Preparation of racemic and enantiomerically enriched α-trifluoromethyl lactic acid amide [NHPh, NH(4-Cl-C6H5), NHBn, NHt-Bu] derivatives have been developed. Ph, 4-Cl-C6H5, and tert-Bu derivatives were found to have substantial magnitude of the self-disproportionation of enantiomers (SDE) via sublimation. For example, when the optically enriched Ph, 4-Cl-C6H5, and tert-Bu amide derivatives were subjected to sublimation under kinetic conditions (Petri dish in open air), the enantiomeric excess of the remainder has noticeably increased. On the other hand, the SDE of Bn amide derivative by sublimation resulted in almost no change in the optical purity of the remainder. These preliminary results on the SDE of the compounds under study, as well as their excellent chemical and physico-chemical characteristics, render these amide derivatives as readily available and very promising substrates for systematic study of SDE via sublimation.N-Phenyl-, N-(4-Cl-C6H5)-, and N-tert-Bu-α-trifluoromethyl lactic acid amides were found to strongly exhibit the phenomenon of self-disproportionation of enantiomers (SDE) via sublimation. The results described in this paper support the hypothesis that compounds containing –CF3 group directly bonded to a stereogenic carbon center can induce a SDE effect.

Preparation of racemic and enantiomerically enriched N-phenyl- and N-benzyl-3,3,3-trifluorolactic acid amides has been developed. These compounds were found to have substantial magnitude of the self-disproportionation of enantiomers (SDE) via sublimation. For example, when N-phenyl-3,3,3-trifluorolactic acid amide of 87% ee was sublimed (12 h) from a Petri dish at 80 °C open to the atmosphere, the enantiomeric excess of the remainder increased to 96% ee. On the other hand, when a sample of the same compound of 67% ee was subjected to SDE via sublimation under the same conditions, the enantiomeric excess has decreased to 18% ee. These preliminary results as well as excellent chemical and physico-chemical characteristics of these amide derivatives render them as readily available and very promising substrates for systematic study of SDE via sublimation.N-Phenyl- and N-benzyl-3,3,3-trifluorolactic acid amides were found to strongly exhibit the phenomenon of self-disproportionation of enantiomers (SDE) via sublimation. The results described in this paper support the hypothesis that compounds containing –CF3 group directly bonded to a stereogenic carbon center can induce an SDE effect.

The presented results convincingly demonstrate that self-disproportionation of enantiomers via sublimation is substantially more complex phenomenon then was previously believed. We demonstrate that the racemic form of isopropyl 3,3,3-trifluoro-2-hydroxypropanoate (1) sublimed faster regardless of the starting enantiomeric composition of the enantiomerically enriched mixtures studied in the range from 20.8, 36.8, 58.7 to 79.4% ee. This preferential sublimation of the racemic form allowed for, the most possibly simple, preparation of optically pure samples of compound 1. In this work we also suggest some general experimental procedures, which may be easily used to facilitate the interpretation of the data collected in different laboratories.

This study present a full account of continuous-flow reaction conditions for biomimetic reductive amination of fluorinated carbonyl compounds to corresponding amines and amino acids of biomedical importance. We demonstrate that simple silica-adsorbed DBU can be used as efficient catalysts for on-column 1,3-proton shift reaction, a key transformation in the biomimetic reductive amination process. This new on-column process features operationally convenient conditions, higher chemical yields, enantioselectivity and purity of the corresponding products as compared with traditional in-flask reactions. Moreover the removal of base-catalyst, the most delicate problem of the in-flask reactions, is not an issue in the on-column process, as the silica-adsorbed DBU or polymer-bound guanidine remains on the column and can be reused. This feature renders the overall process substantially more economical and synthetically efficient, in particular, for large-scale synthesis of the corresponding fluorinated amines and amino acids target.

This review article provides a critical overview of several different synthetic approaches developed for asymmetric preparation of fluorine-containing amines, amino alcohols, α- and β-amino acids. The common feature of these methods is the application of sulfinyl group as a chiral auxiliary to control the stereochemical outcome of the reactions under study. In particular, the following general methods are critically discussed: diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto-γ-fluoroalkyl sulfoxides as a general approach for preparation of various α-fluoroalkyl α-sulfinylalkyl oxiranes. The resulting compounds were used as true chiral synthons for their further elaboration via oxidative or reductive desulfurization, to numerous fluorine-containing and biologically relevant amino- and hydroxy-containing derivatives. Another general approaches discussed here are asymmetric additions to CN double bond. One of them is addition of chiral sulfoxide stabilized carbon nucleophiles to fluorine-containing imines, leading to convenient preparation of alpha-fluoroalkyl derivatives of alpha amino acids and amines. Another approach is asymmetric Reformatsky reaction between N-sulfinyl imines and ethyl bromodifluoroacetate allowing operationally convenient preparation of α,α-difluoro-β-amino acids in enantiomerically pure form. Finally, structurally similar but mechanistically different addition reactions of diethyl difluoromethylphosphonate to N-sulfinyl imines, as a general approach to asymmetric synthesis of α,α-difluoro-β-aminophosphonates and phosphonic acids, are discussed. Effect of fluorine on the mechanism and stereochemical outcome of these reactions is discussed in detail and compared, where it is possible, with that of the analogous reactions of fluorine-free substrates.

