Org. Process Res. Dev. 2019, 23, 1970. DOI:10.1021/acs.oprd.9b00245
◆The first-generation route to fluoropyrrolidine 1 was used to support exploratory toxicology and was processed on a 250 g scale.
◆As an alternative to the first-generation approach to the chiral fluoropyrrolidine, 1 can be accessed from C2-symmetric pyrrolidine diol 10
◆A more efficient method for selective double displacement of the two hydroxyls was found in methodology developed by Nicolaou that involved conversion of diol 10 to cis-cyclic sulfamate 22 by reaction with 2 equiv of the Burgess reagent 20. The C2-symmetric nature of the trans-diol results in the formation of a single enantiomer of the sulfamate while activating the remaining C−O bond for a second nucleophilic substitution by a fluoride nucleophile.
◆The Burgess reagent 20 and 25 had poor stability when heated under the reaction conditions, which led to poor conversion and the formation of side products.
◆We were able to track the decomposition of 25 through in situ IR monitoring.
◆We investigated an alternate order of addition while using in situ IR monitoring to determine intermediate stability and found that carbamate 28 was stable at 10°C for up to 24 h
◆Unfortunately, the rate of ring opening by liberated chloride is competitive with cyclization. As a result, we observed high levels of chloro side product 29 (10−30%). This degradant can be avoided by removal of the HCl·TEA salt through filtration
◆Fluorination with TBAF initially forms tetrabutylammonium sulfamate salt 30, which is fully soluble in the reaction mixture. Acidification leads to sequential formation of zwitterionic species 31, loss of the sulfamate group to generate Boc-protected amine 32, and finally Boc deprotection of the nitrogen and formation of free amine 1.
◆An alternative process was designed to isolate the zwitterion intermediate 31 in order to gain an additional purge point for process impurities and provide more flexibility in the choice of the salt form of deprotected amine 1.
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