Quantum Dot-Catalyzed Photoreductive Removal of Sulfonyl-Based Protecting Groups

This Communication describes the use of CuInS₂/ZnS quantum dots (QDs) as photocatalysts for the reductive deprotection of aryl sulfonyl-protected phenols. For a series of aryl sulfonates with electron-withdrawing substituents, the rate of deprotection for the corresponding phenyl aryl sulfonates increases with decreasing electrochemical potential for the two electron transfers within the catalytic cycle. The rate of deprotection for a substrate that contains a carboxylic acid, a known QD-binding group, is accelerated by more than a factor of ten from that expected from the electrochemical potential for the transformation, a result that suggests that formation of metastable electron donor–acceptor complexes provides a significant kinetic advantage. This deprotection method does not perturb the common NHBoc or toluenesulfonyl protecting groups and, as demonstrated with an estrone substrate, does not perturb proximate ketones, which are generally vulnerable to many chemical reduction methods used for this class of reactions.     

Coupling of an advanced tri-functional building block by reductive amination leads to a protected backbone of a new archetype of foldamer

In order to advance our project to explore a new archetype of foldamer that preferentially folds in water, we designed two types of tri-functional building blocks with increasingly favorable ketone deprotection properties. Both were selected for their ease of synthetic access and the availability of bulk starting material. While the first building block proved unsuitable for efficient coupling by reductive amination, the second gave rise to almost quantitative yields according to mass spectral monitoring. It was thus effectively turned into a protected dimer and a tetramer. Although their subsequent purification prior to exhaustive ketone deprotection was preparatively impractical in view of their high polarity/water solubility, the stage is now set for transfer of the oligomer synthesis onto the solid phase on resin in view of the efficient five-step synthetic access from affordable bulk material, the favorable deprotection properties, the perspective for introduction of a variety of backbone substituents, and the possibility to protect the amine terminus by Boc or Fmoc protection.     

Quantum Dot‐Catalyzed Photoreductive Removal of Sulfonyl‐Based Protecting Groups

This Communication describes the use of CuInS₂/ZnS quantum dots (QDs) as photocatalysts for the reductive deprotection of aryl sulfonyl‐protected phenols. For a series of aryl sulfonates with electron‐withdrawing substituents, the rate of deprotection for the corresponding phenyl aryl sulfonates increases with decreasing electrochemical potential for the two electron transfers within the catalytic cycle. The rate of deprotection for a substrate that contains a carboxylic acid, a known QD‐binding group, is accelerated by more than a factor of ten from that expected from the electrochemical potential for the transformation, a result that suggests that formation of metastable electron donor–acceptor complexes provides a significant kinetic advantage. This deprotection method does not perturb the common NHBoc or toluenesulfonyl protecting groups and, as demonstrated with an estrone substrate, does not perturb proximate ketones, which are generally vulnerable to many chemical reduction methods used for this class of reactions.     

Development of trityl-based photolabile hydroxyl protecting groups

A series of trityl-based photolabile hydroxyl protecting groups have been examined. These PPGs evolve from the traditional acid-labile trityl protecting group with proper electron-donating substituents. Structure-reactivity relationships have been explored. A m-dimethylamino group is crucial to achieve high photochemical deprotection efficiency. The o-hydroxyl group in 8 greatly improves the yield of the photochemical deprotection reaction, compared with the corresponding o-methoxyl-substituted counterpart 7. However, comparison between the photoreactions of 9 and 11 does not show similar structural relevance. The PPG in ether 1 (i.e., DMATr group) is structurally simple and easy to prepare and install. Its deprotection can be successfully carried out with irradiation of sunlight without requirement of photochemical devices.     

Palladium mediated direct coupling of silylated arylalkynes with propargylic chlorides: an efficient access to functionalized conjugated allenynes

Pd/Cu-catalyzed one-pot reaction of 1-trimethylsilyl-2-arylalkynes with propargylic chlorides in the presence of TBAF is described. The present new procedure is applicable to a wide range of silylated arylalkynes with both electron-withdrawing and electron-donating substituents. Functionalized allenynes can thus be obtained in good yields without prior deprotection of the alkynes.     

