Synthesis Of Indolizidines Research Articles

Modified Julia Olefination on Pyrrolidinone: Application to the Total Synthesis of Indolizidine 209D

AbstractWe report the olefination of Boc‐ protected pyrrolidinone through a modified Julia olefination. Boc‐protected exo‐enamides can then be easily converted into spirobicyclic structure or can be used as useful intermediate for the preparation of natural indolizidine 209D. This application demonstrates the synthetic potential of our methodology for the synthesis of bicyclic alkaloids.

Improved Total Synthesis of Indolizidine and Quinolizidine Alkaloids via Nickel-Catalyzed (4 + 2) Cycloaddition.

A Ni-catalyzed (4 + 2) cycloaddition of bicyclic 3-azetidinones and alkynes was developed to access indolizidine and quinolizidine alkaloids. A key element was the development of a diazomethylation procedure that allows the efficient synthesis of bicyclic azetidinones from pyroglutamic and 6-oxopiperidine-2-carboxylic acid. A ligand screening led to improved regioselectivity and enantiopurity during the Ni-catalyzed (4 + 2) cycloaddition. This straightforward methodology was leveraged to synthesize (+)-ipalbidine, (+)-septicine, (+)-seco-antofine, and (+)-7-methoxy-julandine.

Pd-Catalyzed Ring Restructuring of Oxazolidines with Alkenes Leading to Fused Polycyclic Indolizines.

A palladium-catalyzed reaction of N-propargyl oxazolidines with alkenes for the synthesis of indolizidines has been developed. Through a sequential 6-exo-dig cyclization/proton transfer/[3+2] cycloaddition/cycloreversion/aromatization process, a series of fused polycyclic indolizines are obtained in moderate to good yields with high functional group tolerance. Experimental and theoretical studies suggest that the [3+2] cycloaddition/cycloreversion of the oxazolidine ring probably involves C-C and C-O bond cleavage, providing a new ring restructuring approach for the synthesis of heterocycles.

Chiral Indolizidine Synthesis through the Ir-Catalyzed Asymmetric Hydrogenation of Cyclic Pyridinium Salts

The Ir-catalyzed asymmetric hydrogenation of cyclic pyridinium salts is presented as a new strategy for the convenient and efficient synthesis of chiral indolizidines. The asymmetric hydrogenation of cyclic pyridinium salts derived from 2-(2-acylphenyl)pyridines proceeded smoothly in the presence of [Ir(cod)Cl]2 and (R)-DM-SegPhos to provide the desired chiral 7,8-benzoindolizidines 6 in high to excellent yields with moderate enantioselectivity (up to 86:14 er) and excellent diastereoselectivity (>20:1 dr). The enantiomeric purity of 6j was increased to 92:8 through recrystallization.

C‐H Functionalization of Amino Alcohols by Osmium Tetroxide/NMO or TPAP/NMO: Protecting Group‐Free Synthesis of Indolizidines (–)‐223AB and 3‐epi‐(–)‐223AB

The oxidative cyclization of amino alcohols by osmium tetroxide/NMO or tetrapropylammonium perruthenate (TPAP)/NMO was found to provide an N,O‐acetal moiety through the trapping of the resulting iminium ion by the alcohol. These two transformations were demonstrated in the synthesis of indolizidines (–)‐223AB and 3‐epi‐(–)‐223AB.

Formal Synthesis of Indolizidine and Quinolizidine Alkaloids from Vinyl Cyclic Carbonates.

Cyclic carbonates have long been considered relatively inert molecules acting as protecting groups in complex multistep synthetic routes. This study shows that a concise, yet modular synthesis of indolizidine and quinolizidine alkaloids can be developed from vinyl-substituted cyclic carbonate (VCC) intermediates. Through a highly stereoselective palladium-catalyzed allylic alkylation reaction, these alkaloid motifs can be assembled in four synthetic and only two column purification steps. The combined results help to further advance functionalized cyclic carbonates as useful and reactive intermediates in natural product synthesis.

