Enantioselective synthesis of the C-14 to C-5 cyclopentane segment of jatrophane diterpenes

The enantioselective synthesis of the C-14 to C-5 cyclopentane segment of jatrophane diterpenes is reported. An Evans aldol addition, a Horner-Wadsworth-Emmons olefination and a thermal intramolecular carbonyl ene reaction of an α-keto ester served as key C/C-connecting transformations.     

Hydrogen atom transfer methodology for the synthesis of C-22, C-23, and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple synthesis of all eight C-22, C-23, and C-25 diastereoisomers of the cephalostatin north 1 side chain has been accomplished from (25R)-5α-spirostan-3β-ol (tigogenin). The synthesis involves selective hydroxylations at C-23 and C-25 and reductive opening of the 1,6-dioxaspiro[4.5]decane spirostan system to give a conveniently protected 5α-furostan-3β,23,25,26-tetrol. The construction of the required 1,6-dioxaspiro[4.4]nonane system entailed an intramolecular hydrogen abstraction reaction promoted by the C-25 alkoxyl radical as the key step. Acid-catalyzed isomerization of the spiroketal unit suggested that 22R isomers are the thermodynamic products while the 22S isomers are the result of kinetic control. The acid-catalyzed equilibrium between 1,6-dioxaspiro[4.4]nonane and 1,6-dioxaspiro[4.5]decane systems was also studied. In the 1,6-dioxaspiro[4.4]nonane units, the observed ³J_23,24 coupling constants suggest that the five-membered puckered ring-F undergoes substantial conformational changes on going from 22S to 22R isomers.     

Route selection in the synthesis of C-4 and C-6 substituted thienopyrimidines

Three different routes have been investigated for the preparation of 6-aryl-N-(1-arylethyl)thienopyrimidin-4-amines. First the possibilities of selective Suzuki reactions on 6-bromo-4-chlorothienopyrimidine were investigated. The preference for mono arylation at C-6 could be increased, in the case of Pd(PPh₃)₄ catalysis, by reducing the water content of the reaction, or by using less electron rich Pd-ligands. The highest selectivity was obtained with Pd(OAc)₂ or Pd₂(dba)₃, while reactions with the more electron rich Pd(PPh₃)₄ and especially XPhos gave a lower mono- to dicoupled product ratio. Secondly, two alternative strategies avoiding this selectivity issue were tested. Suzuki reaction on C-6 of 6-bromothienopyrimidin-4(3H)-one (three examples) proceeded in 70-89% yield using Pd(PPh₃)₄ in dioxane/water. Similar conditions on 4-amino-6-bromo-thienopyrimidine (eight examples) gave 67-95% yield. The reaction could be performed with boronic acids containing nonprotected phenolic groups in the ortho, meta and para positions. By prolonging the reaction time, coupling with sterically crowded arylboronic acids was also efficient. Diarylation of 6-bromo-4-chlorothienopyrimidine gave the corresponding 4,6-diarylated derivatives in 71-80% yield depending on the nature of the arylboronic acid.     

Concise synthesis of the C-1-C-12 fragment of amphidinolides T1-T5

The C-1-C-12 segment of the amphidinolides T1-T5 has been synthesised in an efficient manner. The key transformations are highly diastereoselective rearrangement of an oxonium ylide, or metal-bound ylide equivalent, produced by intramolecular reaction of a copper carbenoid with an allylic ether, and macrocyclic fragment coupling by one-pot ring-closing metathesis and hydrogenation.     

An Efficient Synthesis of New 3,4-Dihydropyrimidin- 2(1H)-ones Incorporating a Phenyl Moiety at C-5 and C-6 Catalyzed by TMSCl and Co(OAc)2.4H2O

New 3,4-dihydropyrimidin-2-ones having a phenyl moiety at C-5 and C-6 have been prepared by a microwave-assisted Biginelli–like reaction by a three-component, one-pot condensation of an aromatic aldehyde, deoxybenzoin and urea, or thiourea using TMSCl and Co(OAc) ₂ .4H ₂ O as an efficient Lewis acid catalyst.     

A facile and stereoselective synthesis of the C-2 epimer of (+)-deacetylanisomycin

A short, simple and efficient synthesis of the C-2 epimer of (+)-deacetylanisomycin starting from d-mannitol, utilizing an epoxide opening with a Grignard reagent and acid catalysed unusual intramolecular 5-endo-tet cyclization as key steps has been reported.     

