Unprecedented dithiolation of enals via their NHC-catalysed umpolung reaction with organic disulfides

A novel one-pot N-heterocyclic carbene (NHC)-catalysed dithiolation of α,β-unsaturated aldehydes (enals) with organic disulfides is reported. The protocol involves homoenolate reactivity of enals, where the homoenolate attacks on the disulfide as a d(3) nucleophile followed by thioesterification to afford β-aryl/alkylsulfanyl thioesters with complete atom economy.     

NHC-catalysed retro-aldol/aldol cascade reaction enabling solvent-controlled stereodivergent synthesis of spirooxindoles

An N-heterocyclic carbene (NHC)-catalysed retro-aldol/aldol cascade reaction of spirooxindole-based β-hydroxyaldehyde has been developed. The ring opening-closure process enables the diastereodivergent synthesis of spirocyclopentaneoxindole products with four consecutive stereocenters by simply changing the reaction solvents (THF or DCE). The Michael/aldol/retro-aldol/aldol sequential protocol allows the diastereodivergent synthesis of spirocyclopentaneoxindoles from 3-substituted oxindole and α,β-unsaturated aldehyde under the relay catalysis of a chiral secondary amine and an NHC catalyst. Moreover, four stereoisomers of the product can be selectively provided by using different combinations of a chiral secondary amine and a solvent.     

Highly enantioselective organocatalytic cascade reaction for the synthesis of piperidines and oxazolidines

The synthesis of piperidines and piperidines derivatives in enantiopure fashion has been a challenging goal for organic chemists. In this report we developed a nice cascade reaction for piperidine derivatives based in an amidomalonate Michael addition to enals followed by an intramolecular hemiaminal formation with good yields and enantioselectivities. Moreover we studied the ‘in situ’ intramolecular cyclization of this hemiaminals with alcohols forming fused piperidine-oxazolidines.     

Three-component diastereoselective cascade synthesis of thiohydantoins

A new three-component cascade reaction for the synthesis of thiohydantoins is reported. The reaction between α-amino esters, nitrostyrenes, and aromatic isothiocyanates is efficiently promoted by organic bases to afford highly substituted thiohydantoins in moderate to good yields and diastereoselectivities.     

Chemo- and diastereoselective synthesis of new oxa[3.3.3]propellane via a domino cascade four-component reaction based on diketene

A highly convergent, eco-friendly and straightforward synthesis of new O-fused heterocycles, functionalized indeno[1,2-b]furan derivatives was successfully accomplished through a one-pot four-component cascade reaction involving, ninhydrin, malononitrile, diketene and various primary amines in the presence of a catalytic quantity of triethylamine in ethanol at ambient temperature, in one pot fashion. This new efficient cascade reaction generates two rings by the simultaneous construction of C-N (one), C-O (two) and C-C (two) multiple bonds, presumably through a sequence of Knoevenagel reaction/Michael addition/intramolecular O-cyclization and imine-enamine/keto-enol tautomerization. The merits of this protocol are highlighted as utilization of inexpensive commercially accessible starting materials, operational simplicity, atom economy, clean reaction profile, simple work-up procedure being conducted at ambient temperature in relatively short reaction times, preventing chromatographic purification, giving excellent yields, and tolerance to a wide variety of functional groups.     

Highly diastereoselective arylations of substituted piperidines

A highly diastereoselective methodology for the preparation of various substituted piperidines via Negishi cross-couplings with (hetero)aryl iodides was developed. Depending on the position of the C-Zn bond relative to the nitrogen (position 2 vs position 4), the stereoselectivity of the coupling can be directed toward either the trans- or cis-2,4-disubstituted products. Density functional theory calculations on the relative stabilities of the Zn and Pd intermediates were performed to explain the high diastereoselectivities obtained. A novel 1,2-migration of Pd further expands this method to the stereoselective preparation of 5-aryl-2,5-disubstituted piperidines.     

