(S)-Proline-derived new chiral ligands with phosphino,organosulfur or organoselenenyl functionality as an enantiocontrollable coordinating element

The synthesis of (S)-proline-derived chiral ligands bearing phosphino, organosulfur or selenenyl groups and their use as chiral ligands in palladium-catalyzed asymmetric allylic alkylations has been accomplished. In particular, the (S)-proline-derived phosphine ligands bearing alkylsulfenyl groups provided high enantioselectivity, and the degree of asymmetric induction was dependent upon the steric bulk of the alkyl substituents in sulfenyl groups. The stereochemical results are rationalized by a plausible mechanism involving the assistance of chelates formed by the participation of the two preferred heteroatoms involved.     

Synthesis of two new chiral fluorous bis(oxazolines) and their applications as ligands in catalytic asymmetric reactions

Two new chiral fluorous bis(oxazolines) with a fluorous content of 56.9% and 59.3%, respectively, have been prepared starting from (S)-serine and (S)-tyrosine. Applications of these compounds as fluorous box ligands in asymmetric alkylations gave ees up to 92%, and in allylic oxidations ees up to 50%. Recycling and reuse of the ligands in asymmetric alkylation and of the catalytic system in allylic oxidation gave the same enantioselectivities.     

Reduction of carbonyl compounds via hydrosilylation: V. Synthesis of optically active allylic alcohols via regioselective asymmetric hydrosilylation

Regioselective asymmetric reduction of prochiral α,β-unsaturated ketones to optically active allylic alcohols was performed via hydrosilylation catalyzed by a rhodium(I) complex with (+)-BMPP, (+)-DIOP and (?)-DIOP as chiral ligands. The allylic alcohols with optical purity up to 69% e.e. were obtained in good yields. The extent of asymmetric induction was found to depend on the stereo-electronic matching of the chiral ligand, ketone and hydrosilane employed. In the asymmetric reduction of (R)-carvone, leading to carveol, the extent of asymmetric induction was found to depend markedly on the ligand/rhodium ratio. Either trans-(5R,1S)-carveol or cis-(5R,1R)-carveol was obtained with good stereoselectivity by using (?)-DIOP or (+)-DIOP as chiral ligand, and it turned out that the chiral center present in carvone had only a slight influence on the asymmetric induction by the chiral catalysts.     

A novel method for asymmetric synthesis of both enantiomers of α-substituted carboxylic acid derivatives from optically active 1-chlorovinyl p-tolyl sulfoxides and lithium ester enolates with 1,4-chiral induction from the sulfur chiral center

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent at the α-position with high 1,4-chiral induction from the sulfur chiral center in high yields. The adducts were converted to optically active esters and carboxylic acids having a chiral center at the α-position. When this addition reaction was carried out with the ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolates, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was realized.     

A new C2-symmetric chiral diphosphine ligand: palladium-catalyzed enantioselective allylic alkylation of cycloalkenyl substrate

A novel C₂-symmetric chiral diphosphine ligand 1 was developed using (2S)-2-amino-1-(diphenylphosphino)-3-methylbutane 2 which was derived from l-valine as in the previous work for the chiral amidine ligand, VALAP. Ligand 1 demonstrated extremely high levels of asymmetric induction, over 99% ee in palladium-catalyzed allylic alkylations of 2-cyclohexen-1-yl pivalate 5.     

Studies on the Pauson–Khand reaction of alkynyl sulfoxides. Unexpectedly easy racemization of their dicobalt hexacarbonyl complexes

The scope and limitations of the Pauson–Khand reactions of alkynyl sulfoxides with strained alkenes have been studied. (S)-1-Hexynyl p-tolyl sulfoxide and (S)-2-phenylethynyl p-tolyl sulfoxide afforded β-(p-tolylsulfinyl)enones in moderate yields and low diastereoselectivities. The diastereomeric mixtures were easily separated by column chromatography and the sulfinyl group could be cleaved by a sequence involving reduction to sulfide, carbonyl reduction and enol thioether hydrolysis to afford 1,3-rearranged enantiomerically enriched α-butyl and α-phenyl enones. The absolute configuration of the Pauson–Khand adducts was determined by X-ray diffraction. The decreased enantiomeric excess of the final products uncovered an unprecedented low temperature racemization of the hexacarbonyl dicobalt complexes of alkynyl sulfoxides.     

An asymmetric synthesis of carboxylic acid derivatives,including lactic acid and α-amino acid derivatives,from optically active 1-chlorovinyl p-tolyl sulfoxides and ester lithium enolates with creation of chirality at the α-position

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones or methyl formate and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent (alkyl, alkoxy, or dibenzylamino group) at the α-position with high 1,4-chiral induction from the sulfur chiral center. The adducts were converted to optically active esters, lactic acid, and α-amino acid derivatives having a chiral center at the α-position. When this addition reaction was carried out with an ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolate, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was achieved.     

