High E-selectivity Research Articles

1-Methyl-1H-tetrazol-5-yl (MT) sulfones in the Julia-Kocienski olefination: Comparison with the PT and the TBT sulfones

The stability and the stereoselectivity of newly prepared n-pentyl 1-methyl-1H-tetrazol-5-yl (MT) sulfone 1a in the Julia-Kocienski reactions were compared with those of the PT sulfone 1b and the TBT sulfone 1c. The improved stability of the anion derived from the n-pentyl MT sulfone 1a enhanced the efficiency of the olefination reactions and gave higher yields of the product alkenes 3 compared with the PT sulfone 1b. Especially high E-selectivity and high yields were obtained from the reaction with aromatic aldehydes and α,β-unsaturated aldehydes. The selectivity of 1a was not so sensitive to the change of base counter ion compared with the PT sulfone 1b. The reaction of the MT sulfones having either ethyl or a longer alkyl chain also gave E-alkenes selectively in high yields.

Enantioselective syntheses of (E)-γ,δ-disubstituted homoallylic alcohols via BF3·OEt2-catalyzed aldehyde allylboration and analysis of the origin of E-selectivity: A1,2 allylic strain vs. syn-pentane interaction

Enantioselective allylboration of aldehydes with α-substituted β-methyl allylboronate was reported. By using BF3·OEt2 as the catalyst, γ,δ-disubstituted homoallylic alcohols were obtained in good yields with high E-selectivities and enantioselectivities. Transition state analysis revealed that the disfavored transition state suffers from a syn-pentane interaction between the BF3 catalyst and axially oriented α-substituent of the allylboron reagent. Such a syn-pentane interaction is severe enough to overcome the A1,2 allylic strain between the β-methyl group and the α-substituent of the boron reagent that is present in the favored competing transition state. Consequently, the reaction proceeded with equatorial placement of the α-substituent to furnish γ-methyl substituted homoallylic alcohols with high E-selectivity.

Deacylative 1,6-addition of Bestmann-Ohira reagent to p-quinone methides for the synthesis of α-diazo-β-diarylphosphonates and cis-stilbenyl phosphonates

The role of Bestmann-Ohira Reagent (BOR) as a conjugate addition partner is reported for the first time. Deacylation of BOR in the presence of ethanolic KOH and 1,6-addition of the resulting diazophosphonate anion to p-quinone methides (PQMs) provides β-disubstituted α-diazophosphonates in good to excellent yields in most cases. Such 1,6-adducts further undergo Rh-catalyzed elimination of the diazo group and 1,2-migration of the phenolic group to afford cis-stilbenylphosphonates with high E-selectivity. The migration of the phenolic group presumably takes place via a spirocyclopropane intermediate derived from the Rh-carbenoid.

Ionic Ga-Complexes of Alkylidene- and Arylmethylidenemalonates and Their Reactions with Acetylenes: An In-Depth Look into the Mechanism of the Occurring Gallium Chemistry.

A new synthetic concept was suggested in the chemistry of substituted methylidenemalonates that enables their utilization as 1,2-zwitterionic synthons. This strategy is to generate liquid ionic Ga complexes from methylidenemalonates and GaHal3 with a strict 3/4 composition and then use them in further synthesis. A number of complexes with different metal halides have been synthesized and studied in detail. The unique properties of gallium among all metals have been demonstrated and explained. On the basis of the discovered new class of gallium complexes of methylidenemalonates, a number of novel reactions with acetylenes have been elaborated, which are unknown in the conventional chemistry of methylidenemalonates. The main demonstrated process is a three-component addition to a triple bond involving halide anions, leading to the formation of polyfunctional vinyl halides with high E-selectivity. The mechanism has been studied experimentally in fine detail. Application of specially optimized 71Ga NMR spectroscopy makes it possible to take an in-depth look into the gallium chemistry in a new light. In particular, the key participation of GaHal4- anions in the occurring transformations has been established.

Switchable Decarboxylative Heck-Type Reaction and Oxo-alkylation of Styrenes with N-Hydroxyphthalimide Esters under Photocatalysis.

The switchable visible-light-mediated decarboxylative Heck-type reaction and oxo-alkylation reaction of N-hydroxyphthalimide esters under photocatalysis were developed. Disubstituted or trisubstituted alkenes were obtained in good yield with high E-selectivity in the presence of Brønsted acid as the additive, while ketones resulted in the absence of the acidic additive.

