Building Block For Synthesis Research Articles

Late-Stage Diversification of Phosphinic Dehydroalanine Pseudopeptides Based on a Giese-Type Radical C-Alkylation Strategy.

A straightforward, late-stage diversification strategy for the installation of side chains on readily accessible unsaturated phosphinopeptidic scaffolds based on a Giese-type addition of alkyl radicals has been investigated. Among different alternatives, the preferred methodology is operationally simple as it can be carried out in an open flask with no need for protection of acidic moieties. Direct application to the synthesis of SPPS-compatible building blocks or to longer peptides is also reported.

A Stereoselective Synthesis of the ACE Inhibitor Trandolapril

A conceptually novel and stereoselective synthesis of the enantiopure octahydroindole building block and its conversion into the ACE inhibitor trandolapril was achieved. Key steps include the α-allylation of a protected l-pyroglutamic acid derivative, a highly diastereoselective Hosomi–Sakurai reaction and a Ru-catalyzed ring-closing metathesis of a 4,5-diallylated proline. This way, the synthesis of trandolapril was efficiently achieved in 25% overall yield (12 steps).

A molecular overview of the primary dystroglycanopathies.

Dystroglycan is a major non‐integrin adhesion complex that connects the cytoskeleton to the surrounding basement membranes, thus providing stability to skeletal muscle. In Vertebrates, hypoglycosylation of α‐dystroglycan has been strongly linked to muscular dystrophy phenotypes, some of which also show variable degrees of cognitive impairments, collectively termed dystroglycanopathies. Only a small number of mutations in the dystroglycan gene, leading to the so called primary dystroglycanopathies, has been described so far, as opposed to the ever‐growing number of identified secondary or tertiary dystroglycanopathies (caused by genetic abnormalities in glycosyltransferases or in enzymes involved in the synthesis of the carbohydrate building blocks). The few mutations found within the autonomous N‐terminal domain of α‐dystroglycan seem to destabilise it to different degrees, without influencing the overall folding and targeting of the dystroglycan complex. On the contrary other mutations, some located at the α/β interface of the dystroglycan complex, seem to be able to interfere with its maturation, thus compromising its stability and eventually leading to the intracellular engulfment and/or partial or even total degradation of the dystroglycan uncleaved precursor.

Stereodivergent Synthesis through Catalytic Asymmetric Reversed Hydroboration.

The control of chemo-, regio-, diastereo-, and enantioselectivity is a central theme in organic synthesis. The capability to obtain the full set of stereoisomers of a molecule would significantly enhance the efficiency for the synthesis of natural product analogues and creation of chiral compound libraries for drug discovery. Despite the tremendous progress achieved in the field of asymmetric synthesis in the past decades, the precise control of both relative and absolute configurations in catalyst-controlled reactions that create multiple stereocenters remains a significant synthetic challenge. We report here the development of a catalyst-controlled hydroboration with hitherto unattainable selectivity. The Rh-catalyzed hydroboration of α, β-unsaturated carbonyl compounds with pinacolborane proceeds with high levels of regio-, diastereo-, and enantioselectivities to provide a hydroboration product with two vicinal stereocenters. Through the appropriate choice of substrate geometry ( E or Z) and ligand enantiomer ( S or R), all the possible diastereoisomers are readily accessible. The boron-containing products underwent many stereospecific transformations, thus providing a strategy for collective stereodivergent synthesis of diverse valuable chiral building blocks.

