Synthesis Of Allenes Research Articles

Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies

Chiral molecules with multiple stereocenters are widely present in natural products and pharmaceuticals, whose absolute and relative configurations are both critically important for their physiological activities. In spite of the fact that a series of ingenious strategies have been developed for asymmetric diastereodivergent catalysis, most of these methods are limited to the divergent construction of point chirality. Here we report an enantioselective and diastereodivergent synthesis of trisubstituted allenes by asymmetric additions of oxazolones to activated 1,3-enynes enabled by chiral phosphoric acid (CPA) catalysis, where the divergence of the allenic axial stereogenicity is realized by modifications of CPA catalysts. Density functional theory (DFT) calculations are performed to elucidate the origin of diastereodivergence by the stacking- and stagger-form in the transition state (TS) of allene formation step, as well as to disclose a Münchnone-type activation mode of oxazolones under Brønsted acid catalysis.

Copper-Catalyzed Enantioselective Radical 1,4-Difunctionalization of 1,3-Enynes.

Chiral allenes are important structural motifs frequently found in natural products, pharmaceuticals, and other organic compounds. Asymmetric 1,4-difunctionalization of 1,3-enynes is a promising strategy to construct axial chirality and produce substituted chiral allenes from achiral substrates. However, the previous state of the art in 1,4-difunctionalization of 1,3-enynes focused on the allenyl anion pathway. Because of this, only electrophiles can be introduced into the allene backbones in the second functionalization step, consequently limiting the reaction and allene product types. The development of asymmetric 1,4-difunctionalization of 1,3-enynes via a radical pathway would complement previous methods and support expansion of the toolbox for the synthesis of asymmetric allenes. Herein, we report the first radical enantioselective allene formation via a group transfer pathway in the context of copper-catalyzed radical 1,4-difunctionalization of 1,3-enynes. This method addresses a longstanding unsolved problem in asymmetric radical chemistry, provides an important strategy for stereocontrol with free allenyl radicals, and offers a novel approach to the valuable, but previously inaccessible, chiral allenes. This work should shed light on asymmetric radical reactions and may lead to other enantioselective group transfer reactions.

Organocatalytic Enantioselective Synthesis of Chiral Allenes: Remote Asymmetric 1,8‐Addition of Indole Imine Methides

AbstractAn organocatalytic enantioconvergent synthesis of chiral tetrasubstituted allenes is disclosed. With suitable chiral phosphoric acid catalysts, a range of racemic indole‐substituted propargylic alcohols reacted with nucleophiles to provide efficient access to a series of enantioenriched allenes with high enantioselectivities. Control experiments suggested a mechanism involving remotely controlled asymmetric 1,8‐addition of the in situ generated indole imine methide via a bifunctional transition state.

Copper(I)-catalyzed diastereo- and enantio-selective construction of optically pure exocyclic allenes

Among about 150 identified allenic natural products, the exocyclic allenes constitute a major subclass. Substantial efforts are devoted to the construction of axially chiral allenes, however, the strategies to prepare chiral exocyclic allenes are still rare. Herein, we show an efficient strategy for the asymmetric synthesis of chiral exocyclic allenes with the simultaneous control of axial and central chirality through copper(I)-catalyzed asymmetric intramolecular reductive coupling of 1,3-enynes to cyclohexadienones. This tandem reaction exhibits good functional group compatibility and the corresponding optically pure exocyclic allenes bearing cis-hydrobenzofuran, cis-hydroindole, and cis-hydroindene frameworks, are obtained with high yields (up to 99% yield), excellent diastereoselectivities (generally >20:1 dr) and enantioselectivities (mostly >99% ee). Furthermore, a gram-scale experiment and several synthetic transformations of the chiral exocyclic allenes are also presented.

Organocatalytic Enantioselective Synthesis of Chiral Allenes: Remote Asymmetric 1,8-Addition of Indole Imine Methides.

An organocatalytic enantioconvergent synthesis of chiral tetrasubstituted allenes is disclosed. With suitable chiral phosphoric acid catalysts, a range of racemic indole-substituted propargylic alcohols reacted with nucleophiles to provide efficient access to a series of enantioenriched allenes with high enantioselectivities. Control experiments suggested a mechanism involving remotely controlled asymmetric 1,8-addition of the in situ generated indole imine methide via a bifunctional transition state.

Synthesis of New Exocyclic Allenes with Diterpene Fragments

New stable allenes with exocyclic cumulene groups were synthesized from N-maleopimarimide-substituted amino acids using phenyl(triphenylphosphoranylidene)succinimide, 2-fluorophenyl(triphenylphosphoranylidene)-succinimide, and benzyl(triphenylphosphoranylidene)succinimide.

