Theoretical investigation toward organophosphine‐catalyzed [3 + 3] annulation of Morita–Baylis–Hillman carbonates with azomethine imines: Mechanism,origin of stereoselectivity,and role of catalyst

A computational study on the detailed mechanism and stereoselectivity of the chiral phosphine‐catalyzed C(sp²)? H activation/[3 + 3] annulation between Morita–Baylis–Hillman (MBH) carbonates and C,N‐cyclic azomethine imines has been performed. Generally, the catalytic cycle consists of two stages, that is, C(sp²)? H activation companied by the dissociation of the t‐BuO group forming phosphonium enolate, and [3 + 3] cycloaddition process followed by regeneration of the catalyst. The calculated results indicate that C(sp²)? H activation is rate‐determining while [3 + 3] cycloaddition is stereoselectivity‐determining. Furthermore, the advantageous hydrogen bond interactions and less steric hindrance in the RR configurational C? C bond forming transition states should be responsible for the favorability of RR‐configured product among the four possible products. The special role of the organocatalyst was also identified by natural bond orbital (NBO) and global reactivity index (GRI) analyses. The mechanistic insights obtained in the present study should be useful for understanding the novel organocatalytic C(sp²)? H activation and cycloaddition cascade reaction of MBH carbonates, and thus provide valuable clues on rational design of efficient organocatalysts for the C(sp²)? H activation/functionalizations.     

Stereoselective hetero-Diels–Alder reaction of 3-(polyfluoroacyl)chromones with enol ethers. Novel synthesis of 2-R-containing nicotinic acid derivatives

3-(Polyfluoroacyl)chromones undergo heterodiene cycloaddition to 3,4-dihydro-2H-pyran, 2,3-dihydrofuran and ethyl vinyl ether under mild conditions, producing novel fused pyrans with high stereoselectivity and in good yields. Some of these pyrans were transformed into 2-R^F-containing pyridines on treatment with ammonium acetate in ethanol.     

Stereochemistry of the [3+2] Cycloaddition of Acrylonitrile to the N-Oxide of 5-Methyl-4,5-dihydro-3H-spiro[benz-2-azepine-3,1'-cyclohexane]

The [3+2] cycloaddition of acrylonitrile to the N-oxide of 5-methyl-4,5-dihydro-3H-spiro[benz-2-azepine-3,1'-cyclohexane] under conditions of both kinetic and thermodynamic control proceeds without regioselectivity or stereoselectivity with the formation of eight isomeric 1-cyano- and 2-cyano-7-methyl-1,2,4,6,7,11b-hexahydro-5H-spiro[isoxazolidino[3,2-a]benz-2-azepine-5,1'-cyclohexanes], six of which were isolated in an individual state. Their structure and stereochemistry were established by ¹H NMR.     

Total Synthesis of (R,R,R)‐α‐Tocopherol Through Asymmetric Cu‐Catalyzed 1,4‐Addition

By introducing a disposable activating substituent at C‐3, the asymmetric 1,4‐addition to a notoriously unreactive 2‐substituted chromenone was achieved with high levels of (2R)‐stereoselectivity in the presence of a chiral Cu^I‐phosphoramidite complex as a catalyst. This paved the way for an efficient and conceptually novel synthesis of (R,R,R)‐α‐tocopherol from readily available starting materials.     

Unprecedented influence of remote substituents on reactivity and stereoselectivity in Cu(I)-catalysed [2 + 2] photocycloaddition. An approach towards the synthesis of tricycloclavulone

Cu(I)-catalysed [2 + 2] photocycloaddition of 1,6-dienes embedded in a furano sugar is described in connection to a synthetic approach to an abnormal marine prostanoid tricycloclavulone. An unprecedented influence of remote substituents on the reactivity and stereoselectivity of the photocycloaddition reaction has been uncovered during this investigation. While an alkene substituent inhibits cycloaddition through steric effects, a substituent having a hydroxyl or alkoxy group at the same location facilitates cycloaddition exclusively from its own side. This investigation has led to the synthesis of a functionalised 5,4-fused core unit of tricycloclavulone.     