Direct dehydrogenative alkyl Heck-couplings of vinylarenes with umpolung aldehydes catalyzed by nickel

Alkenes are fundamental functionalities in nature and highly useful intermediates in organic synthesis, medicinal chemistry and material sciences. Transition-metal-catalyzed Heck couplings with organic halides as electrophiles have been established as a powerful protocol for the synthesis of this valuable building block. However, the requirement of organic halides and the generation of stoichiometric hazardous halide wastes may cause significant sustainable concerns. The halide-free oxidative Heck alkenylations involving organometallics or arenes as the coupling partners provide a facile and alternative pathway. Nonetheless, stoichiometric amounts of extra oxidant are essential in most cases. Herein, we present a direct dehydrogenative alkyl Heck-coupling reaction under oxidant-free conditions, liberating hydrogen, nitrogen and water as the side products. Excellent regioselectivity is achieved via neighboring oxygen atom coordination. Broad substrate scope, great functional group (ketone, ester, phenol, free amine, amide etc) tolerance and modification of pharmaceutical candidates and biological molecules exemplified its generality and practicability.

Superstructures of Multielement Colloidal Molecules: Efficient Pathways to Construct Reconfigurable Photonic and Phononic Crystals

AbstractMotivated by recent advances in synthesis and characterization of complex colloidal building blocks, the self‐assembly behavior and transport properties of novel superstructures of multielement colloidal molecules are explored with applications in areas such as phononics, photonics, and photovoltaics. Using an analytical/computational framework, the connectivity landscape of various shapes of colloidal molecules is examined to propose new multicomponent superstructure phases that can self‐assemble from binary mixtures of these building blocks. The identified superstructures are then investigated in terms of their tunable photonic/phononic properties. The dependence of photonic bandgaps on various features of the superstructures such as building block size and shape is studied. Each superstructure is composed of at least four different types of elements, which provides a desirable framework to obtain reconfigurable metamaterials. The calculations show that a binary superstructure of tetrahedral units can result in photonic bandgaps with sizes as large as 27% for material compositions with dielectric constant difference of 15. The new superstructures formed by colloidal molecules expand the existing self‐assembly paradigms for colloidal particles. This paper also promotes future experimental and theoretical work for discovering more complex colloidal phases with a higher number of degrees of freedom to be utilized for engineering desired functional materials.

Exploring a glycosylation methodology for the synthesis of hydroxamate-modified alginate building blocks

Alginate, an anionic polysaccharide, is an important industrial biomaterial naturally harvested from seaweed. Many of its important physicochemical properties derive from the presence of charged carboxylate groups presented as uronic acids within the polysaccharide backbone. An ability to modify these carboxylates with alternate functional groups would enable the design and implementation of new alginate systems possessing different physicochemical properties. We present herein our approach to the chemical synthesis of alginate disaccharides, modified at the carboxylate C6 position with bioisosteric hydroxamate residues. The synthesis and utilisation of C6-hydroxamate donor and acceptor building blocks enables a first access to protected α- and β-linked hydroxamate-containing disaccharides, additionally equipped with a functional tether at the reducing terminus. The evaluation of these building blocks for chemical glycosylation demonstrates the incorporation of bioisosteric functional groups into an alginate disaccharide backbone and highlights the important contribution of both acceptor and donor reactivity underpinning uronate glycosylations.

Second-Generation Synthesis of a Chiral Building Block for Oxygenated Terpenoids via a Ring-Contractive Coupling with a Secondary Alcohol

Second-Generation Synthesis of a Chiral Building Block for Oxygenated Terpenoids via a Ring-Contractive Coupling with a Secondary Alcohol

Production of 5-Hydroxymethylfurfural from D-Fructose in Low-Transition-Temperature Mixtures Enhanced by Chloride Anions and Low Amounts of Organic Acids.

The use of safe and sustainable solvents able to solvate reagents and to catalyze their reactions at temperatures below 100 °C is an innovative strategy to develop future lignocellulosic biorefineries. Many low-transition-temperature mixtures (LTTMs) have been investigated for this purpose. Among them, natural deep eutectic solvents (NADESs) have been proposed as cheap and renewable alternatives to ionic liquids for the synthesis of bio-based chemical building blocks. We compare herein the ability of several organic acids/choline chloride/water LTTMs to perform D-fructose dehydration to 5-hydroxymethylfurfural (5-HMF). The addition of chloride salts as well as an increased proportion of choline chloride promotes 5-HMF formation, which seems to indicate a beneficial effect of chloride anions on D-fructose dehydration. Besides improving selectivity by at least 10 %, increasing the choline chloride/acid ratio could enhance the biodegradability of the LTTMs. Unlike other acidic components, maleic and citric acids are especially selective at early D-fructose conversion. Maleic acid was the most selective acidic component among the tested chemicals, achieving an 80 % 5-HMF molar yield in 1 h at 90 °C.

