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.     

An efficient approach to 2-substituted N-tosylpiperdines: asymmetric synthesis of 2-(2-hydroxy substituted)piperidine alkaloids

We have developed an efficient and a general approach to chiral 2-substituted N-tosylpiperidines starting from chiral α-substituted-N-tosylaziridines. Using this approach, we have synthesized (+)-coniine. The synthesis of chiral N-tosyl-2-piperidinylethanol 15 and ent-15, was achieved from l- and d-aspartic acids, respectively in few steps. Piperidine 15 was converted into 2-(2-hydroxysubstituted)piperidines of type 2 in optically active form. By applying this strategy, asymmetric syntheses of halosaline (R,R)-2a, (+)- and (−)-sedamine 2b, (+)- and (−)-allosedamine 2c, (+)- and (−)-sedridine 2d, (+)- and (−)-allosedridine 2e, (+)-tetraponerine T-3 3a, T-4 3c, T-7 3b, and T-8 3d have been achieved in high yields. These stereoisomers can be interconverted via Mitsunobu inversion in excellent yields.     

Synthesis, structure, and catalytic activity of titanium complexes with new chiral 11,12-diamino-9,10-dihydro-9,10-ethanoanthracene-based ligands

A new series of organo-titanium complexes have been prepared from the reaction between Ti(NMe₂)₄ and C₂-symmetric ligands, (R,R)-11,12-bis(pyrrol-2-ylmethyleneamino)-9,10-dihydro-9,10-ethanoanthracene (1H₂), and (R,R)-bis(diphenylthiophosphoramino)-9,10-dihydro-9,10-ethanoanthracene (2H₂), (R,R)-11,12-bis(mesitylenesulphonylamino)-9,10-dihydro-9,10-ethanoanthracene (3H₂) and (R,R)-bis(diphenylthiophosphoramino)-1,2-cyclohexane (4H₂). Treatment of Ti(NMe₂)₄ with 1 equiv of 1H₂ gives, after recrystallization from a benzene solution, the binuclear double helicate titanium amide (1)₂[Ti(NMe₂)₂]₂⋅(5) in 71% yield. While under similar reaction conditions, reaction of Ti(NMe₂)₄ with 1 equiv of 2H₂, 3H₂ or 4H₂ gives, after recrystallization from a toluene or benzene solution, the mononuclear single helicate titanium amides (2)Ti(NMe₂)₂ (6), (3)Ti(NMe₂)₂ (7) and (4)Ti(NMe₂)₂ (8), respectively, in good yields. All new compounds have been characterized by various spectroscopic techniques, and elemental analyses. The solid-state structures of complexes 5-8 have further been confirmed by X-ray diffraction analyses. The titanium amides are active catalysts for the polymerization of rac-lactide, leading to the isotactic-rich polylactides.     

Autoxidation of isotachysterol

Isotachysterol, the acid-catalyzed isomerization product of vitamin D₃, produces seven previously unknown oxygenation products in a self-initiated autoxidation reaction under atmospheric oxygen in the dark at ambient temperature. They are (5R)-5,10-epoxy-9,10-secocholesta-6,8(14)-dien-3β-ol (6a), (5S)-5,10-epoxy-9,10-secocholesta-6,8(14)-dien-3β-ol (6b), (10R)-9,10-secocholesta-5,7,14-trien-3β,10-diol (7a), (10S)-9,10-secocholesta-5,7,14-trien-3β,10-diol (7b), (7R,10R)-7,10-epoxy-9,10-secocholesta-5,8(14)-dien-3β-ol (8), 5,10-epidioxyisotachysterol (9) and 3,10-epoxy-5-oxo-5,10-seco-9,10-secocholesta-6,8(14)-dien-10-ol (10). The formation of these products is explained in terms of free radical peroxidation chemistry.     

An expedient approach to tetrahydrofuro[3,2-b]pyridine-2(3H)-ones via activation of pyridine N-oxide by triflic anhydride

The double addition of bis(trimethylsilyl) ketene acetals [R₁, R₂ = CH₃, -(CH₂)₅-] to pyridine N-oxide promoted by triflic anhydride under mild conditions generates N-[(trifluoromethane)sulfonyl-1,2-dihydropyridine-2,4-dicarboxylic acids 2a-b. Subsequent reaction of these acids upon iodolactonization conditions affords tetrahydrofuro[3,2-b]pyridine-2(3H)-ones 3a-b containing an exo-insaturation on the products as a result of an unexpected decarboxylation.     

