Design, synthesis and evaluation of new α-nucleophiles for the hydrolysis of organophosphorus nerve agents: application to the reactivation of phosphorylated acetylcholinesterase

A series of new α-nucleophiles including oximes and amidoximes have been synthesized, and their ability to efficiently and selectively cleave the P-S bond of organophosphorus nerve agents has been evaluated. The relationship between the chemical structure of the α-nucleophiles and their reactivity towards PhX hydrolysis is reported. A significant effect induced by an ortho-hydroxyl group of aryl- and pyridyl-oximes, amidoximes on their organo-phosphono-thioase reactivity was discovered. The evaluation of the initial rates of PhX hydrolysis reaction in the presence of α-nucleophiles allowed the discovery of new uncharged molecules with increased reactivity compared to positively charged 2-pralidoxime used as antidote. The mechanism of their action was studied in details by kinetic analysis, HPLC and LC-MS methods. The most promising structures were then considered as potent in vitro reactivators of phosphylated acetylcholinesterase (AChE), which was confirmed by the preliminary results of AChE reactivation initially inhibited by VX.     

An efficient access to N-tert-butanesulfinyl aldimines in water: Application to one-pot synthesis of homoallylic amines, (+)-crispine A and (−)-coniine

An Efficient method for the syntheses of N-tert-butanesulfinyl aldimines in water was developed using Amberlyst-15 as catalyst. Subsequently, chiral homoallylic amines were synthesized in one pot from aldehydes by combining with In-promoted allylation in aqueous media. The total syntheses of (+)-Crispine A and (?)-Coniine were conducted to demonstrate the utility of this one-pot approach.     

Dramatic lithium chloride effect on the reaction stereocontrol in Zn-mediated asymmetric cinnamylation: highly practical synthesis of β-aryl homoallylic amines

An extremely mild and practical approach for the preparation of enantiomerically enriched β-aryl substituted homoallylic amines bearing two adjacent stereogenic centers was realized by room temperature zinc-mediated highly stereoselective cinnamylation of N-sulfinyl imines.     

Protecting-group-free catalytic asymmetric total synthesis of (−)-rosmarinecine

The protecting-group-free asymmetric total synthesis of (?)-rosmarinecine was achieved in only four steps from the commercially available (±)-3-hydroxypyrrolidine hydrochloride (2a). The key steps include the direct oxidation of (±)-2a to (±)-3-hydroxy-1-pyrroline N-oxide (1a) using the Davis reagent and the domino reaction; viz., the lipase-catalyzed dynamic kinetic resolution of (±)-1a with 1-ethoxyvinyl ethyl maleate followed by the intramolecular [3+2] dipolar cycloaddition reaction of the generated optically active ester. Some insights into the mechanism of the racemization of the optically active 1a, observed during the enzymatic process, were also obtained.     

De novo asymmetric synthesis of (−)-nanaomycin A

The de novo asymmetric total synthesis of (?)-nanaomycin A is described. The entirely linear route required only 13 steps from commercially available starting materials (3% overall yield). Key transformations include a Claisen rearrangement, an asymmetric dihydroxylation, a regioselective tosylation, a diastereoselective intramolecular Friedel-Crafts alkylation and a nitrile hydrolysis. As the route relies on a Sharpless asymmetric dihydroxylation it is equally amenable for the synthesis of (+)-nanaomycin A.     

MNBA-mediated β-lactone formation: mechanistic studies and application for the asymmetric total synthesis of tetrahydrolipstatin

Various β-lactones were prepared from β-hydroxycarboxylic acids by intramolecular dehydration condensation using MNBA, an effective coupling reagent, along with a nucleophilic catalyst. The transition state that provides the desired 4-membered ring model system is disclosed by density functional theory (DFT) calculations, and the structural features of the transition form are discussed. This method was successfully applied to the asymmetric total synthesis of tetrahydrolipstatin (THL), an antiobestic drug used in clinical treatment to inhibit the activity of pancreatic lipase.     

Synthesis of (−)-benzolactam-V8 by application of asymmetric aziridination

(?)-Benzolactam-V8, an artificially-designed cyclic dipeptide with strong tumor-promoter activity, was synthesized from benzyl (S)-N-(2-formylphenyl)-N-methylvalinate by application of guanidinium ylide-participated asymmetric aziridination followed by the reductive ring-opening reaction of 3-arylaziridine-2-carboxylate formed.     

(S)-(−)-Fluorenylethylchloroformate (FLEC); preparation using asymmetric transfer hydrogenation and application to the analysis and resolution of amines

Fluorenylethylchoroformate (FLEC) is a valuable chiral derivatisation reagent that is used for the resolution of a wide variety of chiral amines. Herein, we describe an improved preparation of (S)-(−)-FLEC using an efficient asymmetric catalytic transfer hydrogenation as the key step. We also demonstrate the application of FLEC as a chiral Fmoc equivalent for chiral resolution, with facile deprotection, of tetrahydroquinaldines, and its capacity for inducing regioselective outcomes in nitration reactions.     

Ring-closing metathesis and palladium-catalyzed formate reduction to 3-methyleneoxepanes. Formal synthesis of (−)-zoapatanol

A sequence of ring-closing metathesis and palladium-catalyzed formate reduction was developed for preparing O-heterocycles with an exocyclic olefin and applied to the asymmetric synthesis of zoapatanol. The key vicinal stereocenters in zoapatanol were constructed from the l-malic acid-derived lactone by successive chelation-controlled addition of alkyl groups. The O-allylations to prepare the dienes for RCM were achieved with the tertiary alcohols bearing internal olefins. The ring opening of oxepane, a new reaction pathway for the Pd-formate reduction, is also reported.     