Conjugated Polymers Based on Thiazole Flanked Naphthalene Diimide for Unipolar n-Type Organic Field-Effect Transistors

This paper reports the rational design and synthesis of a novel electron-withdrawing building block, thiazole flanked naphthalene diimide (TzNDI), which offers a coplanar conformation and deep-lying highest-occupied molecular orbitals energy level in resulting conjugated polymers. A series of conjugated polymers (PTzNDI-2FT, PTzNDI-T, PTzNDI-Se, and PTzNDI-2T) consisting of TzNDI and different donor units were synthesized and characterized. The polymers all possess a high molecular weight and excellent thermal property. Their intense light absorption in low energy bands suggests an enhanced intramolecular charge transfer. The organic field-effect transistors (OFETs) based on these polymers exhibit unipolar n-type transport characteristics with low off current and high on–off current ratio. More importantly, all the devices exhibit near ideal transfer curves with kink-free transfer characteristics. Among these polymers, PTzNDI-2FT exhibits the highest electron mobility (μe) of 0.57 cm2 V–1 s–1, outperformi...

An Electrophilic Bromine Redox Catalysis for the Synthesis of Indole Alkaloid Building Blocks by Selective Aliphatic C-H Amination.

A new homogeneous bromine(-I/I) redox catalysis is described, which is based on monomeric bromine(I) compounds containing transferable phthalimidato groups. These catalysts enable intermolecular C-H amination reactions at previously unaccessible aliphatic positions and thus enlarge the synthetic potential of direct C-N bond formation, including its application in the synthesis of alkaloid building blocks. This aspect is demonstrated by a new synthetic approach to aspidospermidine. In addition to the development of the catalyst system, the structures of the involved bromine(I) key catalysts were fully elucidated, including by X-ray analyses.

Synthesis of Trinucleotide Building Blocks in Solution and on Solid Phase.

We have developed two methods, in solution and on solid phase, that give easy access to trinucleotide phosphoramidites capable of undergoing coupling reactions by the solid-phase phosphoramidite approach. The solution protocol is characterized by application of 5'-O-dimethoxytrityl (DMT) and 3'-O-tert-butyldimethylsilyl (TBDMS) as a pair of orthogonal protecting groups and 2-cyanoethyl (CE) for protection of the phosphate. Starting with suitably functionalized monomers, synthesis proceeds in the 3'- to 5'-direction, delivering the fully protected trinucleotide. The 3'-O-protecting group is cleaved followed by phosphitylation of the free 3'-OH group. The solid-phase protocol is based on standard phosphoramidite chemistry in conjunction with a dithiomethyl linkage connecting the 3'-starting nucleoside to the polymer. The disulfide bridge can be cleaved under neutral conditions for release of the trinucleotide from the support preserving all other protecting groups. © 2018 by John Wiley & Sons, Inc.

Total Synthesis of (−)‐Cylindrocyclophane F: A Yardstick for Probing New Catalytic C−C Bond‐Forming Methodologies

A short and efficient total synthesis of the C2 -symmetric (-)-cylindrocyclophane F is presented, using a cross olefin metathesis dimerization strategy for construction of the [7,7]-paracyclophane macrocycle. The synthesis of the dimerization building block includes a Pd-catalyzed sp3 -sp2 Negishi cross coupling of a sterically hindered Zn-reagent with an aromatic triflate, an enantiospecific Zn-catalyzed sp3 -sp3 cross coupling of an α-hydroxy ester triflate with a Grignard reagent and the application of an enantioselective Rh-catalyzed C-allylation of an electron rich arene.

