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).     

Lewis acid-Lewis acid heterobimetallic cooperative catalysis: mechanistic studies and application in enantioselective aza-Michael reaction

The full details of a catalytic asymmetric aza-Michael reaction of methoxylamine promoted by rare earth-alkali metal heterobimetallic complexes are described, demonstrating the effectiveness of Lewis acid-Lewis acid cooperative catalysis. First, enones were used as substrates, and the 1,4-adducts were obtained in good yield (57-98%) and high ee (81-96%). Catalyst loading was successfully reduced to 0.3-3 mol % with enones. To broaden the substrate scope of the reaction to carboxylic acid derivatives, alpha,beta-unsaturated N-acylpyrroles were used as monodentate, carboxylic acid derivatives. With beta-alkyl-substituted N-acylpyrroles, the reaction proceeded smoothly and the products were obtained in high yield and good ee. Transformation of the 1,4-adducts from enones and alpha,beta-unsaturated N-acylpyrroles afforded corresponding chiral aziridines and beta-amino acids. Detailed mechanistic studies, including kinetics, NMR analysis, nonlinear effects, and rare earth metal effects, are also described. The Lewis acid-Lewis acid cooperative mechanism, including the substrate coordination mode, is discussed in detail.     

Direct catalytic asymmetric Michael reaction of hydroxyketones: asymmetric Zn catalysis with a Et2Zn/linked-BINOL complex

Full details of our direct Michael addition of unmodified ketones using new asymmetric zinc catalysis are described. Et(2)Zn/(S,S)-linked-BINOL complexes were successfully applied to direct 1,4-addition reactions of hydroxyketones. The first generation Et(2)Zn/(S,S)-linked-BINOL 1 = 2/1 system was effective for 1,4-addition of 2-hydroxy-2'-methoxyacetophenone (3). Using 1 mol % of (S,S)-linked-BINOL 1 and 2 mol % of Et(2)Zn, we found that a 1,4-addition reaction of beta-unsubstituted enone proceeded smoothly at 4 degrees C to afford products in high yield (up to 90%) and enantiomeric excess (up to 95%). In the case of beta-substituted enones, however, the first generation Et(2)Zn/(S,S)-linked-BINOL 1 = 2/1 system was not at all effective. The second generation Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 with MS 3A system was developed and was effective for various beta-substituted enones to afford products in good dr, yield (up to 99%), and high enantiomeric excess (up to 99% ee). With the Et(2)Zn/1 = 4/1 systems, catalyst loading for beta-unsubstituted enone was reduced to as little as 0.01 mol % (substrate/chiral ligand = 10 000). The new system was also effective for 1,4-addition reactions of 2-hydroxy-2'-methoxypropiophenone (9) to afford chiral tert-alcohol in high enantiomeric excess (up to 96% ee). Mechanistic investigations as well as transformations of the Michael adducts into synthetically versatile intermediates are also described.     

Highly enantioselective addition of in situ prepared arylzinc to aldehydes catalyzed by a series of atropisomeric binaphthyl-derived amino alcohols

The direct addition of in situ prepared arylzinc to aldehydes with chiral binaphthyl-derived amino alcohols as catalysts can afford optically active diarylmethanols in high yields and with excellent enantioselectivities (up to 99 % ee, ee = enantiomeric excess). By using a single catalyst, both enantiomers of many pharmaceutically interesting diarylmethanols can be obtained by the proper combination of various arylzinc reagents with different aldehydes; this catalytic system also works well for the phenylation of aliphatic aldehydes to give up to 96 % ee.     

Enantioselective synthesis of 2,2-disubstituted terminal epoxides via catalytic asymmetric Corey-Chaykovsky epoxidation of ketones

Catalytic asymmetric Corey-Chaykovsky epoxidation of various ketones with dimethyloxosulfonium methylide using a heterobimetallic La-Li(3)-BINOL complex (LLB) is described. The reaction proceeded smoothly at room temperature in the presence of achiral phosphine oxide additives, and 2,2-disubstituted terminal epoxides were obtained in high enantioselectivity (97%-91% ee) and yield ( > 99%-88%) from a broad range of methyl ketones with 1-5 mol% catalyst loading. Enantioselectivity was strongly dependent on the steric hindrance, and other ketones, such as ethyl ketones and propyl ketones resulted in slightly lower enantioselectivity (88%-67% ee).     

