An Efficient Cationic Cyclization Approach for the Construction of Labdane Diterpenoid Decalin Ring Skeleton

An effective approach for the construction of the decalin ring skeleton of labdane diterpenoids was developed based on a key biomimetic cationic polyene cyclization of an epoxy allylsilane precursor. The synthetic approach demonstrated here would be useful in the enantioselective and diastereoselective total synthesis of natural labdane diterpenoids in general.     

Recent advances in the total synthesis of pharmaceutically relevant diterpenes

A detailed overview is presented of recent total synthesis approaches to four different diterpenoids--the ginkgolides, tonantzitlolone, ingenol and eleutherobin. Due to their structural complexity, all pose major challenges for total synthesis, guaranteeing diverse strategic tours de force and a rich synthetic chemistry. Additionally, all four diterpenoids are of major relevance because of their biological (target) or pharmaceutical properties.     

Divergent Total Synthesis of Atisane‐Type Diterpenoids

Atisane‐type diterpenoids are the principal constituent of tetracyclic C₂₀‐diterpenoids, widely isolated from the plant kingdom with varying degrees of structural complexity and pharmacological activity. The tetracarbocyclic system with the unique bicyclo[2.2.2]octane skeleton of this natural product family has generated interest within the synthetic community. Divergent total synthesis is an effective tactic to synthesize several atisane‐type diterpenoids using structural interconversion from a common intermediate. This account summarizes the divergent total synthesis of atisane‐type diterpenoids.     

Chemical Protein Synthesis by Native Chemical Ligation and Variations Thereof

For a long time, the total synthesis of proteins was considered as a “mission impossible” because of the tedious and complex synthetic steps and demanding purification processes. However, with the development of modern synthetic methodologies, many protein syntheses have now been reported. More importantly, through chemical synthesis, desired modifications can be installed to target proteins precisely, which is a major advantage over traditional bio‐synthesis approaches. This review summarizes the techniques developed for protein assembly, including native chemical ligation, Se‐mediated ligation, and a range of other ligation methods. A few synthetic examples, whereby synthetic proteins with desired modifications have been utilized for related biological research, are also included. We believe that chemical synthesis can provide alternative pathways to solve problems that have hitherto proved insurmountable by traditional biological approaches.     

FR901464: total synthesis, proof of structure, and evaluation of synthetic analogues

The natural product FR901464 (1) was isolated by the Fujisawa Pharmaceutical Co. and shown to have intriguing biological properties including impressive antitumor activity. In this paper we describe the first total synthesis of 1 in full detail. A chiral building block synthetic strategy was used to assemble the target: optically active components were generated using asymmetric catalytic reactions, and these fragments were coupled together at a late stage in a convergent synthesis. In particular, a versatile, asymmetric hetero-Diels-Alder (HDA) reaction was developed in the context of this synthesis and used with great effectiveness for the preparation of the two densely functionalized pyran rings. The flexible nature of the synthetic route also allowed us to prepare a series of analogues of 1. These compounds were used to prove the relative stereochemistry of the natural product as well as to probe the importance of certain structural features of FR901464 with regard to biological activity.     

On resin synthesis of sulfated oligosaccharides

Sulfated glycans are involved in many biological processes, making well-defined sulfated oligosaccharides highly sought molecular probes. These compounds are a considerable synthetic challenge, with each oligosaccharide target requiring specific synthetic protocols and extensive purifications steps. Here, we describe a general on resin approach that simplifies the synthesis of sulfated glycans. The oligosaccharide backbone, obtained by Automated Glycan Assembly (AGA), is subjected to regioselective sulfation and hydrolysis of protecting groups. The protocol is compatible with several monosaccharides and allows for multi-sulfation of linear and branched glycans. Seven diverse, biologically relevant sulfated glycans were prepared in good to excellent overall yield.

Well-defined sulfated oligosaccharides are important synthetic targets. We present an on resin approach for the synthesis of sulfated glycans with a broad reaction scope that overcomes previous limitations associated with on resin synthesis.     

An Efficient and Modular Route to Sequence‐Defined Polymers Appended to DNA

Inspired by biological polymers, sequence‐controlled synthetic polymers are highly promising materials that integrate the robustness of synthetic systems with the information‐derived activity of biological counterparts. Polymer–biopolymer conjugates are often targeted to achieve this union; however, their synthesis remains challenging. We report a stepwise solid‐phase approach for the generation of completely monodisperse and sequence‐defined DNA–polymer conjugates using readily available reagents. These polymeric modifications to DNA display self‐assembly and encapsulation behavior—as evidenced by HPLC, dynamic light scattering, and fluorescence studies—which is highly dependent on sequence order. The method is general and has the potential to make DNA–polymer conjugates and sequence‐defined polymers widely available.     