Mechanoenzymatic resolution of racemic chiral amines, a green technique for the synthesis of pharmaceutical building blocks

Very recently, several successful biocatalytic processes using mechanical activation to carry out enantioselective reactions have been reported. The present work describes the use of Candida antarctica Lipase B (CALB) in the kinetic resolution of racemic chiral amines by means of High-Speed Ball Milling (HSBM), minimizing the use of solvent and reducing reaction times. This approach provides an efficient and easily scalable strategy that was used for the green synthesis of enantiopure Rasagiline, as an illustrative example.

Mixed and Matched Metallo‐Nanotexaphyrin for Customizable Biomedical Imaging

The discovery and synthesis of multifunctional organic building blocks for nanoparticles have remained challenging. Texaphyrin macrocycles are multifunctional, all-organic compounds that possess versatile metal-chelation capabilities and unique theranostics properties for biomedical applications. Unfortunately, there are significant difficulties associated with the synthesis of texaphyrin-based subunits capable of forming nanoparticles. Herein, the detailed synthesis of a texaphyrin-phospholipid building block is reported via a key 1,2-dinitrophenyl-phospholipid intermediate, along with stable chelation of two clinically relevant metal ions into texaphyrin-lipid without compromising their self-assembly into texaphyrin nanoparticles or nanotexaphyrin. A postinsertion methodology to quantitatively insert a variety of metal-ions into preformed nanotexaphyrins is developed and employed to synthesize a structurally stable, mixed 111 indium-manganese-nanotexaphyrin for dual modal single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). In vivo dual SPECT/MRI imaging of 111 In-Mn-nanotexaphyrins in an orthotopic prostatic PC3 mouse model demonstrates complementary signal enhancement in the tumor with both modalities at 22 h post intravenous administration. This result highlights the utility of hybrid metallo-nanotexaphyrins to achieve sensitive and accurate detection of tumors by accommodating multiple imaging modalities. The power of this mixed and matched metallo-nanotexaphyrin strategy can be unleashed to allow a diverse range of multifunctional biomedical imaging.

Fullerene Building Blocks with Tailor-Made Solubility and New Insights into Their Hierarchical Self-Assembly.

Herein, the synthesis of fullerene derivatives with adjustable polarities and lyotropic aggregation properties is reported. The polarity range spans from superhydrophobic to hydrophilic, while simultaneously providing a further reactive position with a view to graft them onto other materials. The synthetic strategy relies on a selective protection with an isoxazoline moiety. The remaining octahedral positions were further functionalized with the desired groups to tune their solubility, yielding mixed [5:1] hexakisadducts. The subsequent deprotection by clean photolytic reaction led to fullerene pentakisadducts with an incomplete octahedral addition pattern, which are useful forerunners for the synthesis of building blocks. Their hydrophobic/hydrophilic behavior has been characterized both in solution and surface through octanol/water partition coefficients (log P) and contact angle measurements. Furthermore, these derivatives can form supramolecular constructions which have been studied by dynamic light scattering (DLS) and cryo‐TEM.

Synthesis of Trifluoromethyl Ketone Containing Amino Acid Building Blocks for the Preparation of Peptide-Based Histone Deacetylase (HDAC) Inhibitors

Trifluoromethyl ketones (TFMKs) are electrophilic moieties which hydrate readily in aqueous media to give geminal diols. This ability has been exploited for the development of histone deacetylase (HDAC) inhibitors, because HDAC enzymes contain a Zn2+ ion which may be chelated by this functionality. Interestingly, TFMKs are exceptional Zn2+-binding groups for targeting the intriguing class IIa HDAC isozymes, involved in transcription factor recruitment and gene regulation. Here, we have developed a scalable and inexpensive synthetic procedure for preparation of the enantiomerically pure TFMK-containing amino acid building block (S)-2-amino-9,9,9-trifluoro-8-oxononanoic acid (Atona). In addition, we propose a protecting group strategy applicable to automated solid-phase peptide synthesis and demonstrate the ability of Atona-containing peptides to inhibit the enzymatic activity of class IIa HDACs with nanomolar potency. We envision that this synthesis will motivate the further development of peptide-based probes for the study of class IIa HDACs.