Bargellini condensation of coumarins. Expeditious route to o-carboxyvinylphenoxyisobutyric acids and application to the synthesis of sesquiterpenes helianane, heliannuol A and heliannuol C

The direct Bargellini condensation of coumarins involving reaction with chloroform and acetone in the presence of aqueous sodium hydroxide furnished o-carboxyvinylphenoxyisobutyric acids in good yields. The utility of this new useful protocol was demonstrated by the transformation of the three diesters 9b, 9f and 9g to the sesquiterpenes helianane 4, heliannuol A 2 and heliannuol C 3, respectively.     

Asymmetric allylation of N-benzoylhydrazones promoted by novel C2-symmetric bis-sulfoxide organocatalysts

Novel C₂-symmetric bis-sulfoxide/N-oxide (R,R)-5 was prepared in good yield according to the Andersen protocol with (S)-menthyl p-tolyl sulfinate (2 equiv) and the dilithium derivate of 2,6-dimethylpyridine N-oxide. Reduction of (R,R)-5 to pyridine/bis-sulfoxide (R,R)-6 was accomplished by means of Katritzky’s procedure (Fe⁰/AcOH). Both bis-sulfoxides (R,R)-5 and (R,R)-6 are efficient chiral organocatalysts in the asymmetric allylation of N-benzoyl hydrazones derived from both aldehydes and ketones.     

Simple entry into isonucleosides: synthesis of 6-amino-9-[(3S,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl]purine

A simple and efficient method for the preparation of isonucleoside 7 is described. The preparation of 1,4-anhydroxylitol 4, a key intermediate, is described by intramolecular cyclization of (2S,3R,4R)-3,5-dibenzyloxypentan-1,2,4-triol 3 using diethyl carbonate and NaH.     

Synthesis of 12-aza analogs of epothilones and (E)-9,10-dehydroepothilones

N-Boc-12-aza-epothilone analog (azathilone) 1 is a potent inhibitor of human cancer cell growth and represents a structurally new class of natural product-derived microtubule-stabilizing agents. Compound 1 has been prepared employing a convergent strategy that is based on the consecutive assembly of building blocks 3, 4, and 19 into diene 20 and subsequent RCM-mediated macrocycle formation. The aldol reaction between aldehyde 3 and ketone 4 delivered the required 6R,7S diastereoisomer 5 with good selectivity and provided a reliable entry into the stereoselective synthesis of carboxylic acid 12. RCM with diene 20 was highly E-selective, thus giving efficient access to (E)-9,10-dehydro-1 (2). The latter is a key analog in SAR studies with 1.     

Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-d-ribonamide 10a. Methanolysis of 10a, with sodium methoxide, afforded the N-ethyl-d-ribonolactam 11a in 51% overall yields. Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-d-ribonolactams 11b-e were obtained in good yields (48-53%).     

Study on the reactions of fluoroalkanesulfonyl azides with N-alkylindoles

The reactions of fluoroalkanesulfonyl azides R_fSO₂N₃1 with N-alkylindoles 2 have been studied in detail. It was found that both solvent and the amount of the azides seriously affected the product distribution. 1 reacted with an equimolar amount of 2 in ether or 1,4-dioxane affording 2-(N-substituted-indolinylidene)fluoroalkane sulfonylimines 3 as major product; While, the treatment of 2 with two equivalent of 1 in ethanol afforded N-substituted-2-fluoroalkanesulfonimino-3-diazo-indolines 4 as an unexpected product in good yields. The reaction mechanism was discussed.     

Synthesis of (−)-lentiginosine, its 8a-epimer and dihydroxylated pyrrolizidine alkaloid from d-glucose

The d-glucose derived α,β-unsaturated ester 5 on 1,2-acetonide deprotection, oxidative diol cleavage followed by treatment with N-benzylamine in the presence of NaBH₃CN undergoes reductive amination and a concomitant intramolecular conjugate addition reaction leading to the formation of dihydroxypyrrolidine-ester 6a and monohydroxypyrrolidine-γ-lactone 6b. Intermediates 6a and 6b were efficiently converted to (−)-lentiginosine 3a, its 8a-epimer 3b, and pyrrolizidine azasugar 4 in good overall yield.     

