Analysis of MS/MS fragmentation of taxoids

The fragmentation pathways of seven types of taxoids were investigated by using a LC-MS/MS method, namely: (1) neutral taxoids with a C-4(20) double bond; (2) taxoids with a C-4(20) double bond and oxygenation at C-14; (3) 5-cinnamoyl taxoids with a C-4(20) double bond; (4) a basic taxoid with a C-4(20) double bond; (5) a taxoid with a C-4(20) epoxide; (6) taxoids with an oxetane ring; and (7) taxoids with an oxetane ring and a phenylisoserine C-13 side chain. Depending on the class of core structure and the substitution pattern, each taxoid gave either the molecular adduct ion [M+NH4]+ or [M+H]+. In the MS/MS, the molecular adduct ion gave characteristic product ions corresponding to the loss of water, acetic acid, benzoic acid, and cinnamic acid or the phenylisoserine group. These could reflect the difference of the substitutions and structural modifications and should be utilized for the structure elucidation oftaxoids by LC-MS.     

Synthesis of novel taxoid analogue containing sulfur group on C-13 side-chain: 2′-deoxy-2′-epi-mercaptopaclitaxel

Paclitaxel analogues with a thiol group in place of the hydroxyl group on the C-13 side-chain constitute an interesting avenue of research for the study of new taxoid compounds. A synthetic route for the preparation of 2′-deoxy-2′-epi-mercaptopaclitaxel with high ee has been developed. The key step is the regio-controlled ring-opening reaction of the trans-oxazoline derivative with thiolacetic acid, which allows the introduction of the sulfur-containing group onto the side-chain.     

Regio- and stereoselective methods for the conversion of (2S,3R)-β-phenylglycidic acid esters to taxoids and other enantiopure (2R,3S)-phenylisoserine esters

A novel efficient method was proposed for the synthesis of enantiopure precursors of taxane-containing cytostatics, i.e., methyl esters of (2R,3S)- and (2S,3R)-N-benzoylphenylisoserine and similar taxoid esters. The method is based on the regio- and stereoselective hydrobromolysis of the corresponding trans-β-phenyl glycidate enatiomers, consecutive reactions of O-acylcarbamoylation of the obtained 3-bromohydrins, intramolecular cyclization to 4-phenyloxazolidin-2-one-5-carboxylic acid derivatives, and oxazolidinone ring opening.     

Synthesis of functionalized CF3-containing heterocycles via [2,3]-sigmatropic rearrangement and sequential catalytic carbocyclization

A new efficient access to functionalized CF₃-substituted and nitrogen or sulfur-containing heterocycles has been developed directly from diazocompounds CF₃C(N₂)Z (Z=CO₂Me, P(O)(OEt)₂). The method is based on the direct selective synthesis of doubly unsaturated substrates followed by metal-mediated carbocylization. The first step has been performed by Cu(II)-catalyzed [2,3]-sigmatropic rearrangement of propargyl- or/and allyl-containing sulfur and nitrogen ylides leading to fluorinated enynes, diolefins, and especially allenynes derivatives. The second step involves their carbocyclization via ring closing metathesis and Pauson-Khand reaction.     

A facile,catalyst-free synthesis of new polycyclic pyrrolo[1,2-b]pyrazolone derivatives

A convenient and efficient procedure has been developed for the synthesis of a new ring system, pyrrolo[1,2-b]pyrazolone, via two-component coupling reaction followed by base mediated intramolecular cyclization. Single-pot synthesis replacing the two step process has also been successfully carried out. A series of polycyclic pyrrolo[1,2-b]pyrazolone derivatives have been obtained by employing the procedure along with some fused pyrrol-1-ylamine system. The products were formed very rapidly in catalyst free condition in a good yield (up to 75%) and also it had tolerance to a wide scope of substrates.     

Taxol biosynthesis: Molecular cloning and characterization of a cytochrome P450 taxoid 7 beta-hydroxylase

Biosynthesis of the anticancer drug Taxol in yew species involves eight cytochrome P450-mediated oxygenations and four coenzyme A-dependent acylations of the diterpenoid core. A family of cytochrome P450 genes, obtained from a yew cell cDNA library, were functionally expressed and screened with taxusin (taxa-4(20),11(12)-dien-5 alpha,9 alpha,10 beta,13 alpha-tetraol tetraacetate) as a surrogate substrate. One clone converted this substrate to an oxygenated derivative that was identified as 7 beta-hydroxytaxusin. The structure and properties of this 7 beta-hydroxylase are similar to those of other taxoid hydroxylases. Kinetic and binding assays indicated selectivity of the 7 beta-hydroxylase for polyoxygenated and acylated taxoid substrates, an observation consistent with the operation of this enzyme in the central portion of the Taxol biosynthetic pathway. Although the 7 beta-hydroxyl of Taxol is not essential for antimitotic activity, this functional group provides a convenient means for preparing taxoid derivatives.     

The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide

The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues.     

