Resolution and absolute configuration of dimethyl hydroxy-(ferrocenylmethyl)phosphonate

Racemic dimethyl hydroxy-(ferrocenylmethyl)phosphonate rac-1 was resolved via the formation of diastereomeric esters with (S)-α-methoxy-α-phenylacetic acid. The diastereomers, separated by column chromatography, were stereospecifically hydrolyzed by dissolution in trifluoroacetic acid at −30 °C and quenching with water. The absolute configuration of one enantiomer of 1 was assigned by X-ray diffraction.     

Resolution,absolute configuration and antifilarial activity of coumarinyl amino alcohols

The resolution of racemic coumarinyl amino alcohols 5–10 was achieved by using the inexpensive and readily accessible chiral resolving agent N-carbethoxy-l-proline (S)-11. Direct esterification of rac-5–10 with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography. The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5–10 and (R)-(?)-5–10 in good yields with high enantiomeric excess on saponification. The absolute configurations were determined by X-ray crystal analysis and/or by comparison of the specific rotations. Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(?)-9 and (S)-(+)-10, (R)-(?)-10 were found to be less efficient in affecting the viability of macrofilariae of Brugia malayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enantiomers in evoking antifilarial action.     

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 of both enantiomers of cyclic methionine analogue: (R)- and (S)-3-aminotetrahydrothiophene-3-carboxylic acids

A method of synthesizing an optically active cyclic methionine analogue, 3-aminotetrahydrothiophene-3-carboxylic acid (At₅c), is described. A Bucherer–Bergs reaction of 4,5-dihydro-3(2H)-thiophenone and the subsequent alkaline hydrolysis of a hydantoin, followed by Cbz protection of the amine, afforded racemic Cbz-At₅c (±)-3 in excellent yield. Diastereomeric esters derived from Cbz-At₅c (±)-3 and (R)-BINOL could be separated by column chromatography to give both diastereomers with >99% de. X-ray crystallographic analysis revealed the absolute configuration of the synthesized amino acid derived from the less polar diastereomeric ester to be (S).     

Electron transfer-initiated asymmetric photocyclization of chiral auxiliary-substituted N-acyl-α-dehydro(1-naphthyl)alaninamides to the corresponding 3,4-dihydrobenzo[f]quinolinone derivatives

Photoinduced electron transfer reactions of the title N-acyl-α-dehydronaphthylalaninamides [(Z)-1] with (S)-1-phenylethylamino and (S)-alaninamide auxiliary groups in methanol containing a tertiary amine were shown to form (R,S)- and (S,S)-3,4-dihydrobenzo[f]quinolinone derivatives (2) in excess at rt, respectively. The magnitude of diastereomeric excess (de) was varied in the range of −5-26% for (R,S)-2 and 16-92% for (S,S)-2, depending on the chiral auxiliary and reaction temperature. The mechanism of asymmetric induction in the photocyclization process eventually affording diastereomeric 2 was discussed based on solvent, tertiary amine, chiral auxiliary and temperature effects on the de value as well as on MM2 and PM5 calculations for the diastereomeric enol intermediates.     

Resolution of (±)-[2.2]paracyclophane-4,12-dicarboxylic acid

The resolution of (±)-[2.2]paracyclophane-4,12-dicarboxylic acid (±)-1 has been realized through the diastereomeric esters of (1S)-hydroxymethyl-4,7,7-trimethyl-2-oxabicyclo-[2.2.1]heptan-3-one, simply separated by flash chromatography and hydrolyzed with ^tBuOK/H₂O. (R)-(−)-1 and (S)-(+)-1 were obtained in high enantiomeric excesses (>97%) while the determinations of the absolute configurations of (R)-1 and (S)-1 were carried out by X-ray diffraction.     

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.     

(2-Formyl-1-phenylcyclopropyl)phosphonates as building blocks for (2-aminomethyl-cyclopropyl)phosphonates

A diastereomeric mixture of dimethyl (2-formyl-2-methyl-1-phenylcyclopropyl)phosphonate ((Z)-6, (E)-6) was obtained by thermally induced cyclopropanation of α-methylacrolein with α-diazobenzylphosphonate 5. Application of proline or proline-derived organocatalysts accelerated the reaction, but had a minor effect on the Z/E ratio of 6. By reaction with benzylamine or methyl esters of glycine, (S)-alanine, and (S)-phenylalanine, the Z/E-mixture of 6 was converted into cyclopropylaldimines, which after reduction gave the corresponding N-substituted (2-aminomethyl-cyclopropyl)phosphonates.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Synthesis and epimerization of 10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-(11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione

The reaction of the 1,2:3,4-di-O-isopropylidene-6-O-tosyl-α-d-galactopyranose 2 with (11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione 1, prepared from l-proline and isatoic anhydride, gave two products which were previously reported as conformational isomers. In this work, an X-ray crystallographic study showed these to be the diastereomeric pair (11aS)- and (11aR)-10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones as a consequence of C(11a) epimerization in the benzodiazepine moiety during glycosylation under basic reaction conditions. The hydrosolubility of the deprotected products were compared with those of the analogous benzodiazepine derivatives.     