Efficient and Direct Synthesis of γ‐Amino‐α,β‐Unsaturated Amides by Catalyzed Allylic Substitution of α‐Fluoroenamides: Toward to Synthesis of Hybrid Peptides and Indolizidines

A variety of γ‐amino‐α,β‐unsaturated amides have been synthesized from readily available α‐fluoroenamides precursors via an unprecedented intermolecular and intramolecular conjugative catalytic amination process. These γ‐amino‐α,β‐unsaturated amides are useful intermediates for accessing rarely synthesized hybrid peptides, αγα sequences, and various classes of alkaloids containing a pyrrolidine ring, as illustrated by total synthesis of the indolizidine alkaloid coniceine.

Ag(I)-Catalyzed Synthesis of Azabicyclic Alkaloid Frameworks from Ketimine-Tethered Ynones: Total Synthesis of Indolizidine 209D

An efficient Ag(I)-catalyzed π-acid activation method for the cyclization of cyclic ketimine-tethered ynones is reported. Various nitrogen-containing scaffolds commonly found in bioactive alkaloids can be prepared in high yields, and the utility of the method is demonstrated by a formal synthesis of (±)-lasubine II and in a short total synthesis of (±)-indolizidine 209D.

Cp*Co(III)-Catalyzed C-H Functionalization Cascade of N-Methoxyamides with Alkynedione for the Synthesis of Indolizidines.

Cp*Co(III)-catalyzed C-H functionalization cascade of N-methoxyamides with alkynedione has been reported for the synthesis of indolizidine scaffolds under redox-neutral conditions. The reaction displays broad functional group tolerance along with excellent yield. The reaction proceeds with kinetically relevant C-H bond activation through carboxylate assistance with excellent diastereoselectivity and complete opposite selectivity with respect to alkyne insertion.

Asymmetric synthesis of functionalized pyrrolizidines by an organocatalytic and pot-economy strategy

An enantioselective synthesis of indolizidines was achieved with a one-step purification by sequential asymmetric Michael–oxidative esterification–Michael–reduction–reductive Mannich–amidation reactions.

A convenient entry to indolizidine alkaloids using Kharasch type reactions

A convenient entry to indolizidine alkaloids based on a free-radical atom transfer reaction (ATRA or Kharasch reaction) as the key step is reported. The strategy is based on the free radical reaction between ethyl iodoacetate and an l-proline derivative serving as a radical acceptor. The key intermediate obtained after the radical reaction is used for the synthesis of indolizidine (−)-167B and of an advanced intermediate for the synthesis of (+)-dendroprimine.

ChemInform Abstract: A Highly Efficient Asymmetric Synthesis of Quaternary Stereocenter‐Containing Indolizidine and Quinolizidine Alkaloids Using Aldehydes, Nitroalkenes, and Unactivated Cyclic Ketimines.

A highly efficient approach for the construction of indolizidines and quinolizidines bearing a bridged quaternary stereocenter has been established in a one-pot fashion using aldehydes, nitroalkenes, and cyclic ketimines with excellent enantioselectivities and in high yields. Moreover, this method could be applied to the synthesis of indolizidines in the gram scale.

Redox cycloisomerization approach to 1,2-dihydropyridines.

The phosphine-catalyzed synthesis of 1,2-dihydropyridines via an alkyne isomerization/electrocyclization sequence is described. Propargylidenecarbamate substrates were prepared following a one-pot procedure between a terminal alkyne, a benzonitrile, and a chloroformate in the presence of trimethylaluminum. This methodology gives access to a diverse set of 2,6-disubstituted 1,2-dihydropyridines in high yield. The products can be easily converted into substituted piperidines or pyridines, and this methodology was applied to the synthesis of indolizidines.

ChemInform Abstract: 2,3‐Dihydropyridin‐4(1H)‐ones and 3‐Aminocyclohex‐2‐enones: Synthesis, Functionalization, and Applications to Alkaloid Synthesis

AbstractReview: [51 refs.

Synthesis of Polyhydroxylated Quinolizidine and Indolizidine Scaffolds from Sugar-Derived Lactams via a One-Pot Reduction/Mannich/Michael Sequence

A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartz's reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky's diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives.

