P-stereogenic P/N hybrid ligands: a remarkable switch in enantioselectivity in palladium-catalyzed asymmetric allylation

Optically active P-stereogenic phosphine/oxazoline bidentate ligands (1) were prepared and applied to palladium-catalyzed allylic substitution of 1,3-diphenyl-1-acetoxy-2-propene with dimethyl malonate. The absolute configuration of the allylation product was remarkably switched by changing a palladium/ligand ratio between 1/1 and 1/2.     

A new class of chiral P,N-ligands and their application in palladium-catalyzed asymmetric allylic substitution reactions

An efficient and modular synthesis of a series of chiral nonracemic P,N-ligands is reported. The P,N-ligands were prepared from 2-chloro-4-methyl-6,7-dihydro-5H-[1]pyrindine-7-one and a series of substituted chiral C(2)-symmetric 1,2-ethanediols (R = Me, i-Pr, and Ph). The ligands were evaluated for use in catalytic asymmetric synthesis in the palladium-catalyzed allylic substitution reactions of a racemic allylic acetate and dimethyl malonate. In the case of the P,N-ligand (R = Ph), the reaction was found to be highly stereoselective (90% ee).     

Palladium-catalyzed asymmetric [3 + 2] trimethylenemethane cycloaddition reactions

Transition-metal-catalyzed trimethylenemethane (TMM) [3 + 2] cycloadditions provide direct routes to functionalized cyclopentanes. This reaction has been shown to be a highly chemo-, regio-, and diastereoselective process. We report a palladium-catalyzed asymmetric [3 + 2] trimethylenemethane (TMM) cycloaddition between 3-acetoxy-2-trimethylsilylmethyl-1-propene and various di- and trisubstituted olefins. Yields of exo-methylenecyclopentane products range from 59 to 99%, and enantiomeric excesses range from 58 to 92% ee.     

A case for enantioselective allylic alkylation catalyzed by palladium nanoparticles

Palladium nanoparticles (4 nm, fcc) were prepared through decomposition of [Pd2(dba)3] by H2 in the presence of a chiral xylofuranoside diphosphite. These particles catalyze the allylic alkylation of rac-3-acetoxy-1,3-diphenyl-1-propene with dimethyl malonate leading to an almost total conversion of the (R) enantiomer and almost no reaction with the (S). This gives rise to 97% ee for the alkylation product and a kinetic resolution of the substrate recovered with ca. 90% ee. This behavior was compared to that of a molecular catalyst at various dilutions, and the differences between the two systems are discussed. This is the first colloidal system shown to display such a high enantioselectivity besides the well-known Pt/cinchonidine system.     

新型双膦配体及钯催化的烯丙基烷基化反应用于构筑季碳手 性中心

从二茂铁恶唑啉膦化合物(Sp)-1出发,合成了严平面手性二茂铁修饰的口袋型双膦配体(R,R,Sp,Sp)-4和(S,S,Sp,Sp)-4。这类配体在前手性亲核试剂的不对称烯丙基化构筑手性季碳中心的反应中,显示了较好的反应活性及对映选择性。当利用亚胺的氨基酸酯衍生物时,可以得到一些非天然的季碳氨基酸衍生物,ee值最高可以达到75.3%。一些简单的酮的烯醇负离子也可用作亲核试剂,产物为α-位双取代的具有季碳中心的酮,ee值可高达95%。     

New homochiral amino-phosphine ligands: application in asymmetric palladium catalyzed allylic alkylation

A new series of homochiral amino-phosphine ligands was prepared. The use of these ligands in the palladium catalyzed allylic alkylation of 1,3-diphenyl-1-acetoxy-2-propene with sodium malonate gave substitution products with up to 76% e.e. The enantioselectivity was largely dependent on the nitrogen substituent.     

