Multigram Preparation of BRD4780 Enantiomers and Assignment of Absolute Stereochemistry

  • J Org Chem. 2021 Mar 5;86(5):4281-4289. doi: 10.1021/acs.joc.0c02520.
Brian T Chamberlain  1 ,  Mathilde Vincent  1 ,  Jordan Nafie  2 ,  Peter Müller  3 ,  Anna Greka  4  5 ,  Florence F Wagner  1
Affiliations
  • 1. Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
  • 2. BioTools, Inc., 17546 Bee Line Highway, Jupiter Florida 33458, United States.
  • 3. Massachusetts Institute of Technology, Massachusetts Avenue 2-235, Cambridge, Massachusetts 02139, United States.
  • 4. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States.
  • 5. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 33618515 DOI: 10.1021/acs.joc.0c02520
Abstract

The development of a multigram synthesis of 3-exo-isopropylbicyclo[2.2.1]heptan-2-endo-amine hydrochloride (1) (also known as BRD4780 and AGN-192403) is described. The process involves protection of the amine as 4-nitrobenzyl carbamate, pNZ, which enables chiral SFC chromatography. The absolute configuration (AC) of the individual enantiomers has been determined by Mosher's amide method, VCD spectroscopy, and X-ray crystallography. We highlight the VCD approach as a rapid and effective means of AC determination that can be deployed directly on the target compounds.

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