An efficient green synthesis of dispirohydroquinolines via a diastereoselective one-pot eight-component reaction

The one-pot eight-component reaction between Meldrum's acid, an aromatic aldehyde, and an aryl amine was achieved in the presence of citric acid catalyst. The corresponding dispirohydroquino-lines were obtained in good yields with excellent diastereoselectivity. This method is a combination of the Knoevenagel and Michael reactions.     

Practical stereoselective synthesis of an alpha-trifluoromethyl-alpha-alkyl epoxide via a diastereoselective trifluoromethylation reaction

A practical stereoselective synthesis is reported for an alpha-trifluoromethyl-alpha-alkyl epoxide (1), which is an important pharmaceutical intermediate. The key step involves a chiral auxiliary-controlled asymmetric trifluoromethylation reaction for the introduction of the unique trifluoromethyl-substituted tertiary alcohol stereogenic center in the target molecule. The fluoride-initiated CF3 addition to chiral keto ester 6a proceeded with a diastereoselectivity up to 86:14. The major diastereomer was readily obtained with a >99.5:0.5 dr through a simple crystallization of the crude product mixture.     

A diastereoselective synthesis of 2,4-disubstituted piperidines: scaffolds for drug discovery

A method for the diastereoselective synthesis of 2,4-disubstituted piperidines has been developed which enables the complete control of reaction selectivity merely by changing the order of the reaction sequence. These targets provide convenient platforms for drug discovery which contain easily modified points of diversity.     

Chemo-selective cross reaction of two enals via carbene-catalyzed dual activation

A dual catalytic chemo-selective cross-coupling reaction of two enals is developed. One enal (without α-substitution) is activated by an NHC catalyst to form an acylazolium enolate intermediate that undergoes Michael-type addition to another enal molecule bearing an alkynyl substituent. Mechanistic studies indicate that non-covalent interactions between the alkynyl enal and the NHC·HX catalyst play important roles in substrate activation and enantioselectivity control. Many of the possible side reactions are not observed. Our reaction provides highly chemo- and diastereo-selective access to chiral lactones containing functionalizable 1,3-enyn units with excellent enantioselectivities (95 to >99% ee).

An NHC-catalyzed dual activation of two different enals is disclosed with both covalent and non-covalent activation pathways involved.

