Stereoselective reactions of acyclic allylic phosphates with organocopper reagents

A series of acyclic allylic alcohols of general structure R(1)CH==CHCH(OH)R(2) were resolved by Sharpless kinetic resolution. The hydroxyl groups of these enantiomerically enriched alcohols were derivatized to diethyl phosphates, and the derivatives were reacted with organocopper reagents. Cleanest substitution reactions were observed with reagents R(3)(2)CuCNLi(2). With R(1) = Me and R(3) = n-Bu, the size of R(2) affected both the regioselectivity and stereoselectivity of the displacement. Larger R(2) groups gave higher regio- and stereoselectivities: with R(2) = 3-pentyl, >98% S(N)2' regioselectivity and >98% anti stereoselectivity were observed. Bn(2)CuCNLi(2) gave stereoselectivities comparable to those observed with n-Bu(2)CuCNLi(2) but t-Bu(2)CuCNLi(2) exhibited much lower diastereofacial preference.     

Reversible 1,3-anti/syn-stereochemical courses in copper-catalyzed γ-selective allyl-alkyl coupling between chiral allylic phosphates and alkylboranes

The stereochemical courses of the copper-catalyzed allyl-alkyl coupling between enantioenriched chiral allylic phosphates and alkylboranes were switchable between 1,3-anti and 1,3-syn selectivities by the choice of solvents and achiral alkoxide bases with different steric demands. The reactions with γ-silylated allylic phosphates allow efficient synthesis of enantioenriched chiral allylsilanes with tertiary or quaternary carbon stereogenic centers. Cyclic and acyclic bimodal participation of alkoxyborane species in an organocopper addition-elimination sequence is proposed to account for the phenomenon of the anti/syn-stereochemical reversal.     

Rapid injection NMR reveals η3 'π-allyl' Cu(III) intermediates in addition reactions of organocuprate reagents

By using rapid injection NMR, it has now been possible to prepare and characterize the η(3) 'π-allyl' copper(III) intermediate that has been proposed for addition reactions of organocopper(I) reagents and α,β-unsaturated carbonyl compounds.     

Regio- and stereoselective synthesis of (E)-alkene trans-Xaa-Pro dipeptide mimetics utilizing organocopper-mediated anti-S(N)2' reactions

Proline dipeptides (Xaa-Pro) exist as an equilibrium mixture of cis- and trans-rotamers, which depends on the energy barriers for imide isomerization. This conformation mixture contributes to both structure and function of proline-containing peptides and proteins. Structural motifs resembling these cis- or trans-conformers have served as useful tools for elucidating contributions of proline residues in the physicochemical and biological profiles of structures which contain them. Among such motifs are alkene dipeptide isosteres which mimic cis- or trans-imide using (Z)- or (E)-alkene, respectively. In this report, the first regio- and stereoselective syntheses of (E)-alkene dipeptide isosteres (20, 31, and 35) corresponding to trans-proline dipeptides are described. Key to the synthesis of these mimetics is the anti-S(N)2' reaction of vinyl aziridines such as 15 or vinyl oxazolidinones such as 28 and 32 with organocopper reagents "RCu" (R = CH(2)SiMe(2)(Oi-Pr)). Reaction of cis-vinylaziridine 15 derived from L-serine with organocopper reagent gave a precursor of the trans-L-Ser-D-Pro type alkene isosteres 20, accompanied by an S(N)2 side product. One limitation with the use of such aziridine-mediated methodology is formation of the corresponding trans-aziridine 22, which leads to L-L type isosteres, that is unstable and obtainable only in low yield. On the other hand, both isomers of oxazolidinone derivatives can be easily obtained from N-Boc-protected amino alcohols. The reaction of trans- 28 or cis-oxazolidinone derivative 32 with organocopper reagents proceeds quantitatively with high regio- and diastereoselectivities in anti-S(N)2' fashion. Subsequent oxidative treatment of the newly introduced isopropoxydimethylsilylmethyl group yields trans-L-Ser-L-Pro 31 or trans-L-Ser-D-Pro type isosteres 35, respectively. Of note, synthesized isostere 31 can also be converted to trans-phosphoSer-Pro 42 and trans-Cys-Pro mimetics 44. The present synthetic methodology affords trans-Xaa-Pro alkene-type dipeptide isosteres in high yield with relatively simple manipulation.     

Synthesis of C2-symmetric 1,4-diketones from tartaric acid dichloride

Cross-coupling reactions of tartaric acid dichloride with organocopper reagents, derived from Grignard reagents, cuprous bromide and lithium bromide, provide a simple and straightforward method for the synthesis of C₂-symmetric 1,4-diketones.     

