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.     

Uncommon transformations of methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate initiated by bases

Methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate prepared in two stages from D-ribose acetonide underwent a series of uncommon transformations under the treatment with bases providing the following different products depending on the base applied: methyl 3-(5-acetyl-2,2-dimethyl-1,3-dioxol-4-yl)propionate (DBU), methyl 2,3-isopropylidenedioxy-7-oxabicyclo[2.2.1]heptane-6-carboxylate (t-BuOK), methyl {(5R)-2,2-dimethyl-5-[(2R)-oxiranyl]-1,3-dioxolan-4-ylidene}propionate and methyl-(E)-3-{(4S,5R)-2,2-dimethyl-5-[(1R)-(2-oxiranyl)]-1,3-dioxolan-4-yl}-2-propenoate (t-BuOK and LDA).     

New Chiral Diamines of the Dioxolane Series: (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(diphenylaminomethyl)- 1,3-dioxolane and (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(methyl- aminomethyl)-1,3-dioxolane

The reaction of sodium diphenylamide with 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane gave (+)-(4S,5S)-2,2-dimethyl-4,5-bis(diphenylaminomethyl)-1,3-dioxolane, which was brought into complex formation with cobalt chloride. Treatment of 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane with sodium N-methylanilide resulted in cleavage of the SÄO bond in the p-toluenesulfonate moiety with formation of N-methyl-N-phenyl-p-toluenesulfonamide and 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane disodium salt. Diethyl (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate reacted with methylamine to give the corresponding dicarboxamide which was reduced with lithium aluminum hydride to (4S,5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane having chiral carbon and nitrogen atoms.     

Preliminary studies on a novel synthesis of β-amino acids: stereocontrolled transformation of d- and l-glyceraldehyde into 3-amino-2-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoic acids

A stereocontrolled synthesis of the methyl ester of (2S)-3-amino-2-((4′S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoic acid from d-glyceraldehyde is described for the first time. This method involves the stereoselective Michael addition of the lithium salt of tris(phenylthio)methane to (S)-2,2-dimethyl-4-((E)-2-nitrovinyl)-1,3-dioxolane followed by hydrolysis of the resulting (4S)-2,2-dimethyl-4-((2′S)-3′-nitro-1′,1′,1′-tris(phenylthio)propan-2′-yl)-1,3-dioxolane to (2S)-methyl 2-((4′S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-3-nitropropanoate, which was finally reduced to the target compound. A similarly stereocontrolled transformation of l-glyceraldehyde into (2R)-methyl 3-amino-2-((4′R)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoate is also described.     

An improved process for chiron synthesis of the atorvastatin side chain

An improved and practical synthesis of tert-butyl ((4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate 3 has been developed for supplying this key chiral side-chain of atorvastatin by using a Blaise reaction of (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile 7 and the Raney Ni catalyzed hydrogenation of tert-butyl 2-((4R,6R)-6-(-2-oximeethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 12 as the key steps. This nine-step route from (R)-epichlorohydrin afforded the target compound in 55% overall yield of high chemical and enantiomeric purity.     

A P,N ligand with central and axial chiral elements: synthesis and application in allylic alkylation

Two epimers of 4-({5-[(diphenylphosphino)methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl)-4,5-dihydro-3H-dinaphtho[1,2-e:2′,1′-c]azepine were prepared starting from (2S,3S)-4-amino-2,3-O-isopropylidenebutane-1,2,3-triol and (R)- and (S)-binaphthol. These ligands, in association with Pd(0) gave enantioselectivities up to 89% (S) and 36% (R) ee for the (S_A,4S,5R) and the (R_A,4S,5R) ligands in the alkylation of racemic 1,3-diphenylprop-2-enyl acetate with dimethyl malonate, showing that the binaphthyl moiety is the most important structure in the enantioselective creation of the new stereogenic center.     

Borohydride reduction of acetophenone and esters of dehydrocarboxylic acids in the presence of chiral cobalt(<Emphasis Type="SmallCaps">II</Emphasis>) diamine complexes

The catalytic reduction of acetophenone, methyl α-acetamidocinnamate, and dimethyl itaconate with alcohol-modified sodium borohydride was studied in the presence of complexes CoCl₂·L₂ (L₂ are chiral C ₂-symmetric diamines: (4S,5S)-2,2-dimethyl-4,5-bis(aminomethyl)-1,3-dioxolane, (4S, 5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane, (4S, 5S)-2,2-dimethyl-4,5-bis(dimethylaminomethyl)-1,3-dioxolane, and (4S, 5S)-2,2-dimethyl-4,5-bis(diphenylaminomethyl)-1,3-dioxolane). The maximum enantiomeric excess of (S)-1-phenylethanol was 24%, that of dimethyl α-methylsuccinate was 38%.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 342–347, February, 2005.     