Application of the Pictet-Spengler reaction to aryl amine substrates linked to deactivated aromatic heterosystems

Three new substrates with an aryl amine moiety attached to quinoxalines, triazoles and tetrazoles either via C or N have been used for the Pictet-Spengler reaction. The substrates have been designed by applying the concept of ‘aryl amine attached to a deactivated heteroaromatic ring’ in a manner to facilitate endo cyclization. This is in contrast to the substrates used traditionally and reported earlier by us that are based on either aliphatic or aryl amine, respectively, attached to an activated heterocyclic ring. The Pictet-Spengler condensation of the three substrates with aldehydes led to the synthesis of novel N-rich polyheterocyclic system hitherto not reported. Our modified strategy opens up possibilities to design novel substrates with aryl amines linked via C or N to either deactivated or activated heterocyclic privileged structure, which in turn can be used for the synthesis of novel fused polyheterocyclic skeletons.     

A facile synthesis of (Z)-1, 6-disubstituted-7H-benzo[b][1,5]diazonin-7-one derivatives via arylation-allylation-RCM pathway of anthranilamide and isatoic anhydride

A facile and efficient method has been developed for the synthesis of (Z)-6-allyl-1-phenyl-1,2,5,6-tetrahydro-7H-benzo[b][1,5]diazonin-7-one and (Z)-1,6-diphenyl-1,2,5,6-tetrahydro-7H-benzo[b][1,5]diazonin-7-one from anthranilamide via N-arylation/N-allylation and from isatoic anhydride via ring opening/N-arylation/N-allylation followed by ring closing metathesis using Grubbs-II catalyst as a key step. Grubbs-II catalyst was found to be superior over Grubbs-I catalyst in terms of reaction time and yield of the product, and the routes developed were suitable to synthesize benzo fused nine membered nitrogen heterocycles. The requirement of diallylated substrates with protected amine and amide nitrogen is suitable for RCM has been established for the synthesis of diazoninone derivatives.     

Imidazopyridine and pyrimidinopyridine systems from perfluorinated pyridine derivatives

Annelation of pentafluoropyridine via an intramolecular nucleophilic aromatic substitution process with benzamidine gave an imidazopyridine system in high yield in a two step process whilst alkyl amidines gave 4-aminotetrafluoropyridine by a competing elimination reaction. 4-Phenylsulfonyl tetrafluoropyridine reacts with amidines to give the corresponding imidazo[4,5-b]pyridine systems. In contrast, 4-cyanotetrafluoropyridine gave a [6,6]-fused pyrimidinopyridine system arising from initial nucleophilic substitution at the C-3 position of the pyridine ring followed by intramolecular cyclization onto the pendant cyano group. The systems prepared by this annelation methodology further demonstrate the utility of perfluorinated heterocyclic substrates for the synthesis of heterocyclic scaffolds that possess multiple functionality and have potential applications in the drug discovery arena.     

DFT study on the reaction mechanism and regioselectivity for the [1,2]-anionic rearrangement of 2-benzyloxypyridine derivatives

The reaction mechanism of the [1,2]-anionic rearrangement of 2-benzyloxypyridines has been investigated using DFT calculations. Calculated results indicate that: the deprotonation step is relatively fast and the rearrangement step is the rate-determining step; electron-donating group on the benzene ring decreases the activation energy of the rearrangement, which correlates with an increase in reaction yield, while electron-withdrawing groups show the opposite effect. The rearrangement is calculated to proceed by way of an oxirane-like transition state that had previously been postulated as a transient intermediate. Furthermore, the mechanism for the rearrangement of 2-(benzyloxy)nicotinonitrile was discussed. The quick formation of the five membered ring intermediate leads to the predominant formation of 2-phenylfuro[2,3-b]pyridin-3-amine. The calculation results indicate the possibilities of derivatizing the starting pyridyl ether as well as facilitating the rearrangement reaction by adding an appropriate electron-donating group on the benzene ring or electron-withdrawing group on the pyridine ring for future studies.     

Application of modified Pictet-Spengler reaction for the synthesis of thiazolo- and pyrazolo-quinolines

Two new thiazole and pyrazole-based arylamine substrate have been used for the Pictet-Spengler reaction. This is in contrast to the traditionally used indole/imidazole-based aliphatic amine substrates that has remained in use for the last ∼100 years. The condensation of both the substrates with a variety of aldehydes in the presence of 2% TFA-DCM at 0° for 30 min or pTsOH in toluene at reflux led to the synthesis of thiazoloquinolines and pyrazoloquinolines, respectively. Unlike aliphatic amine substrates, our substrates readily underwent Pictet-Spengler cyclization even with aldehydes having electron donating group. The studies are based on a new concept proposed by us that arylamines linked to an activated heterocyclic ring can lead to a variety of second-generation substrates for the Pictet-Spengler cyclization. Our studies open up new avenues for the application of Pictet-Spengler reaction beyond syntheses of the tetrahydroisoquinolines and tetrahydro-β-carbolines.     