Synthesis of enantiomerically pure (purin-6-yl)phenylalanines and their nucleosides, a novel type of purine-amino acid conjugates

[Chemical reaction: See text] Enantiomerically or diastereomerically pure 4-(purin-6-yl)phenylalanines, a novel type of stable amino acid-purine conjugates, were synthesized by palladium-catalyzed cross-coupling reactions of protected 4-boronophenylalanines or 4-(trimethylstanyl)phenylalanines with diverse 6-halopurines (9-benzyl-6-halopurines and 9-(tetrahydropyran-2-yl)-6-halopurines as well as acyl- and silyl-protected 6-halopurine ribonucleosides and 2-deoxyribonucleosides). Free purine bases and nucleosides bearing (S)- or (R)-phenylalanine in position 6 were obtained after complete deprotection of the products of cross-coupling reactions. Reactivity trends for both of these cross-coupling and deprotection protocols have been compared in terms of practicability, efficiency, and stereoselectivity.     

Aryldithioethyloxycarbonyl (Ardec): a new family of amine protecting groups removable under mild reducing conditions and their applications to peptide synthesis

The development of phenyldithioethyloxycarbonyl (Phdec) and 2-pyridyldithioethyloxycarbonyl (Pydec) protecting groups, which are thiol-labile urethanes, is described. These new disulfide-based protecting groups were introduced onto the epsilon-amino group of L-lysine; the resulting amino acid derivatives were easily converted into N alpha-Fmoc building blocks suitable for both solid- and solution-phase peptide synthesis. Model dipeptide(Ardec)s were prepared by using classical peptide couplings followed by standard deprotection protocols. They were used to optimize the conditions for complete thiolytic removal of the Ardec groups both in aqueous and organic media. Phdec and Pydec were found to be cleaved within 15 to 30 min under mild reducing conditions: i) by treatment with dithiothreitol or beta-mercaptoethanol in Tris.HCl buffer (pH 8.5-9.0) for deprotection in water and ii) by treatment with beta-mercaptoethanol and 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) in N-methylpyrrolidinone for deprotection in an organic medium. Successful solid-phase synthesis of hexapeptides Ac-Lys-Asp-Glu-Val-Asp-Lys(Ardec)-NH2 has clearly demonstrated the full orthogonality of these new amino protecting groups with Fmoc and Boc protections. The utility of the Ardec orthogonal deprotection strategy for site-specific chemical modification of peptides bearing several amino groups was illustrated firstly by the preparation of a fluorogenic substrate for caspase-3 protease containing the cyanine dyes Cy 3.0 and Cy 5.0 as FRET donor/acceptor pair, and by solid-phase synthesis of an hexapeptide bearing a single biotin reporter group.     

New persubstituted 1,3,5-trisethynyl benzenes via Sonogashira coupling

Starting from 1,3,5-trifluoro-2,4,6-triiodobenzene, selective Sonogashira coupling gave trisalkynylbenzenes, which can be further functionalized making use of the reactive fluorine substituents on the benzene core. Along the way, a conceivably trivial deprotection step unexpectedly led to a pentasubstituted benzene derivative the structure of which was revealed by X-ray crystallography.     

Versatile assembly of 5-aminothiazoles based on the Ugi four-component coupling

A flexible route to novel 5-aminothiazoles has been developed based on cyclisation of diamide adducts, prepared using the Ugi reaction, in the presence of Lawesson’s reagent. The Walborsky reagent (1,1,3,3-tetramethylbutyl isocyanide) was used as the isonitrile component, facilitating subsequent deprotection of the N-alkyl group to yield free 5-aminothiazoles, which were prepared with a variety of substituents at the 2- and 4-positions.     

Preparation and antitumor activity of 2'-O-, 3'-O- and 2',3'-di-O-substituted derivatives of etoposide.

The 2'-O-, 3'-O- and 2',3'-di-O-substituted derivatives (4a--p) of etoposide were prepared by nucleophilic substitution of 4'-O-benzyloxycarbonyletoposide (2) followed by deprotection. Controlled reaction (a limited amount of reagents and low temperature) was required for preparing the mono-O-substituted derivatives. In terms of ED125 values, doses which show 125% of T/C against P388 leukemia in mice, both the 2'-O-acetate (4a, ED125 = 0.18 mg/kg) and 3'-O-acetate (4b, 0.23 mg/kg) were nearly as active as etoposide (1, 0.19 mg/kg), while the 2',3'-di-O-acetate (4c, 1.9 mg/kg) was somewhat less potent. In the replacement with other substituents, antitumor activity of the 2'-O-substituted derivatives was affected much more by the difference of the substituents as compared with that of the corresponding 3'-O-substituted derivatives. In the 2',3'-di-O-substituted derivatives, the activity was decreased additively on the substituents.     

