Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway

Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addition of 1,3-dipole to C2-C3 π bond of allenic esters/ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza Diels-Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dienophile components in the proposed intermediate C have revealed that conformational constraints imposed by the alkyl groups (R=Me, Et) favor intramolecular aza-Diels-Alder cycloaddition. An alternative domino route to benzoindolizines (9a,d,g) involving sequential one-pot cycloaddition of azadienes (22a-c) with silyl-enol ether (23) followed by palladium(0)-catalyzed Heck coupling reaction has also been developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.     

New pinene-derived pyridines as bidentate chiral ligands

A synthesis of new bidentate pyridines 8a-d, 9, and 10 has been developed, starting from triflate 14, readily available from β-pinene 11. A copper complex of the pyridine-oxazoline ligands 8a has been found to catalyze asymmetric allylic oxidation of cyclic olefins 36a-c with good conversion rates and acceptable enantioselectivity (≤67% ee). The imidazolium salt 10 has been identified as a precursor of the corresponding N,N′-unsymmetrical N-heterocyclic carbene ligand, whose complex with palladium catalyzed the intramolecular amide enolate α-arylation leading to oxindole 45 in excellent yield but with low enantioselectivity.     

3-Amino- and 3-acylamido-2-phosphonopyridines: synthesis by Pd-catalyzed P-C coupling, structure and conversion to pyrido[b]-anellated PC-N heterocycles

Palladium catalyzed cross-coupling of 3-amino- and 3-acylamido-2-bromopyridines 1a-f with triethyl phosphite allowed the synthesis of 3-amino- and 3-acylamido pyridine-2-phosphonic acid diethyl esters 2a-f, whereas nickel catalysts, although providing access to related anilido-2-phosphonates, proved inactive. Reduction of the aminophosphonate 2a with LiAlH₄ afforded 3-amino-2-phosphinopyridine (3a), which was cyclocondensed with dimethylformamide dimethyl acetal (DMFA) via phosphaalkene intermediates 4a to the novel pyrido[b]-anellated 1,3-azaphosphole 5a. Reaction of amidophosphonates 2b-f with LiAlH₄ did not result in the expected reductive cyclization, as shown by closely related anilido-2-phosphonates, but led to product mixtures containing N-secondary 3-amino-2-phosphinopyridines 3b-f as the main or major component. The conversion of 3b,d,e with DMFA to 5b,d,e provides first examples of N-substituted pyrido[b]-anellated azaphospholes. Structures were confirmed by multinuclear NMR and X-ray crystallography (for 2c, 3b).     

Rapid, microwave-assisted synthesis of N1-substituted 3-amino-1,2,4-triazoles

A robust, regioselective synthesis of 3-amino-1,2,4-triazoles is described. This reaction employs a key intermediate 2, which is coupled to carboxylic acids in good yields to afford intermediates 3a-d. These entities, in turn, react with a variety of hydrazines or hydrazine hydrochlorides to provide proposed intermediates 4a-j, which under microwave conditions cyclize to the desired 3-amino-1,2,4-triazoles (compounds 5a-j). This approach permits the rapid synthesis of regioselective N1-substituted 3-amino-1,2,4-triazoles, and is shown to afford a variety of such compounds in 34-70% isolated yields.     

Synthesis and evaluation of the antitumor agent TMC-69-6H and a focused library of analogs