Palladium-catalyzed enantioselective allylic alkylation of thiocarboxylate ions: asymmetric synthesis of allylic thioesters and memory effect/dynamic kinetic resolution of allylic esters

The palladium-catalyzed allylic alkylation of KSAc and KSBz with racemic cyclic and acyclic allylic esters by using N,N'-(1R,2R)-1,2-cyclohexandiylbis[2-(diphenylphosphino)-benzamide] as ligand frequently gave the corresponding allylic thioesters with high ee values and yields. The reaction of the cyclic allylic carbonates with KSAc in the presence of H(2)O was accompanied by a partial palladium-catalyzed enantioselective "hydrolysis" of the substrates with formation of the corresponding enantioenriched allylic alcohols. The degree of the "hydrolysis" was strongly dependent on the solvent and the thiocarboxylate ion. Highly selective kinetic resolutions (KRs) were observed in the palladium-catalyzed reaction of the racemic cyclohexenyl and cycloheptenyl acetates with KSAc. While the KR of the cyclohexenyl acetate is characterized by a selectivity factor S = 72 +/- 19, that of the cycloheptenyl acetate afforded (R)-cycloheptenyl acetate of >or=99% ee in 48% yield and (S)-cycloheptenyl thioacetate of 98% ee in 50% yield. The palladium-catalyzed reaction of the racemic cyclopentenyl acetate with KSAc showed a strong "memory effect" (ME), that is, both enantiomers reacted with different enantioselectivities. The ME was probed by studying the palladium-catalyzed reactions of both the matched acetate of >or=99% ee and the mismatched acetate of >or=99% ee with KSAc. The acetates not only reacted with different enantioselectivities and rates but also suffered an unexpected and concomitant palladium-catalyzed racemization in the presence of the chiral ligand. This led in the case of the mismatched acetate to a temporary dynamic kinetic resolution (DKR) that featured a racemization of the mismatched acetate by the chiral catalyst. Studies of the palladium-catalyzed reaction of the racemic cyclopentenyl acetate, carbonate, and naphthoate with KSAc in the presence of the chiral ligand also showed the ME to be strongly dependent on the nucleofuge. This also allowed the synthesis of (S)-cyclopentenyl thioacetate of 92% ee in high yield from the racemic cyclopentenyl naphthoate.     

Importance of planar chirality in chiral catalysts with three chiral elements: the role of planar chirality in 2'-substituted 1,1'-P,N-ferrocene ligands on the enantioselectivity in Pd-catalyzed allylic substitution.

A series of novel planar chiral 2'-substituted 1,1'-P,N-ferrocene ligands 9-11, 14, and 16 were prepared with diastereopurity >99:1 and found to be effective in asymmetric allylic alkylation and amination reactions. Ligand 14 furnished the highest enantiomeric excess, 98.5% and 96.5% ee in alkylation and amination reactions, respectively. The role of planar chirality in asymmetric reactions has been examined, and decisive effects on enantioselectivity as well as the control of absolute configuration in palladium-catalyzed allylic alkylation and amination reactions were observed. To clarify why and how the planar chirality governed the stereochemical outcome, X-ray crystallographic structures of eta(3)-diphenylallyl Pd complexes, (1)H NMR, (31)P NMR spectra of palladium dichloride complexes, and eta(3)-diphenylallyl Pd complexes of three 1,1'-P,N-ferrocene ligands were analyzed with the aid of COSY and 2D NOESY experiments. All results led to the conclusion that planar chirality influences the stereochemical outcome by changing or even inverting the ratio of two rotamers because of the steric interaction between a planar chiral group and the coordination site.     

Role of planar chirality of S,N- and P,N-ferrocene ligands in palladium-catalyzed allylic substitutions

Palladium-catalyzed asymmetric allylic substitutions using thioether and phosphino derivatives of ferrocenyloxazoline as ligands have been investigated with a focus on studying the role of planar chirality. In allylic alkylation, up to 98% ee and 95% ee were achieved with S,N- and P,N-ligands, respectively. In allylic amination, 97% ee was realized with P,N-ligands in the presence of TBAF. Several palladium allylic complexes were characterized by X-ray diffraction and/or solution NMR. Thioether derivatives of ferrocenyloxazolines with only planar chirality showed lower enantioselectivity in the allylic alkylation except 5c because of the formation of a new chirality on sulfur atom during the coordination of sulfur with palladium. On the other hand, in the planar chiral P,N-ligands without central chirality, (Sp)-11a-c there was no such disturbance and comparatively higher enantioselectivity in both palladium-catalyzed allylic alkylation and amination was provided.     

