Efficient regio- and stereoselective access to novel fluorinated β-aminocyclohexanecarboxylates

Abstract

SummaryA regio- and stereoselective method has been developed for the synthesis of novel fluorinated 2-aminocyclohexanecarboxylic acid derivatives with the fluorine attached to position 4 of the ring. The synthesis starts from either cis- or trans-β-aminocyclohex-4-enecarboxylic acids and involves regio- and stereoselective transformation of the ring C–C double bond through iodooxazine formation and hydroxylation, followed by hydroxy–fluorine or oxo–fluorine exchange.

Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: a patent evaluation of WO2014072419

“…With the advent of safe and selective fluorinating agents and rapid development of the synthesis methodology of asymmetric fluorination [57,58], there is still great scope for the exploitation of compounds featuring a fluorine atom on (or around) a suitable stereocenter in the key pharmacophoric site of promising NNRTI scaffolds. …”

Selective Synthesis of Fluorine‐Containing Cyclic β‐Amino Acid Scaffolds

“…The synthetic method towards monofluorinated and difluorinated β‐amino esters involving hydroxylation via iodine‐induced cyclization through iodooxazine formation was efficiently extended to the synthesis of six‐membered analogs (±)‐52 , (±)‐53, (±)‐54 and (±)‐55 (Figure ) …”

“…The regioselectivity of the oxirane opening in (±)‐63 , again, may be explained on the basis of the favored diaxial chair conformation as discussed above. Hydroxylated amino ester (±)‐73 in reaction with Deoxofluor afforded the corresponding fluorinated cyclohexane amino ester (±)‐74 (Scheme ) . Noteworthy, compound (±)‐74 was also synthetized on an alternative route through the iodooxazination methodology.…”

Application of nucleophilic fluorinating reagents for the synthesis and transformations of cyclic β-amino acid derivatives

“…It raised the interest in the Institute of Pharmaceutical Chemistry, and a high number of such derivatives were synthesized from unsaturated bicyclic β-lactams. [25][26][27][28][29][30][31][32][33][34] Usually, the first step was regio-and stereo-selective introduction of a hydroxy group followed by either hydroxy-fluorine exchange or oxidation into keto derivatives and subsequent carbonyl→difluoromethylene transformation. [25][26][27][28][29]31,33] A new aziridine ring-opening method with XtalFluor-E was developed too.…”

“…With the help of nucleophilic fluorinating reagents, preparation of a high number of such derivatives was accomplished. [25][26][27][28][29][30][31][32][33][34] The present PhD work focused on the synthesis of various types of fluorinated functionalized cyclic β-amino acid derivatives. The aim of the research was to obtain such compounds through new synthetic pathways starting from selectively epoxidated or dihydroxylated cyclic β-amino acid derivatives, utilizing deoxyfluorinating reagents.…”