- Development of a Stereoselective Synthesis of (1 R,4 R)- and (1 S,4 S)-2-Oxa-5-azabicyclo[2.2.2]octane
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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.
- 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
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supporting information
(2021/07/01)
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- METHODS OF USING RAD51 INHIBITORS FOR TREATMENT OF PANCREATIC CANCER
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This application is directed to inhibitors of RAD51 represented by the following structural formula, and methods for their use, such as to treat pancreatic cancer.
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Paragraph 1238-1240
(2021/01/22)
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- RAD51 Inhibitors
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This application is directed to inhibitors of RAD51 represented by the following structural formula, and methods for their use, such as to treat cancer, autoimmune diseases, immune deficiencies, or neurodegenerative diseases.
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Paragraph 0539-0540
(2019/03/30)
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- Synthetic methods for (1S,4S)-2,5-diazabicyclo[2.2.2] octane and derivatives thereof
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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.
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Paragraph 0068; 0069; 0070
(2016/12/16)
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