Development of chiral (S)-prolinol-derived ligands for palladium-catalyzed asymmetric allylic alkylation: effect of a siloxymethyl group on the pyrrolidine backbone

A series of novel chiral aminophosphine ligands are designed and readily prepared from (S)-prolinol. The reactivity and selectivity in the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with a dimethyl malonate-BSA-LiOAc system using these chiral ligands are evaluated, and the structural elucidation of ligands and palladium complex is also conducted. Moreover, a series of trialkylsilylated chiral aminophosphine ligands are prepared and applied to palladium-catalyzed asymmetric allylic alkylation (up to 98% ee).     

Novel C2-symmetric planar chiral diphosphine ligands and their application in pd-catalyzed asymmetric allylic substitutions

Novel C(2)-symmetric diphosphine ligands possessing only the planar chirality of ruthenocene, 1,1'-bis(diphenylphosphino)-2,2'-disubstituted-ruthenocenes (4), were prepared. With this kind of ligands, excellent enantioselectivity and especially highly catalytic activity in palladium-catalyzed asymmetric allylic substitutions of rac-1,3-diphenyl-2-propenyl acetate (9) were observed, compared to their ferrocene analogues 1. Good enantioselectivity and highly catalytic activity were also obtained with 4 in palladium-catalyzed asymmetric allylic substitutions of cyclohexen-1-yl acetate (12). Further study on the effect of R in ester group on enantioselectivity of 4 showed an opposite trend compared with their ferrocene analogues 1 in asymmetric allylic substitutions. For ruthenocene ligands 4, the one with the smaller R in the ester group gave higher enantioselectivity for the palladium-catalyzed asymmetric allylic substitutions of 9, while a converse trend had been observed with 1. However, for the palladium-catalyzed asymmetric allylic substitutions of 12, ligand 4 with a larger R in the ester group resulted in somewhat higher enantioselectivity but still an opposite trend with ligand 1. The X-ray diffraction study of crystal structures of 4 and 1 with Pd(II) was carried out and showed that the enantioselectivity was correlated to the twist angle existing in the palladium complex.     

New phosphorus dendrimers with chiral ferrocenyl phosphine-thioether ligands on the periphery for asymmetric catalysis

Chiral ferrocenyl phosphine-thioether ligands have been covalently bound on the periphery of 4 phosphorus dendrimers (generations 1-4) having a cyclotriphosphazene core and on one model compound. These new dendrimers proved to be efficient ligands for the palladium-catalyzed asymmetric allylic substitution reaction (ee up to 93%).     

Allylic alkylations catalyzed by palladium-bis(oxazoline) complexes derived from heteroarylidene malonate derivatives

A series of simple heteroarylidene malonate-type bis(oxazoline) ligands 4 and 5 were applied to the palladium-catalyzed allylic alkylation reaction, and the ligand 4a bearing a phenyl group afforded excellent enantioselectivity (up to 96% ee) for the allylic alkylation product. Other substrates were also examined, giving the allylic alkylated products in high yield but with poor ee values.     

Modular furanoside phosphite ligands for asymmetric Pd-catalyzed allylic substitution.

A series of diphosphite, phosphine-phosphite, and thioether-phosphite ligands 1-5 with a furanoside backbone have been used in the enantioselective palladium-catalyzed allylic substitution of rac-1,3-diphenyl-2-propenyl acetate giving low to high enantioselectivies (from close to 0% to 97% ee). The modular nature of these ligands enables systematic investigations of the effect of the ligand structure on the enantioselectivity. The enantioselectivity is mainly determined by the configuration of the stereogenic center C-3 of the furanose backbone. From this we conclude that the attack of the nucleophile takes place trans toward the donating group at the stereogenic C-5 atom. Systematic variation of the donor group attached to the carbon atom C-5 indicated that the presence of a bulky phosphite functionality has a positive effect on enantioselectivity. Thus, the highest ee's are obtained using the bulky diphosphite ligand 1b containing a xylofuranoside backbone.     

