Diastereomeric Mixture Research Articles

Catalytic Diastereo‐ and Enantioconvergent Synthesis of Vicinal Diamines from Diols through Borrowing Hydrogen

AbstractWe present herein an unprecedented diastereoconvergent synthesis of vicinal diamines from diols through an economical, redox‐neutral process. Under cooperative ruthenium and Lewis acid catalysis, readily available anilines and 1,2‐diols (as a mixture of diastereomers) couple to forge two C−N bonds in an efficient and diastereoselective fashion. By identifying an effective chiral iridium/phosphoric acid co‐catalyzed procedure, the first enantioconvergent double amination of racemic 1,2‐diols has also been achieved, resulting in a practical access to highly valuable enantioenriched vicinal diamines.

Meso-tetra(dioxanyl)porphyrins: Neutral, low molecular weight, and chiral porphyrins with solubility in aqueous solutions

The synthesis of the low-molecular weight, meso-tetra(dioxan-2-yl)porphyrin with considerable solubility in aqueous solution is described. The key intermediate dioxan-2-carbaldehyde is accessible in either racemic or in stereo-pure forms from commercially available starting materials in three steps. Using 4 × 1 or 2 + 2-type syntheses provide the porphyrin in modest yields. While the racemic aldehyde created an intractable mixture of diastereomers, the enantiopure aldehyde created a single enantiomer of the target porphyrin. The porphyrin was spectroscopically characterized. As its free base or zinc complex, it showed excellent solubility properties in organic and aqueous solvents, though free water-solubility was not achieved. The work expands on the availability of chiral porphyrins and neutral porphyrins with considerable solubility in aqueous solution.

Perimeter Coordinated Diastereomeric Rh(I) Complex of Helically Twisted Weakly Aromatic Hybrid Singly N-Confused β-β Fused Ferrocenoporphyrinoids.

Expedient synthesis, spectroscopic, solid state structural proof, and theoretical study of helically twisted weakly aromatic hybrid singly N-confused ferrocenoporphyrinoids and the peripheral coordinated Rh(I) complex are reported. The X-ray crystal structure of the macrocycles reveals an ambiguously inverted pyrrole ring reinforcing regioselective β,β-linkage with the spatially adjacent N-confused N-methyl pyrrole ring leading to endocyclic extension of macrocyclic π-conjugation via tricyclic [5.5.5] moiety. The three-dimensional structure with built-in fused tricyclic [5.5.5] moiety has paved way to three-dimensional weak diatropicity with vis-NIR absorptions. The peripheral coordinated Rh(I) complex owing to helical chirality about the macrocyclic ring and planar chirality about the square planar Rh coordination site exists as a mixture of diastereomers (5:3) with well resolved 1H NMR spectra anticipating weak aromaticity. The experimental spectroscopic measurements are in agreement with theoretically determined electronic structure and properties strongly elucidating sustained weak diatropic ring currents in twisted macrocycles both in neutral form and in the metalated complex. Further fragment molecular orbital approach and molecular orbital theory gave insights on the stability of N-confused β-β fused oxo-ferrocenoporphyrinoids and formation of the selective peripheral coordinated Rh(I) complex.

Single Diastereomers of the Clinical Anticancer ProTide Agents NUC-1031 and NUC-3373 Preferentially Target Cancer Stem Cells In Vitro.

A 3'-protected route toward the synthesis of the diastereomers of clinically active ProTides, NUC-1031 and NUC-3373, is described. The in vitro cytotoxic activities of the individual diastereomers were found to be similar to their diastereomeric mixtures. In the KG1a cell line, NUC-1031 and NUC-3373 have preferential cytotoxic effects on leukemic stem cells (LSCs). These effects were not diastereomer-specific and were not observed with the parental nucleoside analogues gemcitabine and FUDR, respectively. In addition, NUC-1031 preferentially targeted LSCs in primary AML samples and cancer stem cells in the prostate cancer cell line, LNCaP. Although the mechanism for this remains incompletely resolved, NUC-1031-treated cells showed increased levels of triphosphate in both LSC and bulk tumor fractions. As ProTides are not dependent on nucleoside transporters, it seems possible that the LSC targeting observed with ProTides may be caused, at least in part, by preferential accumulation of metabolized nucleos(t)ide analogues.

