Diastereoselective Synthesis Research Articles

Highly diastereoselective multicomponent synthesis of pyridinium-substituted piperidin-2-ones with three stereogenic centres

The Michael–Mannich–cyclization cascade of dicyano olefins, 1-(2-alkoxy-2-oxoethyl)pyridin-1-ium halogenides, aromatic aldehydes and ammonium acetate provides convenient stereoselective formation of (4,6-diaryl-5,5-dicyano-2-oxo-piperidin-3-yl)pyridin-1-ium halogenides with three stereogenic centres. Ammonium acetate plays dual role acting as a base and as a nitrogen source.

Diastereoselective Synthesis of Carbohydrate Conjugates: Pyrano[3,2-c]quinolones

AbstractA facile and efficient protocol for the diastereoselective synthesis of pyrano[3,2-c]quinolone carbohydrate derivatives from Perlin aldehydes and 4-hydroxyquinolones has been developed using a one-pot condensation at room temperature. In this investigation, glucose and galactose were employed as inexpensive starting materials to synthesize two sets of pyrano[3,2-c]quinolone-based carbohydrate conjugates. A total of sixteen novel compounds were successfully synthesized using this methodology in good to excellent yields. The reaction exhibited remarkable diastereoselectivity, resulting in a single diastereomeric product with a diastereomeric excess (dr) 97:3 for glucose, while a diastereomeric mixture with a diastereomeric excess (dr) 67:33 was obtained for galactose. The structural characterization of all sixteen compounds was carried out using various analytical techniques, including IR, 1H NMR, 13C NMR, 1H-1H COSY, 1H-13C HETCOR experiments, 2D NOESY NMR, and HRMS data. Additionally, the scalability of the protocol was successfully demonstrated by synthesizing one of the compounds on a gram scale, highlighting its potential for large-scale production.

Prins Cyclization: Novel Strategy towards the Diastereoselective Total Synthesis of (–)-Cryptocaryolone

AbstractA highly diastereoselective total synthesis of TBDPS-protected (–)-cryptocaryolone has been achieved in 12 linear steps with an overall yield of 7.1%, following a recently developed Prins cyclization strategy for the construction of trans-2,6-disubstituted 3,4-dihydropyrans. Another key intermediate, i.e. syn-1,3-diol, was prepared by the Wacker oxidation followed by a hydroxyl-directed syn-reduction of the keto functionality. In this report, the versatility of Prins cyclization in the total synthesis of TBDPS-protected (–)-cryptocaryolone is demonstrated. The key steps involved in the approach are Prins cyclization for the construction of the trans-2,6-disubstituted dihydropyran, Wacker oxidation and a hydroxyl-directed syn-reduction reaction.

Diastereoselective Synthesis of Fused Tricyclic Pyridopyrimidines via Tandem Cyclization of Allenoates and Cyclic Amidines.

The tandem cyclization of easily accessible allenoates and cyclic amidines for the synthesis of functionalized tricyclic pyridopyrimidines is reported herein. The annulation featured a broad substrate scope with good functional group tolerance under very mild conditions (35 examples, 32-85% yields). The pyridopyrimidines were obtained in a very short reaction time (1 min), at room temperature, under neat conditions, which offers an alternative way to the sustainable synthesis of functionalized pyridopyrimidines. The scalability of the developed protocol is further demonstrated by a gram-scale synthesis.

Highly diastereoselective multicomponent synthesis of 2-piperidone-substituted pyridinium salts with three and four stereogenic centers

Highly diastereoselective multicomponent synthesis of 2-piperidone-substituted pyridinium salts with three and four stereogenic centers

Highly Diastereoselective Synthesis of Multifunctionalized Dihydrofurans by a K3PO4‐Promoted Michael Addition‐Alkylation Reaction

AbstractA simple and beneficial strategy for the construction of 2,3‐dihydrofurans from α‐bromochalcones and α‐substituted cyanoketones via Michael addition‐alkylation reaction has been realized. This transformation was well compatible with various α‐bromochalcones and α‐substituted cyanoketones, and the corresponding multifunctionalized 2,3‐dihydrofurans were obtained in up to 98 % yield. A highly diastereoselective variant of the reaction was also developed. Moreover, the reaction could be performed on gram‐scale.

Stereoselective Synthesis of Densely Substituted Pyrrolidines via a [3 + 2] Cycloaddition Reaction between Chiral N-tert-Butanesulfinylazadienes and Azomethine Ylides.