Asymmetric PTC C-alkylation mediated by TADDOL—novel route to enantiomerically enriched α-alkyl-α-amino acids

Compound (4R,5R)- or (4S,5S)-2,2-dimethyl-α,α,α′,α′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (TADDOL) was shown to catalyze C-alkylation of aldimine Schiff's bases of alanine esters under phase-transfer catalysis conditions (solid NaOH, toluene, ambient temperature, 10% TADDOL) with the e.e. of the final α-methylphenylalanine or α-allylalanine reaching 82%.     

Chemoenzymatic synthesis of enantiopure geminally dimethylated cyclopropane-based C2- and pseudo-C2-symmetric diamines

Enantiopure (−)-(1S,3S)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxamide 2 and (+)-(1R,3R)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylic acid 3 were easily obtained from a multigram scale biotransformation of racemic amide or nitrile in the presence of Rhodococcus erythropolis AJ270 whole cell catalyst under very mild conditions. Coupled with efficient and convenient chemical manipulations, comprising mainly of the Curtius rearrangement, oxidation, and reduction reactions, chiral C₂-symmetric (1S,2S)-3,3-dimethylcyclopropane-1,2-diamine 6 and ((1R,3R)-3-(aminomethyl)-2,2-dimethylcyclopropyl)methanamine 8 and pseudo-C₂-symmetric (1S,3S)-3-(aminomethyl)-2,2-dimethylcyclopropanamine 11 were prepared. These were also transformed into the corresponding chiral salen derivatives 12, 13, and 14, respectively, in almost quantitative yields.     

An improved synthesis of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine

Alkylation of 2-amino-6-chloropurine with 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan ($\text{7}$) and subsequent acid hydrolysis provides an improved procedure for synthesis of the antiviral acyclonucleoside 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine ($\text{3}$).     

Highly diastereoselective alkylation of vicinal dianions of chiral succinic acid derivatives: a new general strategy to (R)-β-arylmethyl-γ-butyrolactones

The vicinal dianions derived from chiral succinic acid derivatives, 1,4-bis[(4R,5S)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione and 1,4-bis[(4S,5R)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione react with arylmethyl bromides with high diastereo- and regio-selectivity to provide the corresponding chiral α-arylmethylated succinic acid derivatives; the (R)-products are converted into (R)-β-arylmethyl-γ-butyrolactones and (R)-α-arylmethyl-γ-butyrolactones.     

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.     

Optical Resolution of Two Pharmaceutical Bases with Various Uses of Tartaric Acid Derivatives and Their Sodium Salts: Racemic Ephedrine and Chloramphenicol Base

The optically active dibenzoyltartaric acid, tartaric acid, and its sodium salts were successfully applied to the optical resolution of (1R,2S)(1S,2R)-2-(methylamino)-1-phenylpropan-1-ol (EPH) and (1R,2R)(1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (AD) as resolving agents. It was observed that both compounds’ resolution using a mixture of salts of quasi-racemic resolving agents showed a change in chiral recognition under the same conditions compared to the result of the use of the single enantiomeric resolving agent. The changes are followed by detailed analytical (XRD, FTIR, and DSC) studies. Meanwhile, the DASH indexing software package was also tested on powder XRD patterns of pure initial materials and intermediate salt samples of high diastereomeric excess.     

Synthesis, resolution and assignment of absolute configuration of trans 3-amino-1-oxyl-2,2,5,5-tetramethylpyrrolidine-4-carboxylic acid (POAC), a cyclic, spin-labelled β-amino acid

Racemic trans 3-(9-fluorenylmethyloxycarbonylamino)-1-oxyl-2,2,5,5-tetramethylpyrrolidine-4-carboxylic acid (Fmoc-POAC-OH), prepared by conventional methods, was resolved upon esterification with (aR)-2,2′-dihydroxy-1,1′-binaphthyl. Separation of the obtained diastereomeric monoesters Fmoc-(±)-trans-POAC-O-(aR)-binaphthol by crystallization/chromatography, and removal of the chiral auxiliary by saponification of the aryl ester function furnished both enantiomers (+)-(3R,4R)-Fmoc-POAC-OH and (−)-(3S,4S)-Fmoc-POAC-OH. The absolute configuration of the asymmetric C³, C⁴ carbons of POAC were assigned from the induced circular dichroism of a flexible biphenyl probe present in the terminally protected dipeptide derivatives Boc-Bip-(+)-POAC-OMe and Boc-Bip-(−)-POAC-OMe (Bip, 2′,1′:1,2;1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid). This assignment was confirmed by X-ray diffraction analysis of the diastereomeric monoester Fmoc-(+)-trans-POAC-O-(aR)-binaphthol, shown to be (aR,3R,4R). Solution synthesis of peptides to the hexamer level, based on the (3R,4R)-POAC enantiomer combined with (1S,2S)-2-aminocyclopentane-1-carboxylic acid, was carried out to examine coupling conditions at both C- and N-termini of the POAC residue, in view of further syntheses and 3D-structural investigations.     