Rh-catalyzed highly enantioselective formation of functionalized cyclopentanes and cyclopentanones

A catalyst system, [Rh(COD)Cl](2)-BINAP-AgSbF(6), has been developed as a second-generation catalyst for the cycloisomerization of 1,6-enynes tethered by carbon chains. Cyclopentanes and cyclopentanones, which can contain functional groups, such as the 1,4-dienes, vinyl ether, aldehyde etc., were obtained from readily available starting materials in high yields and selectivities. Both regioselectivities and enantioselectivities are excellent: only 1,4-dienes were observed and in over 99% ee.     

Iterative tandem catalysis of secondary diols and diesters to chiral polyesters

The well-known dynamic kinetic resolution of secondary alcohols and esters was extended to secondary diols and diesters to afford chiral polyesters. This process is an example of iterative tandem catalysis (ITC), a polymerization method where the concurrent action of two fundamentally different catalysts is required to achieve chain growth. In order to procure chiral polyesters of high enantiomeric excess value (ee) and good molecular weight, the catalysts employed need to be complementary and compatible during the polymerization reaction. We here show that Shvo's catalyst and Novozym 435 fulfil these requirements. The optimal polymerization conditions of 1,1'-(1,3-phenylene) diethanol (1,3-diol) and diisopropyl adipate required 2 mol% Shvo's catalyst and 12 mg Novozym 435 per mmol alcohol group in the presence of 0.5 M 2,4-dimethyl-3-pentanol as the hydrogen donor. With these conditions, chiral polyesters were obtained with peak molecular weights up to 15 kDa, an ee value up to 99% and with 1-3 % ketone end groups. Also with the structural isomer, 1,4-diol, a chiral polyester was obtained, albeit with lower molecular weight (8.3 kDa) and slightly lower ee (94%). Aliphatic secondary diols also resulted in enantio-enriched polymers but at most an ee of 46 % was obtained with molecular weights in the range of 3.3-3.7 kDa. This low ee originates from the intrinsic low enantioselectivity of Novozym 435 for this type of secondary aliphatic diols. The results presented here show that ITC can be applied to procure chiral polyesters with good molecular weight and high ee from optically inactive AA-BB type monomers.     

Rhodium catalyzed asymmetric 1,4-addition of arylboronic acids to β,γ-unsaturated α-keto ester using chiral tert-butanesulfinylphosphines ligands

Rh-Catalyzed asymmetric 1,4-selective addition of arylboronic acids to β,γ-unsaturated α-keto ester was developed using chiral tert-butanesulfinylphosphine as ligand, good yields (up to 87%), good 1,4-regioselectivities (up to 96:4), and high enantioselectivities (up to 94% ee) were achieved.     

Synthesis of both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand via convergent routes and application to rhodium-catalyzed asymmetric hydrogenation of CI-1008 (pregabalin)

Both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand are synthesized via two convergent methods. The first method relies on the chiral alkylation of 1-((-)-menthoxy)phospholaneborane using a s-BuLi/(-)-sparteine derived chiral base. Only one enantiomer of the catalyst could be synthesized via this method because only one antipode of sparteine is available in nature. The second route relies on the combination of methylphosphine borane and a chiral 1,4-diol. Either enantiomer of the ligand can be synthesized via the second route from the appropriate enantiomer of the 1,4-diol. Asymmetric hydrogenation using catalyst precursor 36 on acetamidoacrylic acid derivatives provided modest to good enantioselectivity (77-95% ee) under low H(2) pressure (30 psi). Asymmetric hydrogenation of CI-1008 (pregabalin) precursors, 39 and 40, provided good enantioselectivities (92%) at high catalyst loading (1 mol %) and low pressure (30 psi). Enantiomeric excesses dropped sharply with catalyst loading at this pressure. Increasing the pressure of H(2) caused a significant increase in enantiomeric excess for low catalyst loading reactions. Several studies were undertaken to further investigate the enantioselectivity dependence on both pressure and catalyst loading.     