2,3-Dihydropyridin-4(1H)-ones and 3-Aminocyclohex-2-enones: Synthesis, Functionalization, and Applications to Alkaloid Synthesis

This account summarizes our recent investigations into the chemistry of 2,3-dihydropyridin-4(1<i>H</i>)-ones and 3-aminocyclohex-2-enones (enaminones). These enaminones are exceptionally versatile chemical scaffolds that serve as valuable intermediates in the synthesis of indolizidine and quinolizidine alkaloids and other bioactive compounds. Since we reported our first method for constructing enaminones in 2006, we have developed a number of additional approaches to the synthesis and derivatization of enaminones and we have explored their applications in natural product synthesis. 1 Background 2 Ynone Cyclization 2.1 Initial Discovery 2.2 Optimization of Reaction Conditions 2.3 Scope and Limitations 2.4 Mechanistic Studies 2.4 Application to Quinolone Synthesis 2.6 <i>N</i>-Butoxycarbonyl β-Lactam Approach 2.7 Synthesis of 3,4-Dihydro-1,2-oxazepin-5(2<i>H</i>)-ones and Their Conversion into Enaminones 3 Ketene Cyclization 3.1 Chiral-Pool Approach 3.2 Three-Component Synthesis 4 C5 Functionalization 4.1 Suzuki Coupling of Iodoenaminones 4.2 Suzuki-Type Direct Cross-Coupling 4.3 Suzuki-Type Direct Cross-Coupling with Arylboronic ­Acids 4.4 Hiyama-Type Direct Cross-Coupling 4.5 Direct Coupling with Aryl Iodides 4.6 Alkenylation by the Fujiwara–Moritani Reaction 4.7 Alkenylation of Uracils 4.8 Aerobic Alkenylation and its Application to the Synthesis of 1,3,5-Trisubstituted Benzenes 4.9 Lithium Perchlorate-Catalyzed Alkylation 5 Applications to Total Synthesis 5.1 Total Synthesis of (+)-Ipalbidine and (+)-Antofine 5.2 Total Synthesis of (<i>R</i>)- and (<i>S</i>)-Boehmeriasin A 5.3 Total Synthesis of Tylocrebrine and Related Phenanthropiperidines 6 Summary and Outlook

ChemInform Abstract: Kinetic Resolution of 2‐Substituted 2,3‐Dihydro‐4‐pyridones by Palladium‐Catalyzed Asymmetric Allylic Alkylation: Catalytic Asymmetric Total Synthesis of Indolizidine (‐)‐209I (IV).

ChemInform Abstract: Kinetic Resolution of 2‐Substituted 2,3‐Dihydro‐4‐pyridones by Palladium‐Catalyzed Asymmetric Allylic Alkylation: Catalytic Asymmetric Total Synthesis of Indolizidine (‐)‐209I (IV).

Kinetic Resolution of 2-Substituted 2,3-Dihydro-4-pyridones by Palladium-Catalyzed Asymmetric Allylic Alkylation: Catalytic Asymmetric Total Synthesis of Indolizidine (−)-209I

The kinetic resolution of 2-substituted-2,3-dihydro-4-pyridones was realized via a Pd-catalyzed allylic substitution reaction using a commercially available (S)-P-Phos as a ligand, affording optically active dihydropyridones and C-allylated dihydropyridones in high yields and good enantioselectivities with the S-factor up to 43. With this protocol, a catalytic asymmetric total synthesis of indolizidine (-)-209I was realized for the first time.

A highly efficient asymmetric synthesis of quaternary stereocenter-containing indolizidine and quinolizidine alkaloids using aldehydes, nitroalkenes, and unactivated cyclic ketimines.

A highly efficient approach for the construction of indolizidines and quinolizidines bearing a bridged quaternary stereocenter has been established in a one-pot fashion using aldehydes, nitroalkenes, and cyclic ketimines with excellent enantioselectivities and in high yields. Moreover, this method could be applied to the synthesis of indolizidines in the gram scale.

Samarium-Mediated Synthesis of Indolizidines, Quinolizidines, and Piperidines

Samarium-Mediated Synthesis of Indolizidines, Quinolizidines, and Piperidines