Chalice-Type Tridentate Silicon Lewis Acids of C3 Symmetry in a Single Step Starting from Hexadehydrotribenzo[12]annulene

Tridentate Lewis acids with aligned functions were synthesized based on the rigid framework hexadehydrotribenzo[12]annulene. The backbone and its fluorinated analogue were synthesised in one-pot syntheses, with alkyne deprotection and Sonogashira cross coupling reaction being carried out in one step. Hydrosilylation of the annulene with chlorohydrosilanes proceeded highly selectively and afforded rigid poly-Lewis acids with three SiCl₃ or SiCl₂Me substituents perfectly oriented to one side of the molecule in a single step. The progress of hydrosilylation was investigated by time-correlated NMR spectroscopic studies. The crystal structures show that the framework is symmetrically functionalised and the silyl substituents are aligned in one direction. To increase the acidity of the Lewis acids the chlorosilyl substituents were fluorinated with SbF₃. Further investigation of hydrometallation reactions (M=B, Al, Ga, Sn) did not lead to corresponding structures.     

Synthesis of 3-substituted isocoumarins and their inhibitory effects on degranulation of RBL-2H3 cells induced by antigen

Eleven 3-substituted isocoumarins and a benzylidenephthalide were synthesized through thermal cyclization reaction of delta- and gamma-ketoamides, respectively. Subsequent deprotection of the hydroxyl groups of the resulting isocoumarin and benzylidenephthalide compounds afforded thunberginols A, B, and F, respectively, which originated from the processed leaves of Hydrangea macrophylla SERINGE var. thunbergii MAKINO. The synthesized isocoumarins and thunberginols were evaluated for their anti-allergic activity, in which thunberginol B exhibited the highest inhibitory potency on the degranulation of RBL-2H3 cells induced by antigen. Structure-activity relationship studies were carried out to determine the necessary substituents on the 3-phenylisocoumarin skeleton for inhibitory activity.     

Synthesis and Structural Characterization of Three Unique Helicobacter pylori α‐Cholesteryl Phosphatidyl Glucosides

Steryl glycosides produced by bacteria play important biological roles in the evasion and modulation of host immunity. Step‐economical syntheses of three cholesteryl‐6‐O‐phosphatidyl‐α‐D ‐glucopyranosides (αCPG) unique to Helicobacter pylori have been achieved. The approach relies upon regioselective deprotection of per‐O‐trimethylsilyl‐α‐D ‐cholesterylglucoside at C6 followed by phosphoramidite coupling. Global TMS ether deprotection in the presence of oxygen and subsequent deprotection of the cyano ethyl phosphoester afforded the target compounds in 16–21 % overall yield starting from D ‐glucose. The structures of these natural products were determined using a combination of 2D NMR methods and mass spectrometry. These robust synthesis and characterization protocols provide analogues to facilitate glycolipidomic profiling and biological studies.     

Toward solution-phase automated iterative synthesis: fluorous-tag assisted solution-phase synthesis of linear and branched mannose oligomers

We report herein the first synthesis of linear and branched mannose oligosaccharides using fluorous-tag assistance with reagents and FSPE protocols that are amenable to automation. The particular fluorous linker proved to maintain solubility of the growing oligosaccharide chain such that identical reaction solvent conditions and purification protocols could be used between glycosylation and deprotection reactions, thereby rendering the procedures amenable to automation.     

