Desymmetrization and degree of chirality

Chiral objects, viewed as distorted derivatives of achiral ones, may be represented by points in a configuration space that is spanned by a set of symmetry coordinates derived for the symmetry group of the achiral object of highest symmetry. We propose a measure (d) that quantifies the displacement of the representative point for a chiral object away from thenearest point representing an achiral object in such a multi-dimensional configuration space. If the symmetry coordinates are chosen so as to yield a similarity invariant measure, then the valuesd; obtained for a series ofi chiral objects can serve as a basis for comparing the degrees of chirality of these objects. The chirality of triangles inE ² is studied by this method, and it is shown that the most chiral triangle in terms of this measure corresponds to one that is infinitely flat, and that may be approached but is never attained. This result is compared to others obtained previously for the same system by the use of different measures of chirality.On leave from the Department of Chemistry, University of the Western Cape, Bellville 7530, South Africa.     

Copper-Catalyzed Asymmetric Sulfonylative Desymmetrization of Glycerol

Glycerol is the main side product in the biodiesel manufacturing process, and the development of glycerol valorization methods would indirectly contribute the sustainable biodiesel production and decarbonization. Transformation of glycerol to optically active C3 units would be one of the attractive routes for glycerol valorization. We herein present the asymmetric sulfonylative desymmetrization of glycerol by using a CuCN/(R,R)-PhBOX catalyst system to provide an optically active monosulfonylated glycerol in high efficiency. A high degree of enantioselectivity was achieved with a commercially available chiral ligand and an inexpensive carbonate base. The optically active monosulfonylated glycerol was successfully transformed into a C3 unit attached with differentially protected three hydroxy moieties. In addition, the synthetic utility of the present reaction was also demonstrated by the transformation of the monosulfonylated glycerol into an optically active synthetic ceramide, sphingolipid E.     

Desymmetrization of pibrentasvir for efficient prodrug synthesis

A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc protection and formaldehyde adduct formation sequence, both enabled by crystallization-induced selectivity. The first step represents the only known application of the Horeau principle of statistical amplification for C₂-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.

Horeau principle statistical amplification and solubility-driven selectivities allow C₂-desymmetrization of pibrentasvir without typically required internal functionalization or steric proximity effects.     

Desymmetrization of glycerol derivatives with peptide-based acylation catalysts

[reaction: see text] Nucleophile-loaded peptides have been evaluated as catalysts for the desymmetrization of glycerol derivatives through an enantioselective acylation process. Enantiomeric excesses of up to 97% have been obtained for the monoacylated products. A range of other substrates have been examined that shed light on the mechanistic basis of the desymmetrizations.     

Room-Temperature Alkyl-Diphenylpyrene Liquefication by Molecular Desymmetrization

Achieving the lowest phase transition temperature with minimal chemical modification in highly crystalline π-conjugated molecules is a universal problem in related research fields. This paper reports room-temperature liquefication of diphenylpyrene isomers by introducing bulky yet flexible branched alkyl chains through molecular desymmetrization. Six isomers with different symmetries depending on the positions of the phenyl groups and alkyl groups were synthesized, and three of the isomers were found to be liquids at 25 °C, a state in which they have remained for more than five years. Although it is generally believed that the lower the symmetry of a molecule, the less likely it is to crystallize, one molecule with a relatively high molecular symmetry unexpectedly did not crystallize, which was evidenced by the kinetic inhomogeneity of this amorphous material (practically stable liquid) assessed by rheological analysis.     

Desymmetrization of meso-dialdehydes with optically active cyclopentadienyldialkoxyallyltitanium complexes

Optically active cyclopentadienyldialkoxyallyltitanium complexes have been employed for the desymmetrization of meso-dialdehydes. Allylation of these dialdehydes and subsequent oxidation afford chiral lactones with good diastereoselectivity and excellent enantioselectivity.     

Desymmetrization of 1,4-cyclohexadienyltriisopropoxysilane using copper catalysis

The first catalytic desymmetrization in the field of allylsilane chemistry is presented. Desymmetrization of cyclohexadienyltriisopropoxysilane is achieved using coppper catalysis. High diastereo- and enantioselectivities are obtained, and the product dienes are highly valuable building blocks for natural product synthesis.     

Norbornanoid Chiral Ketones by Desymmetrization of Dibromoalkenes

New optically active polycyclic ketones 6a – 6d , amenable to a large variety of synthetic applications, have been prepared from readily available 2,3‐dibromonorbornene and analogs (Scheme 2) via desymmetrization with (?)‐ephedrine, followed by hydrolysis under mild acidic conditions. At variance with substrates 4a – 4d , the sterically hindered norbornene derivative 4e reacts with the solvent N‐methylpyrrolidin‐2‐one (NMP) leading to the formation of the unusual cyclopropanoid products 8a and 8b .     

