Enantioselective Palladium(II)‐Catalyzed Intramolecular Aminoarylation of Alkenes by Dual N−H and Aryl C−H Bond Cleavage

An asymmetric palladium‐catalyzed intramolecular oxidative aminoarylation of alkenes has been developed with quinoline–oxazoline chiral ligands and Ag₂CO₃ as the oxidant. Various indolines containing a quaternary stereogenic center were synthesized in high yield with excellent enantioselectivity. Preliminary mechanistic studies suggest that the addition of a catalytic amount of phenylglyoxylic acid significantly accelerates the reaction and slightly enhances the enantioselectivity.     

Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael Reaction of Nitroalkanes and β,β‐Disubstituted α,β‐Unsaturated Aldehydes for the Construction of All‐Carbon Quaternary Stereogenic Centers

The asymmetric Michael reaction of nitroalkanes and β,β‐disubstituted α,β‐unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4‐addition products with an all‐carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β‐substituents such as β‐aryl and β‐alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)‐ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β‐unsaturated aldehydes, the retro‐Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.     

Chiral aminophosphine phosphinite–palladium catalysts in asymmetric allylic alkylations

Palladium complexes of chiral aminophosphine phosphinites were investigated for the asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. The chirality of the carbon bonded to O-PPh₂ in the ligands was found to be very important to the enantioselectivity of the catalysts. Introduction of this stereogenic center has led to significantly improved enantioselectivities.     

Total synthesis of (+)-brasilenyne. Application of an intramolecular silicon-assisted cross-coupling reaction

The first enantioselective total synthesis of (+)-brasilenyne (1) has been achieved in 19 linear steps, with 5.1% overall yield from l-(S)-malic acid. The construction of the oxonin core containing a 1,3-cis,cis diene unit was accomplished with a tandem ring-closing metathesis/silicon-assisted intramolecular cross-coupling reaction. In addition, a key propargylic stereogenic center was created through a novel, highly diastereoselective ring opening of a 1,3-dioxolanone promoted by TiCl(4). This reaction proceeded through an oxocarbenium ion intermediate and the asymmetric induction was fully controlled by l-malic acid residue. The C(8) stereogenic center was set by a reagent-controlled asymmetric allylboration.     

Development of an asymmetric trimethylenemethane cycloaddition reaction: application in the enantioselective synthesis of highly substituted carbocycles

A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane (TMM) with electron-deficient olefins has been developed. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic pyrrolidine and azetidine structures, is discussed. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes with high levels of enantioselectivity. The donor scope was also explored, and substituted systems were tolerated, including one bearing a nitrile moiety. These donors were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity.     

Asymmetric hydroformylation of styrene using rhodium and platinum complexes of diphosphites containing chiral chelate backbones and chiral 1,3,2-dioxaphosphorinane moieties

Several chiral diphosphite ligands containing six stereogenic centres were synthesised and tested in order to study chiral cooperativity in the Rh- and Pt-catalysed asymmetric hydroformylation of styrene. The ligands were prepared either by the reaction of 2,4-pentanediol enantiomers with (4R,6R)-4,6-dimethyl-2-chloro-1,3,2-dioxaphosphorinane or that of (1S,3S)-1,3-diphenyl-1,3-propanediol with 4,6-dimethyl-2-chloro-1,3,2-dioxaphosphorinane enantiomers. Thus the chirality was varied both in the chelate backbone and in the terminal groups of the ligands. In case of Pt-catalysed hydroformylation, the stereogenic elements in the bridge have been found to be determinate for the product configuration with a cooperative effect from the terminal groups when the constellations are matched with 40% e.e. maximum enantioselectivity. Some coordination chemistry and the crystal structure determination of these ligands are also reported.     

Evaluation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol for catalytic asymmetric addition of organozinc reagents to aldehydes

A facile and practical approach to preparation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol was developed from cheap and easily available l-(+)-methionine. Synthetic highlights include the three-step, one-pot construction of the chiral azetidine ring and the development of an improved one-step procedure for the synthesis of the key intermediate l-2-amino-4-bromobutanoic acid. Enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol was evaluated for catalytic asymmetric addition of organozinc reagents to aldehydes. The asymmetric ethylation, methylation, arylation, and alkynylation of aldehydes achieved enantioselectivity of up to 98.4%, 94.1%, 99.0%, and 84.6% ee, respectively, in the presence of a catalytic amount of chiral N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol. Our results demonstrated further that the four-membered heterocycle-based backbone was a good potential chiral unit for the catalytic asymmetric induction reaction, and the hindrance of the bulky ferrocenyl group, compared to a phenyl group, played an important role in the enantioselectivities. A possible transition for the catalytic asymmetric addition has been proposed on the basis of the crystal structure of the chiral ligand 3b including two HOAc molecules and previous studies.     

