Prolinol Derivatives Research Articles

Electrochemical Synthesis of Azanucleoside Derivatives Using a Lithium Perchlorate-Nitromethane System

Azanucleosides are one of the sugar modified nucleoside analog, which contain a nitrogen atom instead of an oxygen atom of furanose ring in nucleoside. They have been known to have anti cancer and anti virus activity, thus the therapeutic application of them has been attracted much attention. However, the synthetic method of them has some issues to be addressed, and they have precluded the derivatization of azanucleoside based on the modification of nitrogen atom. In this report, we developed the easy and mild synthetic method of azanucleoside by using lithium perchlorate-nitromethan (LiClO4/MeNO2) electrolysis system. In this method, reactive intermediates were anodicaly generated from prolinol derivatives and accumulated in LiClO4/MeNO2 solution, and reacted with nucleophiles in the same pot. We synthesized azanucleoside derivatives having diversity on nucleobase, nitrogen substituent and pyrrolidinyl ring from prolinol derivatives directly.

Bioactivity of a family of chiral nonracemic aminobenzylnaphthols towards Candida albicans.

Chiral nonracemic aminobenzylnaphthols were obtained by a Betti multi-component reaction between 2-naphthol, aryl aldehydes and enantiopure arylethylamine. Moreover, some new aminobenzylnaphthols were synthesized by a similar reaction between 2-naphthol, aryl aldehydes and prolinol. These aminobenzylnaphthols, synthesized from different components and thus having different structural features, were tested as anti-yeast agents inhibiting Candida albicans. The effect towards the test strain was studied with a microdilution approach and three different concentrations (150, 300 and 450 µg/mL) were tested. The best results were found for the aminobenzylnaphthols obtained from 1-naphthylethylamine and from natural prolinol. The use of the two-way ANOVA highlighted the better performances of the prolinol derivative among the differently structured aminobenzylnaphthols that were screened. The activity towards C. albicans of this prolinol derivative resulted to be interesting and could represent a promising alternative to overcome the problem of the strains resistant to the traditional antifungals.

Electrochemical Synthesis of Azanucleoside Derivatives Using a Lithium Perchlorate-Nitromethane System

Nucleoside analogues have played an important role in the viral decease and cancer therapy. To date, various nucleosides analogous have been investigated to improve their therapeutic effects and toxic properties. The modification of the sugar moiety has produced new active analogous. Especially, the design of furanose rings that include various heteroatoms has been one of the most useful approaches in the search for new nucleoside analogues with beneficial biological activity.Azanucleosides, in which the furanose oxygen atom is replaced by a nitrogen atom, have attracted interest because of possibility of their further modification through the nitrogen atom and structural similarity to the franose ring system. Considerable efforts have been dedicated to develop the efficient method for the synthesis of azanucleoside derivatives. Most of the synthetic strategies have been designed in order that N-glycosyl bond has been formed through an iminium ion intermediate. This process is necessary to incorporate a leaving group into the pyrrolidinyl precursor to generate the key reactive intermediate. However, access to such precursors requires a multi-step synthetic sequence, which includes cumbersome operations and harsh reaction condition. Indeed, this process often removes the opportunity of providing diverse azanucleosides based on further modification of the nitrogen atom.To address this challenge, we reasoned that direct and selective insertion of a nucleobase to the N-a position of prolinol moiety would avoid the redundant multi-step synthetic operation. We proposed that an electro-organic method might provide such an approach to overcome the challenge of direct introduction of a nucleobase into an unactivated pyrrolidine moiety. Previously, we have demonstrated the direct modification of pyrrolidine derivatives using LiClO4-CH3NO2 electrochemical oxidation system. This reaction system can accumulate desired iminium ion intermediates, anodically derived from N-protected pyrrolidine derivatives by C-H bound activation, enabling coupling with a variety of nucleophiles in one-pot reaction. In this conference, we report the electrochemical azanucleoside synthesis by coupling an unactivated prolinol derivative with a nucleobase through anodic oxidation using LiClO4-CH3NO2 solution system, and demonstrate the utility of this transformation by addition of various nucleophiles to readily available prolinol derivatives in a regioselective manner.

ChemInform Abstract: Electrochemical Synthesis of Azanucleoside Derivatives Using a Lithium Perchlorate—Nitromethane System.

AbstractAzanuclesides and their analogues are readily prepared by an anodic oxidation of chiral prolinol derivatives followed by a reaction of iminium cation intermediates with nucleobases.

ChemInform Abstract: Asymmetric Michael Reaction of Acetaldehyde with Nitroolefins Catalyzed by Highly Water‐Compatible Organocatalysts in Aqueous Media.

AbstractThis method uses prolinol derivatives as organocatalysts.

