A convenient and new approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain-transformation. Part 2: Synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid

Making use of amide activation, a convenient and short path synthesis of optically pure ω-heterocyclic-β-amino acids has been achieved from (1R,3R)- and (1R,3S)-5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester. The key step of the synthesis involves a regiospecific ring-chain-transformation of the enaminones when subjected to 1,2-binucleophilic attacks. The method is illustrated by the synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid.     

Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl (1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate. From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.     

Asymmetric synthesis of anti-diastereoisomers of β-heterocycle substituted (S)-α-aminobutyric acids

A new efficient method for the asymmetric synthesis of β-heterocycle substituted (2S,3S)-α-aminobutyric acids through the diastereoselective addition of 5-thioxo-4-allyl-1,2,4-triazoles, containing various substituents at the 3-position, to the CC double bond of (E)- and (Z)-dehydroaminobutyric acid in the Ni^II complexes of their Schiff base with chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide [(S)-BPB], (S)-N-(2-benzoylphenyl)-1-(3,4-dichlorobenzyl)pyrrolidine-2-carboxamide [(S)-3,4-DCBPB], (S)-N-(2-benzoylphenyl)-1-(3,4-dimethylbenzyl)pyrrolidine-2-carboxamide [(S)-3,4-DMBPB], and (S)-N-(2-benzoylphenyl)-1-(2-chlorobenzyl)pyrrolidine-2-carboxamide [(S)-2-CBPB] has been elaborated upon. The nucleophilic addition proceeds with high diastereoselectivity with a preferential formation of (S,S,S)-diastereoisomers. After decomposition of a mixture of diastereomeric complexes, optically active β-heterocycle substituted (2S,3S)-α-aminobutyric acids with high diastereomeric purity (de >98%) were isolated.     

The use of (S)-(−)-1-(1-naphthyl)ethylamine as a resolving agent for α-methoxy fatty acids

A general method was developed for the diastereoselective resolution of α-methoxy fatty acids utilizing (S)-(−)-1-(1-naphthyl)ethylamine as resolving agent. The diastereomeric amides can be easily separated by silica gel column chromatography and/or capillary gas chromatography, thus allowing for a preparative and analytical method for determining the enantiomeric purity of naturally occurring and/or synthetic α-methoxy fatty acids. The first synthesis of the naturally occurring (R)-2-methoxyhexadecanoic acid was also accomplished in four steps starting from commercially available (±)-2-hydroxyhexadecanoic acid.     

Synthesis of enantiomerically pure diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates

The synthesis and ee determination of diethyl 3-azido-2-hydroxypropylphosphonates from 2,3-epoxypropylphosphonates have been optimised. Enantiomerically enriched diethyl (R)- and (S)-2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates (R)-3a–j and (S)-3a–h as well as (S)-3j were synthesised from diethyl (R)- and (S)-2,3-epoxypropylphosphonates in a reaction sequence including azidolysis followed by 1,3-dipolar cycloaddition with selected alkynes.     

New analogues of fosfomycin—synthesis of diethyl (1R,2R)- and (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1R,2R)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised via the intramolecular Williamson reaction from 3-O-protected (trityl or TBDMS) or even unprotected diethyl (1S,2R)-2,3-dihydroxy-1-mesyloxypropylphosphonate, which was obtained from the known diethyl (1S,2R)-2,3-O-cyclohexylidene-1,2,3-trihydroxypropylphosphonate. On the other hand, the cis-analogue, diethyl (1S,2R)-1,2-epoxy-3-hydroxypropylphosphonate, could only be prepared from diethyl (1R,2R)-2-hydroxy-1-mesyloxy-3-trityloxypropylphoshonate.     

Resolution of 1-phenyl-2-(p-tolyl)ethylamine via diastereomeric salt formation

(S)-1-Phenyl-2-(p-tolyl)ethylamine (S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of (S)-isopropylidene glycerol (R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of (S)-1] was achieved by a simple precipitation of (S)-1·(R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble (R)-1·(R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the (S)-1·(R)-2/(R)-1·(R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of (S)-1·(R)-2.     

