High Cis-selectivity Research Articles

Cis-Selective Double Spirocyclization via Dearomatization and Isomerization under Thermodynamic Control.

Spiro compounds have been considered key scaffolds for pharmaceutical applications. Although many synthetic methods exist for monospirocycles, fewer approaches are known for dispirocycles. Here, we report a highly cis-selective method for constructing a 5/6/5-dispirocyclic structure containing pyrrolidine and γ-lactam rings with various substituents from a series of N-arylpropiolamides. The high cis-selectivity would result from isomerization under thermodynamic control. Cis- and trans-diastereomers can be in equilibrium, favoring cis-adducts.

Stereodivergent Assembly of 2,6-cis- and -trans-Tetrahydropyrans via Base-Mediated Oxa-Michael Cyclization: The Key Role of the TMEDA Additive.

The stereodivergent synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans (THPs) via sodium hexamethyldisilazide-promoted oxa-Michael cyclization of (E)-ζ-hydroxy α,β-unsaturated esters is presented. The cyclization affords the kinetically favored trans-THPs with high stereoselectivity (dr up to 93:7) at a low temperature (-78 °C), while the room-temperature reaction does not produce the thermodynamically preferred cis-THPs as major products and occurs with poor stereocontrol. The addition of tetramethylethylenediamine (TMEDA) significantly improves the stereochemical outcome of the room-temperature cyclization and allows attaining high cis-selectivity (dr up to 99:1). The remarkable effect of TMEDA indicates that the sodium cation plays an important role in controlling the stereoselectivity of the thermodynamically driven process, that is, complexation of the cation with the cyclization products results in diminished selectivity. DFT calculations support this conclusion, indicating a greater difference in Gibbs energies of sodium-free cis- and trans-enolates compared to the respective sodium chelate complexes. The synthetic utility of the method has been demonstrated by the formal syntheses of (+)-Neopeltolide and (-)-Diospongin B and the total synthesis of (-)-Diospongin A.

(Digital Presentation) Diastereoselective Electrocatalytic Hydrogenation of Mono-Substituted Cyclohexanones in a Proton Exchange Membrane Reactor

Cyclic alcohols are important building blocks of pharmaceuticals, perfumes, and liquid crystals. For instance, 4-tert-butylcyclohexyl acetate, which is derived from 4-tert-butylcyclohexanol (1), is a commercialized synthetic fragrance that is used more than 106 kg per year. The fragrance of its cis-isomer is more potent odorant than that of its trans-isomer, and hence, cis-4-tert-butylcyclohexyl acetate is obtained by acetylation of the corresponding alcohol, i.e., cis-1.On the other hand, cis-1 is generally obtained by the reduction of 4-tert-butylcyclohexanone (2). The use of sterically hindered L-selectride as a reductant gave 1 with 93% cis-isomer selectivity [1]. The stereoselective hydrogenation of ketone 2 to 1 with ruthenium-aminophosphine complexes using hydrogen gas and base also afford 96% cis-isomer [2]. Although high cis-selectivity is achieved by these methods, the use of hazardous reagents and their separation problems in the workup humper the large-scale application. Replacement of such homogeneous reductions (hydrogenations) by heterogeneous catalytic systems brings several economic and technical advantages. A major advantage of using heterogeneous catalysts is that the catalyst can be recovered from the reaction mixture by simple filtration. Therefore, the highly diastereoselective reduction (hydrogenation) of cyclic ketones using heterogeneous catalysts is a meaningful and challenging topic for sustainable chemistry.Here, we demonstrate the electrocatalytic hydrogenation of mono-substituted cyclohexanones in a proton exchange membrane (PEM) reactor (Figure 1a). We have investigated the effect of catalyst materials and current density on the current efficiency and cis-selectivity of the desired products. As a result, it was found that the use of the PEM reactor with Rh catalyst gave 1 with high cis-selectivity (94%) and high current efficiency (93%), as shown in Figures 1b and c. In addition, it was also confirmed that the present system was capable of continuous operation for several tens of hours and gram-scale electrolysis without loss of diastereoselectivity. Unlike conventional hydrogenation methods that are carried out under high temperature and high pressure, the PEM reactor can carry out the desired hydrogenation reaction under ambient temperature and pressure, which also suggests a significant improvement in energy efficiency. Furthermore, the reaction products are easily separated and the catalyst is highly recyclable. Thus, the hydrogenation using PEM reactors can realize energy-saving and clean organic reaction processes.The authors gratefully acknowledged support by JST CREST Grant No. JPMJCR18R1, Japan.