A concise, efficient and flexible total synthesis of the potent antitumor agent TMC-69-6H (2) is described. Key steps involve the palladium catalyzed regioselective addition of 4-hydroxy-2-pyridone 5 to pyranyl acetate 6 which is accompanied by a spontaneous 1,4-addition of the phenolic -OH group to the emerging enone to give the tricyclic product 7 in excellent yield. When this reaction is carried out with optically enriched (S)-6 (conveniently prepared by a lipase catalyzed kinetic dynamic resolution) in the presence of the chiral ligand (S,S)-12 and allylpalladium chloride dimer, the ensuing matched situation delivers the key building block (−)-7 in 96% ee. Its further elaboration into 2 involves a Julia-Kocienski olefination with tetrazolylsulfone 19 and a final N-oxidation effected by the peroxomolybdenum complex [(pyridine)MoO₅(HMPA)] to form the hydroxamic acid motif. The flexibility inherent to this route allows for the preparation of a focused library of analogues for biochemical evaluation. The results obtained show that N-hydroxy-2-pyridone derivatives constitute a promising new class of selective phosphatase inhibitors. In contrast to previous reports in the literature, however, TMC-69-6H and congeners are found to exhibit pronounced activities against the tyrosine protein phosphatase PTB1B, the dual specific phosphatase VHR, and the serine/threonine phosphatase PP1, while being only weak inhibitors for the dual specific phosphatases Cdc25 A and B. Two key intermediates of the synthesis route have been characterized by X-ray crystallography.     

Palladium-benzimidazolium salt catalyst systems for Suzuki coupling: development of a practical and highly active palladium catalyst system for coupling of aromatic halides with arylboronic acids

Palladium-benzimidazolium salt catalyst systems have been studied for the Suzuki coupling. A different substitutent effect has been uncovered with respect to nitrogen substituents in the benzimidazolium salts from the palladium-imidazolium salt analogs. A practical and highly active palladium catalyst system, PdCl₂/N,N′-dibenzylbenzimidazolium chloride 2, has been identified for the Suzuki coupling of aromatic halides with arylboronic acids. The coupling of a wide array of aromatic halides with arylboronic acids with the PdCl₂-2 catalyst system gave good to excellent yields. The effective palladium loading could be as low as 0.0001 mol% and 0.01-0.1 mol% for iodide and bromide substrates, respectively. The coupling of unactivated aromatic chlorides with arylboronic acids also gave good results using Cs₂CO₃ as base with a 2 mol% palladium loading. The electronic factors from aromatic halides exert a significant influence on the Suzuki coupling catalyzed by the PdCl₂-2 system while the electronic effect from the arylboronic counterparts is negligible. The aromatic halides with modest steric hindrance could also couple smoothly with phenylboronic acids using the PdCl₂-2 catalyst system.     

A simple approach for the synthesis of new classes of dithiocarbamate-linked peptidomimetics

An efficient protocol for the synthesis of a new series of dithiocarbamate-linked peptidomimetics is described. The in situ generated dithiocarbamic acid intermediate formed by the reaction of an amino acid ester and carbon disulfide in the presence of triethylamine was treated with N-protected amino alkyl iodide to afford title compounds 3a-g in good to moderate yields. The synthesis of N-Fmoc-protected tripeptidomimetics 4a-e containing two dithiocarbamate linkages is also described. The protocol was further extended to synthesize N,N′-orthogonally protected dithiocarbamate-linked dipeptidomimetics 7a-c as well. The mild reaction conditions and non-toxic reagents are the advantages of the present method.     

Synthesis of 2′,3′-dideoxy-6′,6′-difluoro-3′-azanucleosides

The straightforward synthesis of four novel 2′,3′-dideoxy-6′,6′-difluoro-3′-azanucleosides 1a-d is described. Efficient construction of the fluorine-containing pyrrolidine ring through two different ways and installation of pyrimidine rings using the amino groups in the intermediates 12, 26 were the key steps of our synthesis.     

Synthesis and reactivity of pyrrolo[3,2-d][1,3]oxazine-2,4-dione. Access to new pyrrolo[3,2-e][1,4]diazepine-2,5-diones

A convenient synthesis of pyrrolo[3,2-d][1,3]oxazine-2,4-dione 4 is described and its reactivity towards various nucleophiles studied. The regioselective ring opening of anhydride 4 or its N-alkylated analog 25 in the presence of alanine or proline afforded, respectively, imidazolidinedione 22 and N-protected pyrrolo[3,2-e][1,4]diazepines 30 and 31 in a one-pot process. In a last part of this study, an alternative route to produce a library of eight non protected pyrrolo[3,2-e][1,4]diazepine-2,5-diones 35a–h is described to overcome the limited reactivity of anhydride 4.     

