Diastereomeric Purity Research Articles

Recent advances in the total synthesis of polyhydroxylated alkaloids via chiral oxazines.

This review summarizes recently established methodologies developed for the enantioselective and diastereoselective synthesis of chiral 1,3-oxazines. These compounds are of interest as advanced synthetic intermediates in the total synthesis of structurally complex and biologically active polyhydroxylated alkaloids such as (+)-1-deoxynojirimycin, (-)-anisomycin, (+)-castanospermine, (+)-casuarine, (-)-conduramine F-1, (-)-sphingofungin B, Neu5Ac methyl ester, and other natural products. The devised synthetic approach aims to offer a direct, efficient, and adaptable method for obtaining both pure enantiomers and pure diastereomers. It revolves around utilizing chiral building blocks like syn,syn-, syn,syn,anti-, syn,anti-, syn,anti,syn-, anti,syn-, anti,syn,syn-, and anti,syn,anti-oxazines. By integrating oxazine chemistry with established and innovative transformations, this approach enabled the synthesis of 30 polyhydroxylated amines across various studies conducted between 2007 and 2022.

Synthesis and characterization of four diastereomers of β-lactamase inhibitor drug intermediate

A short and efficient stereo-specific synthesis of three stereoisomers (two diastereomer and one enantiomer) of Oxalate salt of benzyl (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate (8) has been described. Compound 8 is a key intermediate in the synthesis of β-lactamase inhibitors, was synthesized in high diastereomeric excess using chirally pure L-pyroglutamic acid. In this report, we also describe a chiral high performance liquid chromatography (CHPLC) method to separate these isomers. The developed CHPLC method was validated for the accurate determination of the diastereomeric purity of compound 8.

In Situ Photoisomerization of an Azobenzene-Based Triple Helicate with a Prolonged Thermal Relaxation Time.

The phosphate-coordination triple helicates A2 L3 (A=anion) with azobenzene-spaced bis-bis(urea) ligands (L) have proven to undergo a rare in situ photoisomerization (without disassembly of the structure) rather than the typically known, stepwise "disassembly-isomerization-reassembly" process. This is enabled by the structural self-adaptability of the "aniono" assembly arising from multiple relatively weak and flexible hydrogen bonds between the phosphate anion and bis(urea) units. Notably, the Z→E thermal relaxation rate of the isomerized azobenzene unit is significantly decreased (up to 20-fold) for the triple helicates compared to the free ligands. Moreover, the binding of chiral guest cations inside the cavity of the Z-isomerized triple helicate can induce optically pure diastereomers, thus demonstrating a new strategy for making light-activated chiroptical materials.

In Situ Photoisomerization of an Azobenzene‐Based Triple Helicate with a Prolonged Thermal Relaxation Time

AbstractThe phosphate‐coordination triple helicates A2L3 (A=anion) with azobenzene‐spaced bis‐bis(urea) ligands (L) have proven to undergo a rare in situ photoisomerization (without disassembly of the structure) rather than the typically known, stepwise “disassembly‐isomerization‐reassembly” process. This is enabled by the structural self‐adaptability of the “aniono” assembly arising from multiple relatively weak and flexible hydrogen bonds between the phosphate anion and bis(urea) units. Notably, the Z→E thermal relaxation rate of the isomerized azobenzene unit is significantly decreased (up to 20‐fold) for the triple helicates compared to the free ligands. Moreover, the binding of chiral guest cations inside the cavity of the Z‐isomerized triple helicate can induce optically pure diastereomers, thus demonstrating a new strategy for making light‐activated chiroptical materials.

