Synthesis Of Piperidines Research Articles

Enantioselective synthesis of piperidines through the formation of chiral mixed phosphoric acid acetals: experimental and theoretical studies.

An enantioselective intramolecular chiral phosphoric acid-catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two-step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S(N)2'-like displacement to yield the product with stereoselectivity in agreement with experimental observations.

Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies

AbstractAn enantioselective intramolecular chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two‐step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous SN2′‐like displacement to yield the product with stereoselectivity in agreement with experimental observations.

ChemInform Abstract: Regio‐ and Stereoselective 1,2‐Dihydropyridine Alkylation/Addition Sequence for the Synthesis of Piperidines with Quaternary Centers.

AbstractThis is the first example of a C‐alkylation of 1,2‐dihydropyridines with alkyl triflates and Michael acceptors to yield products with quaternary stereocenters with high regio‐ and diastereoselectivity.

ChemInform Abstract: Synthesis of Polyhydroxylated Indolizidines and Piperidines from Garner′s Aldehyde: Total Synthesis of (‐)‐Swainsonine, (+)‐1,2‐Di‐epi‐swainsonine, (+)‐8,8a‐Di‐epi‐castanospermine, Pentahydroxy Indolizidines, (‐)‐1‐Deoxynojirimycin, (‐)‐1‐Deoxy‐altro‐nojirimycin, and Related Diversity.

AbstractDiastereoselective and diverse syntheses of polyhydroxylated indolizidines and piperidines are described, where the common chiral intermediate 2‐(hydroxymethyl) piperidine‐3‐ol is converted into 1‐deoxy‐altro‐nojirimycin derivatives (I), 1‐deoxynojirimycin (II), 1,2‐di‐epi‐swainsonine (III), swainsonine (IV), 8,8a‐di‐epi‐castanospermine (V), and isomeric pentahydroxy indolizidines (VI) and (VII).

Fully diastereoselective synthesis of polysubstituted, functionalized piperidines and decahydroquinolines based on multicomponent reactions catalyzed by cerium(IV) ammonium nitrate.

The cerium(IV) ammonium nitrate (CAN)-catalyzed, three-component reaction between primary amines, β-dicarbonyl compounds, and α,β-unsaturated aldehydes in ethanol heated to reflux, constitutes a general, one-pot synthesis of 1,4-dihydropyridines. Their reduction with sodium triacetoxyborohydride furnished piperidine derivatives bearing up to five substituents with full diastereoselectivity in a hitherto inaccessible stereochemical arrangement. The reaction proceeded with no significant loss of enantiomeric purity under mild reduction conditions that are compatible with several functional groups that are normally sensitive to reduction. Octahydroquinolin-5-one derivatives, which were prepared by a modified version of the initial multicomponent reaction, were not suitable substrates for the sodium triacetoxyborohydride mediated reduction, but they were transformed into the corresponding decahydroquinolines, including a precursor of the amphibian alkaloid pumiliotoxin C, by catalytic hydrogenation under a variety of conditions.

Synthesis of Iminosugars from Tetroses

Iminosugars continue receiving a great deal of attention from chemists and biochemists for their potential as pharmaceutics. This is a comprehensive review of the methods found in the literature for the synthesis of piperidine, pyrrolidine, indolizidine, and pirrolizidine iminosugars, starting from D/L-erythrose and D/L-threose carbon chains (tetroses). This review shows the crescent popularity of small molecules to build up iminosugar molecules. Methodologies described herein utilize inexpensive commercial materials. The synthesis of the four tetroses is included referring old and modern methodologies. Keywords: Erythose, indolizidines, piperidines, pyrrolidines, pyrrolizidines, threose.

Investigations on intramolecular 1,3-dipolar cycloadditions for the synthesis of isoxazolo-annulated pyrrolidines, piperidines and azepanes

Pyrrolidines, piperidines, and azepanes with annulated isoxazole, isoxazoline or isoxazolidine rings were prepared by intramolecular 1,3-dipolar cycloadditions of nitrones or nitrile oxides. The corresponding 1,3-dipoles were obtained from N-Boc-protected and N-allyl-, N-propargyl- or N-(3-butenyl)-substituted 2-aminoethanal or 3-aminopropanal.

BF3-Mediated Oxidative Cross-Coupling of Pyridines with Alkynyllithium Reagents and Further Reductive Functionalizations of the Pyridine Scaffold

A set of functionalized alkynylpyridines can be readily obtained using Et₂O·BF₃ as promoter. Alkynyllithium reagents undergo an addition reaction at position C-2 of pyridines that are rearomatized by oxidative treatment with chloranil. These substituted pyridines can be easily converted into more valuable intermediates. Examples of applications are given as well. Finally, the synthesis of piperidines and lactams via first an oxidative BF₃-mediated addition reaction followed by a NaBH₄ reduction or acidic workup is also described.

