Catalytic and highly enantioselective reactions of alpha-sulfonyl carbanions with chiral bis(oxazoline)s

The enantioselective reactions of lithiated benzyl trifluoromethyl sulfones with a substoichiometric amount of a bis(oxazoline) and various aldehydes is disclosed. The products were formed with excellent diastereo- and enantioselectivities. Fluorination of the sulfone with N-fluorobenzenesulfonimide and a stoichiometric amount of a bis(oxazoline) gave products with extremely high enantioselectivities (up to 99% ee; ee=enantiomeric excess). The enantioselective reaction was confirmed to proceed through a dynamic thermodynamic resolution pathway.     

A novel method for the preparation of benzylidenecyclohexanes with high optical purity

The enantioselective reaction of the α-thio carbanion derived from 1-phenyl-1-(phenylthio)-1-(tributylstannyl)methane with 4-substituted cyclohexanones in the presence of bis(oxazoline)s gave the products as a diastereomeric mixture. Each diastereomer obtained had high optical purity. The reaction of the α-seleno carbanion derived from the bis(phenylseleno)acetal also showed high enantioselectivity. The stereospecific elimination of the isolated diastereomers on treatment with methanesulfonyl chloride and triethylamine afforded axially chiral benzylidenecyclohexanes with high enantioselectivities up to 99% ee.     

Chemoselective conjugate addition of dimethylzinc-mediated ether and acetal radicals to alkylidenemalonates and asymmetric reactions

Cyclic and acyclic ether or acetal radicals were generated directly from ethers or acetals by the action of dimethylzinc-air, and their subsequent conjugate addition reaction with alkylidenemalonates afforded the corresponding conjugate adducts in reasonably high yields. The reaction with benzylidenemalonates bearing formyl and imino groups gave chemoselectively the conjugate addition products. The asymmetric reaction of bis(8-phenylmenthyl) benzylidenemalonate proceeded diastereoselectively to provide the adduct with 93:7 dr.     

From carbon dioxide to methane: homogeneous reduction of carbon dioxide with hydrosilanes catalyzed by zirconium-borane complexes

A mixture of a zirconium benzyl phenoxide complex and tris(pentafluorophenyl)borane is reported that catalyzes the hydrosilation reaction of carbon dioxide to generate methane via a bis(silyl)acetal intermediate.     

The synthesis of a new class of chiral pincer ligands and their applications in enantioselective catalytic fluorinations and the Nozaki-Hiyama-Kishi reaction

A new class of chiral tridentate N-donor pincer ligands, bis(oxazolinylmethylidene)isoindolines (boxmi), was synthesized in three steps starting from readily available phthalimides. Their reaction with ethyl (triphenylphosphoranylidene)acetate by means of a key-step Wittig reaction gave the ligand backbones, which were condensed with amino alcohols and then cyclized to obtain the corresponding ligands. These ligands were subsequently applied in the nickel(II)-catalyzed enantioselective fluorination of oxindoles and β-ketoesters to obtain the corresponding products with enantioselectivities of up to >99% ee and high yields. Application of the chiral pincer ligands in the chromium-catalyzed enantioselective Nozaki-Hiyama-Kishi reaction of aldehydes gave the corresponding alcohols with an optimal enantioselectivity of 93%.     

Bialkyls from dialkylmetals I. Photochemistry and mass spectra of some (2-cyanoethyl)- and [2-(methoxycarbonyl)ethyl]metals

We have studied the photolysis and the fragmentation in the mass spectrometer of bis(2-cyanoethyl)mercury, bis(2-cyanoethyl) selenide, bis(2-cyanoethyl) sulphide, dibutylbis(2-cyanoethyl)stannane, and bis[2-(methoxycarbonyl)ethyl] selenide. The mercury compound gave a high yield of adiponitrile on photolysis and in the mass spectrometer it gave the fragmentation pattern of adiponitrile, including the molecular ion, as part of the total fragmentation pattern. A low yield of bialkyl was also formed on photolysis of the bis[2-(methoxycarbonyl)ethyl] selenide but no peaks corresponding to biakyl were observed in the mass spectrum. None of the other compounds yielded alkyl dimer.

A preliminary discussion of the results in terms of orbital symmetry is presented.     

Intramolecular Diels-Alder reaction of selenoaldehydes

Intramolecular Dieis-Alder reaction of selenoaldehydes which were generated from bis(trimethylsilyl) selenide and dienals gave the corresponding bicyclic adducts.     

Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir

An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol.     

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.     

