Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones

We report Ir‐catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β‐unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62–94 % yield with 90–98 % ee and >20:1 branched‐to‐linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI‐9826.     

Synthesis of Branched Alkylboronates by Copper‐Catalyzed Allylic Substitution Reactions of Allylic Chlorides with 1,1‐Diborylalkanes

Reported herein is a copper‐catalyzed S_N2′‐selective allylic substitution reaction using readily accessible allylic chlorides and 1,1‐diborylalkanes, a reaction which proceeds with chemoselective C?B bond activation of the 1,1‐diborylalkanes. In the presence of a catalytic amount of [Cu(IMes)Cl] [IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene] and LiOtBu as a base, a range of primary and secondary allylic chlorides undergo the S_N2′‐selective allylic substitution reaction to produce branched alkylboronates. The synthetic utilities of the obtained alkylboronates are also presented.     

Palladium‐Catalyzed Cascade Double C—N Bond Activation: A New Strategy for Aminomethylation of 1,3‐Dienes with Aminals

A new palladium‐catalyzed selective aminomethylation of conjugated 1,3‐dienes with aminals via double C—N bond activation is described. This simple method provides an effective and rapid approach for the synthesis of linear α,β‐unsaturated allylic amines with perfect regioselectivity. Mechanistic studies disclosed that one palladium catalyst cleaved two distinct C—N bond to furnish a cascade double C—N bond activation, in which an allylic 1,3‐diamine and allylic 1,2‐diamine were initially formed as key intermediates through the palladium‐catalyzed C—N bond activation of aminal and the α,β‐unsaturated allylic amine was subsequently produced via palladium‐catalyzed C—N bond activation of the allylic diamines.     

Homologous SNV Reaction: Synthesis of l‐Methyl‐4‐[4′‐phenylsulfonyl‐1′,3′‐butadienyl]pyridinium Iodide and Its Reactivity with Thiol Groups Giving Rise to the Chromophoric Thioether

Thioether 4‐[(1′E,3′E)‐4′‐phenylsulfanyl‐1,3′‐butadienyl]pyridine 8 and sulfone 4‐(4′‐phenylsulfonyl‐1′,3′‐butadienyl)pyridine 14 were prepared by reaction of the carbanions derived from allylic thioether or allylic sulfone with isonicotinaldehyde. The reaction with the sulfonyl carbanion occurred at the α position and on heating the alcolate gave the dienic sulfone 14 . The corresponding pyridinium iodide 10 and 15 were prepared by reaction with methyl iodide, respectively, on pyridine derivates 8 and 14 . The dienic pyridinium thioether 10 showed a long wavelength absorption band centered at 420 nm. The reaction of dienic pyridinium sulfone 15 with thiophenol gave the dienic pyridinium thioether 10 by a nucleophilic vinylic substitution. The reaction of sulfone 15 with glutathione was of second order and the rate constant was 8.5 M^?1s^?1 at 30°C and pH 7, about 500 times smaller than the rate constant observed with (E)‐1‐methyl‐4‐(2‐methylsulfonyl‐1‐ethenyl)pyridinium iodide 1 . The dienic pyridinium thioether 10 was a negative solvatochrome.     

A Mechanistic Analysis of the Palladium‐Catalyzed Formation of Branched Allylic Amines Reveals the Origin of the Regio‐ and Enantioselectivity through a Unique Inner‐Sphere Pathway

A recently reported palladium‐catalyzed allylic substitution of vinyl‐substituted cyclic carbonates (VCCs) with aryl amines represents a rare example of a regio‐ and enantioselective synthesis of α,α‐disubstituted allylic N‐aryl amines. However, the underlying reasons for this unusual selectivity profile remain elusive. In the present work, density functional theory (DFT) calculations in combination with mechanistic control experiments were performed to elucidate in detail this allylic amination manifold and the origin of the regio‐ and enantioselectivity. The combined data show that after oxidative addition of the VCC to Pd⁰, the nucleophilic attack via an originally proposed outer‐sphere pathway gives, however, the opposite regioisomer compared to the experimental results. Instead, nucleophilic attack of the amine reagent via a unique type of chelation‐assisted, inner‐sphere pathway accounts for the experimentally observed “branched” regioselectivity and high enantio‐control.     

Chromium‐Mediated Dearomatization: Application to the Synthesis of Racemic 15‐Acetoxytubipofuran and Asymmetric Synthesis of Both Enantiomers

An efficient dearomatization process of [Cr(arene)(CO)₃] complexes initiated by a nucleophilic acetaldehyde equivalent is detailed. It generates in a one‐pot reaction three C? C bonds and two stereogenic centers. This process allowed a rapid assembly of a cis‐decalin ring system incorporating a homoannular diene unit in just two steps starting from aromatic precursors (Scheme 2). The method was applied to the total synthesis of the eudesmane‐type marine furanosesquiterpene (±)‐15‐acetoxytubipofuran ( 2 ). Two routes were successfully used to synthesize the γ‐lactone precursor of the furan ring. The key step in the first approach was a Pd‐catalyzed allylic substitution (Scheme 3), while in the second approach, an Eschenmoser–Claisen rearrangement was highly successful (Scheme 4). The Pd‐catalyzed allylic substitution could be directed to give either the (normal) product with overall retention as major diastereoisomer or the unusual product with inversion of configuration (see Table). For the synthesis of the (?)‐enantiomer (R,R)‐ 2 of 15‐acetoxytubipofuran, an enantioselective dearomatization in the presence of a chiral diether ligand was implemented (Scheme 7), while the (+)‐enantiomer (S,S)‐ 2 was obtained via a diastereoselective dearomatization of an arene‐bound chiral imine auxiliary (Scheme 8). Chiroptical data suggest that a revision of the previously assigned absolute configuration of the natural product is required.     