Efficient synthesis of cephalotaxine- and deoxyharringtonine analogues by a trimethylaluminium-mediated domino reaction

The synthesis of cephalotaxine- and cephalotaxine amide analogues 14a-c and 16a-c as well as of the deoxyharringtonine analogues 5a,b was performed employing a trimethylaluminium-mediated domino reaction of 9a-c and 8 to give the spirocyclic compounds 7a-c, which was followed by a palladium catalyzed α-arylation.     

SnCl4-mediated oxidative biaryl coupling reaction of 1-naphthol and subsequent ring closure of 2,2′-binaphthol to the dinaphthofuran framework

A simple method for the direct synthesis of 2,2′-binaphthols 2 and dinaphtho[1,2-b;2′,1′-d]furans 3 under mild conditions was developed, utilizing a biaryl coupling reaction via electron donor-acceptor complexes of 1-naphthols with SnCl₄. Heating of the complex in a sealed tube for (18-24 h) afforded the corresponding o-o coupled product 2 in excellent yield. Prolonged reaction (56-65 h) under the same conditions afforded 3 in high yield in one step. We also found that in the case of α-naphthol without substituents other than a hydroxyl group at the C-1 position, regioselective o-o coupling reaction proceeded. The products 2a, 2b and 2g should be useful as synthetic intermediates for naturally occurring 3,3′-bijuglone, 3,3′-biplumbagin and elliptinone.     

cis-Palladium(II) complexes of derivatives of di-(2-pyridyl)methane: Study of the influence of the bridge group in the coordination mode

Palladium(II) complexes containing di-(2-pyridyl)-N-methylimine (1), di-(2-pyridyl)methanol (2) and di-(2-pyridyl)methyl-N,N-diethyldithiocarbamate (4) ligands were synthesized and characterized by ¹H and ¹³C NMR in solution, IR and X-ray single crystal diffraction. Crystal structures of cis-dichloro[di-(2-pyridyl)-N-methylimine]palladium(II) (5), cis-dichloro[di-(2-pyridyl)methanol]palladium(II) (6) and cis-dichloro[di-(2-pyridyl)methyl-N,N-diethyldithiocarbamate]palladium(II) (7) showed a bidentate coordination mode of the di-(2-pyridyl)methane derivatives 1, 2 and 4. In these complexes is observed the formation of a five-membered chelate ring with the iminic ligand 1 and six-membered chelate rings with the pyridinic ligands 2 and 4. In all complexes the palladium atom displays a distorted square planar geometry.     

Synthesis of (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one: an alternative, enaminone based, route to unsaturated cyclodipeptides

A series of racemic and enantiopure (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (cyclic Pro-ΔTrp) dipeptide analogues were prepared. Racemic analogues 6a-c were prepared by direct coupling of racemic cyclodipeptide enaminone (R,S)-5 with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction in which acyclic (S)-Pro-ΔTrp dipeptide analogues 20 and 21 were formed. Acyclic dipeptides were cyclized to enantiopure (S)-Pro-ΔTrp dipeptide analogues 24 and 25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (7), enaminone 8 was prepared and coupled with 2-methylindole and 2-phenylindole to give 9 and 10. Direct bromination of 3-(indole-3-yl)propenoates 9 and 10 at position 2 results in vinyl bromides 11 and 12. The Boc protecting group on the indole nitrogen 1′ in vinyl bromides 11 and 12 was introduced, before the copper(I) catalyzed coupling with N-Boc prolinamide 18 was performed. Enantiomeric purity of chiral intermediates and final products was determined mostly by HPLC or ¹H NMR spectroscopy and X-ray diffraction.     

