Total Synthesis of Amphidinolide E and Amphidinolide E Stereoisomers

Four amphidinolide E stereoisomers, amphidinolide E (1), 2-epi-amphidinolide E (2), 19-epi-amphidinolide E (3), and 2-epi-19-epi-amphidinolide E (4), have been synthesized via the judicious union of aldehyde 5, allylsilanes 7 or 8, acids 9 or 10, and vinylstannane 6. The C19 stereocenters of the C19 epimeric allylsilanes 7 and 8 were introduced via crotylboration reactions early in the synthesis. [3+2] Annulation reactions of aldehyde 5 with allylsilanes 7 and 8 were employed to set the core tetrahydrofuran units of 1-4. Finally, the C2 stereocenter was installed by esterification using acid 9, without incident, or with acid 10, in which case an unexpected and completely stereoselective inversion of C2 occurs.     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).     

Synthesis of fluorine containing glycolurils and oxazolines from oxides of internal perfluoroolefins

The reaction of oxides of internal perfluoroolefins 1-3 with urea gave two kinds of novel fluorine containing N-heterocyclic compounds depending on the solvent nature: 1,5-bis(perfluoroalkyl)tetraazabicyclo[3.3.0]octane-3,7-diones 4a-c and 2-amino-5-fluoro-4,5-bis(perfluoroalkyl)-4,5-dihydrooxazol-4-ols 7a-d. Use of polar dimethylsulfoxide, N,N-dimethylacetamide and acetonitrile afforded glycolurils 4a-c in moderate yields. In dioxane, unexpected cyclization occurred resulting in oxazolines 7a-d in high yields. A similar reaction of oxiranes 2, 3 with urea in aqueous dioxane gave mixtures of 4,5-dihydroxy-4,5-bis(perfluoroalkyl)imidazolidine-2-ones 9b, c, glycolurils 4b, c and oxazolines 7b-d. The molecular structure of trans-isomers of oxazoline 7b and imidazolidine 9b has been established by X-ray crystallography.     

Regioselective synthesis of 4- and 5-oxazole-phosphine oxides and -phosphonates from 2H-azirines and acyl chlorides

A simple and efficient regioselective synthesis of 4-oxazole-phosphine oxides 11 and -phosphonates 12 from 2H-azirine-phosphine oxides 1 and -phosphonates 6 is described. The key step for the synthesis of oxazoles 11 is a base-mediated ring closure of vinylogous α-aminophosphorus compounds derived from phosphine oxides 4 and from phosphonates 8. These derivatives 4 and 8 are obtained by reaction of functionalized azirines 1 and 6 with acyl chlorides 2 and subsequent acid-catalyzed ring opening of N-acylaziridine-phosphine oxides 3 and -phosphonates 7. Regioselective thermal ring cleavage of N-acylaziridine-phosphine oxides 3 leads α-chloro-β-(N-acylamido)-phosphine oxides 13 and their treatment with bases gives 5-oxazole-phosphine oxides 16.     

The reaction of 4-amino-2-oxazolines with isocyanates and isothiocyanates. Synthesis and X-ray structures of polysubstituted 2-imidazolidinones, 1,3-oxazolidines and 1,3-thiazolidines

Reactions of 4-alkylamino-2-phenyl-2-oxazolines 1 with isocyanates and isothiocyanates provide unprecedented efficient and regioselective heterocycle-heterocycle transformations. Compounds 1 reacted rapidly with tosyl isocyanate yielding directly 3-alkyl-4-benzamido-1-tosyl-2-imidazolidinones 4 in almost quantitative yields. The corresponding ureido intermediates 2 were not isolable species. However, the reactions with non-sulfonylated isocyanates or isothiocyanates were slower, leading to the expected ureido and thioureido derivatives 5, which were easily and efficiently transformed to either polysubstituted 2-imino-1,3-oxazolidine or 2-imino-1,3-thiazolidine hydrochlorides 7, respectively, by treatment with hydrochloric acid. The possible reasons for this disparity in chemical behaviour are discussed. X-ray crystallographic structures for 4-benzamido-3-methyl-1-tosyl-2-imidazolidinone 4b, 4-[1-isopropyl-3-(4-nitrophenyl)ureido]-2-phenyl-2-oxazoline 5e, (Z)-3-benzyl-4-benzamido-2-phenylimino-1,3-oxazolidine hydrochloride 7a and (Z)-3-benzyl-4-benzamido-2-phenylimino-1,3-thiazolidine hydrochloride 7b have been determined.     

