Efficient sequential segment coupling using N-alkylcysteine-assisted thioesterification for glycopeptide dendrimer synthesis

A highly pure MUC1-derived glycopeptide dendrimer of 22 kDa was prepared by a sequential segment coupling, achieved by an N-alkylcysteine (NAC)-assisted thioesterification. The glycopeptide having C-terminal NAC was prepared by the Fmoc method and converted to the thioester by 3-mercaptopropionic acid treatment. The thioester was condensed with a lysine trimer carrying NAC to afford tetramer, which was then converted to the thioester. Two tetramers were condensed with ethylenediamine to give the octameric glycopeptide dendrimer.     

Efficient synthesis of immolative carbamate dendrimer with olefinic periphery

An efficient synthetic strategy for immolative carbamate dendrons and dendrimers is described that requires no protection/deprotection in the convergent growth step. 1,3-Diamino-2-propanol was used as AB₂ building block and 4-nitrophenyl chloroformate as carbamate forming reagent. The method was demonstrated with a G3-dendron. A combination of convergent and divergent growth method was used to couple G2-dendrons to a G2-core or G3-dendrons to a tetrahedral G1-core with amine functional groups to form a spherical carbamate dendrimer (G4) possessing an olefinic periphery.     

Efficient enantiomeric synthesis of pyrrolidine and piperidine alkaloids from tobacco

An enantiomeric synthesis of six piperidine and pyrrolidine alkaloids, (S)-nornicotine 1, (S)-nicotine 2, (S)-anatabine 3, (S)-N-methylanatabine 4, (S)-anabasine 5, and (S)-N-methylanabasine 6, known as natural products in tobacco, was established from a common chiral homoallylic (S)-3-(1-azido-but-3-enyl)-pyridine 15. An intramolecular hydroboration-cycloalkylation of the homoallylic azide intermediate 15 served as the key step in the pyrrolidine ring formation. A ring closing metathesis reaction (RCM) of a diethylenic amine intermediate (S)-allyl-(1-pyridin-3-yl-but-3-enyl)-carbamic acid benzyl ester 20 served as the key step in the piperidine ring formation. From the commercially available 3-pyridinecarboxaldehyde 13, a short and convenient enantiomeric synthesis of tobacco alkaloids is described: (S)-nornicotine 1 (5 steps, with an overall yield of 70%), (S)-nicotine 2 (6 steps, 65%), (S)-anatabine 3 (8 steps, 30%), (S)-N-methylanatabine 4 (8 steps, 25%), (S)-anabasine 5 (8 steps, 35%), and (S)-N-methylanabasine 6 (8 steps, 25%).     

Efficient synthesis of thiazoloquinazolinone derivatives

An original route to the rare 8H-thiazolo[5,4-f]quinazolin-9-one 1 and the novel 7H-thiazolo[4,5-h]quinazolin-6-one 2 is described. Access to the regioisomers was realized by fusion of a thiazole and a quinazoline ring via Appel's salt chemistry. Thermal reactions were carried out using a focused microwave reactor, reducing the overall time of the multi-step synthesis.     

Asymmetric synthesis of functionalized piperidine derivatives: synthesis of (S)-anatabine

A short and efficient chiral synthesis of 6-aryl-5-phenylsulfonyl-1,2,5,6-tetrahydropyridines was achieved in moderate yield and with good selectivity. The absolute configurations were assigned by extending the methodology to (S)-anatabine and as well with NMR experiments.     

Efficient synthesis of tetrazole derivatives of cytisine using the azido-Ugi reaction

The azido-Ugi reaction with natural alkaloid cytisine was investigated. It was demonstrated that the reaction could be performed with various carbonyls (both aldehydes and ketones) and isocyanides. The transformation proceeded under mild conditions in methanol using TMSN3 as a source of hydrazoic acid to give target tetrazole derivatives of cytisine in up to 98% yield. The diastereoselectivity of this reaction was studied using both aliphatic and aromatic aldehydes. A family of tetrazole derived cytisine compounds was prepared. Selective deprotection of tetrazoles was elaborated to synthesize the corresponding NH-tetrazoles.     

