During the biosynthesis of certain tropane alkaloids, littorine ( 1 ) is rearranged to hyoscyamine ( 3 ). Recent evidence indicates that this isomerisation is a two‐step process in which the first step is an oxidation/rearrangement to give hyoscyamine aldehyde ( 2 ). This step is catalysed by CYP80F1, a cytochrome P450 enzyme, which was recently identified from the plant Hyoscyamus niger; CYP80F1 also catalyses the hydroxylation of littorine at the 3′‐position. The mechanisms of the reactions catalysed by CYP80F1 were probed with synthetic deutero and arylfluoro analogues of 1 . Measurement of the primary kinetic isotope effects indicates that C3′ hydrogen abstraction is the rate‐limiting step for the oxidation/rearrangement of natural littorine, and for the 3′‐hydroxylation reaction of the unnatural S enantiomer of littorine. The character of the intermediates in the oxidation/rearrangement and hydroxylation reaction was probed with the use of arylfluorinated analogues of (R)‐littorine (natural stereoisomer) and (S)‐littorine (unnatural stereoisomer) as substrates for CYP80F1. The relative conversions of ortho‐, meta‐ and para‐fluorolittorine analogues were used to obtain information on the likely intermediacy of either a benzylic radical or benzylic carbocation intermediate. The data suggest that hydroxylation takes place via a benzylic carbocation intermediate, whereas the product profile arising from rearrangement is more consistent with a benzylic radical intermediate.相似文献
A new copper‐catalyzed, efficient method for the synthesis of heterodiarylmethanes through the coupling of imidazo[1,2‐a]pyridines with indoles employing N,N‐dimethylformamide as a methylenating reagent has been developed. A library of 3‐(1H‐indol‐3‐ylmethyl)‐imidazo[1,2‐a]pyridine derivatives has been synthesized under aerobic reaction conditions. This protocol is also applicable for the synthesis of (4‐imidazo[1,2‐a]pyridin‐3‐ylmethyl)(phenyl)dimethylamines. The method is highly selective for the hetero‐coupling.
Two silver(I) complexes—{[Ag(4‐pmOpe)]NO3}n and [Ag(2‐bimOpe)2]NO3—and three copper(II) complexes—[Cu4Cl6O(2‐bimOpe)4], [CuCl2(4‐pmOpe)2], and [CuCl2(2‐bis(pm)Ope]—were synthesized by reaction of silver(I) nitrate or copper(II) chloride with phosphate derivatives of pyridine and benzimidazole, namely diethyl (pyridin‐4‐ylmethyl)phosphate (4‐pmOpe), 1H‐benzimidazol‐2‐ylmethyl diethyl phosphate (2‐bimOpe), and ethyl bis(pyridin‐2‐ylmethyl)phosphate (2‐bis(pm)Ope). These compounds were characterized by 1H, 13C, and 31P NMR as well as IR spectroscopy, elemental analysis, and ESIMS spectrometry. Additionally, molecular and crystal structures of {[Ag(4‐pmOpe)]NO3}n and [Cu4Cl6O(2‐bimOpe)4] were determined by single‐crystal X‐ray diffraction analysis. The antimicrobial profiles of synthesized complexes and free ligands against test organisms from the ATCC and clinical sources were determined. Silver(I) complexes showed good antimicrobial activities against Candida albicans strains (MIC values of ~19 μM ). [Ag(2‐bimOpe)2]NO3 was particularly active against Pseudomonas aeruginosa and methicillin‐resistant Staphylococcus epidermidis, with MIC values of ~5 and ~10 μM , respectively. Neither copper(II) complexes nor the free ligands inhibited the growth of test organisms at concentrations below 500 μg mL?1. 相似文献
Inhibition of drug efflux pumps such as P‐glycoprotein (P‐gp) is an approach toward combating multidrug resistance, which is a significant hurdle in current cancer treatments. To address this, N‐substituted aryloxymethyl pyrrolidines were designed and synthesized in their homochiral forms in order to investigate the stereochemical requirements for the binding site of P‐gp. Our study provides evidence that the chiral property of molecules could be a strategy for improving the capacity for interacting with P‐gp, as the most active compounds of the series stereoselectively modulated this efflux pump. The naphthalene‐1‐yl analogue (R)‐2‐[(2,3‐dichlorophenoxy)methyl]‐1‐(naphthalen‐1‐ylmethyl)pyrrolidine) [(R)‐ 7 a ] emerged foremost for its potency and stereoselectivity toward P‐gp, with the S enantiomer being nearly inactive. The modulation of P‐gp by (R)‐ 7 a involved consumption of ATP, thus demonstrating that the compound behaves as a P‐gp substrate. 相似文献