The development of chemo-selective reactions of two or more substrates bearing similar functional groups remains a classic challenge in organic synthesis.¹ Enals (α,β-unsaturated aldehydes) are common building blocks that offer multiple useful modes of reactions. For instance, enals are readily used as Michael acceptors in many reactions including organic catalytic reactions mediated by amines.² In the area of N-heterocyclic carbene (NHC) organocatalysis,³ enals are used as precursors of several NHC-bound intermediates, including Breslow acyl anion intermediates,⁴ homoenolate intermediates,⁵ enolate intermediates,⁶ and acylazolium intermediates.⁷ Somewhat surprisingly, on the other hand, there is little success in using enals as Michael acceptors to react with any of these NHC-bound intermediates.⁸ Elegant studies in this direction are from Scheidt, in which they showed that in the presence of an NHC catalyst, a homo coupling reaction of enals (with one enal molecule as the Michael acceptor) occurred effectively (Fig. 1a, top side).^8a,c Berkessel reported an intramolecular reaction of two enal moieties (in one molecule) to form a bicyclic lactone adduct in the presence of an achiral NHC catalyst (Fig. 1a, bottom side).^8b To the best of our knowledge, the intermolecular Michael addition reaction of two different enal substrates mediated by NHC catalysts has not been reported.⁹ Possible reasons for the difficulties of enals to behave as effective Michael acceptors likely include: (a) the relatively low electrophilicity of the α,β-unsaturated bonds of enals under the typical NHC catalytic conditions and (b) the presence of competing reactions involving both the alkene and aldehyde moieties of enals.Open in a separate windowFig. 1NHC-catalyzed reactions (a) with enals as Michael acceptors, (b) via cross intermolecular reactions of two enals, and (c) bio-active molecules bearing alkyne units.Here we disclose the first cross intermolecular reaction of two enals catalyzed by NHC catalysts (Fig. 1b). We envisioned that installation of an alkynyl substituent at the α-position of an enal can likely promote its reactivity as a Michael acceptor.¹⁰ The presence of an α-substituent can interrupt π-conjugations and thus minimize its reactivity via the corresponding enal-derived enolate/homoenolate intermediate formed with NHC, as shown by Bode, Glorius and others.^6b,11 In addition, the alkynyl substituent can promote hydrogen-bonding interactions to increase the electrophilicity of the enal to react as a Michael acceptor, as observed in Jørgensen''s amine-catalyzed reactions.¹² In our present study, a non-linear effect was observed regarding enantiomeric excesses of the NHC catalyst and the catalytic reaction product. The reaction enantioselectivity was also found to be sensitive to solvents and bases. These results suggested that the NHC and its azolium salt pre-catalyst (NHC·HX) played dual roles in our reaction: one is to activate the α-unsubstituted enal via the formation of the NHC-bound enolate intermediate,⁶ the other is to activate the α-alkynyl substituted enal via the acidic proton of the chiral NHC·HX (Fig. 1b, intermediate I & transition state TS-I).¹³ With respect to applications, carbon–carbon triple bonds are found in a good number of bioactive molecules such as cleviolide, (+)-prelaureatin, and oxamflatin (Fig. 1c).¹⁴ We demonstrated that our products containing these alkynyl units could be readily transformed into a diverse set of molecules.Cinnamaldehyde 1a and α-alkynyl enal 2a were chosen as the model substrates to search for suitable cross coupling reaction conditions (Table 1). The reactions were first carried out with Et₃N as the base and THF as the solvent. When aminoindanol derived azoium salt A¹⁵ was used as the NHC pre-catalyst, the desired formal [4 + 2] product (3a) was obtained in a very encouraging yield (52%) with excellent ee and dr values (entry 1). The reactions appeared to be very sensitive to the structure of the NHC pre-catalysts, as similar azolium salts with N-phenyl or N–C₆F₅ substituents (B¹⁶ and C¹⁷) were completely ineffective, leading to no product formation (entries 2 & 3). Additional studies on the NHC pre-catalysts finally revealed that introduction of a Br substituent in the indane phenyl ring of the catalyst (D)¹⁸ led to 3a in 85% yield with 99% ee as nearly a single diastereomer (entry 4). Replacing Et₃N with DIEA led to similar results (entry 5). Very interestingly, when the bases were replaced with DABCO or K₃PO₄, a significant drop in the enantioselectivity was observed (entries 6 & 7; see the ESI^† for more details). Changing the solvent from THF to CHCl₃ or EtOAc has moderate effects on reaction yields (entries 8 & 9).Optimization of reaction conditions^a

Three-component, one-pot diastereoselective synthesis of 4-amidotetrahydropyrans via the Prins-Ritter reaction sequence

Three-component coupling of carbonyl compounds, homoallylic alcohols, and nitriles has been achieved using 20 mol % of phosphomolybdic acid (PMA) at ambient temperature via the Prins-Ritter sequence to furnish 4-amidotetrahydropyrans in high yields with all cis selectivity. Spirocyclic-4-amidotetrahydropyrans are obtained using cyclic ketones.     

Facile and highly diastereoselective synthesis of 3-aminooxindoles via AgOAc-catalyzed vinylogous Mannich reaction

A novel AgOAc-catalyzed vinylogous Mannich reaction between easily prepared imines 1 derived from isatins and trimethylsilyloxyfuran 2 (TMSOF) was developed. This method provided a facile synthetic route to get access to synthetically useful quaternary 3-aminooxindole in excellent yields (94–99%) and diastereoselectivities (>99:1).     

A novel diastereoselective synthesis of (Z)-fluoroalkenes via a Nozaki-Hiyama-Kishi-type reaction

A highly diastereoselective and straightforward synthesis for (Z)-2-fluoroallylic alcohols via a Nozaki-Hiyama-Kishi-type reaction with the corresponding bromofluoroolefins was developed, providing an easy access to highly interesting fluorinated synthons.     