Synthesis and conformational and configurational studies of diastereoisomeric O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols

Chiral sulfoximines have applications as transition-state mimicking enzyme inhibitors, as peptide isosteres and as chiral auxiliaries in synthesis. To access the required O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols, 4S,5S-di(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (prepared from diethyl R,R-tartrate) was converted into its monobenzyl ether. Mitsunobu-like coupling with thiophenols gave 4S,5R-4-(benzyloxymethyl)-2,2-dimethyl-5-(arylthiomethyl)-1,3-dioxolanes. Sulfoxidation and S-imination (trifluoroacetamide, iodosobenzene diacetate, rhodium acetate) proceeded without stereoselectivity, giving inseparable diastereomeric mixtures of 4S,5R,S(±)-4-(benzyloxymethyl)-2,2-dimethyl-5-(N-(trifluoroacetyl)arylsulfonimidoylmethyl)-1,3-dioxolanes. Removal of the trifluoroacetyl protection allowed chromatographic separation of the diastereomeric 4S,5R,S(±)-4-(benzyloxymethyl)-2,2-dimethyl-5-(arylsulfonimidoylmethyl)-1,3-dioxolanes. The configurations at sulfur were determined by X-ray crystallography and some analysis of the solution and solid-state conformations was carried out. The resulting O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols are of use in developing enzyme inhibitors.     

Enantioselective synthesis of phosphonate analogues of (R)- and (S)-homoserine

The enantioselective synthesis of (R)- and (S)-1-amino-3-hydroxypropylphosphonic acid, the phosphonate analogues of (S)- and (R)-homoserine, has been accomplished in four steps and good overall yield starting from diethyl (3R,5R)- or (3S,5S)-5-(hydroxymethyl)-2-[(S)-1-phenylethyl]isoxazolidinyl-3-phosphonate, respectively.     

Prostaglandin chemistry—V : Synthesis of new prostaglandin synthons; 4(R)-(+)- and 4(S)-(−)-t-butyldimethylsiloxycyclopent-2-en-1-one

Optically active prostaglandin intermediates, 4(R)-(+)- and 4(S)-(?)-hydroxycyclopent-2-en-1-one derivatives, were synthesized from 3(R),5(R)-diacetoxycyclopent-1-ene, 3(R)-acetoxy-5(R)-hydroxycyclopent-1-ene and 3(S),5(S)-dihydroxycyclopent-1-ene obtained by microbiological hydrolysis of 3,5-diacetoxycyclopent-1-ene. The absolute configurations of all these compounds were determined by the exciton chirality method and the induced CD method. The optical purities were determined by NMR measurements of the diastereomeric esters of a versatile optically pure acid, (+)-α-methoxy-α-trifluoromethylphenylacetic acid.     

Chemoenzymatic preparation of (2S,3S)- and (2R,3R)-2,3-butanediols and their esters from mixtures of d,l- and meso-diols

An efficient method of preparing the pure enantiomers of 2,3-butanediol from commercially available mixtures of the d,l- and meso-isomers was developed. It furnished (2S,3S)-2,3-butanediol with >99% e.e. and a >99.5/0.5 diastereomeric ratio and (2R,3R)-2,3-butanediol in 95% e.e. and >95/<5 diastereomeric ratio.     

Synthesis of four enantiomers of 2,3-di(N-Boc-amino)-1-hydroxypropylphosphonates

Enantiomerically pure diethyl (1S,2R)-, (1S,2S)-, (1R,2R)- and (1R,2S)-2,3-di(tert-butoxycarbonyl)amino-1-hydroxypropylphosphonates were synthesised from diethyl (1S,2R,1′S)-, (1S,2S,1′R)-, (1R,2R,1′S)- and (1R,2S,1′R)-[N-(1-phenylethyl)]-2,3-epimino-1-hydroxypropylphosphonates, respectively, via aziridine ring opening with neat TMSN₃ followed by hydrogenolysis in the presence of Boc₂O. A plausible mechanism for the aziridine ring opening in 2,3-epimino-1-hydroxypropylphosphonates involving the intermediate aziridinium ions was proposed. Significant differences in the rates of the aziridine ring opening between diastereoisomeric phosphonates (1S,2R,1′S) and (1S,2S,1′R) were rationalised taking into account different conformations of the 1-phenylethyl group in both diastereoisomers.     

