Enantioselective synthesis of Fmoc-l-3-(2-benzothienyl)alanine (2-BtAla) via diastereoselective alkylation of a glycine equivalent

Stereoselective alkylation of the anion derived from (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with 2-chloromethylbenzothiophene afforded the corresponding trans-monosubstituted product, (2S,5R)-2-((1-benzo[b]thiophen-2-yl)methyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihyropyrazine in 88% yield. Hydrolysis of the alkylated product using 40% TFA/H₂O at 0?°C and subsequent protection of the α-amino functional group with Fmoc-OSu afforded Fmoc-l-3-(2-benzothienyl)alanine methyl ester in 88% yield. Hydrolysis of the methyl ester with aqueous LiOH gave Fmoc-l-3-(2-benzothienyl)alanine in 62% overall yield.     

Scalable synthesis of (−)-trans-3-hydroxypipecolic acid via a useful chiral building block

A scalable synthesis of (−)-trans-2-(hydroxymethyl)-1,2,3,6-tetrahydropyridin-3-ol, a versatile chiral building block is described along with its transformation to (−)-trans-3-hydroxypipecolic acid.     

Stereoselective synthesis of (S)-dapoxetine: a chiral auxiliary mediated approach

An imidazolidin-2-one chiral auxiliary mediated acetate aldol reaction was explored in the enantioselective synthesis of (S)-dapoxetine (SSRI). The diastereoselective aldol adduct was transformed to highly enantiopure (S)-dapoxetine with overall good yield.     

Catalytic,Enantioselective Synthesis of α-Aminonitriles with a Novel Zirconium Catalyst

Strecker reactions of aldimines with Bu₃SnCN in the presence of the novel chiral zirconium binuclear catalyst 1 provide α-aminonitriles in good yields and with high enantioselectivities. The reaction can be applied to a wide range of substrates. Since both enantiomers of the chiral sources are readily avaibable, both enantiomers of the α-aminonitriles are easily prepared according to this method. L=N-methylimidazole.     

Operationally convenient asymmetric synthesis of (S)-2-amino-3,3-bis-(4-fluorophenyl)propanoic acid

This study demonstrated that alkylation of chiral glycine Schiff base 3 with chloride 4 can be efficiently conducted in acetonitrile as a solvent using commercial-grade potassium tert-butoxide as a base. High reaction rate (1 h) chemical (>90%) and stereochemical (>95% de) outcomes of the alkylation step render this procedure reliable and operationally convenient for multi-gram synthesis of enantiomerically pure amino acid 1. Due to the simplicity of experimental procedures and commercial availability all reagents involved, this procedure can be easily reproduced in regular biochemistry laboratories allowing for systematic biological studies and medicinal applications of compound 1.     

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.     

A new polymer-supported Evans-type chiral auxiliary derived from α-hydroxy-β-amino acid, phenylnorstatine: synthesis and application in solid-phase asymmetric alkylation reactions

Based on a new anchoring strategy, a polymer-supported chiral oxazolidinone was prepared starting from (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (phenylnorstatine, Pns) and Wang resin. Solid-phase asymmetric alkylation on this resin proceeded in high diastereoselectivity comparable to that of conventional solution-phase model experiments. This study suggests that anchoring through the 5-position of oxazolidinone is highly suited to achieving diastereoselective alkylation reactions on solid-support.     

Design and synthesis of a new polymer-supported Evans-type oxazolidinone: an efficient chiral auxiliary in the solid-phase asymmetric alkylation reactions

Wang resin-supported Evans' chiral auxiliary (23) was designed based on a novel polymer-anchoring strategy, which utilizes the 5-position of the oxazolidinone ring, and its new synthetic route applicable to multi-gram preparation in just a day was developed. Solid-phase Evans' asymmetric alkylation on 23-derived N-acylimide resin and following lithium hydroperoxide-mediated chemoselective hydrolysis afforded the corresponding α-branched carboxylic acids in desired high stereoselectivities (up to 97% ee) and moderate to good overall yield (up to 70%, for 3 steps), which were comparable to those of the conventional solution-phase methods. Furthermore, recovery and recycling of the polymer-supported chiral auxiliary were successfully achieved without decreasing the stereoselectivity of the product. Therefore, this is the first successful example that the solid-phase Evans' asymmetric enolate-alkylation was efficiently performed on the solid-support, and it is concluded that the connection to the solid-support via the 5-position of the oxazolidinone ring is an ideal strategy in the solid-phase Evans' chiral auxiliary.     