The N-tert-butanesulfinylimine group behaves as a suitable electron-withdrawing group in 1-azadienes, allowing the diastereoselective synthesis of densely substituted pyrrolidines by 1,3-dipolar cycloadditions (1,3-DCs) with azomethylene ylides. The use of Ag2CO3 as catalyst has allowed one to obtain a wide variety of proline derivatives with high regio- and diastereoselectivities. Subsequent efficient transformations provide valuable proline derivatives, some of which can be used as organocatalysts. The influence of the N-tert-butanesulfinyl group on the diastereoselectivity was studied by computational methods.

B(C6F5)3‐Catalyzed One‐Pot Tandem Diastereoselective Synthesis of cis‐2,3‐Disubstituted 1,2,3,4‐Tetrahydroquinoxalines and cis‐2,4‐Disubstituted 2,3,4,5‐Tetrahydro‐1H‐1,5‐benzodiazepines

AbstractB(C6F5)3‐catalyzed one‐pot tandem cyclization/hydrosilylation of easily accessible 1,2‐diaminobenzenes and 1,2‐ and 1,3‐diketones with polymethylhydrosiloxane (PMHS) has been developed for step‐economic diastereoselective synthesis of cis‐2,3‐disubstituted 1,2,3,4‐tetrahydroquinoxalines and cis‐2,4‐disubstituted 2,3,4,5‐tetrahydro‐1H‐1,5‐benzodiazepines. This metal‐free catalytic protocol provides access to various differently substituted products in 53–95% yield and with diastereoselectivities ranging from 6:1 to 20:1. The diastereoselectivity strongly depends on the choice of hydrosilane, with PMHS being optimal. The reaction is operationally simple and readily scaled up, and proceeds without exclusion of air and moisture.

Diastereoselective Synthesis of α-Aryl-Substituted LnDOTA Chelates from Achiral Starting Materials by Deracemization Under Mild Conditions.

Substituted derivatives of the DOTA framework are of general interest to alter chelate properties and facilitate the conjugation of chelates to other molecular structures. However, the scope of substituents that can be introduced into the α-position has traditionally been limited by the availability of a suitable enantiopure starting materials to facilitate a stereoselective synthesis. Tetra-substituted DOTA derivatives with phenyl and benzoate substituents in the α-position have been prepared. Initial syntheses used enantiopure starting materials but did not afford enantiopure products. This indicates that the integrity of the stereocenters was not preserved during synthesis, despite the homo-chiral diastereoisomer being the major reaction product. The homochiral diastereoisomer could be produced as the major or sole reaction product when starting from racemic or even achiral materials. Deracemization was found to occur during chelation through the formation of an enolate stabilized by the aryl substituent. This general ability of aryl groups to enable deracemization greatly increases the range of substituents that can be introduced into DOTA-type ligands with diastereochemical selectivity.

Stereoselective Synthesis of Iminosugar‐C‐Glycosides through Addition of Organometallic Reagents to N‐tert‐Butanesulfinyl Glycosylamines: A Comprehensive Study

AbstractA comprehensive study of the preparation and reactivity of N‐tert‐butanesulfinyl glycosylamines with simple Grignard and organo lithium reagents in batch vs. continuous flow chemistry is reported. As they readily react as latent imine equivalents with a variety of carbon nucleophiles, these carbohydrate derivatives constitute very useful precursors for the diastereoselective synthesis of bioactive compounds such as iminosugar‐C‐glycosides. A hybrid protocol, involving the addition of benzylmagnesium chloride to a (SR)‐arabinofuranosylamine substrate in flow, at room temperature, combined with a cyclization protocol in batch is also described for the first time. Of note, this semi‐continuous flow process shortens the synthesis of imino‐C‐glycoside scaffolds to a single workday.

Diastereoselective Reductive Etherification Via High-Throughput Experimentation: Access to Pharmaceutically Relevant Alkyl Ethers.

This manuscript describes the development of the first diastereoselective intermolecular synthesis of alkyl ethers via reductive etherification of diverse ketones or aldehydes with alcohols. Key to this development was the use of low-temperature high-throughput experimentation (HTE) technologies that enabled rapid reaction optimizations and parallel synthesis. A broad scope of pharmaceutically relevant substrates was surveyed, which formed alkyl ethers effectively. In addition, we demonstrated that the diastereoselectivity of this transformation can be readily modulated by prudent selection of the reductant.

Diastereoselective Synthesis of Phosphinic Dipeptide Isosteres: Domino Chirality Transfer during a Stereocontrolled P-Michael Reaction.

A highly diastereoselective P-Michael addition of chiral aminophosphinic acids to achiral acrylates has been developed, leading to phosphinic dipeptide isosteres in high yields and dr of up to >50:1. The method allows for the diastereoselective preparation of target compounds without the need for chiral auxiliaries or P-chiral substrates. A possible mechanistic explanation involves a domino chirality transfer from the aminophosphinic acid to the P center, amplified by a crucial benzhydryl ester group, and then to the α-carbon.