Synthesis of (1R)‐1‐(4‐Bromophenyl)‐2,2,2‐trifluoroethan‐1‐amine Hydrochloride through Diastereoselective Trifluoromethylation of a Chiral Sulfinimine

AbstractAn efficient three‐step synthesis of (1R)‐1‐(4‐bromophenyl)‐2,2,2‐trifluoroethan‐1‐amine hydrochloride (1) starting from inexpensive and readily available starting materials was developed. The sequence features a highly diastereoselective trifluoromethylation of a chiral sulfinimine using the Rupert–Prakash reagent TMSCF3 in combination with K3PO4 as an initiator. The diastereomeric purity of the resulting sulfinamide was further improved by direct precipitation of the desired diastereomer from the reaction mixture upon addition of water. The chiral auxiliary was then removed under acidic conditions, resulting in the isolation of chiral benzylamine 1 as its hydrochloride salt in 71 % overall yield and excellent purity (LC/MS: >99 % a/a; e.r.=99 : 1).

Total Synthesis of Thiamyxins A-C and Thiamyxin E, a Potent Class of RNA-Virus-Inhibiting (Cyclo)depsipeptides.

We present the first total synthesis of the thiamyxins A-C and the now fully characterized thiamyxin E, an interesting class of thiazole- and thiazoline-rich depsipeptides with diverse antiviral activity. The synthesis features a parallel closing of two methyl thiazoline units, with low epimerization of the very labile adjacent stereocenter. It also includes the three-step synthesis of an uncommon hydroxy acid and the oxidation-free elimination of a phenylselenide to form a dehydroalanine moiety. The exploitation of the acid-labile stereocenter at the isoleucine moiety and the reopening of the macrolactones gave access to the four thiamyxins with good yields and diastereomeric purities from a single precursor. The modular total synthesis allows further testing of the biological activity and gives opportunities to explore the pharmacophore and antiviral target through derivatization.

Totalsynthese von Thiamyxin A–C und Thiamyxin E, potente RNA‐Virus inhibierende (Cyclo)depsipeptide

AbstractWir präsentieren die erste Totalsynthese der Thiamyxine A–C und des jetzt vollständig charakterisierten Thiamyxins E, einer interessanten Klasse thiazol‐ und thiazolinreicher Depsipeptide mit vielfältiger antiviraler Aktivität. Die Synthese zeichnet sich aus durch einen parallelen Ringschluss zu zwei Methylthiazolin‐Einheiten unter geringer Epimerisierung des sehr labilen benachbarten stereogenen Zentrums. Des Weiteren wird die dreistufige Synthese einer ungewöhnlichen Hydroxysäure sowie die oxidationsfreie Eliminierung eines Phenylselenids zum Dehydroalanin gezeigt. Die Ausnutzung des säurelabilen Stereozentrums am Isoleucin‐Rest und die erneute Öffnung der Makrolactone ermöglichen den Zugang zu den vier Thiamyxinen in guten Ausbeuten und Diastereomerenverhältnissen aus einem einzigen Vorläufer. Durch die modular gestaltete Totalsynthese sind weitere Bioaktivitätstests und die Erforschung eines Pharmakophors über die Synthese weiterer Derivate möglich.

Reversible Light-Induced Dimerization of Secondary Face Azobenzene-Functionalized β-Cyclodextrin Derivatives.

β-cyclodextrin (βCyD) derivatives equipped with aromatic appendages at the secondary face exhibit tailorable self-assembling capabilities. The aromatic modules can participate in inclusion phenomena and/or aromatic-aromatic interactions. Supramolecular species can thus form that, at their turn, can engage in further co-assembling with third components in a highly regulated manner; the design of nonviral gene delivery systems is an illustrative example. Endowing such systems with stimuli responsiveness while keeping diastereomeric purity and a low synthetic effort is a highly wanted advancement. Here, we show that an azobenzene moiety can be "clicked" to a single secondary O-2 position of βCyD affording 1,2,3-triazole-linked βCyD-azobenzene derivatives that undergo reversible light-controlled self-organization into dimers where the monomer components face their secondary rims. Their photoswitching and supramolecular properties have been thoroughly characterized by UV-vis absorption, induced circular dichroism, nuclear magnetic resonance, and computational techniques. As model processes, the formation of inclusion complexes between a water-soluble triazolylazobenzene derivative and βCyD as well as the assembly of native βCyD/βCyD-azobenzene derivative heterodimers have been investigated in parallel. The stability of the host-guest supramolecules has been challenged against the competitor guest adamantylamine and the decrease of the medium polarity using methanol-water mixtures. The collective data support that the E-configured βCyD-azobenzene derivatives, in aqueous solution, form dimers stabilized by the interplay of aromatic-aromatic and aromatic-βCyD cavity interactions after partial reciprocal inclusion. Photoswitching to the Z-isomer disrupts the dimers into monomeric species, offering opportunity for the spatiotemporal control of the organizational status by light.