Highly enantioselective conjugate additions of potassium organotrifluoroborates to enones by use of monodentate phosphoramidite ligands

The use of phosphoramidite ligands in the rhodium-catalyzed asymmetric conjugate addition of potassium organotrifluoroborates to various enones in the absence of water is described. A systematic search for effective catalysts has been performed by use of high-throughput screening methods. Initially, we have screened reaction conditions, catalyst precursors, and focused ligand libraries. In the next stage we have used the monodentate ligand combination approach, and finally we have made a library of 96 different phosphoramidites by parallel synthesis in the robot (instant ligand libraries) and have tested these in the vinylation of cyclohexenone (up to 88% enantiomeric excess, ee) and 4-phenyl-3-buten-2-one (up to 42% ee). Arylation of cyclohexenone by use of potassium phenyltrifluoroborate gave 3-phenylcyclohexanone with 99% ee.     

Catalytic, highly enantioselective Friedel-Crafts reactions of aromatic and heteroaromatic compounds to trifluoropyruvate. A simple approach for the formation of optically active aromatic and heteroaromatic hydroxy trifluoromethyl esters.

A new catalytic enantioselective synthetic method for the formation of optically active aromatic and heteroaromatic hydroxy-trifluoromethyl ethyl esters is presented. This catalytic enantioselective Friedel-Crafts reaction of trifluoromethyl pyruvate with aromatic and heteroaromatic compounds is catalyzed by a chiral bisoxazoline copper(II) complex and proceeds in good yield and with high enantiomeric excess. For a series of substituted indoles, the corresponding 3-substituted hydroxy-trifluoromethyl ethyl esters are formed in up to 93% yield and 94% ee. Pyrrole and 2-substituted pyrroles also react with trifluoromethyl pyruvate in a highly enantioselective aromatic electrophilic reaction and up to 93% ee and good yields are obtained. Furanes and thiophenes give the corresponding 2-hydroxy-trifluoromethyl ethyl esters in high enantiomeric excess; however, the yields of the products are only moderate. Various types of aromatic compounds react in this catalytic reaction with trifluoromethyl pyruvate to give the aromatic electrophilic addition product in good yield. To obtain high enantiomeric excess (> 80% ee) it is necessary that aromatic amines are protected with sterically demanding protecting groups such as benzyl or allyl. This prevents coordination of the amine nitrogen atom to the catalyst, as aromatic amines having a N,N-dimethyl group probably coordinate to the catalyst, leading to a significant reduction of the enantioselective properties of the catalyst. On the basis of the experimental results and the absolute configuration of the formed chiral center, the mechanism for the catalytic enantioselective Friedel-Crafts reaction is discussed.     

High performance of a chiral diene-rhodium catalyst for the asymmetric 1,4-addition of arylboroxines to alpha,beta-unsaturated ketones

[reaction: see text] A rhodium complex coordinated with (S,S)-2,5-dibenzylbicyclo[2.2.2]octa-2,5-diene (Bn-bod) showed high catalytic activity and high enantioselectivity in the asymmetric 1,4-addition of arylboroxines to cyclic alpha,beta-unsaturated ketones, 0.005-0.01 mol % of the catalyst giving high yields of the addition products with not lower than 94% ee. The turnover frequency of the catalyst is up to 1.4 x 10(4) h(-1).     

Squaramide-catalyzed enantioselective Michael addition of malononitrile to chalcones

A highly enantioselective Michael addition of malononitrile to chalcones catalyzed by a chiral quinine-derived squaramide catalyst has been developed. This organocatalytic reaction at a very low catalyst loading (0.5 mol%) led to chiral γ-cyano carbonyl compounds in good yields with high enantioselectivities (up to 96% ee) under mild reaction conditions.     

Enantioselective 1,6-Michael addition of anthrone to 3-methyl-4-nitro-5-alkenyl-isoxazoles catalyzed by bifunctional thiourea-tertiary amines

A simple and efficient method for the enantioselective 1,6-Michael addition reaction of anthrone to a series of 3-methyl-4-nitro-5-alkenyl-isoxazoles with a bifunctional thiourea-tertiary amine as catalyst is described. This transformation proceeds smoothly with 10 mol % catalyst and provides a series of Michael adducts bearing 3-methyl-4-nitro-isoxazole and anthrone units with good to high enantioselectivities (up to 96% ee) and in very high yields (up to 99%).     