Regio‐ and Stereoselective 1,2‐Dihydropyridine Alkylation/Addition Sequence for the Synthesis of Piperidines with Quaternary Centers

AbstractThe first example of C alkylation of 1,2‐dihydropyridines with alkyl triflates and Michael acceptors was developed to introduce quaternary carbon centers with high regio‐ and diastereoselectivity. Hydride or carbon nucleophile addition to the resultant iminium ion also proceeded with high diastereoselectivity. Carbon nucleophile addition results in an unprecedented level of substitution to provide piperidine rings with adjacent tetrasubstituted carbon atoms.

Regio‐ and Stereoselective 1,2‐Dihydropyridine Alkylation/Addition Sequence for the Synthesis of Piperidines with Quaternary Centers

The first example of C alkylation of 1,2-dihydropyridines with alkyl triflates and Michael acceptors was developed to introduce quaternary carbon centers with high regio- and diastereoselectivity. Hydride or carbon nucleophile addition to the resultant iminium ion also proceeded with high diastereoselectivity. Carbon nucleophile addition results in an unprecedented level of substitution to provide piperidine rings with adjacent tetrasubstituted carbon atoms.

ChemInform Abstract: Applications and Limitations of the I2‐Mediated Carbamate Annulation for the Synthesis of Piperidines: Five‐ versus Six‐Membered Ring Formation.

AbstractDepending on the substrates ‐ which are derived from carbohydrates ‐ the I2‐mediated cyclization yields either furan or piperidine derivatives.

Selective Synthesis of Functionalized Trifluoromethylated Pyrrolidines, Piperidines, and Azepanes Starting from 1‐Tosyl‐2‐(trifluoromethyl)aziridine

This paper reports on the generation and alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with ω,ω'-dihaloalkanes, followed by a novel ring-expansion protocol toward 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. A variety of halogen, oxygen, nitrogen, sulfur, and carbon nucleophiles was used to trigger this ring rearrangement, resulting in CF3-azaheterocycles bearing different types of functionalized side chains.

Expedient Synthesis of α-Heteroaryl Piperidines Using a Pd-Catalyzed Suzuki Cross-Coupling–Reduction Sequence

A method for the modular synthesis of α-heteroaryl piperidines is reported. The two-step procedure consists of an initial Pd-catalyzed Suzuki cross-coupling of the heteroaryl bromide with a boronate ester derived from N-Boc piperidone, followed by subsequent tetrahydropyridine reduction. Using this method, α-heteroaryl piperidine products featuring a broad range of pharmaceutically relevant azine and diazine substitutions have been prepared.

Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance.

ChemInform Abstract: Ring Expansion of Vinylaziridines Through the Strain‐Release Pericyclic Reaction: Recent Developments and Applications

AbstractReview: 29 refs.

Synthesis of polyhydroxylated indolizidines and piperidines from Garner's aldehyde: total synthesis of (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity

Diastereoselective and diverse synthesis of polyhydroxylated indolizidines and piperidines have been described, where a common chiral intermediate 2-(hydroxymethyl) piperidine-3-ol is converted into (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity. The key steps were hydroxy directed intramolecular aminomercuration, Mitsunobu cyclization, and diastereoselective dihydroxylation.

Applications and Limitations of the I2-Mediated Carbamate Annulation for the Synthesis of Piperidines: Five- versus Six-Membered Ring Formation

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.

α,β-Unsaturated Diazoketones as Versatile Building Blocks for the Synthesis of Hydroxylated Piperidines, Indolizidines and Quinolizidines

A four-step approach for the synthesis of dihydroxylated piperidine, quinolizidine and indolizidine systems is described employing α,β-unsaturated diazoketones as versatile building blocks. Unsaturated diazoketones were readily prepared from a Horner-Wadsworth-Emmons reaction between a diazophosphonate and amino-aldehydes. The strategy employs an asymmetric dihydroxylation reaction as the key step and is simple and straightforward enough to be extended to other nitrogen heterocycles.

Ring expansion of vinylaziridines through the strain-release pericyclic reaction: recent developments and applications.

Recent syntheses of azetidines, pyrrolidines, piperidines and azepines through cycloaddition or sigmatropic rearrangements of vinylaziridines are described. Applications to natural product synthesis and mechanistic investigations are also summarized.

Samarium-Mediated Synthesis of Indolizidines, Quinolizidines, and Piperidines

Samarium-Mediated Synthesis of Indolizidines, Quinolizidines, and Piperidines