A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a-k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l-o. Benzamides 7a-k and 7′l-o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a-k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l-o in good overall yields.     

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.     

New phlegmarane-type, cernuane-type, and quinolizidine alkaloids from two species of Lycopodium

Two new phlegmarane-type alkaloids, cermizines A (1) and B (2), three new quinolizidine alkaloids, cermizine C (3) and senepodines G (4) and H (5), and a new C₁₆N₂ type alkaloid consisting of a quinolizidine and a piperidine ring, cermizine D (6), as well as two new cernuane-type alkaloids, cernuine N-oxide (7) and lycocernuine N-oxide (8), have been isolated together with cernuine (9) and lycocernuine (10) from the club moss Lycopodium cernuum and L. chinense. The relative stereochemistry of 1-4 and 6, and the absolute stereochemistry of 5, 7, and 8 were elucidated by combination of NOESY correlations, modified Mosher's method, chemical transformations, and computational methods. Cermizine D (6) might be a biosynthetic intermediate of cernuane-type alkaloids such as 7-10.     

Simple and efficient synthesis of highly functionalized cyclohexanes; formal total synthesis of ovalicin and fumagillin

Two chiral cyclohexanes 4 and 6, which are key intermediates for the total synthesis of ovalicin 1 and fumagillin 2, respectively, were synthesized from (2R,3S) 1,2-epoxy-4-penten-3-ol. The key steps involve an efficient construction of divinylalcohol 7 using methallyl Grignard reagent 9c, and an intramolecular olefin metathesis of 7.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Syntheses, crystal structures and coordination modes of tri- and di-organotin derivatives with 2-mercapto-4-methylpyrimidine

The organotin (IV) derivatives of 2-mercapto-4-methylpyrimidine (Hmpymt) R₃SnL (R = Ph 1, PhCH₂2, n-Bu 3), R₂SnCl_mL_n (m = 1, n = 1, R = CH₃4, Ph 5, n-Bu 6, PhCH₂7; m = 0, n = 2, R = CH₃8, n-Bu 9, Ph 10, PhCH₂11) were obtained by the reaction of the organotin(IV) chlorides R₃SnCl or R₂SnCl₂ with 2-mercapto-4-methylpyrimidine hydrochloride (HCl · Hmpymt) in 1:1 or 1:2 molar ratio. All complexes 1-11 were characterized by elemental analyses, IR, ¹H, ¹³C and temperature-dependent ¹¹⁹Sn NMR spectra. Except for complexes 3 and 6, the structures of complexes 1, 2, 4, 5, 7, 8-11 were confirmed by X-ray crystallography. Including tin-nitrogen intramolecular interaction, the tin atoms of complexes 1-7 are all five-coordinated and their geometries are distorted trigonal bipyramidal. While the tin atoms of complexes 8-11 are six-coordinated and their geometries are distorted octahedral. Besides, the ligand adopts the different coordination modes to bond to tin atom between the complexes 1, 6, 7 and 2, 3, 4, 5, 8-11. Furthermore, intermolecular Sn?N or Sn?S interactions were recognized in crystal structures of complexes 4, 7 and 11, respectively.     

Cyanuric and thiocyanuric esters as carriers of boron-containing fragments and their fragmentation in mass spectrometry

Tripropargylic esters 2 and 10 of cyanuric and thiocyanuric acids were synthesized. Interaction of these compounds with disubstituted amines gives monoaminoderivatives of dipropargyloxy-s-triazine 4 and 11. Diaminosubstituted propargyloxy-s-triazine 6 was prepared from the corresponding diaminochloroderivative 5. First examples of boron-containing s-triazines 7, 8, 12, 13 were prepared by reaction of propargyl esters 4, 6, 10, 11 with decaborane. New rearrangements of the molecular ions of the 2-aminoderivatives of 4,6-dipropargyloxy-1,3,5-triazine in mass spectrometry were found.     