Solvent-induced chirality switching in the enantioseparation of regioisomeric hydroxyphenylpropionic acids via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol

The enantioseparation of three hydroxyphenylpropionic acid isomers via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol has been demonstrated. The racemates of all three acid isomers were successfully separated with high efficiency (0.56–0.84) after single crystallization. For 2-hydroxy-3-phenylpropionic acid 4, the configuration of the less-soluble salt was controlled by the crystallization solvent: the (R)-4 salt was crystallized from water, while 2-propanol afforded the (S)-4 salt. The chiral recognition mechanism of the three acids was discussed based on the crystal structures of the diastereomeric salts.     

Effects of steric bulk and stereochemistry on the rates of diketopiperazine formation from N-aminoacyl-2,2-dimethylthiazolidine-4-carboxamides (Dmt dipeptide amides)—a model for a new prodrug linker system

A peptide-like self-immolative molecular clip is required for release of active drugs from prodrugs by endopeptidases. Upon cleavage from the carrier, this clip must collapse and release the drug rapidly. A series of aminoacyl-5,5-dimethylthiaproline (Aaa-Dmt) N-(2-(4-nitrophenyl)ethyl)amides were designed. Boc-l-aminoacyl fluorides were coupled with R-DmtOH to give Boc-l-Aaa-R-DmtOH, which were converted to the Boc-l-Aaa-R-Dmt N-(2-(4-nitrophenyl)ethyl)amides. The l,S diastereomeric series was prepared by the reaction of Boc-Aaa PFP esters with S-DmtOH. The l-Aaa-Dmt N-(2-(4-nitrophenyl)ethyl)amides were allowed to cyclise to diketopiperazines (DKPs) in aqueous buffers, expelling 2-(4-nitrophenyl)ethylamine as a model for amine-containing drugs. Reaction rates were dependant on pH. In the l,R diastereomeric series, increasing steric bulk of the Aaa side-chain (Gly, Ala, Phe, Val) led to decrease in the reaction rate. However, in the l,S series, the greatest rate of reaction was observed for the most bulky amino-acid (Val), with t_½=15 min at pH 8.0. The effects of steric bulk and stereochemistry are rationalised through conformational analysis (NMR and X-ray crystallography) of the starting dipeptide amides, the product diketopiperazines and key analogues. Since the dipeptides are (almost) exclusively in the cis-amide conformation, trans-cis interconversion is not relevant. The data suggest that steric interactions in the reacting conformations of the dipeptide amides, as they form the tetrahedral intermediates, are the controlling factors. Thus, l-Aaa-S-Dmt amides are shown to be excellent candidates for incorporation into the design of novel prodrugs.     

Absolute configuration of the four stereoisomers of valnoctamide (2-ethyl-3-methyl valeramide), a potentially new stereospecific antiepileptic and CNS drug

Valnoctamide (2-ethyl-3-methyl valeramide, Nirvanil^®, VCD), a mild tranquilizer endowed with anticonvulsant properties, exhibits diastereoselective and enantioselective pharmacokinetics in healthy subjects and epileptic patients. The purpose of this paper is to assign the absolute configuration of the four VCD stereoisomers and to describe the stereoselective synthesis used to prepare two-key VCD stereoisomers. We have synthesized two out of the four stereoisomers, with high diastereomeric excess, by two different synthetic methods. In both methods the (S) configuration at C-3 of VCD was fixed by synthesizing (S)-3-methyl valeric acid from l-isoleucine. In the first method the diastereomeric mixture (2RS,3S)-VCD was prepared. This mixture gave one of the diastereomers via repeated crystallizations, and its absolute configuration (2R,3S)-VCD, was established by X-ray crystallography using a single crystal. The absolute configuration of all four VCD stereoisomers, separated by chiral gas chromatography, was established on the basis of diastereomeric and enantiomeric correlations. In order to assess stereoselective pharmacodynamic properties of VCD, the single stereoisomers have to be synthesized. Stereoselective synthesis of (2R,3S)-VCD and (2S,3S)-VCD was accomplished by using chiral oxazolidinone auxiliaries. These diastereomers were obtained in 99.6% diastereomeric excess.     