A novel dynamic kinetic resolution accompanied by intramolecular transesterification: asymmetric synthesis of a 4-hydroxymethyl-2-oxazolidinone from serinol derivatives

Reaction paths of the one-pot reaction of (R)-2-(α-methylbenzyl)amino-1,3-propanediol (1) and 2-chloroethyl chloroformate with DBU giving (4S,αR)-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone [(4S)-2] (94% de) were investigated. Intermediates of this reaction, 2-chloroethyl (2S)- and 2-chloroethyl (2R)-3-hydroxy-2-[(αR)-α-methylbenzyl]aminopropyl carbonates [(2S)-4 and (2R)-4], were synthesized individually. After the addition of DBU to the respective solution of the carbonate (2S)-4 and that of (2R)-4 in dichloromethane, the intramolecular transesterification between (2S)-4 and (2R)-4 and the diastereoselective intramolecular cyclization proceeded to afford (4S)-2 in high diastereomeric excess. Therefore, two monocarbonates (2S)-4 and (2R)-4 were kinetically resolved by this cyclization during the intramolecular transesterification between (2S)-4 and (2R)-4. We found that this process involved dynamic kinetic resolution accompanied by intramolecular transesterification.     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

2-Methoxy-2-(1-naphthyl)propionic acid,a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)-2a and (−)-2b, the separation factor α=1.83 being unusually large. The ¹H NMR chemical shift differences, Δδ=δ(R)–δ(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the ¹H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids (S)-(+)-1 and (R)-(−)-1, which are useful for enantioresolution of racemic alcohols.     

Synthesis and crystal structure of (S)-pindolol

Racemic 3-(4-indolyloxy)-1,2-propanediol 2 has been effectively resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Non-racemic (S)-2 was converted into (S)-4-(2,3-epoxypropoxy)-1H-indole (S)-4 via a Mitsunobu reaction and then into (S)-pindolol (S)-1. The crystalline (S)-1 was studied by single crystal X-ray diffraction. A large number of symmetry independent molecules (Z′ = 6) led to a weakening of the system of strong intermolecular hydrogen bonds, which combined with a loose packing (PI = 64.6%), may be the cause of the abnormally low melting point of (S)-1 as compared with rac-1.     

The reaction of (Sp)-2-(diphenylphosphino)ferrocenecarboxylic acid with carbodiimide reagents: Characterisation of the acid anhydride and urea products

Interaction of (S_p)-2-(diphenylphosphino)ferrocenecarboxylic acid [(S_p)-1] with N,N′-dicyclohexylcarbodiimide (DCC) and N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide (EDC) have been investigated in order to study the reacting system itself and to characterise side-products typically arising during the diimide-promoted condensation of acid (S_p)-1 with nucleophiles. The reaction between (S_p)-1 and DCC was found to give preferentially the respective urea derivative in the absence of a base, and (S_p)-2-(diphenylphosphino)ferrocenecarboxylic anhydride [(S_p,S_p)-3] when the same reaction was performed in the presence of 4-(dimethylamino)pyridine (DMAP). With EDC, the preference for a reaction pathway was less pronounced: whereas the reaction without the base afforded exclusively the corresponding urea, that in the presence of DMAP yielded a mixture of the urea and anhydride (S_p,S_p)-3.     

