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An operationally simple, efficient and convenient approach for the synthesis of highly substituted thiophene frameworks has been developed via the organoindium mediated coupling of α-enolic dithioesters and C2–C3 centres of propargylic bromides. The in situ generated propargyl indium species efficiently guides the unusual mode of fusion through an unprecedented Csp3–S cross-coupling/migratory C-allenylation/thioannulation cascade to furnish the corresponding thiophenes in a single synthetic operation. Furthermore, this protocol does not require any co-catalyst or activator.

3-Aryltetrahydrobenzisoxazoles prepared en route to the coleophomone natural products and analogues, were found to undergo a remarkable base-mediated rearrangement to 2-aryltetrahydrobenzoxazoles. The scope of this unprecedented, facile transformation was probed: a range of analogues was produced, a mechanism proposed, and an application demonstrated by synthesis of a known herbicidal compound.

An operationally simple and highly atom-economic anionic quadruple domino reaction sequence for the synthesis of hexacyclic indeno-fused naphthalene/quinoline molecules having structural resemblance with the C-nor-D-homo-steroid nucleus has been developed. Promoter and solvent specificity, regioselectivity and mechanistic details were experimentally established. Catalyst concentration and solvent dependent switching of domino steps creating four new C–C bonds are discussed.

A range of N-acylpyrrolo[3,4-c]isoxazoles and derived N-acyltetramides has been prepared via a nitrile oxide dipolar cycloaddition approach, as analogues of the acyltetramic acid metabolite reutericyclin, of interest for its antibiotic potential against Gram-positive bacteria including hospital-acquired infections of resistant Clostridium difficile.

An operationally simple, facile, and convenient one-pot straightforward method for the construction of 3,4,5-trisubstituted 1,2-dithioles has been explored and developed via palladium catalyzed self-coupling of α-enolic dithioesters for the first time. Pd(0) efficiently catalyzes the activation and cleavage of S–H and C–S bonds to achieve cascade coupling, which results in the concomitant formation of new S–S and C–C bonds. Optimization data, substrate scope, and mechanistic insights are discussed.

Alcohols (I) are readily converted into aromatic ketones (II) under the action of catalytic hydrochloric acid.

Title compounds (VI) and (XVI) are synthesized starting from esters (I) or (XII), resp., via dipolar cycloaddition of nitrile oxides derived from the latter in situ with enamino-ester (III).

4,5-Dihydroimidazolium ylides generated by conjugate addition-proton transfer from dihydroimidazoles and double-activated electron-deficient alkenes afford 2 : 1 or 1 : 1 : 1 adducts in a one-pot process.

Histone lysine methylation is a dynamic chromatin modification that plays key regulatory roles in gene expression and other genomic functions. Methylation of Lys9 in histone H3 (H3K9) is a prominent modification that has been implicated in diverse processes, including transcriptional silencing, heterochromatin formation, and DNA methylation. In this review, we summarize recent advances in understanding the structure and substrate specificity of the H3K9-specific methyltransferases G9A and GLP and explore current efforts to develop inhibitors of these enzymes. In addition, we discuss the structure and specificity of the recently discovered PHF8 family of histone demethylases that target H3K9 as well as other methylation sites in histones H3 and H4. Finally, we conclude by comparing the H3K9 binding modes displayed by these enzymes and examine the relevance of these studies to their biological functions and to structure-based inhibitor design.

Azomethine ylides, prepared from imidazolinium salts, undergo 1,3-dipolar cycloaddition with a variety of dipolarophiles to produce hexahydropyrrolo[1,2- a ]imidazoles, which are reduced to pyrrolidines; with 2-chloroacrylonitrile as dipolarophile, pyrroles can be prepared from the cycloadducts by elimination.

The synthesis of 3-(poly)enoyltetramic acids from 2,2,6-trimethyl-1,3-dioxen-4-one via N-(3-oxo-4-alkenoyl)-α-amino-acids is described.

Cycloaddition of diethylphosphonomethyl nitrile oxide to the enamine from ethyl acetoacetate produces 4-ethoxycarbonyl-3-diethoxyphosphonylmethyl-5-methylisoxazole; condensation of the phosphonate with aldehydes and ketones gives 3-alkenylisoxazoles that are cleaved by hexacarbonylmolybdenum to afford unsaturated α-alkoxycarbonyl-β-diketones.

