A new strategy for the synthesis of hydroxylated pyrrolizidinic alkaloids by highly stereoselective indium-mediated allylation of pyrrolidinic aldehydes

Indium-mediated allylation of N-Cbz-l-prolinal 3, under Grignard conditions, was carried out with high yield and stereoselectivity (de = 90%) to afford intermediate (2S,1′R)-N-benzyloxycarbonyl-2-(1′-hydroxybut-3′-en-1′-yl)pyrrolidine 4, which was transformed in two steps into (1R,3R,7aS)-1-hydroxy-3-hydroxymethylpyrrolizidine 9. Commercial Cbz-l-proline was a source of functionalization and chirality.     

Studies on two different diastereoselective reaction pathways from a serinol derivative to 4-hydroxymethyl-2-oxazolidinones using 2-chloroethyl chloroformate and N,N′-disuccinimidyl carbonate

Two reaction pathways and their diastereoselectivity-determining steps of the asymmetric desymmetrization of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 2-chloroethyl chloroformate (CCF) and with N,N′-disuccinimidyl carbonate giving (4S,αR)-4-hydroxymethyl-3-α-methylbenzyl-2-oxazolidinones (4S)-3 and its (4R,αR)-diastereomer (4R)-3 were investigated. The reaction of serinol 1 and CCF to give the corresponding carbonates was not a diastereoselectivity-determining step. The carbonates gave (R)-5-(α-methylbenzyl)amino-1,3-dioxan-2-one 4 after addition of DBU, and an intramolecular acyl transfer of 4 was found to be a diastereoselectivity-determining step to give (4S)-3. Conversely, the reaction of serinol 1 and N,N′-disuccinimidyl carbonate afforded directly the opposite diastereomer (4R)-3 but not via the intermediate 4. Thus, their diastereoselectivities depended on the acylating reagent.     

On the mechanism of the Leuckart reaction. Enantiospecific preparation of (1R,2R)- and (1S,2S)-N-(3,3-dimethyl-2-formylamino-1-norbornyl)acetamide

The Leuckart reaction of 2-norbornanone and (1R)-N-(3,3-dimethyl-2-oxo-1-norbornyl)acetamide ent-1b furnishes the expected N-(2-norbornyl)formamides 11 and ent-10 in good yield. Surprisingly, under the same reaction conditions, the (1R)-N-(7,7-dimethyl-2-oxo-1-norbornyl)acetamide 1a gives only 10, the enantiomeric form of the product obtained from ent-1b. An explanation of these results is given and a reaction mechanism, based on an unprecedented intramolecular transamidation, is proposed.     

Novel asymmetric total syntheses of (R)-(−)-pyridindolol, (R)-(−)-pyridindolol K1, and (R)-(−)-pyridindolol K2 via a mild one-pot aromatization of N-tosyl-tetrahydro-β-carboline with (S)-2,3-O-isopropylidene-l-glyceraldehyde as the source of chirality

Novel total syntheses of (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 are described. By using l-tryptophan methyl ester and (S)-2,3-O-isopropylidene-l-glyceraldehyde as the starting materials, (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 were synthesized in 5–7 steps in 66%, 41%, and 55% overall yields, respectively. The characteristic step of the total syntheses is a mild one-pot aromatization of N-tosyl-1,2,3,4-tetrahydro-β-carboline (N-Ts-THBC), which was obtained via Pictet–Spengler reaction of l-tryptophan methyl ester with (S)-2,3-O-isopropylidene-l-glyceraldehyde, and subsequent N-tosylation.     

Optimisation of a key cross-coupling reaction towards the synthesis of a promising antileishmanial compound

During the course of a research program aimed at identifying novel antileishmanial compounds, a multi-gram synthesis of N-(trans-4-((4-methoxy-3-((R)-3-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)-2-methylpropane-1-sulfonamide ((R)-1) was required. This letter describes optimisation of the reaction conditions and protecting group strategy for a key Buchwald-Hartwig coupling, delivering the required quantities of (R)-1, as well as further compounds in the series.     

