Iridium-catalyzed [2 + 2 + 2] cycloaddition of α,ω-diynes with nitriles

[Ir(cod)Cl](2)/DPPF or BINAP efficiently catalyzed the cycloaddition of α,ω-diynes with nitriles to give pyridines. The reaction can accommodate a very wide range of nitriles. Both aliphatic and aromatic nitriles smoothly reacted with α,ω-diynes to give pyridines. Ten equivalents of unactivated aliphatic nitrile were enough to give the product in high yield. Aliphatic nitriles bearing an acetal or amino moiety could be used for the reaction. The highly regioselective cycloaddition of unsymmetrical diyne bearing two different internal alkyne moieties was achieved. The observed regioselectivity could be reasonably explained by considering the different reactivities of the α-position in iridacyclopentadiene. Regioselective cycloaddition was successfully applied to the synthesis of terpyridine and quinquepyridine. This chemistry was extended to a new and efficient synthesis of oligoheteroarenes. Five aromatic or heteroaromatic rings were connected in a single operation. [Ir(cod)Cl](2)/chiral diphosphine catalyst can be applied to enantioselective synthesis. Kinetic resolution of the racemic secondary benzyl nitrile catalyzed by [Ir(cod)Cl](2)/SEGPHOS gave a central carbon chiral pyridine in 80% ee. The mechanism was analyzed on the basis of the B3LYP level of density functional calculations.     

Iridium-catalyzed [2+2+2] cycloaddition of α,ω-diynes with isocyanates

[Ir(cod)Cl](2)/BINAP was found to be an efficient catalyst for the [2+2+2] cycloaddition of α,ω-diynes with isocyanates to give 2-pyridones. A wide range of isocyanates can be used for this reaction. Both aliphatic and aromatic isocyanates smoothly reacted with α,ω-diynes to give 2-pyridones in high yields. Aliphatic isocyanates were more reactive than aromatic isocyanates. For aromatic isocyanates, the electronic properties of the substituents affected the reactivity: electron-donating substituents enhanced the reaction. The reaction of unsymmetrical α,ω-diynes possessing two different internal alkyne moieties with isocyanates was regiospecific and gave a single product. This regioselectivity could be explained by the reaction of iridacyclopentadiene with a nitrogen-carbon double bond. The regioselectivity of the reaction of malonate-derived diyne was controlled by a steric effect, while that of the reaction of ester-tethered diyne was controlled by an electronic effect. [Ir(cod)Cl](2)/chiral diphosphine catalyst could be used for the enantioselective synthesis of C-N axially chiral 2-pyridone. The reaction of diyne 1a with o-methoxyphenyl isocyanate (7a) gave C-N axially chiral 2-pyridone (R)-8aa in 78% yield with 94% ee.     

Iridium-catalyzed [2+2+2] cycloaddition of α,ω-diynes with alkynyl ketones and alkynyl esters

We found that the combination of [Ir(cod)Cl]₂ and rac-BINAP served as an efficient catalyst for the [2+2+2] cycloaddition of 2,7-nonadiyne derivatives and related compounds with alkynyl ketones and alkynyl esters. The corresponding products were obtained in high yields under mild reaction conditions.     

Asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives

Herein we report the asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 22, 25 and 26, key intermediates of a novel immunomodulator, using Seebach’s method. This synthetic method can be applied to the large scale synthesis of chiral sphingosine 1-phosphate-1 (S1P₁) receptor agonists, with significant improvements to the previously reported method with regard to the reaction temperature.     

Enantioselective synthesis of α,α-disubstituted amines from nitroalkenes

Disubstituted nitroalkenes were converted into enantiomerically enriched amines (isolated as their hydrochloride salts) with enantiomeric excesses of 88 to >95% in three steps: (a) highly stereoselective conjugate addition of the potassium salt of 4-phenyloxazolidin-2-one; (b) radical-mediated removal of the nitro group; (c) cleavage of the oxazolidinone.     

Conformational studies on peptides containing α,α-disubstituted α-amino acids: chiral cyclic α,α-disubstituted α-amino acid as an α-helical inducer

Four types of α,α-disubstituted amino acids {i.e., α-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Ac(5)c), (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)] and its enantiomer (R,R)-Ac(5)c(dOM)} were introduced into l-leucine-based hexapeptides and nonapeptides. The dominant conformations of eight peptides: Cbz-(L-Leu-L-Leu-dAA)(2)-OMe [dAA = 1: Aib; 2: Ac(5)c; 3: (S,S)-Ac(5)c(dOM); 4: (R,R)-Ac(5)c(dOM)] and Boc-(L-Leu-L-Leu-dAA)(3)-OMe [dAA = 5: Aib; 6: Ac(5)c; 7: (S,S)-Ac(5)c(dOM); 8: (R,R)-Ac(5)c(dOM)], were investigated by IR, CD spectra and X-ray crystallographic analysis. The CD spectra revealed that Aib hexapeptide 1 and Ac(5)c hexapeptide 2 formed right-handed (P) 3(10)-helices, while Ac(5)c(dOM) hexapeptides 3 and 4 formed a mixture of (P) 3(10)- and α-helices. The Aib nonapeptide 5 formed a (P) 3(10)-helix, the Ac(5)c nonapeptide 6 formed a mixture of (P) 3(10)- and α-helices, and the Ac(5)c(dOM) nonapeptides 7 and 8 formed (P) α-helices. X-Ray crystallographic analysis revealed that the Aib hexapeptide 1 formed a (P) 3(10)-helix, while (S,S)-Ac(5)c(dOM) hexapeptide 3 formed a (P) α-helix. In addition, the Ac(5)c nonapeptide 6 and (R,R)-Ac(5)c(dOM) nonapeptide 8 formed (P) α-helices. The Aib and achiral Ac(5)c residues have the propensity to form 3(10)-helices in short peptides, whereas the chiral Ac(5)c(dOM) residues have a penchant for forming α-helices.     

