A highly efficient asymmetric organocatalytic aldol reaction in a ball mill

Anti-aldol products with up to >99 % enantiomeric excess (ee) have been obtained by proline catalysis in excellent yields under experimentally simple solvent-free conditions. Efficient mixing of all the components is accomplished by applying a mechanochemical technique (ball milling). The catalysis is air and moisture tolerant and can be performed with non-purified starting materials. Even mixtures of solely solid compounds react, giving (mostly solid) products through a partially homogeneous (honey-like) intermediate melt. Since the reactant ratio is almost 1:1 (avoiding the common excess of ketone), the product isolation is easy leading to high aldol product yields.     

A library of chiral imidazoline-aminophenol ligands: discovery of an efficient reaction sphere

A library of imidazoline-aminophenol ligands was synthesized on solid supports. After immobilization of chiral chloromethylimidazolines 1 and 2 onto the polystyrylsulfonyl chloride, nucleophilic substitution with (R)- or (S)-phenylethylamine (3 and 4) provided four combinations of polymer-supported imidazoline-amine ligands. Further reductive alkylation using salicylaldehydes 7-10 provided a series of imidazoline-aminophenol ligands (L9-L24). Analysis by solid-phase catalysis/circular dichroism high-throughput screening of a copper-catalyzed Henry reaction revealed that ligand L25, comprising a (S,S)-diphenylethylenediamine-derived imidazoline, (S)-phenylethylamine, and dibromophenol, was highly efficient, thus providing the adduct of nitromethane and benzaldehyde in 95 % ee. The combination of stereogenic centers was crucial in promoting the highly stereoselective reactions. The unique reaction sphere of L25 was also examined in a Friedel-Crafts alkylation of indole and nitroalkene to give the adduct in up to 83 % ee.     

N-Salicyl-β-aminoalcohols as a new class of ligand for catalytic asymmetric Strecker reactions

An enantioselective Strecker synthesis employing novel chiral titanium complex catalysts derived from structurally simple chiral N-salicyl-β-amino alcohols is described. Reactions of N-benzylidenebenzylamine with trimethylsilyl cyanide in the presence of the catalyst (10 mol%) gave the corresponding α-aminonitrile in good to excellent yields, along with relatively high enantioselectivity (up to 86% ee). Similar reactions with various imines derived from aromatic aldehydes resulted in moderate to good enantioselectivity (44-81% ee).     

One-pot enantioselective aziridination of olefins catalyzed by a copper(I) complex of a novel diimine ligand by using PhI(OAc)(2) and sulfonamide as nitrene precursors

A novel chiral C(2)-symmetric 1,4-diamine with multistereogenic centers at the backbone of the ligand has been synthesized from cheap natural product D-mannitol through multistep transformations. Its diimine derivative (3 a) was found to be highly effective for the enantioselective control of the copper-catalyzed asymmetric aziridination of olefin derivatives with PhI==NTs as the nitrene source, affording the corresponding N-sulfonylated azirindine derivatives in good to excellent yields with up to 99 % ee (ee=enantiomeric excess). The catalyst system discovered in the present work was also extended to a one-pot enantioselective aziridination by using sulfonamide/iodobenzene diacetate as the nitrene source. In this case, most reactions proceeded smoothly to give the corresponding products in moderate yields with good to excellent enantiomeric excesses (75-96 % ee).     

Organocatalyzed regioselective and enantioselective synthesis of 1,4- and 1,2-dihydropyridines

Abstract

Herein, we introduce one of the first examples of asymmetric organocatalyzed synthesis of 1,2-dihydropyridines, affording enantioselective access to and partially solving regioselectivity challenges in the synthesis of dihydropyridines. We demonstrate that through modification of organocatalysts both 1,2- and 1,4-dihydropyridines (1,2- and 1,4-DHPs) can be obtained with high regioselectivity (ratio of 1,2-DHP/1,4-DHP from 95/5 to 0/100) and enantioselectivity (33% ee for 1,2-DHPs and up to 98% ee for 1,4-DHPs) in good yields (up to 87%).     

