Diastereoselective Pd/In bimetallic inter-intramolecular (class 2) cascade reactions of allenyl-imines and aryl iodides

A new diastereoselective Pd/In bimetallic inter-intramolecular cascade reaction employing allenyl-sulfinimines and aryl iodides is described. The tert-butanesulfinyl chiral auxiliary affords chiral, highly substituted cis-pyrrolidines and piperidines.     

Chiral linker. Part 3: Synthesis and evaluation of aryl substituted m-hydrobenzoins as solid supported open chain chiral auxiliaries for the diastereoselective reduction of α-keto esters

Five partly novel aryl substituted m-hydrobenzoins were synthesized and the corresponding desymmetrized hydrobenzoin ethers evaluated as open chain chiral auxiliaries in the L-Selectride^® mediated stereoselective reduction of phenylglyoxylates, resulting in de values of up to 91%. Two optimized auxiliary structures were immobilized on commercially available Wang-resin and applied as a reusable solid supported chiral auxiliary in the same type of reaction.     

Direct asymmetric aldol reaction of aryl ketones with aryl aldehydes catalyzed by chiral BINOL-derived zincate catalyst

Direct asymmetric aldol reaction of aryl ketones with aryl aldehydes catalyzed by chiral metal complex is reported for the first time herein. Two novel semicrown chiral ligands 1a and 1b were synthesized from (S)- and (R)-BINOL, respectively, and then employed to catalyze the direct asymmetric aldol addition of aryl ketones to aryl aldehydes. Introduced with 2.0 equiv of diethylzinc, 1b had higher enantioselectivity than 1a. Up to 97% yield and up to 80% enantioselectivity were achieved.     

Enantioselective synthesis of primary 1-(aryl)alkylamines by nucleophilic 1,2-addition of organolithium reagents to hydroxyoxime ethers and application to asymmetric synthesis of G-protein-coupled receptor ligands

(E)-Arylaldehyde oxime ethers bearing a (1S)-2-hydroxy-1-phenylethyl or (2R)-1-hydroxy-2-phenylethyl group as a chiral auxiliary, both derived from a single precursor, methyl (R)-mandelate, underwent nucleophilic addition with organolithium reagents via six-membered chelates to give the diastereomerically enriched (R)- and (S)-adducts, respectively, which, after chiral auxiliary removal by reductive N-O bond cleavage, led to the corresponding (R)- and (S)-1-(aryl)ethylamines. This organolithium addition protocol using methyllithium was applied in an enantiodivergent fashion to the preparation of both enantiomers of 1-(2-hydroxyphenyl)ethylamine, which has been previously used as an efficient chiral auxiliary for the synthesis of natural products in this laboratory. The synthetic utility of this methodology involving diastereoselective methyl addition was demonstrated by further application to the asymmetric synthesis of a new type of calcium receptor agonist (calcimimetics), (R)-(+)-NPS R-568 and its thio analogue. Furthermore, diastereoselective vinylation was accomplished by application of the hydroxy oxime ether-based protocol using vinyllithium, which allowed the development of the enantioselective synthesis of the NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721.     

Modular chiral thiazolidine catalysts in asymmetric aryl transfer reactions

Modular chiral thiazolidine derivatives were synthesized in a single step from inexpensive and commercially available starting materials. These ligands catalyzed enantioselective arylation of different aldehydes using aryl boronic acids as a source of transferable aryl groups. The products were obtained in excellent yields and good enantioselectivities.     

Formation of chiral aryl ethers from enantiopure amine or alcohol substrates

Three methods for the preparation of chiral aryl ethers are demonstrated. N,N-Disulfonylimide derivatives are used in the stereoselective formation of aryl ethers from chiral amines. Nucleophilic attack of aryloxide anions on the cyclic N,N-disulfonylimide derivative of (S)-1-phenylethylamine afforded the (R)-1-phenylethyl phenyl and 2-naphthyl ethers with 83–87 and 70–79% inversion of configuration, respectively. The results are compared with results from alternative methods for the preparation of homochiral aryl ethers from chiral alcohols with complete retention and inversion of configuration, respectively.     