A new chiral iminophosphine ligand derived from (1S,4S)-fenchone in palladium-catalyzed asymmetric allylic alkylations

A new chiral iminophosphine ligand derived from (1S,4S)-fenchone has been developed, and its usefulness as a chiral ligand in asymmetric synthesis was demonstrated in palladium-catalyzed allylic alkylations.     

Ferrocenyl bis-phosphine ligands bearing sulfinyl,sulfonyl or sulfenyl groups: applications in asymmetric hydrogenation and allylic alkylation reactions

A new series of chiral ferrocenyl bis-phosphine ligands have been synthesized. Elements of planar and central chirality have been incorporated into a ferrocene backbone through sulfinyl, sulfonyl and sulfenyl groups at the ortho-position to the phosphines. The effectiveness of these ligands has been demonstrated in Rh-catalyzed hydrogenations and Pd-catalyzed allylic alkylations.     

Diamidophosphites with remote P1-stereocentres and their performance in Pd-catalyzed enantioselective reactions

Diamidophosphite ligands based on 1,1′-bis(hydroxymethyl)ferrocene or N¹,N²-bis((S)-1-hydroxy-3,3-dimethylbutan-2-yl)oxalamide and bearing 1,3,2-diazaphospholidine rings with stereogenic phosphorus atoms were obtained. The use of these ligands provides up to 96% ee in Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate, up to 70% ee in Pd-catalyzed desymmetrizations of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol bis-carbamate and up to 80% ee in Pd-catalyzed allylic alkylations of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate. Results obtained with a diamidophosphite containing an oxalamide framework show the considerable potential of such ligands in enantioselective catalysis.     

A new synthesis, including asymmetric synthesis, of spiro[4.n]alkenones from three components: cyclic ketones, chloromethyl p-tolyl sulfoxide, and acetonitrile; and a formal total synthesis of racemic acorone

1-Chlorovinyl p-tolyl sulfoxides were synthesized from several kinds of cyclic ketones and chloromethyl p-tolyl sulfoxide in good yields. Treatment of the 1-chlorovinyl p-tolyl sulfoxides with cyanomethyllithium at −78°C to room temperature gave spirocyclic enaminonitriles in high yields. Acidic treatment of the enaminonitriles afforded spiro[4.n]alkenones in good yields. By using an unsymmetrical cyclic ketone, α-tetralone, and optically active chloromethyl p-tolyl sulfoxide, this procedure afforded enantiomerically pure spiro[4.5]decenone in good yield with excellent asymmetric induction from the sulfoxide chiral center. By using this method a formal total synthesis of a racemic spirocyclic sesquiterpene, acorone, was realized.     

Influence on the enantioselectivity in allylic alkylation of the anomeric position of the phosphine-amide ligands derived from d-glucosamine

The synthesis of a new series of chiral phosphine amides derived from d-glucosamine is described. The palladium-catalyzed asymmetric allylic alkylations of racemic (E)-1,3-diphenyl-2-propenyl acetate with dimethyl malonate using these ligands have been investigated. The results obtained and the NMR studies of free ligands and of their Pd-complexes obtained from dimer [(η³-C₃H₅)PdCl]₂ revealed the mode of complexation and the influence of the configuration and of the nature of the substituent at the anomeric position on the enantioselectivity of the studied asymmetric allylic alkylation reactions.     

The first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis with enantiopure cyclopropylmagnesium carbenoids

The reaction of lithium α-sulfinyl carbanion of enantiopure dichloromethyl p-tolyl sulfoxide with α,β-unsaturated carbonyl compounds gave optically active 1-chlorocyclopropyl p-tolyl sulfoxides having a carbonyl group with high asymmetric induction from the sulfur chiral center. Reduction of the carbonyl group followed by treatment with Grignard reagent, the 1-chlorocyclopropyl p-tolyl sulfoxides resulted in the formation of enantiopure allenic alcohols via the Doering-LaFlamme-type rearrangement of enantiopure cyclopropylmagnesium carbenoid intermediates. This is the first example for the asymmetric synthesis of allenes by the Doering-LaFlamme allene synthesis.     