Iridium-catalyzed asymmetric allylation of sodium triisopropylsilanethiolate: a new way to form chiral thiols

The iridium phosphoramidite complex-promoted regio- and enantioselective reaction of allylic carbonates with sodium triisopropylsilanethiolate produced allylic sulfides in 40-77% yields with up to 97 : 3 (branched?:?linear) and 89% ee, which were readily transformed into chiral thiol in 68% yield with 87% ee or disulfides with two chiral C-S bond centers in 40-73% yields with up to 90 : 10 dr and 99% ee.     

Asymmetric Michael addition of 2-alkoxyphenyl α-substituted nitroacetates to non-prochiral α,β-unsaturated carbonyl compounds catalyzed by podand-type alkali metal 2′-substituted 1,1′-binaphthalen-2-oxides

The asymmetric Michael addition of 2-alkoxyphenyl α-substituted nitroacetates to non-prochiral α,β-unsaturated carbonyl compounds catalyzed by 10 mol % of sodium 2′-[2-(2-methoxyethoxy)ethoxy]-1,1′-binaphthalen-2-oxide gave the desired adducts in high yields with up to 95% ee.     

基于α-溴代酮的催化不对称合成3,3-螺环丙基吲哚酮和乙烯基环丙烷

在甲基化奎尼丁(20mol%)的催化下,分别实现了α-溴代酮与3-(取代亚甲基)吲哚酮和缺电子1,3-二烯的高度非对映选择性和对映选择性的环丙烷化反应,以46%~99%收率、高达98%ee和20∶1 dr生成相应的3,3-螺环丙基吲哚酮和乙烯基环丙烷.通过催化的氮叶立德策略,成功发展了一种用于上述手性化合物的简便合成方法.     

Studies on ZnBr2-mediated synthesis of axially chiral aryl-substituted allenes from terminal alkynes,aromatic aldehydes and (S)-α,α-diphenylprolinol

The studies on the ZnBr₂-mediated synthesis of axially chiral aryl-substituted allenes from terminal alkynes, aromatic aldehydes, and commercially available chiral amine (S)-α,α-diphenylprolinol were conducted. Axially chiral aryl-substituted allenes can be obtained in moderate yields with up to 96% ee.     

Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated ketones with DIFLUORPHOS and SYNPHOS analogues

Applications of electron-deficient DIFLUORPHOS and SYNPHOS analogues in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to α,β-unsaturated ketones afford the 1,4-addition adducts in yields up to 92% and with 99% ee. Particularly, a Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to nonsubstituted maleimide substrates using the (R)-3,5-diCF(3)-SYNPHOS ligand is also reported. This protocol provides access to various enantioenriched 3-substituted succinimide units of biological interest, in high yields and good to excellent ee up to 93%, which could be upgraded up to 99% ee, after a single crystallization.     

A flexible and versatile strategy for the covalent immobilization of chiral catalysts based on pyridinebis(oxazoline) ligands

[reaction: see text] Flexible and versatile methods have been developed for the immobilization of chiral pyridinebis(oxazoline) ligands by covalent bonding to a solid support, either by grafting or by polymerization. Different spacers can easily be introduced to modulate the support-ligand distance and the electronic properties of the chiral ligand. As an example, 2,6-bis[(S)-4-isopropyloxazolin-2-yl]pyridine has been immobilized on polystyrene resins, both on a Merrifield-type resin by grafting and on supports prepared by polymerization of 4-vinyl-substituted ligands. The corresponding Ru complexes have been tested as catalysts in the cyclopropanation reaction between styrene and ethyl diazoacetate. The catalytic activity, the enantioselectivity, and the recyclability are strongly dependent on the catalyst preparation method and the total exclusion of oxygen and moisture in the filtration process. Under such optimized conditions, yields over 60% with up to 90% ee can be obtained in four successive reactions-the best cyclopropanation results described to date for a chiral solid ruthenium catalyst.     