The Castagnoli-Cushman Reaction.

Since the first reports of the reaction of imines and cyclic anhydrides by Castagnoli and Cushman, this procedure has been applied to the synthesis of a variety of lactams, some of them with important synthetic or biological interest. The scope of the reaction has been extended to the use of various Schiff bases and anhydrides as well as to different types of precursors for these reagents. In recent years, important advances have been made in understanding the mechanism of the reaction, which has historically been quite controversial. This has helped to develop reaction conditions that lead to pure diastereomers and even homochiral products. In addition, these mechanistic studies have also led to the development of new multicomponent versions of the Castagnoli-Cushman reaction that allow products with more diverse and complex molecular structures to be easily obtained.

Gambogic acid: Multi-gram scale isolation, stereochemical erosion toward epi-gambogic acid and biological profile.

Extracted from gamboge resin, gambogic acid (GBA) is a natural product that displays a complex caged xanthone structure and exhibits promising antitumor properties. However, efforts to advance this compound to clinical applications have been thwarted by its limited availability that in turn, restricts its pharmacological optimization. We report here an efficient method that allows multigram scale isolation of GBA in greater than 97% diastereomeric purity from various sources of commercially available gamboge. The overall process includes: (a) isolation of organic components from the resin; (b) separation of GBA from the organic components via crystallization as its pyridinium salt; and (c) acidification of the salt to isolate the free GBA. We found that GBA is susceptible to epimerization at the C2 center that produces epi-gambogic acid ( epi-GBA), a common contaminant of all commercial sources of this compound. Mechanistic studies indicate that this epimerization proceeds via an ortho-quinone methide intermediate. Although the observed stereochemical erosion accounts for the chemical fragility of GBA, it does not significantly affect its biological activity especially as it relates to cancer cell cytotoxicity. Specifically, we measured similar levels of cytotoxicity for either pure GBA or an equilibrated mixture of GBA/ epi-GBA in MBA-MB-231 cells with IC50 values at submicromolar concentration and induction of apoptosis after 12 hours of incubation. The results validate the pharmacological promise of gambogic acid and, combined with the multigram-scale isolation, should enable drug design and development studies.

Facile synthesis of new N-(aminocycloalkylene)amino acid compounds using chiral triflate esters with N-Boc-aminopyrrolidines and N-Boc-aminopiperidines.

In this study, we prepared a series of new N-(aminocycloalkylene)amino acid derivatives for use in chiral building blocks. The method was based on the conversion of enantiopure α-hydroxy acid esters into the corresponding chiral triflate esters, which were displaced by a nucleophilic substitution SN2 reaction with aminopyrrolidine and aminopiperidine derivatives, and the inversion of the configuration to give methyl 2-[(Boc-amino)cycloamin-1-yl]alkanoates with good yield and high enantiomeric and diastereomeric purity. Synthesized 2-[(Boc-amino)piperidin-1-yl]propanoates combined with ethyl l-phenylalaninate gave new chiral N-Boc- and N-nosyl-dipeptides containing a piperidine moiety. The structures were elucidated by 1H-, 13C-, and 15N-NMR spectroscopy, high-resolution mass spectrometry, and X-ray crystallography analyses.

19F NMR enantiodiscrimination and diastereomeric purity determination of amino acids, dipeptides, and amines.

