Concise enantioselective synthesis of 3,5-dialkyl-substituted indolizidine alkaloids via sequential cross-metathesis-double-reductive cyclization

An efficient stereoselective synthesis of two 3,5-dialkyl-substituted indolizidine alkaloids is reported. The convergent syntheses are based on a novel sequence of a cross-metathesis (CM) reaction of an alpha,beta-unsaturated ketone and a chiral homoallylic amine followed by a domino reaction involving hydrogenation, N-deprotection, and two diastereoselective reductive aminations. Our concept presents one of a few examples of a highly selective CM reaction in the synthesis of a natural product.     

Concise synthesis of two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids

A concise five-step approach to indolizidinones 10 and 11, two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids, has been developed by using N-Cbz pyrrolidin-2-yl pyridin-2-yl sulfide 13 as the chiral building block. The method features a SmI₂-mediated coupling of sulfide 13 with functionalized aldehyde 14 and a tandem N-deprotection-lactamization, which constitutes a stepwise “2 + 4” annulation method for the construction of the indolizidinone ring system of 12a.     

Efficient synthesis of highly functionalized tetrahydropyridopyrimidines by a novel three-component coupling reaction

We report the development of a novel three-component coupling reaction (3CC) for the synthesis of alkoxy tetrahydropyridopyrimidines. Systematic optimization of reaction parameters identified 3CC conditions tolerant of a wide array of functionality at all three sites of diversity, providing densely functionalized products in moderate to excellent yields. The newly developed chemistry has since been applied to the lead optimization process on a novel drug discovery program, facilitating rapid compound advancement.     

Palladium-catalyzed one-pot synthesis of highly substituted furans by a three-component annulation reaction

A new three-component cyclization-coupling reaction catalyzed by palladium was developed, producing polysubstituted furans in good yields from readily available substrates. The reaction conditions and the scope of the process were examined, and a possible mechanism is proposed.     

Synthesis of (+/-)-strychnofoline via a highly convergent selective annulation reaction

Studies aimed at preparing (+/-)-strychnofoline by total synthesis are detailed. The route described makes use of a recently developed MgI(2)-mediated ring-expansion reaction of spiro[cyclopropan-1,3'-oxindole] with a cyclic disubstituted aldimine. The ring-expansion product was formed as a single diastereoisomer in 55 % yield, possessing the same stereochemical pattern found in strychnofoline. In addition, our synthetic effort has led to the development of new reaction methodology to access 3,4-disubstituted cyclic aldimines.     

An unusual solvent effect in the cuprate displacement reaction of indolizidin-5-yl-methyl p-toluenesulfonate: stereoselective synthesis of indolizidine alkaloids

An unusual solvent effect in the cuprate displacement reaction of indolizidin-5-yl-methyl p-toluenesulfonate with dialkyl cuprates, derived from an alkyllithium and Grignard reagents, during the synthesis of indolizidine alkaloids 167B and 209D is described.     

Highly diastereoselective synthesis and NMR characterization of natural indolizidine alkaloids

A diastereoselective, general and versatile access to disubstituted indolizidines is described. The nmr conformational analysis permits us to establish preferred conformations.     

Practical highly enantioselective synthesis of propargylamines through a copper-catalyzed one-pot three-component condensation reaction

The one-pot three-component reaction of terminal alkynes, aldehydes and secondary amines in the presence of copper(I) bromide/quinap is reported. The reaction scope has been determined and a broad variety of all three components has been used, which afforded the corresponding propargylamines in good to excellent yields and moderate to very good enantioselectivities. The reaction showed a strong positive nonlinear effect. The transformation of a propargylamine intermediate into the alkaloid (S)-(+)-coniine has also been described.     

Facile synthesis of sulfur-substituted allenes by a three-component reaction

The three-component reaction of lithium alkylthiolate, 1-alkynylphosphine oxide and aldehyde in THF affords sulfur-substituted allenes in good to excellent yield.     

Diastereoselective synthesis of highly functionalized quinolizines via a pyridine-based three-component reaction and a DFT investigation on the reaction mechanism

Novel, one-pot, three-component reactions of the zwitterions generated in situ from pyridine and acetylenic esters with alkoxymethylenemalononitriles via 1,4-dipolar cycloadditions are described. The reactions afforded dialkyl 1,1-dicyano-2-alkoxy-1,9a-dihydro-2H-quinolizine-3,4-dicarboxylate derivatives in good to high yields without using any catalyst or activation. Structural, electronic, energetic, and mechanistic details of the reaction are also revealed by density functional theory (DFT) calculations, which strongly support the exclusive formation of the observed products.     

A practical method for the synthesis of pyrrolizidine, indolizidine and pyrroloazepinolizidine nucleus

The alkylation of α,ω-dibromoalkanes, with the sodium salt of succinimide, followed by the reduction with sodium borohydride gives the respective N-ω-bromoalkyl-5-hydroxy-2-pyrrolidinones. These substrates are precursors of N-acyliminium ions under acidic conditions. The condensation of these intermediates with ethyl malonate in the presence of TiCl₄ and diisopropylethylamine following the intramolecular cyclization provides a convenient route to substituted pyrrolizidinone, indolizidinone and pyrroloazepinolizidinone nucleus in a good yield.     

One-pot synthesis of quinoline-based tetracycles by a tandem three-component reaction

A practical one-pot synthetic strategy for the efficient synthesis of a range of structurally interesting and bioactive quinoline-based tetracycles has been developed. A key step in the synthesis is a tandem three-component reaction of heteroaromatic amine, methyl 2-formylbenzoate and (t)butyl isonitrile, followed by TFA-mediated lactamization via intramolecular aminolysis of an adjacent ester. Results related to a kinase-panel screening for several selected compounds are also discussed in this article.     

A novel pyridine-based three-component condensation reaction: synthesis of highly substituted quinolizines

Reaction of the zwitterions generated from pyridine or pyridine derivatives and dialkyl acetylenedicarboxylate with electron-deficient tetracyanoethylene lead to highly substituted quinolizines without using any catalyst or activation.     

Enantioselective synthesis of piperidine,indolizidine, and quinolizidine alkaloids from a phenylglycinol-derived delta-lactam

Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (1), or its enantiomer, the enantioselective synthesis of 2-alkylpiperidines and cis- and trans-2,6-dialkylpiperidines is reported. The potential of this approach is illustrated by the synthesis of the piperidine alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)-solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.     

Annulation of pyrrole: application to the synthesis of indolizidine alkaloids

The nucleophilicity of pyrrole has been exploited to rapidly assemble the bicyclic skeleton of the indolizidine alkaloids. The key sequence is the annulation of a second ring onto pyrrole from a γ-lactone and has been exploited in the synthesis of the natural products (±)-monomorine and (±)-indolizidine 209D.     

Metal-complex catalysis during the reduction of functional groups by sodium borohydride in the synthesis of pyrrolidine derivatives

A selective method was developed for the reduction of functional groups with sodium borohydride using complexes of CoCl₂ and CuCl₂ with triethylbenzylammonium chloride and cobalt and copper mesotetra[4-(2-hydroxyethyl)pyridyl]porphyrinates as catalysts. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 205–208, February, 2006.