A concise and efficient route to the Alzheimer's therapeutic agent (R)-arundic acid

A short and efficient procedure for the preparation of (R)-arundic acid, a therapeutic agent for the treatment of Alzheimer's disease, has been developed. Based on cheap and commercially available (1R)-(+)-camphor as the source of chiral information, (R)-arundic acid is synthesized in a four-step cyclic sequence with 55% overall yield and high optical purity, ≥98% ee. Alkyl halide and acetylene constitute the only consumable carbon sources of this method, which allows obtaining of both enantiomers and recycling of chiral auxiliary.     

Stereodivergent approach to Alzheimer's therapeutic agent (R)-(−) and (S)-(+)-arundic acid employing chiral 4-pentenol derivatives as building blocks

An efficient stereodivergent total synthesis of anti-Alzheimer agent (R)-(?) and (S)-(+)-arundic acid has been achieved from both chiral and nonchiral materials. This strategy features an efficient approach to separable diastereomeric C-2 chiral 4-pentenol intermediates employing proline catalysed asymmetric α-aminooxylation and [3,3] sigmatropic Claisen rearrangement are the highlights of present synthesis.     

Concise access to enantiopure (S)- and (R)-α-trifluoromethyl pyroglutamic acids from ethyl trifluoropyruvate-based chiral CF3-oxazolidines (Fox)

A straightforward synthesis of enantiopure (S)- and (R)-α-Tfm-pyroglutamic acid is reported. The strategy is based on the use of a chiral CF₃-hydroxymorpholinone intermediate conveniently obtained from ethyl trifluoropyruvate-based chiral CF₃-oxazolidines (Fox). The key step is an oxidative cyclization followed by a reductive cleavage of the (R)-phenylglycinol chiral auxiliary.     

Asymmetric synthesis of suitably protected γ-hydroxy-aza-β3-homothreonine building blocks

An efficient and easily applicable method for the enantioselective synthesis of γ-Hydroxy aza-β³-homothreonine (aza-β³-Hyht) has been established. The method involves stereoselective reductive amination of glyoxylic acid and the corresponding Fmoc protected chiral hydrazine. A stereoselectivity of 99% was achieved for each step using (R)-2,3-O-isopropylideneglyceraldehyde as the chiral auxiliary. This new synthetic monomer is a useful building block for the solid-phase synthesis of new peptidomimetics.     

Palladium-catalyzed diastereoselective synthesis of β,β-diarylpropionic acid derivatives and its application to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718

Palladium-catalyzed diastereoselective synthesis of optically active β,β-diarylpropionic acid derivatives employing 4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary under an air atmosphere in excellent yields with high diastereoselectivity is reported. The catalytic system is applied to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718.     

Synthesis of α-chiral-β,γ-unsaturated carboxylic acid derivatives using chiral auxiliaries

We report an efficient and reliable method for the synthesis of α-chiral-β,γ-unsaturated carboxylic acid derivatives using chiral auxiliaries and vinylacetic acid. Two well-established chiral auxiliaries ((S,S)-pseudoephedrine and (R)-benzyl-oxazolidinone) were chosen to test the merits of this method. Six different electrophiles were examined in the diastereoselective alkylation with both auxiliaries. The pseudoephedrine auxiliary provided isolated yields between 61 and 85% and diastereomeric ratios all greater than 96:4. Employing the same reactions as with the pseudoephedrine derivative, the corresponding oxazolidinone auxiliary provided isolated yields between 0 and 80% with diastereomeric ratios from 80:20 to 93:7.     

Synthesis of (2S)-2-amino-3-(1H-4-indolyl)propanoic acid,a novel tryptophan analog for structural modification of bioactive peptides

A convenient, multigram synthesis of a novel α-amino acid (2S)-2-amino-3-(1H-4-indolyl)propanoic acid (1a), is reported. An Fmoc–t-Boc derivative of this novel regioisomer of the natural aromatic amino acid tryptophan could be readily incorporated into bioactive synthetic peptides using standard solid phase synthesis. The synthesis featured the use of Schöllkopf chiral auxiliary reagents for chirality induction during a key step.     

Diastereoselective synthesis of β-amino ketone and acid derivatives by palladium-catalyzed conjugate addition

The first diastereoselective synthesis of β-amino ketone and β-amino acid derivatives by palladium-catalyzed conjugate addition of arylboronic acids to chiral β-enamino ketones and β-enamino esters is reported. The catalytic system employing (S)-4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary in water under an air atmosphere provides β-amino ketone and β-amino acid derivatives in high yields with excellent diastereoselectivity.     

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.     

