A novel design of a levoglucosenone derived chiral auxiliary

A two-step general approach to a new chiral auxiliary starting from levoglucosenone is reported. The compound is obtained by a [4+2] cycloaddition reaction with anthracene followed by a diastereoselective reduction of the C-2 keto function in high overall yield. The auxiliary has been used as chiral template in an asymmetric Diels-Alder reaction of the corresponding acrylic ester derivative with cyclopentadiene and shown to be efficient for asymmetric induction.     

Preparation and Reactions of Amino Acid Ester Sulfones as New Remote Asymmetrical Induced Reagents

The development of chiral auxiliary-controlled asymmetric synthesis has been receiving increasing interest in recent yearsfi,2] Various chiral auxiliary reagents have been observed[3] and a lot of results showed that variation of the chiral auxiliary could influence asymmetric induction. Recently, it has been reported the reaction of the aminated sulfones as a remote chiral auxiliary with α,β-unsaturated carbonyl compounds.[4] Here we would like to report the preparation of amino acid ester sulfones as new remote asymmetrical induced reagents and their reactions with α,β-unsaturated esters.     

The use of 1,2-O-isopropylidene-α-d-xylofuranose as a chiral auxiliary in asymmetric cyclopropanation reactions

The stereoselective synthesis of cyclopropylmethylidene acetals derived from 1,2-O-isopropylidene-d-xylofuranose, as a chiral auxiliary, is described. The Simmons–Smith cyclopropanation reaction of the corresponding alkenylidene derivatives with CH₂I₂/ZnEt₂, in different reaction conditions, took place with high stereoselectivity. The diastereomeric excess in each case depended on the solvent and the temperature used in the reaction. The absolute configuration of the new stereogenic centres formed was determined by acid hydrolysis of the cyclopropane moiety of the chiral auxiliary, which was also recovered.     

Diastereoselective aziridination of chiral electron-deficient olefins with N-chloro-N-sodiocarbamates catalyzed by chiral quaternary ammonium salts

Chiral quaternary ammonium salt-catalyzed diastereoselective aziridination of electron-deficient olefins that possess a chiral auxiliary with N-chloro-N-sodiocarbamates was developed. The key to high stereoselectivity was found to be the employment of the "matching" stereochemical combination of chiral auxiliary/ammonium salt. For example, when 3-phenyl-(4R,7S)-4-methyl-7-isopropyl-4,5,6,7-tetrahydroindazole (L-menthopyrazole) as a chiral auxiliary and a cinchonidine-derived chiral ammonium salt as a catalyst were applied to the reaction system, perfect diastereoselectivity was realized. Furthermore, the preparation of enantiomerically pure aziridines by removal of the chiral auxiliary was demonstrated.     

Chiral linker. Part 2: Synthesis and evaluation of a novel,reusable solid-supported open chain chiral auxiliary derived from m-hydrobenzoin for the diastereoselective reduction of α-keto esters

Three novel m-hydrobenzoin derived chiral hydrobenzoin mono-alkyl ethers were synthesized and evaluated as open chain chiral auxiliaries in the L-selectride^R/ZnCl₂ mediated stereoselective reduction of their corresponding phenyl glyoxylates, resulting in des of up to 91%. The optimized auxiliary structure was immobilized on commercially available Wang-resin by using the ether substituent as a sublinking unit and applied as a reusable solid-supported chiral auxiliary in the same type of reaction with only little loss of stereofacial selectivity.     

A stereoselective intramolecular 1,3-dipolar nitrone cycloaddition for the synthesis of substituted chromanes

A stereoselective intramolecular 1,3-dipolar nitrone cycloaddition useful in the synthesis of chromanes is described. The reaction relies on the use of a chiral auxiliary on the nitrone partner. Key to the success of the reaction is the choice of auxiliary and the choice of Lewis acid catalyst. Utilizing an auxiliary with a pendant coordinating group, and Zn(OTf)(2) as the Lewis acid, diastereoselectivities up to 22:1 could be achieved.     

New perspective for natural products synthesis: concise synthesis of (+)-sch 642305 by chiral auxiliary multiuse methodology

The synthesis of (+)-Sch 642305 is an example of chiral auxiliary multiuse methodology, which shows a new perspective for the synthesis of compounds with multiple asymmetric centers. Thus, (+)-Sch 642305 was concisely synthesized from the known compound. Every reaction is stereoselective, and the chiral nonracemic hydrobenzoin worked as chiral auxiliary for desymmetrization of diene, as a template for attaining regio- and stereoselective reactions, as an oxygen source at the C4-position, and as a protecting group of hydroxyl functions. Namely, the chiral auxiliary played a role in every step throughout the synthesis. Furthermore, the synthesis contains a new protocol for obtaining alpha'-alkylated enone compounds.     