Green synthesis of dihydropyrano[3,2-c]chromene derivatives using amino-terminated PAMAM dendrimer as catalyst

d-Sorbitol-cored PAMAM dendrimer (SOR-G1) was effectively synthesized by the ring opening polymerization of epichlorohydrin. The dendrimer was characterized using different spectroscopic and analytical techniques including IR and NMR spectroscopy, TG–DTA, and GPC. Dihydropyrano[3,2-c]chromene derivatives were synthesized using SOR-G1 as a catalyst, and it was synthesized within 30 min in ethanol/water medium and excellent yield was obtained. SOR-G1 acted as a good base catalyst on the basis of amine capacity and good thermal stability. The prepared dihydropyrano[3,2-c]chromene derivatives were characterized using GCMS, LCMS, IR, ¹H NMR, and ¹³C NMR spectra. The catalyst could be reused up to three reaction cycles without losing its catalytic activity.

Graphic abstract

     

A facile aminocyclization for the synthesis of pyrrolidine and piperidine derivatives

Bromination of an isolated double bond followed by aminocyclization furnishes a highly stereoselective protocol for the intramolecular formation of pyrrolidine and piperidine ring containing subunits that are presented in numerous biologically active natural products.     

Efficient synthesis of novel Pyrroloquinoline derivatives

The zwitterion derived from quinoline and dialkylacetylenedicarboxylates on reaction with C–H acids such as: dialkylchloromalonates, and 3-chloro acetyl acetone afforded pyrroloquinoline derivatives in moderate yields (44–55 %).     

Efficient stereocontrolled synthesis of sphingadienine derivatives

Sphinga-4,8-dienines, principal long-chain bases of glycolipids in plants and fungi, were efficiently synthesized from l-serine. Hydrozirconation of pentadec-5-en-1-ynes followed by ZnBr₂-catalyzed addition to Garner's aldehyde afforded protected sphinga-4,8-dienines stereoselectively. The (2S,3R,4E,8E)-9-methyl-sphingadienine derivative was then coupled with 2(R)-acetoxypalmitic acid derivative prepared via asymmetric dihydroxylation to give a protected ceramide, which was converted into the corresponding glucocerebroside in two steps.     

Efficient solid-phase synthesis of isocytosine derivatives

We have investigated the potential use of a solid-phase synthesis of novel 6-(arylmethyl)-5-methyl-isocytosine derivatives based on the immobilization of the corresponding 2-thiothymine on a Merrifield resin, oxidation of the immobilized form to the sulfone, and aminolysis of the latter under mild conditions.     

Efficient synthesis of piperidine derivatives. Development of metal triflate-catalyzed diastereoselective nucleophilic substitution reactions of 2-methoxy- and 2-acyloxypiperidines.

Nucleophilic substitution reactions of 2-methoxy- and 2-acyloxypiperidines were investigated. First, new and efficient methods for the preparation of the starting piperidine derivatives were developed. N-Benzyloxycarbonyl-2-methoxypiperidine (3) and 3-substituted-2-acyloxy-N-benzyloxycarbonylpiperidines (4a-d), which are recognized as the simplest imino-sugars, were prepared and were examined as substrates for nucleophilic substitution reactions with silyl enolates under the influence of catalytic amounts of metal triflates (Sc(OTf)3, Sn(OTf)2, Cu(OTf)2, Hf(OTf)4, etc). Among the triflates tested, Sc(OTf)3 gave the best results. It was found that 2-acetoxy-3-benzyloxy-N-benzyloxycarbonylpiperidine (4a) reacted with silyl enolates to afford the 2-alkylated adducts in high cis-selectivity, while 2,3-diacyloxy-N-benzyloxycarbonylpiperidines (4b-d) showed transselectivity. The stereochemical assignments were carefully performed using NMR analysis, X-ray crystallography, and synthetic transformations. Febrifugine (1), a potent antimalarial alkaloid, was successfully synthesized from 2,3-diacetoxy-N-benzyloxycarbonylpiperidine (4b) on the basis of these diastereoselective nucleophilic substitution reactions.     

