Short Enantioselective Synthesis Research Articles

Synthesis of Antiepileptic Drug (R)-Lacosamide and Chronic Pain Reliever (S)-Lacosamide from Chiral Glycine Enolate Equivalent.

A short enantioselective and azide-free synthesis of antiepileptic drug (R)-lacosamide and pain reliever (S)-lacosamide on a large scale has been articulated from an uncommon chiral synthon "glycine enolate equivalent of 4-benzyl-N-glycinyl oxazolidinone". Evans' asymmetric alkylation using N-(N-Boc-glycinyl) oxazolidinone was standardized to ensure the stereoselective formation of (Z)-enolate for a diastereofacial selection in the C-alkylation process of chiral glycine enolate equivalent with different alkyl halides such as methyl iodide, methoxymethyl chloride, benzyl bromide, p-NO2C6H4CH2Br, allyl bromide, and p-OCH3C6H4CH2Br in the presence of lithium diisopropyl amide at -78 °C in THF. This optimized asymmetric C-alkylation method with methoxymethyl chloride on lithium-mediated (Z)-enolate of (4S/4R)-4-benzyl-N-glycinyl oxazolidinones was extended following other subsequent reactions to produce the final lacosamides with no racemization in ∼36 to 45% overall yields from commercially available 4-benzyl-2-oxazolidinone and N-Boc-glycine.

A Short Enantioselective Synthesis of (S)-Levetiracetam through Direct Palladium-Catalyzed Asymmetric N-Allylation of Methyl 4-Aminobutyrate

AbstractAn exceedingly short and enantioselective synthesis of the antiepileptic drug (S)-levetiracetam was elaborated. As the chirogenic key step, a Pd-catalyzed asymmetric N-allylation of methyl 4-aminobutyrate was achieved in the presence of only 1 mol% of a catalyst prepared in situ from [Pd(allyl)Cl]2 and a tartaric acid-derived C 2-symmetric diphosphine ligand.

Enantioselective Synthesis of Ozanimod, the Active Pharmaceutical Ingredient of a New Drug for Multiple Sclerosis

AbstractWe report here a short enantioselective synthesis of Ozanimod, a potent modulator of the enzyme Sphingosine‐1‐phosphate receptor (S1PR), recently approved by FDA and EMA for the treatment of relapsing‐remitting multiple sclerosis. Amongst different synthetic approaches explored, we achieved the best result introducing the stereogenic centre in the last step through imine asymmetric transfer hydrogenation (ATH) using Wills’ catalysts. Besides the reduced numbers of enantiomeric purity controls required, this process culminates in an exceptionally high enantioselective reductive amination obtained with commercially available tethered Ru catalysts. Starting from commercially available 4‐cyano‐indanone, enantiomerically pure Ozanimod was obtained in 5 steps in 62 % overall yield and 99 % ee.

β-Ketoesters as Mono- or Bisnucleophiles: A Concise Enantioselective Total Synthesis of (-)-Englerin A and B.

A short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring-group-participating [4+3] cycloaddition, a novel one-pot Heck coupling/regioselective 1,4-hydrosilylation/Tamao-Fleming oxidation cascade, and a kinetic CBS reduction, generating the optically pure natural product in 6.7 % overall yield over twelve steps starting from methylglyoxal. Selective saponification of the more reactive glycolic ester moiety of englerin A also gave (-)-englerin B.

β‐Ketoesters as Mono‐ or Bisnucleophiles: A Concise Enantioselective Total Synthesis of (−)‐Englerin A and B

AbstractA short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring‐group‐participating [4+3] cycloaddition, a novel one‐pot Heck coupling/regioselective 1,4‐hydrosilylation/Tamao–Fleming oxidation cascade, and a kinetic CBS reduction, generating the optically pure natural product in 6.7 % overall yield over twelve steps starting from methylglyoxal. Selective saponification of the more reactive glycolic ester moiety of englerin A also gave (−)‐englerin B.

Modular Enantioselective Synthesis of an Advanced Pentahydroxy Intermediate of Antimalarial Bastimolide A and of Fluorinated and Chlorinated Analogues.