Total Synthesis of Homo- and Heterodimeric Bispyrrolidinoindoline Dioxopiperazine Natural Products.

Total synthesis and structural confirmation of homo- and heterodimeric bispyrrolidinoindoline dioxopiperazine alkaloids isolated from fungi and bacteria, namely, ditryptoleucine A, ditryptoleucine B (11), the N,N'-bis-demethylated analogue (+)-12, (-)-dibrevianamide F (13), (-)-SF-5280-451 (14), tetratryptomycin A (15), (-)-tryprophenaline (17), and (-)-SF-5280-415 (18), has been carried out starting from the corresponding bispyrrolidinoindolines derived from tryptophan. Our efforts to synthesize all possible diastereomers of the natural ditryptoleucine isolates uncovered structural factors that determine the rate and efficiency of dioxopiperazine ring formation, leading in some cases to mixtures of diastereomers by concomitant epimerization, to the formation of their putative monomeric dioxopiperazine dipeptide biogenetic precursors, and to the alternative formation of a dimer with a fused 1,3,5-triazepan-6-one heterocycle.

Reconstruction of Carbon Bond Frameworks via Oxapalladacycles Promoted by the Synergistic Effect of Palladium Catalyst and Triethylborane

AbstractPd-catalyzed β-carbon elimination of 3-hydroxy-4-pent­enoic acid derivatives promoted by triethylborane proceeds to form conjugated dienes via a decarboxylation process. The formed conjugated dienes undergo the Prins reaction with aldehydes in situ to afford conjugated homoallylic alcohols. These sequential transformations enable the conversion of diastereomeric mixtures of 3-hydroxy-4-pentenoic acids, which are readily prepared from the simple crossed aldol reaction of esters and α,β-unsaturated aldehydes, into 3,5-hexadienyl alcohols with high regio- and stereoselectivities in a single manipulation.

Hemi-synthesis, in-vitro and in-silico bioactivities of new chiral-Schiff bases and benzodiazepine derivatives from Ammodaucus leucotrichus(S)-perillaldehyde

A new series of benzodiazepines and chiral Schiff bases have been prepared by an in situ condensation of (S)-(-)-perillaldehyde, occurring naturally in the essential oil of Ammodaucus leucotrichus subsp. Leucotrichus, with various amines, hydrazines, and oxalyl dihydrazide. Pure enantiomeric compounds TK1-6 have been obtained in moderate to good yields, after spontaneous precipitation in ethanol. The structures have been identified by one- and two-dimensional NMR experiments, FTIR, and single-crystal X-ray. To confirm the formation of unique Schiff base enantiomers and diastereomeric mixtures of benzodiazepines, chiral HPLC was used. All the new derivatives were screened for their antioxidant and antibacterial activities. The antioxidant activity has been evaluated using the DPPH-scavenging activity method, in which the benzodiazepines show an excellent activity compared to gallic acid. The antimicrobial studies revealed the highest inhibition of the chloro-benzodiazepine derivative against MSSA, MRSA, and M. luteus with MIC values between 0.125-0.25mg/mL when compared with metronidazole used as reference. Molecular docking performed on the penicillin-binding protein (PBP2a) from methicillin-resistant S. aureus MRSA has demonstrated sensitivity towards the novel Schiff Bases.

Isobornanyl sulfoxides and isobornanyl sulfone: Physicochemical characteristics and the features of crystal structure

The physico-chemical characteristics and crystal structure of newly synthesized isobornanyl sulfoxides and sulfone are presented. After purification, diastereomeric sulfoxides were obtained in a 2:1 eutectic ratio, which did not allow either separation or enrichment of the mixture. Based on thermochemical data, the form of the phase diagram of the system was reconstructed, showing that diastereomers have significantly different melting points. According to the X-ray data, the same supramolecular open–chain S=O⋅⋅⋅H–O synthon is built up in the crystals of diastereomeric sulfoxides. The isobornanyl sulfone crystal is formed in a complex way – two crystallographically independent molecules playing different roles in the formation of H-bonds. The IR spectra of a diastereomeric sulfoxides mixture demonstrate the averaging of the synthon-forming functional groups bands. In a counterbalance, the IR spectrum of isobornanyl sulfone shows a doubling of the key bands of synthon-forming functional groups belonging to homochirally homogeneous but crystallographically nonequivalent molecules.

