Reduction Of Enamines Research Articles

Development of a Scalable, Stereoselective Second-Generation Route for CXCR7 Antagonist ACT-1004-1239 via Chiral Enamine Reduction and a Novel Telescoped Sequence of Transesterification, cis-to-trans Epimerization, and Saponification

Development of a Scalable, Stereoselective Second-Generation Route for CXCR7 Antagonist ACT-1004-1239 via Chiral Enamine Reduction and a Novel Telescoped Sequence of Transesterification, <i>cis</i>-to-<i>trans</i> Epimerization, and Saponification

Stereoselective Synthesis of the Decahydroquinoline Alkaloid cis-195J.

The first enantioselective synthesis of two C-5 diastereomers of the proposed structure of the decahydroquinoline alkaloid cis-195J has been achieved. The key step of our strategy is the highly stereoselective vinylogous Mukaiyama-Mannich reaction (VMMR), which gave rise to the first two stereogenic centers at the ring fusion with excellent diastereo- and enantiocontrol. Through alkyne cyclization and enamine reduction the correct cis-configuration between C-2, C-4a, and C-8a in the decahydroquinoline backbone was established. Subsequently, a radical cyclization of a tethered alkyl iodide onto the enoate assembled the bicyclic cis-decahydroquinoline as a mixture of two C-5 diastereomers. Further elaboration of the C-5 side chain eventually provided both diastereomers of cis-195J, which were readily separated, and their constitution and configuration were thus unambiguously proven for the first time.

Glycerol Boosted Rh-Catalyzed Hydroaminomethylation Reaction: A Mechanistic Insight.

We report a Rh-catalyzed hydroaminomethylation reaction of terminal alkenes in glycerol that proceeds efficiently under mild conditions to produce the corresponding amines in relatively high selectivity towards linear amines, moderate to excellent yields by using a low catalyst loading (1 mol % [Rh], 2 mol % phosphine) and relative low pressure (H2 /CO, 1:1, total pressure 10 bar). This work sheds light on the importance of glycerol in enabling enamine reduction via hydrogen transfer. Moreover, evidence for the crucial role of Rh as chemoselective catalyst in the condensation step has been obtained for the first time in the frame of the hydroaminomethylation reaction by precluding deleterious aldol condensation reactions. The hydroaminomethylation proceeds under a molecular regime; the outcome of catalytically active species into metal-based nanoparticles renders the catalytic system inactive.

Catalytic Asymmetric 1,3-Dipolar Cycloaddition/Hydroamination Sequence: Expeditious Access to Enantioenriched Pyrroloisoquinoline Derivatives.

A three-step reaction sequence has been developed to prepare a variety of enantioenriched pyrroloisoquinoline derivatives. The process involves a catalytic asymmetric azomethine ylide 1,3-dipolar cycloaddition followed by an intramolecular AuI-catalyzed alkyne hydroamination and enamine reduction.

ChemInform Abstract: One‐Pot Synthesis of GABA Amides via the Nucleophilic Addition of Amines to 3,3‐Disubstituted Cyclopropenes.

AbstractThe title synthesis follows the nucleophilic addition, ring‐opening of the resulting cyclopropanes, and in‐situ reduction of enamine or imine intermediates sequence.

Enantioselective synthesis of the apremilast aminosulfone using catalytic asymmetric hydrogenation

Celgene’s Otezla® 1 (apremilast) is the first and only PDE4 inhibitor approved by the US FDA for the treatment of plaque psoriasis and psoriatic arthritis. The active pharmaceutical ingredient 1 has been historically prepared via resolution to obtain the enantioenriched aminosulfone intermediate. Herein we have investigated the use of catalytic asymmetric hydrogenation for the enantioselective synthesis of the key aminosulfone intermediate in order to identify a higher yielding and greener synthesis route. Asymmetric reduction of enamine 7 and ketone 11 both proceeded with high selectivity, generating their respective products with >95% ee.

Seven-membered ring scaffolds for drug discovery: Access to functionalised azepanes and oxepanes through diazocarbonyl chemistry

Functionalised azepane and oxepane scaffolds were prepared using diazocarbonyl chemistry and elaborated to show their potential use in library synthesis. Key dicarbonyl containing seven-membered rings were functionalised via diastereoselective Luche reduction of the ketone followed by manipulation of the ester and amine groups. Further scaffolds could be accessed by C-alkylation of the dicarbonyl compounds. In addition, an oxepane containing amino acid could be prepared via a diastereoselective enamine reduction.

One-pot synthesis of GABA amides via the nucleophilic addition of amines to 3,3-disubstituted cyclopropenes.

A one-pot synthesis of various GABA amides has been demostrated, employing the nucleophilic addition of primary and secondary amines across the double bond of cyclopropene-3-carboxamides, followed by ring-opening of the resulting donor-acceptor cyclopropanes and subsequent in situ reduction of enamine (imine) intermediates.

ChemInform Abstract: Trichlorosilane‐Mediated Stereoselective Synthesis of β‐Amino Esters and Their Conversion to Highly Enantiomerically Enriched β‐Lactams.