Preparation of a new chiral acridino-18-crown-6 ether-based stationary phase for enantioseparation of racemic protonated primary aralkyl amines

Starting from commercially available and relatively cheap chemicals first enantiopure dimethyl-substituted monoaza-18-crown-6 ether (R,R)-21 containing a diphenylamine unit was prepared, which was then transformed to dimethyl-substituted acridino-18-crown-6 ligand (R,R)-19 having an N-allyl-carbamoyl linker by several steps. The terminal double bond of the latter made possible to attach (R,R)-19 to γ-mercaptopropyl-functionalized spherical HPLC quality silica gel obtaining a new chiral stationary phase (R,R)-CSP-37. Based on electronic circular dichroism (ECD) studies the N-allyl-carbamoyl group attached to the acridine ring of the chiral host (R,R)-19 does weaken exciton interaction between the host and guest molecules, but does not destroy the discriminating power of the chiral host. An HPLC column filled with (R,R)-CSP-37 was tested for the enantioseparation of racemic 1-(1-naphthyl)- and 1-(2-naphthyl)ethylamine hydrogenperchlorates using isocratic conditions.     

Enantioselective sorption of some chiral carboxylic acids by various cyclodextrin-grafted iron oxide magnetic nanoparticles

A new enantioselective sorption approach to chiral carboxylic acid molecules such as (R)-(?)-N-(3,5-dinitrobenzoyl)phenylglycine (R)-(?)DNBPG, (S)-(+)-N-(3,5-dinitrobenzoyl)phenylglycine (S)-(+)DNBPG, (R)-(+)-N-(1-phenylethyl)phthalamic acid (R)-(+)PEPA and (S)-(?)-N-(1-phenylethyl)phthalamic acid (S)-(?)PEPA regarding their complexation with three diversely functionalized β-cyclodextrin grafted iron oxide nanoparticles in the aqueous phase, was developed. The sorption efficiencies of these carboxylic acids were carried out by high-performance liquid chromatography (HPLC) with an Ace 5 C18 column. The effects of temperatures on the sorption were also investigated. The results showed that the ether functionalized derivative of β-cyclodextrin Al-CD-MNPs has a specific affinity for (R)-(?)DNBPG at 30 °C and pH 7.0. The amine functionalized derivative of β-cyclodextrin Am-CD-MNPs has a greater affinity towards not only (S)-(?)DNBPG, but also (R)-(+)PEPA compared with their other isomers, which are the (R)-isomer of DNBPG and the (S)-isomer of PEPA at 30 °C and pH 7.0. In addition, although amide functionalized derivatives of β-cyclodextrin (Amd-CD-MNPs) have an affinity towards both isomers of some chiral carboxylic acids; no selective affinity was observed at 30 °C and pH 7.0.     

Asymmetric allylation of N-benzoylhydrazones promoted by novel C2-symmetric bis-sulfoxide organocatalysts

Novel C₂-symmetric bis-sulfoxide/N-oxide (R,R)-5 was prepared in good yield according to the Andersen protocol with (S)-menthyl p-tolyl sulfinate (2 equiv) and the dilithium derivate of 2,6-dimethylpyridine N-oxide. Reduction of (R,R)-5 to pyridine/bis-sulfoxide (R,R)-6 was accomplished by means of Katritzky’s procedure (Fe⁰/AcOH). Both bis-sulfoxides (R,R)-5 and (R,R)-6 are efficient chiral organocatalysts in the asymmetric allylation of N-benzoyl hydrazones derived from both aldehydes and ketones.     

Enantioselective synthesis of β-amino acids. Part 9: Preparation of enantiopure α,α-disubstituted β-amino acids from 1-benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one,

Double alkylation of enantiopure N,N-acetal pyrimidinone (S)-1, a masked chiral derivative of β-alanine prepared from (S)-asparagine, proceeds with high stereoselectivity to give C(5) disubstituted adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7, and (2S,5S)-7. Acid hydrolysis of these derivatives affords enantiopure α,α-dialkylated β-amino acids (R)-8, (S)-8, (R)-9, and (S)-9 in very good yields.     

Easy generation of an enantiopure general indolalkaloid building block by kinetic resolution

On treatment of racemic 1-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydrocarboline 7 with Boc-l-Ala and DCC the (1S)-enantiomer (1S)-7 reacted much faster than (1R)-7 and gave rise to 1-(2,2-dimethoxyethyl)-2-(N-t-Boc-l-alanyl)-1,2,3,4-tetrahydrocarboline. The untouched (1R)-enantiomer (1R)-7 could be reisolated in enantiopure form.     

Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives

Efficient procedures for the synthesis of (R)-N-benzyl-2-amino-3-methoxypropionamide ((R)-3), 2-acetamido-3-methoxypropionic acid (4), and O-methylserine (5) are described beginning from (R)-Cbz-serine ((R)-7). The reactions proceeded with little or no racemization and permitted the synthesis of the potent anticonvulsant (R)-N-benzyl-2-acetamido-3-methoxypropionamide ((R)-2). The anticonvulsant activities of 2–4 were determined revealing the surprising activity of (R)-2.     

Practical and highly stereoselective method for the preparation of several chiral arylsulfinamides and arylsulfinates based on the spontaneous crystallization of diastereomerically pure N-benzyl-N-(1-phenylethyl)-arylsulfinamides

A novel and simple process for the preparation of enantiomerically pure (S_S)-benzenesulfinamide (S_S)-3a, (S_S)-p-toluenesulfinamide (S_S)-3b, (S_S)-p-chloro-benzenesulfinamide (S_S)-3c and (S_S)-p-fluorobenzenesulfinamide (S_S)-3d has been developed. The treatment of arylsulfinyl chlorides with (R)-N-benzyl-1-phenylethanamine in the presence of excess triethylamine gave diastereomeric mixtures of N-benzyl-N-(1-phenylethyl)-arylsulfinamides 1, which underwent spontaneous crystallization to furnish diastereomerically pure (R,S_S)-N-benzyl-N-(1-phenylethyl)-arylsulfinamides (R,S_S)-1a-1d in 28%, 29%, 27% and 31% yields, respectively. The diastereomerically pure compounds (R,S_S)-1 were then converted into four enantiopure (R_S)-methyl arylsulfinates (R_S)-2, and finally into four enantiopure (S_S)-arylsulfinamides (S_S)-3 in good yields.     

Dielectrically controlled resolution (DCR) of 3-aminopiperidine via diastereomeric salt formation with N-tosyl-(S)-phenylalanine

A useful key intermediate for the dipeptidyl peptidase-4 (DPP-4) inhibitor, 3-aminopiperidine 1, was successfully resolved with an enantiomerically pure resolving agent, N-tosyl-(S)-phenylalanine 2, to give both stereoisomers (R)-1 and (S)-1 as a less-soluble diastereomeric salt with (S)-2, via a dielectrically controlled resolution (DCR) phenomenon.     

Continuous-flow enzymatic resolution strategy for the acylation of amino alcohols with a remote stereogenic centre: synthesis of calycotomine enantiomers

Both enantiomers of calycotomine (R)-5 and (S)-5 were prepared through the CAL-B-catalysed asymmetric O-acylation of N-Boc-protected (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol [(±)-3)]. The optimum conditions for the enzymatic resolution were determined under continuous-flow conditions, while the preparative-scale resolution of (±)-3 was performed as a batch reaction with high enantioselectivity (E >200). The resulting amino alcohol (S)-3 and amino ester (R)-4, obtained with high enantiomeric excess (ee = 99%), were transformed into the desired calycotomine (S)-5 and (R)-5 (ee = 99%). A systematic study was carried out in a continuous-flow system on the O-acylation of tetrahydroisoquinoline amino alcohol homologues (±)-1 to (±)-3 containing a remote stereogenic centre.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

Monomeric and polymeric structures of oxovanadium(IV) complexes with Schiff base ligands derived from (R,R)-2,4-pentanediamine: Synthesis and crystal structure