C,C- and C,N-Chelated Organocopper Compounds

Copper-catalyzed and organocopper-involved reactions are of great significance in organic synthesis. To have a deep understanding of the reaction mechanisms, the structural characterizations of organocopper intermediates become indispensable. Meanwhile, the structure-function relationship of organocopper compounds could advance the rational design and development of new Cu-based reactions and organocopper reagents. Compared to the mono-carbonic ligand, the C,N- and C,C-bidentate ligands better stabilize unstable organocopper compounds. Bidentate ligands can chelate to the same copper atom via η²-mode, forming a mono-cupra-cyclic compounds with at least one acute C-Cu-C angle. When the bidentate ligands bind to two copper atoms via η¹-mode at each coordinating site, the bimetallic macrocyclic compounds will form nearly linear C-Cu-C angles. The anionic coordinating sites of the bidentate ligand can also bridge two metals via μ₂-mode, forming organocopper aggregates with Cu-Cu interactions and organocuprates with contact ion pair structures. The reaction chemistry of some selected organocopper compounds is highlighted, showing their unique structure–reactivity relationships.     

First asymmetric synthesis of trans-3,4-dimethyl-4-arylpiperidines

The first asymmetric synthesis of the trans-3,4-dimethyl-4-arylpiperidine opioid antagonist scaffold is reported. C-3 stereochemistry was established via CBS reduction and stereoselective anti-SN2' cuprate displacement of the derived allylic phosphonate. The resultant vinyl bromide was then elaborated to the target compound by Suzuki coupling and trans-selective 4-methylation. Extension of this methodology should allow general enantioselective access to highly substituted piperidine ring systems.     

Copper-catalyzed regioselective allylic substitution reactions with indium organometallics

The first nucleophilic allylic substitution reactions of triorganoindium compounds with allylic halides and phosphates are reported. The reactions of trialkyl- and triarylindium reagents with cinnamyl and geranyl halides and phosphates, with the aid of copper catalysis [Cu(OTf)(2)/P(OEt)(3)], are described. In general, the reaction proceeds efficiently to give good yields and regioselectively to afford the S(N)2' product.     

Synthesis and selective carbocupration reaction of fluorine-containing enynic esters, enynylphosphine oxides, and enynylphosphates

Some new fluorine-containing enynic esters, enynylphosphine oxides, and enynylphosphates were synthesized stereoselectively in good yields by the dehydrohalogenation reaction of fluoroalkylated 3-iodoacrylates, 2-iodovinylphosphonates, and 2-iodovinylphosphine oxides under basic conditions. These fluorine-containing enynic compounds could undergo carbocupration reaction with organocopper reagents and the vinylcopper intermediates formed in situ could further react with some electrophiles such as allyl bromide, phenylselenyl bromide, and iodine to give the corresponding polysubstituted fluorine-containing dienoic esters, phosphates, and phosphine oxides with high regio- and stereoselectivity.     

Studies of the reaction of 3-bromo-2,5-dimethylthiophene 1,1-dioxide with some organocopper reagents

The coupling reactions of some organocopper reagents with 3-bromo-2,5-dimethylthiophene 1,1-dioxide leading to 3-alkyl and 3-aryl substituted 2,5-dimethylthiophene 1,1-dioxides have been found to proceed in high yields (50–100%). The less stable organocopper reagents reacted faster and at lower temperatures than the more stable ones. It is more convenient to use alkylcopper than lithium dialkylcuprate reagents, which give higher yields without side reactions.     

Copper-catalyzed tandem reaction of isocyanides with N-(2-haloaryl)propiolamides for the synthesis of pyrrolo[3,2-c]quinolin-4-ones

The copper-catalyzed tandem reaction of isocyanides with N-(2-haloaryl)propiolamides is very efficient for the synthesis of pyrrolo[3, 2-c]quinolin-4-ones. Highly reactive cyclic organocopper intermediates were proposed to be generated in the copper-catalyzed formal [3 + 2] cycloaddition reaction of isocyanides with triple bonds. Intramolecular trapping of the organocopper intermediates can lead to aryl C-C bond formation, which offered an efficient method for constructing fused pyrrole structures.     

Regioselective synthesis of [60]fullerene eta 5-indenide R3C60- and eta 5-cyclopentadienide R5C60- bearing different R groups

Treatment of a 1,7-diorgano[60]fullerene with Grignard reagents or organocopper reagents affords a [60]fullerene indenide or a [60]fullerene cyclopentadienide regioselectively in good to excellent yields. These reactions gave an insight into the reaction mechanism of the organocopper penta-addition reaction of [60]fullerene, giving [60]fullerene cyclopentadienide in quantitative yield.     

Diastereoselective synthesis of psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]- type dipeptide isosteres based on organocopper-mediated anti-S(N)2' reaction

[reaction: see text] A straightforward synthetic route for the synthesis of diastereomerically pure psi[(E)-CMe=CH]- and psi[(E)-CMe=CMe]-type dipeptide isosteres was developed on the basis of regio- and stereoselective anti-S(N)2' alkylation of 3-(N-Boc-5-methyl-4-substituted-oxazolidin-2-on-5-yl)acrylates with organocopper reagents.     