Asymmetric [2,3]-Wittig rearrangement of the dienolates of chiral secondary alcohol-substituted β-pyrrolidinyl-γ-allyloxyl-α,β-unsaturated esters: total synthesis of (+)-eldanolide

The asymmetric [2,3]-Wittig rearrangement of the dienolates of various chiral β-pyrrolidinyl-γ-allyloxyl-α,β-unsaturated esters was investigated using different chiral secondary alcohol substitutions. When (1S,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2,2,1]heptane-1-carboxylic acid diisopropylamide was used as chiral auxiliary, it provided the best enantioselectivity in the rearrangement. When various γ-allyloxy substitutions underwent temperature and additive studies, 1,1-dimethylpropenoxy substitution was found to give the best enantioselectivity. The methodology was applied to the total synthesis of (+)-eldanolide.     

Synthesis of a new chiral oxazolidinone auxiliary based on d-xylose and its application to the Staudinger reaction

The synthesis of a new chiral oxazolidinone auxiliary based on d-xylose is described which is employed in diastereoselective Staudinger-type β-lactam syntheses. Using 2-chloro-1-methylpyridinium iodide as the dehydrating reagent, the reaction of auxiliary tethered acetic acid with acyclic or cyclic imines gave the desired β-lactams in good yields with excellent cis- or trans-selectivity depending on the geometry of the imine. X-Ray structure determination of one of the obtained compounds corroborated the absolute configuration for all cis products.     

An enantioselective synthesis of (S)- and (R)-curcuphenol

The enantioselective synthesis of the phenolic sesquiterenses (S)- and (R)-curcuphenol is reported. The key step in this synthesis is the asymmetric conjugate addition using a readily available enantiomerically pure sulfoxide as the chiral auxiliary.     

Asymmetric synthesis of (R)- and (S)-4-methyloctanoic acids. A new route to chiral fatty acids with remote stereocenters

The enantioselective synthesis of both enantiomers of 4-methyloctanoic acid, one major aggregation pheromone component of the rhinoceros beetles of the genus Oryctes and an important aroma compound, is described. The key step of the synthesis is based on a stereospecific alkylation with an alcohol-protected alkyl iodide using a pseudoephedrine derivative as a chiral auxiliary followed by subsequent removal of the auxiliary. Both enantiomers are obtained in excellent yields and enantioselectivities (93–94% ee). The strategy outlined allows preparation of a wide variety of enantiopure methyl-branched saturated and unsaturated fatty acids.     

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.     

O-(α-Phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’: synthesis and resolution of 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids

An approach to the synthesis and resolution of five- and six-membered lactams (i.e., 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids) is described. The method relies on the one-pot Michael reaction—cyclization of itaconic acid or diethyl homoitaconate and enantiopure O-(α-phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’. It is shown that this chiral auxiliary can be used for the separation of diastereomeric lactam products and then easily removed by catalytic hydrogenolysis.     

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.     

First asymmetric syntheses of 6-substituted nipecotic acid derivatives

Various nipecotic acid derivatives are known to be potent GABA uptake inhibitors thus being useful in the treatment of a number of neurological and psychological disorders. In this paper, the first asymmetric syntheses of 6-substituted nipecotic acid derivatives are presented. The synthetic strategy was designed to provide access to a large variety of enantiomerically pure 6-substituted nipecotic acid derivatives. The synthesis starts from the chiral N-acyldihydropyridines 15 and 16 obtained via asymmetric electrophilic α-amidoalkylation reaction of a chiral N-acylpyridinium ion. These were utilized for the preparation of enantiomerically pure 6-(4,4-diphenylbutyl)nipecotic acids and 6-(4,4-diphenylbutenyl)nipecotic acids in a multistep synthesis, including the removal of the dimethylphenylsilyl blocking group from the dihydropyridine ring, the reduction of the dihydropyridine heterocycle, a Horner-Wittig reaction and the removal of the chiral auxiliary. The obtained target molecules, however, showed only negligible affinity to the GAT-1- and GAT-3 transport proteins.     

A facile synthesis of (S)-felodipine

A short and facile synthesis of (S)-felodipine was developed starting from (R)-glycidol as the source of the chiral auxiliary. 2-Hydroxyethyl esters were found to undergo selective transesterification reactions in the presence of other esters. This selective transesterification reaction was applied to the synthesis of (S)-felodipine through selective substitution of the 2-hydroxyethyl group possessing chiral ester with sodium methoxide.     

Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy

An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.     

Cascade enantioselective synthesis of γ-aryl-γ-butyrolactones with a delayed stereoselective step

Enantioselective synthesis of γ-aryl-γ-butyrolactones is achieved using (S)-1-phenylethylamine as a chiral auxiliary. The synthesis involves cascade formation-destruction-formation of the chiral centre with a delayed stereoselective step. The actual stereoselective step has been found to be intramolecular nucleophilic attack on a diastereotopic carbocation formed, thereby resulting in the formation of non-racemic γ-aryl-γ-butyrolactones.