Enantioselective syntheses of candenatenins B and C using a chiral anthracene auxiliary

The asymmetric syntheses of two anticancer natural products, candenatenins B and C, are described, leading to a revision of the originally assigned stereochemistries. The syntheses follow a Diels-Alder/retro-Diels Alder strategy using a chiral anthracene auxiliary to access both targets with 90% ee. The inherent structural qualities of the auxiliary allow for both regio- and diastereoselective transformations.     

Lewis acid mediated diastereoselective keto-ene cyclization on chiral perhydro-1,3-benzoxazines: synthesis of enantiopure cis-3,4-disubstituted 3-hydroxypyrrolidines

Chiral 2-acyl-3-allyl-perhydro-1,3-benzoxazines derived from (−)-8-aminomenthol were easily cyclized in the presence of Lewis acids at 0 °C. The diastereoselectivity of the cyclization was dependent on the nature of the Lewis acid. The cyclization compounds can be transformed into enantiopure cis-3,4-disubstituted 3-hydroxypyrrolidines by ring opening of the N,O-acetal moiety and subsequent elimination of the menthol appendage.     

Preparation of novel analgesics via diastereoselective nucleophilic addition to 1-dimethylamino-2-methylpentan-3-one

The diastereoselective synthesis of naphthyl amino alcohols via nucleophilic addition to racemic 1-dimethylamino-2-methylpentan-3-one was studied. The use of the appropriate experimental conditions allowed the synthesis of both diastereoisomers. The relative configurations were established via NOESY experiments.     

Enantioselective desymmetrization of meso-N-(heteroarenesulfonyl)aziridines with TMSN3 catalyzed by chiral Lewis acids

A catalytic enantioselective desymmetrization of meso-N-(heteroarenesulfonyl)aziridines with TMSN₃ using chiral Lewis acids afforded products with high enantioselectivity. As proof of the utility of this procedure, the precursor of selective κ-opioid agonist (1S,2S)-(−)-U-50,488 was synthesized.     

Comparison of the chiral resolution on cis-trans isomeric chiral stationary phases derived from (S)-1-(1-naphthyl)ethylamine

A pair of cis-trans isomeric chiral stationary phases (CSPs) derived from (S)-1-(1-naphtyl)ethylamine was prepared. The chromatographic behaviours on both CSPs with regard to the resolution of enantiomeric amino acids, amino alcohols, amines, and carboxylic acid were studied. According to separation factors, the trans-CSP showed better chiral recognition ability for the separation of most analytes chosen in this study. Three homologous series of the alkyl esters of racemic amino acids were resolved on both CSPs using n-hexane-2-propanol and n-hexane-dichloromethane as mobile phases. The trans-CSP also showed better enantioselectivity for the resolution of homologues. A reverse of elution order was observed for the resolution of the homologous series of phenylglycine alkyl esters on both CSPs. It was found that the relationship between the separation factor and the alkyl chain length of the ester homologous series depended upon the components of mobile phase. A higher magnitude of difference between the two CSPs in enantioselectivity for the resolution of a given homologue was obtained when n-hexane-dichloromethane was used as a mobile phase. A chiral recognition process, in which steric repulsion, face-to-face π-π interaction, face-to-edge π-π interaction and hydrogen bonding interaction were involved, was also suggested to describe the separation of enantiomeric homologues on both CSPs. This study clearly indicates that the chiral resolution is influenced by the geometry of the double bond in a CSP.     

