Allene Unit Research Articles

A Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and Na-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure−activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies.

Cu-Catalyzed γ-Addition to Form Unnatural Amino Acid Bearing Allene Units

Cu-Catalyzed γ-Addition to Form Unnatural Amino Acid Bearing Allene Units

Regio- and Diastereoselective Formal [2+2] Cycloaddition of Allenes with Amino-Functionalized Alkenes by Rare-Earth-Catalyzed C(sp2 )-H Activation.

The [2+2] cycloaddition of allenes with alkenes is of much interest and importance as a straightforward route for the construction of four-membered carbocycles but has remained much underexplored to date. Herein we report for the first time the intermolecular regio- and diastereoselective formal [2+2] cycloaddition of a wide range of allenes with amino-functionalized alkenes by half-sandwich rare-earth catalysts. The reaction proceeded through an allene C(sp2 )-H activation mechanism initiated by the site-selective deprotonation of the allene unit by a rare-earth metal alkyl species followed by alkene insertion into the resulting metal-allenyl bond and the subsequent intramolecular cycloaddition to an allene C=C bond. This protocol offers a unique route for the synthesis of a new family of cyclobutane and cyclobutene derivatives which were difficult to access previously.

Regio‐ and Diastereoselective Formal [2+2] Cycloaddition of Allenes with Amino‐Functionalized Alkenes by Rare‐Earth‐Catalyzed C(sp2)−H Activation

AbstractThe [2+2] cycloaddition of allenes with alkenes is of much interest and importance as a straightforward route for the construction of four‐membered carbocycles but has remained much underexplored to date. Herein we report for the first time the intermolecular regio‐ and diastereoselective formal [2+2] cycloaddition of a wide range of allenes with amino‐functionalized alkenes by half‐sandwich rare‐earth catalysts. The reaction proceeded through an allene C(sp2)−H activation mechanism initiated by the site‐selective deprotonation of the allene unit by a rare‐earth metal alkyl species followed by alkene insertion into the resulting metal‐allenyl bond and the subsequent intramolecular cycloaddition to an allene C=C bond. This protocol offers a unique route for the synthesis of a new family of cyclobutane and cyclobutene derivatives which were difficult to access previously.

Basicity of five-membered cyclic allenes: Proton and cation affinity evaluation using density functional theory calculations

The proton affinity (PA) of stable five-membered cyclic allenes 1–13 in the gas phase was studied by DFT/B3LYP computational method in conjunction with the 6-311+G(d,p) basis set. The PAs of the title compounds are large. Their protonation at the central carbon introduces super- and hyperbases as evidenced by their enthalpies of protonation ΔH = 272–315 kcal/mol, which are above the threshold of superbasicity and in some cases close to the hyperbasicity. The trends of PA correlate quite well with the energy level of the HOMO orbitals and the molecular electrostatic potential maps of the studied allenes. The Wiberg bond order analysis gives a reasonable explanation of the exocyclic delocalization involving the π-donor substituents with the allenic unit of the studied compounds. Protonation of central carbon in the cyclic allenes leads to a change in the structural arrangement and an increment in the aromaticity of the pyrazole ring, which was evaluated by the HOMA index. Furthermore, the B3LYP/6-311+G(d,p) calculated cation affinities for the cyclic allene 6 increases as K+<Na+<Li+<Cu+<Mg2+<Fe2+<Cu2+. Cation affinity is strongly dependent on the charge-to-size ratio of the Mn+.

Engaging Yne‐Allenes in Cycloaddition Reactions: Recent Developments

Comprehensive SummaryYne‐allenes bearing both a C—C triple bond and an allene unit are a class of focal substrates in organic synthesis, in view of their structure diversity, high reactivity and intermediate variety in the past years. Engaging yne‐allenes in numerous annulation cascades provides efficient and direct accesses to elaborate functionalized polycyclic molecular architectures in a convergent manner. There are lots of types of catalytic chemical reactions such as intramolecular cyclizations, cycloisomerizations, intermolecular annulations, and bicyclizations as well as tricyclizations with the assistance of Lewis acids, Brønsted acids, bases, transition metals, and other catalysts. This review provides an overview of the chemistry developed with transformations of yne‐allenes by discussing their general and specific reactivities, presenting and commenting on their mechanisms as well as their applications.

Design, Synthesis, Evaluation and Structure of Allenic 1α,25-Dihydroxyvitamin D3 Analogs with Locked Mobility at C-17.