Sustainable Pd(OAc)2/Hydroquinone Cocatalyst System for Cis‐Selective Dibenzoyloxylation of 1,3‐Cyclohexadiene

AbstractThe 1,4‐diacyloxylation of 1,3‐cyclohexadiene (CHD) affords valuable stereochemically defined scaffolds for natural product and pharmaceutical synthesis. Existing cis‐selective diacyloxylation protocols require superstoichiometric quantities of benzoquinone (BQ) or MnO2, which limit process sustainability and large‐scale application. In this report, reaction development and mechanistic studies are described that overcome these limitations by pairing catalytic BQ with tert‐butyl hydroperoxide as the stoichiometric oxidant. Catalytic quantities of bromide enable a switch from trans to cis diastereoselectivity. A catalyst with a 1:2 Pd:Br ratio supports high cis selectivity while retaining good rate and product yield. Further studies enable replacement of BQ with hydroquinone (HQ) as a source of cocatalyst, avoiding the handling of volatile and toxic BQ in large‐scale applications.

Sustainable Pd(OAc)2 /Hydroquinone Cocatalyst System for Cis-Selective Dibenzoyloxylation of 1,3-Cyclohexadiene.

The 1,4-diacyloxylation of 1,3-cyclohexadiene (CHD) affords valuable stereochemically defined scaffolds for natural product and pharmaceutical synthesis. Existing cis-selective diacyloxylation protocols require superstoichiometric quantities of benzoquinone (BQ) or MnO2 , which limit process sustainability and large-scale application. In this report, reaction development and mechanistic studies are described that overcome these limitations by pairing catalytic BQ with tert-butyl hydroperoxide as the stoichiometric oxidant. Catalytic quantities of bromide enable a switch from trans to cis diastereoselectivity. A catalyst with a 1:2 Pd:Br ratio supports high cis selectivity while retaining good rate and product yield. Further studies enable replacement of BQ with hydroquinone (HQ) as a source of cocatalyst, avoiding the handling of volatile and toxic BQ in large-scale applications.

Intramolecular Umpolung Allylation of Imines.

An intramolecular umpolung allylation of imines is reported. This reaction occurs via the intermediacy of 2-azaallyl anions. It could proceed either under transition-metal-catalyzed conditions or under transition-metal-free conditions. Importantly, this approach afforded trans-3-vinyl-4-aminochromanes with high diastereoselectivity, while conventional, nonumpolung methods often display high cis-selectivity.

A Versatile and Highly Z-Selective Olefin Metathesis Ruthenium Catalyst Based on a Readily Accessible N-Heterocyclic Carbene

A ruthenium catalyst for Z-selective olefin metathesis has been synthesized from a readily accessible N-heterocyclic carbene (NHC) ligand that is prepared using an efficient, practical, and scalable multicomponent synthesis. The desired ruthenium complex with cyclometalated NHC ligand is obtained by means of selective C(sp3)-H activation at the adamantyl fragment and X-ray diffraction analysis unambiguously confirmed the structure of the precatalyst. The catalyst demonstrated attractive catalytic performance in self- and cross-metathesis at low catalyst loading to afford the desired internal olefins with high conversion and very high Z-selectivity (up to >99%). The versatility of the chelated catalyst is illustrated by the high cis-selectivity (up to >98%) and high tacticity control (up to >98% syndiotactic) achieved in ring-opening polymerization, allowing for the production of highly microstructurally controlled norbornene-, norbornadiene-, and cyclopropene-derived polymers.