Stereoselective Desymmetrization of gem-Diborylalkanes by “Trifluorination”

An efficient and general method for the chemoselective synthesis of unsymmetrical gem-diborylalkanes is reported. This method is based on a late-stage desymmetrization through nucleophilic “trifluorination”, providing chiral gem-diborylalkanes bearing a trifluoroborate group. The reaction offers a highly modular and diastereoselective approach towards the synthesis of gem-diborylcyclopropanes. The utility of the gem-diborylalkane building blocks was demonstrated by selective post-functionalization of the trifluoroborate group. These functionalizations include inter- and intra- Pd-catalyzed Suzuki–Miyaura coupling reactions.     

Desymmetrization of malonamides via an enantioselective intramolecular Buchwald-Hartwig reaction

A new form of enantioselective nitrogen arylation reaction is described. Beginning with symmetrical α-(2-bromobenzyl)malonamides, intramolecular palladium-catalyzed cross-coupling using a catalyst system including 3.3 mol % Pd(OAc)₂ and 6.6 mol % of the chiral biaryl monophosphine (R)-MOP, desymmetrized quinolinone products are obtained in nearly quantitative yields in enantiomeric ratios up to 88:12. This Letter represents a rare example of enantioselective Buchwald-Hartwig reaction.     

Desymmetrization of metallated cyclohexadienes with chiral N-tert-butanesulfinyl imines

This communication describes the desymmetrization of various achiral metallated cyclohexadienes with a series of chiral N-tert-butanesulfinyl imines. Depending on the metal used, either the symmetrical diene (dicyclohexadienyl-zinc) or the desymmetrized diene (cyclohexadienyl-MgCl) is obtained in a good regioselectivity with excellent diastereoselectivity. The products formed should be useful building blocks for natural product synthesis. The symmetrical 1,4-dienes are readily oxidized to the corresponding diarylmethylamine derivatives.     

Desymmetrization of 2,4,5,6-tetra-O-benzyl-D-myo-inositol for the synthesis of mycothiol

An efficient chemical synthesis of mycothiol involving the regioselective ketopinyl desymmetrization of 2,4,5,6-tetrabenzylated D-myo-inositol as the key step is described. Together with a highly α-stereoselective D-glucosaminylation, the whole procedure was accomplished in eight steps with an overall yield of 40%.     

外消旋化合物生物催化去对称化研究进展

手性化合物外消旋体的生物催化去对称化是目前生物与有机合成领域的重点、难点和热点,也是制备光学纯手性化合物的重要途径.我们将近年来发展起来的手性化合物生物催化去对称化的方法归纳为立体转化去对称化法、线性去对称化法、循环去对称化法、对映体收敛去对称化法和一步去对称化法5大类,对这些方法的原理、特点及其应用进展分别进行介绍,...     

Desymmetrization of meso-hydrobenzoin using chiral, nucleophilic phosphine catalysts

The desymmetrization of meso-hydrobenzoin is described using chiral phosphine catalysts 8b-d and 9-11. The best enantioselectivity at room temperature was obtained with the newly synthesized phospholane 8c and benzoic anhydride, but the reaction is very slow. Much faster reactions, but somewhat lower enantioselectivities were observed using the bicyclic phosphine catalyst 9. To obtain product 5a with >90% ee required conditions where the ee is upgraded due to the formation of the dibenzoate 6a. Among the new phospholane catalysts, 8b has the best selectivity in the kinetic resolution of benzylic alcohols, but not at the level observed previously with catalyst 11.     

Enantioselective Desymmetrization of 1,4-Dihydropyridines by Oxidative NHC Catalysis

The unprecedented desymmetrization of prochiral dialdehydes catalyzed by N-heterocyclic carbenes under oxidative conditions was applied to the highly enantioselective synthesis of 1,4-dihydropyridines (DHPs) starting from 3,5-dicarbaldehyde substrates. Synthetic elaboration of the resulting 5-formyl-1,4-DHP-3-carboxylates allowed for access to the class of pharmaceutically relevant 1,4-DHP-3,5-dicarboxylates (Hantzsch esters). DFT calculations suggested that the enantioselectivity of the process is determined by the transition state involving the oxidation of the Breslow intermediate by the external quinone oxidant.     

Desymmetrization of meso-dienyne by asymmetric Pauson-Khand type reaction catalysts

Desymmetrization of the meso dienynes, such as propargyl 1-vinylallyl N-tosylamides (1a-c) and propargyl 1-vinylallyl ethers (1d-e), by asymmetric Pauson-Khand type reaction catalysts was studied. The corresponding vinyl substituted bicyclic pentenones (2 and 3) were obtained with high diastereoselectivity and enantioselectivity.     

Desymmetrization of spiro-activated meso-cyclopropanes via nucleophilic substitution

The spiro-activated cyclopropane 1 undergoes desymmetrization either with Li-thiophenoxide in the presence of a chiral complexing ligand, or with ion pairs formed from thiophenols and aromatic chiral amines. The latter procedure is more efficient and provides the ring-opened thioether 6 in up to 79% yield and up to 60% ee.