478409-64-2Relevant articles and documents
Development of a Stereoselective Synthesis of (1 R,4 R)- and (1 S,4 S)-2-Oxa-5-azabicyclo[2.2.2]octane
Alam, Mahbub,Cleator, Ed,Dieguez-Vazquez, Alejandro,Gibb, Andrew,Goodyear, Adrian,Keen, Stephen,Kirtley, Andy,Kong, Lingzhu,Lam, Yu-Hong,Maddess, Matthew L.,Morimoto, Mariko,Oliver, Steven F.,Qi, Ji,Wang, Jie,Wen, Xin
supporting information, (2021/07/01)
Despite the prevalence of morpholine derivatives and bridged heterocycles in medicinally relevant compounds, bridged bicyclic morpholines remain scarce because of the challenges associated with their synthesis. MRK A, an IDH1mut inhibitor for the treatment of glioma, derives its potency in part from substitution of a zigzag 2,5-bicyclic morpholine, 2-oxa-5-azabicyclo[2.2.2]octane, at C8. While existing entries suffered from low yields and lack of stereochemical control, we developed concise stereospecific routes toward both enantiomers of the zigzag morpholine antipode. The key common intermediate in the two routes was a chiral bicyclic lactone, which was readily synthesized following our previous synthesis of relebactam from optically pure (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (HPA). The desired (R,R) enantiomer for incorporation into MRK A required inversion of both stereocenters of the bicyclic lactone intermediate, which was accomplished by epimerization via a crystallization-induced diastereomer transformation process followed by a key Ti(OiPr)4-mediated intramolecular SN2 ring closure. By this method, the (R,R)-zigzag morpholine was synthesized in six steps from HPA in 25% overall yield.
Studies on the selectivity of proline hydroxylases reveal new substrates including bicycles
Smart, Tristan J.,Hamed, Refaat B.,Claridge, Timothy D.W.,Schofield, Christopher J.
supporting information, (2019/11/26)
Studies on the substrate selectivity of recombinant ferrous-iron- and 2-oxoglutarate-dependent proline hydroxylases (PHs) reveal that they can catalyse the production of dihydroxylated 5-, 6-, and 7-membered ring products, and can accept bicyclic substrates. Ring-substituted substrate analogues (such hydroxylated and fluorinated prolines) are accepted in some cases. The results highlight the considerable, as yet largely untapped, potential for amino acid hydroxylases and other 2OG oxygenases in biocatalysis.
Synthetic methods for (1S,4S)-2,5-diazabicyclo[2.2.2] octane and derivatives thereof
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Paragraph 0068; 0069; 0070, (2016/12/16)
The invention discloses synthetic methods for (1S,4S)-2,5-diazabicyclo[2.2.2] octane and derivatives thereof, and belongs to the field of organic chemical synthesis. According to the method, 5-hydroxypyrazine-2-formate as a compound II is taken as a raw material, and high selectivity of a reaction is guaranteed through selective protection of hydroxyl and amino groups. A product obtained with the method has high yield, the by-product content is low, and the method is applicable to industrial production.