Naphthyridines. Part 3: First example of the polyfunctionally substituted 1,2,4-triazolo[1,5-g][1,6]naphthyridines ring system

Treatment of 1,2,4-triazoles (1) with diethylmalonate in bromobenzene gave 1,2,4-triazolo-[1,5-a]pyridines 2. Chlorination of 2 using POCl₃/DMF (Vilsmeier reagent) led to the isolation of 7-chloro-6-formyl-1,2,4-triazolo[1,5-a]pyridine derivative 4, which reacted with the stabilized ylid 5 to afford 6-ethoxycarbonylvinyl-1,2,4-triazolo[1,5-a]-pyridines 6. Azidation of 6 yielded the corresponding azido compound 7, (Scheme 2). Reduction of 7 with Na₂S₂O₄ gave the corresponding 7-amino compound 8, which cyclized in boiling DMF to give the novel 1,2,4-triazolo[1,5-g][1,6]naphthyridines 9. On the other hand, reacting 7 with one equivalent of PPh₃ (aza-Wittig reaction) in CH₂Cl₂ gave 7-imino-phosphorane derivative 10, and subsequent cyclization in boiling DMF afforded the new 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 11 (Scheme 3). However, treatment of 10 with phenyl isothiocyanate in 1,2-dichlorobenzene at reflux temperature gave the new 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 14 (Scheme 4). Refluxing 6 with excess of a primary amines 15a,b in absolute. EtOH yielded the corresponding 7-alkyl-amino-1,2,4-triazolo[1,5-a]pyridines 16a,b. These obtained amines 16a,b underwent intramolecular heterocyclization in boiling DMF to give the novel 9-alkyl-1,2,4-triazolo[1,5-g][1,6]-naphthyridines 17a,b, in excellent yields (Scheme 5).     

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron-rich 2-azadienes

tert-Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2H-azirine 3 leading to Diels-Alder cycloadducts in moderate yields. The reactions are endo- and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b, 4b. There are two isomers (4 and 5) from 1a, 1c and 1d. A different result was obtained with the diene 1e. Diene 1e formed products 4e and 8. Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7. Compound 8 gave aziridine 9.     

Bioactive meroterpenoids and alkaloids from the fungus Eurotium chevalieri

Five new meroterpenoids, chevalones A-D (1-4), aszonapyrone B (8), and a new sequiterpene alkaloid, eurochevalierine (5), together with four known compounds, sequiterpene (6), terpenoid pyrrolobenzoxazine named CJ-12662 (7), meroterpenoid, aszonapyrone A (9), and ergosterol were isolated from the fungus Eurotium chevalieri. The structures were established on the basis of spectroscopic evidence. The configurations of 1 and 5 were determined by X-ray analysis. The biosynthetic pathway of 1-3, 8, and 9 were proposed. Chemical transformation of aszonapyrone A (9) was also studied. Compounds 4, 5, and 7 exhibited antimalarial activity against Plasmodium falciparum, while 3, 5, and 7 showed antimycobacterial activity against Mycobacterium tuberculosis. In addition, compounds 2-7 showed cytotoxicity against cancer cell lines.     

Total synthesis of apigenin 7,4′-di-O-β-glucopyranoside, a component of blue flower pigment of Salvia patens, and seven chiral analogues

We have succeeded in the first total synthesis of apigenin 7,4′-di-O-β-d-glucopyranoside (1a), a component of blue pigment, protodelphin, from naringenin (2). Glycosylation of 2 according to Koenigs-Knorr reaction provided a monoglucoside 4a in 80% yield, and this was followed by DDQ oxidation to give apigenin 7-O-glucoside (12a). Further glycosylation of 4′-OH of 12a with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl fluoride (5a) was achieved using a Lewis acid-and-base promotion system (BF₃·Et₂O, 2,6-di-tert-butyl-4-methylpyridine, and 1,1,3,3-tetramethylguanidine) in 70% yield, and subsequent deprotection produced 1a. Synthesis of three other chiral isomers of 1a, with replacement of d-glucose at 7 and/or 4′-OH by l-glucose (1b-d), and four chiral isomers of apigenin 7-O-β-glucosides (6a,b) and 4′-O-β-glucosides (7a,b) also proved possible.     