Palladium-catalyzed asymmetric ring expansion of allenylcyclobutanols: an asymmetric Wagner-Meerwein shift

In this study, we developed a palladium-catalyzed atom economic asymmetric Wagner-Meerwein shift of allenylcyclobutanol substrates. It is an excellent method for creating functionalized cyclopentanones with an alpha-chiral O-tertiary center by ring expansion of allenylcyclobutanols. This reaction was initiated by hydropalladation and afforded excellent enantioselectivity as well as atom economy. This method provides an efficient route toward the synthesis of natural products such as trans-kumausyne's family, spiro ring systems. In addition, we obtained excellent diastereoselectivity and enantioselectivity at the same time by using 3-monosubstituted allenylcyclobutanol.     

Asymmetric Synthesis of Biaryl Atropisomers Using an Organocatalyst-Mediated Domino Reaction as the Key Step

A three-pot synthetic method that features the use of an organocatalyst as the key step was developed for the preparation of biaryl atropisomers. The first reaction is an asymmetric domino Michael–Henry reaction catalyzed by diphenylprolinol silyl ether to afford the substituted nitrocyclohexanecarbaldehyde with four stereogenic centers and one defined configuration of a stereogenic axis with excellent enantioselectivity. Removal of the central chirality from the domino products afforded biaryl atropisomers having axial chirality with excellent enantioselectivity.     

Copper‐Catalyzed Asymmetric Conjugate Addition with Chiral SimplePhos Ligands

SimplePhos ligands represent a novel class of monodentate chiral ligands based on a chiral amine moiety and flexible diaryl groups on the phosphorous atom. They can be easily prepared by two different pathways and they can be highly functionalised. Herein we report the copper‐catalysed asymmetric conjugate addition of diethyl zinc and trialkylaluminium reagents with SimplePhos ligands, which gives high enantioselectivity with cyclic enones, acyclic enones and nitro‐olefins, with up to 98.6 % ee. Of particular interest is the reaction of trialkylaluminium reagents with a wide range of 3‐substituted enones, thus allowing the formation of stereogenic quaternary carbon centres.     

Asymmetric epoxidation of enones using cumyl hydroperoxide and in situ generated zinc complexes of chiral pyrrolidinyl alcohols

The homogeneous asymmetric epoxidation of a range of enones was carried out using cumyl hydroperoxide, diethylzinc, and chiral pyrrolidinyl alcohol-containing ligands to afford the corresponding epoxy ketones with enantioselectivities of ≤97% ee. Examination of the enantioselectivities obtained in the asymmetric epoxidation of enones using a range of chiral ligands indicated that synergy between the sterically bulky bicyclo[2.2.2]octane skeleton and the substituents attached to the carbinol moiety played an important role in determining the reaction enantioselectivity. The position and nature of the substituent on the aromatic ring of the enone also had a pronounced effect on the observed enantioselectivity.     

Chiral Cooperativity: The Effect of Distant Chiral Centers in Ferrocenylamine Ligands upon Enantioselectivity in the Gold(I)-Catalyzed Aldol Reaction

Long-range chiral cooperativity in enantiomerically pure ferrocenylamine ligands containing both planar and multiple centers of chirality (multiple stereogenic C-atoms) was demonstrated in the Au^I-catalyzed reaction of aldehydes and isocyanoesters. Synthetic methodology was developed for the synthesis of ferrocenylamine ligands with two and three chiral centers of known absolute configuration in the C-side chain in addition to the planar chirality of the molecule. The diastereo- and enantioselectivity of the Au^I-catalyzed formation of the trans- and cis-dihydrooxazoles 5 and 6 , respectively, from benzaldehyde ( 1 ) and methyl isocyanoacetate ( 2 ) depend upon the sequence of chirality (absolute configuration of the chiral centers) in the side chain of the ferrocenylamine ligands. Particularly significant effects were observed upon the enantioselectivity for the minor cis-dihydrooxazole 6 , for which, in certain cases, resulted in a change in the enantiomeric dihydrooxazole 6 produced in excess with a change in the absolute configuration of a distant chiral center. Significant effects upon diastereo- and enantioselectivity were observed when chiral ferrocenylamine ligands containing free OH groups were utilized. Using ligands containing a free OH group gave 6 with an absolute configuration opposite to that produced by the corresponding ester and carbamate derivatives. The possible mechanisms for the transmission of chiral information in the proposed stereoselective transition state (TS) was discussed, including both the formation of a stereogenic N-atom and steric effects based upon Newman's rule of six.     

Proline-based P, N ligands in asymmetric allylation and the Heck reaction.