Asymmetric hydrosilylation of styrenes catalyzed by palladium-MOP complexes: ligand modification and mechanistic studies

In the palladium-catalyzed asymmetric hydrosilylation of styrene (3a) with trichlorosilane, several chiral monophosphine ligands, (R)-2-diarylphosphino-1,1'-binaphthyls (2a-g), were examined for their enantioselectivity. The highest enantioselectivity was observed in the reaction with (R)-2-bis[3,5-bis(trifluoromethyl)phenyl]phosphino-1,1'-binaphthyl (2g), which gave (S)-1-phenylethanol (5a) of 98% ee after oxidation of the hydrosilylation product, 1-phenyl-1-(trichlorosilyl)ethane (4a). The palladium complex of 2g also efficiently catalyzed the asymmetric hydrosilylation of substituted styrenes on the phenyl ring or at the beta position to give the corresponding chiral benzylic alcohols of over 96% ee. Deuterium-labeling studies on the hydrosilylation of regiospecifically deuterated styrene revealed that beta-hydrogen elimination from 1-phenylethyl(silyl)palladium intermediate is very fast compared with reductive elimination giving hydrosilylation product when ligand 2g is used. The reaction of o-allylstyrene (9) with trichlorosilane catalyzed by (R)-2g/Pd gave (1S,2R)-1-methyl-2-(trichlorosilylmethyl)indan (10) (91% ee) and (S)-1-(2-(propenyl)phenyl)-1-trichlorosilylethanes (11a and 11b) (95% ee). On the basis of their opposite configurations at the benzylic position, a rationale for the high enantioselectivity of ligand 2g is proposed.     

Palladium-catalyzed asymmetric allylic alkylation of indoles by C–N bond axially chiral phosphine ligands

The palladium-catalyzed asymmetric allylic alkylation of indoles with 1,3-diphenyl-2-propenyl acetate using P/N-type ligands such as N-aryl indole, C–N bond axially chiral aminophosphine (aS)-L4, gave the desired products 1 in good yields and with moderate to high enantioselectivities (up to 90% ee).     

Palladium-catalyzed deracemization of allylic carbonates in water with formation of allylic alcohols: hydrogen carbonate ion as nucleophile in the palladium-catalyzed allylic substitution and kinetic resolution

The palladium-catalyzed deracemization of racemic cyclic and acyclic allylic methyl carbonates in water in the presence of N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphophino)benzamide] proceeds with high enantioselectivities to give the corresponding allylic alcohols in high yields. This deracemization involves a palladium-catalyzed allylic substitution with the in-situ-formed hydrogen carbonate ion and an irreversible decomposition of the intermediate allylic hydrogen carbonates, with formation of the corresponding allylic alcohols. The palladium-catalyzed reaction of racemic cyclic allylic acetates with potassium hydrogen carbonate in water in the presence of the chiral bisphosphane proceeds with a highly selective kinetic resolution to give the corresponding allylic alcohols and allylic acetates.     

Dendritic oxazoline ligands in enantioselective palladium-catalyzed allylic alkylations

First to fourth generation dendritic substituents based on 2,2-bis(hydroxymethyl)propionic acid and (1R,2S,5R)-menthoxyacetic acid were attached to 2-(hydroxymethyl)pyridinooxazoline and bis[4-(hydroxymethyl)oxazoline] compounds. The new ligands obtained were assessed in palladium-catalyzed allylic alkylations. The first type of ligands exhibited enantioselectivity similar to that of a benzoyl ester derivative, whereas the latter type of ligands afforded products with higher selectivity than the analogous benzoyl ester. The activity of the dendritic catalysts decreased with increasing generation.     

Hammett studies of enantiocontrol by PHOX ligands in Pd-catalyzed allylic substitution reactions

Electronically modified PHOX ligands 3a-e were synthesized to probe the mechanism of the enantioselective palladium-catalyzed allylic alkylation and amination reactions. Alkylation with dimethyl sodiomalonate produced only a small variation in the ee (89.3% to 93.4%), but amination with benzylamine gave a much wider variation in the ee (16.4% to 66.6%). Hammett analysis suggests that the substituents interact more significantly with phosphorus and supports a combined electronic and steric basis for enantioselection. [reaction: see text]     

2.2]Paracyclophane-derived chiral P,N-ligands: design, synthesis, and application in palladium-catalyzed asymmetric allylic alkylation

With the idea of tuning structural flexibility and rigidity, several [2.2]paracyclophane-derived P,N-ligands were designed and synthesized. A full investigation of the relationship between the ligands' structures and their abilities to induce asymmetry in palladium-catalyzed asymmetric allylic alkylations of malonates with 1,3-diphenyl 2-propenyl acetate was carried out, and high yields and enantioselectivities (i.e., 99% yield, 97% ee) were observed while using ligands bearing matched planar and central chirality.