induce good levels of enantioselectivity when used stoichiometrically and also lowering its loading to 20 mol%.

dibromacionNot happy with this incredible contribution Burns and co-workers have very recently published a follow up paper extending the methodoly to an enantioslective Bromochlorination version. Same strategy different actors, in this case Chlorotitanium triisopropoxide as the chloride source and N-bromosuccinimide as the bromonium source serve as a non-disproportionating equivalent to bromine monochloride and a tridentate Schiff base is used as chiral promoter.

These new methodology will enable enantioselective synthesis of a wide variety of polyhalogenated natural products. As a proof of concept the paper also includes a short chemo-, regio-, and enantioselective synthesis of (+)-bromochloromyrcene and model subtrates leading to bromochlorocyclohexane motifs that can be found within several natural products including obtuso and preintricatol.

natural products           Do you want to know more? Why don’t you take a look to these references?

-Dennis X. Hu , Grant M. Shibuya , and Noah Z. Burns. Catalytic Enantioselective Dibromination of Allylic Alcohols. J. Am. Chem. Soc., 2013, 135, 12960–12963.

– Dennis X. Hu , Frederick J. Seidl , Cyril Bucher , and Noah Z. Burns. Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols. J. Am. Chem. Soc., 2015, 137, 3795–3798.


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