Synthesis of Optically Active N-(4-Hydroxynon-2-enyl)pyrrolidines: Key Building Blocks in the Total Synthesis of Streptomyces coelicolor Butanolide 5 (SCB-5) and Virginiae Butanolide A (VB-A)

AbstractStarting from 5-methylhexanal and (S)-configured N-propargylprolinol ethers, coupling delivered N-(4-hydroxynon-2-ynyl)prolinol derivatives as mixtures of C4 diastereomers. Resolution of the epimers succeeded after introduction of an (R)-mandelic ester derivative and subsequent HPLC separation. Alternatively, suitable oxidation gave the corresponding alkynyl ketone. Midland reagent controlled diastereoselective reduction afforded a defined configured propargyl alcohol with high selectivity. LiAlH4 reduction and Mosher analyses of the allyl alcohols enabled structure elucidation. The suitably protected products are used as key intermediates in enantioselective Streptomyces γ-butyrolactone signaling molecule total syntheses.

The brominated flame retardants TBECH and DPTE alter prostate growth, histology and gene expression patterns in the mouse

The brominated flame retardants (BFRs), 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) bind to the androgen receptor (AR). in vitro bioassays have shown that TBECH is a potent androgen agonist while DPTE is a potent AR antagonist. Both TBECH and DPTE alter gene expression associated with AR regulation. However, it remains to be determined if TBECH and DPTE can affect the prostate. For this reason, we exposed CD1 mice to a 1:1 mixture of TBECH diastereomers α and β, a 1:1 mixture of γ and δ, and to DPTE, and tested their effects on prostate growth, histology and gene expression profiles. Castrated mice were used to study the androgenic effects of TBECHαβ and TBECHγδ while the antagonistic effects of DPTE were studied in non-castrated mice. We observed that testosterone and TBECHγδ increased body and prostate weights while TBECHαβ affected neither of them; and that DPTE had no effect on body weight but reduced prostate weight drastically. Histomorphometric analysis of the prostate revealed epithelial and glandular alterations in the TBECHγδ group comparable to those in testosterone group while alterations in the TBECHαβ group were less pronounced. DPTE displayed androgen antagonist activity reminiscent of castration. The transcription profile of the prostate was altered by castration and exposure to testosterone and to TBECHγδ reversed several of these changes. Testosterone and TBECHγδ also regulated the expression of several androgen responsive genes implicated in prostate growth and cancer. While DPTE resulted in a drastic reduction in prostate weight, it only affected a small number of genes. The results indicate that TBECHγδ and DPTE are of high human health concern as they may contribute to changes in prostate growth, histology and function.

Organocatalytic Stereoselective [8+2] Cycloaddition of Tropones with Azlactones

Organocatalytic Stereoselective [8+2] Cycloaddition of Tropones with Azlactones

C2-Symmetric P-Stereogenic Ferrocene Ligands with Heavier Chalcogenophosphinous Acid Ester Donor Sites.

tert-Butyl-substituted diphospha[2]ferrocenophane was used as a stereochemically confined diphosphane to investigate the addition of various dichalcoganes (R2Ch2; Ch = S, Se, Te and R = Me, Ph). Bischalcogenophosphinous acid esters bearing four soft donor sides were obtained as a mixture of rac and meso diastereomers and characterized by means of multinuclear NMR and X-ray analysis. The coordination chemistry of multidentate ligand 3b was explored toward d10 coinage metal centers (Cu(I), Ag(I), and Au(I)), yielding various bimetallic complexes.

