2-Nitroferrocenyloxazolines: precursors to nitrofulvalenes and derivatives of (pS)- and (pR)-2-aminoferrocenecarboxylic acids

Diastereoselective lithiation of (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline, followed by addition of N₂O₄, gave (S)-2-[(_pS)-2-nitroferrocenyl]-4-(1-methylethyl)oxazoline which was subsequently converted into derivatives of (_pS)-2-aminoferrocenecarboxylic acid. The corresponding (_pR)-derivatives were obtained through use of a removable TMS blocking group. The 2-nitroferrocenyloxazolines produced in this work underwent facile photo-decomplexation to give 2-nitrocyclopentadienyliden-1,3-oxazolidenes.     

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.     

Synthesis of α,α-disubstituted 4-phosphonophenylalanine analogues as conformationally-constrained phosphotyrosyl mimetics

Syntheses of N-Boc (S)-4-(diethylphosphono)-(α-methyl)phenylalanine [Boc-(α-Me)Phe(4-PO₃Et₂)-OH] (9) and N-Boc (S)-2-amino-6-(diethylphosphono)tetralin-2-carboxylic acid [Boc-Atc(6-PO₃Et₂)-OH] (18) are reported as conformationally-constrained phosphotyrosyl mimetics suitably protected for peptide synthesis. Both syntheses proceeded through chiral arylhalides that are converted to arylphosphonates by palladium-catalyzed cross coupling with diethylphosphite. These amino acid analogues may be useful in the study of cellular signal transduction processes.     

First enantioselective synthesis of the novel antiinfective TAN-1057A via its aminomethyl-substituted dihydropyrimidinone heterocycle

Enantiomerically pure N²-Z-N²-MeAsnOH [(S)-14], prepared in 8 steps (23% overall yield) from asparaginic acid, was first subjected to a Hofmann degradation with PhI(OCOCF₃)₂ yielding (S)-N²-Z-N²-methyl-2,3-diaminopropanoic acid [N²-Z-N²-Me-L-A₂pr, (S)-15], and this in turn was protected to give N²-Z-N³-Boc-N²-Me-L-A₂pr [(S)-17]. Condensation of (S)-17 with HNC(SMe)NHCONH₂ followed by removal of the tert-butoxycarbonyl protecting group, cyclization and hydrogenolytic removal of the Z-group gave the heterocycle of TAN-1057A [(S)-1] with an e.e. of 87 in 36% yield [from (S)-14]. Coupling of (S)-1 with (S)-tris-Z-β-homoarginine (20a) in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) and iPr₂NEt in N,N-dimethylacetamide followed by hydrogenolysis afforded the most active A-diastereomer of the natural antibiotic TAN-1057 in 52% yield (from (S)-1 and 20a). Similarly, starting from (S)-1, a single diastereomer of the potent, less toxic TAN-1057A analogue 22b with a β-lysine side chain has been prepared. All described synthetic steps do not require column chromatography for purification of the products.     

On the mechanism of the Fe(CO)5-catalyzed Kbarasch reaction

Addition of BrCCl₃ to methylN-acryloyl-(S)-prolinate (1) catalyzed by Fe(CO)₅ or Fe(CO)₅-PPh₃ at 75–80 °C in benzene solution affords in good total yield methylN-((S)-2-bromo-3,3,3-trichlorobutyryl)-(S)-prolinate (2) and methylN-((R)-2-bromo-3,3,3-trichlorobutyryl)-(S)-prolinate (3) in an ～1.5 : 1 ratio, which does not depend on the catalytic system employed or its concentration. Catalysis by the Fe(CO)₅-PPh₃ system substantially increases the adducts yield.     

A mild and efficient cyanosilylation of ketones catalyzed by a Lewis acid-Lewis base bifunctional catalyst

A new family of bifunctional catalysts (N-oxides-Ti(OⁱPr)₄ (2:1)) containing a Lewis acid and a Lewis base was developed and applied to the catalytic cyanosilylation of ketones. Utilizing rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex as catalysts, the cyanosilylation products were obtained in 42-97% yield. Based on experimental phenomena and kinetic studies, a catalytic cycle was proposed to explain the remarkable activities of these catalysts. Investigations indicated that rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex should promote the reaction via a dual activation of the ketone by the titanium and TMSCN by the N-oxide.     

A practical enantioselective synthesis of (S)-3-hydroxytetradecanoic acid

(S)-3-Hydroxytetradecanoic acid 1 has been synthesized in an overall yield of 27% from (S)-epichlorohydrin 2 as follows: (1) regio and chemoselective epoxide opening of 2 with a Grignard reagent under the catalysis by Cu(I) followed by consecutive epoxide formation; (2) regioselective epoxide opening of (S)-1,2-epoxytridecane 4 with cyanide anion under pH controlled conditions followed by consecutive nitrile hydrolysis with alkaline H₂O₂ gave crude 1; (3) its purification via the N,N-dicyclohexylammonium salt 6. The method thus devised is practical and scalable for the industrial production of 1.     