Microwave-assisted synthesis of triazole derivatives conjugated with piperidine as new anti-enzymatic agents

The current study was aimed for the study of piperidine-based triazole compounds for their biological potential against various enzymes. A novel library of compounds, 9a-r , having piperidine, 1,2,4-triazole, and propanamides was synthesized through consecutive steps including the formation of sulfonamide, hydrazide, 1,2,4-triazole, and thio-ether. Initially, 4-methoxybenzenesulfonyl chloride ( 1 ) and ethyl isonipecotate ( 2 ) were utilized to develop ethyl 1-(4-methoxyphenylsulfonyl)-4-piperidinecarboxylate ( 3 ). The product 3 was converted into respective hydrazide ( 4 ) which was further cyclized into 1,2,4-triazole ( 5 ) nucleus. A series of propanamides, 8a-r , were synthesized from different amines, 6a-r . These electrophiles, 8a-r , were reacted with compound 5 under conventional and microwave-assisted protocols to acquire the library of hybrids, 9a-r . The structural confirmations were availed by ¹H-NMR, ¹³C-NMR, and IR techniques. The whole series was evaluated for biological potential against acetylcholinesterase (AChE) and α-glucosidase enzymes. The biological evaluation ranges low to high in potential for different compounds based on the structural variations of synthesized compounds. Almost all the compounds remained active against both the enzymes except a few ones. The bovine serum albumin (BSA) binding study demonstrated the flow of drug in the body, and the docking study explained the interactions responsible for active behavior of synthesized compounds.     

Efficient synthesis of 3-oxygenated benzothiophene derivatives

An efficient synthesis of 2-bromo-3-aryloxybenzothiophene derivatives by a conjugate addition-elimination sequence of 2,3-dibromo benzothiophene dioxides with phenolic nucleophiles has been developed. These benzothiophene derivatives serve as important intermediates for the synthesis of SERM analogues.     

Efficient solid-phase synthesis of symmetric norbinaltorphimine derivatives

[reaction: see text] We describe an efficient solid-phase synthesis of symmetric norbinaltorphimine (norBNI) derivatives 2. Pyrrole formation involving the homocoupling of two solid-supported ketones 6, followed by chemoselective and sequential N-alkylation, provided N-substituted norBNI derivatives 2. Use of this methodology led to the combinatorial synthesis of 120 norBNI derivatives.     

Efficient and selective synthesis of quinoline derivatives

The bromination reaction of 1,2,3,4-tetrahydroquinoline (7) was investigated by NBS and molecular bromine. One-pot synthesis is described for synthetically valuable 4,6,8-tribromoquinoline (3) and 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6) on bromination of 1,2,3,4-tetrahydroquinoline (7) in efficient yields (75 and 90%, respectively). 6-Bromo- (4) and 6,8-dibromo-1,2,3,4-tetrahydroquinolines (6) were converted to 6-bromo- (1) and 6,8-dibromo quinolines (2), respectively, by aromatization with DDQ in 83 and 77% yields, respectively. Several novel trisubstituted quinoline derivatives were efficiently prepared via lithium-halogen exchange reactions of tribromide 3. Treatment of 4,6,8-tribromoquinoline with BuLi followed by quenching with electrophiles [Si(CH₃)₃Cl, S₂(CH₃)₂, I₂] regioselectively proceeded at C-4 and C-8 sites and afforded corresponding 4,8-disubstituted-6-bromoquinolines. Similarly, lithiation of tribromide 3 followed by addition of water to the intermediate produced 6-bromoquinoline in 65% yield. Copper-induced nucleophilic substitution of tribromide 3 with NaOMe afforded 4,6,8-trimethoxyquinoline (17) in 60% yield.     

Efficient synthesis of 1,4,5,12-tetraazatriphenylene and derivatives

Condensation of 5,6-diamino-4,7-phenanthroline with glyoxal provides 1,4,5,12-tetraazatriphenylene in quantitative yield. This procedure avoids the 50% loss of product inherent in previous methods. Derivatives were also prepared by using alpha-dicarbonyl compounds other than glyoxal. Additional derivatives were prepared from 1,4,5,12-tetraazatriphenylene-2,3-dicarbonitrile, produced by condensation of diaminomaleonitrile with 4,7-phenanthroline-5,6-dione.     

Efficient microwave-assisted synthesis of 5-deazaflavine derivatives

A series of pyrimido[4,5-b]quinolines (5-deazaflavines), were synthesized by microwave assisted intramolecular cyclization. The N?-substituted-2,4-diamino-6-chloro-pyrimidine-5-carbaldehydes, were prepared by selective monoamination of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde with aliphatic and aromatic amines.