ChemInform Abstract: Organocatalytic Asymmetric anti‐Selective Michael Reactions of Aldehydes and the Sequential Reduction/Lactonization/Pauson—Khand Reaction for the Enantioselective Synthesis of Highly Functionalized Hydropentalenes.

AbstractIn the presence of DBU and the prolinol derivative, unsaturated aldehydes undergo asymmetric anti‐selective Michael addition to malonates of type (VI).

ChemInform Abstract: Broensted Acid Assisted Intramolecular Aminohydroxylation of N‐Alkenylsulfonamides under Heavy Metal Free Conditions.

AbstractThe reaction allows a simple and environmentally friendly access to prolinol derivatives.

Electrochemical synthesis of azanucleoside derivatives using a lithium perchlorate–nitromethane system

We have developed a highly efficient synthetic method for azanucleosides using a lithium perchlorate-nitromethane reaction medium, allowing direct and exclusive installation of various nucleophiles, including protected nucleobases into prolinol derivatives at the preferred 5-position.

C–C bond fragmentation by Grob/Eschenmoser reactions, applications in dendrimer synthesis

C-C bond fragmentation of structurally diverse carbocycles has been applied to the divergent synthesis of dendrimers. The fragmentation has been paired to deprotection or thio-Michael reaction, allowing the preparation of a fourth generation dendrimer of narrow molecular weight distribution. Methodologies to increase water solubility have been examined using appended carboxylic acid or oligoether moieties. In addition, incorporation of chiral prolinol derivatives has resulted in the synthesis of dendrimers that have been shown to catalyse the α-amination of aldehydes in good yield and modest enantioselectivity.

Brønsted Acid-assisted Intramolecular Aminohydroxylation of N-Alkenylsulfonamides under Heavy Metal-free Conditions

The intramolecular aminohydroxylation of N-alkenylsulfonamides proceeded under heavy metal-free conditions to give substituted prolinol derivatives in high yields. Oxone activated by catalytic Brønsted acid worked well as an electrophilic oxidant for this reaction.

A flexible enantioselective approach to 3,4-dihydroxyprolinol derivatives by SmI2-mediated reductive coupling of chiral nitrone with ketones/aldehydes

A flexible enantioselective approach to polyhydroxylated prolinol derivatives was described, which is based on the samarium diiodide-mediated reductive coupling of the chiral nitrone (3S,4R)-8, derived from d-isoascorbic acid with aldehydes/ketones. Thereby, polyhydroxyprolinol derivatives 9a–e and 9h–j were obtained from aromatic ketones and aliphatic aldehydes in good to excellent yields of 65–91%. These reductive hydroxyalkylations are highly diastereoselective in establishing the C-4 stereogenic center. By this way, the asymmetric syntheses of (−)-8a-epi-swainsonine (4) and (−)-8,8a-di-epi-swainsonine (5) have been achieved.

(S)-α,α-Diphenylprolinol Trimethylsilyl Ether

One of the most important sections of modern organic chemistry is asymmetric synthesis, and in this field particularly attractive are problems relating to asymmetric catalysis. In the recent two decades, special attention is focused on (S)-proline and its derivatives, which are known as versatile organocatalysts (‘aminocatalysts’).[1] [2] It was found that the introduction of the protecting silyl moiety into the prolinol structure results in a remarkable increase of catalytic activity, thus allowing decrease in catalyst loading and shorter reaction times without compromising the level of enantioselectivity.[ 3 ] In addition, this modification leads to significant broadening of the substrate scope. First examples of applications of the O-silyl prolinol derivatives in asymmetric synthesis were independently reported by Hayashi[ 3 ] and Jørgensen.[ 4 ] Since then these compounds have been used efficiently as ‘privileged catalysts’[ 2b ] in diverse organic transformations, such as epoxidations, aldol, anti-selective Mannich, ­Friedel–Crafts and Diels–Alder reactions, etc.[5] [6] Probably, the most prominent representative of diarylprolinol derivatives containing the silyl moiety is (S)-α,α-diphenyl­prolinol trimethylsilyl ether (1).

Zwitterionic Aza‐Claisen Rearrangements Controlled by Pyrrolidine Auxiliaries – Useful Key Steps in Convergent Enantioselective Syntheses

AbstractChiral pyrrolidine substituents served as efficient auxiliaries in diastereoselective zwitterionic ketene aza‐Claisen rearrangements. Palladium‐catalysed N‐allylation starting from optically active proline and prolinol derivatives, as well as from (2S,5S)‐2,5‐dimethoxymethylpyrrolidine, gave various allylamines bearing trisubstituted olefin moieties. Treatment with complex carboxylic acid fluorides in the presence of trimethylaluminium induced activated ketene addition to the nitrogen and subsequent [3,3] sigmatropic rearrangement to give γ,δ‐unsaturated amides with excellent simple diastereoselectivities and up to 11:1 auxiliary‐induced diastereomeric ratios. Cleavage of the pyrrolidine amide was achieved through iodolactonization, with the option for recovery of the auxiliary pyrrolidine. The stereochemical outcomes of the rearrangements and the iodocyclizations were established by X‐ray and NOEDS analyses of suitable amides and lactones. Overall, both enantiomers were accessible selectively. The optically active amides and lactones of defined configurations formed in this way should be useful as key intermediates in convergent steroidal natural and pharmaceutically important product synthesis.