Highly enantioselective Michael addition of 2-alkoxyphenyl esters of α-substituted β-keto acids to non-prochiral α,β-unsaturated carbonyl compounds catalyzed by sodium 2′-[2-(2-methoxyethoxy)ethoxy]-1,1′-binaphthalen-2-oxide

The enantioselective Michael addition of 2-alkoxyphenyl esters of α-substituted β-keto acids to non-prochiral α,β-unsaturated carbonyl compounds catalyzed by 5–10 mol % of sodium 2′-[2-(2-methoxyethoxy)ethoxy]-1,1′-binaphthalen-2-oxide afforded the desired adducts in high yields with up to 97% ee.     

Enantioselective conjugate addition of both aromatic ketones and acetone to nitroolefins catalyzed by chiral primary amines bearing multiple hydrogen-bonding donors

A new class of chiral primary amine catalysts bearing multiple hydrogen-bonding donors have been designed and synthesized. The newly developed bifunctional organocatalysts efficiently catalyzed not only enantioselective conjugate addition of aromatic ketones to nitroolefins in good yields (up to 87%) with excellent enantioselectivities (97→99% ee) but also enantioselective conjugate addition of acetone to nitroolefins in excellent yields (90-96%) with high enantioselectivities (up to 97% ee).     

Stereoselective allylation of aldehydes on solid support and its application in biology-oriented synthesis (BIOS)

A systematic study on the asymmetric allylation of aldehydes on solid support is reported. Different kinds of chiral allylboron reagents with complementary direction of stereoinduction were applied successfully in this reagent-controlled transformation. The homoallylic alcohol products are generated with high levels of stereoselectivity and in high yields. The crotylation of aldehydes on solid support employing (E)- and (Z)-Ipc₂crotylborane also proceeds with very high levels of stereoinduction and in high yields. Applications of this methodology for the synthesis of compound collections by subsequent modifications of the allylic moiety are described. In particular, a collection of γ- and δ-lactones has been synthesized by means of a cyclo-release approach including a natural product. In addition, a procedure for the long-standing problem of the hydrogenation of double bonds on solid support is reported. We have also demonstrated the feasibility of applying the stereoselective allylation of aldehydes on solid support in an iterative fashion to generate polyol structures.     

A chiral primary-tertiary-1,2-diamine as an efficient catalyst in asymmetric aldehyde–ketone or ketone–ketone aldol reactions

A novel chiral 1,2-diaminocyclohexane derivative, (1R,2R)-N¹-n-pentyl, N¹-benzyl-1,2-cyclohexanediamine, was designed, synthesized and applied as a catalyst in a number of aldol reactions between ketones and aryl aldehydes. Reactions between acetone and aryl aldehydes gave aldol products with moderate to good yields and with excellent enantioselectivity (up to yield 85%, ee 98%), while reactions between cyclohexanone and aryl aldehydes provided anti-β-hydroxyketone products with excellent yields, diastereoselectivity and with enantioselectivity (up to 82% yield, anti/syn ratio 99:1, ee 99%). The aldol reactions between acetone and isatins were investigated, which afforded excellent yields and enantioselectivity (up to 95% yield, 98% ee). The (R)- and (S)-isomers of convolutamydine A were obtained with 95% yield and 96% ee, and 95% yield and 94% ee, respectively.     