A novel method for the separation of bis(alpha-hydroxyalkyl)phosphinic acid diastereoisomers via formation of novel cyclic phosphinic acids

The reaction of aromatic and aliphatic aldehydes with hypophosphorus acid under microwave irradiation was examined. The reaction gave a mixture of a racemic pair of bis(alpha-hydroxyalkyl)phosphinic acids and acetal derivatives from the corresponding bis(alpha-hydroxyalkyl)phosphinic acids of meso-stereochemistry in good yield. The difference in solubility in organic solvents due to polarity allowed us to readily separate these compounds. This method constitutes an easy, rapid, and good-yielding preparation and separation of bis(alpha-hydroxyalkyl) phosphinic acid diastereoisomers from simple starting materials using microwave irradiation.     

Inter- and intramolecular differentiation of enantiotopic dioxane acetals through oxazaborolidinone-mediated enantioselective ring-cleavage reaction: kinetic resolution of racemic 1,3-alkanediols and asymmetric desymmetrization of meso-1,3-polyols

Acetals derived from racemic 1,3-alkanediols undergo kinetic resolution in chiral oxazaborolidinone-mediated ring-cleavage reaction with nucleophiles such as enol silanes and allylic silanes. Enantioselectivity of the reaction is affected by nucleophiles, the N-sulfonyl groups of oxazaborolidinones, and the substituents attached to the acetal carbon. For disubstituted acetals rac-1 and for trisubstituted acetal rac-2, derived from syn-2,4-dimethyl-1,3-pentanediol, satisfactory enantioselectivity is obtained by using methallylsilane 7b,c as a nucleophile in combination with N-mesyloxazaborolidinone 4a. On the other hand, enantioselective reaction of trisubstituted acetal rac-3b, derived from anti-2,4-dimethyl-1,3-pentanediol, is realized by using silyl ketene acetal 5e in combination with N-tosyloxazaborolidinone 4b. The reaction conditions optimized for the kinetic resolution, or enantiomer differentiating reaction, of the racemic acetals are successfully applied to asymmetric desymmetrization of meso-1,3-polyols through intramolecular differentiation of the enantiotopic acetal moieties of the bis-acetal derivatives. The utility of the ring-cleavage reaction as a method for enantioselective terminal differentiation of prochiral polyols is demonstrated in convergent asymmetric synthesis of pentol derivative 35 corresponding to the C(19)[bond]C(27) ansa-chain of rifamycin S.     

Enantioselective

Even with only a catalytic amount of chiral bis(dihydrooxazole) 1 as external ligand, the rearrangement of benzyl ethers to alcohols [Eq. (1)] proceeds with high enantioselectivity (over 60 % ee). This reaction represents the first example of an enantioselective [1,2] Wittig rearrangement.     

Enantioselective Oxidative Aerobic Dealkylation of N‐Ethyl Benzylisoquinolines by Employing the Berberine Bridge Enzyme

N‐Dealkylation methods are well described for organic chemistry and the reaction is known in nature and drug metabolism; however, to our knowledge, enantioselective N‐dealkylation has not been yet reported. In this study, exclusively the (S)‐enantiomers of racemic N‐ethyl tertiary amines (1‐benzyl‐N‐ethyl‐1,2,3,4‐tetrahydroisoquinolines) were dealkylated to give the corresponding secondary (S)‐amines in an enantioselective fashion at the expense of molecular oxygen. The reaction is catalyzed by the berberine bridge enzyme, which is known for C? C bond formation. The dealkylation was demonstrated on a 100 mg scale and gave optically pure dealkylated products (ee>99 %).     

Synthesis of bis(3,3-dinitrobutyl)polysiloxanes

Phenyl groups were used as silicon-protecting groups in the synthesis of bis-(3,3-dinitrobutyl)polysiloxanes. The addition of diphenylsilane to acrolein dimethyl acetal, followed by reactions with methyllithium and phosphorus tribromide gave bis(3-bromobutyl)diphenylsilane. Sodium nitrite displacement gave bis(3-nitrobutyl)diphenylsilane, and oxidative nitration gave bis(3,3-dinitrobutyl)diphenylsilane. Dephenylation with bromine and hydrolysis gave cyclic polysiloxanes.     

Enantioselective reaction of alpha-lithiated dithioacetals using chiral bis(oxazoline)s: new chiral formyl anion equivalents

The enantioselective reaction of various alpha-lithiated dithioacetals with aldehydes or a ketone in the presence of bis(oxazoline)s was examined. Among them, unsymmetrical dithioacetals were found to be the best choice for attaining high enantioselectivity. The reaction of lithiated tert-butylthio(2-pyridylthio)methane with aldehydes proceeded with good diastereoselectivity as well as with good enantioselectivity. The enantioselective reaction was shown to proceed through dynamic thermodynamic resolution. Mercury(II) chloride effected hydrolysis of the dithioacetal moiety of the products to 2-hydroxyaldehydes, which were directly reduced to give the optically active 1,2-diols.     

