Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols

Abstract

The discovery of new catalysts that can generate complex organic compounds via enantioselective transformations is central to advances in the life sciences;i for this reason, many chemists try to discover catalysts that can be used to produce chiral molecules with a strong preference for one mirror image isomer.ii The ideal catalyst should be devoid of precious elementsiii and should bring reactions to completion in a few hours using operationally simple procedures. In this manuscript, we introduce a set of small organic molecules that can catalyze reactions of unsaturated organoboron reagents with imines and carbonyls; the products of the reactions are enantiomerically pure amines and alcohols, which can be used to synthesize more complex, biologically active molecules. A distinguishing feature of this new catalyst class is the presence of a 'key' proton embedded within their structure. The catalyst is derived from the abundant amino acid valine and was prepared in large quantities in four steps using inexpensive reagents. Reactions are scalable, do not demand stringent conditions, and can be performed with as little as 0.25 mol % catalyst in less than six hours at room temperature to generate products in >85% yield and ≥97:3 enantiomeric ratio. The efficiency, selectivity and operational simplicity of the transformations and the range of boron-based reagents render this advance vital to future progress in chemistry, biology and medicine.

Combined heterogeneous metal/organic catalysts for eco-friendly synthesis

“…Recently, the concept of merging metal catalysis and organocatalysis in one-pot ("metal/organo cooperative catalysis") has grown [15][16][17][18][19][20][21][22][23]. Here we have discovered that transition metal catalysis could be Scheme 1: Combined heterogeneous metal/chiral amine relay catalysis strategy.…”

“…The development of asymmetric relay catalysis (ARC), which combines organic and homogeneous metal catalysts [9,[15][16][17][18][19][20][21][22][23], has attracted considerable attention in recent years. It allows for novel reactivity, which cannot be accomplished employing the catalysts separately.…”

Catalytic enantioselective addition of organoboron reagents to fluoroketones controlled by electrostatic interactions

“…3a) afforded 6a in 93:7 e.r. [<2% homopropargyl alcohol: >98% net α addition (“double-γ” mechanism 20 ]. Without 1a , there was 80% conversion to rac - 6a , pointg to high chiral catalyst efficiency.…”

“…with an allyl-indium reagent) 17 . We are not aware of any reports of catalytic enantioselective allenyl addition to ketones (except isatins 20 ), the products from which may be subjected to site- and/or stereoselective procedures. 21 …”

“…1b) and shown to promote additions of unsaturated organoboron reagents to phosphinoylimines, 20 tert -butoxycarbonyl (Boc-) imines 21 or isatins 20 . A protonated amine within the catalyst's structure is key to high efficiency and enantioselectivity 20 , allowing substrates with a second Lewis basic site to react with high stereoselectivity (other than interaction with the catalyst's boron center). Association of the additional Lewis basic unit with the imbedded proton signals a preference for addition to one of the C=N or C=O bond enantiotopic faces.…”