Hybrid QM/MM study of thio effects in transphosphorylation reactions

Results of a series of hybrid quantum mechanical/molecular mechanical (QM/MM) activated dynamics simulations of thio effects in the transphosphorylation (methanolysis) of a 2'-ribose, 5'-methyl phosphate-diester under basic conditions are presented. Single and double substitutions in the nonbridging oxygen positions exhibit thio effects in accord with experimental data and show the existence of a stable intermediate. Thio substitution at the 2' and 5' positions resulted in reactions having a single transition state with increased and decreased free energy barriers, respectively, relative to the unsubstituted reaction. In all of the reactions except for the 5' substitution, the rate-limiting step corresponds to exocyclic cleavage. In the 5' substitution reaction, the rate-limiting step corresponds to endocyclic cleavage and shows a considerable reverse thio effect, in accord with experimental observations of phosphates with enhanced leaving groups. Thio substitution at the 3' position results in a mild reverse thio effect that arises from electronic stabilization of the dianionic transition state. The results presented here provide an important step toward the development and application of new hybrid QM/MM methods that, combined with experiment, may provide a detailed picture of the molecular mechanisms of RNA catalysis.     

Coinage metals-catalyzed cascade reactions of aryl alkynylaziridines: silver(I)-single vs gold(I)-double cyclizations

Alkynylaziridines carrying an aryl group could be efficiently converted into aminoallenylidene isochromans, isoquinolines, or tetrahydronaphtalenes with silver(I) salts and into 1-azaspiro[4.5]decane derivatives with gold(I) complexes. Mechanistic investigations revealed that both Ag- and Au-catalyzed reactions involved a Friedel-Crafts type intramolecular reaction leading to an allene and that Au also rapidly promoted a second intramolecular cyclization of the aminoallene intermediate to the corresponding spiro derivative. Stereochemical investigations suggested an anti-SN(2)'-type pathway for the first cyclization leading to a stereodefined allene, which could then be cyclized to the corresponding stereodefined spiro product. These results highlight the duality between oxo- or azaphilicity and alkynophilicity of Ag and Au as well as their complementarity in terms of reactivity.     

A new preparation and some reactions of organocopper(I) isonitrile complexes

A new preparation and some reactions of organocopper(I) isonitrile complexes are described. In the presence of isonitrile (RNC), some active hydrogen compounds (R'H) react smoothly with Cu₂O and with metallic copper, evolving H₂O and hydrogen, respectively, to produce organocopper(I) isonitrile complexes, R'Cu(RNC)₂. The isonitrile insertion and the oxidative coupling by iodine of these complexes are described here.     

Regio- and enantioselective copper-catalyzed addition of dialkylzinc reagents to cyclic 2-alkenyl aziridines

The reactions of some organocopper reagents with cyclic 2-alkenyl aziridines were examined. The stereoselectivity of the addition reaction of dialkylzinc can be strongly influenced by the use of phosphoramidites as ligands for copper. Chiral copper complexes of 2,2′-binaphthyl-based phosphoramidites were shown to be highly effective catalysts for the regio- (S_N2′) and anti-stereoselective addition of dialkylzinc reagents to these compounds according to a kinetic resolution protocol. The corresponding new cyclic allylic amine reaction products were obtained with a good enantioselectivity (83% ee).     

Regio- and Stereoselective Syntheses with Organocopper Reagents

Of all of the organometallic reagents currently used to form carbon–carbon bonds, organocopper reagents rank amongst the most important. Interest in these reagents centers not only on their regioselectivity, but also increasingly on their application in stereoselective transformations (principally Michael additions and S_N2′ reactions); the use of suitable substrates or chirally modified cuprates can lead to highly diastereo- and enantioselective reactions. Simultaneously, extensions of methods for the preparation and application of these reagents (for example functionalized organocopper species and Lewis acid catalysis, respectively) have opened up new horizons for organocopper reagents. Mechanistically, the reactions are well-documented and understood, but this aspect of the subject has not kept pace with the many rapid developments in preparative chemistry. Organocopper ragents have proved to be indispensable in the synthesis of complex natural products and pharmaceuticals, chiral auxiliaries, and molecules with interesting structural features. In this review we will discuss some of the more recent important developments in this area; the organization will follow the type of selectivity (regio-, diastereo-, and enantioselectivity).     

The cross-coupling reactions of organic halides with organic derivatives of tin,mercury and copper catalyzed by palladium

The palladium-catalyzed cross-coupling of organic halides with organometallic compounds of tin, mercury and copper is discussed. It is shownn that the “ligandless” palladium complexes RPdXL₂ (L = solvent), in which solvent molecules act as weak donating ligands, are the most active catalysts for reactions of organotin compounds. It is found that nucleophilic catalysis is an efficient method of activatioin of organomercury and organocopper compounds in cross-coupling reactions. In the presence of iodide ion the palladium-catalyzed reactions of these compounds proceed under mild conditions giving high yields of cross-coupling products.     

Conjugate addition of organocopper reagents in dichloromethane to α,β-unsaturated esters

Organocopper reagents in conjunction with Lewis acid activators provide greater stability than traditional cuprate reagents while maintaining the reactivity needed for conjugate addition reactions in dichloromethane. Whereas cuprates engage in cross-coupling pathways, organocopper nucleophiles are more selective for conjugate addition. The utility of organocopper reagents in dichloromethane for the conjugate addition to α,β-unsaturated esters is expanded upon herein.