Applications of Transition‐Metal‐Catalyzed Asymmetric Allylic Substitution in Total Synthesis of Natural Products: An Update

Metal‐catalyzed asymmetric allylic substitution (AAS) reaction is one of the most synthetically useful reactions catalyzed by metal complexes for the formation of carbon‐carbon and carbon‐heteroatom bonds. It comprises the substitution of allylic substrates with a wide range of nucleophiles or S_N2′‐type allylic substitution, which results in the formation of the above‐mentioned bonds with high levels of enantioselective induction. AAS reaction tolerates a broad range of functional groups, thus has been successfully applied in the asymmetric synthesis of a wide range of optically pure compounds. This reaction has been extensively used in the total synthesis of several complex molecules, especially natural products. In this review, we try to highlight the applications of metal (Pd, Ir, Mo, or Cu)‐catalyzed AAS reaction in the total synthesis of the biologically active natural products, as a key step, updating the subject from 2003 till date.     

Dihydrobenzoxazines and tetrahydroquinoxalines by a tandem reduction‐reductive amination reaction

A tandem reduction‐reductive amination reaction has been applied to the synthesis of 3,4‐dihydro‐2H‐1,4‐benzoxazines and 1‐acetyl‐1,2,3,4‐tetrahydroquinoxalines. The nitroketones required for the benzoxazine ring closures were prepared by (A) alkylation of the anion derived from 2‐nitrophenol with an allylic halide or (B) nucleophilic aromatic substitution of an allylic alkoxide on 2‐fluoro‐1‐nitrobenzene followed by ozonolysis. Precursors for the quinoxalines were prepared by alkylation of the anion of 2‐nitroacetanilide with an allylic halide followed by ozonolysis. Catalytic hydrogenation of the nitroketones using 5% palladium‐on‐carbon in methanol then gave the target heterocycles by a reduction‐reductive amination sequence. The N‐methyl derivatives for both ring systems were easily prepared by adding 5‐10 equivalents of aqueous formaldehyde prior to the reduction. The dihydrobenzoxazines were isolated in high yield following purification by chromatographic methods; tetrahydroquinoxalines were isolated in a similar manner and possessed differentiated functionality on the two nitrogens.     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).     

Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Silyl Dienolates Derived from Dioxinones

Reported herein is the iridium‐catalyzed regio‐ and enantioselective allylic substitution reactions of unstabilized silyl dienolates derived from dioxinones. Asymmetric allylic substitution of a variety of allylic trichloroethyl carbonates with these silyl dienolates gave γ‐allylated products selectively in 60–84 % yield and 90–98 % ee.     

Gold‐Catalyzed Cascade Reactions of Furan‐ynes with External Nucleophiles Consisting of a 1,2‐Rearrangement: Straightforward Synthesis of Multi‐Substituted Benzo[b]furans

A gold‐catalyzed cycloisomerization of silyl‐protected 2‐(1‐alkynyl)‐2‐alken‐1‐(2‐furanyl)‐1‐ols with various nucleophiles including water, alcohol, aniline, sulfonamide, and electron‐rich arene has been developed. The method provides a highly efficient access to 5,7‐disubstituted or 2,5,7‐trisubstituted benzo[b]furans with a wide diversity of substituents under mild reaction conditions, which are not easily available by other methods. Remarkably, an interesting rearrangement of the alkyl group from C2 to the C3 position of the furan ring takes place during the cyclization process. The following gold‐assisted allylic substitution enables an elaboration of benzo[b]furans on its side chain of the C5 position with a wide range of functional groups.     

Copper‐Catalyzed Borylcupration of Allenylsilanes

A highly regio‐ and stereoselective copper‐catalyzed borylcupration of 1,2‐allenylsilanes affords an unexpected regioreversed allylic boronate bearing an extra C?Si bond at the 3‐position, with a thermodynamically disfavored Z geometry. Such stereodefined allylic boronates containing an extra alkenyl silane moiety are very useful organodimetallic reagents for organic synthesis.     

Enantioselective Pd‐Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2‐a]indolone Substrates: Efficient Syntheses of (−)‐Goniomitine, (+)‐Aspidospermidine,and (−)‐Quebrachamine

The successful application of dihydropyrido[1,2‐a]indolone (DHPI) substrates in Pd‐catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross‐coupling downstream. The first catalytic enantioselective total synthesis of (?)‐goniomitine, along with divergent formal syntheses of (+)‐aspidospermidine and (?)‐quebrachamine, are reported herein.     