Aigialomycins and related polyketide metabolites from the mangrove fungus Aigialus parvus BCC 5311

Reinvestigation of the secondary metabolites from the marine mangrove fungus Aigialus parvus BCC 5311 led to the isolation of six new nonaketide metabolites, aigialomycins F (4) and G (5a/5b), 7′,8′-dihydroaigialospirol (7), 4′-deoxy-7′,8′-dihydroaigialospirol (8), and rearranged macrolides 9 and 10, along with six previously described compounds, hypothemycin (1), aigialomycins A (2) and B (3), aigialospirol (6), 4-O-demethylhypothemycin (11), and aigialone (12). The structures of the new compounds were elucidated by analyses of the NMR spectroscopic and mass spectrometry data in combination with chemical means.     

Regio- and stereoselective reactions of a rhodanine derivative with optically active 2-methyl- and 2-phenyloxirane

The reaction of a rhodanine derivative (=(Z)-5-benzylidene-3-phenyl-2-thioxo-1,3-thiazolidin-4-one; 1) with (S)-2-methyloxirane (2) in the presence of SiO₂ in dry CH₂Cl₂ for 10 days led to two diastereoisomeric spirocyclic 1,3-oxathiolanes 3 and 4 with the Me group at C(2) (Scheme 2). The analogous reaction of 1 with (R)-2-phenyloxirane (5) afforded also two diastereoisomeric spirocyclic 1,3-oxathiolanes 6 and 7 bearing the Ph group at C(3) (Scheme 3). The structures of 3, 4, 6, and 7 were confirmed by X-ray crystallography (Figs. 1 and 2). These results show that oxiranes react selectively with the thiocarbonyl group (CS) in 1. Furthermore, the nucleophilic attack of the thiocarbonyl S-atom at the SiO₂-activated oxirane ring proceeds with high regio- and stereoselectivity via an S_N2-type mechanism.     

Sodium dithionite initiated regio- and stereoselective radical addition of polyfluoroalkyl iodide with norbornene analogs

Sodium dithionite initiated free-radical addition of polyfluoroalkyl iodides (2m-2s) with norbornene 1a and its derivatives, such as norbornene-2-carboxylates 1b and 1c, and norbornene-2-carboxylic acids 1d and 1e was investigated. In all the cases, the addition of R_F group was stereoselectively delivered at exo-position and the predominant configuration of products was trans. Under the similar condition, norbornene-2-carboxylic ethyl ester 1b reacted with 2p to give 6-exo-R_F-5-endo-iodo adduct 3bp and 5-exo-R_F-6-endo-iodo adduct 5bp in the ratio of 4:1. While 1c, which has a heavy crowded group in the 2-endo-position, gave 6-exo-R_F-5-endo-iodo adduct 3cp and polyfluoroalkylated product 4cp retaining the trans-configuration and the exo-orientation of R_F group. The fluoroalkylation-lactonization reaction occurred in the reaction of norbornene-2-endo-carboxylic acids 1d and 1e with polyfluoroalkyl iodides to afford the corresponding fluoroalkylated γ-lactone products (7dp-7ds, and 7em-7er). The configuration of the products was further confirmed by 2D NMR and X-ray diffraction analyses for the first time.     

Formation of new 4-isocyanobut-2-enenitriles by thermal ring cleavage of 3-pyridyl azides

A new thermal ring cleavage of 3-pyridyl nitrenes for the formation of 4-isocyanobut-2-enenitrile products is reported. Thermolysis of 4-(thien-3-yl)-3-pyridyl azide 1 and 3-azido-4-(1-TIPS-1H-pyrrol-3-yl)pyridine 5 afforded two new isonitrile-nitrile products by ring cleavage; 4-isocyano-2-(thiophen-3-yl)but-2-enenitrile (3, 27%) and 4-isocyano-2-(1-TIPS-1H-pyrrol-3-yl)but-2-enenitrile (7, 20%), in addition to our previously reported pyrido[3,4-b]thienopyrrole (2, 29%) and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (6, 71%) products. Minor amounts of 2-(thien-3-yl)-1H-pyrrole-3-carbonitrile (4, 6%), formed by ring contraction, were also isolated after thermolysis of azide 1. Isonitriles 3 and 7 underwent degradation into amine 3b and formamide 7a by acidic hydrolysis. The nature and chemistry of compounds 3, 4 and 7 were investigated.