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.     

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.     

P-stereogenic wide bite angle diphosphine ligands

Two modular synthetic approaches for the preparation of novel wide bite angle diphosphine ligands containing stereogenic P-atoms have been developed, leading to compounds (S,S)-2,2′-bis(methylphenylphosphino)diphenyl ether (L1) and (S,S)-2,2′-bis(ferrocenylphenylphosphino)diphenyl ether (L2) in very good diastereomeric ratios. Both protocols involve diphenyl ether as backbone and (2R_P,4S_C,5R_C)-(+)-3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine borane (R_P)-5 as initial auxiliary to induce chirality at phosphorus. The absolute configuration of intermediates (S,S)-9-(BH₃)₂ and (R,R)-10-(BH₃)₂ as well as the ligands (S,S)-L1-BH3 and (S,S)-L2 was determined by X-ray crystallographic analysis.     

Stereoselective synthesis of 3-deoxy-piperidine iminosugars from l-lysine

A new method using electrochemical oxidation and/or OsO₄ oxidation has been used for the stereoselective synthesis of 2,3,6-trihydroxylated (5S)-piperidine derivatives. The electrochemical method was successively used for the conversion of N-protected piperidines to N-protected 1-methoxypiperidines and for the conversion of 2,3-didehydro-1-methoxypiperidine derivatives to 2,3-trans-1,2,3-triacetoxypiperidine derivatives. These triacetates were easily transformed into (2S,3S)-6-triacetoxy-(5S)-methylpiperidine and (2R,3R)-6-triacetoxy-(5S)-methylpiperidine. In addition, the 2,3-cis-dihydroxylation of 2,3-didehydro-1-methoxypiperidine derivatives with OsO₄ afforded (2R,3S)-6-triacetoxy-(5S)-methylpiperidine and (2S,3R)-6-triacetoxy-(5S)-methylpiperidine.     

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.     

Asymmetric synthesis of 2-alkyl-4-hydroxycyclohex-2-en-1-ones by scandium(III) triflate-catalyzed fragmentation of 2-alkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones

Fragmentation of (2S,3S,4S)-2-allyl-3-iodo-1-oxocyclohexan-2,4-carbolactone to (4S)-2-allyl-4-hydroxycyclohex-2-en-1-one, a chiral building block of (−)-platensimycin, proceeded efficiently by using scandium(III) triflate in DMF-H₂O (1:3) at 100 °C.     

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.     

New efficient ruthenium catalysts for racemization of alcohols at room temperature

(η⁵-Pentaphenylcyclopentadienyl)RuCl(CO)₂ was found to catalyze efficiently the racemization of chiral alcohols such as (S)-1-phenylethanol, (S)-1-phenylpropan-2-ol, (S)-4-phenylbutan-2-ol and (S)-4-methoxy-1-phenylethanol at room temperature in the presence of a base. The catalytic activity of three other Ru(II) complexes was also investigated. The effects of halide and solvent were studied as well.     

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.     

Stereoselective synthesis,solution structure and metal complexes of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids

The highly stereoselective synthesis of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids was achieved by addition of dimethyl phosphite to N-protected aminoaldehydes. Relative configuration and solution conformations of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids (in D₂O) and their dimethyl esters (in CDCl₃ and CD₃OD) were established by means of NMR basing on the dependence between observed values of coupling constants (³J_HH, ³J_PC, ³J_HP) and corresponding dihedral angles. Potentiometric and spectroscopic methods were used for the evaluation of the structure of the complexes of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids with Zn(II) and Cu(II) ions in aqueous solutions.     

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.     

Synthesis of (+)-1,3,5,7 -tetrakis[2-(1S,3S,5R,6S,8R,10R)-D3-trishomocubanylbuta-1,3-diynyl]adamantane : The first optically active organic molecule with t symmetry and of known absolute configuration

(-)-(1S,3S,5R,6S,8R,10R)-Trishomocubanethanoic acid (5) of known absolute configuration and absolute rotation was converted into (+)-(1S,3S,5S,6S,8R,10R)-2-bromoethynyl-D₃-trishomocubane (27) of C₃ symmetry. 1,3,5,7-Tetraethynyladamantane (22), with Td symmetry, was prepared from 1,3,5,7-tetrakis(hydroxymethyl)adamantane(13). Coupling of the C₃-component 27 with the Td component 22 was successfully accomplished by Chodkiewicz and Cadiot's procedure providing (+)-1,3,5,7-tetrakis[2-(1S,3S,5R,6S,8R,10R)-D₃-trishomocubanylbuta-1,3-diynyl]adamantane(4) whose highest attainable static and time-averaged dynamic symmetry are T and (C₃)⁴ XXX T,respectively.     

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.     

Stereoselective synthesis of fluorine-containing analogues of anti-bacterial sanfetrinem and LK-157

The synthesis of (1′S,3R,4R)-4-acetoxy-3-(1′-trimethylsilyloxy-2′,2′,2′-trifluoroethyl)-2-azetidinone (10) precursor of modified carbapenems is described relying upon [Ru(C₆Me₆)(S,S)-(CH₂)₅NSO₂DPEN]-catalyzed asymmetric transfer hydrogenation under dynamic kinetic resolution using HCO₂H-Et₃N. This fluorine-containing precursor yielded the targeted trinems 1 and 2 via a stereoselective key step condensation with lithium (S)-6-methoxy-cyclohexenolate.     