A Configurational Switch Based on Iridium‐Catalyzed Allylic Cyclization: Application in Asymmetric Total Syntheses of Prosopis,Dendrobate, and Spruce Alkaloids

A method for the stereoselective synthesis of 2,6‐disubstituted piperidines has been developed that is based on the use of an intramolecular iridium‐catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2‐vinylpiperidines with enantiomeric excesses (ee) of greater than 99 %. As applications, total syntheses of piperidine alkaloids have been elaborated, most often by using Ru‐catalyzed cross‐metatheses as a key step for introduction of a side chain. Asymmetric total syntheses of the prosopis alkaloids (+)‐prosopinine, (+)‐prosophylline, (+)‐prosopine, and of the dendrobate alkaloid (+)‐241D and its C6 epimer are described.     

Enantioselective Pd‐Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2‐a]indolone Substrates: Efficient Syntheses of (−)‐Goniomitine, (+)‐Aspidospermidine,and (−)‐Quebrachamine

The successful application of dihydropyrido[1,2‐a]indolone (DHPI) substrates in Pd‐catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross‐coupling downstream. The first catalytic enantioselective total synthesis of (−)‐goniomitine, along with divergent formal syntheses of (+)‐aspidospermidine and (−)‐quebrachamine, are reported herein.     

The Synthesis and Biological Evaluation of N‐Substituted 1H‐Benzimidazol‐2‐yl‐1H‐pyrazole‐3,5‐diamines

The synthesis of 1H‐benzimidazol‐2‐yl‐1H‐pyrazole‐3,5‐diamines has been developed. Synthesized bisheteroaryls contain two privileged medicinal scaffolds, aminopyrazole and benzimidazole, with two diversity positions at N1 of benzimidazole and C3 of pyrazole, respectively. The three‐step synthesis includes the Mitsunobu N‐alkylation of benzimidazole and subsequent one‐pot formation of aminopyrazole involving substitution of methylthio groups with amine and hydrazine followed with final ring closure. Inhibitory activity toward cyclin‐dependent kinase 2/cyclin E and cytotoxicity against two cancer cell lines were evaluated for all novel pyrazoles. Two compounds showed modest cyclin‐dependent kinase inhibition activity and cytotoxicity against cancer cell lines K562 and MCF7.     

Total Syntheses of (+)‐Grandilodine C and (+)‐Lapidilectine B and Determination of their Absolute Stereochemistry

Enantioselective total syntheses of the Kopsia alkaloids (+)‐grandilodine C and (+)‐lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)‐grandilodine C was achieved by palladium‐catalyzed intramolecular allylic amination and ring‐closing metathesis to give 8‐ and 5‐membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)‐lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies.     

Regio‐ and Enantioselective Synthesis of N‐Allylindoles by Iridium‐Catalyzed Allylic Amination/Transition‐Metal‐Catalyzed Cyclization Reactions

Regio‐ and enantioselective synthesis of N‐allylindoles was realized through an iridium‐catalyzed asymmetric allylic amination reaction with 2‐alkynylanilines and subsequent transition‐metal‐catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir‐catalysis were treated with catalytic amount of NaAuCl₄ ? 2 H₂O or PdCl₂ providing various substituted N‐allylindoles in excellent yields and enantioselectivities.     

Rhodium‐catalysed hydroformylation of 1‐octene using aryl and ferrocenyl Schiff base‐derived ligands

Monometallic and heterobimetallic complexes of Rh(I) bearing chelating N ,O ‐bidentate aryl‐ and ferrocenyl‐derived ligands have been synthesised via Schiff base condensation reactions, and characterised fully using ¹H NMR, ¹³C{¹H} NMR and Fourier transform infrared spectroscopies, elemental analysis and mass spectrometry. The new monometallic and heterobimetallic complexes were evaluated as potential catalyst precursors in the hydroformylation of 1‐octene at 95°C and 40 bar. The ferrocenylimine mononuclear compounds were inactive in the hydroformylation experiments. The Rh(I) monometallic and the ferrocene–Rh(I) heterobimetallic pre‐catalysts displayed good activity and conversion of 1‐octene as well as outstanding chemoselectivity towards aldehydes in the hydroformylation reaction.     

Nickel‐Catalyzed Allylic Alkylation with Diarylmethane Pronucleophiles: Reaction Development and Mechanistic Insights

Palladium‐catalyzed allylic substitution reactions are among the most efficient methods to construct C?C bonds between sp³‐hybridized carbon atoms. In contrast, much less work has been done with nickel catalysts, perhaps because of the different mechanisms of the allylic substitution reactions. Palladium catalysts generally undergo substitution by a “soft”‐nucleophile pathway, wherein the nucleophile attacks the allyl group externally. Nickel catalysts are usually paired with “hard” nucleophiles, which attack the metal before C?C bond formation. Introduced herein is a rare nickel‐based catalyst which promotes substitution with diarylmethane pronucleophiles by the soft‐nucleophile pathway. Preliminary studies on the asymmetric allylic alkylation are promising.