Cyclic 1,2‐Diketones as Core Building Blocks: A Strategy for the Total Synthesis of (−)‐Terpestacin

We report a full account of our work towards the total synthesis of (?)‐terpestacin ( 1 ), a sesterterpene originally isolated from fungal strain Arthrinium sp. FA1744. Its promising anti‐HIV and anti‐cancer activity, as well as its novel structure, make terpestacin an attractive synthetic target. A strategy based on the unique reactivity of cyclic 1,2‐diketones (diosphenols) was developed and total synthesis of 1 was achieved in 20 steps, in the longest linear sequence, from commercially available 2‐hydroxy‐3‐methyl‐2‐cyclopenten‐1‐one. The key feature of our synthesis is the double usage of a “Pd AAA‐Claisen” protocol (AAA=asymmetric allylic alkylation), first in the early stages to generate the C1 quaternary center and then in the late stages to install the side chain. In addition, a rather unusual ene‐1,2‐dione moiety was synthesized and utilized as an excellent Michael acceptor to attach the C15 substituent. Several possible routes towards the total synthesis have been examined and carefully evaluated. During our exploration many interesting chemoselectivity issues have been addressed, such as a highly selective ring‐closing metathesis and a challenging oxidation of a disubstituted olefin in the presence of three trisubstiuted ones.     

Potentials of phyto-fabricated nanoparticles as ecofriendly agents for photocatalytic degradation of toxic dyes and waste water treatment,risk assessment and probable mechanism

Nanotechnology is a promising field and has diverse applications. Primarily, nanoparticles have been synthesized via chemical and physical methods. Dyes are synthetic organic compounds that are abundantly used in industries especially in textile industry. The use of these dyes is major contributors towards environmental pollution. Their hazardous nature raises great concerns in general public. Advancement in nanotechnology can efficiently help in mitigating this problem as nanoparticles can efficiently convert these harmful dyes into less harmful chemical byproducts through a process called Photocatalysis. Although, different approaches have been used for the synthesis of nanoparticles and their Photocatalytic activity but the most efficient approach is the green synthesis using different plants. This approach is environment-friendly and cost-effective. In order to reduce the toxic effects of synthetic dyes that pollutes the environment, it is important to look for such environmental friendly approaches and highlight the role of green nanotechnology in photocatalysis. In the present review paper, we for the first time have summarized the application of biogenic nanoparticles used as Photocatalytic agent in the degradation of different dyes such MB, MO and MR. We have presented a comprehensive review of chemistry/engineering approach of the technology along with mechanistic aspects. Furthermore, key applications of nanotechnology in Photocatalysis have been discussed along with futuristic insight.     

Chemoenzymatic synthesis of O-mannosylpeptides in solution and on solid phase

O-mannosyl glycans are known to play an important role in regulating the function of α-dystroglycan (α-DG), as defective glycosylation is associated with various phenotypes of congenital muscular dystrophy. Despite the well-established biological significance of these glycans, questions regarding their precise molecular function remain unanswered. Further biological investigation will require synthetic methods for the generation of pure samples of homogeneous glycopeptides with diverse sequences. Here we describe the first total syntheses of glycopeptides containing the tetrasaccharide NeuNAcα2-3Galβ1-4GlcNAcβ1-2Manα, which is reported to be the most abundant O-mannosyl glycan on α-DG. Our approach is based on biomimetic stepwise assembly from the reducing end and also gives access to the naturally occurring mono-, di-, and trisaccharide substructures. In addition to the total synthesis, we have developed a "one-pot" enzymatic cascade leading to the rapid synthesis of the target tetrasaccharide. Finally, solid-phase synthesis of the desired glycopeptides directly on a gold microarray platform is described.     

Divergent Total Synthesis of Euphoranginol C,Euphoranginone D,ent-Trachyloban-3β-ol,ent-Trachyloban-3-one,Excoecarin E,and ent-16α-Hydroxy-atisane-3-one

A divergent synthetic approach to biogenetically related diterpenoids such as ent-kauranes, ent-trachylobanes, ent-beyerane, and ent-atisane has been developed. The unified synthetic route involves the De Mayo reaction to rapidly generate the bicyclo[3.2.1]-octane moiety of ent-kaurane. The key reactions also include bioinspired nucleophilic cyclopropanation generating the [3.2.1.0^2,7]-tricyclic core of ent-trachylobane and regioselective cyclopropane fragmentation furnishing ent-beyerane and ent-atisane through the nucleophilic attack and protonation of the cyclopropane ring. This strategy enables the asymmetric total syntheses of six diterpenoids from the commercially available geraniol.     