Asymmetric Synthesis of Oxa‐Bridged Oxazocines through a Catalytic RhII/ZnII Relay [4+3] Cycloaddition Reaction

Oxa‐bridged oxazocines bearing three chiral carbon centers were synthesized efficiently through a bimetallic catalytic asymmetric tandem reaction of β,γ‐unsaturated α‐ketoesters with diazoimides. The process contained a rhodium‐promoted in situ generation of isomünchnone from diazoimide decomposition, and a [4+3]‐cycloaddition of β,γ‐unsaturated α‐ketoester catalyzed by a chiral N,N′‐dioxide‐Zn^II complex. Ligand‐accelerated catalysis was found, and a possible transition‐state model was proposed to explain the origin of stereoselectivity.     

Diastereodivergent Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Ylides and β‐Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies

A Cu^II‐catalyzed asymmetric 1,3‐dipolar cycloaddition using β‐fluoroalkyl alkenyl arylsulfones as dipolarophiles and glycine/alanine iminoesters as azomethine ylide precursors has been developed. Remarkably, a catalyst loading as low as 0.5 mol % is highly efficient. Accordingly, a wide range of enantioenriched 3‐fluoroalkyl pyrrolidines, as well as Δ²‐pyrroline and pyrrole derivatives, are generated in good to excellent yields with high asymmetric induction. This synthetic approach is diastereodivergent in that exo‐adducts could be converted into the corresponding exo′‐adducts by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene mediated epimerization at C2 of the pyrrolidine core. The free‐energy profiles from DFT calculations suggest the Michael addition of the 1,3‐dipole to be the rate‐ and enantiodetermining step, and the origin of stereoselectivity is studied by means of the noncovalent interaction (NCI) analysis.     

Control of N‐Heterocyclic Carbene Catalyzed Reactions of Enals: Asymmetric Synthesis of Oxindole‐γ‐Amino Acid Derivatives

A strategy to control the switch between a non‐cycloaddition reaction and a cycloaddition reaction of enals, using N‐heterocyclic carbene (NHC) catalyisis, has been developed. The new scalable protocol leads to γ‐amino‐acid esters bearing a tetrasubstituted stereocenter in good yields and high stereoselectivities by homo‐Mannich reactions of enals and isatin‐derived ketimines. By simply changing the N‐ketimine substituent to an ortho‐hydroxy phenyl group, the corresponding spirocyclic oxindolo‐γ‐lactams are obtained.     

An Agostic Iridium Pincer Complex as a Highly Efficient and Selective Catalyst for Monoisomerization of 1‐Alkenes to trans‐2‐Alkenes

A unique Ir complex (^tBuNC^CP)Ir with the pyridine–phosphine pincer as the sole ligand, featuring a dual agostic interaction between the Ir and two σ C−H bonds from a t Bu substituent, has been prepared. This complex exhibits exceptionally high activity and excellent regio‐ and stereoselectivity for monoisomerization of 1‐alkenes to trans ‐2‐alkenes with wide functional‐group tolerance. Reactions can be performed in neat reactant on a more than 100 gram scale using 0.005 mol % catalyst loadings with turnover numbers up to 19000.     

A computational study on the substituent effects and product stereoselectivity of the intermolecular formal aza-[3+3] cycloaddition reaction between vinylogous amides and α,β-unsaturated imine cations

The substituent effects and product stereoselectivity of the title reaction has been studied using density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level of theory. It was found that the substituents do not perturb the mechanism of intermolecular formal aza-[3+3] cycloaddition. Our calculations also show that methyl or benzyl groups on the N atom of vinylogous amide favor the addition step, but alkyl substituents on the either N atom or terminal C atom of α,β-unsaturated imine cation have opposite effects. Alkyl substituents on the N atom of α,β-unsaturated imine cation may lower the activation barriers for elimination of amide. The steric interaction between two substituents leads to the formation of major product both thermodynamically and kinetically.     