Asymmetric synthesis of 1,2-bis(diphenylphosphino)-1-phenylethane via a chiral palladium template promoted hydrophosphination reaction

An organopalladium(II) complex derived from (S)-N,N-dimethyl-1-(1-naphthyl)-ethylamine was employed as the chiral auxiliary to promote the asymmetric hydrophosphination reactions between diphenylphosphine and (E) or (Z)-diphenylphosphinostyrene in high regio- and stereoselectivities at low temperature with triethyl amine as external base. Optically active free ligand (R)-1,2-bis(diphenylphosphino)-1-phenylethane was obtained in high yield subsequently. Mechanistic pathways explaining the stereoselectivity of the chiral organopalladium template promoted hydrophosphination reactions are also proposed.     

Asymmetric synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivatives

The use of several chiral trifluoromethylated building blocks 1a, 1b, 9a and 9b was attempted to synthesize of syn-(3-trifluoromethyl)cysteine. A novel and efficient enantioselective synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivatives 12a and 12b was successfully achieved.     

A versatile approach for the asymmetric synthesis of 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones

Based on the use of (R)-p-benzyloxyphenylglycinol (10) as a new oxidatively cleavable chiral auxiliary, a flexible approach to (R)-3-alkyl-2,3-dihydro-1H-isoindolin-1-ones via a diastereoselective reductive-alkylation is developed. The oxidative cleavage of the chiral auxiliary by CAN under mild conditions ensured the access to (R)-3-alkyl-2,3-dihydro-1H-isoindolin-1-ones with ee at least 92%.     

Rhodium-catalyzed Reformatsky-type reaction for asymmetric synthesis of difluoro-β-lactams using menthyl group as a chiral auxiliary

We developed a new methodology for the asymmetric Reformatsky-type reaction of (−)-menthyl bromodifluoroacetate (2) with imine in the presence of RhCl(PPh₃)₃. Ester 2 with the cost-effective chiral auxiliary gave (S)-difluoro-β-lactams in moderate to good yields and high diastereoselectivities through spontaneous removal of the auxiliary.     

Catalytic asymmetric synthesis of ethyl (1R,2S)-dehydrocoronamate

A synthesis of (1R,2S)-dehydrocoronamic acid ethyl ester was developed employing a regio- and enantioselective palladium-catalysed nucleophilic ring-opening of 3,4-epoxy-1-butene with a glycine anion equivalent as the key enantiodifferentiating step. The desired selectivity was achieved using Trost’s naphthyl ligand. The subsequent activation of the free hydroxyl group and ring-closure by intramolecular S_N2 reaction gave the desired amino acid ethyl ester.     

Asymmetric Synthesis of β2‐homo‐tert‐Leucine via Radical Addition to Enantiopure N‐Fumaroylhexahydrobenzooxazolidin‐2‐one

β‐Amino acids are key structural elements in unnatural peptides, peptidomimetics, and many other physiologically active compounds. In view of their importance, we have developed an efficient synthetic route that provides highly enantiomerically enriched (R)‐ and (S)‐H‐β²‐h^tLeu‐OH via highly diastereo‐ and regioselective addition of tert‐butyl radical to enantiomerically pure N‐fumaroyloxazolidinones, followed by removal of the chiral auxiliary, Curtius rearrangement, ester hydrolysis, and catalytic hydrogenolysis.     

Diastereoselective synthesis of enantioenriched homopropargyl amino alcohols from α-dibenzylamino aldehydes and their use as chiral synthons

Homochiral α-dibenzylamino aldehydes, prepared from the corresponding α-amino acids, react with propargyl bromide and zinc in DMF/THF (1:1) or DMF/Et₂O (1:1) at 20 °C to afford, in good yields and dr, homopropargylic 1,2-amino alcohols. anti Diastereomers were always formed as major products in this reaction. These compounds are versatile intermediates for a variety of synthetic targets: γ-amino-β-hydroxy-ketones, 4-amino-1,3-diols, 1,7-diamino-2,6-diols, and ω-amino-δ-hydroxy esters.