Catalytic enantioselective arylation of aryl aldehydes by chiral aminophenol ligands

The catalytic enantioselective arylation of aryl aldehydes using boronic acids as the source of transferable aryl groups is described; the reaction is found to proceed in good yields and in good to high enantioselectivities (up to 99% ee) in the presence of a chiral aminophenol ligand.     

Asymmetric additive-free aryl addition to aldehydes using perhydrobenzoxazines as ligands and boroxins as aryl source

A highly efficient enantioselective aryl addition to aldehydes using boroxins as aryl source and conformationally restricted perhydro-1,3-benzoxazines as ligands is reported. Both enantiomeric forms of chiral arylphenylmethanols and 1,1'-disubstituted diarylmethanols are afforded with excellent yields and enantioselectivities using the same ligand by means of an appropriate combination of boroxin and aromatic aldehyde. The enantiocontrol is not significantly influenced by electronic effects or steric hindrance, even with substituted boroxins. Very homogeneous ee's are reached when substituted arylboroxins are employed, without the use of any class of additive or pre-treatment.     

Atroposelective radical aryl migration reactions from sulfur to carbon

The paper describes stereoselective radical aryl migration reactions from sulfur in sulfonates to aryl radicals for the synthesis of axially chiral biaryls. A chirality center in secondary benzylic sulfonates is used to diastereoselectively (atroposelectively) install a stereogenic axis via a 1,5 aryl migration reaction. Atroposelectivity has not been investigated in stereoselective radical chemistry before. Good yields (53-82%) but low selectivities (up to 2 to 1) were obtained.     

Control of axial chirality in absence of transition metals based on arynes

The modular construction of enantioenriched biaryl derivatives is presented. This approach is based on (1) an almost quantitative access to polybrominated precursors via a transition metal-free aryl–aryl coupling, the ARYNE coupling, (2) the regioselective introduction of a traceless chiral auxiliary (an enantiopure para-tolylsulfinyl group), (3) the chemoselective functionalization of this auxiliary, and (4) subsequent regioselective functionalization of the remaining bromine atoms without any racemization during these steps. Next, the atroposelective coupling of in situ generated arynes and aryllithiums bearing various chiral auxiliaries (tert-butyl sulfoxide, para-tolyl sulfoxide, and tartrate-derived chiral diethers and oxazolines) is described and applied to the formal synthesis of (−)-steganacin.     

Pseudoephedrine‐Directed Asymmetric α‐Arylation of α‐Amino Acid Derivatives

Available α‐amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′‐aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′‐aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy‐metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.     

Enantioselective addition of diethylzinc to aryl aldehydes catalyzed by 1,2,3,4-tetrahydroisoquinoline β-amino alcohol

<正>A highly effective,new chiral 1,2,3,4-tetrahydroisoquinoline catalyst 1 for the diethylzinc addition to aryl aldehydes has been investigated.Using 10 mol%of this chiral catalyst,secondary alcohols can be obtained in up to 87%yield and 99.5%ee under mild conditions.     

(S)-Pyrrolidine sulfonamide catalyzed asymmetric direct aldol reactions of aryl methyl ketones with aryl aldehydes

A (S)-pyrrolidine sulfonamide catalyzed asymmetric direct aldol reaction of aryl methyl ketones with aromatic aldehydes has been developed with moderate to good enantioselectivities. The study considerably broadens the substrate scope of chiral amines promoted aldol processes.     

Palladium-catalyzed C-N cross coupling of sulfinamides and aryl halides

The palladium-catalyzed C-N cross coupling of sulfinamides and aryl halides is reported. In the presence of Pd(2)(dba)(3), tBuXPhos, NaOH, and a small amount of water, the C-N cross coupling of chiral tert-butanesulfinamide and aryl halides was accomplished to give N-aryl tert-butanesulfinamide without racemization, and the coupling of racemic p-toluenesulfinamide smoothly afforded N-aryl p-toluenesulfinamides. 2-Bromopyridine was also suitable for the coupling. Addition of a small amount of water to the catalytic system was of importance to obtain high yields.     