Domino Reaction with Ionic Liquid Immobilized Prolinol Derivatives

Domino Reaction with Ionic Liquid Immobilized Prolinol Derivatives

ChemInform Abstract: The Asymmetric Diels-Alder Reaction of α,β-Unsaturated Aldehydes with Dienes Using a Chiral Boron Reagent as a Catalyst.

The asymmetric Diels–Alder reaction of α,β-unsaturated aldehydes with cyclopentadiene is catalyzed by a novel chiral boron reagent generated in situ from boron tribromide and a chiral prolinol derivative, to afford the corresponding adducts in good yields with fairly good to excellent ees.

Chiral Aryloxyalkylamines: Selective 5‐HT1B/1D Activation and Analgesic Activity

A series of chiral 2,3-dichlorophenoxy and 1-naphthyloxy alkylamines were synthesized, and their binding affinities towards 5-HT(1D) and h5-HT(1B) receptors were evaluated. In the naphthyloxy series, the (R)-prolinol derivative was the most selective 5-HT(1D) ligand, while (S)-N-methyl-2-(1-naphthyloxy)propan-1-amine showed the highest selectivity for h5-HT(1B). Both compounds performed as 5-HT(1D) agonists in the isolated guinea pig assay and showed higher analgesic activity than both sumatriptan and the achiral analogue 20 b in the mouse hot-plate test. Neither ligand displayed any affinity for nicotinic ACh receptors present in mouse brain membranes, thus indicating that their analgesic activity does not arise through interaction with these receptors.

Copper‐Catalyzed Amine–Alkyne–Alkyne Addition Reaction: An Efficient Method For the Synthesis of γ,δ‐Alkynyl‐β‐amino Acid Derivatives

A simple and efficient method for the synthesis of gamma,delta-alkynyl-beta-amino acid derivatives by a copper-catalyzed three-component amine-alkyne-alkyne addition reaction was developed. Various gamma,delta-alkynyl-beta-amino acid derivatives were synthesized in moderate to good yields in one step. With chiral prolinol derivatives employed as the amine component, excellent diastereoselectivities (up to >99:1 diastereomeric ratio (dr)) were obtained. The scope of the reaction and further transformations of the resulting amino acid derivatives, such as deprotection and cyclization are also described.

Asymmetric Organocatalytic Formal Alkynylation and Alkenylation of α,β-Unsaturated Aldehydes

A highly stereoselective organocatalytic one-pot protocol for the formal alkynylation and alkenylation of alpha,beta-unsaturated aldehydes using novel chemistry based on beta-keto heterocyclic sulfones is presented. The organocatalytic step is catalyzed by a prolinol derivative and allows for the formation of important optically active compounds. Further transformations of the beta-keto heterocyclic sulfone moiety, based on new developments of the Smiles rearrangement through a process parallel to the Julia-Kocienski reaction, were performed leading to beta-alkynylated aldehydes and 3-alkenylated alcohols. The scopes of both transformations are demonstrated by the synthesis of various optically active alkynes and alkenes. Furthermore, different transformations of the aldehyde and the alcohol functionality were performed. Finally, the proposed mechanisms for both the alkynylation and alkenylation of alpha,beta-unsaturated aldehydes are outlined.

Enantioselective Conjugate Addition of N-Heterocycles to α,β-Enones Mediated by Diarylprolinols

Enantioselective conjugate addition of benzotriazole to α,β-enones catalyzed by prolinol derivatives with moderate yields and enantioselectivities was reported. Studies of stereoelectronic effects of the catalyst showed that the transition state could be of a hydrogen bonding activation mode, and fine tuning of the substituents on the aryl moiety of the catalyst is important for the reaction stereoselectivities. Keywords: Organocatalysis, conjugate addition, diarylprolinols, enones, asymmetric, benzotriazole

Memory of Chirality in the Electrochemical Oxidation of N-o-Phenylbenzoylated Prolinols

- Memory of chirality in electrochemical carbon-carbon bond cleavage of N-o-phenylbenzoylated (S)-prolinol derivatives was observed. Substituents of the α-position affected the ee of the products. The reaction of a,a-diarylated (S)-prolinol derivatives proceeded smoothly to afford optically active α-methoxylated pyrrolidine with up to 73% ee.