Scalable organocatalytic asymmetric Strecker reactions catalysed by a chiral cyanide generator

Abstract

The Strecker synthesis is one of the most facile methods to access racemic a-amino acids. However, feasible catalytic asymmetric Strecker reactions for the large-scale production of enantioenriched a-amino acids are rare. Here we report a scalable catalytic asymmetric Strecker reaction that uses an accessible chiral variant of oligoethylene glycol as the catalyst and KCN to generate a chiral cyanide anion. Various a-amido sulphone substrates (alkyl, aryl and heteroaryl) can be transformed into the optically enriched Strecker products, a-aminonitriles, with excellent yields and enantioselectivities. Moreover, the robust nature of the catalyst enables a 'one-pot' synthesis of enantiomerically pure a-amino acids starting from a-amido sulphones and simple catalyst recycling. These features can make this protocol easily adaptable to the practical synthesis of unnatural a-amino acids.

Biomimetic catalytic transformation of toxic α-oxoaldehydes to high-value chiral α-hydroxythioesters using artificial glyoxalase I

“…As per our expectations, the hemithioacetal 4a was formed as a racemic form almost spontaneously under the reaction conditions and its enantioselective isomerization proceeded smoothly, affording the desired enantioenriched 5a . Based on our knowledge of the catalytic performance of chiral oligoEGs 1 (refs 26, 27, 28, 29, 30), the presence of the polyether backbone, the ether chain length (entries 6 and 7) and the acidity of phenolic protons (entry 2 versus entry 4) are crucial in achieving the catalytic activity and enantioselectivity. Although ( R )- 1c showed distinguished catalytic activity and enantioselectivity (see, entry 3) compared to ( R )- 1a and ( R )- 1b (entries 1 and 2, respectively), the observed activity and enantioselectivity were still unsatisfactory (68% conversion and 87% ee after 48 h).…”

“…Therefore, developing powerful biomimetic catalytic system is highly interesting from the perspectives of both biology and chemistry. Given our previous studies on our evolved cation-binding catalyst 1 (refs 26, 27, 28, 29, 30), we presumed that catalyst 1 could act as a synthetic glyoxalase I for the enantioselective isomerization of the spontaneously formed hemithioacetal adduct between thiols and α-oxoaldehydes into enantio-enriched α-hydroxythioesters. The hydrogen-bond chelating interaction between the acidic phenolic protons of the catalyst and two oxygen atoms of hemithioacetals would enhance the electrophilicity of the carbonyl carbon atom, consequently increasing the acidity of the α-proton.…”

Synthesis of 2 C‐14 labeled cathepsin C inhibitors: The use of a cyanide to displace a Benzotriazole

“…The asymmetric Strecker reaction is well known and could be of use in this instance . A recent report of an asymmetric catalyst for the Strecker reaction is of particular interest (Scheme ) . It uses an α‐amido sulphone as starting material, and sulfone 13 could be prepared in a manner analogous to that reported for the Katritzky precursor or from by‐product 11 .…”

“…15 A recent report of an asymmetric catalyst for the Strecker reaction is of particular interest (Scheme 6). 16 It uses an α-amido sulphone as starting material, and sulfone 13 could be prepared in a manner analogous to that reported for the Katritzky precursor 17 or from by-product 11. This route would also necessitate the synthesis of the catalyst as well.…”

Towards Enzyme‐like, Sustainable Catalysis: Switchable, Highly Efficient Asymmetric Synthesis of Enantiopure Biginelli Dihydropyrimidinones or Hexahydropyrimidinones

“…[13] After provingt he NCHB (network of cooperative hydrogen bonds) concept, we aimed at moving as tep aheadt owards enzyme-like, sustainablec atalysis, convincedt hat the limitations found in using preformed,t hough unstable, arylideneureas could be removed by using a-ureidosulfones as precursors. [14] The incoming challenge was to avoid the undesirable effects that the incorporationo fapreliminarya cid-base step mighti nduce upon stereoselectivity and chemical yield, as both the organocatalyst and the NuH reactw ith bases.W e, now,w ould like to report ao ne-pot, scalable, highly efficient, [15] and switchable asymmetric synthesiso feither enantiopure HHPMs or DHPMs starting from a-ureidosulfones, based on an NCHB organocatalyst [16,17] that also functions in the presence of suitable organic bases (Scheme 2).…”