Studying the reactivity of (phthalazin-1(2H)-on-2-yl)methyl trichloroacetimidate towards different C- and O-nucleophiles

A simple and efficient synthesis of phthalazin-1(2H)-one 2-substituted derivatives is achieved in very good yields via reaction of a phthalazinone-trichloroacetimidate with various C- and O-nucleophiles such as aromatic, heteroaromatic and olefinic reagents, sugars and cholesterol in CH₂Cl₂ in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf).     

A convenient synthesis of C-22 and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple transformation of the eight-carbon side chain of a natural spirostan sapogenin into the cephalostatin north 1 spiroketal moiety is described. This methodology, based on an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals, permits the synthesis of C-22 and C-25 stereoisomers of the dioxaspiro[4.4]nonane cephalostatin ring system. The acid-catalyzed isomerization of the spirocenter in the different isomers is studied. [reaction: see text]     

Design and Synthesis of C-1 Methoxycarbonyl Derivative of Narciclasine and Its Biological Activity

A 15-step chemoenzymatic total synthesis of C-1 methoxycarbonyl narciclasine (10) was accomplished. The synthesis began with the toluene dioxygenase-mediated dihydroxylation of ortho-dibromobenzene to provide the corresponding cis-dihydrodiol (12) as a single enantiomer. Further key steps included a nitroso Diels–Alder reaction and an intramolecular Heck cyclization. The C-1 homolog 10 was tested and evaluated for antiproliferative activity against natural narciclasine (1) as the positive control. Experimental and spectral data are reported for all novel compounds.     

Neighboring-group participation by C-2 ether functions in glycosylations directed by nitrile solvents

Ether-protecting functions at C-2 hydroxy groups have been found to play participating roles in glycosylations when the reactions are conducted in nitrile solvent mixtures. The participation mechanism is based on intramolecular interaction between the lone electron pair of the oxygen atom of the C-2 ether function and the nitrile molecule when they are positioned in a cis configuration. A 1,2-cis glycosyl oxazolinium intermediate is formed. This participation, in conjunction with the anomeric effect of the glycosyl donor, confers high 1,2-trans selectivities on glycosylations. Further application of this concept has led to efficient preparations of α-(1→5)-arabinan oligomers.     

Stereoselective Functionalization at C-2 and C-3 of the Gibberellin via an Intramolecular Free Radical Cyclization Approach

The gibberellins (GAs) are a group of naturally-occurring tetracyclic diterpenoid plant growth hormones which are widely present in higher plants and some fungal species. To date over one hundred GAs have been identified and found to be involved in almost every aspect and stage of the growth and development of plants1.Among the GAs identified to date, gibberellic acid (GA3) 1 is the most active and widely used naturally occurring gibberellin. However structure-activity relationship studies …     

A rapid,mild, and efficient method for C-5 iodination/thiocyanation of 2-aminothiazoles

An efficient, green, rapid multitasking protocol for the selective C-5 substitution of 2-aminothiazole using iodic acid and aqueous PEG-400 was developed. The method found suitable for C-5 substitution i.e. iodination and thiocyanation of 2-amino thiazole using iodine and ammonium thiocyanate respectively. Iodic acid was found to be a good oxidant and aqueous PEG-400 as green reaction solvent.     

Synthesis of C-11 linked active ester derivatives of vitamin D3 and their conjugations to 42-residue helix-loop-helix peptides

Derivatives of vitamin D₃ carrying an 8-carbon linker at C-11 terminating in an active ester were synthesized from commercial vitamin D₃ using a disassembly-reassembly strategy. Vitamin D₃ was cleaved at the C6-C7 double bond and the ‘upper’ fragment was converted, via a series of reactions, to derivatives substituted at C-11 with an 8-carbon linker terminating in an ethyl ester. Reassembly with modified ‘lower’ fragments using Horner-Wittig olefination followed by linker ester hydrolysis and re-esterification with p-nitrophenol gave C-11 substituted p-nitrophenyl esters. These vitamin D derivatives were conjugated to 42-amino acid helix-loop-helix peptides by reaction of their p-nitrophenyl esters with lysyl side-chain amino groups on the peptides. The vitamin D—peptide conjugates, being potential specific binder candidates for vitamin D-binding protein, were characterized by mass spectroscopy and CD measurements.     