Synthesis of chiral β-3-amino-2-hydroxyalkanoates and 3-alkyl-3-hydroxy-β-lactams by double asymmetric induction

Reactions of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic, mandelic, and phenyllactic acids, with aliphatic (S_S)- and (S_R)-tert-butylsulfinyl aldimines afforded conformationally restrained C2-disubstituted N,O-orthogonally protected 3-amino-2-hydroxyalkanoates in the form of N-sulfinyl protected 1′-aminodioxolan-4-ones. The product distribution showed that there is significant kinetic selectivity, due to the presence of ‘matched’ and ‘mismatched’ components, between the (S)- or (R)-tert-butylsulfinyl aldimines and the (2S)-enolates of the 1,3-dioxolan-4-ones. Selective methoxide-induced removal of the acetal group of the N-sulfinyl-1′-aminodioxolanones yielded the corresponding N-sulfinyl protected methyl alkanoates. In addition, the selective acid-induced removal of the sulfinyl group of the N-sulfinyl-1′-aminodioxolanones provided the corresponding N-unprotected 1′-aminodioxolanones, whose base-induced cyclization afforded the corresponding β-lactams.     

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.     

Synthesis of enantiomerically pure 2-amino alcohols from amino acids mediated by sulfoxides

Enantiomerically pure (R₁,S₂)- and (S₁,S₂)-2-amino alcohols can be easily synthesized by stereodivergent reduction of α′-(N-Boc)amino β-keto sulfoxides (easily synthesized from readily available N-Boc amino ester hydrochlorides) with DIBAH (de 82–92%) and DIBAH/ZnBr₂ (de 80%), followed by hydrogenolysis of the C–S bond of the resulting hydroxy sulfoxides and final hydrolysis of the N-Boc protecting group.     

Diels–Alder reactions of enantiopure [(1S)-isoborneol-10-sulfinyl]- and [(1S-exo)-2-bornylsulfinyl]vinylcyclohexenes with maleimides

Uncatalyzed cycloadditions of enantiopure [(1S)-isoborneol-10-sulfinyl]- and [(1S-exo)-2-bornylsulfinyl]vinylcyclohexenes with N-phenylmaleimide occur with good facial diastereoselectivity, controlled by the sulfur configuration, even if the extent of this stereoselection appears influenced by the structural features of the terpene residue directly linked to the sulfoxide moiety. Complete endo diastereoselectivity is observed in LiClO₄ catalyzed cycloadditions of (R_S)-1-{1-[(1S)-isoborneol-10-sulfinyl]- and (S_S)-1-{1-[(1S-exo)-2-bornylsulfinyl]vinyl}cyclohexenes 4 and 5, respectively. The Diels–Alder reactivity of 5 and (S_S,E)-1-{2-[(1S-exo)-2-bornylsulfinyl]vinyl}cyclohexene 7, with the chiral auxiliary being in a different position with respect to the diene moiety, is also compared, and the results obtained comfirm that 1-sulfinyldienes are less reactive than 2-sulfinyldienes. SnCl₄ catalyzed cycloaddition of 7 with N-methylmaleimide is also performed.     

Improved procedures for the synthesis of (S)-2-[N-(N′-benzylprolyl)amino]benzophenone (BPB) and Ni(II) complexes of Schiff's bases derived from BPB and amino acids

(S)-N-Benzylproline (BP) was obtained by the reaction of (S)-proline and benzylchloride in high chemical yield (89%). (S)-2-[N-(N′-Benzylprolyl)amino]benzophenone (BPB) was synthesized in amounts greater than 100 g by the SOCl₂ promoted condensation of BP with 2-aminobenzophenone (yield 82%). Ni(II) complexes of Schiff's bases derived from BPB and amino acids were prepared by an improved procedure involving the use of KOH as a base and MeOH as solvent (yield 90–91%).     

A stereoselective total synthesis of (−)-andrachcinidine via an olefin cross-metathesis protocol

A stereoselective total synthesis of 1-(2S,6R)-6-[(2S)-2-hydroxypentyl]-hexahydro-2-pyridinylacetone, (−)-andrachcinidine is reported. The strategy utilizes olefin cross-metathesis and intramolecular S_N2 cyclization as the key steps.     