A series of phosphine-oxazoline ligands based on proline are reported. These ligands are synthesized from commercially available trans-4-hydroxy-L-proline in four steps. The ability of this type of ligand to catalyze allylic alkylation in an asymmetric fashion as well as the asymmetric Heck reaction is reported. The best of these ligands gave a palladium complex, which catalyzed the addition of dimethylmalonate to cyclopentenyl acetate in excellent yield and up to 96% ee. This same system catalyzed the Heck reaction between dihydrofuran and cyclohexene in up to 86% ee. These ligands appear to differ from the traditional phosphine-oxazoline ligands in that the stereochemistry of the stereogenic carbon next to the oxazoline is not necessarily the dominant chiral center in the induction of selectivity.     

New class of bifunctional thioureas from l-proline: highly enantioselective Michael addition of 1,3-dicarbonyls to nitroolefins

A new class of bifunctional tertiary amine thiourea was synthesized from l-proline. The reported thiourea is amenable to steric and electronic modifications at the stereogenic center bearing a thiourea moiety. Excellent enantioselectivity was obtained in the Michael addition of 2,4-pentanedione to various nitro olefins using the new organocatalyst. The construction of contiguous stereocenters via the Michael reaction of substituted 1,3-dicarbonyls to nitro olefins was also carried out with very good yield, enantioselectivity, and diastereoselectivity.     

Synthesis and application of quinazoline-oxazoline-containing (quinazox) ligands

A practical synthesis of potentially tridentate P,N,N-ligands containing two stereogenic elements incorporated into the axially chiral Quinazolinap and centrally chiral 2-oxazoline subunits is reported. The application of these novel hybrid ligands in Pd(0)-catalyzed asymmetric allylic alkylation revealed the matched and mismatched diastereomer, dominant stereogenic element, as well as the effect of the oxazoline R substituent on the level of enantioselectivity (ee's up to 81%). [structure: see text]     

Application of P-stereogenic aminophosphine phosphinite ligands in asymmetric hydroformylation

New chiral aminophosphine phosphinite ligands with a stereogenic center at the aminophosphine phosphorus atom were prepared based on (R,S)-ephedrine as the chiral auxiliary and backbone. Substituents at the chiral aminophosphine as well as at the phosphinite phosphorus atom were varied. These new ligands were applied to the rhodium-catalyzed asymmetric hydroformylation of vinyl arenes. The enantiomeric excess reached up to 77%. 1H and 31P NMR studies of the Rh complexes under syngas pressure reveal that [HRh(CO)2(PP)] complexes with the NP* moiety in an axial position are responsible for enantioselectivity.     

Asymmetric Dearomatization of β‐Naphthols through a Bifunctional‐Thiourea‐Catalyzed Michael Reaction

An intermolecular asymmetric dearomatization reaction of β‐naphthols with nitroethylene through a chiral‐thiourea‐catalyzed Michael reaction is described. Enantioenriched functionalized β‐naphthalenones with an all‐carbon quaternary stereogenic center could thus be easily constructed from simple naphthol derivatives in good yields and excellent enantioselectivity (up to 79 % yield, 98 % ee).     

Achiral Trisubstituted Thioureas as Secondary Ligands to CuI Catalysts: Direct Catalytic Asymmetric Addition of α‐Fluoronitriles to Imines

Thioureas have emerged as effective hydrogen‐bonding catalysts over the last two decades, and they are broadly utilized in asymmetric catalysis. We report that achiral trisubstituted thioureas function as beneficial secondary ligands to Cu^I catalysts, thereby enabling highly diastereo‐ and enantioselective addition of α‐fluoronitriles to imines. The structure of the thiourea significantly affects the reaction outcome, and kinetic experiments indicate that the thioureas enhance the stereocontrol by binding to the Cu^I complex. The reaction products can be readily transformed into valuable β‐amino acid derivatives bearing a fluorinated tetrasubstituted stereogenic center.     

Structural and electronic effects of oxazolidine ligands derived from (1R,2S)-ephedrine in the asymmetric addition of diethylzinc to aldehydes

The purpose of this research was to determine the activity of chiral oxazolidine ligands prepared from (1R,2S)-ephedrine for the enantioselective addition of diethylzinc to aldehydes. The configuration on the newly formed C2 stereogenic center was determined as (2S) by X-ray structural analysis. Oxazolidine ligands reveal medium enantioselectivity with the ee exceeding 57%, and the yields obtained being 68–99%. The results indicate that the absolute configuration of the addition product depends not only on the N3-methyl as an important stereocontrol element but also on both the electronic and steric effects of the substrates and oxazolidine ligands.     

Spiro indane-based phosphine–oxazoline ligands for palladium-catalyzed asymmetric arylation of cyclic N-sulfonyl imines

Palladium complexes of indane-based phosphine–oxazoline ligands with a spirocarbon stereogenic center were examined for asymmetric addition of arylboronic acids to cyclic N-sulfonyl imines. Excellent reaction activities (up to 99% yield) and enantioselectivities (up to 99% ee) were obtained with a broad scope of substrate.