A synthesis, including asymmetric synthesis, of α-quaternary α-amino aldehydes from ketones and chloromethyl p-tolyl sulfoxide via sulfinylaziridines

Treatment of 1-chlorovinyl p-tolyl sulfoxides, prepared from ketones and chloromethyl p-tolyl sulfoxide, with N-lithio arylamines resulted in the formation of sulfinylaziridines in good to high yields. The sulfinylaziridines were treated with N-lithio aniline or N-lithio p-chloroaniline to afford α-quaternary α-amino aldehydes in good yields. From α-quaternary α-amino aldehydes, α-quaternary α-amino acid esters and β-quaternary β-amino alcohols were obtained. When optically active chloromethyl p-tolyl sulfoxide was used in this procedure, a method for the synthesis of optically active α-quaternary α-amino aldehydes was realized. The reaction mechanism, including asymmetric induction, for the formation of the sulfinylaziridines is described.     

A new chiral sulfinyl-NH-pyridine ligand for Ir-catalyzed asymmetric transfer hydrogenation reaction

A new flexible C₁-symmetric tridentate ligand (S)-N-(2-(tert-butylsulfinyl)benzyl)-1-(pyridin-2-yl)methanamine sulfoxide (L1) was successfully prepared and utilized as a chiral ligand for Ir(I)-catalyzed ATH (asymmetric transfer hydrogenation) reactions. Without any cooperation of other chiral center, encouraging ee and conversion values have been achieved, which provide us a better understanding on these types of ligands and a new strategy to develop new high-efficiency chiral catalysts for asymmetric reaction.     

Efficient novel 1,2-diphosphite ligands derived from d-mannitol in the Pd-catalyzed asymmetric allylic alkylation

A novel Pd/1,2-diphosphite catalyzed asymmetric allylic alkylation of 1,3-diarylpropenyl acetate with malonates was developed. Catalyst optimization via a variation in the protecting groups at the 1,2- and/or 5,6-positions of d-mannitol skeleton and in biaryl moieties of the ligands led to a ‘lead’ catalyst, which efficiently mediated the allylic alkylations. The activities and enantioselectivities of the reaction clearly showed that the stereogenic centers of the skeleton and the axially chiral diaryl moieties of the ligands had a synergic effect. The ligand 1,2:5,6-di-O-isopropylidene-3,4-bis[(S)-1,1′-binaphthyl-2,2′-diyl]phosphite-d-mannitol afforded excellent yields (up to 99%) and high levels of enantioselectivies (ee up to 98%) in 1,4-dioxane/CH₂Cl₂ mixture (v/v, 1:1) using [Pd(π-allyl)Cl]₂ as catalytic precursor and LiOAc as base. Dramatic changes in the sense and in the degree of the enantioselectivity depending on the configuration of the diaryl moieties of the ligands and reaction conditions were observed.     

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).     

Application of novel enantiopure hydroxymethyl-substituted pyridine derivatives in asymmetric catalysis

The synthetic modification of enantiopure hydroxymethyl-substituted pyridine derivatives leading to novel chiral ligands is described. A set of these pyridine derivatives was examined as ligands in asymmetric transformations such as enantioselective alkylations or alkynylations of aldehydes, the asymmetric copper-catalyzed Henry reaction and the asymmetric allylation of benzaldehyde with allyl(trichloro)silane. This first screening revealed that several of the pyridine derivatives prepared are effective ligands affording high yields and good enantioselectivities. The asymmetric alkylation of aldehydes with diethylzinc provided yields of up to 93% with an enantiomeric excess of up to 88%. The asymmetric Henry reaction was also efficiently catalyzed by one of the prepared ligands affording (S)-2-nitro-1-phenylethanol in 68% yield and with 70% ee.     

Highly stereoselective aziridination of imines with (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide

Addition of (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide to N-tosyl imines afforded the corresponding sulfinyl aziridines with full enantio- and diastereoselectivity. The chiral sulfinyl substituent was removed without ring opening leading to enantiopure 2-substituted aziridines.     

Synthesis and resolution of 2,2′-bis[di(p-tolyl)stibano]-1,1′-binaphthyl (BINASb); the first example of an optically active organoantimony ligand for asymmetric synthesis

Racemic 2,2′-bis[di(p-tolyl)stibano]-1,1′-binaphthyl (BINASb) (±)-2 has been prepared from 2,2′-dibromo-1,1′-binaphthyl 1 via 2,2′-dilithio-1,1′-binaphthyl intermediate, and has been resolved via the separation of a mixture of the diastereomeric Pd complexes 4A and 4B, derived from the reaction of (±)-2 with di-μ-chlorobis{(S)-2-[1-(dimethylamino)ethyl]phenyl-C,N}dipalladium(II) 3. The optically active BINASbs (S)-(+)-2 and (R)-(−)-2 have been shown to be effective chiral ligands for the rhodium-catalyzed asymmetric hydrosilylation of ketones.