Self-assembled monolayers from biphenyldithiol derivatives: optimization of the deprotection procedure and effect of the molecular conformation

A series of biphenyl-derived dithiol (BDDT) compounds with terminal acetyl-protected sulfur groups and different structural arrangements of both phenyl rings have been synthesized and fully characterized. The different arrangements were achieved by introducing hydrocarbon substituents in the 2 and 2' positions of the biphenyl backbone. The presented model compounds enable the investigation of the correlation between the intramolecular conformation and other physical properties of interest, like, e.g., molecular assembly or electronic transport properties. Here, the ability of these model compounds to form self-assembled monolayers (SAMs) on Au(111) and Ag(111) is investigated in details. The deprotection of the target molecules was performed in situ using either NH4OH or triethylamine (TEA) deprotection agent. The fabricated films were characterized by synchrotron-based high-resolution photoelectron spectroscopy and near-edge absorption fine structure spectroscopy. Whereas the deprotection by NH4OH was found to result in the formation of multilayer films, the deprotection by TEA allowed the preparation of densely packed BDDT SAMs with a noticeably higher orientational order and smaller molecular inclination on Ag than on Au. Introduction of the alkyl bridge between the individual rings of the biphenyl backbone did not lead to a noticeable change in the structure and packing density of the BDDT SAMs as long as the molecule had a planar conformation in the respective SAM. The deviation from this conformation resulted in the deterioration of the film quality and a decrease of the orientational order.     

Demand-based thiolate anion generation under virtually neutral conditions: influence of steric and electronic factors on chemo- and regioselective cleavage of aryl alkyl ethers

Thiolate anions have been generated in a "demand-based" fashion under virtually neutral conditions for chemoselective deprotection of aryl alkyl ethers. Solvents play the critical role in making the reaction effective and should have high values of epsilon (>30), molecular polarizabilities (>10), and DN (>27) and low values of AN (<14). However, it is the combined effect of all of these physical properties that make a particular solvent effective. The reaction rates of cleavage of various aryl alkyl ethers are dependent on the steric crowding around the O-alkyl carbon and follow the order propargyl approximately allyl approximately benzyl > methyl > ethyl. Electron-withdrawing substituents increase the rate of ether cleavage reaction. The influence of the steric and electronic factors have been successfully exploited for selective deprotection of aryl alkyl ethers during inter- and intramolecular competitions.     

Synthesis of (+)-dumetorine and congeners by using flow chemistry technologies

An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2-(piperidin-2-yl)ethanol 4 with 29% overall yield. Most of the reactions were carried out by exploiting solvent superheating and by using packed columns of immobilized reagents or scavengers to minimize handling. New protocols for performing classical reactions under continuous flow are disclosed: the ring-closing metathesis reaction with a novel polyethylene glycol-supported Hoveyda catalyst and the unprecedented flow deprotection/Eschweiler-Clarke methylation sequence. The new protocols developed for the synthesis of (+)-dumetorine were applied to the synthesis of its simplified natural congeners (-)-sedamine and (+)-sedridine.     

New insights into the solubilization of Bodipy dyes

Several Bodipy dyes were synthesized with various substituents designed to improve the water solubility. Among the different synthetic strategies protection of sulfonate groups by pyrrole of indopyrrole appears efficient but the deprotection step does not offer viable routes. Conversion of the bromopyrene or iodo Bodipy compounds to sulfobetaine derivatives is feasible either by cross-coupling directly the ethynylsulfobetaine or by first cross-coupling 1-(N,N-dimethylamino)-prop-2-yne followed by quaternization of the dimethylamino residue with 1,3-propanesultone. Some of these dyes (Bodipy’s and pyrene) are reasonably soluble in water and remain highly fluorescent in polar solvents and water.     

Synthesis of biphenylamines via Suzuki-Miyaura cross-coupling reactions

A small library of meta- and para-biphenylamines substituted by various alkyl, alkoxy, phenoxy, or halogeno groups on their aromatic rings was synthesized via Suzuki-Miyaura cross-coupling between bromoanilines and arylboronic acids using palladium catalysts. The experimental conditions were carefully adjusted to accommodate a wide range of substituents, in terms of electron-withdrawing or -donating ability and steric bulk. In some cases, protection and deprotection of the amine function via its trifluoroacetamide were added to the reaction sequence in order to facilitate the cross-coupling step.     

Catalytic,asymmetric Mannich-type reactions of alpha-imino esters bearing readily removable substituents on nitrogen

[reaction: see text] Catalytic, enantioselective Mannich-type reactions of alpha-imino esters bearing readily removable substituents on nitrogen are described. Several N-carbamate-protected alpha-imino esters, which are readily prepared from 2-bromoglycine esters using a polymer-supported amine, reacted with silicon enolates to afford the desired adducts in high yields with high enantioselectivity using a copper(II)-diamine complex. Easy deprotection of the product amine and transformation to free alpha-amino acid derivatives have also been demonstrated.