Absolute asymmetric synthesis of stereochemically labile aldehyde helicates and subsequent chirality transfer reactions

Helical complexes formed between aluminum tris(2,6-diphenylphenoxide) (ATPH) and five different aldehydes have been prepared and structurally characterized by X-ray diffraction. It was found that [Al(OC6H3Ph2)3PhCHO] (2), [Al(OC6H3Ph2)3(4-CH3C6H4CHO)] (3), [Al(OC6H3Ph2)3(4-tBuC6H4CHO)] (4), and [Al(OC6H3Ph2)3(p-CH3OC6H4CHO)] (5) all crystallize as conglomerates, while crystals of [Al(OC6H3Ph2)3(o-CH3OC6H4CHO)] (6) are racemic. Supramolecular CH/pi interactions between molecules in crystals of 2-5 that enable stereochemical information to be mediated in three dimensions have been identified and explain the high frequency of conglomerate formation among ATPH helicates. Since 2-5 are stereochemically labile and thus enantiomerize rapidly in solution, the conglomerates can be resolved by crystallization-induced asymmetric transformation. The determination of the enantiomeric excess (ee) in solid samples of stereochemically labile molecules is not trivial, but solid-state CD spectroscopic data, anomalous dispersion data, and the ee values in alkylation reactions all indicate that preferential crystallization of 2-5 yields an essentially enantiopure product. Thus the preparation of 2-5 constitute new examples of absolute asymmetric synthesis. The helical chirality can be transferred (and thus trapped) to alcohols (with ee values of up to 16%) in crystal-to-crystal reactions with achiral organometallic reagents.     

Catalytic asymmetric bromination and chlorination of beta-ketoesters

The first general catalytic asymmetric bromination and chlorination of beta-ketoesters has been developed. The reactions proceed for both acyclic and cyclic beta-ketoesters catalyzed by chiral bisoxazolinecopper(II) complexes giving the corresponding optically active alpha-bromo- and alpha-chloro-beta-ketoesters in high yields and moderate to good enantioselectivities. For the optically active chlorinated products the isolated yields are in the range of 88-99 % and the enantiomeric excesses up to 77 % ee, while the optically active brominated adducts are formed in 70-99 % isolated yield and up to 82 % ee. Based on the absolute configuration of the optically active products, the face selectivity for the catalytic enantioselective halogenation is discussed based on a bidentate coordination of the beta-ketoester to the chiral catalyst and a X-ray structure of chiral alpha,gamma-diketoesterenolatebisoxazolinecopper(II) complex.     

Enantioselective Friedel-Crafts alkylation of indoles with trifluoroethylidene malonates by copper-bis(oxazoline) complexes: construction of trifluoromethyl-substituted stereogenic tertiary carbon center

An enantioselective alkylation of indoles with trifluoroethylidene malonates catalyzed by copper(II)-bis (oxazoline) complexes has been developed. The expected adducts with a stereogenic tertiary carbon center bearing a trifluoromethyl group were obtained in excellent yields (up to 99%) and ee values (up to 96% ee). The synthetic utility of this asymmetric catalytic reaction was demonstrated by the preparation of β-CF(3)-tryptophan and 4-CF(3)-β-carboline in high ee.     

Organocatalytic asymmetric alpha-bromination of aldehydes and ketones

The first organocatalytic enantioselective alpha-bromination of aldehydes and ketones is presented; a C2-symmetric diphenylpyrrolidine catalyst afforded the alpha-brominated aldehydes in good yields and up to 96% ee, while ketones were alpha-brominated by a C2-symmetric imidazolidine in up to 94% ee; furthermore, the organocatalytic enantioselective alpha-iodination of aldehydes is also demonstrated to proceed with up to 89% ee.     

Asymmetric Michael addition of malonic diesters to acrylates by phase-transfer catalysis toward the construction of quaternary stereogenic α-carbons

A highly enantioselective construction of an all-carbon quaternary stereogenic center at the α-position of malonic diesters has been achieved by Michael addition using phase-transfer catalysis. The reaction of α-monosubstituted malonates with acrylates in the presence of N-(9-anthracenylmethyl)quininium chloride as a phase-transfer catalyst afforded the corresponding α,α-disubstituted malonic diesters in high chemical yields (up to >95% yield) with high enantioselectivities (up to 95% ee). Furthermore, the product was amenable to chemoselective transformation and could be successfully converted to the corresponding α,α-disubstituted amino acid derivatives through Curtius rearrangement.