An efficient synthesis of (R)- and (S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene

Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as a potent inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on tumor cell lines, we designed a novel synthesis for (R)-S14161 and (S)-S14161 using a chemical resolution and derivation strategy. The readily available 3-(tert-butyldimethylsilyloxy)-salicylaldehyde underwent a tandem oxa-Michael–Henry reaction with trans-4-fluoro-β-nitrostyrene in the presence of a catalytic amount of l-proline and triethylamine to give the 3-nitro-2H-chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2H-chromene was achieved via diastereomeric ester formation using (S)-(+)-α-methoxyphenylacetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each enantiomer furnished (R)-S14161 and (S)-S14161 in enantiomerically pure forms. The absolute configurations of these chiral molecules were determined by a circular dichroism method. The two enantiomers showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.     

Diastereomeric P,N-bidentate amidophosphites based on (S,S)- and (R,R)-hydrobenzoin as ligands in the Pd-catalyzed asymmetric allylation

New P,N-bidentate diastereomeric amidophosphite ligands were obtained by phosphorylation of (S)-2-[(phenylamino)methyl]pyrrolidine involving (4S,5S)- and (4R,5R)-2-chloro-4,5-diphenyl-1,3,2-dioxaphospholanes. Their efficiency in the Pd-catalyzed enantioselective allylic substitution was compared, it was found that the reaction involving (E)-1,3-diphenylallyl acetate and pyrrolidine gives up to 75% ee.     

Aggregation behaviour of chiral ionic liquids

The diastereomeric ionic liquid (IL) (1R,2S)-ephedrinium (RS)-methoxytrifluorophenylacetate 1 was synthesized and its aggregation behavior and diastereomeric interaction were investigated using two independent methods. The aggregation number of the IL in methylene chloride was determined by diffusion ordered NMR spectroscopy. Furthermore the concentration dependence of the signal split of the two diastereomeric ILs (1R,2S)-ephedrinium (R)-methoxytrifluorophenylacetate and (1R,2S)-ephedrinium (S)-methoxytrifluorophenylacetate was measured and could be linked to the aggregation number.     

Asymmetric synthesis and retroracemisation of amino acids via copper(II) complexes with schiff bases between chiral 1-(N,N-dimethylaminomethyl)-2-formylcymantrene and dipeptides

1-(N,N-Dimethylaminomethyl)-2-formylcymantrene (AFCMT) has been resolved into enantiomers through an intermediate formation of diastereomeric complexes with (S)-Ala-(S)-Ala, (S)-Ala-Gly and Gly-(S)-Ala. By the X-ray anomalous dispersion method the absolute configuration of its enantiomers has been determined: (-)₄₃₆ AFCMT-(S), (+)₄₃₆ AFCMT-(R).Alkylation of enantiomeric complexes (R)-and (S)-AFCMT-(GlyGly) Cu(II) with acetaldehyde gives, respectively, (R)-and (S)-Thr with an asymmetric yield of 92–98% and (R)- and (S)-allo-Thr with an asymmetric yield of 95–100%, only the N-terminal glycine being alkylated.The AFCMT enantiomers were also employed for retroracemisation of (R,S)-Ala-(R,S)-Nva; in this case an excess of (S)-Ala and (R)-Nva is obtained for (S)-AFCMT. (R)- and (S)-AFCMT are not liable to racemisation in the course of the threonine synthesis and retroracemisation of depeptides and can be repeatedly employed for these transformations.     

Diastereoselective cycloaddition of (S)-N-(1-phenylethylimino)trifluoropropionate and trifluoroethylphosphonate with diazomethane

The cycloaddition reaction of (S)-(α-phenylethylimino)trifluoropropionate with diazomethane leads to a diastereomeric mixture (4.5:1) of 5-trifluoromethyl-1,2,3-triazoline-5-carboxylates. Enantiopure diastereomers were isolated by column chromatography and converted into their respective non-racemic 2-trifluoromethyl-aziridine-2-carboxylates and carboxylic acids. The absolute configuration of newly formed stereogenic centers was determined by XRD analysis. The stereoselective reaction between (S)-N-(α-phenylethyl)trifluoroacetimidoylphosphonate and diazomethane produces a diastereomeric mixture (2.5:1) of 5-trifluoromethyltriazoline-5-phosphonates readily separated by column chromatography in diastereomerically pure forms.