Efficient and environmentally benign synthetic protocol for the synthesis of structurally diverse annulated pyridopyrimidines

Structurally diverse annulated pyridopyrimidines have been synthesized by an efficient and environmentally benign synthetic protocol involving catalyzed four-component reaction of 2-aminobenzothiazoles with thiophene-2-carbaldehyde and carbonyl compounds in ethanol. Mild reaction conditions, operational simplicity, and structural diversity with excellent yields are some special attractions of the present protocol.     

Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality

Diketopiperazines (DKPs) are a common motif in various biologically active natural products, and hence they may be useful scaffolds for the rational design of receptor probes and therapeutic agents. We constructed a new bicyclic scaffold that combines a DKP bridged with a 10-membered ring. In this way we obtained a three-dimensional molecular skeleton, with several amendable sites that provide a starting point to design a new combinatorial library having diverse substituent groups. Structural variation is based upon the flexibility of alkylation of the nitrogen atoms of the DKP and on the side-chain olefin. We obtained a 10-membered secondary ring through a ring-closure metathesis reaction using the second generation Grubbs catalyst. Rings containing both O-ethers and S-ethers were compared. N-Alkyl or arylalkyl groups were introduced optionally at the two Nalpha-atoms. This is a general scheme that will allow us to test rings of varying sizes, linkages, and stereochemical parameters. The DKP derivatives were tested for activity in astrocytoma cells expressing receptors coupled to phospholipase C. Inhibitory effects were observed for signaling elicited by activation of human nucleotide P2Y receptors but not m3 muscarinic receptors. Compound 20 selectively inhibited calcium mobilization (IC50 value of 486 +/- 16 nM) and phosphoinositide turnover elicited by a selective P2Y1 receptor agonist, but this compound did not compete for binding of a radiolabeled nucleotide-competitive receptor antagonist. Therefore, the new class of DKP derivatives shows utility as pharmacological tools for P2Y receptors.     

Combinatorial liquid-phase synthesis of structurally diverse benzimidazole libraries

An expedient liquid-phase synthesis for construction of the diverse benzimidazole libraries is described. Nucleophilic aryl substitution of poly(ethylene glycol)-supported 4-fluoro-3-nitrobenzoic acid 3 with several primary amines under basic conditions, followed by Zn/NH(4)Cl mediated nitro group reduction, gave the PEG bound diamines 5. Subsequent cyclization of immobilized o-phenylenediamine 5 using thiocarbonyldiimidazole (TCD) or thiophosgene in dichloromethane furnished benzimidazole-2-thiones 6. Treatment of 6 with alkyl halides and benzylic halides in the presence of triethylamine provided 1-substituted-2-alkylthio-5-carbamoylbenzimidazoles on the support. The desired products 8 were severed from the PEG under mild conditions in high yield and high purity.     

Fine synthetic nucleoside chemistry based on nucleoside natural products synthesis

Synthetic nucleoside chemistry based on nucleoside natural products synthesis were described. First, a samarium diiodide (SmI 2)-promoted aldol reaction with the use of alpha-phenylthioketone as an enolate was developed. The characteristics of this reaction are that the enolate can be regioselectively generated and the aldol reaction proceeds under near neutral condition. This reaction is proved to be a powerful reaction for the synthesis of complex nucleoside natural products, and herbicidin B and fully protected tunicaminyluracil, which were undecose nucleoside natural products, were synthesized. Next, the synthetic methodology of the caprazamycins, which are promising antibacterial nucleoside natural products, was also developed by the strategy including beta-selective ribosylation without using a neighboring group participation. Our synthetic route provided a range of key analogues with partial structures to define the pharmacophore. Simplification of the caprazamycins was further pursued to develop diketopiperazine analogs.     

Total synthesis of siphonazole and its O-methyl derivative, structurally unusual bis-oxazole natural products

The details of the first syntheses of the unusual bis-oxazole natural products siphonazole and its O-methyl derivative are reported. The cinnamyl substituted oxazole was constructed using diazocarbonyl chemistry, whereby the cinnamamide was reacted with the rhodium carbene derived from methyl 2-diazo-3-oxobutanoate to give a beta-ketoamide that was cyclodehydrated to the corresponding oxazole-4-ester. Reduction to the corresponding aldehyde was followed by coupling with a zinc reagent derived from methyl 2-iodomethyl-5-methyloxazole-4-carboxylate, also prepared using rhodium carbene chemistry, to give, after oxidation of the resulting secondary alcohol, the desired bis-oxazole ketone. The syntheses were completed by hydrolysis of the ester and coupling of the 2,4-pentadienylamine side chain.     