Chiral auxiliary based approach toward the synthesis of C-glycosylated amino acids

[reaction in text] In a chiral auxiliary based method C-glycosylated amino acids can be obtained by a 1,3-dipolar cycloaddition of a chiral glycine equivalent and C-1 allyl- or vinyl-derived carbohydrate building blocks as the key step. The products are formed regio- and diastereoselectively. Reductive cleavage of the N-O bond of the isoxazolidine and of the chiral auxiliary leads to C-glycosylated amino acids. The use of (-)-menthone to (+)-menthone as the auxiliary leads to the corresponding diastereomers.     

Novel stereochemistry, reactivity, and stability of an arsenic heterocycle in a metal-promoted asymmetric cycloaddition reaction

The organopalladium complex containing ortho-metalated (S)-[1-(dimethylamino)ethyl]phenylene as the chiral auxiliary has been used as the chiral template to promote the asymmetric cycloaddition reaction between diphenylvinylphosphine and 3,4-dimethyl-1-phenylarsole. A diphenylphosphino-substituted asymmetrical heterobidentate arsanorbornene (As-P) ligand was obtained stereoselectively on the chiral palladium template in moderate yield. The chiral benzylamine auxiliary could be removed chemoselectively from the template by treatment with HCl to produce the neutral complex [(As-P)PdCl2]. In contrast to their reported P-P analogue, the arsenic donor in the dichloro complex could be eliminated stereospecifically under mild reaction conditions to generate the corresponding 1-(diphenylphosphino)-3,4-dimethyl-2,4-cyclohexadiene, which remained as a bidentate ligand at the PdCl2 unit via phosphorus and the eta2-C4-C5 double bond. The arsenic-elimination process was found to be influenced by the halo ligand in [(As-P)PdX2]. A similar process was observed with the analogous dibromo complex, but the corresponding diiodo species did not show similar reactivity. All of the novel As-Pd complexes have been characterized by X-ray crystallography.     

Diastereoselective Aldol Reaction with an Acetate Enolate: 2,6-Bis(2-isopropylphenyl)-3,5-dimethylphenol as an Extremely Effective Chiral Auxiliary

A C ₂ -symmetrical phenol was used as a chiral auxiliary in the asymmetric aldol reaction of chiral acetates with various aldehydes [Eq. (a)]. The reaction proceeds readily under mild conditions to provide aldol adducts with high enantioselectivity. LDA=lithium diisopropylamide.     

A new entry to asymmetric synthesis of optically active alpha,gamma-substituted gamma-butyrolactones, using a carbohydrate derived amide as both a chiral auxiliary and a proton source

A new entry for the asymmetric synthesis of optically active alpha,gamma-substituted gamma-butyrolactones was developed by using a carbohydrate-derived amide as both a chiral auxiliary and a proton source. Unlike the previously reported examples, the chiral auxiliary employed in this reaction also successfully functioned as a protonating agent. Excellent asymmetric induction could be achieved by this dual stereoselective control in the reaction process.     

Asymmetric intermolecular C-H functionalization of benzyl silyl ethers mediated by chiral auxiliary-based aryldiazoacetates and chiral dirhodium catalysts

[reaction: see text] C-H functionalization of benzyl silyl ethers by means of rhodium-catalyzed insertions of aryldiazoacetates can be achieved in a highly diastereoselective and enantioselective manner by judicious choice of chiral catalyst or auxiliary. The dirhodium tetraprolinates such as Rh2((S)-DOSP)4 have been widely successful as chiral catalysts in the C-H functionalization chemistry of aryldiazoacetates, but give poor enantioselectivity in the reactions of aryldiazoacetates with benzyl silyl ether derivatives. The use of (S)-lactate as a chiral auxiliary resulted in C-H functionalization with moderately high diastereoselectivity (79-88% de) and enantioselectivity (68-85% ee). The best results (91-95% de, 95-98% ee), however, were achieved using Hashimoto's Rh2((S)-PTTL)4 catalyst.     

Aziridine ring-opening reactions with chiral enolates. Stereocontrolled synthesis of 5-substituted-3-methyl-pyrrolidin-2-ones

A procedure for performing stereocontrolled aziridine ring-opening reactions with chiral enolates derived from (S,S)-(+)-pseudoephedrine amides has been developed leading to gamma-aminoamides in good yields. The diastereoselectivity of the reaction becomes controlled by the presence of the chiral auxiliary on the enolate, although the stereogenic center contained in the structure of the aziridine has a striking influence on the stereochemical course of the reaction which results in the presence of the corresponding matched and mismatched combinations. Besides, the sense of the asymmetric induction of the chiral auxiliary has resulted to be the opposite to the one found with other type of electrophiles, although it is in good agreement with the trend observed in the reaction of the same kind of enolates with epoxides. Finally, the obtained gamma-aminoamide adducts were converted into enantiopure gamma-amino acids, gamma-aminoesters, and pyrrolidin-2-ones using easy to perform and high yielding reactions.     