Stereocontrolled synthesis of 2,5-linked bistetrahydrofurans via the triepoxide cascade reaction

A complementary set of stereochemically controlled approaches to the preparation of twelve diastereomers of the bistetrahydrofurans 11 is described. The key transformation involves a series of nucleophilic displacement reactions within triepoxides 19-the “end-to-end” triepoxide cascade reaction—which leads, presumably via 22 and 23, after acetylation to bistetrahydrofuran tetraacetates 24. The “inside-out” cyclization of 30 exemplifies a useful variation with significant stereochemical consequences. The role of symmetry in these approaches is discussed. A general mathematical analysis for conceptualizing isomer distribution within multistep sequences is presented.     

A formal synthesis of ezetimibe via cycloaddition/rearrangement cascade reaction

A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.     

Asymmetric synthesis of trifluoromethyl substituted dihydropyrans via organocatalytic cascade Michael-hemiketalization reaction

Asymmetric conjugate addition of ethyl 4,4,4-trifluoroacetoacetate and other trifluoromethyl substituted nucleophiles to β,γ-unsaturated α-keto esters has been developed. The reaction efficiently provided dihydropyrans via cascade Michael-hemiketalization pathways. Quinine-derived thiourea was identified to be the best catalyst. A number of trifluoromethyl substituted dihydropyrans with three consecutive chiral centers were obtained in excellent yields, diastereoselectivities, and enantioselectivities. The product was readily transformed to the corresponding tetrahydropyridine without the loss of the optical purity.     

Visible-light-activated selective synthesis of sulfoxides via thiol-ene/oxidation reaction cascade

A convenient, highly selective and metal-free synthesis of sulfoxides from alkenes and thiols using NHPI as an inexpensive and reusable organophotoredox catalyst is reported. The protocol involves radical thiol-ene/oxidation reaction cascade and utilizes visible light and air (O₂) as inexpensive, readily available, non-toxic and eco-sustainable reagents to afford up to 96% yields of the product at room temperature.     

Highly diastereoselective synthesis of tetrahydropyridines by a C-H activation-cyclization-reduction cascade

A versatile reaction cascade leading to highly substituted 1,2,3,6-tetrahydropyridines has been developed. It comprises rhodium(I)-catalyzed C-H activation-alkyne coupling followed by electrocyclization and subsequent acid/borohydride-promoted reduction. This one-pot procedure affords the target compounds in up to 95% yield with >95% diastereomeric purity.     

Novel synthesis of substituted pyrrolidines and piperidines via radical addition-ionic cyclization reaction of oxime ethers

We have developed a novel synthetic route to nitrogen-containing heterocycles via radical addition-ionic cyclization reaction. Treatment of oxime ethers carrying the tosyloxy group with Et₃B and alkyl iodide in the presence of Lewis acid gave the substituted pyrrolidines and piperidines. The reaction of oxime ethers carrying the methoxycarbonyl group proceeded under the same conditions to give the amino esters, which were easily converted into the corresponding lactams by the treatment with concd HCl. On the other hand, the oxime ether bearing the phenoxycarbonyl group afforded directly alkylated lactams under the radical reaction conditions. The utility of this domino reaction was demonstrated by the synthesis of (±)-bgugaine and the formal synthesis of 5,8-disubstituted indolizidine alkaloids.     

N-heterocyclic carbene-catalyzed reaction of chalcones and enals via homoenolate: an efficient synthesis of 1,3,4-trisubstituted cyclopentenes

Nucleophilic heterocyclic carbene-catalyzed cyclopentannulation of enals and chalcones via homoenolate has been observed for the first time. Serendipitously, the reaction lead to a very efficient synthesis of 3,4-trans-disubstituted-1-aryl cyclopentenes instead of the expected cyclopentanones. The strategy works well with thienylidene tetralone also, leading to the tricyclic cyclopentene derivative.