Synthesis of modular building blocks using glycosyl phosphate donors for the construction of asymmetric N-glycans

Glycosyl phosphates are known as versatile donors for the synthesis of complex oligosaccharides both chemically and enzymatically. Herein, we report the stereoselective construction of modular building blocks for the synthesis of N-glycan using glycosyl phosphates as donors. We have synthesized four trisaccharide building blocks with orthogonal protecting groups, namely, Manβ2GlcNAc(OAc)3β6GlcNAc (9), Manβ2GlcNAc-β6GlcNAc(OAc)3 (15), Manβ2GlcNAc(OAc)3β4GlcNAc (18) and Manβ2GlcNAcβ4GlcNAc(OAc) (22) for further selective elongation using glycosyltransferases. The glycosylation reaction using glycosyl phosphate was found to be high yielding with shorter reaction time. Initially, The phthalimide protected glucosamine donor was exploited to ensure the formation of β-glycosidic linkage and later converted to the N-acetyl group before the enzymatic synthesis. The selective deprotection of O-benzyl group was performed prior to enzymatic synthesis to avoid its negative interference.

Metal‐Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing

AbstractMany pharmaceuticals feature biaryl motifs that are crucial for their binding to the target. Yet, benchmark methods for selective cross‐couplings rely on highly toxic heavy metal catalysts, which are unfavorable in the synthesis of pharmaceuticals. Metal‐free coupling reactions, on the other hand, may require harsh conditions and lack selectivity. We report a novel, metal‐free cross‐coupling reaction that involves the tethering of two phenyl groups by a temporary, traceless sulfonamide linker that directs a photochemical aryl fusion into a single coupling product. The perfect regio‐ and chemoselectivity of the reaction could be rationalized by a cyclic intermediate, which fragments into the biaryl and volatile side products. Using a flow reactor, we synthesized numerous substituted biaryl building blocks for important therapeutics in high yields, such as antibiotics, antitumor, neuroprotective and cholesterol‐lowering agents as well as antiarthritic non‐steroidal antiinflammatory drugs (NSAIDs). The new method was successfully employed in a total synthesis of cannabinol, an important analgesic and antiemetic therapeutic. We also report a metal‐free synthesis of key building blocks used for the preparation of sartans, antihypertensive agents that rank among the top blockbuster drugs worldwide. This safe and convenient protocol is a valuable alternative for the widely used metal‐dependent aryl cross‐coupling methods.

Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing.

Many pharmaceuticals feature biaryl motifs that are crucial for their binding to the target. Yet, benchmark methods for selective cross-couplings rely on highly toxic heavy metal catalysts, which are unfavorable in the synthesis of pharmaceuticals. Metal-free coupling reactions, on the other hand, may require harsh conditions and lack selectivity. We report a novel, metal-free cross-coupling reaction that involves the tethering of two phenyl groups by a temporary, traceless sulfonamide linker that directs a photochemical aryl fusion into a single coupling product. The perfect regio- and chemoselectivity of the reaction could be rationalized by a cyclic intermediate, which fragments into the biaryl and volatile side products. Using a flow reactor, we synthesized numerous substituted biaryl building blocks for important therapeutics in high yields, such as antibiotics, antitumor, neuroprotective and cholesterol-lowering agents as well as antiarthritic non-steroidal antiinflammatory drugs (NSAIDs). The new method was successfully employed in a total synthesis of cannabinol, an important analgesic and antiemetic therapeutic. We also report a metal-free synthesis of key building blocks used for the preparation of sartans, antihypertensive agents that rank among the top blockbuster drugs worldwide. This safe and convenient protocol is a valuable alternative for the widely used metal-dependent aryl cross-coupling methods.