A Titanium(III)-Catalyzed Reductive Umpolung Reaction for the Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines

Luu, Hieu-Trinh; Wiesler, Stefan; Frey, Georg; Streuff, Jan

doi:10.1021/acs.orglett.5b00987

Cited by 39 publications

(35 citation statements)

References 60 publications

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“…3‐[(Trimethylsilyl)oxy]propanenitrile (7d): , In a flame‐dried 250 mL round‐bottom flask equipped with a magnetic stirrer bar, chlorotrimethylsilane (7.66 mL, 60.0 mmol, 1.01 equiv.) was dissolved in Et 2 O (50 mL).…”

Section: Methodsmentioning

confidence: 99%

“…rac ‐1‐[1‐(But‐3‐en‐1‐yl)‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinolin‐1‐yl]‐3‐hydroxypropan‐1‐one (5c): Representative procedure: Table , entry 6. A flame‐dried Schlenk‐tube was charged under argon with a magnetic stir bar, Cp 2 Ti(OPh) 2 (18.2 mg, 0.05 mmol, 10 mol‐%), Et 3 N · HCl (34.4 mg, 0.25 mmol, 0.5 equiv.)…”

Section: Methodsmentioning

confidence: 99%

“…rac ‐10b‐(But‐3‐en‐1‐yl)‐8,9‐dimethoxy‐1‐oxo‐2,3,4,5,6,10b‐hexahydro‐1 H ‐pyrrolo[2,1‐ a ]isoquinolin‐4‐ium Chloride (25): Compound 2 (60.3 mg, 0.200 mmol) was dissolved in CHCl 3 (2 mL) and HCl in Et 2 O (2.0 m , 150 µL, 0.300 mmol, 1.5 equiv.) was added dropwise at 0 °C.…”

Section: Methodsmentioning

confidence: 99%

“…This included a reductive iminonitrile cyclization giving α‐aminoketones or pyrrolidinones and corresponding intermolecular imine–nitrile couplings providing acyclic α‐aminoketones . Recently, this approach has been advanced to a selective reductive C1‐acylation of dihydroisoquinolines, which was applied to the synthesis of functionalized tetrahydroisoquinolines and a total synthesis of 3‐demethoxyerythratidinone ( 1 ) . In this full paper, we describe in detail the synthetic efforts to 1 via an intramolecular and an intermolecular titanium(III)‐catalyzed imine–nitrile coupling, the latter of which ultimately evolved into an operationally convenient and protecting group free six‐step synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…[9] Recently, this approach has been advanced to a selective reductive C1-acylation of dihydroisoquinolines, which was applied to the synthesis of functionalized tetrahydroisoquinolines and a total synthesis of 3demethoxyerythratidinone (1). [10] In this full paper, we describe in detail the synthetic efforts to 1 via an intramolecular and an intermolecular titanium(III)-catalyzed imine-nitrile coupling, the latter of which ultimately evolved into an operationally convenient and protecting group free six-step synthesis. It demonstrates the viability and strengths of titanium(III)-catalyzed reductive couplings for applications in alkaloid synthesis.…”

Section: Introductionmentioning

confidence: 99%

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Development of an Efficient Synthesis of rac‐3‐Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine‐Nitrile Coupling

Luu

Streuff

2018

Eur J Org Chem

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We herein describe the evolution of a rapid, high‐yielding synthesis of the erythrina alkaloid 3‐demethoxyerythratidinone. The natural product is assembled in six steps from commercial precursors in 30–35 % overall yield and with only two chromatographical purification operations. The key step is a titanium(III) catalyzed umpolung reaction in form of a reductive imine–nitrile coupling that can be combined with a subsequent cyclization reaction on a 50 mmol scale. Furthermore, optimized Wacker oxidation conditions enable the selective alkene oxidation in the presence of a tertiary amine functionality, which has been a problem in previous syntheses of erythrina alkaloids. The racemic route can be used to prepare the natural product on gram scale and the results may be useful for the synthesis of related alkaloids.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Development of an Efficient Synthesis of rac‐3‐Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine‐Nitrile Coupling

Luu

Streuff

2018

Eur J Org Chem

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Diastereoselective Synthesis of Substituted Tetrahydroisoquinolines and Isoindolines via a Silver(I) Triflate‐Promoted Tandem Reaction