Concise total synthesis of honokiol via Kumada cross coupling

A concise four-step efficient synthesis of honokiol 1 in 68% overall yield is described here. The present method involves tetrakis(triphenylphosphine)palladium [Pd(Ph₃)₄] catalyzed Kumada coupling in two key steps. First coupling generates biaryl backbone intermediate 5 and second generates 2,4′-O-dimethylhonokiol 3. Final demethylation under AlCl₃/DMS condition affords honokiol in quantitative yield.     

Chemoenzymatic resolution of epimeric cis 3-carboxycyclopentylglycine derivatives

Epimeric 3-carboxycyclopentylglycines (+)-10/(−)-10 and (+)-11/(−)-11 were efficiently prepared by the way of a sequence of Diels-Alder and retro-Claisen reactions. The synthesis incorporates a concise and inexpensive chemoenzymatic resolution of racemic compounds 4,5a, the N,O-protected derivatives of amino acids 10,11. Systematic screening with different enzymes and microorganisms was performed to select a very efficient catalyst for the separation of the racemic mixtures. The reaction conditions allowing deprotection of both ester and amino functions and to avoiding epimerization processes were studied. Enantiomers (i.e., (+)-10/(−)-10 and (+)-11/(−)-11) were obtained in high enantiopurity. The absolute configuration of all stereocenters was unequivocally assigned.     

Synthesis of variolin B

The total synthesis of variolin B from 4-methoxy-7-azaindole is described. The preparation of the protected amino derivative 10 and a coupling reaction of the iodo derivative 12 with 2-acetylamino-4-trimethylstannylpyrimidine are the key steps of the sequence. The use of N-tosyldichloromethanimine for the cyclisation step afforded a good entry to the 9-aminopyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine system. Variolin B was obtained from the triply protected tetracyclic compound 13 in two steps.     

Synthesis of polycyclic indolizine derivatives via one-pot tandem reactions of N-ylides with dichloro substituted α,β-unsaturated carbonyl compounds

Convenient and regioselective syntheses of 1,2-annulated, and 1,2-, 5,6- and 1,2-, 7,8-bisannulated polycyclic indolizine derivatives have been achieved by one-pot tandem reactions of cyclic N-ylides derived from the corresponding N-substituted pyridinium, quinolinium, and isoquinolinium salts 1-3 with dichloro substituted α,β-unsaturated carbonyl compounds 4-7. The reactions of the N-ylides with 2,3-dichloroindenone 4, 3,4-dichlorocoumarin 5, and 4a,6,7,8a-tetrachloro-1,4-methanonaphthalene-5,8-dione 6 proceed by sequential [3+2] cycloaddition and elimination of hydrogen chlorides from the cycloadducts. On the other hand, reactions of the N-ylides with 2,3-dichloro-1,4-naphthoquinone 7 take place via a novel reaction sequence to give the products 15-17.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

Parallel kinetic resolution of propargyl ketols: formal synthesis of (+)-bakkenolide A

We describe an intriguing new example of a parallel kinetic resolution; an asymmetric cyclization-carbonylation of propargyl ketols catalyzed by palladium(II) with chiral bisoxazoline (box) ligands. The 2S,3S enantiomer of (±)-6 was preferentially converted to 13 (45-49% yields, 37-46% ee), and the 2R,3R enantiomer of (±)-6 was preferentially converted to 14 (21-23% yields, 92-97% ee). As an application of this reaction, formal synthesis of (+)-bakkenolide A was achieved.     

An efficient and regioselective one-pot multi-component synthesis of pyrimido[4,5-d]pyrimidine derivatives in water

Pyrimido[4,5-d]pyrimidine derivatives 4 have been prepared in an efficient and regioselective manner in water via multi-component reaction of isothiocyanate 1, aromatic aldehyde 2, N,N-dimethyl-6-amino uracil 3 in the presence of p-toluenesulfonic acid (p-TSA) as a Lewis acid catalyst.