Total,asymmetric synthesis of ethyl d-ido-4-heptulosuronate derivatives starting from diethyl 4-oxopimelate

Bromination of diethyl 4-oxopimelate, followed by double elimination of HBr and ketalization provided diethyl (E,E)-4,4-(ethylidenedioxy)hepta-2,5-dienedioate 4. Sharpless asymmetric dihydroxylation of 4 produced diethyl (2S,3S)-4,4-(ethylidenedioxy)-2,3-dihydroxyhept-5-enedioate (+)-5, with 78% e.e. The corresponding tetrol could not be obtained in one step. Silylation of (+)-5 and a second asymmetric dihydroxylation, followed by silylation led to 20% of meso-diester 9 and 60% of diethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis[(t-butyl)dimethylsilyloxy]-4,4-(ethylidenedioxy)heptanedioate (−)-10. Reductive desymmetrization of (−)-10 with DIBAL-H furnished, after selective oxidation, ethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis-[(t-butyl)dimethylsilyloxy]-4,4-(ethylidenedioxy)-7-oxoheptanoate (+)-13 which was then converted into ethyl 1,2,3,6-O-tetraacetyl-4,4-ethylidenedioxy-α- and β-d-ido-heptapyranuronate (−)-15α,β and into the corresponding 3-(α-d-pyranosyl)propene (−)-16.     

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.     

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.     

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.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-thiochroman S-oxide

We have determined the absolute configuration of the chiral sulfoxide 1-thiochroman S-oxide 1 using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of a CCl₄ solution of 1 was analyzed using density functional theory (DFT), which predicts three stable conformations of 1, separated by <1 kcal/mol. The VCD spectrum predicted using the DFT/GIAO methodology for the equilibrium mixture of the three conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The absolute configuration of 1 is therefore (R)-(−)/(S)-(+). (+)-1 and (−)-1 of high enantiomeric excess (e.e.) were synthesized in high yields via asymmetric oxidation of 1-thiochroman 2 using Ti(iso-PrO)₄/(R,R)-1,2-diphenylethane-1,2-diol/H₂O/tert-butyl hydroperoxide and Ti(iso-PrO)₄/l-diethyl tartrate/H₂O/cumene hydroperoxide, respectively.     

Facile synthesis of enantiomerically pure tert-butyl(methyl)phenylsilanes

A method for the preparation of both enantiomers of tert-butyl(methyl)phenylsilane 2 is presented. Racemic tert-butyl(methyl)phenylsilyl chloride 3 was allowed to react with (R)-(−)-2-amino-1-butanol 4 to give hydrochloride 5. Diastereomer separation via treatment of the respective free amine 6 with 0.5 mol equivalent of HCl in hexane-2-propanol yielded crystalline diastereomerically pure hydrochloride (R)Si-5. The corresponding free amine (R)Si-6 was reduced with LiAlH₄ to give (S)-2. The mother liquors obtained after separation of (R)Si-5 on treatment with oxalic acid provided a crystalline salt that eventually afforded (R)-2. The optical purity of (S)-2 (98% ee) was documented by its reaction (hydrosilylation) with propargylic alcohol derivative 10 and HPLC analysis of product 11 using a chiral column.     

Synthesis of (S)-(−)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz–Fritsch–Bobbitt methodology

Laterally lithiated (S)-(−)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (−)-7 along with acyclic products, (−)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (−)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(−)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.     

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.     

Approaches to (R)- and (S)-1′-(1-aminoethyl)ferrocene-1-carboxylic acid derivatives

Lipase-catalyzed esterification of (±)-methyl 1′-(1-hydroxyethyl)ferrocene-1-carboxylate 4 afforded its (R)-acetate (−)-5 (ee = 99%) and (S)-(+)-4 (ee = 90%). Stereoretentive azidation/amination/acetylation of (R)-(−)-5 gave (R)-(+)-methyl 1′-(1-acetamidoethyl)ferrocene-1-carboxylate (R)-3 (ee = 98%). In a similar manner (S)-(+)-4 was converted into (S)-(−)-3 (ee = 84%). Both enantiomers of 3 were obtained in high chemical yields without a loss of enantiomeric purity. The title compounds can be coupled with natural amino acids and peptides on both C- and N-termini.     