Antifeedant, cytotoxic, and anti-inflammatory neo-clerodane diterpenoids in the peltate glandular trichomes and fresh leaves of Ajuga forrestii

The Lamiaceae plant Ajuga forrestii Diels is a traditional Chinese herbal medicine with abundant glandular trichomes (GTs), but their chemistry and biological functions remain uninvestigated. Here, a panel of six highly functionalized neo-clerodane diterpenoids was localized to the peltate GTs of A. forrestii using laser microdissection coupled with HPLC analysis, indicating that the GTs of A. forrestii are an excellent material for the elucidation of the yet unclear biosynthetic pathway of natural neo-clerodane diterpenoids. In addition, four undescribed neo-clerodane diterpenoids with an acyclic C-9 side chain including two pairs of 1:1 mixture of inseparable diastereomers, ajuforrestins D-G, were isolated from the fresh leaves of A. forrestii together with six known compounds. The structures of the undescribed compounds were elucidated by spectroscopic (including 1D and 2D NMR and HR-ESI-MS) analyses. Biological assays indicated that the major GT compound ajugacumbin B and undescribed ajuforrestins D/E showed antifeedant activity against Helicoverpa armigera, suggesting that neo-clerodanes in A. forrestii should be involved in plant defence against insects. Moreover, the abietane diterpenoid ajuforrestin B exhibited significant anti-inflammatory activity on the secretion of interleukin-2 (IL-2) and cytotoxicity against three cancer cell lines, NCI-H1975, HepG2 and MCF-7, suggesting that ajuforrestin B could positively contribute to the therapeutic effects of this traditional Chinese medicine.

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams.

Pyrrolidones are common heterocyclic fragments in various biologically active compounds. Here, a two-step radical-based approach to γ-lactams bearing three to four stereocenters starting from epoxides, N-allylic silylacetamides and TEMPO is reported. The sequence starts with a new tandem nucleophilic substitution/Brook rearrangement/single electron transfer-induced radical oxygenation furnishing orthogonally protected α,γ-dioxygenated N-allylamides with wide scope, mostly good yields, and partly good diastereo- and enantioselectivity for defined combinations of chiral epoxides and chiral amides. This represents a very rare example of an oxidative geminal C–C/C–O difunctionalization next to carbonyl groups. The resulting dioxygenated allylic amides are subsequently subjected to persistent radical effect-based 5-exo-trig radical cyclization reactions providing functionalized pyrrolidones in high yields as diastereomeric mixtures. They converge to 3,4-trans-γ-lactams by base-mediated equilibration, which can be easily further diversified. Stereochemical models for both reaction types were developed.

Expanding amphiphilic architectures by ring-opening of epoxides and polyepoxides with N-methyl-d-glucamine: Structure, chiral bias and gelation

The facile reaction of a readily available aminopolyol from the chiral pool, N-methyl-d-glucamine, which avoids the side reactions usually associated to anomers of amino sugars, with epoxide and polyepoxide derivatives, enables the preparation of new non-ionic surfactant-like structures combining hydrophilic and hydrophobic moieties. The molecular architectures thus obtained range from linear to tripodal and pyramidal structures. The resulting substances containing multiple chiral centers exist as diastereomeric mixtures, for which various conformations are likewise possible by virtue of inter-chain interactions. The stability and chirality preferences of all possible stereoisomers have been evaluated in detail by DFT methods. Given the amphiphilic structure of both protected and O-protected derivatives obtained by acetylation, self-aggregation could eventually lead to solvent entrapment. Unfortunately, only one compound behaves as efficient hydrogelator and DMSO-gelator at low concentrations. The issue is also discussed in terms of the different molecular arrangements.

Unusual stereoselectivity of methionine-γ-lyase from Citrobacterfreundii toward diastereomeric (S)-methionine S-oxide

Using a diastereomeric mixture of (S)-methionine S-oxide as an example, kinetic preference of methionine-γ-lyase toward a stereogenic center at the γ-sulfur atom of the (2S, RS) diastereomer was discovered for the first time.

Practical Remdesivir Synthesis through One-Pot Organocatalyzed Asymmetric (S)-P-Phosphoramidation.

Remdesivir, an inhibitor of RNA-dependent RNA polymerase developed by Gilead Sciences, has been used for the treatment of COVID-19. The synthesis of remdesivir is, however, challenging, and the overall cost is relatively high. Particularly, the stereoselective assembly of the P-chirogenic center requires recrystallization of a 1:1 isomeric p-nitrophenylphosphoramidate mixture several times to obtain the desired diastereoisomer (39%) for further coupling with the d-ribose-derived 5-alcohol. To address this problem, a variety of chiral bicyclic imidazoles were synthesized as organocatalysts for stereoselective (S)-P-phosphoramidation employing a 1:1 diastereomeric mixture of phosphoramidoyl chloridates as the coupling reagent to avoid a waste of the other diastereomer. Through a systematic study of different catalysts at different temperatures and concentrations, a mixture of the (S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9 ratio when 20 mol % of the chiral imidazole-cinnamaldehyde-derived carbamate was utilized in the reaction at -20 °C. A 10-g scale one-pot synthesis via a combination of (S)-P-phosphoramidation and protecting group removal followed by one-step recrystallization gave remdesivir in 70% yield and 99.3/0.7 d.r. The organocatalyst was recovered in 83% yield for reuse, and similar results were obtained. This one-pot process offers an excellent opportunity for industrial production of remdesivir.

