Isothiourea Catalyst Research Articles

Kinetic Resolution of Alcohols by Using a Recyclable Isothiourea Catalyst

Kinetic Resolution of Alcohols by Using a Recyclable Isothiourea Catalyst

Acylative Kinetic Resolution of Alcohols Using a Recyclable Polymer-Supported Isothiourea Catalyst in Batch and Flow

A polystyrene-supported isothiourea catalyst, based on the homogeneous catalyst HyperBTM, has been prepared and used for the acylative kinetic resolution of secondary alcohols. A wide range of alcohols, including benzylic, allylic, and propargylic alcohols, cycloalkanol derivatives, and a 1,2-diol, has been resolved using either propionic or isobutyric anhydride with good to excellent selectivity factors obtained (28 examples, s values up to 600). The catalyst can be recovered and reused by a simple filtration and washing sequence, with no special precautions needed. The recyclability of the catalyst was demonstrated (15 cycles) with no significant loss in either activity or selectivity. The recyclable catalyst was also used for the sequential resolution of 10 different alcohols using different anhydrides with no cross-contamination between cycles. Finally, successful application in a continuous flow process demonstrated the first example of an immobilized Lewis base catalyst used for the kinetic resoluti...

Multicomponent, Enantioselective Michael-Michael-Aldol-β-Lactonizations Delivering Complex β-Lactones.

Optically active, tertiary amine Lewis bases react with unsaturated acid chlorides to deliver chiral, α,β-unsaturated acylammonium salts. These intermediates participate in a catalytic, enantioselective, three-component process delivering bi- and tricyclic β-lactones through a Michael-Michael-aldol-β-lactonization. In a single operation, the described multicomponent, organocascade process forms complex bi- and tricyclic β-lactones by generating four new bonds, two rings, and up to four contiguous stereocenters. In the racemic series, yields of 22-75% were achieved using 4-pyrrolidinopyridine as Lewis base. In the enantioselective series employing isothiourea catalysts, a kinetic resolution of the initially formed racemic Michael adduct appears operative, providing yields of 46% to quantitative (based on 50% max) with up to 94:6 er. Some evidence for a dynamic kinetic asymmetric transformation for tricyclic-β-lactone 1d was obtained following optimization (yields up to 61%, 94:6 er) through a presumed reversible Michael.

Insights into the isothiourea-catalyzed asymmetric [4 + 2] annulation of phenylacetic acid with alkylidene pyrazolone.

A density functional theory (DFT) study was performed to explore the possible reaction mechanisms and the origin of stereoselectivity for the isothiourea-catalyzed [4 + 2] annulation reaction of in situ activated phenylacetic acid with alkylidene pyrazolone. The computed results reveal that the reaction contains several steps, including complexation of isothiourea with substrate, dissociation of the t-BuCO2- group, α-C-H deprotonation of the acyl ammonium intermediate, stepwise [4 + 2] cycloaddition processes, and the dissociation of isothiourea. The C-C bond formation involved in the [4 + 2] cycloaddition process was identified as the stereoselectivity-determining step, in which the two chiral carbon centers emerge. The pathway associated with the RR configurational isomer is calculated to be most energetically favorable, which is consistent with the experimental observations. The origin of stereoselectivity was further studied through analyses of distortion/interaction and non-covalent interaction (NCI), and the role of isothiourea was discovered by the analyses of the global reaction index (GRI) and Parr functions. By analyzing the activity of different isothiourea catalysts, it was found that a stronger nucleophilicity of the center N atom of the isothiourea catalysts would result in a lower energy barrier of the reaction. The novel insights obtained in the present study would be useful for the rational design of more efficient catalysts for this kind of reaction.

Evaluating polymer-supported isothiourea catalysis in industrially-preferable solvents for the acylative kinetic resolution of secondary and tertiary heterocyclic alcohols in batch and flow

Highly recyclable isothiourea catalysts on various polymer supports are reported for the kinetic resolution of alcohols.

Diastereo- and Enantioselective Synthesis of Bi- and Tricyclic N-Heterocycle-Fused β-Lactones.

The utility of the nucleophile-catalyzed (Lewis base) aldol lactonization (NCAL) process for the diastereo- and enantioselective synthesis of N-heterocycle-fused-β-lactones from N-linked ketoacids is described. A series of bi- and tricyclic, N-heterocycle-fused, β-lactones were first synthesized in racemic fashion via the NCAL process with excellent diastereoselectivity (>19:1) utilizing 4-pyrrolidinopyridine as an effective achiral Lewis base. A catalytic, enantioselective version of this NCAL process using isothiourea catalysts provided access to bicyclic β-lactone-fused, N-heterocycles in moderate to good yields (up to 80%) with high enantiocontrol (up to >99:1 er). An unusual diastereodivergent NCAL process was discovered that leads to two different products; a tricyclic N-heterocycle-fused β-lactone and a bicyclic enamine derived from in situ decarboxylation of the diastereomeric tricyclic β-lactone. The reactivity of these adducts was briefly explored.