Chiral amino-group compounds are of significance for human health, such as biogenic amino acids (AAs), dipeptides, and even various drugs. Enantiospecific discrimination of these chiral compounds is vital in diagnosing diseases, identifying pathological biomarkers and enhancing pharmaceutical chemistry research. Here, we report a simple and rapid 19F NMR-based strategy to differentiate chiral AAs, dipeptides, and amines, that were derivatized with (R)-2-(2-fluorophenyl)-2-hydroxyacetic acid ((R)-2FHA). As a result, 19 proteinogenic AAs (37 isomers) as well as Gly could be concurrently resolved. Moreover, various mirror-image dipeptides, such as Ser-His, Leu-Leu, and Ala-Ala, were commendably recognized. Intriguingly, we found that the absolute configuration of AAs in the N-terminus of dipeptides decided the relative 19F chemical shifts between two enantiomers. Besides, the ability of this method for enantiodiscrimination was further demonstrated by non-AA amines, including aromatic and aliphatic amines, and even amines having chiral centers several carbons away from the amino-group. The structurally similar antibiotics, amoxicillin and ampicillin, were well discriminated. Furthermore, this method accurately determines the de or dr values of non-racemic mixtures. Therefore, our strategy provides an effective approach for 19F NMR-based enantiodiscrimination and diastereomeric purity determination of amino-group compounds.

Synthesis and Functionalization of Tertiary Propargylic Boronic Esters by Alkynyllithium-Mediated 1,2-Metalate Rearrangement of Borylated Cyclopropanes.

Implementing the use of alkynyllithium reagents in a stereospecific 1,2-metalate rearrangement-mediated ring opening of polysubstituted cyclopropyl boronic esters provides a variety of tertiary pinacol boranes bearing adjacent tertiary or quaternary carbon stereocenters with high levels of diastereomeric purity. The potential of this strategy was demonstrated through a selection of α- and γ-functionalization of the propargyl boronic esters.

Asymmetric Synthesis of Isotopic Atropisomers based on ortho-CH3/CD3 Discrimination and Their Structural Properties.

N-C axially chiral 3-(2-trideuteriomethyl-4,6-dimethylphenyl)-2-ethylquinazolin-4-ones and 3-(2-trideuteriomethyl-4,6-dimethylphenyl)-2-(1-phenylpropan-2-yl)quinazolin-4-ones were prepared in high enantio- and diastereomeric purities (98% ee). These quinazolinone derivatives are isotopic atropisomers based on ortho-CH3/CD3 discrimination and were revealed to possess a slight optical rotation and high rotational stability.

Asymmetric Synthesis of Methoxylated Ether Lipids: A Glyceryl Glycidyl Ether Key Building Block Design, Preparation, and Synthetic Application.

The report describes the preparation and use of a double-C3 building block intended as a head group synthon in the synthesis of saturated, mono-, and polyunsaturated 1-O-alkyl-sn-glycerol type methoxylated ether lipids (MELs). The resulting head piece, an enantiopure isopropylidene-protected glyceryl glycidyl ether diastereomer, was accomplished in 49% yield (max 50%) from a 1:1 diastereomeric mixture obtained from R-solketal and racemic epichlorohydrin after treatment with the Jacobsen (S,S)-Co(III)salen catalyst for the hydrolytic kinetic resolution of terminal epoxides. The diol hydrolytic product obtained in 47% yield from the unwanted diastereomer was reconverted into epoxide with an inversion of configuration in a three-step operation involving a highly regioselective lipase. This enabled the recovery of a substantial amount of diastereopure material after a subsequent treatment with the Jacobsen catalyst to furnish the oxirane head piece in altogether 72% yield of higher than 99% diastereomeric purity. A modified synthesis of a monounsaturated 16:1 MEL confirmed the correct stereochemistry and excellent enantiopurity of the head piece and resulted in a dramatic improvement in yields, efficiency, and economy of the synthesis.