New tetradentate Schiff base–oxovanadium(IV) complexes which have electron donating or withdrawing groups at the 5-position of the salicylaldehyde moieties, [VO{Xsal-(R,R)-2,4-ptn}] (H₂{Xsal-(R,R)-2,4-ptn}: N,N′-di-Xsalicylidene-(R,R)-2,4-pentanediamine; X=5-MeO (methoxy), 5-Br, and 5-NO₂) were prepared. The structures and redox potentials for the V(V)/V(IV) couple of the complexes were compared with those of other [VO{Xsal-(R,R)-2,4-ptn}] (X=3-EtO (ethoxy), 3-MeO, and H). The 5-MeO substituted complex which has electron donating groups at the 5-position of the salicylaldehyde moieties forms a monomeric structure in the solid state. The 3-EtO substituted complex has both monomeric and polymeric structures. On the other hand, the other [VO{Xsal-(R,R)-2,4-ptn}] (X=H, 3-MeO, 5-Br, 5-NO₂) complexes have only polymeric structures. X-ray crystal structure analysis of [VO{5-MeOsal-(R,R)-2,4-ptn}]⋅CH₃OH (1) was carried out. Complex 1 has a monomeric five-coordinate square–pyramidal structure. The six-membered N–N chelate ring forms a distorted flattened boat form with two methyl groups in the axial positions.     

Highly diastereoselective Henry reaction of nitro compounds with chiral derivatives of glyoxylic acid

N-Glyoxyloyl-(2R)-bornane-10,2-sultam and (1R)-8-phenylmenthyl glyoxylate react stereoselectively with simple nitro compounds giving diastereoisomeric nitroalcohols with high asymmetric induction. N-Glyoxyloyl-(2R)-bornane-10,2-sultam 1a is shown to be a highly efficient chiral inducer, superior to (1R)-8-phenylmenthyl glyoxylate 1b. In all cases, the absolute (2S) configuration at the center bearing the hydroxy group and the relative syn configuration for the major diastereoisomers were determined.     

Substrate engineering: Effects of different N-protecting groups in the CAL-B-catalysed asymmetric O-acylation of 1-hydroxymethyl-tetrahydro-β-carbolines

In the frame of substrate engineering, the steric effect of different N-protecting groups on the enantioselectivity and reaction rate of CAL-B-catalysed (S)-selective O-acylation of N-protected 1-hydroxymethyl-tetrahydro-β-carbolines was investigated. Excellent enantioselectivities (E?>?200) were observed when the acylation of N-Boc [(±)-1], N-Cbz [(±)-3], and N-Fmoc-protected [(±)-4] substrates was performed with the use of CAL-B and acetic anhydride in toluene at 60?°C. The resolution of N-acetyl-protected substrate (±)-2 showed excellent E (>200) after 30?min, but as the reaction progressed, E started decreasing after 2 days, because of N→O and O→N acyl migrations. Preparative resolutions of (±)-3 and (±)-4 resulted in unreacted amino alcohols (R)-3 and (R)-4 and esters (S)-7a and (S)-8a with good enantiomeric excesses (≥88%) and high yields (≥44%).     

Total synthesis of (+) methyl β-d-vicenisaminide

The total synthesis of methyl β-d-vicenisaminide 1 has been achieved. In this approach, the synthesis of enantiomerically pure methyl (4R,5S)- and (4S,5R)-4-azido-5-hydroxy-2(E)-hexenoates 2 was established by enzymatic resolution of (±)-anti-5-acetoxy -4-azido-2(E)-hexenoate 4. Another stereogenic center was introduced by base-catalyzed intramolecular conjugate addition of a hemiacetal-derived alkoxide nucleophile obtained by the reaction of methyl (4S,5R)-N-4-tert-butoxycarbonyl-N-methylamino-5-hydroxyl-2(E)-hexenoate 8 and benzaldehyde in the presence of a base.     

Chiral 1,2,4-triazoles: stereoselective acylation and chlorination

Acyl groups are transferred from diverse N- and O-acyl derivatives of chiral 3,5-bis-(1-hydroxyethyl)-[1,2,4]-triazole to amino acid esters enantioselectively, with 7% to 68% ee, depending on the temperature conditions and nature of the reagents. Thionyl chloride replaced the hydroxyl groups of (S)-1-[4-amino-5-((S)-1-hydroxy-ethyl)-[1,2,4]-triazol-3-yl]-ethanol 3 stereospecifically with inversion, as confirmed by X-ray analysis, which also revealed unusual crystal structures with asymmetric units comprising three molecules of 4-amino-3,5-bis(R-1-chloroethyl)-1,2,4-triazole 5 and four of 3,5-bis((R)-1-chloroethyl)-1H-1,2,4-triazole 6.