Microwave‐Induced Stereocontrol of β‐Lactam Formation with an N‐Benzylidene‐9,10‐dihydrophenanthren‐3‐amine via Staudinger Cycloaddition

The synthesis of 3‐substituted 4‐phenyl‐1‐(9,10‐dihydrophenanthren‐3‐yl)azetidin‐2‐ones was achieved following Staudinger cycloaddition under microwave‐induced conditions. The stereoselectivity of β‐lactam formation depended on the power level of the microwave irradiation used in the experiments.     

Sequential Intramolecular Diels–Alder Reaction of 3‐Heteroaryl‐2‐propenylamides of Ethenetricarboxylate

The reaction of 1,1,2‐ethenetricarboxylic acid 1,1‐diethyl ester with E‐3‐(2‐furyl)‐2‐propenylamines under the amide condensation conditions (EDCI/HOBt/Et₃N) on heating at 80–110°C afforded cis‐fused tricyclic compounds, furo[2,3‐f]isoindoles as major product. On the other hand, the reaction with E‐3‐(3‐furyl)‐2‐propenylamines afforded trans‐fused tricyclic compounds predominantly. The formation of amide/[4 + 2] cycloaddition/hydrogen‐shift reactions proceed sequentially. The observed stereoselectivity of the fused rings has been investigated by the density functional theory calculations. The reaction of 1,1,2‐ethenetricarboxylic acid 1,1‐diethyl ester with 3‐(3‐pyridinyl)‐2‐propen‐1‐amine under the amide condensation conditions afforded HOBt‐incorporated 3,4‐trans‐pyrrolidine selectively. The chemoselectivity and stereoselectivity of the reactions with (3‐heteroaryl)‐2‐propen‐1‐amines depend on the nature of heteroarenes.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XIX. Synthesis of N,N-disubstituted 4-amino-3-phenyl-2H-furo[2,3-h]-1-benzopyran-2-ones (4-amino-3-phenylangelicins). Crystal and molecular structure of 3-Phenylangelicin

1,4-Cycloaddition of phenylchloroketene to N,N-disubstituted 5-aminomethylene-6,7-dihydrobenzo[b]- furan-4(5H)-ones gave the corresponding adducts, namely N,N-disubstituted 4-amino-3-chloro-3,4,5,6-tetra- hydro-3-phenyl-2H-furo[2,3-h]-l-benzopyran-2-ones II , which were dehydrochlorinated with DBN to N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-furo[2,3-h]-1-benzopyran-2-ones III . Compounds III afforded the title compounds IV by dehydrogenation with DDQ. In the cycloaddition step, 3-phenylangelicin V , whose structure was confirmed by ¹H-nmr shift reagents data and by X-ray crystal structure determination, was almost always formed, probably starting from II by dehydrochlorination, dehydrogenation and hydrogenolysis of the disubstituted amino group. Separation of V was achieved by alumina chromatography either in the cycloaddition step or, in most cases, in the dehydrochlorination step. 3-Phenylangelicin crystallizes in the trigonal system, space group R3, with cell parameters (hexagonal axes) a = b = 41.021(10), c = 3.888(2) Å. The angelicin moiety forms a dihedral angle of 42.1(1)° with the phenyl substituent. Disordered solvent molecules of ethyl acetate are clathrated in channels in the direction of the crystallographic axis c.     

Stereoselective β‐Mannosylation with 2,6‐Lactone‐bridged Thiomannosyl Donor by Remote Acyl Group Participation

Stereoselective β‐mannosylation has been recognized as one of the greatest challenges of carbohydrate chemistry. Herein, we described a practical method for stereoselective construction of β‐mannosides by using a 2,6‐lactone‐bridged thiomannosyl donor through the remote acyl‐group participation as well as the steric effect of O‐4 substituent. The two effects are enabled through the conversion of a regular mannopyranosyl ⁴C₁ conformation into a 2,6‐lactone bridged conformation. The lactone donor could be readily prepared in three steps on a gram scale and the β‐mannosylation proceeded smoothly with high stereoselectivity for primary, secondary and tertiary alcohol acceptors. In addition, this strategy was successfully applied to the synthesis of a naturally occurring trisaccharide.     