A short enantioselective catalytic synthesis of the key C15-C27 fragment of bastimolide A, a natural product showing promising antimalarial bioactivity, is disclosed. The strategic insertion of halogen atoms such as fluorine and chlorine by enantioselective organocatalytic halogenations allowed an excellent stereochemical control for the formation of complex acyclic fragments bearing up to four stereogenic centers. Furthermore, besides the formation of the 1,5,7,9,13-pentahydroxy fragment of the natural product, this strategy opens the route to the modulation of the bioactivity by halogenohydrins.

Short Enantioselective Formal Synthesis of (-)-Platencin.

A short enantioselective formal synthesis of the antibiotic natural product platencin is reported. Key steps in the synthesis include enantioselective decarboxylation alkylation, aldehyde/olefin radical cyclization, and regioselective aldol cyclization.

Application of sequential proline-catalyzed α-chlorination and aldol reactions in the total synthesis of 1-deoxygalactonojirimycin

A short enantioselective total synthesis of 1-deoxygalactonojirimycin (migalastat) has been achieved that does not rely on chiral pool starting materials or biocatalysis. Instead, this synthesis exploits a one-pot proline-catalyzed α-chlorination and aldol reaction of a commercially available aldehyde to assemble the entire carbon skeleton in a single step. The key role played by a nitrogen protecting group in the final epoxide opening reaction is highlighted as is the amenability to access structural analogues using this route.

Synthesis of (E)‐4‐Methylhexa‐3,5‐dien‐1‐ol and Its Diels–Alder Reaction with Thioester Dienophiles: A Short Enantioselective Synthesis of Bicyclic Lactones

The preparation of (E)‐4‐methylhexa‐3,5‐dien‐1‐ol has been achieved in a single step from 3‐methylpenta‐1,4‐diene through deprotonation with BuLi, alkylation with paraformaldehyde and metal‐counterion exchange in situ to promote oxy‐anion‐accelerated [1,3]‐sigmatropic shift. This alcohol is shown to undergo intermolecular Diels–Alder reaction with 3‐isopropyl acrylate thioesters; the so‐formed exclusive endo‐adduct may then be closed to the bicyclic lactone, the product of formal intramolecular Diels–Alder reaction (a much more difficult process). Use of chiral thioesters results in an enantioselective synthesis of this bicyclic lactone, an intermediate with application to eunicellane (cladiellane) diterpene synthesis.

Versatile Construction of 6-Substituted cis-2,8-Dioxabicyclo[3.3.0]octan-3-ones: Short Enantioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C.

A short enantioselective synthesis of 6-substituted cis-2,8-dioxabicyclo[3.3.0]octan-3-ones is described. The pivotal step is coupling of a tertiary radical generated directly from a tertiary alcohol with a 3-chloro-5-alkoxybutenolide. This strategy is applied toward scalable 14-15 step syntheses of three rearranged spongian diterpenoids: cheloviolenes A and B and dendrillolide C.

Proline catalyzed enantioselective synthesis of (2S,3S)-3-hydroxypipecolic acid and formal synthesis of (+)-swainsonine

A short enantioselective synthesis of (2S,3S)-3-hydroxypipecolic acid (overall yield: 18.8%; 96% ee) and formal synthesis of (+)-swainsonine (overall yield: 13.6%; 96% ee) have been described starting from commercially available acrolein. The synthetic strategy involves a high enantioselective l-proline catalyzed sequential α-amination and diastereoselective (dr>99:1) Barbier allylation of aldehyde in one-pot as the key reaction.

α-Amino Aldehydes as Readily Available Chiral Aldehydes for Rh-Catalyzed Alkyne Hydroacylation.

Readily available α-amino aldehydes, incorporating a methylthiomethyl (MTM) protecting group on nitrogen, are shown to be efficient substrates in Rh-catalyzed alkyne hydroacylation reactions. The reactions are performed under mild conditions, employing a small-bite-angle bis-phosphine ligand, allowing for good functional group tolerance with high stereospecificity. Amino aldehydes derived from glycine, alanine, valine, leucine, phenylalanine, isoleucine, serine, tryptophan, methionine, and cysteine were successfully employed, as was an enantiomerically enriched α-OMTM-aldehyde derived from phenyllactic acid. The synthetic utility of the α-amino enone products is demonstrated in a short enantioselective synthesis of the natural product sphingosine.