An efficient and practical asymmetric synthesis of (−)-tasimelteon

Tasimelteon is a useful drug for the treatment of Non-24 in totally blind individuals. An efficient and convenient asymmetric synthesis of tasimelteon has been developed from 4-vinyl-2,3-dihydrobenzofuran through six steps in 53% overall yield using the Corey–Bakshi–Shibata (CBS0 asymmetric reduction of ketone as a key step.     

Three-component synthesis of polysubstituted pyrroles from α-diazoketones, nitroalkenes, and amines

Polysubstituted pyrroles are regiospecifically synthesized via the copper-catalyzed three-component reaction of α-diazoketones, nitroalkenes, and amines under aerobic conditions. The cascade process involves an N-H insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3 + 2] cycloaddition of azomethine ylide.     

Enantioselective 6-endo-trig Wacker-type cyclization of 2-geranylphenols: application to a facile synthesis of (−)-cordiachromene

An enantioselective intramolecular oxidative cyclization of 2-geranylphenols catalyzed by a Pd(II)-spiro bis(isoxazoline) complex is reported. The reaction proceeds in a 6-endo-trig manner to give chromene derivatives in reasonable yields and with moderate enantioselectivities. This transformation can be applied to a protecting-group-free total synthesis of naturally occurring cordiachromene.     

Stereoselective allylation of α-hydroxy aldimines and its application to the formal synthesis of (−)-β-conhydrine

Stereoselective allylation of N-p-methoxyphenyl (PMP)-substituted α-hydroxy aldimines is described. Several Lewis acids (BF₃·OEt₂, SnCl₄, TiCl₄, ZnCl₂, and MgBr₂·OEt₂) were employed to mediate the allylation reactions. The addition of the allyl group generates a new stereocenter and affords the syn vicinal amino alcohol. Formal synthesis of (?)-β-conhydrine (1) was accomplished via syn-selective allyl addition to N-PMP-substituted α-hydroxy aldimine.     

Methods for the synthesis of chiral sulfur heterocycles and their application in the asymmetric Baylis–Hillman reactions

Enantiomerically pure (2S,6S)-2,6-diphenyltetrahydro-2H-thiopyran, (2S)-2-phenyltetrahydro thiophene, and (2S)-2-phenyltetrahydro-2H-thiopyran were prepared in 70–72% yields and with 86–99% ee via cyclization of the corresponding dimesylate in an S_N2 cyclization reaction using sodium sulfide nonahydrate. The results on the application of various chiral sulfides in asymmetric Baylis–Hillman reactions are also described.     

Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377

Chiral phase-transfer catalysts (S)-1a, (S)-1b, and (S)-2 with conformationally fixed biphenyl cores were conveniently prepared from the known, easily available (S)-6,6′-dimethylbiphenyl-2,2′-diol 3 and (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyl-2,2′-dicarboxylic acid 14, respectively, in five steps. The catalysts, (S)-1a and (S)-1b are readily applicable to asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester with excellent enantioselectivity. In particular, catalyst (S)-1b was found to exhibit the unique temperature effect on the enantioselectivity, and asymmetric alkylation of glycine derivatives at room temperature gave higher enantiomeric excess than that at 0 °C. In addition, the catalyst (S)-2 exhibited the high catalytic performance (0.01-1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer catalysts, thereby allowing to realize a general and useful procedure for highly practical enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids. This approach is successfully applied to the short asymmetric synthesis of cell adhesion BIRT-377.     

Fine tuning of the structure of phosphine–phosphoramidites: application for rhodium-catalyzed asymmetric hydrogenations

Diastereomers of (4-(diphenylphosphino)pentan-2-yl)-N-isopropyl-{dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxa-phosphepin-2-yl}-4-amine, (S)-(2S,4S)-1, and (S)-(2R,4R)-3; the octahydro derivative 4 of (S)-(2S,4S)-1, and derivative 2 of (S)-(2S,4S)-1 containing a 1,3-propanediyl backbone, have been synthesized and used for rhodium-catalyzed asymmetric hydrogenations of prochiral olefins in order to study the role of the stereogenic elements in the backbone and in the terminal moiety. The central chirality in the bridge has been found to determine the configuration of the product with a cooperative effect from the terminal groups. Excellent ee’s (up to 99.9%) were obtained in the hydrogenation of methyl (Z)-α-acetamidocinnamate using a rhodium complex with the matched arrangement (S)-(2S,4S)-1. The hydrogenation is accomplished in a highly enantioselective manner by using green solvents such as propylene carbonate.     

Aza-annulation of β-enaminolactones: application to the synthesis of enantiopure difunctionalized bicyclic lactams

Diastereoselective aza-annulation of seven-membered β-enaminolactones 2 gives access to bicyclic heterocyles 5. Fragmentation of molecule 5a with lithium methoxide affords cis or trans bicyclic lactams 8 with excellent stereoselectivities.     

Stereoselective total synthesis of (−)-zeylenol,a key intermediate for the synthesis of (+)-pipoxide, (−)-uvarigranol G and (−)-tonkinenin A

Total synthesis of (?)-zeylenol, a key intermediate for the synthesis of (+)-pipoxide, (?)-uvarigranol G and (?)-tonkinenin A was achieved from commercially available starting material d-mannose. The key steps are mixed aldol condensation, Grignard reaction, ring closing metathesis and regioselective benzoylation.     

Preparation of new chiral pyrrolidinebisphosphines as highly effective ligands for catalytic asymmetric synthesis of R-(−)-pantolactone

New chiral pyrrolidinebisphosphines, MSCPM, PCPM and BCPM, were prepared. Among them, BCPM was found to be the most effective ligand for catalytic asymmetric synthesis of R-(−)-pantolactone.