Catalytic asymmetric cyanosilylation of ketones with chiral Lewis base

The development of broadly applicable and practical catalytic approaches for the enantioselective creation of quaternary stereocenters remains a highly desirable yet challenging goal. In this Communication, we describe a highly enantioselective cyanosilylation of acetal ketones (alpha,alpha-dialkoxy ketones) catalyzed by modified cinchona alkaloids. This reaction is the first highly enantioselective cyanosilylation of ketones catalyzed by an organic chiral Lewis base and is found to be highly efficient with acetal ketones bearing a broad range of alkyl, aryl, alkenyl, and alkynyl substituents. This new catalytic asymmetric reaction, coupled with the versatility of the acetal functionality, provides a broadly useful synthetic method for chiral building blocks bearing quaternary stereocenters. Acetal ketones, readily accessible but previously unexplored in asymmetric synthesis, demonstrate unusual reactivity and selectivity toward the nucleophilic cyanosilylation, thereby suggesting that they may be interesting substrates for other catalytic enantioselective reactions.     

酸性功能化离子液体催化合成叶青素

以含磺酸基离子液体1-(4-磺酸基)丁基-3-甲基咪唑四氟硼酸盐([4-sulfbmim][BF₄])为酸性催化剂,由乙缩醛和苯甲醇合成了叶青素。 采用正交实验方法考察了合成条件的影响,固定反应温度为20 ℃条件下,确定优化合成条件为：n(苯甲醇)∶n(乙缩醛)=1∶8,反应时间60 min,催化剂用量为每摩尔苯甲醇4 g,产率为92.2%。 与H₂SO₄催化剂相比[4-sulfbmim][BF₄]的催化活性相对较弱,但综合效果优于H₂SO₄。 [4-sulfbmim][BF₄]循环使用6次,催化活性基本不变。     

Chalcogenation of 1,3-dichloropropene with elemental chalcogens in the system hydrazine hydrate–base

Sulfur reacts with 1,3-dichloropropene in the system hydrazine hydrate–KOH to form bis(1-chloroprop-1-en-3-yl) sulfide, and in the system hydrazine hydrate–monoethanolamine, bis(1-chloroprop-1-en- 3-yl) disulfide. The reaction of tellurium in the system hydrazine hydrate–KOH leads to diallyl telluride, the product of nucleophilic substitution of the allylic chlorine atom and reductive cleavage of the С_sp2–Cl bond. The reaction of selenium with 1,3-dichloropropene gives a complex mixture of products. At excess KOH (Se: KOH = 1: 5) bis(1-chloroprop-1-en-3-yl) selenide was isolated.     

Catalytic, enantioselective aldol additions to ketones

Catalytic, enantioselective additions of a trichlorosilyl ketene acetal to ketones have been demonstrated. The trichlorosilyl enolate of methyl acetate undergoes a rapid and high-yielding aldol addition to a wide range of ketones (aromatic, olefinic, acetylenic, aliphatic) in the presence of a catalytic amount of pyridine N-oxide. Moreover, in the presence of a catalytic amount (10 mol %) of a chiral bispyridine bis N-oxide (possessing both axial and central chiral elements) the aldol addition takes place again in excellent yield and with good stereoselectivity. The enantioselectivities of the additions are highly variable (7-86% ee) and are strongly dependent on the structure of the ketone acceptor. Aromatic methyl ketones gave the highest selectivity, whereas olefinic ketones were the least selective.     

Synthesis of new functionalized organoselenium compounds by heterocyclization of selenium dihalides with pent-4-en-1-ol

The reaction of selenium dihalides with pent-4-en-1-ol has been carried out for the first time. Efficient procedures for the synthesis of previously unknown bis(tetrahydrofuran-2-ylmethyl) selenide, dihalobis( tetrahydrofuran-2-ylmethyl)-λ⁴-selanes, and bis(tetrahydrofuran-2-ylmethyl) selenoxide have been developed on the basis of this reaction. The product structures have been studied by ¹H, ¹³C, and ⁷⁷Se NMR. Bis(tetrahydrofuran-2-ylmethyl) selenide and dihalobis(tetrahydrofuran-2-ylmethyl)-λ⁴-selanes represent equimolar mixtures of two diastereoisomers which display different signals in the ¹³C and ⁷⁷Se NMR spectra. The oxidation of bis(tetrahydrofuran-2-ylmethyl) selenide with sodium periodate in methanol leads to the corresponding selenoxide consisting of 4 diastereoisomers.