Vitamin D receptor ligands have potential for the treatment of hyperproliferative diseases and disorders related to the immune system. However, hypercalcemic effects limit their therapeutical uses and call for the development of tissue‐selective new analogs. We have designed and synthesized the first examples of 1α,25‐dihydroxyvitamin D3 analogs bearing an allenic unit attached to the D ring to restrict the side‐chain conformational mobility. The triene system was constructed by a Pd0‐mediated cyclization/Suzuki‐Miyaura cross‐coupling process in the presence of an allenic side chain. The allenic moiety was built through an orthoester‐Claisen rearrangement of a propargylic alcohol. The biological activity and structure of (22S)‐1α,25‐dihydroxy‐17,20‐dien‐24‐homo‐21‐nor‐vitamin D3 bound to binding domain of the vitamin D receptor, provide information concerning side‐chain conformational requirements for biological activity.

One Stone Two Birds—Enantioselective Bimetallic Catalysis for α‐Amino Acid Derivatives with an Allene Unit

Main observation and conclusionA highly enantioselective 2,3‐allenylation of acyclic and cyclic α‐imino carboxylates via a synergistic bimetallic Pd/Cu catalysis with the same commercially available (R,Rp)‐iPr‐FOXAP (also as Phosferrox, (R,R)‐[2‐(4’‐i‐propyloxazolin‐2’‐yl)ferrocenyl]diphenyl phosphine) ligand for both metals affording optically active 2,3‐butadienyl α‐amino acid derivatives in high to excellent yields with excellent enantioselectivities has been developed. The synthetic versatility of this reaction has been demonstrated by gram‐scale synthesis, a catalytic enantioselective synthesis of naturally occurring (S)‐2‐amino‐4,5‐hexadienoic acid A, and conversions to several useful chemicals, such as optically active α‐amino acids, β‐amino alcohols, potential chiral oxazoline ligands bearing an allenic moiety, and bicyclic ketone compounds. A mechanism involving the roles of two metals and the single chiral ligand has been extensively studied based on the isolation of key palladium pre‐catalyst and control experiments.

Stretchable chiral pockets for palladium-catalyzed highly chemo- and enantioselective allenylation

Pyrazolones are a vital class of heterocycles possessing various biological properties and much attention is paid to the diversified synthesis of enantiopure pyrazolone derivatives. We describe here the development of diphenylphosphinoalkanoic acid based chiral bisphosphine ligands, which are successfully applied to the palladium-catalyzed asymmetric allenylation of racemic pyrazol-5-ones. The reaction affords C-allenylation products, optically active pyrazol-5-ones bearing an allene unit, in high chemo- and enantioselectivity, with DACH-ZYC-Phos-C1 as the best ligand. The synthetic potential of the C-allenylation products is demonstrated. Furthermore, the enantioselectivity observed with DACH-ZYC-Phos-C1 is rationalized by density functional theory studies.

Catalytic enantioselective construction of axial chirality in 1,3-disubstituted allenes

Metal-catalyzed enantioselective construction of the loosening axial allene chirality spreading over three carbon atoms using a chiral ligand is still a significant challenge. In the literature, steric effect of the substrates is the major strategy applied for such a purpose. Herein, we present a general palladium-catalyzed asymmetrization of readily available racemic 2,3-allenylic carbonates with different types of non-substituted and 2-substituted malonates using (R)-(−)-DTBM-SEGPHOS as the preferred ligand to afford 1,3-disubstituted chiral allenes with 90~96% ee. This protocol has been applied to the first enantioselective synthesis of natural product, (R)-traumatic lactone. Control experiments showed that in addition to the chiral ligand, conducting this transformation via Procedure C, which excludes the extensive prior coordination of the allene unit in the starting allene with Pd forming a species without the influence of the chiral ligand, is crucial for the observed high enantioselectivity.

Palladium-catalyzed intermolecular allenylation reactions of 2,3-disubstituted indoles and allenyl carbonate.

A palladium-catalyzed intermolecular allenylation of non-strained 2,3-disubstituted indoles and allenyl carbonate has been developed, providing convenient access to indolenines bearing an allene unit by taking advantage of the C-3 nucleophilicity of indoles. Decent yields and good functional group tolerance have been achieved with diverse indoles under mild conditions. Gram-scale reaction and various synthetic transformations have been demonstrated.

Tunable Synthesis of 2-Ene-1,4-diones, 4-Hydroxycyclopent-2-en-1-ones, and 2-(Furan-3-yl)acetamides via Palladium-Catalyzed Cascade Reactions of Allenols.

An efficient and regioselective synthesis of 2-ene-1,4-diones, 4-hydroxycyclopent-2-en-1-ones, or 2-(furan-3-yl)acetamides is successfully realized through palladium-catalyzed one-pot multicomponent reactions of allenols with aryl iodides and carbon monoxide in the presence of tertiary amines. Interestingly, the selectivity depends on the substitution patterns of the allenol substrates. To be specific, from the reaction of allenols with no substituent attached on the internal position of the allenic moiety, 2-ene-1,4-diones or 4-hydroxycyclopent-2-en-1-ones were formed selectively through carbonylation of aryl iodide followed by acylation of allenol with the in situ formed acyl palladium species, β-hydride elimination of the in situ formed allyl palladium complex, and further tautomerization or intramolecular aldol reaction. From the reaction of allenols bearing a substituent at the internal position of the allenic unit, on the other hand, diversely substituted 2-(furan-3-yl)acetamides were formed through a cascade process combining carbonylation of aryl iodide, acylation, and carbonylation of allenol followed by intramolecular condensation and amination by tertiary amine featuring an oxidant-free C-N bond cleavage.