Preparation, characterization, and hydrogenation activity of new Rh0–MCM-41 catalysts prepared from as-synthesized MCM-41 and RhCl3

Impregnation of as-synthesized MCM-41 silica by ethanolic solutions of rhodium(III) chloride was tested as an alternative to its introduction into the synthesis gel to get, after calcination and reduction by H 2 , highly dispersed metal(0) nanoparticles throughout the mesopores network. Rh(III) and Rh(0)–based solids thus obtained were analyzed by infrared spectroscopy, elemental analysis, transmission electron microscopy, N 2 sorption, and X-ray diffraction. Materials with 1.6 wt % of rhodium could be obtained as a result of CTA + /Rh 3+ exchange. The determining role of CTA + was emphasized through blank experiments. In a second series of materials, ethanol was also exploited for its ability to reduce Rh(III). All Rh(0)-based solids were tested as catalysts in the hydrogenation of styrene under mild temperature and pressure conditions. Catalysis performances of the most efficient sample (reduced by H 2 ) were further compared with those of a very similar material prepared by the introduction of Rh(III) directly into the synthesis gel of MCM-41 silica. Better cis selectivities in the hydrogenation of disubstituted arene derivatives were achieved with materials issued from the new preparation method. Ammonium template facilitates incorporation of Rh(III) in the as-synthesized MCM-41 in ethanol, thus affording, after an ex situ reduction step, catalytically active dispersions of Rh(0) with a high cis selectivity in the hydrogenation of disubstituted arenes. • The role of cetyltrimethylammonium in the uptake process of rhodium(III) was clearly demonstrated in ethanol. • Relationship between surfactant removal and rhodium incorporated was tested at different nominal molar Si/Rh ratios. • Ethanol can also be used as a reducing agent provided that the reaction is carried out ex-situ. • Differences were highlighted between the materials prepared according to this new path and that of direct hydrothermal synthesis. • Resulting materials lead to a better selectivity in cis hydrogenated compounds compared to samples prepared by DHT.

Cis-Specific Chain Transfer Ring-Opening Metathesis Polymerization Using a Vanadium(V) Alkylidene Catalyst for Efficient Synthesis of End-Functionalized Polymers

Highly efficient synthesis of end-functionalized polymers has been achieved by combined cis-specific ring-opening metathesis polymerization (ROMP) of norbornene with terminal olefins (1-hexene, allyltrimethylsilane (ATMS), etc.) as the chain transfer (cross metathesis) agent at 80 °C in the presence of V(CHSiMe3)(N-2,6-Cl2C6H3)[OC(CF3)3](PMe3)2. The ROMP proceeds with high activity and high cis selectivity (97–98%) upon addition of PMe3, and the Mn values could be controlled by varying the concentration of terminal olefins; the activity at 80 °C was not affected by the ATMS concentrations (5.0–50.0 mol %, TOF 1860–1890 min–1 ((1.12–1.13) × 105 h–1)).

Directed nucleophilic addition of phenoxides to cyclopropenes.

The alkali metal-templated addition of aryloxides across the double bond of non-conjugated cyclopropenes is described. High cis-selectivity is achieved through a directing effect of a strategically positioned carboxamide functionality.

Redox-Divergent Hydrogen-Retentive or Hydrogen-Releasing Synthesis of 3,4-Dihydroisoquinolines or Isoquinolines

A rare Ru-catalyzed highly selective synthesis of 3,4-dihydroisoquinolines or isoquinolines is accomplished via a redox-divergent hydrogen-retentive or hydrogen-releasing fashion. Notably, high cis-selectivity of 3,4-dihydroisoquinolines is achieved. Potential applications are shown by gram-scale reactions and very concise synthesis of N-containing polycyclic aromatic compounds. Primary mechanistic investigations indicate that the sequence of the major pathway involves Ru-catalyzed C-H activation, alkyne insertion, and subsequent 6π-electrocyclization.