Organometallische komplexverbindungen: VIII. Einfluss von achiralen substituenten auf die optische induktion bei der metallinduzierten synthese von 3-methyl-E-4-hexen-2-on

Bis(μ-methyl-1,3-dimethyl-η³-allylnickel) which has been modified by P ligands with a chiral substituent reacts with carbon monoxide under the formation of optically active 3-methyl-E-4-hexen-2-on. The investigated P ligands (PR^★R₂) have one chiral substituent (R^★ = 1R,3R,4S-(?)-menthyl) and the other substituents have been varied by taking the same alkyl or alkoxy groups (R = Me, Et, i-Pr, OMe, OEt, O-i-Pr). It has been found that the extent and the direction of optical induction depends on the concentration of the P-ligand and the kind of the achiral substituents at phosphorus.     

1,3-Heterazolidin-2-one as starting materials for optically active 1,3,2-oxazaborolines and 1,3,2-diazaboroline derived from ephedrines

(4R,5R)-3,4-Dimethyl-5-phenyl-1,3,2-oxazaboroline (1a) derived from pseudoephedrine and (4R,5S)-1,3,4-trimethyl-5-phenyl-1,3,2-diazaboroline (1d) derived from ephedrine have been prepared from the corresponding 1,3-heterazolin-2-one. Hydrolysis of 1d afforded the 1-methyl-3-(methylamine)-2-phenyl-propylamine 5. The structures were established from ¹H, ¹³C and ¹¹B NMR data. The X-ray diffraction analysis of (4R,5S)-(+)-3,4-dimethyl-5-phenyl-1-hydro-1,3-diazolidine-2-one (4e) was performed. Isomeric N-monoborane adducts of the 1,3,2-diazaboroline 1d were prepared, and their structures were deduced from the NMR data.     

Co<Superscript>II</Superscript> and Rh<Superscript>I</Superscript> complexes with <Emphasis Type="Italic">C</Emphasis><Subscript>2</Subscript>-symmetric chiral diamines of the dioxolane series

The reaction of di-μ-chlorobis(1,5-cyclooctadiene)dirhodium with (4S, 5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane (1) gave the complex [Rh(cod)(1)]Cl (cod is 1,5-cyclooctadiene). The composition of the complexes CoCl₂ · L₂ and [Rh(cod)(L₂)]X (L₂ = 1, (4S,5S)-2,2-dimethyl-4,5-bis(aminomethyl)-1,3-dioxolane, and (4S, 5S)-2,2-dimethyl-4,5-bis(dimethylaminomethyl)-1,3-dioxolane; X = Cl, TfO) was studied using IR and ¹H NMR spectroscopy. In the Rh^I cyclooctadienediamine complexes, the diene molecule forms a stronger bond with the metal atom than that in the cyclooctadienediphosphine analogs. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2270–2274, October, 2005.     

Oxidation of bicyclic monoterpene ketones with Caro’s acid

Previously unknown seven-membered lactones, (1R,1??R,5S,5??S)-5,5??-oxybis(1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one), 2,2-dimethyl-1,6-dioxaspiro[2.6]nonan-7-one, 4-(1-hydroxy-1-methylethyl)-7-methyloxepan-2-one, and (4R,4??R,7S,7??S)-4,4??-[oxybis(propane-2,2-diyl)]bis(7-methyloxepan-2-one), were synthesized by the Baeyer-Villiger reaction using Caro??s acid as a result of oxidative and skeletal transformations of bicyclic monoterpene ketones, (+)-camphor, (+)-nopinone, and (?)-isocaranone.     

A new chiral diol derived from tetralone for the complexation of Lewis acids

A new approach to the rational design of Lewis acids based on face-face π-π interactions is described. The synthesis of two novel diols (−)(1R,3R)-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene-1,3-diol (−)-1 and (−)(1S,3R)-trans-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene-1-3-diol (−)-9 is reported in six and five steps respectively starting from α-tetralone. Complexation of (−)(1R,3R)-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene-1,3-diol (−)-1 to phenylboronic acid shows the interplanar distance between the boron atom and the aromatic ring to be 3.05 Å, which is ideal for the proposed interactions.     

Enantioselective synthesis of a key intermediate aldehyde toward the polyene macrolide filipin III,based on a chiral oxazaborolidinone-promoted asymmetric aldol reaction

A versatile preparation of an enantiopure aldehyde useful for the asymmetric total synthesis of filipin III was developed using a chiral oxazaborolidinone-promoted asymmetric aldol reaction with a dithiolane silyl nucleophile. The sign and magnitude of the specific rotation of the aldehyde, (4R,5R)-2,2-dimethyl-5-formyl-4-pentyl-1,3-dioxane, were reconfirmed.