Synthesis of Fluorinated β-Amino Acids

Abstract

The major goal of this review is to provide an overview of the general synthetic methods available in the literature for preparing fluorinated b-amino acids and their derivatives. These compounds have been employed in combination with non-fluorinated amino acids in the design of peptides and peptidomimetics for investigation of their proteolytic stability and influence of molecular composition on the folding properties and biological activity. Fluorinated b-amino acids serve as precursors for the b-lactam antibiotics and fluoroalkene dipeptide isosteres or as structural components of analogues of natural products. There are several general methods available for introducing into b-amino acids either one or two fluorine atoms at the a-position, as well as a-or b-fluoroalkyl substituents; these methods include reduction of fluorinated b-imino esters, biomimetic transamination of fluorinated carbonyl compounds, Michael-type addition to trifluorocrotonate and a-trifluoromethacrylate derivatives, and Reformatsky and Mannich-type reactions of fluorinated substrates. Fluorinated aziridines and b-lactams have been employed as synthetic intermediates for the preparation of the corresponding b-amino acids by facile ring-opening reactions. Other methods discussed in review are fluorination and trifluoromethylation of b-amino acid derivatives, reactions of organometallic reagents with fluorinated imines and related compounds, and metathesis reactions of fluorinated imino esters and imidoyl halides for the synthesis of cyclic derivatives.

Concise Asymmetric Synthesis of β‐Trifluoromethylated α,β‐Diamino Esters through Addition Reactions of Glycine Esters to CF3‐Sulfinylimine

“…White 167.0, 150.4, 138.6, 135.8, 131.4, 129.6, 129.4, 129.0, 128. ν = 1778, 1628, 1476, 1447, 1291, 1262, 1214 ν = 1750, 1625, 1485, 1410, 1266, 1204, 1169, 1145, 1128, 1091, 1068, 1012, 879 13 …”

“…ppm 13. C NMR (101 MHz, CDCl 3 ): δ = 174.5, 167.2, 148.2, 138.6, 136.1, 135.8, 131.3, 130.1, 129.3, 129.0, 128.9, 128.3, 127.2, 124.5 (q, J = 284.9 Hz), 120.7, 64.0, 59.5 (q, J = 29.8 Hz), 57.5, 22.7, 20.9 ppm.…”

Self‐disproportionation of Enantiomers (SDE) of Chiral Nonracemic Amides via Achiral Chromatography

“…Thes elf-disproportionation of enantiomers (SDE) [1] constitutes the nonlinear propertyo fc hiralc ompounds,l eading to the separation, spontaneous or rationally designed, of an onracemic (scalemic) sample into proportionally enantiomerically enriched and depletedp ortions. [2][3][4][5] SDE refers to the end result, that is,t he simultaneous formation of the correspondingly enantiomerically enriched and depletedf ractions, under totally achiral conditions. Them ost commonly knownc ase of SDE is the fractional crystallization of nonracemic compounds.…”

“…[16] Similarlyt ot he distinct crystallographic structures ob-served in the solid state,c hiral compounds in the liquid state or in solution showw ell-defined preferencesf or homochiral/heterochiral dynamicm olecular associations,a ccountingf or various nonlinear effects, [17][18][19][20] including SDE via chromatography. [3][4][5]15,[21][22][23][24] Thus,w hen as olution of an onracemic compoundi ss ubjectedt oc hromatography, such dynamic homochiral/heterochiral moleculara ssociations,h aving very differentc hromatographic behaviour, as compared with the corresponding monomers,r esult in the eluted material of gradually decreasing or increasing variable enantiomeric composition. Since intermolecular interactions are af undamental property of all chemical compounds,S DE is of absolute generality,a lwayso ccurring when an onracemic sample is subjected to physicochemical phase-transitions or chromatography.H owever, the observed magnitude of the nonlineare ffects is af unction of the quality of the corresponding homochiral/heter- ochiral interactions, and therefore heavily depends on ap articular chiralc ompound structure.I np ractical terms, the easiness of SDE observation depends on its magnitude underp articular chromatographic conditions.U nder routinelyu sed conditions of gravity-driven column chromatography,t he difference between enantiomerically enriched and depletedf ractions is usually low (~10 %e nantiomeric excess, ee), precluding the discovery of SDE via achiral chromatography until relativelyr ecently.…”

“…[26] On the other hand, considering the direct relation of amino acids to the emergence of life,t hey put forward an idea that such processesc an work under totally naturalp rebiotic conditions,p roviding significant amounts of highly enantiomerically enriched compounds,l eading eventuallyt ob iological homochirality. [10] This pioneering work was followed by numerous other examples of SDE via achiral chromatography, [1,[3][4][5] as well as the theoretical modelling of chromatographic behaviour of nonracemic compoundsu nder various conditions of achiral chromatography. [27][28][29][30][31][32][33][34] As predicted by Charles and Gil-Av, SDE via achiralc hromatography turned out to be ar emarkably comprehensivep henomenon observed for virtually all types of chiral compounds containing central, [1][2][3][4][5]35] axial, [36][37][38] or helical [39] chirality.I nt his review article,c elebrating the scientificl egacy of ProfessorG il-Av,w ef ocus on our most recent research relating to the subjecto fh is seminal work in this area, [26,30] devoted to SDE via achiral chromatography of chiral amides,i ncluding somey et unpublished results.T he data presented and discussed in this review are divided to threem ajor groups, including amides derived from chiral amines, aamino acids,a nd b-amino acids.I ne ach group,w ed iscuss the observedS DE magnitude as af unction of ac ompoundss tructure,a nd composition of eluent and stationary phases.P articular emphasis is given to the examples which demonstrate the application of SDE via achiral chromatography as an unconventionalm ethod for enan- tiomeric purifications,a ffording,i nm ost of cases,b etter practicalo utcomest han with traditionalf ractional recrystallization.…”