Synthesis and characterization of high cis‐polymyrcene using neodymium‐based catalysts

AbstractThe monomer β‐myrcene, a renewable resource, was polymerized in cyclohexane using two different Ziegler‐Natta catalyst systems based on neodymium Nd(Oi‐Pr)3 and NdV3. The Nd(Oi‐Pr)3 was combined with [HNMe2Ph][B(C6F5)4] (or [CPh3][B(C6F5)4]) and Al(i‐Bu)3 (or Al(i‐Bu)2H). Next, the NdV3 was activated using Al(i‐Bu)3 and AlEt2Cl. Both catalyst systems exhibited high polymer yields near 100 % in the established reaction time, high polymer molecular masses, and broad molecular mass distributions. The catalyst systems gave an effective and stereospecific polymerization reaction of β‐myrcene providing high cis selectivity of 1,4‐polymyrcenes (> 92 %) with a glass transition temperature between −66 and −62 °C. The above‐mentioned features of resulting elastomers in conjunction with the polymer's molecular masses and molecular mass distributions proved to be sensitive to borane and alkylaluminum compounds molar ratios, [B]/[Nd] and [Al]/[Nd] using Nd(Oi‐Pr)3 and [Cl]/[Nd] and [Al]/[Nd] with NdV3.

ChemInform Abstract: Prins—Arylthiolation Reaction on Terpenoids: Diastereoselective Synthesis of 4‐Arylthiooctahydro‐2H‐chromenes.

Abstract(‐)‐Isopulegol undergoes Prins‐arylthiolation with aldehydes and cyclohexanone in the presence of HBF4·OEt2 to generate a library of 4‐arylthio‐octahydro‐2H‐chromene derivatives in good to excellent yields with moderate to high cis selectivity at ambient temperature in CH2Cl2.

Prins–Arylthiolation Reaction on Terpenoids: Diastereoselective Synthesis of 4‐Arylthiooctahydro‐2H‐chromenes

Abstract(–)‐Isopulegol undergoes Prins‐arylthiolation with different aldehydes and cyclohexanone in the presence of HBF4·OEt2 to generate a library of 4‐arylthiooctahydro‐2H‐chromene derivatives in good to excellent yields with moderate to high cis selectivity at ambient temperature in dichloromethane. Readily available HBF4·OEt2 as a catalyst outshines CF3CO2H, which is generally used in excess amounts in Prins cyclization and domino Prins‐arylthiolation reactions.

Cyclopolymerization of Si-Containing α,ω-Diolefins by a Pyridylamidohafnium Catalyst with High Cyclization Selectivity and Stereoselectivity

Cyclopolymerization of unsymmetric and symmetric Si-containing α,ω-diolefins by dimethylpyridylamidohafnium/organoboron catalytic system with high cyclization selectivity and stereoselectivity was first reported here. Compared with the constrained geometry catalyst [Me2Si(η5-Me4C5)(NtBu)]TiCl2 and the typical metallocene catalyst rac-Et(Ind)2ZrCl2, the Hf complex has proved to be one more promising catalyst for the cyclopolymerization of unsymmetric 3,3-dimethyl-3-sila-1,5-hexadiene (DMSHD). The poly(DMSHD) with high molecular weight (up to 953 kg/mol), high cyclization selectivity (100%), high cis selectivity (>90%), and high isotactic selectivity (>90%) could be easily obtained by the Hf catalyst under mild conditions. Moreover, the poly(DMSHD) also possessed a high glass transition temperature (up to 99.8 °C) and high melting temperature (Tm >200 °C). The insertion reaction of the vinyl group into Hf–CAr bond was further investigated, and a possible cyclization mechanism of DMSHD was proposed according...