Stereoselective Synthesis of Pyrrolo/Pyrido[2,1-a]isoindoles via Alkyne Iminium Ion Cyclization of Vinylogous Carbamates.

An efficient, acid-mediated, intramolecular alkyne iminium ion cyclization of oxoisoindolidene for the diastereoselective synthesis of pyrrolo/pyridoisoindole is described. This protocol features broad substrate scope and easy scalability. An unusualNtoC-1,3-alkyl shift is observed with substrates bearing strong electron donating group at the phenyl ring attached to alkyne with concomitant hydration of alkyne to the ketone.

Diastereoselective congested β-amido ketone synthesis via NHC-catalyzed radical-radical coupling

Diastereoselective congested β-amido ketone synthesis via NHC-catalyzed radical-radical coupling

Bridged‐Ring Skeletons from Organoaluminium‐Mediated Nucleophilic Addition‐Cyclization Sequence of p‐Quinone Monoacetals and Grignard Reagents

AbstractDescribed herein is the development of an organoaluminium‐mediated tandem conjugate addition‐cyclization sequence of p‐quinone monoacetals with 2‐siloxyphenyl Grignard reagents to afford a collection of phenol‐bridged cyclohexanone derivatives. Furthermore, a tandem conjugate‐addition and dimerization reaction of p‐quinone monoacetals with Grignard reagents is also reported to offer a straightforward and diastereoselective synthesis of complex bridged‐ring compounds bearing tricyclo[6.2.2.02,7]dodecene skeletons.

Rh-Catalyzed Regio- and Diastereoselective Synthesis of Difluorinated Cyclopentanes via a [3+2] Cycloaddition

Rh-Catalyzed Regio- and Diastereoselective Synthesis of Difluorinated Cyclopentanes via a [3+2] Cycloaddition

Diastereoselective Synthesis of Pyrazolo[1,2‐a][1,2,4]triazine Derivatives via Cross‐1,3‐dipolar Cyclizations of Azaoxyallyl Cations with N,N′‐Cyclic Azomethine Imines

AbstractA cross‐1,3‐dipolar cycloaddition reaction of α‐halohydroxamates (in situ generated azaoxyallyl cations) with N,N′‐cyclic azomethine imines was developed. The synthetic protocol provided facile and rapid access to pyrazolo[1,2‐a][1,2,4]triazine derivatives in good yields and excellent diastereoselectivities under mild metal‐free conditions.

Diastereoselective and Scalable Synthesis of 6-(S)-Hydroxycannabidivarin.

The synthesis of 6-(S)-hydroxycannabidivarin was required to assess its biological activity in the treatment of neurological disorders. A novel and scalable synthesis has been developed where the key step involves a Friedel-Crafts alkylation of phloroglucinol with (1S,2R,5R)-2-hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohex-3-en-1-ylbenzoate. Careful optimization of the reaction conditions identified trifluoromethanesulfonic acid in isopropyl acetate as the best catalyst/solvent combination, providing optimum regioselectivity, diastereoselectivity, and yield for this step. This enabled the multigram synthesis of 6-(S)-hydroxycannabidivarin in 10 steps from S-(+)-carvone.

Diastereoselective Synthesis of Bicyclo[3.2.1]octanes via Catalyst‐Free Cascade Michael/Henry Reaction with a Functionalized Vinylogous Nucleophile

AbstractA readily prepared and functionalized vinylogous nucleophile has been explored and utilized to construct bridged bicyclic compounds. The corresponding cascade Michael/Henry reaction occurred with relatively high reactivity under catalyst‐free and mild conditions. A range of structurally distinct bicyclo[3.2.1]octanes were generated in 40–96% isolated yields with excellent diastereoselectivities (≥10:1 dr). Gram‐scale synthesis was also demonstrated.

Multicomponent diastereoselective synthesis of tetrahydropyridines as α-amylase and α-glucosidase enzymes inhibitors.

Background: Researchers seeking new drug candidates to treat diabetes mellitus have beenexploring bioactive molecules found in nature, particularly tetrahydropyridines (THPs). Methods: A library of THPs (1-31) were synthesized via a one-pot multicomponent reaction and investigated for their inhibition potential against α-glucosidase and α-amylase enzymes. Results: A nitrophenyl-substituted compound 5 with IC50 values of 0.15±0.01 and1.10±0.04μM, and a Km value of 1.30mg/ml was identified as the most significant α-glucosidase and α-amylase inhibitor, respectively. Kinetic studies revealed the competitive mode of inhibition, and docking studies revealed that compound 5 binds to the enzyme by establishing hydrophobic and hydrophilic interactions and a salt bridge interaction with His279. Conclusion: These molecules may be a potential drug candidate for diabetes in the future.