Catalytic enantioselective allylation at the activated benzylic position of prochiral aryl cyano esters: access to quaternary stereogenic centers

Palladium catalyzed asymmetric allylic alkylation of prochiral aryl cyano esters has been carried out in the presence of various chiral ligands. The base and additives have been varied and allowed to produce the allyl derivative presenting a highly functionalized quaternary stereogenic center. The chiral pocket ligands of Trost appears the most appropriate to produce the desired chiral derivative.     

New ligands for the RuCp1-diamine catalysed asymmetric hydrogenation of aryl ketones

New chiral diamine ligands have been synthesized and evaluated in the asymmetric Ru-catalyzed hydrogenation of prochiral aryl ketones. All catalysts showed good conversions with observed enantioselectivities ranging from moderate to good.     

New air-stable planar chiral ferrocenyl monophosphine ligands: Suzuki cross-coupling of aryl chlorides and bromides

[reaction: see text] A novel class of planar chiral electron-rich monophosphine ligands has been developed. The modular design allows a short and efficient synthesis of an array of aryl-ferrocenyl derivatives carrying the donating bis(dicyclohexyl)phosphino moiety. These new ligands have successfully been applied in the palladium-catalyzed Suzuki cross-coupling of activated as well as nonactivated aryl chlorides at room temperature. The asymmetric coupling of an aryl bromide and an aryl boronic acid was also tested, giving ees up to 54%.     

1,6-Asymmetric induction during the conjugate addition of arylcopper reagents to a chiral sulfinyl-substituted pyrrolyl alpha,beta-unsaturated amide.

The asymmetric conjugate addition of arylcopper reagents derived from aryl Grignard reagents and copper(I) iodide to a chiral 1-[2-(p-tolylsulfinyl)]pyrrolyl cinnamide proceeded smoothly to give (3R)-adducts with high diastereoselectivities (> or =92% de) in high yields. Conjugate additions either of the cinnamide with the alkyl Grignard reagent-copper(l) iodide combination or of the crotonamide derivative with aryl Grignard reagent-copper(l) iodide gave moderate to good diastereoselectivities. With these sulfinyl pyrrolyl alpha,beta-unsaturated amides, the chiral auxiliary was efficiently recovered without any loss of optical purity after asymmetric conjugate addition.     

Chiral alpha-substituted carbonyls and alcohols from the S(N)2' displacement of cuprates on chiral carbonates: An alternative to the alkylation of chiral enolates

A highly stereoselective sequence of reactions, based on the anti-selective S(N)2' addition of cuprates to allylic carbonates, transforms alkynes or alkenyl halides into carbonyls having alpha-chiral centers. The method, which uses menthone as a chiral auxiliary, is a useful alternative to the alkylation of chiral enolates with the added advantage of allowing for the "alkylation" of sec- and tert-alkyl and aryl groups.     

Asymmetric synthesis of diverse α,α-diarylmethylamines via aryl Grignard additions to chiral N-2,4,6-triisopropylbenzenesulfinylimines

A mild method has been developed for the asymmetric synthesis of a variety of chiral diarylmethylamines via the addition of aryl Grignard reagents to chiral N-2,4,6-triisopropylbenzenesulfinylimines in high yields and high diastereoselectivities. Higher stereoselectivity was obtained for most of the examples studied when the reactions are performed at ambient temperature as compared to cryogenic conditions. N-2,4,6-Triisopropylbenzenesulfinamide was shown to be the optimal chiral auxiliary as it provided higher diastereoselectivities when compared to the more commonly employed tert-butanesulfinamide or p-toluenesulfinamide in the synthesis of diarylmethylamine synthons. A rationale for the improved selectivity derived from the triisopropylbenzyl auxiliary is presented.