A one-pot copper-catalysed synthesis of all possible stereoisomers of 1,3-amino alcohols from enals and enones

This recent letter produced by the Buchwald group [1] at MIT describes a copper catalysed synthesis of amino alcohols by sequential hydrosilyalation and hydroamination of enals and enones ( Figure 1).yusuffig1

Figure 1. Synthesis of amino alcohols. [1]

The chirality of a drug can have a significant biological impact in drug discovery. The chirality is the ‘handedness’ of a molecule and the various isomers of a chiral compound, known as enantiomers, will exhibit a different 3-dimensional orientation in space and could therefore possess different biological activities as they are different ‘keys’ that could fit into different ‘locks’. The most infamous example of this phenomenon is the sedative thalidomide which resulted 10,000 cases in the 1950s of malformed infants with a 50% survival rate. It was found that (R)-thalidomide possessed sedative effects while (S)-thalidomide was severely teratogenic. Figure 2, taken from the Wikipedia page on thalidomide, clearly shows the differing space occupied by the two enantiomers of thalidomide.yusuffig2

Figure 2. Enantiomers of thalidomide represented as 2D drawings and 3D ball and chain structures

With drug discovery clearly in need of methods to obtain all possible enantiomers of a chiral compound in a relatively easy manner, asymmetric synthesis has come to the rescue over the past few decades with major advancements in enantioselective synthesis. However, what has been lacking are methods that give a unified route to all possible stereoisomers of a given product containing multiple contiguous stereocentres.

The asymmetric hydrosilylation/hydroamination of enals and enones produces optically pure 1,3-amino alcohols which could be required for a target compound or be used as a building block in asymmetric synthesis. The synthesis is a one-pot procedure where the pre-stirred catalytic mixture composed of the copper hydride based catalyst, ligand and silane reagent is added to the enone or enal for 15 minutes followed by addition of the hydroxylamine ester (amine source) which is stirred at 55 °C for 36 h.

The authors show that hydrosilylation occurs regioselectively at the carbonyl over the alkene functionality and that hydroamination also occurs in a regio- and stereoselective manner to ultimately allow all possible amino-alcohols with a high chemo-, regio-, diastereo and enantioselectivity. Catalytic control was achieved by starting from the appropriate choice of enal/enone (E or Z) and ligand enantiomer (R or S).

The method seems to be applicable to a variety of enals/enones and amino –bearing groups with yields above 60 % generally obtained. Yields were generally higher for enals over enones. In all cases diasterometric ratios were >95% and e.e (enantiomeric excess) >99 %. Most notably, it was shown that all 8 possible stereoisomers of the final compound could be achieved in high selectivity from appropriate starting enals and starting enones (Figure 3).



Figure 3. All possible stereoisomers from the reaction of the enone 4 with dibenzylamine aminating reagent [1] (see Figure 1)

This method to synthesise all possible stereoisomers of 1,3-amino alcohols using readily available starting materials in a reliable and easy manner is a good example of asymmetric synthesis methods coming through in the literature in more recent times that allows assembling all possibilities in compounds with multiple sterocentres. I look forward to see further expansion in this particular area of asymmetric synthesis.

Blog writted by Yusuf Ali


[1] Shi SL, Wong ZL, Buchwald SL. Nature. 2016 Mar 28. doi: 10.1038/nature17191 [Epub ahead of print]



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