JACS: catalytic asymmetric Staudinger aza Wittig reaction for the synthesis of heterocyclic amines

Chiral heterocyclic amines are very common structural units in many bioactive natural products and drug-related compounds More than 50% of the unique small molecule drugs approved by FDA in 2012 contain nitrogen heterocycles Six membered heterocyclic amines, especially piperidine and piperazine, account for more than a quarter of heterocyclic amines However, the construction of quaternary ammonium centers in organic molecules is still one of the biggest challenges in synthetic chemistry, which makes it more difficult to synthesize heterocyclic amines with chiral quaternary carbon centers Even today, pharmaceutical companies rely heavily on chemical resolution to separate enantiomers Because enantioselective synthesis can avoid unnecessary waste of enantiomers, it is more economical, more environmentally friendly, and often more desired by synthetic chemists (source: j.am Chem SOC.) recently, Professor ohyun Kwon of UCLA and others realized the first room temperature catalytic asymmetric desymmetry of ketones through Staudinger aza Wittig reaction, which provided an efficient synthesis method for the synthesis of chiral nitrogen heterocycles with quaternary centers The reaction allows the synthesis of potential precursors of drug molecules at gram scale The mild reaction conditions and wide substrate range of this method are expected to accelerate the synthesis of chiral heterocyclic amines with important biological significance Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b04803) In 2006, Marsden and his colleagues reported the first enantioselective Staudinger aza Wittig reaction, in which piperidine was formed by desymmetrization of chiral oxaphosphine heterocyclopentane or diazphosphine heterocyclopentane The Werner team reported the first example of a catalytic asymmetric Wittig reaction under microwave or conventional heating conditions Considering that the ideal condition of catalytic enantioselective Staudinger aza Wittig reaction is to carry out the reaction at room temperature, the key is to determine a kind of chiral phosphine, which can not only induce high enantioselectivity, but also form oxides that can be easily reduced by silane In this paper, we try to use the commercial chiral phosphine "hyphos" derived from L-hydroxyproline (Hyp) It is found that at room temperature, 1 a can be converted into 2 A by 79% ee Furthermore, it was confirmed that 2-nitrobenzoic acid could accelerate the Staudinger aza Wittig reaction By adding molecular sieve as water scavenger in the system, 99% yield and 90% ee could be obtained In order to explore the origin of enantioselectivity, the free energy curve of AZA Wittig reaction of 3 was calculated The results show that the enantioselectivity of the reaction is induced by chiral phosphine and further enhanced by acid In addition to accelerating the reaction rate of AZA Wittig, acid may also accelerate the reduction of phosphine oxide to catalytic active phosphine, thus increasing the catalytic conversion (source: j.am Chem SOC.) next, the author investigated the range of catalytic asymmetric Staudinger aza Wittig reaction (scheme 2) When 2.5G raw material was used for 1A reaction, the yield of product 2a was 97%, and EE was 89.4% The conversion of benzene ring to naphthalene has little effect on the reactivity The electron donor dimethoxy group needs a slightly higher reaction temperature (35 ℃), but it will reduce the enantioselectivity of the product The electron absorbing dichloro group can accelerate the reaction (source: j.am Chem SOC.) in view of the high biological activity of indene piperidine derivatives, the author carried out derivatization reaction on product 2a and prepared several potential useful compounds for drug discovery (scheme 3) (source: j.am Chem SOC.) conclusion: Professor ohyun Kwon, UCLA, et al Proposed the method of preparing chiral heterocyclic amines by using chiral phosphine and Br ø NST acid to catalyze the enantioselective Staudinger aza Wittig reaction at room temperature, which provided a strategic blueprint for adopting standard stoichiometric phosphine mediated reaction and making it have catalysis and enantioselectivity.