Synthesis of Optically Pure (S,E)-2-Amino-5-arylpent-4-enoic Acids by Heck Reactions of Nickel Complexes

Starting from commercially available building blocks a variety of enantiomerically pure (S)-2-amino-4-enoic acids has been synthesized by the Heck reaction using Ni-(S)-BPB {Nickel-N-[(S)-benzylprolyl]aminobenzophenone} as a chiral auxiliary. The reactions proceeded in very good yields and with high E-selectivity.

Transition‐Metal‐Catalyzed Regiodivergent and Stereoselective Access to Branched and Linear Allylated 4‐Pyridones

A regiodivergent and stereoselective transition-metal-catalyzed addition of 4-pyridones to allenes furnishing N-allylated pyridones is reported. Employing a commercially available chiral rhodium catalyst enabled enantioselective branched-selective allylation. Conversely, an achiral palladium catalyst led to linear-selective N-allylation in high E-selectivities. A wide range of functional groups was tolerated and assorted synthetic transformations of the N-allylated pyridones demonstrated their utility for the syntheses of medicinally relevant heterocyclic scaffolds.

Fast-Initiating, Ruthenium-based Catalysts for Improved Activity in Highly E-Selective Cross Metathesis.

Ruthenium-based olefin metathesis catalysts bearing dithiolate ligands have been recently employed to generate olefins with high E-selectivity (>99% E) but have been limited by low to moderate yields. In this report, 1H NMR studies reveal that a major contributing factor to this low activity is the extremely low initiation rates of these catalysts with trans olefins. Introducing a 2-isopropoxy-3-phenylbenzylidene ligand in place of the conventional 2-isopropoxybenzylidene ligand resulted in catalysts that initiate rapidly under reaction conditions. As a result, reactions were completed in significantly less time and delivered higher yields than those in previous reports while maintaining high stereoselectivity (>99% E).

Origin of high E-selectivity in 4-pyrrolidinopyridine-catalyzed tetrasubstituted α,α'-alkenediol: a computational and experimental study.

We have developed 4-pyrrolidinopyridine catalysts for the geometry-selective (E-selective) acylation of tetrasubstituted α,α'-alkenediols. To elucidate the major factors of the high geometry selectivity, experimental and computational studies were carried out. The control experiments with respect to the substituent of the substrate indicated the fundamental hydrogen bonding of the acidic hydrogen of NHNs and the Z-OH in the substrate. Comparison between C2- and C1-symmetric catalysts exhibited the necessity of the C2-symmetric catalyst structure. The computationally proposed transition state (TS) model well explained the experimental results. Whereas the fundamental NH/amide-CO and the two-point free-OH/acetate anion hydrogen bonds stabilize the transition state (TS), affording the E-product, the steric repulsion between the N-protecting group and the amide side chain destabilizes TS, affording the Z-product. The role of the two amide side chains of the catalyst in a C2-symmetric fashion is the enhancement of the molecular recognition ability through the additional hydrogen bond in a cooperative manner.

ChemInform Abstract: Clay‐Supported Copper Nitrate (Claycop): A Mild Reagent for the Selective Nitration of Aromatic Olefins.

AbstractThe method is environmentally benign.

ChemInform Abstract: Toward the Synthesis of Amphidinolide P: Optimization of a Model Ene—Yne Metathesis Fragment Coupling.

Abstract Ene–yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene–yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda–Grubbs carbene complexes.

Toward the synthesis of amphidinolide P: optimization of a model ene–yne metathesis fragment coupling

Ene–yne cross metathesis was assessed for use as a key fragment coupling in a planned total synthesis of amphidinolide P. A terminal alkyne containing a β,γ-epoxide was synthesized and employed as the alkyne partner in an intermolecular ene–yne metathesis. In the alkene substrate, optimal functionality and reaction conditions were determined. An unprotected allyl alcohol was found to be critical for both high yield and high E-selectivity. Fewer equivalents of the alkene resulted in incomplete reaction and side reactions consumed the terminal alkyne. The best ruthenium carbene precatalysts were found to be the Hoveyda–Grubbs carbene complexes.

Synthesis of a chiral phosphonium salt for the preparation of α-substituted alaninol derivatives

We herein report the synthesis of a chiral phosphonium salt, {[(4S)-4-methyl-2-oxo-1,3-oxazolidin-4-yl]methyl}(triphenyl)phosphonium iodide 13 to provide a new Wittig reagent for the general method of synthesizing α-substituted alaninol derivatives. Our method described here is widely applicable to reactions with various types of aldehyde to afford olefin products with high E-selectivity, enabling us to provide a new approach to the synthesis of chiral S1P1 agonists including our key intermediates, and of the trace amine-associated receptor 1 (TAAR1) agonist.