Synthesis of the alkaloid homaline in (±) and natural (S,S)-(–) forms is reported. Linking of 2-azacyclooctanone units either directly or successively using 1,4-dihalogenobutanes or 1,4-dihalogenobut-2-ynes is examined. (±)-5-Methyl-4-phenyl-1,5-diazacyclooctan-2-one is first made by a 2,2′-dithiodipyridine/triphenylphosphine-mediated cyclisation, and then by amination and transamidative ring expansion from N-(3-chloropropyl)-4-phenylazetidin-2-one in liquid ammonia, followed by N-methylation. Coupling through a 1,4-dihalogenobutane of either the N-methylated azalactam, or the unmethylated azalactam followed by methylation, gave homaline in (±) and meso forms.(R)-(–)-Phenylglycine was converted via(S)-β-phenyl-β-alanine into an (S)-β-lactam which was then alkylated with 1-bromo-3-chloropropane, and aminated and ring expanded in liquid ammonia. Coupling of the homochiral azalactam (2 mol) so formed with 1,4-dibromobutane, followed by N-methylation, gave (S,S)-(–)-homaline identical with the natural material.

Synthesis of the unsymmetrical Homalium alkaloids hopromine, hoprominol and hopromalinol, in diastereoisomeric mixture form, is reported. The component eight-membered azalactams are first prepared. N-(3-Halogenopropyl)-4-pentyl- and -4-heptyl-azetidin-2-ones are aminated and ring expanded in liquid ammonia to give, after reductive methylation, the corresponding 4-alkyl-5-methyl-1,5-diazacyclooctan-2-ones. Synthesis of the 4-(2-hydroxyheptyl)-5-methyl-1,5-diazacyclooctan-2-one required for hoprominol and hopromalinol is carried out via 4-allyl β-lactam ring expansion to the eight-membered 4-allylazalactam, followed by methylation, epoxidation and epoxide opening with lithium dibutylcuprate. A similar epoxidation-cuprate sequence was carried out on the epoxypropyl β-lactam, as its N-tert-butyldimethylsilyl derivative, and led to a convenient copper-catalysed N- to O-migration of the protection; this migration is examined. Alkylation gave O-TBDMS-protected N-(3-chloropropyl)-4-(2-hydroxyheptyl)azetidin-2-one which could be aminated and transamidated in excellent yield, to give, after methylation, a superior sequence to the required eight-membered hydroxy azalactam.Although satisfactory for attachment of the first azalactam unit, a dibromobutane coupling system proved unreactive for the second. Couplings with unmethylated, methylated, and benzyloxycarbonylprotected azalactams were examined using (E)-1,4-dibromobutene and (Z)-1,4-dichlorobutene as the bridging unit. Employing the latter, coupling the first N-methylated azalactam with potassium bis(trimethylsilyl)amide as the base, and then the second with bis(trimethylsilyl)amide-sodium hydride as the base system, provided a satisfactory synthetic outcome. Hydrogenation under acidic conditions gave the unsymmetrical structures hopromine, hoprominol and hopromalinol, as well as the more simple and symmetrical alkaloid, homaline.

The synthesis of an enantiomeric pair of enaminoesters from phenylglycine is described. Conjugate addition to α,β-enones, reductive cyclization-fragmentation to octahydroimidazopyridines and further reduction to remove the auxiliary atoms, completes a new route to homochiral piperidines in which the enaminoesters function as homochiral ‘ethanal enamines’.

1, 3-Dipolar cycloaddition of nitrite oxides to enamines formed from protected γ-amino- or γ-hydroxy-β-keto esters affords isoxazolecarboxylic esters that can be converted into 3-acyltetramic acids via dihydropyrroloisoxazol-4-ones, or into 3-acyltetronic acids.

Berninamycins B, C, and D were isolated from fermentation of Streptomyces bernensis and their structures were studied with 13C NMR and FAB mass spectrometry. Berninamycin B has a valine unit in its cyclic peptide loop instead of the beta-hydroxyvaline unit found in berninamycin A. Berninamycin D has two fewer dehydroalanine units attached to the carboxyl carbon of the pyridine ring. Based on FAB-MS results, berninamycin C is postulated to have only one dehydroalanine unit attached to the carboxyl carbon of pyridine. The biogenesis of berninamycins B, C, and D is discussed.