Salen-ligands based on a planar-chiral hydroxyferrocene moiety: Synthesis, coordination chemistry and use in asymmetric silylcyanation

Condensation of the O-protected hydroxyferrocene carbaldehyde (S_p)-1 with suitable diamines, followed by liberation of the hydroxyferrocene moiety leads to a new type of ferrocene-based salen ligands (3). While the use of ethylenediamine in the condensation reaction yields the planar-chiral ethylene-bridged ligand [(S_p,S_p)-3a], reaction with the enantiomers of trans-1,2-cyclohexylendiamine gives rise to the corresponding diastereomeric cyclohexylene-bridged systems [(S,S,S_p,S_p)-3b and (R,R,S_p,S_p)-3c], which feature a combination of a planar-chiral ferrocene unit with a centrochiral diamine backbone. Starting with the ferrocene-aldehyde derivative (R_p)-1, the enantiomeric ligand series (3d/e/f) is accessible via the same synthetic route.The (S_p)-series of these newly developed N₂O₂-type ligands was used for the construction of the corresponding mononuclear bis(isopropoxy)titanium (4a/b/c), methylaluminum (5a/b/c) and chloroaluminum-complexes (6a/b/c), which were isolated in good yields and identified by X-ray diffraction in several cases. The aluminum complexes (5/6) were successfully used in the Lewis-acid catalyzed addition of trimethylsilylcyanide to benzaldehyde, yielding the corresponding cyanohydrins in 45-62% enantiomeric excess.     

Palladium complexes of N-aryl-2-pyridylamines

Palladium complexes of N-phenyl-2-pyridylamine (4) and dipyridylamine substrates (7, 11) have been studied. Due to the coordination ability of the pyridine-nitrogen atoms, the pyridyl substrates, 4, 7, 11 were subjected to Pd(OAc)₂ complexations and a number of N-aryl-2-pyridylamine Pd complexes (13-17) were isolated and characterised, in particular by NMR and ESI-MS. A new method for the preparation of the acetato-bridged six-membered ring palladacycle complex (13) of 4 is reported. The dipyridyl amines 7, 11 formed cis/trans bis-dentate acetato-bridged dimeric Pd₂Lig₂(OAc)₂ (14a,b/16a,b) and Pd₃Lig₂(OAc)₄ complexes (15a,b/17a,b). The N-aryl-2-pyridylamine substrates (4, 7, 11) were prepared by oxidative nucleophilic substitution, by 1,3-cycloaddition reaction or by Buchwald amination.     

Synthesis and decarboxylation of N-acyl-α-triphenylphosphonio-α-amino acids: a new synthesis of α-(N-acylamino)alkyltriphenylphosphonium salts

4-Phosphoranylidene-5(4H)-oxazolones 1 undergo hydrolysis in THF in the presence of HBF₄ at room temperature to give N-acyl-α-triphenylphosphonioglycines 3 (R² = H) in very good yields. 4-Alkyl-4-triphenylphosphonio-5(4H)-oxazolones 2 react with water in CH₂Cl₂/THF solution without any acidic catalyst at 0-5 °C in a few days yielding N-acyl-α-triphenylphosphonio-α-amino acids 3 (R² = Me) or α-(N-acylamino)alkyltriphenylphosphonium salt 4 (R² = CH₂OMe). α-Triphenylphosphonio-α-amino acids 3, on heating up to 105-115 °C under reduced pressure (5 mmHg) or on treatment with diisopropylethylamine in CH₂Cl₂ at 20 °C undergo decarboxylation to give the corresponding α-(N-acylamino)alkyltriphenylphosphonium salts 4, usually in very good yields.     

A new approach to cyclic hydroxamic acids: Intramolecular cyclization of N-benzyloxy carbamates with carbon nucleophiles

N-Alkyl-N-benzyloxy carbamates, 2, undergo facile intramolecular cyclization with a variety of carbon nucleophiles to give functionalized five- and six-membered protected cyclic hydroxamic acids, 3, in good to excellent yields. This method can be extended to prepare seven-membered cyclic hydroxamic acids in moderate yields. The sulfone intermediates 3 from this study can be alkylated while the corresponding phosphonates have been shown to undergo HWE reaction. The α,β-unsaturated synthon, 8, prepared by thermal elimination of sulfoxide 3m, undergoes Michael addition with secondary amines. The usefulness of this approach to prepare polydentate chelators has been demonstrated by the synthesis of bis cyclic hydroxamic acids 12, 14, and 15.     