Nickel-catalyzed oxidative cross-coupling of arylboronic acids with olefins

Abstract A novel and efficient nickel-catalyzed oxidative cross-coupling of arylboronic acids with olefins to synthesize 1,2-diarylalkenes has been developed. By employing Ni(acac)2 as the catalyst, TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) as the oxidant, a variety of arylboronic acids and styrene derivatives could be cross-coupled efficiently to afford the corresponding 1,2-diarylalkenes in moderate-to-good yields. Notably, high E-selectivity of 1,2-diarylalkenes was obtained with the aid of a high temperature of 120°C. Moreover, boric acid esters also proved to be efficient coupling partners. Initial mechanistic studies suggest that this reaction proceeds through a radical pathway.

Ligand mediated iron catalyzed dimerization of terminal aryl alkynes: scope and limitations

Regioselective dimerization of terminal aryl alkynes to produce conjugated enynes has been achieved using FeCl3 and KO(t)Bu in the presence of either DMEDA or dppe. The reaction proceeds smoothly in toluene at 145 °C for 2 h to give the corresponding head-to-head dimers in good to excellent yields (54 to 99%) with high E-selectivity (67 : 33 to 83 : 17 E/Z). Both strongly electron-donating and electron-withdrawing groups are compatible with this procedure. The bidentate phosphine (dppe) ligand exhibits better catalytic activity than the bidentate amine (DMEDA). The aliphatic acetylene fails to react under this catalytic system which suggests that potassium tertiary butoxide activates the conjugated system of aryl acetylene through cation-pi interaction and pi-pi interaction. A radical inhibitor (galvinoxyl or TEMPO) completely suppresses the reaction. Employing FeCl2 as a catalyst instead of FeCl3, only phenyl acetylene afforded the corresponding head to head dimer in good yield. Mechanistic pathways for both FeCl3 catalyzed dimerization of aryl alkynes and FeCl2 catalyzed dimerization of phenyl acetylene have been proposed.

ChemInform Abstract: Stereoselective Synthesis of Tetrasubstituted Olefins Through a Halogen‐Induced 1,2‐Silyl Migration.

AbstractThis method affords tetrasubstituted α‐silyl‐β‐haloenones with high E‐selectivity under mild conditions.

Photodecarboxylative addition of carboxylates to phthalimides: a concise access to biologically active 3-(alkyl and aryl)methylene-1H-isoindolin-1-ones

A series of 3-(alkyl and aryl)methyleneisoindolin-1-one derivatives were synthesized in a simple two-step procedure using a recently established photodecarboxylative addition of carboxylates to phthalimides as the key-step. Subsequent acid-catalyzed dehydration and deprotection furnished the desired target compounds with high E-selectivity. The reaction sequence was applied to the synthesis of the known bioactive phenylethylene derivative, AKS-186. Different analogues, including heteroatom-containing isosteres were also synthesized using this approach.

ChemInform Abstract: β‐Olefination of 2‐Alkynoates Leading to Trisubstituted 1,3‐Dienes.

AbstractThe reaction is mediated by PTA and proceeds mostly with complete (E)‐selectivity.

β-Olefination of 2-Alkynoates Leading to Trisubstituted 1,3-Dienes

A phosphine-mediated olefination of 2-alkynoates with aldehydes forming 1,3-dienes with high E-selectivity and up to 88% yield is described. Reaction conditions are optimized and reactions are demonstrated for various aryl, alkyl, and alkenyl aldehydes and for ethyl 2-alkynoates with different substituents in the δ-position. Proof of concept is shown for the generation of a β,γ-unsaturated lactone by intramolecular olefination, and furthermore the use of the generated 1,3-dienes in the Diels-Alder reaction has been demonstrated.

Highly E-selective solvent-free Horner–Wadsworth–Emmons reaction catalyzed by DBU

The solvent-free Horner–Wadsworth–Emmons reaction of triethyl phosphonoacetate with a variety of aldehydes was catalyzed by DBU in the presence of K2CO3 to give E-α,β-unsaturated esters highly selectively (99 : 1 for most of the reactions). The reaction with ketones gave trisubstituted olefins with good to high E-selectivity by DBU-Cs2CO3.