Z-Selective ruthenium metathesis catalysts: Comparison of nitrate and nitrite X-type ligands

Two new Ru-based metathesis catalysts, 3 and 4, have been synthesized for the purpose of comparing their catalytic properties to those of their cis-selective nitrate analogues, 1 and 2. Although catalysts 3 and 4 exhibited slower initiation rates than 1 and 2, they maintained high cis-selectivity in homodimerization and ring-opening metathesis polymerization reactions. Furthermore, the nitrite catalysts displayed higher cis-selectivity than 2 for ring-opening metathesis polymerizations, and 4 delivered higher yields of polymer.

Highly diastereoselective N-acyliminium ion cyclization reactions of a tethered furan

The acid catalysed cyclization reactions of tethered furan−4,5-dihydroxypyrrolid-2-ones and furan–4,5-diacetoxypyrrolid-2-ones, via their corresponding N-acyliminium ion intermediates, have been studied. In the case of the tethered furan–3,4-dihydroxypyrrolid-2-one 16, having a two carbon tether, the linearly fused tricyclic compound 18 was formed with high cis selectivity (cis/trans=84:16) when BF3·OEt2 was used as a catalyst. However, when the cyclization reaction was carried out on the related tethered furan–4,5-diacetoxypyrrolid-2-one 17, the linearly fused tricyclic compound 20 was formed as a single diastereoisomer with trans selectivity. In contrast, the attempted cyclization of the tethered furan–4,5-dihydroxypyrrolid-2-one 26, having a one carbon tether, did not result in formation of the corresponding linearly fused tricyclic system, instead it formed the dimer 29 as a single diastereoisomer. Cyclization reactions of the related tethered furan–4,5-diacetoxypyrrolid-2-one 27 also failed to give the corresponding linearly fused tricyclic system or macrocycle.

I2-mediated carbamate annulation: scope and application in the synthesis of azasugars

The I2-mediated carbamate annulation provides an efficient and highly stereoselective route for the synthesis of a variety of pyrrolidines and piperidines, both in the presence and absence of protecting groups. Evidence for the formation of an iodoamine intermediate during the annulation is provided and, for the first time, we explore possible mechanisms of the annulation. The high cis-selectivity of the carbamate annulation is also compared to other N-halocyclisations and aminomercurations and some general conclusions about the diastereoselectivity of these types of reactions are made.

Stereoselective Synthesis of 1-Nitrobicyclo[3.1.0]hexanes and Fused Isoxazoline-N-oxides from Primary Nitro Compounds

The one-step preparation of 1-nitrobicyclo[3.1.0]hexane and bicycloisoxazoline-N-oxide was readily achieved from conjugate adducts of nitro alkenes and allylmalonates by treatment with Ag(2)O and iodine under basic conditions. We observed that when a primary alkyl group was present at the β-position of the nitro group, bicyclo[3.1.0]hexane was preferentially formed, whereas if a secondary alkyl group occupied that position, isoxazoline-N-oxide was predominantly produced. High cis-selectivity was observed for the formation of cyclopentane units for both reactions. An iodomethyl adduct, considered an intermediate of the cyclization, was isolated, and its conversion to isoxazoline-N-oxide was successfully achieved. The isoxazoline-N-oxide underwent 1,3-dipolar cycloaddition with alkenes to yield tricycloheterocyclic compounds, which were readily converted to spirolactam in good yield by reductive cleavage of N-O bonds using Raney-Ni. On the other hand, 1,3-dipolar cycloaddition of the isoxazoline-N-oxide to terminal alkynes yielded tricyclic aziridines stereoselectively.

ChemInform Abstract: BF3·OEt2‐Catalyzed Tandem Prins Friedel—Crafts Reaction: A Novel Synthesis of Sugar Fused Diarylhexahydro‐2H‐furo[3,2‐b]pyrans.

d-Glucose based homoallylic alcohol reacts smoothly with various aldehydes in the presence of arenes and a catalytic amount of BF3·OEt2 under mild conditions to afford a novel series of 5,7-diaryl-hexahydro-2H-furo[3,2-b]pyrans in good yields with high cis-selectivity.