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

Abstract

A 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.

Keywords: amino acids; epoxidation; fluorination; hydroxylation; stereoselective reaction.

Scheme 1

Synthesis of all-cis ethyl 4-hydroxylated β-aminocyclohexanecarboxylate 5.

Figure 1

ORTEP diagram of iodooxazinone 2. Thermal ellipsoids have been drawn at the 20 % probability level.

Figure 2

ORTEP diagram of hydroxylated amino ester 5. Thermal ellipsoids have been drawn at the 20% probability level.

Scheme 2

Syntheses of fluorinated amino esters 7 and 9.

Scheme 3

Synthesis of ethyl 4-hydroxy-β-aminocyclohexanecarboxylate 14.

Figure 3

ORTEP diagram of iodooxazinone derivative 12. Thermal ellipsoids have been drawn at the 20% probability level.

Figure 4

ORTEP diagram of hydroxylated amino ester 14. The water molecule oxygen atom O4 is situated on the twofold axis with a population parameter of 0.6. Thermal ellipsoids have been drawn at the 20% probability level.

Scheme 4

Syntheses of fluorinated amino esters 16 and 18.