AbstractThe trichlorosilane‐promoted reduction of enamines (I) and (V) in the presence of an ephedrine‐derived chloropicolinamide catalyst is accomplished.

An Efficient Process for the Manufacture of Carmegliptin

A short and high-yielding synthesis of carmegliptin (1) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using (S,S)-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10 was coupled with (S)-fluoromethyl lactone 31. Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27−31% overall yield with six isolated intermediates.

Chiral Amine Synthesis – Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine Reduction

AbstractThe review examines the chiral amine literature from 2000–2009 (May) concerning enantioselective and diastereoselective methods for N‐acylenamide and enamine reduction, reductive amination, and imine reduction. The reaction steps for each strategy, from ketone to primary chiral amine, are clearly defined, with best methods and yields for starting material preparation and final deprotection noted. Categories of chiral amines have been defined in Section 1 to allow the reader to quickly understand whether their specific target amine falls within a difficult to synthesize, or not, structural class. Amino acids are not considered in this work.

ChemInform Abstract: Dynamic Kinetic Resolution in the Asymmetric Synthesis of β‐Amino Acids by Organocatalytic Reduction of Enamines with Trichlorosilane.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Dynamic Kinetic Resolution in the Asymmetric Synthesis of β‐Amino Acids by Organocatalytic Reduction of Enamines with Trichlorosilane

A new methodology based on the organocatalytic asymmetric hydrosilylation of enamines that allows a direct access to a range of β and β -amino acid derivatives was presented. The results show a successful reduction of aromatic substrates, a sterically more hindered ortho-substituted derivatives, and the thiophenyl analogue exhibiting lower reactivity. Fast enamine-imine equilibration is crucial as imines are chiral but racemic, while α-alkyl β-amino acids can be accessed by the symmetrical Mannich reaction. The α-alkyl derivatives have relative and absolute configuration due to their reduction with LiAlH into a known amino alcohols. Predominant formation of the anti isomer in 3o is consistent with conformation of the imine intermediate in the catalytic reduction.

2,5-Disubstituted pyrrolidines: synthesis by enamine reduction and subsequent regioselective and diastereoselective alkylations

Methodology for the diastereoselective synthesis of 2,5-disubstituted pyrrolidines by reduction of enamines derived from pyroglutamic acid is reported; the nature of nitrogen protection was found to be critical for the stereochemical control of the reaction outcome. Regioselective manipulation of the C-2 and C-5 substituents is possible, providing access to differently substituted pyrrolidines for a limited number of cases.

2,5‐Disubstituted Pyrrolidines: Versatile Regioselective and Diastereoselective Synthesis by Enamine Reduction and Subsequent Alkylation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

2,5-Disubstituted pyrrolidines: versatile regioselective and diastereoselective synthesis by enamine reduction and subsequent alkylation.

A direct and versatile route enabling the regio- and diastereoselective synthesis of 2,5-disubstituted pyrrolidines by reduction of enamines derived from pyroglutamic acid is reported.

ChemInform Abstract: Reduction of Enamines in the 3,3‐Dialkyl‐3,4‐dihydroisoquinoline Series.

AbstractReduction of the enamine (Ia) with lithium aluminum hydride gives the tetrahydroisoquinolylpropanol (II).

ChemInform Abstract: Selective Reductions with Complex Hydride Reducing Agents

This paper describes the selective reductions with thioborane derivatives, zinc—modified cyanoborohydride, and the ate complex from diisobutylaluminum hydride and n-butyllithium. Reaction of carboxylic acids with 1,3,2-dithiaborinane in the presence of stannous chloride or boron trifluoride etherate in tetrahydrofuran gives 1,3-dithianes in high yields. The reaction of acids with thexylphenylthioborane in dichloromethane gives S,S'-diphenyl acetais, whereas esters are converted into phenyl sulfides in the presence of zinc iodide. Zinc-modified cyanoborohydride in ether selectively reduces allylic, benzylic, tertiary alkyl halides without reducing primary and secondary alkyl, vinyl, and aryl halides. Furthermore, the reagent in ether reduces aldehydes, ketones, and acid chlorides to alcohols and the reagent in methanol is very effective in the reduction of enamines, reductive amination of aldehydes and ketones, and deoxygenation of aldehdyes and ketones. The ate complex from diisobutylaluminum hydride and n-butyllithium, capable of reducing most reducible functional groups, is found to be a highly selective reducing agent. The reagent rapidly reduces simple primary alkyl bromides, benzylic, and allylic halides but slowly primary alkyl chlorides and secondary alkyl bromides. Tertiary amides are cleanly reduced to aldehydes and various selective reductions can be achieved by the use of the reagent.

Reduction of enamines of the 3,3-dialkyl-3,4-dihydroisoquinoline series

Lithium aluminum hydride reduced enamines of the 3,3-dialkyl-3,4-dihydroisoquinoline series to the corresponding tetrahydroisoquinolines. In the presence of a hydrogen atom at the Β-carbon atom of the enamino ester the action of lithium aluminum hydride and alkylmagnesium bromide leads to the products from the condensation of two molecules of the initial compound.

Selective reductions with complex hydride reducing agents

Abstract