Lipase-mediated kinetic resolution of allylic(hydroxymethyl)methylenecyclopentane building blocks

Enzymatic-mediated kinetic acylation of allylic(hydroxymethyl)methylenecyclopentane building blocks (±)-1a,b is reported using various commercially available lipases. Lipase Amano AK (Pseudomonas sp.) proved to be the best lipase in the case of (−)-1b which was obtained with a 96% enantiomeric excess. Single crystal X-ray diffraction analysis, using the (1S,4R)-camphanate derivative of (−)-1b, helped us to assign the S absolute configuration of (−)-1b and the enantiomeric specificity of the tested lipases.     

Are the absolute configurations of 2-(1-hydroxyethyl)-chromen-4-one and its 6-bromo derivative determined by X-ray crystallography correct? A vibrational circular dichroism study of their acetate derivatives

The vibrational circular dichroism (VCD) spectra of the acetate derivative, 3, of 2-(1-hydroxyethyl)-chromen-4-one, 1, and the acetate derivative, 4, of 6-bromo-2-(1-hydroxyethyl)-chromen-4-one, 2, in the CO stretching region are reported. Density functional theory (DFT) predictions of the VCD spectra of the CO stretching modes of (R)-3 and (R)-4 are in excellent agreement with the experimental spectra for (+)-3 and (+)-4, demonstrating that the absolute configurations of both molecules are (R)-(+)/(S)-(−). Since acetylation of (+)-1 and (+)-2 yields (+)-3 and (+)-4, this in turn leads to (R)-(+)/(S)-(−) for both 1 and 2. The absolute configurations of (−)-1 and (−)-2 were previously determined using X-ray crystallography to be R and S, respectively. Our results lead to the conclusion that the previously reported absolute configuration of 1 is incorrect.This work is the first to apply the ‘conformational rigidification via chemical derivatisation’ methodology to the determination of absolute configuration using VCD spectroscopy and illustrates its utility in determining the absolute configurations of chiral alcohols and, by extension, other classes of chiral molecules containing flexible functional groups.     

First stereoselective synthesis of (4aS,5R)-4,4a,5,6,7,8-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone

The synthesis of enantiomerically pure (4aS,5R)-hexahydro-4a,5-dimethyl-2(3H)-naphthalenone (−)-1 is described for the first time. The synthesis starts from (R)-3-methylcyclohexanone and involves the preparation of Piers enol lactone 6 in its enantiopure form as the key intermediate. Treatment of (+)-6 with methyl lithium followed by an intramolecular aldol reaction gives the bicyclic enone (−)-1.     

Absolute configuration of 2-methoxy-2-(2-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

2-Methoxy-2-(2-naphthyl)propionic acid 1 and 2-hydroxy-2-(2-naphthyl)propionic acid 2 were prepared by the Grignard reaction of 2-naphthylmagnesium bromide with (1R,2S,5R)-(−)-menthyl pyruvate. The absolute configurations of (+)-1 and (+)-2 were determined to be S by the ¹H NMR anisotropy method.     

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.     

A straightforward synthesis of both enantiomers of allo-norcoronamic acids and allo-coronamic acids,by asymmetric Strecker reaction from alkylcyclopropanone acetals

Methylcyclopropanone hemiacetal (2S)-3a underwent the asymmetric Strecker reaction induced by a chiral amine to provide a useful synthesis of enantiomerically pure (1R,2S)-(+)-allo-norcoronamic acid 1 in good yield and high enantiomeric excess. From racemic alkyl hemiacetal (±)-3, the same methodology also constituted a useful way to prepare both (+)-1 and (−)-1 and (+)-allo-coronamic acid 2 and its antipode (−)-2 with good yield and high enantiomeric excess.     