Research Progress on the Catalytic Enantioselective Synthesis of Axially Chiral Allenes by Chiral Organocatalysts

Chiral allenes are important structural scaffolds found in many natural products and drugs, and in addition, they also serve as building blocks for many organic transformations. The conventional methods for preparing chiral allenes rely on the resolution of racemic allenes and the chirality transfer between non-racemic propargylic derivatives and nucleophilic reagents. In recent years, the synthesis of chiral allenes by asymmetric catalysis has been achieved fruitful results. Among them, enantioselective synthesis of chiral allenes with chiral organic catalysts is particularly prominent. In this paper, the research progress of enantioselective synthesis of chiral allenes catalyzed by chiral organic catalysts in recent years is reviewed, including various reaction systems and synthesis applications.

Pd-Catalyzed Enantioselective Syntheses of Trisubstituted Allenes via Coupling of Propargylic Benzoates with Organoboronic Acids.

Enabled by the newly developed ligand, Ming-Phos, the first example of palladium-catalyzed highly enantioselective coupling of racemic propargylic benzoates with organoboronic acids for chiral allenes synthesis has been developed. Excellent asymmetric induction has been achieved with a decent substrate scope. Synthetic potentials for the construction of polycyclic compounds with multiple chiral centers have been demonstrated.

Synthesis and Functionalization of Allenes by Direct Pd‐Catalyzed Organolithium Cross‐Coupling

AbstractA palladium‐catalyzed cross‐coupling between in situ generated allenyl/propargyl‐lithium species and aryl bromides to yield highly functionalized allenes is reported. The direct and selective formation of allenic products preventing the corresponding isomeric propargylic product is accomplished by the choice of SPhos or XPhos based Pd catalysts. The methodology avoids the prior transmetalation to other transition metals or reverse approaches that required prefunctionalization of substrates with leaving groups, resulting in a fast and efficient approach for the synthesis of tri‐ and tetrasubstituted allenes. Experimental and theoretical studies on the mechanism show catalyst control of selectivity in this allene formation.

Synthesis and Functionalization of Allenes by Direct Pd-Catalyzed Organolithium Cross-Coupling.

A palladium-catalyzed cross-coupling between in situ generated allenyl/propargyl-lithium species and aryl bromides to yield highly functionalized allenes is reported. The direct and selective formation of allenic products preventing the corresponding isomeric propargylic product is accomplished by the choice of SPhos or XPhos based Pd catalysts. The methodology avoids the prior transmetalation to other transition metals or reverse approaches that required prefunctionalization of substrates with leaving groups, resulting in a fast and efficient approach for the synthesis of tri- and tetrasubstituted allenes. Experimental and theoretical studies on the mechanism show catalyst control of selectivity in this allene formation.

Synthesis of Allenes by 1,2-Elimination

Allenes represent an extremely important class of organic molecules, which, as a result of their twisted orthogonal π-systems can possess axial chirality. A wide array of methods for allene synthesis have been reported, such as the substitution of propargylic electrophiles, isomerization of alkynes and sigmatropic rearrangement. An alternative approach for the synthesis of allenes is 1,2-elimination of an appropriately substituted precursor. This mini-review highlights recent examples of 1,2-elimination processes, which target allenes including both polar and radical processes. The main focus is upon how control over the stereospecificity (e.g. syn- or anti-) of the 1,2-elimination process can enable the synthesis of enantioenriched axially chiral allenes. Recent developments in this field are presented including both enantiospecific and catalytic asymmetric methods.

Functionalized Allenes: Generation by Sigmatropic Rearrangement and Application in Heterocyclic Chemistry

The present review article summarizes the synthesis of allenes, which bear an adjacent functional group, by [3,3]- or [2,3]-sigmatropic rearrangement of appropriate propargyl substrates. Functionalized allenes, such as allenyl isothiocyanates, isoelenocyanates, isocyanates, thiocyanates, azides, azo compounds and others, are easily available by these methods. In several cases, however, the title compounds show high reactivity, which leads to rapid intermolecular or intramolecular successive reactions. Consequently, synthesis of the allenes by sigmatropic rearrangement has to be combined with special techniques, for example, flash vacuum pyrolysis or in situ generation and trapping reactions. The high tendency of the presented functionalized allenes to undergo cyclization reactions can be utilized to prepare heterocyclic products, for instance, thiazoles, selenazoles, 1,2,3-triazoles and pyrazoles. The synthesis of functionalized 1,3-butadienes by a second sigmatropic rearrangement of the title compounds is also successful.

Synthesis of aromatic terminal allenes and aliphatic terminal alkynes from hydrazones using calcium carbide as an acetylene source

A simple method for the selective synthesis of aromatic terminal allenes and aliphatic terminal alkynes from the reactions of calcium carbide with ketone and aldehyde p-tosylhydrazones using copper as a mediator is described.