New Bifunctional Bis(azairidacycle) with Axial Chirality via Double Cyclometalation of 2,2'-Bis(aminomethyl)-1,1'-binaphthyl.

As a candidate for bifunctional asymmetric catalysts containing a half-sandwich C–N chelating Ir(III) framework (azairidacycle), a dinuclear Ir complex with an axially chiral linkage is newly designed. An expedient synthesis of chiral 2,2′-bis(aminomethyl)-1,1′-binaphthyl (1) from 1,1-bi-2-naphthol (BINOL) was accomplished by a three-step process involving nickel-catalyzed cyanation and subsequent reduction with Raney-Ni and KBH4. The reaction of (S)-1 with an equimolar amount of [IrCl2Cp*]2 (Cp* = η5–C5(CH3)5) in the presence of sodium acetate in acetonitrile at 80 °C gave a diastereomeric mixture of new dinuclear dichloridodiiridium complexes (5) through the double C–H bond cleavage, as confirmed by 1H NMR spectroscopy. A loss of the central chirality on the Ir centers of 5 was demonstrated by treatment with KOC(CH3)3 to generate the corresponding 16e amidoiridium complex 6. The following hydrogen transfer from 2-propanol to 6 provided diastereomers of hydrido(amine)iridium retaining the bis(azairidacycle) architecture. The dinuclear chlorido(amine)iridium 5 can serve as a catalyst precursor for the asymmetric transfer hydrogenation of acetophenone with a substrate to a catalyst ratio of 200 in the presence of KOC(CH3)3 in 2-propanol, leading to (S)-1-phenylethanol with up to an enantiomeric excess (ee) of 67%.

General Method for the Synthesis of α- or β-Deoxyaminoglycosides Bearing Basic Nitrogen.

The introduction of glycosides bearing basic nitrogen is challenging using conventional Lewis acid-promoted pathways owing to competitive coordination of the amine to the Lewis acid promoter. Additionally, because many aminoglycosides lack a C2 substituent, diastereomeric mixtures of O-glycosides are often produced. Herein, we present a method for the synthesis of α- or β- 2,3,6-trideoxy-3-amino- and 2,4,6-trideoxy-4-amino O-glycosides from a common precursor. Our strategy proceeds by the reductive lithiation of thiophenyl glycoside donors and trapping of the resulting anomeric anions with 2-methyltetrahydropyranyl peroxides. We apply this strategy to the synthesis of α- and β-forosamine, pyrrolosamine, acosamine, and ristosamine derivatives using primary and secondary peroxides as electrophiles. α-Linked products are obtained in 60-96% yield and with >50:1 selectivity. β-Linked products are obtained in 45-94% yield and with 1.7->50:1 stereoselectivity. Contrary to donors bearing an equatorial amine substituent, donors bearing an axial amine substituent favored β-products at low temperatures. This work establishes a general strategy to synthesize O-glycosides bearing a basic nitrogen.

A metal-free Petasis reaction towards the synthesis of N-(α-substituted)alkyl sulfoximines/sulfonimidamides.

Herein, we disclose a metal-free novel approach for the synthesis of N-(α-substituted)alkyl sulfoximines/sulfonimidamides via one-pot multicomponent Petasis reactions of aryl boronic acids, ortho-hydroxyarylaldehydes and sulfoximines/sulfonimidamides in moderate to very good yields. The presence of two chiral centres provides a mixture of diastereomers almost in a 1 : 1 ratio, which are separated successfully in most of the cases. The -OH functionality of Petasis products is further utilized to derive heterocycles via O-allylation, followed by intramolecular Heck cyclization, proving the synthetic utility of the products.