2,2′-Dihydroxy-3,3′-dimethoxy-5,5′-dimethyl-6,6′-dibromo-1,1′-biphenyl: preparation,resolution, structure and biological activity

The preparation and resolution of the titled conformationally stable biphenyl 1 has been performed in high chemical yield starting from creosol 2. Enantiopure biphenyls (aR)-(+)-1 and (aS)-(−)-1 were obtained by the corresponding menthylcarbonate diastereomer and successive reduction. The absolute configuration and specific rotation were correlated by X-ray analysis of the crystal structure of diastereopure menthylcarbonate (aS,1R,1′R,2S,2′S,5R,5′R)-(+)-16. Preliminary biological evaluation of both racemic enantiomers of 1 has been carried out on melanoma cell lines and significant and selective anticancer activity has been observed for the enantiomer (aS)-(−)-1.     

Enzymatic resolution of (±)-conduritol-B,a key intermediate for the synthesis of glycosidase inhibitors

Lipases from porcine pancreas, Candida cylindracea and Mucor miehei (adsorbed on support, Lipozyme^® IM) catalysed in t-butylmethylether the alcoholysis of rac-conduritol-B peracetate, (±)-1, by n-butanol to give enantiopure (2S,3S)-diacetoxy-(1R,4R)-dihydroxycyclohex-5-ene, (−)-3, and (1S,2R,3R,4S)-tetraacetoxy-cyclohex-5-ene, (+)-1. The enantioforms (+)- and (−)-conduritol-B, obtained after chemical hydrolysis of (−)-3 and (+)-1, respectively, may be employed to prepare both the enantiomers of conduritol-B epoxide and cyclophellitol, powerful inhibitors of glycosidases.     

Stereospecific synthesis and hydrolysis of optically active diaryl(acylamino)(acyloxy)spiro-λ4-sulfanes and related cyclic diaryl(acylamino)sulfonium salts

The stereospecific synthesis of diaryl(acylamino)(acyloxy)spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5, (S)-(+)-8, and their conversion into related diaryl(acylamino)sulfonium tetrafluoroborates (R)-(+)-3, (S)-(+)-6, (R)-(+)-9, respectively, is described. The enantiomers of spiro-λ⁴-sulfanes (S)-(+)-2, (R)-(+)-5 and (S)-(+)-8 were prepared by dehydration of the corresponding optically active sulfoxide–carboxylic acids (R)-(+)-1, (R)-(−)-4 and (S)-(+)-7, respectively, which were obtained from the racemic forms by diastereoisomeric salt separation with homochiral organic bases. The stereomechanism of the hydrolysis reaction of spiro-λ⁴-sulfanes and sulfonium tetrafluoroborates that depends on pH, the nature of the axial heteroatom, the size of the spiro rings and carboxyl neighbouring group participation is also discussed.     

Collagen cross-links: a convenient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl)butanoate

An efficient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl) butanoate (5), the key intermediate for preparation of collagen cross-links (+)-pyridinoline (Pyd, 1) and (+)-deoxypyridinoline (Dpd, 2) was described from (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (6) in six steps. Also, an improved synthesis of iodide (2S)-(−)-4b was presented.     

Design,synthesis, resolution,and stereochemical assignment of a conformationally rigid chiral ligand derived from anthracene and a dienophile containing a pyridine moiety

The conformationally rigid chiral ligand, trans-12-(pyridin-2-yl)-9,10-dihydro-9,10-ethanoanthracene-11-carboxylic acid ethyl ester, 1, was designed and synthesized in racemic form. Both isomers were successfully obtained in enantiomerically pure form through classical resolution using l-(+)-tartaric acid in acetonitrile. The nature of the diastereomeric complex formed in this resolution was elucidated using single crystal X-ray crystallographic studies. The absolute configuration of (+)-1 was unambiguously assigned as (11S,12S) by single crystal structural analysis of salt 5 formed from (+)-1 and l-(+)-tartaric acid.