Asymmetric Total Syntheses of (-)-Angustureine and (-)-Cuspareine via Rhodium-Catalyzed Hydroamination.

Concise syntheses of the Hancock alkaloids (-)-angustureine and (-)-cuspareine are presented, applying and refining a recently developed rhodium-catalyzed hydroamination for the stereoselective construction of the chiral secondary amine. Furthermore, the syntheses include an allene synthesis via boron-magnesium exchange as well as the construction of the tetrahydroquinoline motive via a hydroboration/Suzuki-Miyaura coupling sequence.

Recent Advances and Perspectives in Transition Metal‐Catalyzed 1,4‐Functionalizations of Unactivated 1,3‐Enynes for the Synthesis of Allenes

Classic methods for the synthesis of allenes usually introduce only one functional group into products. In this review, we highlight the recent advances and perspectives in the synthesis of allenes by transition metal‐catalyzed 1,4‐functionalization of unactivated 1,3‐enynes.

Enantioselective Synthesis of Multisubstituted Allenes by Cooperative Cu/Pd‐Catalyzed 1,4‐Arylboration of 1,3‐Enynes

AbstractA cooperative Cu/Pd‐catalyzed enantioselective synthesis of multisubstituted allenes is established. By employing chiral sulfoxide phosphine (SOP)/Cu and PdCl2(dppf) complexes as catalysts, the 1,4‐arylboration of 1,3‐enynes provides an efficient approach to trisubstituted chiral allenes with up to 92 % yield and 97:3 er. Furthermore, by using 2‐substituted 1,3‐enynes as substrates, the tetrasubstituted chiral allenes were successfully generated using this strategy. Finally, theoretical calculations indicate that the transmetallation of the allenylcopper species is the rate‐limiting step of this transformation.

Enantioselective Synthesis of Multisubstituted Allenes by Cooperative Cu/Pd-Catalyzed 1,4-Arylboration of 1,3-Enynes.

A cooperative Cu/Pd-catalyzed enantioselective synthesis of multisubstituted allenes is established. By employing chiral sulfoxide phosphine (SOP)/Cu and PdCl2 (dppf) complexes as catalysts, the 1,4-arylboration of 1,3-enynes provides an efficient approach to trisubstituted chiral allenes with up to 92 % yield and 97:3 er. Furthermore, by using 2-substituted 1,3-enynes as substrates, the tetrasubstituted chiral allenes were successfully generated using this strategy. Finally, theoretical calculations indicate that the transmetallation of the allenylcopper species is the rate-limiting step of this transformation.

Palladium-Catalyzed Regioselective Heck Coupling of Alkynes with Aryl Iodides for the Synthesis of Trisubstituted Allenes.

A utility approach toward trisubstituted allenes through Pd-catalyzed alkynyl Heck coupling reaction of alkynes and aryl iodides is reported. This process proceeded via regioselective carbopalladation of 1-aryl-1-alkynes to give alkenyl palladium species, which undergo β-hydride elimination to provide 1,1-diarylallenes in 25-71% yields. This method features unique regioselectivity and high functional group compatibility.

Negishi Coupling for Highly Selective Syntheses of Allenes via Ligand Effect and Mechanistic Study via SAESI‐MS/MS

Summary of main observation and conclusionβ‐H elimination is an intrinsic problem in transition metal‐catalyzed reactions. We describe herein an interesting ligand effect for Et2Zn acting as either ethyl provider or H provider, respectively: by applying SPhos or Gorlos‐Phos as the ligand, β‐H elimination has been successfully controlled in the corresponding Negishi coupling reaction affording different poly‐substituted allenes in good yields and excellent selectivities. SAESI‐MS (Solvent Assisted Electrospray Ionization Mass Spectrometry) has been applied to successfully capture the highly reactive organometallic intermediates, which show the different coordination behaviors of Pd with SPhos or Gorlos‐Phos as the ligand in the catalytic cycle. In addition, the different reactivities of Int 1 and Int 2 towards the formation of the final allene products have been demonstrated via SAESI‐MS/MS experiments. These MS studies visualized the whole catalytic cycle for the Negishi coupling reaction while nicely explain the observed reactivity and selectivity.

The synthesis of methyl triazole-4-carboxylate gold(I) complex and application on allene synthesis and alkyne hydration

The methyl 1H-1,2,3-triazole-4-carboxylate containing a strong electron-withdrawing group was developed and applied as a ligand for gold(I) cations. The resulting ester-triazole gold(I) complex was investigated for its efficiency in catalyzing allene synthesis and alkyne hydration, in which an excellent catalytic efficiency was observed with low catalyst loadings.