Asymmetrical nonbridgehead nitrogen—XXIII: Chiral 3,3-bis(trifluoromethyl)diaziridines

By means of the reaction of O-tosyloxime 1a with propargyl amine, esters of glycine and (S)-α-alanine, β-acetoxyethyl amine and β-dimethylaminoethyl amine functionally substituted 3,3-bis(trifluoromethyl)diaziridines 2a–g have been obtained. In the reactions with more bulky amines, (S)-phenylalanine Et ester, (R, S)-α-phenylethyl amine and t-butyl amine, 1a acts as a tosylating reagent. The ester group in diaziridine 2e is readily saponified by alcoholic alkali, whereas diaziridine 2c is rearranged in these conditions with ring-expansion. Complete asymmetric transformation has been found to take place on the formation of the solid phase of diastereomers 2d and 2j, and a closed cycle of diastereomeric transformations has been accomplished. Diaziridine 2g with chiral centres only at the nitrogen atoms has been obtained with the optical purity of 85.5% by resolution via salt 5c with d-(+)-camphor-3-carboxylic acid. The absolute configuration of (+)-2g and its quaternary salt, (+)-2h, has been determined from CD spectra. Optically active (?)-2h salt (optical purity 2.0%) has been also obtained by asymmetric synthesis on the basis of 1–10-camphorsulphonyl oxime 1b. From the kinetics of 2g, h racemization and 2d, e, i, j, k epimerization the energy parameters of the inversion of N atoms in 3,3-bis (trifluoromethyl)diaziridines have been determined.     

Asymmetric halolactonisation reaction—1 : Asymmetric synthesis of optically active α,α-disubstituted-α-hydroxy acids from α,β-unsaturated acids by the novel use of halolactonisation r

Considering the usefulness of optically active α,α-disubstituted -α -hydroxy acids (1) andα,α- disubstituted-α-hydroxy ketones (2) readily accessible from 1 exploitation of a new asymmetric synthesis of 1 from α,β-unsaturated acids (3) which utilised halolactonisation reaction as its key step, was studied.The asymmetric bromolactonisation of (S) N-(α, β-unsaturated)acylproline((S) 5) derivable from 3 such as tiglic acid (3a) and trans-α methylcinnamic acid (3b), with N-bromosuccinimide in N,N dimethylformamide was found to proceed in a highly stereoselective and regiospecific manner giving a mixture of the two diastereomeric bromolactones (8) in which one diastereomer (8A) was highly predominant. Debromination of 8 followed by acidic hydrolysis readily afforded (R)-1 being 89-98% optically pure.     

Asymmetric halolactonisation reaction-2 : Elucidation of general applicability and mechanism of the asymmetric bromolactonisation reaction

Detailed studies on the asymmetric bromolactonisation were carried out by employing several structural types of α,β-unsaturated acids (2) as reaction substrates and various (S)-α-amino acids as chiral sources.Following several novel aspects of the asymmetric bromolactonisation were uncovered by combining the results obtained in this study with those of the previous report. Thus, the bromolactonisation of (S)-N-(cis(E)-α,β-disubstituted-α,β-unsaturat acylproline((S)-3a,b) proceeds more stereoselectively than that of the trans(Z)-α,β-disubstituted analogue ((S)-3c), to give the 6-membered bromolactone(4A) via the symmetrical and/or the carbocationic bromonium ions (5AB and/or 5AC). While (S)-N-(trans(E)-β-monosubstituted-α,β-unsaturated)acyl-proline((S)-3d) undergoes no bromolactonisation, (S)-N-(β,β-disubstituted-α,β-unsaturated)acylproline((S)-3e) regiospecifically gives the 7-membered bromolactone(11e) via the carbocationic bromonium ion(5AA) when submitted to the bromolactonisation. (S)-Proline((S)-8) is found to the superior chiral source for the asymmetric bromolactonisation among those examined.     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

Natural product synthesis from (8aR)- and (8aS)-bicyclofarnesols: synthesis of (+)-wiedendiol A, (+)-norsesterterpene diene ester and (−)-subersic acid

Both enantiomers (8aR)-7 and (8aS)-7 of bicyclofarnesol were synthesized from the enzymatic resolution products (1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-5 (98% ee) and acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aS)-6 (>99% ee), respectively. The formal synthesis of (+)-wiedendiol 1 was achieved via a coupling reaction of an ate complex derived from 1,2,4-trimethoxybenzene with allyl bromide (8aS)-8 derived from (8aS)-7. The total synthesis of (+)-norsesterterpene diene ester 2 was achieved, based on the synthesis of (13E,10S)-α,β-unsaturated aldehyde 12, derived from (8aS)-7, followed by the selective construction of the (3E,5E)-diene moiety including a C(2)-stereogenic centre in (+)-2. The total synthesis of (−)-subersic acid 3 was carried out based on a Stille coupling between allyl trifluoroacetate congener 25c, derived from (8aR)-7, corresponding to the diterpene part, and aryl stannane congener 26 in the presence of Pd catalyst and CuI as an additive.