Stereoselective hetero-Diels-Alder reaction of 3-(trifluoroacetyl)chromones with cyclic enol ethers: synthesis of 3-aroyl-2-(trifluoromethyl)pyridines with ω-hydroxyalkyl groups

3-(Trifluoroacetyl)chromones undergo heterodiene cycloaddition to 3,4-dihydro-2H-pyran and 2,3-dihydrofuran under mild conditions, producing novel fused pyrans with high stereoselectivity and in good yields. These pyrans were transformed into functionalized pyridines on treatment with ammonium acetate in ethanol. The structures of the endo-cycloadducts were established by ¹H NMR spectroscopy and X-ray diffraction analysis.     

An unusual substituent effect in a cycloaddition of an azolium ylide 1,3-dipole: An inverted V-shaped hammett plot

An unusual inverted V-shaped Hammett plot has been observed for substituent effects at the N-terminus of 1,2,3-triazolium-1-imide 1,3-dipoles in cycloaddition reactions. Theoretical studies (3-21G and 6-31G) suggest strong resonance interactions separately stabilizing both ends of the dipole.     

Stereoselective Photoredox Catalyzed (3+3) Dipolar Cycloaddition of Nitrone with Aryl Cyclopropane

By resorting to the principle of remote activation, we herein demonstrate the first photoredox catalyzed (3+3) dipolar cycloaddition of nitrones with aryl cyclopropanes. Key to the fidelity of the reaction resides in a facile manner of substrate activation by single-electron transfer (SET) oxidation with photoredox catalysis, and the reaction takes place through a stepwise cascade encompassing a three-electron-type nucleophilic substitution triggered cyclopropane ring-opening and a diastereoselective 6-endo-trig radical cyclization manifold. The reaction proceeds under mild conditions with excellent regio- and stereoselectivity, nicely complementing the well-developed Lewis acid catalyzed cycloaddition of donor-acceptor cyclopropanes. Other merits of the protocol include wide scope of aryl cyclopropanes with diversified substitution patterns and good functional-group compatibility. A mechanism involving an aryl radical cation promoted remote activation mode was also proposed and supported by mechanistic experiments.     

Stereoselectivity control by torsional steering in an intramolecular Diels-Alder reaction of vinyl oxocarbenium ions

[reaction: see text] Density functional theory (B3LYP/6-31+G) has revealed the origin of stereoselectivity in intramolecular Diels-Alder reactions of vinyl oxocarbenium ions. The cycloaddition has endo preference and occurs with remote stereocontrol syn to the substituent at the stereogenic center. Torsional steering, the preference for the staggered conformation about forming sigma-bonds, dictates the preferred transition structure.     

A theoretical study of the mechanism and stereoselectivity of the Diels-Alder cycloaddition between difluoro-2-methylencyclopropane and furan

A theoretical study of the molecular mechanism and stereoselectivity of the Diels-Alder cycloaddition reaction between difluoro-2-methylencyclopropane and furan has been carried out at the B3LYP/6-31G+^∗∗ level of theory. The calculation of activation and reaction energies indicates that the 3-endo cycloadduct is favored both kinetically and thermodynamically, which is in agreement with the experimental data. Analysis of the bond order and charge transfer in the transition states shows that this reaction takes place via a synchronous-concerted mechanism.     

Stereochemistry of the reaction of ribonucleoside cyclic 3′,5′-phosphorothioates with oxiranes

The stereochemical course of the epoxide-induced oxidative rearrangement of ribonucleoside cyclic 3′,5′-phosphorothioates into the corresponding 2′,3′-phosphates has been determined using styrene [¹⁸O] oxide and (S_p)-uridine cyclic 3′,5′-phosphorothioate. The evidence of full stereoselectivity of this reaction is presented and mechanistic implications of the presence of the nucleoside 2′-hydroxyl group are discussed in terms of a classical Hamer Mechanism.