Abstract:Hitherto unknown cis‐ and trans‐1‐amino‐3‐fluoro‐3‐methylcyclobutanecarboxylic acids were synthesized as pure diastereomers starting from diisopropyl 3‐oxocyclobutane‐1,1‐dicarboxylate. While pKa values of the carboxylic acid functions are the same for both stereoisomers (pKa = 2.80), the values for the amino groups are slightly different (8.46 or 8.77, respectively) presumably because of different interactions with the fluorine atoms.
“…Stereoselective access to cyclobutane and cyclobutane derived amino acids has been pursued by several groups [ [129] , [130] , [131] ]. One example was reported by Haufe and co-workers who disclosed the synthesis of cis‐and trans‐1‐amino‐3‐fluoro‐3‐methylcyclobutanecarboxylic acids in 2016 ( Scheme 36 ) [ 132 ]. Starting from the commerically available oxo-ester 178 , methylation using AlCl 3 was carried out to generate hydroxyl containing 179 in 69 % yield.…”
“…Interestingly it was found that the amino groups of the two stereiosomers of 184 displayed different basicities whilst the carboxylic acid moiteies of the same compound had identical basicity profiles. Scheme 36 Synthesis of cis‐and trans‐1‐amino‐3‐fluoro‐3‐methylcyclobutanecarboxylic acids by Haufe and co-workers [ 132 ]. …”
“…Stereoselective access to cyclobutane and cyclobutane derived amino acids has been pursued by several groups [ [129] , [130] , [131] ]. One example was reported by Haufe and co-workers who disclosed the synthesis of cis‐and trans‐1‐amino‐3‐fluoro‐3‐methylcyclobutanecarboxylic acids in 2016 ( Scheme 36 ) [ 132 ]. Starting from the commerically available oxo-ester 178 , methylation using AlCl 3 was carried out to generate hydroxyl containing 179 in 69 % yield.…”
“…Interestingly it was found that the amino groups of the two stereiosomers of 184 displayed different basicities whilst the carboxylic acid moiteies of the same compound had identical basicity profiles. Scheme 36 Synthesis of cis‐and trans‐1‐amino‐3‐fluoro‐3‐methylcyclobutanecarboxylic acids by Haufe and co-workers [ 132 ]. …”
“…Continuing our previous investigations on new 3-substituted cyclobutyl amines and amino acids, we present here multigram syntheses of other hitherto unknown α-aminocyclobutane carboxylic acids, 1-amino-3-hydroxy-3-methylcyclobutanecarboxylic acids cis - and trans -10 which can be considered as conformationally restricted analogues of threonine, where the rigid cyclobutane ring is a bioisostere of the C–C single bond (Figure ). Compounds cis - and trans - 10 are achiral due to the plane of symmetry while threonine contains two stereogenic centers.…”
mentioning
confidence: 92%
“…The synthesis started from commercially available ketoester 11 (Scheme ), which was methylated with AlMe 3 using a previously validated procedure . The following monohydrolysis proceeded stereoselectively: only the cis -monoester 13 was isolated in diastereomerically pure form.…”
Hitherto unknown cis- and trans-1-amino-3-hydroxy-3-methylcyclobutanecarboxylic acids were synthesized in multigram scale. The obtained compounds can be considered as achiral conformationally restricted analogues of threonine with fixed spatial orientation of functional groups. pK values are noticeably different for both amino acids. According to the X-ray data the cyclobutane rings in both compounds are almost planar (the corresponding torsion angles are below 7°).
The introduction of fluorine atoms into molecules and materials across many fields of academic and industrial research is now commonplace, owing to their unique properties. A particularly interesting feature is the impact of fluorine substitution on the relative orientation of a C−F bond when incorporated into organic molecules. In this Review, we will be discussing the conformational behavior of fluorinated aliphatic carbo‐ and heterocyclic systems. The conformational preference of each system is associated with various interactions introduced by fluorine substitution such as charge‐dipole, dipole‐dipole, and hyperconjugative interactions. The contribution of each interaction on the stabilization of the fluorinated alicyclic system, which manifests itself in low conformations, will be discussed in detail. The novelty of this feature will be demonstrated by presenting the most recent applications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