et al. 2016

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An ew silver(I) triflate-promoted tandem reaction comprising the ring opening of aziridines and aM ichael reactionh as been developed. Using secondary amines or primary amines as nucleophiles,t his methodologya llows for the synthesis of cis-1-alkyl-4-aminotetrahydroisoquinolineso rcis-1,3-disubstituted isoindolines in good yields with excellent diastereoselectivities,r espectively.B esides, easy operation and mild reactionc onditions are also notable features of this tandemreaction.Keywords: aziridines; cyclization;d omino reactions;Lewis acids;M ichaela ddition Thed evelopment of efficient synthetic approachesf or the construction of cyclicc ompounds is one of the most fertile areasi no rganic synthesis.B ecause of their high efficiencyi nt he formation of chemical bonds,t andem reactions [1] stand out from numerous strategies and play an important role in the synthesis of cyclic compounds.I np articular, Lewis acid-catalyzed tandem reactions [2] have attractedm uch attention from the synthetic community for the advantages of easy operation and mild reactionconditions.TheM ichaela ddition reactiono fe lectron-deficient alkenes with nucleophiles is ap owerful tool for the formation of carbon-carbon [3] and carbon-heteroatom bonds.[4] Basedo ni t, manye legant tandem reactions have been designed for the construction of various molecular skeletons.[5] In addition, N-sulfonylaziridines are easy to react with many carbon-nucleophilic reagents [6] andh eteroatom-nucleophilic reagents, [7] Using these reactions,s everal tandem reactions have been developed for the construction of nitrogen-containing heterocycles, [8] However, to the best of our knowledge,atandem reaction that simultaneously involvesaMichael addition reactiona nd the ring opening of aziridines hasn ot been studied up to now.T he similarr eactivity of electron-deficient alkenes and aziridineswith nucleophiles couldproduce aselectivity problem. There are three possible paths for this tandem reaction( Scheme 1). Path 1: ring opening of the aziridine occurs,a nd then the newly generated nitrogen aniona ttacks the electron-deficient alkene to affordp roduct A; path 2: Michaela ddition followed by ring opening of the aziridine gives rise to product B; path 3: the nucleophile attacks to the electron-deficient alkene and the aziridine at the same timet o provide product C. On the plus side, the diversity of productse nriches the applicationc ategory of tandem reactions.B ut if the reactionc annot be selectively controlled, complexm ixtures would cause it to lose any practical applicationv alue.B esides, the relative stereochemistry in the product also needs to be regulated wells ot hat the tandem reactionc an stereospecifically give the target molecule.With these considerations in mind, we selected amines [4f~k,7c~i] as nucleophiles andb egan our study on the tandem reactioni nvolving the ring opening of aziridinesa nd aM ichael addition.T oo ur delight, the tandem reaction proceeded smoothly in the presence of AgOTf.W hen secondary amines were use...

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A Short Synthesis of (±)‐3‐Demethoxyerythratidinone by Ligand‐Controlled Selective Heck Cyclization of Equilibrating Enamines

Blackham

Booker‐Milburn

2017

Angewandte Chemie

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As hort, 5-step total synthesis of (AE)-3-demethoxyerythratidinone from as imple pyrrole derivative is described. Features include the formation of gram quantities of ak ey tricylic aziridine from ac hallenging photochemical cascade reaction through the use of flowphotochemistry.The final step involved ah ighly unusual Heckc yclization whereby ligand control enabled efficient formation of the natural product in 69 %y ield from the minor isomer present in an equilibrating mixture of labile enamines.The alkaloid (+ +)-3-demethoxyerythratidinone 1 is one of over 100 natural products produced by the Erythrina genus of flowering plants. [1] The Erythrina alkaloids display ab road range of pharmacological activities including hypotensive, sedative,n euromuscular blocking,C NS depressing and curare-like activities.T he key structural feature of this family is the tetracyclic tetrahydroisoquinoline core.S ince the first total synthesis of 1 by Tsuda in 1984, [2] this tetracyclic alkaloid has been used by others in order to demonstrate the utility of various synthetic methodologies.[3] Av ery elegant synthesis was recently reported by Reisman, where chiral sulfinyl imine chemistry was used to control the stereochemistry of the key quaternary center, [3d] giving (À)-3-demethoxyerythratidinone in just six steps overall (Figure 1).Individually both photochemical and Pd-catalyzed crosscoupling methodologies have been shown to be powerful techniques in organic synthesis as well as valuable tools in the synthesis of complex molecular architectures.[4] We have previously reported the photochemical transformation of simple N-butenyl-substituted pyrroles into complex tricyclic aziridines 2.[5] We recently demonstrated that these strained photochemical products undergo arange of thermal and Pdcatalyzed ring-opening/annulation reactions to produce ab road range of fused polyheterocycles,i nj ust two steps from simple pyrroles (Scheme 1).[6] We were therefore keen to exploit the functionality and inherent strain in these aziridines as part of an alkaloid synthesis,i np articular the aziridine carboxylates 3.H erein we report as hort total synthesis of (AE)-1 utilizing ah ighly unusual and selective, ligand controlled intramolecular Heck-reaction onto one of apair of equilibrating enamine intermediates. Our initial strategy to 1 (Scheme 1) involved aryl cyclization onto the iminium ion 4 which itself would be generated by in situ decarboxylation of the amino acid 5.[7] Although iminium ion cyclizations are one of the most frequently used approaches to such alkaloids, [8] these have usually involved the intermediary of N-acyliminium ions.[9] Ther equisite amino-acid 5 should be obtained by Pd 0 -catalyzed acetate ring-opening of the aziridine 3 followed by N-alkylation with the iodide 6.Irradiation of pyrrole 7 (254 nm) gave the aziridine (AE)-8 in a39% yield (Scheme 2). As before,wefound that this two- photon process suffers from low productivity due to al ikely low overall quantum yield and as such was limited to ca. 60 ...

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A Titanium(III)-Catalyzed Reductive Umpolung Reaction for the Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines

Cited by 39 publications

References 60 publications

Development of an Efficient Synthesis of rac‐3‐Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine‐Nitrile Coupling

Development of an Efficient Synthesis of rac‐3‐Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine‐Nitrile Coupling

Diastereoselective Synthesis of Substituted Tetrahydroisoquinolines and Isoindolines via a Silver(I) Triflate‐Promoted Tandem Reaction

A Short Synthesis of (±)‐3‐Demethoxyerythratidinone by Ligand‐Controlled Selective Heck Cyclization of Equilibrating Enamines

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