Efficient palladium-catalyzed C-S cross-coupling reaction of benzo-2,1,3-thiadiazole at C-5-position: A potential class of AChE inhibitors

Functionalization of 2,1,3-benzothiadiazole (BTD) with thiols at C-5 position remains low explored. Moreover, the arylthiol-substitutions at this position are also unexplored and can not be found by a S_N2 or S_N1 reaction. In this sense, herein we present a new palladium-catalyzed methodology for a wide variety of unpublished 5-arylsulfanyl-benzo-2,1,3-thiadiazole derivatives synthesis with moderate to high yields using a low catalytic loading of Pd(L-Pro)₂ as low-coast, and efficient catalyst in low reaction time. Besides, we concluded that the pKa of thiol species has an important role in this catalysis, mainly in the CMD like catalytic cyclo process, which strongly interferes in the reaction yields. Furthermore, arylsulfanyl-benzo-2,1,3-thiadiazoles derivatives have been assessed (in vitro) as potential acetylcholinesterase inhibitors.     

Cobalt(III)‐Catalyzed Intramolecular Cross‐Dehydrogenative C−H/X−H Coupling: Efficient Synthesis of Indoles and Benzofurans

An efficient cobalt(III)‐catalyzed intramolecular cross‐dehydrogenative C?H/N?H coupling of ortho‐alkenylanilines has been developed utilizing O₂ as a terminal oxidant. The developed reaction tolerates various reactive functional groups and allows the synthesis of diverse indole derivatives in good to excellent yields. The method was successfully extended to the synthesis of benzofurans through the intramolecular cross‐dehydrogenative C?H/O?H coupling of ortho‐alkenylphenols.     

A pattern recognition approach to 14-epi-hydrophenanthrene core of the morphine alkaloids based on shikimic acid

An expeditious and stereoselective construction of C-14-epimer of the tetracyclic hydrophenanthrene framework of the morphine alkaloids is described. The core structure is obtained in nine steps in 11% overall yield from shikimic acid via three key transformations: (i) coupling of shikimic acid with 2-iodoisovanillin at C-3 by double S_N2 inversion to form the aryl ether 5; (ii) an intramolecular Heck reaction to construct the dihydrobenzofuran ring and (iii) a McMurry coupling to furnish the hydrophenanthrene core.     

Direct C-3 arylation of N-acetylindoles with anisoles using phenyliodine bis(trifluoroacetate) (PIFA)

The direct C-3 arylation of N-acetylindoles with anisoles was described in this Letter. In the presence of phenyliodine bis(trifluoroacetate) (PIFA) and BF₃·Et₂O, the reaction of N-acetylindoles with anisoles provided C-3 arylindoles with high regioselectivity under mild conditions.     

Stereochemische untersuchungen an C-10-disubstituierten C-9-hydroxyphäophorbiden der a-reihe

The diastereomeric 9-hydroxy pheophorbides 3a, b-1, 2 and 4a, b-1, 2 were prepared by reduction of the 10-alkoxy pheophorbides 1a, b and 2a, b with NaBH₄. Their absolute configuration at C-10 was determined by NMR- and ORD/CD-measurements as well as chemical correlation, the configuration at C-9 by IR- and mainly NMR-spectroscopy. For this purpose, the NMR-spectra of the 9-hydroxy pheophorbides 3a, b-1, 2 had completely to be assigned with the aid of the selectively deuterated alcohols 5a, b-1, 2. The configuration at C-10 is stable under the conditions of the alkaline reduction while C-9 partially epimerizes. The acidic alcoholysis of 3a, b-1, 2, however, proceeds by equilibration at C-10 and almost complete retention at C-9. The H-bonds between the 9-OH group and the C-10 substituents (-COOCH₃, -OCH₃ were investigated by NMR and IR spectroscopy.     

Iodine-mediated one-pot synthesis of C-3 acylated indolizines from pyridines,aryl methyl ketones and acrylate derivatives

An I₂/CuI-promoted multi-component reaction from pyridines, aryl methyl ketones and electron deficient acrylates has been accomplished in a “one-pot” manner, which provides a straightforward and efficient access to C-3 acylated indolizines. The key intermediate of N-ylides is hypothesized to be generated in situ from pyridines and (hetero)aryl methyl ketones in the presence of iodine. This method has been applied in the synthesis of two molecules with anticonvulsant and anti-inflammatory activities.     

Electrophilic aromatic prenylation via cascade cyclization

To gain access to prenylated hexahydroxanthenes, tandem cascade cyclization–electrophilic aromatic substitution reactions have been studied on substrates bearing allylic and propargylic substituents. Both BF₃·OEt₂ and TMSOTf can be used to initiate this reaction sequence, resulting in different ratios of the C-2 and C-6 substitution products. Even though allylic transposition is observed in some cases, the results of a crossover experiment are consistent with an intramolecular reaction sequence. Taken together, these studies now allow preparation of either the C-2 or C-6 prenylated hexahydroxanthene products.