Chemoenzymatic synthesis and application of a new,easily chiral auxiliary for the synthesis of peptidomimetics via an Ugi reaction

A new chiral auxiliary derived from α-phenylethylamine, α-(2,4-dimethoxyphenyl)ethylamine is presented. It significantly expands upon the application of α-phenylethylamine derivatives used as chiral auxiliaries. A straightforward, chemoenzymatic synthesis of non-racemic α-(2,4-dimethoxyphenyl)ethylamine is described and the new chiral auxiliary applied to an asymmetric Ugi reaction. The mild conditions used for the cleavage of the auxiliary allowed to obtain chiral, non-racemic peptidomimetics possessing reactive α,β-unsaturated double bonds.     

Synthesis of novel chiral spirodione, (6R,7R)-7-phenyl-1-oxaspiro[5.5]undec-3-ene-2,5-dione: application to the asymmetric Diels-Alder reaction with high π-facial selectivity

The synthesis of the title spirodione, a new class of auxiliary based chiral synthon using (−)-trans-2-phenylcyclohexanol and its application to the asymmetric Diels-Alder reaction are described. Methodology for detachment of the chiral auxiliary from the cycloadduct has been developed.     

Chiral induction in photochemical reactions. 14. : Linear free energy relationships as an instrument for the prediction of either de values or conformation energies of the auxiliary in the diastereoselective Paternò-Büchi reaction.

To value a stoichometric asymmetric synthesis it is important for a synthetic chemist to gain information about those structural elements of a chiral auxiliary which are responsible for high diastertomeric excesses in a particular reaction. Furtheron it is desirable to have detailed knowledge about the mechanism of the chirality transfer. In this paper an empirical relation is formulated for the correlation of structural variations of a chiral auxiliary and its influence of the diastereomeric excess in the photochemical oxetane formation in correspondance to the Ugi/Ruch concept. For this purpose we use a Linear Free Energy Relationship (LFER) which we have adjusted to reaction (2) in order to obtain quantitative information about the selectivity of this reaction on the basis of special parameters of the auxiliary applied.     

Double diastereoselective intramolecular cyclopropanation to P-chiral [3.1.0]-bicyclic phosphonates

[reaction: see text] A double diastereotopic differentiation strategy on a phosphonoacetate template is described. The approach utilizes Rh(2)(OAc)(4)-catalyzed intramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate. The olefinic diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group selectivity is dictated by the chiral auxiliary. This approach is being developed as an effective method to access bicyclic P-chiral phosphonates.     

New strategy for the stereoselective synthesis of fluorinated beta-amino acids

Racemic and chiral nonracemic alpha-substituted and alpha-unsubstituted beta-fluoroalkyl beta-amino acid derivatives 6 and 9 have been synthesized in two steps starting from fluorinated imidoyl chlorides 1 and ester enolates. This approach is based on the chemical reduction of previously obtained gamma-fluorinated beta-enamino esters 4 by using ZnI(2)/NaBH(4) in a nonchelated aprotic medium (dry CH(2)Cl(2)) as the reducing agent. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction. The process takes place with high yields and with moderate to good diastereoselectivity. The best results related to diastereoselective reduction of chiral beta-enamino esters 4 were provided by the use of (-)-8-phenylmenthol as a chiral auxiliary.     

Synthesis of anti-Alzheimer (R)-arundic acid

The asymmetric synthesis of the anti-Alzheimer agent (R)-arundic acid has been performed via a diastereoselective photodeconjugation reaction as the key-step. The synthetic approach involves a readily available chiral auxiliary, diacetone-d-glucose, and allows access to either enantiomer as illustrated by the synthesis of (S)-arundic acid. Both enantiomers were obtained in 88% ee using the same chiral auxiliary.     

trans-3,4-Disubstituted pyrrolidines by 1,3-dipolar cycloaddition: enantioselective approaches and their limitations

In the presence of a chiral Lewis acid as co-catalyst, the acid-catalysed 1,3-dipolar cycloaddition reaction yielding trans-3,4-disubstituted pyrrolidines from an azomethine ylide and achiral α,β-unsaturated dipolarophiles proceeded with low enantioselectivity. Therefore a number of α,β-unsaturated dipolarophiles linked to chiral auxiliaries were examined as substrates. Camphorsultam was the best auxiliary and gave good diastereoselectivity (dr=74:26). When combining chiral Lewis acids with a dipolarophile linked to a chiral auxiliary, the enantioselectivity could be slightly increased. As judged by ¹³C NMR, the small effect of the chiral Lewis acids on selectivity was probably due to breakdown of the initially formed complex with the dipolarophile caused by the dipole precursor.