Studies on the configuration of nitrogenous stereogenic centres in adducts of rhodium(II) tetraacylates with chiral amines: the application of 1H and 13C NMR spectroscopy

The ¹H and ¹³C NMR spectra of enantiomerically pure amines (S)-N,N-dimethyl-1-phenylethylamine, (S)-N-methyl-1-phenylethylamine, (S)-N-ethyl-1-phenylethylamine and (S)-N-ethyl-N-methyl-1-phenylethylamine in the presence of a twofold molar excess of dirhodium(II) tetratrifluoroacetate and dirhodium(II) Mosher’s acid derivatives [(4S) and (4R)] were measured in CDCl₃ as a solvent. The amines having various substituents at the nitrogen atom (H, CH₃ and CH₂CH₃) formed in such conditions as an equilibrium mixture of C_SN_R and C_SN_S 1:1 adducts. The signals of both diastereoisomers were observed in NMR spectra at either room temperature (303 K) or moderately decreased temperatures (263–273 K). The rates of mutual diastereoisomer conversion were estimated by selective inversion recovery experiments and varied from less than 0.1 to ca. 10 s^?1, depending on the ligand and temperature. Analysis of ¹³C NMR data and NOE experimental data resulted in the unambiguous determination of the configuration at the nitrogen atom with respect to the carbon stereogenic centre.Modelling of adduct structures and calculations of molecular energy and NMR parameters (GIAO) using Density Functional Theory (DFT) were performed in order to support the experimental findings. The calculations were carried out using 3-21G//B3LYP (structure optimizing) and 311G(2d,p)/LanL2DZ//B3LYP theory levels (molecular energy and NMR shielding).     

Synthesis of ACAT inhibitors through substitution using allylic picolinate and copper reagent

Amide of an octanoic acid possessing an aryl group at C3 position is a highly potent ACAT inhibitor. In this paper, we describe a synthetic access to this class of compounds as optically active forms. The key reaction is substitution of the allylic picolinate of (S,Z)-8-(benzyloxy)oct-5-en-4-ol with a copper reagent derived from (benzo[d][1,3]dioxol-4-yl)MgBr and CuBr·Me₂S to produce anti S_N2′ product regio- and stereo-selectively. The product was hydrogenated to afford (S)-3-benzo[d][1,3]dioxol-4-yloctan-1-ol, which upon oxidation furnished the octanoic acid. Finally, the acid was converted with 2,6-(i-Pr)₂C₆H₃NH₂ to the target amide via acid chloride. In a similar way, the one-carbon long homolog was synthesized.     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

Stereospecific ligands and their complexes. IV: Synthesis,characterization and cytotoxicity of novel platinum(IV) complexes with ethylenediamine-N,N′-di-S,S-2-propanoate and halogenido ligands: Crystal structure of s-cis-[Pt(S,S-eddp)Cl2]·4H2O and uns-cis-[Pt(S,S-eddp)Br2]

The syntheses of two novel platinum(IV) complexes of formula [PtX₂(S,S-eddp)]·nH₂O (S,S-eddp = ethylenediamine-N,N′-di-S,S-2-propanoate ion, X = chlorido (1) or bromido (2), n = 4, 0) are reported. The complexes have been obtained by direct reaction of corresponding potassium hexahalogenidoplatinate(IV) with neutralized ethylenediamine-N,N′-di-S,S-2-propanoic acid (H₂-S,S-eddp). The complexes were characterized by elemental analysis, infrared, ¹H and ¹³C NMR spectroscopy. The spectroscopically predicted geometrical configurations of the obtained complexes were confirmed by X-ray analyses of the crystal structures of the s-cis-[Pt(S,S-eddp)Cl₂]·4H₂O and uns-cis-[Pt(S,S-eddp)Br₂]. These complexes displayed significantly lower in vitro cytotoxicity in comparison to cisplatin.     

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.     

Determination of the absolute configuration of an unexpectedly stable N-silylated isomer isolated en route to the trinem antibiotic GV129606

The unexpected (3S,4R)-3-[(R)-1-(hydroxy)ethyl]-4-[(2′R,6′S)-1′-oxo-2′-(N-benzyloxy-N-methyl)aminocyclohexen-6′-yl]-1-(t-butyl-dimethylsilyl)azetidin-2-one was one of the main reaction products of the Lewis acid catalysed condensation of (3S,4R)-3-[(R)-1-(t-butyl-dimethylsilyloxy)ethyl]-4-acetoxyazetidin-2-one with 1-trimethylsilyloxy-6-(N-benzyloxycarbonyl-N-methylamino)cyclohexene. Its absolute configuration was established by NMR experiments on the corresponding, conformationally rigid, acetonide derivative.     

Asymmetric hydrogenation of (E)-α,β-bis(N-acylamino)acrylates catalyzed by a rhodium complex with trans-chelating chiral diphosphine ligand

The asymmetric hydrogenation of (E)-α,β-bis(N-acylamino)acrylates was promoted by a rhodium complex bearing a trans-chelating chiral diphosphine ligand (R,R)-(S,S)-PrTRAP, providing the corresponding optically active (2S,3R)-2,3-bis(N-acylamino)carboxylates with 79–82% ee. The 2,3-bis(N-acylamino)carboxylates isolated were readily hydrolyzed under acid to afford (2S,3R)-2,3-diaminocarboxylic acids in 95% yield without epimerization.