Synthesis of modified H4-BINOL ligands and their applications in the asymmetric addition of diethylzinc to aromatic aldehydes

Two new ligands (S,S)-3-(1,1′-bi-2-naphthol-3-yl)-5,6,7,8-tetrahydro-1,1′-bi-2-naphthol [(S,S)-1] and (S)-3-(morpholin-4-ylmethyl)-H₄-BINOL [(S)-2] have been synthesized via Suzuki cross-coupling reaction and a Mannich-type reaction, respectively. In the presence of titanium tetraisopropoxide, 0.8 mol % of ligand (S,S)-1 catalyzed the asymmetric addition of diethylzinc to aromatic aldehydes in good yield and with high enantioselectivity.     

Asymmetric reduction of 2-bromo-1-phenylethylidenemalononitrile with chiral NAD(P)H models

Reduction of 2-bromo-1-phenylethylidenemalononitrile 1 with the chiral NAD(P)H model (S_S)-1-benzyl-3-(p-tolylsulfinyl)-1,4-dihydropyridine 2 gives the cyclopropane ring product (S)-2-phenylcyclopropane-1,1-dicarbonitrile 3 with 54.5% enantiomeric purity.     

Ring opening of chiral 2-(1-aminoalkyl)epoxides by aliphatic thiols with total selectivity: synthesis of enantiopure 3-amino-1-(alkylthio)alkan-2-ols

We have studied the thiolysis of (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides 1 or 2 in the presence of BF₃·OEt₂. The ring opening took place at C-3 with complete regioselectivity, affording the corresponding enantiopure (2R,3S)- or (2S,3S)-3-amino-1-(alkylthio)alkan-2-ols 3 or 4 in good or high yield. The structures of compounds 3 and 4 have been proposed based on HMBC NMR experiments.     

First asymmetric synthesis of pyrrolizidine alkaloids, (+)-hyacinthacine B1 and (+)-B2

An enantiomerically and diastereomerically pure route has been developed for the first asymmetric synthesis of (1S,2R,3R,5R,7aR)- and (1S,2R,3R,5S,7aR)-1,2-dihydroxy-3,5-dihydroxymethylpyrrolizidine, hyacinthacine B₁ and B₂, featuring efficient and stereodefined elaboration via the asymmetric dihydroxylation (AD) of the functionalized homochiral pyrrolidine derivative prepared from (S)-(−)-2-pyrrolidone-5-carboxylic acid.     

Fluorescence signaling of aromatic oxoanion inclusion within metal-ion activated molecular receptor complexes formed from 2-(9-anthracenylmethylamino)ethyl-appended cyclen

Our observations that 1-[2-[(9-anthracenylmethylamino)ethyl)-4,7,10-tris[(2S)-2-hydroxy-3-phenoxypropyl]-1,4,7,10-tetraazacyclododecane, L¹, complexes Cd(II) to form fluorescent [CdL¹]²⁺ which undergoes a fluorescence change when it acts as an aromatic anion receptor complex has caused us to explore further the potential development of an interesting sequestration/sensor system. Accordingly, three new, octadentate, fluorescent, macrocyclic ligands, 1-[2-[(9-anthracenylmethyl)((2S)-2-hydroxy-3-phenoxypropyl)amino]ethyl]-4,7,10-tris[(2S)-2-hydroxy-3-phenoxypropyl]-1,4,7,10-tetraazacyclododecane, (L²), 1-[2-[(9-anthracenyl-methyl)((2S)-2-hydroxy-3-(4??-methyl)phenoxypropyl)amino]ethyl]-4,7,10-tris[(2S)-2-hydroxy-3-(4??-methyl)phenoxypropyl]-1,4,7,10-tetraazacyclododecane, (L³), and 1-[2-[(9-anthracenylmethyl)((2S)-2-hydroxy-3-(4??-t-butyl)phenoxypropyl)amino]ethyl]-4,7,10-tris[(2S)-2-hydroxy-3-(4??-t-butyl)phenoxypropyl]-1,4,7,10-tetraazacyclododecane, (L⁴), have been prepared with a view to using their metal complexes to study aromatic anion sequestration. The eight-coordinate Cd(II) complexes of L² and L³, [CdL²](ClO₄)₂·5H₂O and [CdL³](ClO₄)₂·2H₂O·2Et₂O are both capable of acting as receptors for a range of aromatic oxoanions. This is demonstrated by perturbation of the anthracene derived fluorescence emission intensity as the guest aromatic oxoanion and the receptor complex combine. In 20% aqueous 1,4-dioxane the receptor complex/aromatic oxoanion association constants are in the range of 10^3.2 M^?1 (guest = p-hydroxybenzoate) to 10^7.3 M^?1 (guest = 3,4,5-trihydroxybenzoate).     

Synthesis, properties and complexation of (pS)-1-isocyano-2-methylferrocene, the first planar-chiral isocyanide ligand

Reaction of enantiomerically pure, planar-chiral (_pS)-1-bromo-2-methylferrocene (1) with phthalimide in the presence of Cu₂O produces (_pS)-1-phthalimido-2-methylferrocene (2), quantitative reduction of which with hydrazine hydrate affords (_pS)-1-amino-2-methylferrocene (3) with >99% ee. Formylation of amine 3 followed by dehydration of the resulting (_pS)-1-formamido-2-methylferrocene (4) provides (_pS)-1-isocyano-2-methylferrocene (5), the first example of a planar-chiral isocyanide ligand, in a good yield. Isocyanide 5 reacts with PdI₂ to give the crystallographically characterized chiral complex trans-[PdI₂{(_pS)-1-isocyano-2-methylferrocene}₂] (6). The redox behavior of 4, 5, and 6, accessed by cyclic voltammetry, is discussed.