Synthesis and X-ray structures of new chiral Ag(I) complexes with biaryl-based N4-donor ligands

Condensation of (R)-2,2′-diamino-1,1′-binaphthyl or (R)-6,6′-dimethylbiphenyl-2,2′-diamine with 2 equiv of 2-pyridine carboxaldehyde in toluene in the presence of molecular sieves at 70 °C gives (R)-N,N′-bis(pyridin-2-ylmethylene)-1,1′-binaphthyl-2,2′-diimine (1), and (R)-N,N′-bis(pyridin-2-ylmethylene)-6,6′-dimethylbiphenyl-2,2′-diimine (3), respectively, in good yields. Reduction of 1 with an excess of NaBH₄ in a solvent mixture of MeOH and toluene (1:1) at 50 °C gives (R)-N,N′-bis(pyridin-2-ylmethyl)-1,1′-binaphthyl-2,2′-diamine (2) in 95% yield. Rigidity plays an important role in the formation of helicate silver(I) complexes. Treatment of 1, or 3 with 1 equiv of AgNO₃ in mixed solvents of MeOH and CH₂Cl₂ (1:4) gives the chiral, dinuclear double helicate Ag(I) complexes [Ag₂(1)₂][NO₃]₂ (4) and [Ag₂(3)₂][NO₃]₂ · 2H₂O (6), respectively, in good yields. While under the similar reaction conditions, reaction of 2 with 1 equiv of AgNO₃ affords the chiral, mononuclear single helicate Ag(I) complex [Ag(2)][NO₃] (5) in 90% yield. [Ag₂(1)₂][NO₃]₂ (4) can further react with excess AgNO₃ to give [Ag₂(1)₂]₃[NO₃]₂[Ag(CH₃OH)(NO₃)₃]₂ · 2CH₃OH (7) in 75% yield. All compounds have been fully characterized by various spectroscopic techniques and elemental analyses. Compounds 1 and 5-7 have been further subjected to single-crystal X-ray diffraction analyses.     

Reaction of 1,2-dibromoethane with primary amines: formation of N,N′-disubstituted ethylenediamines RNH-CH2CH2-NHR and homologous polyamines RNH-[CH2CH2NR]n-H

The reaction of primary amines RNH₂ (R: Me, Et, iPr, tBu and Ph) with 1,2-dibromoethane gave N,N′-disubstituted ethylenediamines R-NH-CH₂CH₂-NH-R (1) in yields ranging from 10% (1a; R=Me) to 70% (1d, R=tBu; 1e, R=Ph). Piperazines and N-substituted polyethyleneimines were identified (¹H NMR, ¹³C NMR and EI-MS) as side products of the reaction and isolated by fractional distillation. The piperazines 2 are formed in yields of 3-10% and can be separated from the diamines 1 in all cases, except for R=Me and Ph. The polyamine homologues RNH-[CH₂CH₂NR]_n-H (3-5) were isolated in yields ranging from 0.1% (n=4, R=iPr) to 14% (n=2, R=iPr). The yields of 1 increase with the size of the substituent R, no obvious trend exists for the yields of the side products.     

Synthesis of some new tertiary amines and their application as co-catalysts in combination with l-proline in enantioselective Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone

A chiral benzodiazepine derivative 1 was synthesized starting from o-nitrobenzoyl chloride and methyl l-prolinate hydrochloride. Diastereomeric (1R,2R,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3a and (1S,2S,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3b were synthesized starting from (S)-α-phenylethylamine and cyclohexene oxide via ring-opening, diastereomer separation and N-methylation. (S,S)-octahydrodipyrrolo[1,2-a:1′,2′-d]pyrazin 5 was synthesized from methyl l-prolinate. Chiral tertiary amines 1, 3a, 3b and 5 almost cannot catalyze the Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone (MVK). However, they functioned as efficient catalysts for this reaction in the presence of l-proline. The corresponding adducts were obtained in good yields with enantioselectivity of 83% ee, 81% ee, 51% ee and 66% ee, respectively.     

Regio- and stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to methyl methacrylate

[3+2] Cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides 1a-e to methyl methacrylate gave the 1-CO₂Me regioisomers 3/3′, exclusively, in 1-67% yields. Stereocontrol was dependent on the ortho-substituents at the 1′-aryl group in dipole 1: ortho-unsubstituted dipoles 1a-c gave the major (1R^∗,3R^∗,5R^∗,6R^∗)-isomers 3a-c, whilst ortho-disubstituted dipoles gave the major (1R^∗,3S^∗,5R^∗,6R^∗)-isomers 3′d,e. The structures of cycloadducts were determined by NMR and X-ray diffraction.