The preliminary results presented in this work show that an enantiomer purification approach based on SDE via sublimation can be extended to non-volatile liquid compounds such as α-(phenyl)ethylamine and its β-fluoro-derivatives by way of their rational modification with a sublimation enabling tag. 3,3,3-Trifluoro-2-(trifluoromethyl)-2-methyl-propanoic acid was found to perfectly serve the role of such a modifying tag. Thus, the corresponding amides derived from the amines and the fluorinated propanoic acid were highly crystalline and reasonably volatile compounds allowing for their sublimation at room temperature under normal pressure. All of these derivatives showed substantial self-disproportionation of enantiomers (SDEs) via sublimation under kinetic conditions (on a Petri dish in the open air). These preliminary results serve as a proof of a new principle that may extend the generality of enantiomer purification via sublimation to various organic compounds with physico-chemical properties of which render them otherwise unsuitable for a sublimation procedure. In particular, the very attractive cost structure of sublimation procedure renders this approach of potentially high practical and economic efficiency.The concept of rational application of self-disproportionation of enantiomers (SDEs), via sublimation, presented here is operationally simple and should be applicable for chiral compounds of virtually any physico-chemical properties. In particular, very attractive cost structure of sublimation procedure renders this approach of potentially high practicality and economical efficiency.2,2-Ditrifluoromethyl-N-(2,2,2-trifluoro-1-phenylehtyl)-propamideC13H10F9NO[α]D23=-68.1 (c 0.73, CHCl3).Source of chirality: (R)-2,2,2-Trifluoro-1-phenylethylamineAbsolute configuration: R2,2-Ditrifluoromethyl-N-(2,2-difluoro-1-phenylehtyl)-propamideC13H11F8NO[α]D23=-60.9 (c 0.99, CHCl3).Source of chirality: (R)-2,2,2-Trifluoro-1-phenylethylamineAbsolute configuration: R2,2-Ditrifluoromethyl-N-(1-phenylehtyl)propamideC13H13F6NO[α]D23=+56.1 (c 0.05, CHCl3).Source of chirality: (R)-1-phenylethylamineAbsolute configuration: R

This work has demonstrated that a previously unexplored approach to separation of enantiomers via formation of diastereomeric derivatives with three stereogenic centers has obvious practical potential and deserves further systematic study. The design reported here is based on the unusual application of a configurationally unstable stereogenic nitrogen, which plays a key role in setting up the stereochemical match between the three stereogenic centers in the corresponding products.

The presented results and the available literature data convincingly suggest that there is a new sterically driven mechanism for the formation of supramolecular helicity in the solid state. This mechanism requires the presence of sterically bulky groups, such as tert-butyl, for which the spiral arrangement in uninterrupted hydrogen-bonding chains, serving as an axis for helical structure and maximizing the repulsive stereochemical interactions, provide for the most efficient, spatially economical accommodation of these groups in a crystallographic unit cell.

This study has demonstrated that conceptually new continuous-flow reaction procedure for biomimetic transamination of perfluoroalkyl-containing ketones is substantially more efficient as compared with conventional in-flask approach, allowing preparation of the target fluorinated amines with generally improved chemical yields and enantioselectivity.

This study presents the first example of continuous-flow reaction conditions for biomimetic reductive amination of fluorinated carbonyl compounds using silica-adsorbed DBU as catalyst for on-column process. This new on-column process features operationally convenient conditions, higher chemical yields and purity of products as compared with traditional in-flask reactions. Furthermore the removal of base-catalyst is not an issue in this process at all, as the catalyst (DBU) remains on the column in the “reaction zone”, the feature which makes the overall process substantially more efficient and inexpensive, in particular, for large-scale synthesis of the target α-perfluoroalkyl amines.