Stereochemical switch driven by crystallization: Interplay between stoichiometry and configuration of the products.

An intriguing example of a crystallization-induced stereochemical switch in the configuration of aza-Michael reaction products is described. Depending on both the stereochemical purity and stoichiometric ratio of the chiral amine used, the reaction delivers crystalline diastereomers of a different stereochemistry. The optically pure diastereomer smoothly converts to its racemic epimer salt upon the addition of a complementary chiral amine.

Isolation of amygdalin epimer at high diastereomeric purity and its structural characterization by spectroscopic and Q-TOF LC-MS methods

Isolation of amygdalin epimer at high diastereomeric purity and its structural characterization by spectroscopic and Q-TOF LC-MS methods

Diastereoselective Double C-H Functionalization of Chiral Ferrocenes with Heteroaromatics.

Diastereoselective double C-H heteroarylation of chiral ferrocenes provides valuable compounds with multiple functionalities using mild reaction conditions and simple reagents. Pd-Complexes with chiral mono-protected amino acids afforded corresponding heteroarylated ferrocenyl amines in good yields and high diastereomeric purities. In this way, a variety of indole, thiophene, pyrrole, or furan substituents were introduced to the ferrocene moiety. Furthermore, a range of relevant functional groups, for example ketone, ester, chloro, nitro, or silyl, are tolerated by this method. An alternative combination of amino acid and ferrocenyl amine configurations was leveraged to provide the complementary diastereomeric products. The products of C-H heteroarylation can be transformed into corresponding phosphines. Absolute configurations of CH-activation products were confirmed by the combination of X-ray crystallographic analysis and CD spectroscopy. 19 F NMR kinetic study and DFT calculations provided insights into the reaction mechanism and reasons governing stereoinduction.

Impact of a Partial Solid Solution and Water Molecules on the Formation of Fibrous Crystals and Fluid Inclusions

Resolution of (±)ibuprofen using S-α-Methylbenzylamine in pure ethanol leads to the enriched S-IBU/S-αMBA diastereomeric salt which crystallizes as very fine needles. In order to improve the filterability and processability of the solid phase, water can be added to the medium and lead to more equant particles that are still elongated. A high fraction of the resulting platelets display on both ends a fluid inclusion containing both liquid and a large bubble of gas. A detailed analysis of the particles reveals that they are not really single crystals but more an ordered association of fibers defined as fibrous crystal. A domain of partial solid solution is evidenced near the pure less soluble diastereomer and its impact on the formation of fibrous crystals is demonstrated. When pure S-IBU/S-αMBA diastereomeric salt is recrystallized in the same medium (e.g., ethanol–water) the crystallinity is improved, but fluid inclusions can still be observed.

Continuous Diastereomeric Kinetic Resolution—Silybins A and B

The natural diastereomeric mixture of silybins A and B is often used (and considered) as a single flavonolignan isolated from the fruit extract of milk thistle (Silybum marianum), silymarin. However, optically pure silybin diastereomers are required for the evaluation of their biological activity. The separation of silybin diastereomers by standard chromatographic methods is not trivial. Preparative chemoenzymatic resolution of silybin diastereomers has been published, but its optimization and scale-up are needed. Here we present a continuous flow reactor for the chemoenzymatic kinetic resolution of silybin diastereomers catalyzed by Candida antarctica lipase B (CALB) immobilized on acrylic resin beads (Novozym® 435). Temperature, flow rate, and starting material concentration were varied to determine optimal reaction conditions. The variables observed were conversion and diastereomeric ratio. Optimal conditions were chosen to allow kilogram-scale reactions and were determined to be −5 °C, 8 g/L silybin, and a flow rate of 16 mL/min. No significant carrier degradation was observed after approximately 30 cycles (30 days). Under optimal conditions and using a 1000 × 15 mm column, 20 g of silybin per day can be easily processed, yielding 6.7 and 5.6 g of silybin A and silybin B, respectively. Further scale-up depends only on the size of the reactor.