Enantioselective Isothiourea-Catalysed Michael–Michael–Lactonisation­ Cascade Reaction for the Synthesis of δ-Lactones and 1,2,3,4-Substituted Cyclopentanes

This manuscript describes the application of α,β-unsaturated acyl ammonium intermediates in a Michael–Michael–lactonisation cascade process to furnish δ-lactones. Generation of α,β-unsaturated acyl ammonium intermediates was achieved upon addition of isothiourea catalyst HyperBTM into α,β-unsaturated acid chlorides. Subsequent reaction with enone-malonates gave access to δ-lactones in 20–64% yield, 72.5:27.5 to 95:5 er and 81:19 to >95:5 dr. Additionally, application of a ring-opening protocol yielded 1,2,3,4-substituted cyclopentanes in 28–77% yield, 76:24 to 98:2 er and 86:14 to >95:5 dr. Interestingly, the highest er was observed at high reaction temperatures, with 70 °C proving optimal. This effect was investigated by conducting an Eyring analysis, which indicated that differential activation entropy rather than differential activation enthalpy is responsible for enantiodiscrimination in this process.

Asymmetric Isothiourea-Catalysed Formal [3+2] Cycloadditions of Ammonium Enolates with Oxaziridines.

A highly enantioselective Lewis base-catalysed formal [3+2] cycloaddition of ammonium enolates and oxaziridines to give stereodefined oxazolidin-4-ones in high yield is described. Employing an enantioenriched oxaziridine in this process leads to a matched/mis-matched effect with the isothiourea catalyst and allowed the synthesis of either syn- or anti-stereodefined oxazolidin-4-ones in high d.r., yield and ee. Additionally, the oxazolidin-4-one products have been derivatised to afford functionalised enantioenriched building blocks.

Diastereoselective and enantioselective silylation of 2-arylcyclohexanols.

The silylation-based kinetic resolution of trans 2-arylcyclohexanols was accomplished by employing a triaryl silyl chloride as the derivatizing reagent with a commercially available isothiourea catalyst. The methodology is selective for the trans diastereomer over the cis, which provides an opportunity to selectively derivatize one stereoisomer out of a mixture of four. By employing this technology, a facile, convenient method to form a highly enantiomerically enriched silylated alcohol was accomplished through a one-pot reduction-silylation sequence that started with a 2-aryl-substituted ketone.

Facile net cycloaddition approach to optically active 1,5-benzothiazepines.

The 1,5-benzothiazepine moiety is well-known as a versatile pharmacophore, and its derivatives are expected to have antagonism against numerous diseases. Thus, it is desirable to develop a synthetic route that enables facile enantioselective preparation of a wide range of such derivatives. Although the cycloaddition approach could be considered a possible route to these compounds, to date, there has been no precedent of such a protocol. We therefore present the first example of a highly enantioselective net [4 + 3] cycloaddition to afford 1,5-benzothiazepines by utilizing α,β-unsaturated acylammonium intermediates generated by chiral isothiourea catalysts, which undergo two sequential chemoselective nucleophilic attacks by 2-aminothiophenols. This protocol provided cycloadducts in extremely high regioselectivity, with a good-to-excellent stereoselectivity being achieved regardless of the steric and electronic properties of the substrates. This method therefore offers promising synthetic routes for the construction of a library of optically active 1,5-benzothiazepines for assay evaluation.

ChemInform Abstract: Isothiourea‐Mediated One‐Pot Synthesis of Functionalized Pyridines.

AbstractThe reaction of a range of α,β‐unsaturated ketimines with (phenylthio)acetic acid in the presence of an isothiourea catalyst is developed to yield 2,4,6‐trisubstituted pyridines.