We report the synthesis of three examples of new classes of sulfurated heterocycles: dithiadiazaphospholidine 3, benzothiadiazacycloheptene 6a and benzotrithiadiazacyclononene 6b arising from strained cyclic N,N-disubstituted diazadisulfides (2 and 5)via oxidation or disproportionation; single-crystal X-ray structural analyses are reported for the phospholidine and the benzocycloheptene.

This work describes the use of a 2,5,5-trisubstituted imidazoline as an amide bond replacement. The replacement is incorporated into dipeptide derivatives of Phe, Trp, Lys and Nle and also into the CCK-4 analogue Trp-Nle-Asp-Phe-NH2 and the pentagastrin analogue Gly-Trp-Nle-Asp-Phe-NH2. The amide bond replacement is synthesised in enantiomerically and diastereomerically pure form.

The site of aminomethylation of N-unsubstituted 3-hydroxy-2-( 1H )-pyridinones and 3-hydroxy-4( 1H )-pyridinones, under Mannich reaction conditions, is directed by the hydroxyl group when this is unprotected and by the kelo group when the hydroxyl is protected as an ether. This offers a convenient route to a variety of Mannich base synthons useful in the synthesis of derivatives of these clinically important, bidentate, metal-ion chelators. This is exemplified by reactions of 3-hydroxy-2-( 1H )-pyridinone, 3-methoxy-2( 1H )-pyridinone, 2-hydroxymethyl- 5-hydroxy- 4( 1H ) pyridinone and 3- benzyloxy- 2- methyl-4( 1H )- pyridinone.

We report the single-crystal X-ray structure determinations of two novel phosphorus-, nitrogen- and sulfur: containing heterocycles, namely, 4,6-bis[2-(2-methyl)propyl]-5-oxo-5-phenyl-1,2,3,4,6,5-trithiadiazaphosphorinane, C 14 H 23 N 2 OPS 3 , and 6,8-bis[2-(2-methyl)propyl]-7-oxo-7-phenyl-1,2,3,4,5,6,8,7-pentathiadiazaphosphocine, C 14 H 23 N 2 HPS 5 . The phosphorinane compound is unusual in that it displays a high degree of steric compression in the S-S-S bond angle, which has a value of only 96.3°. The phosphocine compound has bond angles similar to those found in S 8 rings. One S-S-S-S torsion angle, however, is compressed to 30°. The phosphocine has two conformationally identical molecules in the asymmetric unit.

Whereas 1-benzyl-2-lithiomethyl-4,5-dihydroimidazole undergoes reversible 1,2-addition to aldehydes and ketones, the derived phosphonate salt, 1-benzyl-2-lithio(diethylphosphono)methyl-4,5-dihydroimidazole, affords the condensation products, 2-(1-alkenyl)-4,5-dihydroimidazoles; these latter undergo conjugate addition with carbon nucleophiles.

The intramolecular 1,3-dipolar cycloaddition of homochiral dihydroimidazolium ylides, generated in situ , is the key reaction in a sequence that rapidly affords optically active 2,3,4-trisubstituted pyrrolidines suitably functionalised for further elaboration.

1-Benzyl-2-(ethoxycarbonylmethylene)-2,3,4,5-tetrahydroimidazole undergoes preferred C-alkylation with halogenoalkanes, dihalogenoalkanes and epoxides; subsequent removal of of the ethoxycarbonyl group provides a new route to 2-alkyl-4,5-dihydroimidazoles. 1,3-Dihalogenoalkanes afford imidazo[1,2-a]pyridines via C,N-dialkylation.

1,3-Dipolar cycloadditon of nitrile oxides, formed in situ by dehydration of primary nitro compounds, with pyrrolidine enamines of protected γ-hydroxy-β-keto esters affords isoxazole-4-carboxylates; these are subjected to N–O bond cleavage and lactonisation to afford 3-acyltetronic acids and 3-acyl-4-hydroxytetrahydropyran-2-ones.

4,5-Dihydroimidazolium ylides, formed by N-alkylation of 4,5-dihydroimidazoles, undergo diastereoselective endo 1,3-dipolar cycloaddition with electron-deficient alkene dipolarophiles to afford hexahydropyrrolo[1,2-a]imidazoles; reduction of the aminal functionality in the cycloadducts leads to substituted pyrrolidines. Cycloaddition using 2-chloropropenonitrile, followed by base treatment, affords pyrroles.

