Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols

Abstract

The chirality, or 'handedness', of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation. Despite many advances in asymmetric synthesis, developing general and practical strategies for obtaining all possible stereoisomers of an organic compound that has multiple contiguous stereocentres remains a challenge. Here, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, we synthesized these amino-alcohol products using sequential, copper-hydride-catalysed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino-alcohol products, which contain up to three contiguous stereocentres. We leveraged catalyst control and stereospecificity simultaneously to attain exceptional control of the product stereochemistry. Beyond the immediate utility of this protocol, our strategy could inspire the development of methods that provide complete sets of stereoisomers for other valuable synthetic targets.

Figure 1. Bioactive stereoisomers and strategies for construction of all stereoisomers of amino alcohols

a Different enantiomers give distinct activities in biological systems. b. Stereoisomeric amino alcohols (esters) and their biological activities. c. Top, potential side reactions; Bottom (this work), forming all stereoisomers of amino alcohols via selective hydrosilylation/hydroamination reactions.

Figure 2. Asymmetric hydrosilylation/hydroamination of enals

Top row, reaction studied; Bottom rows, substrate scope. Isolated yields are reported (average of two runs on 0.5 mmol scale). Diastereomeric ratios (d.r.) were determined by GC and NMR analysis. Enantiomeric excesses (e.e.) were determined by HPLC analysis using chiral stationary phases. *Reaction was conducted in 5 mmol scale. See Supplementary Information for details. Bn, benzyl; PMB, p-methoxylbenzyl; RT, room temperature.

Figure 3. All stereoisomers of amino alcohols from enals

a Reaction using (S)-L1 and (E)-2-amyl-cinnamaldehyde (1b) under the standard conditions; *using (R)-L1 instead of (S)-L1; ^†using (Z)-1b instead of (E)-1b. b Reaction using (S)-L1, (E)-2-methyl-cinnamaldehyde (1a) and 2j under the standard conditions; ^*using (R)-L1 instead of (S)-L1; ^‡using (Z)-1a instead of (E)-1a; ^#using ent-2j instead of 2j.

Figure 4. Asymmetric hydrosilylation/hydroamination of enones

Top row, reaction studied; Bottom rows, substrate scope. Isolated yields are reported (average of two runs on 1.0 mmol scale). Diastereomeric ratios (d.r.) were determined by GC and NMR analysis. Enantiomeric excesses (e.e.) were determined by HPLC analysis. * The absolute and relative stereochemistry of 5a was determined to be (S,S,R) by single crystal X-ray diffraction. See Supplementary Information for details.

Figure 5. All eight stereoisomers of amino alcohols from enones

a Access to all stereoisomers via reaction using (E)- or (Z)-4a with catalyst permutation in each step. Isolated yields are reported. Diastereomeric ratios (d.r.) were determined by NMR analysis using a crude reaction mixture. b HPLC traces of all stereoisomeric amino alcohol samples. See Supplementary Information for details.