Structure–activity relationship of dihydroimidazo-, dihydropyrimido, tetrahydrodiazepino-[2,1-b]-thiazoles, and -benzothiazoles as an acylation catalyst

Cyclic isothioureas 1, 2, 3, and 4 were synthesized through a four-step procedure from the corresponding ortho-bromoanilines 10 via Pd- or Cu-catalyzed cyclization–benzothiazole formation. Nonbenzo analogues 7, 8, and 9 were synthesized by a condensation reaction of cyclic thioureas 15 and α-bromoacetophenones 14. Investigations of the acylation reactions of 1-phenylethanol with acid anhydrides in the presence of these cyclic isothiourea catalysts revealed their structure–activity relationships. Remarkable electronic effects resulting from substituent(s) on a benzo or phenyl moiety and the influence of the size of the annulating ring were observed. Introduction of an electron-donating substituent(s) enhanced the reaction rate. A few substitution effects on chiral catalysts of type 3 and 7 were also studied.

Silylation-Based Kinetic Resolution of α-Hydroxy Lactones and Lactams

A silylation-based kinetic resolution has been developed for α-hydroxy lactones and lactams employing the chiral isothiourea catalyst (-)-benzotetramisole and triphenylsilyl chloride as the silyl source. The system is more selective for lactones than lactams, and selectivity factors up to 100 can be achieved utilizing commercially available reagents.

Rapid assembly of complex cyclopentanes employing chiral, α,β-unsaturated acylammonium intermediates

With the intention of improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino processes that generate multiple bonds and stereocentres in a single operation. However, despite the great importance of substituted cyclopentanes, given their prevalence in complex natural products and pharmaceutical agents, the rapid, enantioselective assembly of these carbocycles lags behind cyclohexanes. Here, we describe a Michael-aldol-β-lactonization organocascade process for the synthesis of complex cyclopentanes utilizing chiral α,β-unsaturated acylammonium intermediates, readily generated by activation of commodity unsaturated acid chlorides with chiral isothiourea catalysts. This efficient methodology enables the construction of two C-C bonds, one C-O bond, two rings and up to three contiguous stereogenic centres delivering complex cyclopentanes with high levels of relative and absolute stereocontrol. Our results suggest that α,β-unsaturated acylammonium intermediates have broad utility for the design of organocascade and multicomponent processes, with the latter demonstrated by a Michael-Michael-aldol-β-lactonization.

ChemInform Abstract: Amidines, Isothioureas, and Guanidines as Nucleophilic Catalysts

AbstractReview: 66 refs.

Amidines, isothioureas, and guanidines as nucleophilic catalysts

Over the last ten years there has been a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines are often only thought of as strong organic bases however, a number of small molecules containing basic functional groups have been shown to act as efficient nucleophilic catalysts. This tutorial review highlights the use of amidine, guanidine, and related isothiourea catalysts in organic synthesis, as well as the evidence for the nucleophilic nature of these catalysts. The most common application of these catalysts to date has been in acyl transfer reactions, although the application of these catalysts towards other reactions is an increasing area of interest. In this respect, amidine and guanidine derived catalysts have been shown to be effective in catalysing aldol reactions, Morita-Baylis-Hillman reactions, conjugate additions, carbonylations, methylations, silylations, and brominations.

1,3-Dipolar cycloaddition of unstabilised azomethine ylides by Lewis base catalysis

Lewis base catalysed 1,3-dipolar cycloaddition between α,β-unsaturated acyl fluorides and N-[(trimethylsilyl)methyl]amino ethers has been achieved using 1 mol% DMAP. Competition experiments and (19)F-NMR studies indicate that the cycloaddition occurs preferentially between the α,β-unsaturated acyl fluoride and the unstabilised azomethine ylide. In addition, an enantioselective variant, using chiral isothiourea catalysts, has been achieved with 14% ee.

ChemInform Abstract: Structure—Enantioselectivity Effects in 3,4‐Dihydropyrimido[2,1‐b]‐benzothiazole‐Based Isothioureas as Enantioselective Acylation Catalysts.

AbstractAn isothiourea catalyst is developed for the kinetic resolution of a variety of secondary aromatic alcohols using low catalyst loading (0.1—0.25 mol%).

Structure-enantioselectivity effects in 3,4-dihydropyrimido[2,1-b]benzothiazole-based isothioureas as enantioselective acylation catalysts

The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ~50% conversion). Low catalyst loadings (0.10-0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.

Enantioselective Steglich Rearrangement Using Isothiourea Catalysts

Smith and colleagues report isothiourea catalysts 3 and 4 in the enantioselective carboxy group transfer of oxazolyl carbonates 1 (the Steglich rearrangement). The origin of stereo­control by these nucleophilic catalysts was studied by computational means. C4-α-Alkyl-branched oxazolyl carbonates were demonstrated to undergo the rearrangement with both catalysts (product 2a), expanding the scope of the transformation to this challenging class of substrates.