Effective chiral pool synthesis of both enantiomers of the TRPML inhibitor trans-ML-SI3
- PMID: 34738656
- DOI: 10.1002/ardp.202100362
Effective chiral pool synthesis of both enantiomers of the TRPML inhibitor trans-ML-SI3
Abstract
Two independent chiral pool syntheses of both enantiomers of the TRPML inhibitor, trans-ML-SI3, were developed, starting from commercially available (1S,2R)- and (1R,2S)-configured cis-2-aminocyclohexanols. Both routes lead to the target compounds in excellent enantiomeric purity and good overall yields. For the most attractive (-)-trans-enantiomer, the R,R-configuration was identified by these unambiguous syntheses, and the results were confirmed by single-crystal X-ray structure analysis. These effective synthetic approaches further allow flexible variation of prominent residues in ML-SI3 for future in-depth analysis of structure-activity relationships as both the piperazine and the N-sulfonyl residues are introduced into the molecule at late stages of the synthesis.
Keywords: TRPML cation channels; arylpiperazine; chiral pool synthesis; enantiomers; sulfamidate.
© 2021 The Authors. Archiv der Pharmazie published by Wiley-VCH Verlag GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.
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References
REFERENCES
-
- D. E. Clapham, Nature 2003, 426, 517.
-
- I. S. Ramsey, M. Delling, D. E. Clapham, Annu. Rev. Physiol. 2006, 68, 619.
-
- M. Gees, G. Owsianik, B. Nilius, T. Voets, Compr. Physiol. 2012, 2, 563.
-
- X. Cheng, D. Shen, M. Samie, H. Xu, FEBS Lett. 2010, 584, 2013.
-
- H. Xu, D. Ren, Annu. Rev. Physiol. 2015, 77, 57.
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