Sesquiterpene synthases catalyze with different catalytic fidelity the cyclization of farnesyl pyrophosphate (FPP) into hundreds of known compounds with diverse structures and stereochemistries. Two sesquiterpene synthases, Cop4 and Cop6, were previously isolated from Coprinus cinereus as part of a fungal genome survey. This study investigates the reaction mechanism and catalytic fidelity of the two enzymes. Cyclization of all‐trans‐FPP ((E,E)‐FPP) was compared to the cyclization of the cis–trans isomer of FPP ((Z,E)‐FPP) as a surrogate for the secondary cisoid neryl cation intermediate generated by sesquiterpene synthases, which are capable of isomerizing the C2? C3 π bond of all‐trans‐FPP. Cop6 is a “high‐fidelity” α‐cuprenene synthase that retains its fidelity under various conditions tested. Cop4 is a catalytically promiscuous enzyme that cyclizes (E,E)‐FPP into multiple products, including (?)‐germacrene D and cubebol. Changing the pH of the reaction drastically alters the fidelity of Cop4 and makes it a highly selective enzyme. Cyclization of (Z,E)‐FPP by Cop4 and Cop6 yields products that are very different from those obtained with (E,E)‐FPP. Conversion of (E,E)‐FPP proceeds via a (6R)‐β‐bisabolyl carbocation in the case of Cop6 and an (E,E)‐germacradienyl carbocation in the case of Cop4. However, (Z,E)‐FPP is cyclized via a (6S)‐β‐bisabolene carbocation by both enzymes. Structural modeling suggests that differences in the active site and the loop that covers the active site of the two enzymes might explain their different catalytic fidelities.相似文献
The synthesis of a resin‐supported, carbon dioxide‐protected N‐heterocyclic carbene (NHC) and its use in organocatalysis and organometallic catalysis are described. The resin‐bound carbon dioxide‐protected NHC‐based catalyst was prepared via ring‐opening metathesis copolymerization of 1,4,4a,5,8,8a‐hexahydro‐1,4,5,8‐exo,endo‐dimethanonaphthalene ( DMNH6 ) with 3‐(bicyclo[2.2.1]hept‐5‐en‐2‐ylmethyl)‐1‐(2‐propyl)‐3,4,5,6‐tetrahydropyrimidin‐1‐ium‐2‐carboxylate ( M1 ), using the well‐defined Schrock catalyst Mo[N‐2,6‐(2‐Pr)2‐C6H3](CHCMe2Ph)(OCMe3)2 and was used for a series of organocatalytic reactions, i.e., for the trimerization reaction of isocyanates, as well as for the cyanosilylation of carbonyl compounds. In the latter reaction, turn‐over numbers (TON) up to 5000 were achieved. In addition, the polymer‐supported, carbon dioxide‐protected N‐heterocyclic carbene served as an excellent progenitor for various polymer‐supported metal complexes. It was loaded with a series of rhodium(I), iridium(I), and palladium(II) precursors and the resulting Rh‐, Ir‐, and Pd‐loaded resins were successfully used in the polymerization of phenylacetylene, in the hydrogen transfer reaction to benzaldehyde, as well as in Heck‐type coupling reactions. In the latter reaction, TONs up to 100,000 were achieved. M1 , as a non‐supported analogue of poly‐M1‐b‐DMNH6 , as well as the complexes PdCl2[1,3‐bis(2‐Pr)tetrahydropyrimidin‐2‐ylidene]2 ( Pd‐1 ) and IrBr[1‐(norborn‐5‐ene‐2‐ylmethyl)‐3‐(2‐Pr)‐3,4,5,6‐tetrahydropyrimidin‐2‐ylidine](COD) ( Ir‐1 ) were used as homogeneous analogues and their reactivity in the above‐mentioned reactions was compared with that of the supported catalytic systems. In all reactions investigated, the TONs achieved with the supported systems were very similar to the ones obtained with the unsupported, homogeneous ones, the turn‐over frequencies (TOFs), however, were lower by up to a factor of three. 相似文献
The ONN‐tridentate unsymmetrical pincer 2‐[6‐(pyrrolidin‐1‐ylmethyl)pyridin‐2‐yl]phenol and N‐tert‐butyl‐1‐{[6‐(2‐hydroxyphenyl)pyridin‐2‐yl]methyl}pyrrolidine‐2‐carboxamide ligands were synthesized by an easy method in high purity and good yields. All the organic compounds were characterized by elemental analysis, mass spectrometry, IR and 1H and 13C NMR spectroscopy. Palladium(II) and gold(III) complexes have been prepared as air‐stable solids, with the ONN‐tridentate ligand after deprotonation of the hydroxy group, the coordination of the metal ion is completely stereospecific and gives rise to only one diastereoisomer. These complexes were shown to be very active catalysts in the hydrogenation (80 % ee was achieved with the chiral gold complex), hydrosilylation and C C coupling, Suzuki and Heck, reactions, under mild conditions. 相似文献