Two novel tetradentate Mannich bases of kojic acid were synthesised exhibiting altered specificity for either oxovanadium(IV) or copper(II) ions determined by the presence or absence of a single methylene group in a cyclic diamine backbone.

N-alkyl-3-hydroxy-2-methyl-4(1H)-pyridinones can be synthesised in reasonable yield from either 1-(3-hydroxy-2-furanyl)ethanone or O-galactosylisomaltol. Since these carbohydrate precursors can be produced from the disaccharide, a-D-lactose, a simple and inexpensive transformation into pyridinones is possible.

The 1,3-dipolar cycloaddition of the β-aminonitrile oxide, formed from β-alanine, to the enamine of a β-ketoester affords a 3-(2-aminoalkyl)isoxazole-4-carboxylic ester that is converted via isoxazolo[4,5-c]pyridin-4-ones into 3-acetyl-4-hydroxypyridin-2-ones.

1,3-Dipolar cycloaddition of nitrile oxides, formed in situ by dehydration of primary nitro compounds, with pyrrolidine enamines of protected γ- or δ-amino-β-keto esters affords isoxazole-4-carboxylates; these undergo lactam formation and N–O bond cleavage to afford 3-acyltetramic acids and 3-acyl-4-hydroxypyridin-2-ones.

The potential of pyrones as precursors to 3-acyltetramic acids is demonstrated by the conversion of 5-ethoxycarbonyl-4-methoxy-6-methyl-2-pyrone into a 3-acyltetramic acid.

The mammalian aromatic amino acid hydroxylases (phenylalanine, tyrosine, and tryptophan hydroxylase (PheOH, TyrOH, TrpOH, respectively)) are functionally and structurally closely related enzymes (e.g. 65% sequence identity and 80% sequence homology in the catalytic domains)1 (Figure 1). This family of enzymes shares a common catalytic mechanism, in which dioxygen is used by an active site containing a single, reduced iron atom to hydroxylate an unactivated aromatic substrate (i.e., monooxygenase activity), concomitant with a two-electron oxidation of tetrahydropterin cofactor to its quinonoid dihydropterin form (Figure 2).2 The enzymes play an important role in mammalian metabolism: PheOH initiates the catabolism/detoxification of high levels of phenylalanine, while TyrOH and TrpOH catalyze the rate-limiting steps in the biosynthesis of the neurotransmitters/hormones dopamine/noradrenaline/adrenaline and serotonin, respectively. In 1959, Kaufman3 related a deficiency in hPheOH to the genetic disease phenylketonuria (PKU), and more recently a deficiency in hTyrOH has been related to the genetic disease L-DOPA responsive dystonia4 and juvenile parkinsonism.5 Current research is close to linking TyrOH with bipolar affective disorder6 and studying the relationship between DNA polymorphism of the TyrOH gene and schizophrenia7 (see section 4). Reduced biosynthesis of L-DOPA by TyrOH as a result of progressive degeneration of dopaminergic neurons in the nigrostriatal pathway is characteristic of idiopathic parkinsonism (Parkinson’s disease), and evidence has recently been presented that the TyrOH enzyme system itself may contribute to the oxidative stress considered to be responsible for the neurodegeneration.8 While the enzymes operate on different amino acid substrates, the similarity of substrate structure is apparent, and recent data have provided important sequence and mechanistic links between the different hydroxylases. In solution, the aromatic amino acid hydroxylases form homotetramers with molecular mass ranging from 204 to 217 kDa. Sequence homologies, sitedirected mutagenesis, and partial proteolysis experiments have demonstrated that these enzymes are composed of an N-terminal region (PheOH 1-142; TyrOH 1-155; TrpOH 1-177) with regulatory properties and a C-terminal region (PheOH 143-452; TyrOH 156-498; TrpOH 178-445) known to be * Corresponding author. 2137 Chem. Rev. 1999, 99, 2137−2160

A route to porphyrins bearing trans-thiols is described using a thioacetyl-containing aldehyde or a thioacetyl-containing dipyrromethane in the presence of catalytic BF3·OEt2 followed by oxidation....