Chiral bis(2-oxazolinyl)xanthene (xabox)/transition-metal complexes catalyzed 1,3-dipolar cycloaddition reactions and Diels-Alder reactions

A series of chiral 4,5-bis(2-oxazolinyl)-(2,7-di-tert-butyl-9,9-dimethyl)-9H-xanthenes (xabox) and their transition-metal complexes were synthesized. The X-ray analysis of xabox-RhCl₃ complex shows a unique facial type structure. Xabox-Bn-Mn(II) and xabox-Bn-Mg(II) complexes were found to be efficient catalysts in nitrone 1,3-dipolar cycloaddition (1,3-D.C.) reaction resulting in good to excellent enantioselectivities ranging from 96:4 to >99:1of endo/exo ratio and 91-96% ee for the endo adduct. The correlation between enantiomeric excess of the ligand and the product in the nitrone 1,3-D.C. reaction shows a clear linear relationship, which suggests xabox-metal catalyst worked as a single molecular catalyst. In addition, xabox-i-Pr-Mn(II) complex was also found to be an active catalyst for Diels-Alder (D-A) reaction of acryloyloxazolidinone and cyclopentadiene affording the corresponding cycloadduct in quantitative yield along with 82% ee and 98:2 endo/exo ratio.     

Asymmetric 1,4-addition of organoboronic acids to α,β-unsaturated ketones and 1,2-addition to aldehydes catalyzed by a palladium complex with a ferrocene-based phosphine ligand

A combination of palladium with ferrocene-based phosphine ligand with a carbon–bromine bond was found to be a good catalyst for the 1,4-addition of arylboronic acids to α,β-unsaturated ketones and the 1,2-addition to aldehydes. Using Pd(dba)₂ and (S,R_p)-[1-(2-bromoferrocenyl)ethyl]diphenylphosphine (S,R_p)-1, 3-phenylcyclohexanone was obtained from the reaction of 2-cyclohexen-1-one with phenylboronic acid in the presence of K₂CO₃ in toluene at room temperature after 3 h in 92% yield with 76% ee. In the 1,2-addition of 4-methylphenylboronic acid to benzaldehyde, 96% of (4-methylphenyl)phenylmethanol was afforded after 24 h, while the enantiomeric excess was only 6%.     

Desymmetrization of meso 1,3- and 1,4-diols with a dinuclear zinc asymmetric catalyst

A dinuclear asymmetric zinc catalyst generated by mixing a 2:1 ratio of diethylzinc and 2,6-bis[5-2-diarylhydroxy methyl-1-pyrrolidinyl]-4-methylphenol has been contrasted with enzymes for the desymmetrization of some meso diols. The best ligand has a p-biphenylyl group as the aromatic substituent defining the chiral space. A series of 2-substituted propanediols were examined. The best acyl transfer agent proved to be vinyl benzoate. Diacylation normally did not occur. The phenyl substituted substrate gave 91-95% ee which compares favorably with the best ee of 92% reported for an enzymatic desymmetrization. The methyl substituted substrate gave significantly better results with the dinuclear zinc catalyst (89% yield, 82% ee) as compared to the best enzymatic esterification (70% yield, 60% ee). One case of a 1,4-diol, cis-1,2-bis(hydroxymethyl) cyclohexane, also gave much better results with the dinuclear zinc catalysts (93% yield, 91% ee) as compared to the reported enzymatic process (44% yield, 7% ee). A model to rationalize the results is presented.     

New chiral Schiff base as a tridentate ligand for catalytic enantioselective addition of diethylzinc to aldehydes

We have developed new chiral Schiff base catalysts for the enantioselective addition of diethylzinc reagents to aldehydes. The reaction of benzaldehyde with diethylzinc in the presence of 1 mol % of the chiral Schiff base catalyst proceeded to afford 1-phenyl-1-propanol in 96% enantiomeric excess (ee).     

Highly enantioselective reductive amination of simple aryl ketones catalyzed by Ir-f-Binaphane in the presence of titanium(IV) isopropoxide and iodine

Using an Ir-f-Binaphane complex as the catalyst, complete conversions and high enantioselectivies (up to 96% ee) were achieved in the asymmetric reductive amination of aryl ketones in the presence of Ti(O(i)()Pr)(4) and I(2). A simple and efficient method of synthesizing chiral primary amines has been realized.     

Organocatalytic asymmetric 1,4-addition of aldehydes to acridiniums catalyzed by a diarylprolinol silyl ether

The organocatalytic enantioselective 1,4-addition of aldehydes to acridiniums catalyzed by diarylprolinol silyl ether was achieved to furnish chiral acridanes in both high yields (82-96%) and excellent enantioselectivities (up to 99% ee), which also provides the highly enantioselective intermolecular α-alkylation of aldehydes with acridiniums salt.