Concise enantioselective synthesis of (+)-sertraline and (−)-CP-52002 using proline catalysis

A short enantioselective synthesis of (+)-sertraline and its C4 epimer (−)-CP-52002 with an overall yield of 30%, respectively, as its hydrochloride has been described. The key steps are the proline catalyzed Mannich reaction of acetaldehyde and acid catalyzed intramolecular Friedel–Crafts’ alkylation reaction of olefin proceeding with high optical purities.

A short enantioselective synthesis of ephedrine, amphetamine and their analogues via two stereocentered Co(III)-catalyzed hydrolytic kinetic resolution of racemic syn-benzyloxy epoxide

An efficient route for the synthesis of 6 drugs belonging to phenethylamine and amphetamine classes in excellent overall yields and high optical purity has been described. The strategy involves introduction of stereogenic centers by means of two-stereocentered Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of racemic syn-benzyloxy epoxide followed by Pd-catalyzed regioselective cationic hydrogenation of amino alcohols as the key reactions.

Concise Enantioselective Synthesis of Naturally Active (S)-3-Hydroxypiperidine

A short and efficient enantioselective synthesis of natural product (S)-3-hydroxypiperidine has been achieved starting from commercially available raw materials employing two catalytic routes: (i) cocatalyzed hydrolytic kinetic resolution (HKR) of racemic methyl-3-(oxiran-2-yl)propanoate; (ii) proline-catalyzed α-aminooxylation followed by Horner–Wardsworth–Emmons olefination in high enantiomeric purity (97% ee) and high overall yield (38%).

ChemInform Abstract: A Short Enantioselective Synthesis of 3‐epi‐Jaspine B (I) and (+)‐Oxybiotin (II) via an Intramolecular Tandem Desilylation oxa‐Michael Addition Strategy.

ChemInform Abstract: A Short Enantioselective Synthesis of 3‐epi‐Jaspine B (I) and (+)‐Oxybiotin (II) via an Intramolecular Tandem Desilylation oxa‐Michael Addition Strategy.

ChemInform Abstract: Assignment of the Absolute Configuration and Total Synthesis of (+)‐Caripyrin.

The antifungal secondary metabolite (+)-caripyrin was studied by vibrational circular dichroism spectroscopy. Analysis of the recorded data, with the Boltzmann weighted-average of the spectra calculated at the B3LYP/6-311G(d,p) level of theory for all relevant conformers, unequivocally proved the (R,R)-configuration for the dextrorotatory natural product. Based on this finding, a short enantioselective synthesis of (+)-caripyrin was developed.

A short enantioselective total synthesis of (R)- and (S)-pipecolic acid

A convenient and practical total synthesis of (R)- and (S)-pipecolic acid has been achieved by utilizing chiral cis-aziridine-2-carboxylate as the common synthetic precursor. The synthesis involves regioselective reductive cleavage of the aziridine ring and Wittig olefination as key reactions.

Assignment of the Absolute Configuration and Total Synthesis of (+)‐Caripyrin

AbstractThe antifungal secondary metabolite (+)‐caripyrin was studied by vibrational circular dichroism spectroscopy. Analysis of the recorded data, with the Boltzmann weighted‐average of the spectra calculated at the B3LYP/6‐311G(d,p) level of theory for all relevant conformers, unequivocally proved the (R,R)‐configuration for the dextrorotatory natural product. Based on this finding, a short enantioselective synthesis of (+)‐caripyrin was developed.

Short and Straightforward Enantioselective Synthesis of Both Enantiomers of Mequitazine through Iridium-Catalyzed Asymmetric Hydrogenation of a Nonfunctionalized Cyclic Enamine

A short and straightforward asymmetric synthesis of both enantiomers of the antihistaminic drug mequitazine is reported. This atom-economical and attractive method features an iridium-catalyzed asymmetric hydrogenation of a nonfunctionalized cyclic enamine as a key step to install the C 3-stereogenic center. After a full investigation of the effects of catalyst precursors, ligands, solvents, temperature, and hydrogen pressure, mequitazine (1) is obtained in good yield (up to 80%) and with acceptable enantiomeric excesses up to 47%.