Enantioselective synthesis of α-amino acids in chiral reverse micelles

Through alkylation of ethyl 2-phthalimidoacetate in chiral reverse micelles formed from chiral surfactants, followed by hydrazinolysis and hydrolysis of the resulting products, optically active α-amino acids were synthesized. The highest enantioselectivity was 59.5%. Meanwhile, we have found that the asymmetric induction depends on the reaction temperature, the alkyl chain length of surfactant and the strucure of the surfactants.     

Catalytic, asymmetric synthesis of α,α-disubstituted amino acids

Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the reactions is presented.     

Enantioselective rhodium-catalyzed [4+2] cycloaddition of α,β-unsaturated imines and isocyanates

A [4+2] cycloaddition of α,β-unsaturated imines and isocyanates catalyzed by a phosphoramidite-rhodium complex provides pyrimidinones in good yields and high enantioselectivities.     

Enantioselective synthesis of α-alkyl,α-vinyl amino acids via [2,3]-sigmatropic rearrangement of selenimides

Chiral α-alkyl,α-vinyl amino acids (quaternary vinyl glycine derivatives) are prepared with high levels of enantiomeric purity by [2,3]-sigmatropic rearrangement of allylic selenimides. The required trisubstituted allylic selenides are prepared by an organocatalytic α-selenenylation of aldehydes followed by Horner-Wadsworth-Emmons (HWE) olefination. Both (E)-and (Z)-geometrical isomers are available giving access to both enantiomers of the desired products.     

Enantioselective synthesis of β-amino acids. Part 10: Preparation of novel α,α- and β,β-disubstituted β-amino acids from (S)-asparagine

Perhydropyrimidinone (S)-1 is alkylated with very high diastereoselectivity to give trans products (2S,5R)-3, (2S,5R)–4 and (2S,5R)-5. Dialkylation of (S)-1 also proceeds with complete stereoselectivity to afford adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7 and (2S,5S)-7. Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2S,5R)-3 gives enantiopure α-substituted β-amino acid (R)-8. Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure α,α-disubstituted β-amino acids (R)- or (S)-9 and (R)- or (S)-10. Related iminoester (2S,6S)-2 is alkylated with complete diastereoselectivity to give products (2S,6S)-11–13 whose hydrolysis under relatively mild conditions (2N CF₃CO₂H, CH₃OH, 100°C) affords enantiopure N-benzoylated β,β-disubstituted β-amino acid esters (S)-14–16, with intact double bonds in the olefinic substituents.     

Enantioselective synthesis of β-amino acids. Part 9: Preparation of enantiopure α,α-disubstituted β-amino acids from 1-benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one,

Double alkylation of enantiopure N,N-acetal pyrimidinone (S)-1, a masked chiral derivative of β-alanine prepared from (S)-asparagine, proceeds with high stereoselectivity to give C(5) disubstituted adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7, and (2S,5S)-7. Acid hydrolysis of these derivatives affords enantiopure α,α-dialkylated β-amino acids (R)-8, (S)-8, (R)-9, and (S)-9 in very good yields.     

Preparation of sugar derived β,β′-dihydroxy α,α-disubstituted α-amino acids

A novel strategy for the preparation of β,β′-dihydroxy α,α-disubstituted α-amino acids bearing a sugar moiety has been developed. The procedure is based on two Henry reactions: the first Henry reaction involves a sugar aldehyde and nitroethanol to furnish a sugar derived α-hydroxymethyl α-nitroalkanol while the second Henry reaction is between this nitro sugar and formaldehyde. This sequence provided the expected epimers of sugar derived α,α-dihydroxymethyl α -nitroalkanols, from which the corresponding β,β′-dibenzyloxy α-N-benzyloxycarbonylamino esters were easily obtained. All rights reserved.     

Enantioselective organocatalytic synthesis of quaternary α-amino acids bearing a CF3 moiety

A highly enantioselective Friedel-Crafts reaction catalyzed by a chiral phosphoric acid was developed. N-Boc-protected ethyl trifluoropyruvate imine was activated by 6 mol % of catalyst and reacted with a wide variety of indole derivatives to afford quaternary α-amino acids in excellent yields (up to 99%) and high enantioselectivities (up to 98:2 er).     

Cu-catalyzed asymmetric [3+2] cycloaddition of α-iminoamides with activated olefins

A variety of 2-amido pyrrolidines, including Weinreb-type amides, have been prepared with very high exo diastereoselectivity and enantioselectivitiy in the reaction of α-iminoamides with activated alkenes catalyzed by Cu(I)-Segphos ligands.     

3-Nitro-2H-chromenes in [3+2] cycloaddition reaction with azomethine ylides derived from N-unsubstituted α-amino acids and isatins: regio- and stereoselective synthesis of spirochromeno[3,4-c]pyrrolidines

Chemistry of Heterocyclic Compounds - A regio- and stereoselective method was developed for the synthesis of tetrahydro-4H-spiro[chromeno[3,4-c]pyrrole-1,3'-indolin]-2'-ones in 72−96%...     

Asymmetric synthesis of α-amino acids by reduction of N-tert-butanesulfinyl ketimine esters

A highly regio- and diastereoselective reduction of various N-tert-butanesulfinyl ketimine esters with L-Selectride resulting in the formation of α-amino acids is reported. This method is quite general and also practical for the preparation of both enantiomers of aryl or aliphatic α-amino acids in high yields.