Cyclocopolymerization Based on Alternating Insertions of Isocyanide and Allene Units into a Palladium–Carbon Bond

A new mode of polymerization has been developed that involves the alternating heteroinsertion of isocyanide and allene. Aryl isocyanides that contain both isocyano and allenyl moieties were designed and synthesized. The molecules rapidly polymerized in the presence of [bis(triphenylphosphino)methyl]palladium chloride through the fully alternating insertions of the isocyanide and allene moieties into a palladium–carbon bond to afford novel polymers that contain quinoline backbones. The polymer chain was elongated by the addition of further monomer following its initial consumption, and the present polymerization is living in nature through retention of chain end active species. This is the first polymerization involving alternating incorporation of isocyanide and allene.

ChemInform Abstract: Synergistic Kinetic Resolution and Asymmetric Propargyl Claisen Rearrangement for the Synthesis of Chiral Allenes.

AbstractThe kinetic resolution of racemic propargyl vinyl ethers (I) through an enantioselective Claisen rearrangement affords chiral allenes (II) and enantiopure ethers (S)‐(I).

Synergistic Kinetic Resolution and Asymmetric Propargyl Claisen Rearrangement for the Synthesis of Chiral Allenes.

The asymmetric propargyl Claisen rearrangement provides a convenient entry to chiral allene motifs. Herein, we describe the development of a kinetic resolution and asymmetric rearrangement of racemic propargyl vinyl ethers. This transformation afforded chiral allene products along with the enantiomerically enriched substrate in good yields with excellent diastereo- and enantioselectivity. The complete chirality transfer and facially selective rearrangement enabled the simultaneous construction of an axially chiral allenic unit and a quaternary carbon stereocenter.

Synergistic Kinetic Resolution and Asymmetric Propargyl Claisen Rearrangement for the Synthesis of Chiral Allenes

AbstractThe asymmetric propargyl Claisen rearrangement provides a convenient entry to chiral allene motifs. Herein, we describe the development of a kinetic resolution and asymmetric rearrangement of racemic propargyl vinyl ethers. This transformation afforded chiral allene products along with the enantiomerically enriched substrate in good yields with excellent diastereo‐ and enantioselectivity. The complete chirality transfer and facially selective rearrangement enabled the simultaneous construction of an axially chiral allenic unit and a quaternary carbon stereocenter.

Investigations on the [2,3]-Wittig Rearrangement of Chiral 4-Aminopropargyloxy Acetates to Novel α-Hydroxy-γ-amino Acids Containing an Allene Unit

The [2,3]-Wittig rearrangement of propargyloxy acetates bearing a propargylic stereocenter opposite to the oxyacetic acid moiety gives α-hydroxy-γ-amino acids containing an allene unit under high stereocontrol. The resulting product displays a novel type of γ-amino acid with a potentially intriguing biological profile.

ChemInform Abstract: The Au(I) Catalyzed Activation of Allenamides and Their Subsequent Transformation into Chromanes: A Method for the Regiocontrolled Addition to the α‐ and γ‐Positions of the Allene Unit.

AbstractThe formal [3 + 3] cycloaddition of phenols with oxazolidinone derived allenamides in the presence of Au(I)‐catalysts is developed.

An Enantioselective Synthesis of (R)‐5,6‐Octadecadienoic Acid

AbstractA convenient, scalable, and highly enantioselective total synthesis of (R)‐5,6‐octadecadienoic acid was developed by using the recently established ATA (allenylation of terminal alkynes) reaction of TBS‐protected (TBS = tert‐butyldimethylsilyl) propargyl alcohol with n‐dodecanal in the presence of (R)‐α,α‐diphenylprolinol as the chiral source. The axial chirality of the allene unit withstood the many common organic transformations that were needed to achieve the total synthesis with a high ee (enantiomeric excess) value.

The Au(I) catalyzed activation of allenamides and their subsequent transformation into chromanes: a method for the regiocontrolled addition to the α- and γ-positions of the allene unit.

Au(I) activation of allenamides in the presence of phenols leads to the formation of chromanes in moderate to good yields. This catalytic process is dependent on the counterion which facilitates the activation of the in situ formed imine. Furthermore, this iminium can be intercepted by trimethylallyl silane, via the Hosomi-Sakurai reaction, giving a formal procedure for the regioselective intermolecular addition of two carbon nucleophiles to an allenamide at the α- and γ-positions.