Synthesis of allenylzinc reagents by 1,2-rearrangement of alkynyl(disilyl)zincates derived from acetylenic epoxides and acetylenic aziridines

Lithium alkynyl(disilyl)zincates obtained from metalated ethynyloxiranes, as well as from N-tert-butanesulfinyl(ethynyl)aziridines or N-tert-butanesulfonyl(ethynyl)aziridines, undergo 1,2-migration of the organosilyl group with ring opening of the oxirane or aziridine ring by S_Ni displacement. A developed protocol that involves nBuLi for the metalation step offers a straightforward approach to the corresponding δ-oxy- and δ-amino α-silyl allenylzinc intermediates. The reagents derived from the epoxides are amenable to subsequent in situ condensation with aldehydes or ketones to provide 1,3-diols but not those derived from aziridines that only react sluggishly in similar condensations.     

Stereoselective synthesis of imidazolidin-2-ones via Pd-catalyzed alkene carboamination. Scope and limitations

A method for the synthesis of imidazolidin-2-ones from N-allylureas and aryl or alkenyl bromides via Pd-catalyzed carboamination reactions is described. The N-allylurea precursors are prepared in one step from readily available allylic amines and isocyanates, and the Pd-catalyzed reactions effect the formation of a C-C bond, a C-N bond, and up to two stereocenters in a single step. Good diastereoselectivities are obtained for the conversion of substrates bearing allylic substituents to 4,5-disubstituted imidazolidin-2-ones, and excellent selectivity for the generation of products resulting from syn-addition across the alkene is observed when substrates derived from cyclic alkenes or E-1,2-disubstituted alkenes are employed. A brief discussion of reaction mechanism and product stereochemistry is presented.     

Reactions of fluoronitrobenzenes with MTBD strong base in acetonitrile in the presence of water molecules

Products of the reactions between three fluorinated nitrobenzenes (2,3,4,6-tetrafluoronitrobenzene, mNF4; 2,3,4,5-tetrafluoronitrobenzene, oNF4; pentafluoronitro-benzene, NF5) and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) in the presence of the water molecules in acetonitrile were isolated and identified by analytical and spectroscopic methods. The reaction products included ortho- and para-substituted nitro-compounds. The kinetics of these reactions is independent of the substrates studied. The rate-determining step of these reactions is the hydrolysis of one ring of the MTBD molecule after the fast formation of the Meisenheimer complex. The mechanism of these reactions and the structures of the products are discussed.     

Synthetic studies on (−)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (2)

Construction of the ABCD ring system of (−)-FR182877 via the intramolecular Diels-Alder (IMDA) reaction and the highly diastereoselective intramolecular hetero-Diels-Alder (IMHDA) reaction is described. The IMHDA reactions of the substrates incorporating the oxabutadiene with the E- or Z-alkene were examined, revealing that the sole product was obtained from both substrates and the E-alkene geometry was found to be crucial to obtaining the desired product.     

Diastereoselective synthesis of linear‐fused tricyclic nitrogen heterocycles by a tandem reduction‐reductive amination reaction

A two‐step diastereoselective synthesis of linear‐fused tricyclic nitrogen heterocycles has been developed from cyclic β‐ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2‐oxo‐cycloalkanecarboxylates with 2‐nitrobenzyl bromide. Hydrogenation of these substrates initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the resulting hydroxyl‐amine or aniline nitrogen with the cycloalkanone and (3) reduction of the imine. The products are isolated in high yield as single diastereomers having the trans‐fused ring junction. The observed selectivity is rationalized in terms of a steric effect imposed by the ester group in the final reductive amination step which directs the incoming hydrogen to the opposite face of the molecule. By comparison, reductive cyclizations of substrates lacking the stereodirecting ester group give mixtures of cis and trans products with a preference for the cis‐fused heterocycle.     

6-endo Versus 5-exo radical cyclization: streamlined syntheses of carbahexopyranoses and derivatives by 6-endo-trig radical cyclization

Three factors that can direct 6-endo radical cyclization over 5-exo ring closure: substitution at C-5, vinyl radical cyclization and ring strain, have been considered in the context of the preparation of carbapyranoses from carbohydrate derivatives. As a result, alkyl radicals in substrates containing a strain inducing 2,3-O-isopropylidene ring, and vinyl radical in non-strained compounds undergo a completely regioselective 6-endo-trig ring closure leading to carbasugar derivatives.     

Kinetic resolution of 2,2-difluoro-3-hydroxy-3-aryl-propionates catalyzed by organocatalyst (R)-benzotetramisole

Kinetic resolution of a series of ethyl 2,2-difluoro-3-hydroxy-3-aryl-propionates catalyzed by (R)-benzotetramisole has been performed. It was found that when the aryl group was phenyl or phenyl substituted with electron-donating group (such as -Me, -OMe, and -SMe) or naphthyl groups, the enantio-selectivity factor (s) could reach 20 or higher; electron-withdrawing (such as fluorine) substitution on the benzene ring dramatically lowers the s value. Kinetic resolution in preparative scale for some of the substrates demonstrated the applicability of this method.     

Studies towards the total synthesis of taxoids: a rapid entry into bicyclo[6.4.0]dodecane ring system. Part 1

We report a short and stereocontrolled synthesis of the taxoid BC-subunit (+)-5 embodying the whole carbon framework and most of the required oxygen functionalities for further elaboration. Enantiomeric purity was secured at an early stage by resolution involving derivatization with (S)-2-acetoxypropionyl chloride on (±)-10b.