The functionalized pyroglutamate core unit, (2R,4R)-3, which could be converted into the β-lactone/pyrrolidine or γ-lactone/pyrrolidine ring system of oxazolomycin A 1 and neooxazolomycin 2, and which possesses an exomethylene group at C3 as a scaffold for the construction of their C3 polyene segment, was synthesized by the Michael reaction of a glycine Schiff base 4 with the α,β-disubstituted acrylate 8 as the key step.(R)-3-((E)-4-(Benzyloxy)but-2-enoyl)-4-phenyloxazolidin-2-oneC20H19NO4[α]D20.9=-69.9 (c 1.07, CHCl3)Source of chirality: (R)-α-phenylglycineAbsolute configuration: (R)(2R,3R)-Methyl 3-((benzyloxy)methyl)-5-oxopyrrolidine-2-carboxylateC14H17NO4[α]D27.0=-27.3 (c 1.0, CHCl3)Source of chirality: (R)-α-phenylglycineAbsolute configuration: (2R,3R)(S)-3-((E)-4-(Benzyloxy)-2-methylbut-2-enoyl)-4-phenyloxazolidin-2-oneC21H21NO4[α]D20.5=+12.9 (c 0.77, CHCl3)Source of chirality: (R)-α-phenylglycineAbsolute configuration: (S)N-(2-Benzoyl-phenyl)-2-piperidyl-acetamide Ni(II) complex of (2S,3S,4R,4′S)-3-benzyloxymethyl-4-methyl-5-[3′-(4′-phenyl-2′-oxazolidinonyl)] glutamic acid schiff baseC43H44N4O7Ni[α]D21.2=+2376.3 (c 0.4, CHCl3)Source of chirality: (S)-4-phenyloxazolidin-2-oneAbsolute configuration: (2S,3S,4R,4′S)(2S,3S,4R)-3-((Benzyloxy)methyl)-4-methyl-5-oxopyrrolidine-2-carboxylic acidC14H17NO4[α]D25.7=+24.3 (c 1.0, CHCl3)Source of chirality: (–)-verbenone and stereoselective synthesisAbsolute configuration: (2S,3S,4R)(2S,3S,4R)-tert-Butyl 3-((benzyloxy)methyl)-4-methyl-5-oxopyrrolidine-2-carboxylateC18H25NO4[α]D25.4=+14.9 (c 1.4, CHCl3)Source of chirality: (–)-verbenone and stereoselective synthesisAbsolute configuration: (2S,3S,4R)(2S,3S,4R)-tert-Butyl-3-((benzyloxy)methyl)-1,4-dimethyl-5-oxopyrrolidine-2-carboxylateC19H27NO4[α]D26.1=+25.8 (c 1.1, CHCl3)Source of chirality: (–)-verbenone and stereoselective synthesisAbsolute configuration: (2S,3S,4R)((2S,3S,4R)-2-(tert-Butoxycarbonyl)-1,4-dimethyl-5-oxopyrrolidin-3-yl)methyl methyl carbonateC14H23NO6[α]D27.0=+27.5 (c 3.4, CHCl3)Absolute configuration: (2S,3S,4R)(3R,3aS,6aR)-tert-Butyl-hexahydro-1,3-dimethyl-2,6-dioxo-1H-furo[3,4-b]pyrrole-6a-carboxylateC13H19NO5[α]D25.1=+88.7 (c 1.8, CHCl3)Absolute configuration: (3R,3aS,6aR)(2R,3S,4R)-2-tert-butyl 2-methyl 1,4-dimethyl-5-oxo-3-((phenylselanyl)methyl) pyrrolidine-2,2-dicarboxylateC20H27NO5Se[α]D26.7=-52.8 (c 0.9, CHCl3)Absolute configuration: (2R,3S,4R)(2R,4R)-2-tert-Butyl 2-methyl 1,4-dimethyl-3-methylene-5-oxopyrrolidine-2,2-dicarboxylateC14H21NO5[α]D25=-84.0 (c 1.3, CHCl3)Absolute configuration: (2R,4R)(2R,4R)-tert-Butyl 2-(hydroxymethyl)-1,4-dimethyl-3-methylene-5-oxopyrrolidine-2-carboxylateC13H21NO4[α]D25=-85.7 (c 1.2, CHCl3)Absolute configuration: (2R,3S,4R)

The standard reaction conditions commonly used for the condensation of carbonyl compounds with amines were found to be synthetically inefficient for preparation of the imines derived from trifluoroacetophenone and benzylamines owing to the susceptibility of these imines to 1,3-proton shift. Application of a “low-basicity” method, using instead of free benzylamines their salts formed from acetic acid (AA), allowed synthesis of the target compounds in chemically pure form and excellent chemical yields.Graphic