Multicomponent assembly strategies for the synthesis of diverse tetrahydroisoquinoline scaffolds

Several novel multicomponent assembly processes have been developed for the rapid and efficient assembly of various heterocyclic scaffolds bearing a tetrahydroisoquinoline core, each of which allows for facile derivatization to access a diverse array of compounds. This work led to the serendipitous discovery of a new method for the synthesis of a fused quinazolone ring system, which was applied to a one-step total synthesis of the quinazolinocarboline alkaloid rutaecarpine.     

Site-selective modification of proteins for the synthesis of structurally defined multivalent scaffolds

A combination of classical site-directed mutagenesis, genetic code engineering and bioorthogonal reactions delivered a chemically modified barstar protein with one or four carbohydrates installed at specific residues. These protein conjugates were employed in multivalent binding studies, which support the use of proteins as structurally defined scaffolds for the presentation of multivalent ligands.     

Applications of multicomponent reactions for the synthesis of diverse heterocyclic scaffolds

A four-component coupling process involving sequential reactions of aldehydes, primary amines, acid chlorides, and nucleophiles has been developed to prepare multifunctional substrates that may be employed in subsequent ring-forming reactions to generate a diverse array of functionalized heterocyclic scaffolds. This new approach to diversity-oriented synthesis was then applied to the first total synthesis of the isopavine alkaloid (+/-)-roelactamine.     

Total synthesis of eupomatilones 4 and 6: structurally rearranged and atropisomerically fluxional lignan natural products

[structure: see text] A convergent and diastereocontrolled total synthesis of eupomatilones 4 and 6 is reported and was based on a diastereoselective hydroboration/oxidation sequence and a convergent Lipshutz biarylcuprate cross-coupling reaction. The structure of eupomatilone 6 is revised.     

Marine natural products: synthetic aspects

An overview of marine natural products synthesis during 2003 is provided. The emphasis on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure conformation or stereochemical assignments.     

Marine natural products: synthetic aspects

An overview of marine natural products synthesis during 2006 is provided. As with earlier installments in this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.     

Marine natural products: synthetic aspects

An overview of marine natural products synthesis during 2004 is provided. As with the previous installment of this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.     

Marine natural products: synthetic aspects

An overview of marine natural products synthesis during 2005 is provided. In a similar vein to earlier installments in this series, the emphasis is on total syntheses of molecules of contemporary interest, new total syntheses, and syntheses that have resulted in structure confirmation or stereochemical assignments.     

Efficient synthesis of taurine and structurally diverse substituted taurines from aziridines

Taurine and substituted taurines were synthesized efficiently from aziridines via ring-opening reaction with thioacetic acid, oxidation with performic acid, and hydrolysis in hydrochloric acid. The current method shows more benefit in purification and efficiency in the preparation of taurine and structurally diverse 2-substituted, 2,2-disubstituted, and 1,2-, 2,2-, and 2,N-alkylene taurines.     

A pyrone remodeling strategy to access diverse heterocycles: application to the synthesis of fascaplysin natural products

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described. The pyrido[1,2-a]indole core was demonstrated to be a versatile scaffold that can be site-selectively functionalized. The utility of this novel annulation strategy was showcased in a concise formal synthesis of three fascaplysin congeners.

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described.     

Synthesis of structurally diverse biflavonoids

Synthetic biflavonoids are associated with interesting biological activities, yet they remain poorly explored within drug discovery. Recent years have witnessed a growing interest in synthetic approaches that can provide access to structurally novel biflavonoids so that the biological usefulness of this compound class can be more fully investigated. Herein, we report upon the exploration of strategies based around Suzuki-Miyaura cross-coupling and alcohol methylenation for the synthesis of two classes of biflavonoids: (i) rare ‘hybrid’ derivatives containing flavonoid monomers belonging to different subclasses, and (ii) homodimeric compounds in which the two flavonoid monomers are linked by a methylenedioxy group. Application of these strategies enabled the preparation of a structurally diverse collection of novel biflavonoids from readily-available starting materials, thereby facilitating the probing of uncharted regions of biologically interesting chemical space.     

A synthetic route to 1,3-dihydroisobenzofuran natural products: the synthesis of methyl ethers of pestacin

A synthetic route to 1-(2,6-dihydroxyphenyl)phthalan natural products is described. It is typified by the synthesis of permethyl and monomethyl ethers (21 and 22) of pestacin (1), a 1,3-dihydroisobenzofuran natural product. The key step is hydrodeoxygenation of the corresponding isobenzofuranone 19 in 2 steps: reduction and intramolecular etherification. A route involving hydrodesulfurization of a thionophthalide to a phthalan (e.g., 8) is also reported.