Synthesis of 2,3,4,7-tetrahydro-1H-azepines as privileged ligand scaffolds for the design of aspartic protease inhibitors via a ring-closing metathesis approach

We have developed a short and highly efficient synthetic strategy towards the hitherto hardly known 3,5- and 3,6-disubstituted 2,3,4,7-tetrahydro-1H-azepine scaffold via a ring-closing metathesis approach utilizing inexpensive and readily available starting material such as methyl acrylate and allylamine. Both seven-membered azacycle scaffolds bearing suitable functional groups, which can easily be modified by means of standard synthetic chemistry, serve as non-peptidic heterocyclic core structures for the further design and synthesis of aspartic protease inhibitors. Through specific decoration with appropriate side chains, individual inhibitors can be tailored with respect to selectivity towards particular family members. A first generation of this class of non-peptidic inhibitors have been tested against the aspartic proteases Plasmepsin II and HIV-I protease, respectively, showing promising activity as well as selectivity with IC₅₀ values in the micromolar range.     

A general approach to 3-n-butyl-5-alkylindolizidines: total synthesis of (-)-indolizidine 195B

Indolizidine type alkaloids have been attractive synthetic targets due to their biological activity. The total synthesis of (-)-indolizidine 195B via a general route, which could potentially be used to prepare other indolizidine alkaloids such as (-)-gephyrotoxin 223AB and (-)-myrmicarin 237A, is described.     

Absolute quantification of cardiac troponin T by means of liquid chromatography/triple quadrupole tandem mass spectrometry

A liquid chromatography/tandem mass spectrometric method for absolute quantification of cardiac troponin T (cTnT) in mouse heart tissue is presented. Even in such a complex biological sample, the multiple reaction monitoring acquisition mode allowed the selective and sensitive determination of a specific peptide, obtained by cTnT enzymatic digestion. The concentration of this cTnT-specific peptide was considered as a representation of the concentration of its parent protein. Quantification was carried out by means of the matrix-matched calibration curve, constructed by adding the synthetic standard of the target peptide and another synthetic structurally analogous peptide as internal standard. Method identification limit and method quantification limit were estimated as 60 and 110 ng of cTnT per mg of total extracted proteins, respectively. The developed label-free approach has been applied for the absolute quantitation of cTnT because of its diagnostic and prognostic value as cardiac disease marker. However, the method could be of general application, since it requires only the synthesis of two suitable peptides, a protein tryptic cleavage product and an internal standard.     

Evolution of a Synthetic Strategy for Garsubellin A

Garsubellin A is a thirty-carbon meroterpenoid capable of enhancing the enzyme choline acetyltransferase whose decreased level is associated with the symptoms of Alzheimer's disease. Due to the potentially useful biological activity along with the novel molecular architecture, this plant metabolite has remained a popular synthetic target. Herein we report a full account of our synthetic investigations that have led to the enantioselective total synthesis of garsubellin A, establishing its absolute stereostructure. The protecting group-free, twelve-step synthetic route has enabled the syntheses of the natural (−)-garsubellin A and its unnatural (+)-antipode.     

Synthesis of novel fluorobenzofuroxans by oxidation of anilines and thermal cyclization of arylazides

The synthesis of several fluorobenzofuroxans by oxidation of fluoroanilines and thermal cyclization of fluoroarylazides is presented. The fluorobenzofuroxans prepared in this study presented tautomerism as evidenced by their NMR data. Benzofuroxans in general have biological activity and are synthetic intermediates for the preparation of several compounds with important pharmaceutical applications.     

Biological activity of bicyclic and tricyclic diterpenoids from Salvia species of immediate pharmacological and pharmaceutical interest

Diterpenoids are a class of compounds that derive from the condensation of four isoprene units that leads to a wide variety of complex chemical structures, including acyclic bi-, tri-and tetra-cyclic compounds; in Salvia species, only bi-, tri-and tetra-cyclic compounds have been found. This review covers a wide range of biological activities and mode of action of diterpenoids isolated from Salvia species that might raise some pharmacological and pharmaceutical interest. We have produced a synoptic table where the biological activities of the main active principles are summarized. Our analysis emphasizes that diterpenoids from Salvia species continue to be a plant defence system since their antimicrobic activity. Experimental studies show that most of diterpenoids considered have cytotoxic and/or antiproliferative activity. Some of them have also cardiovascular and central effects. In a less extended manner, diterpenoids from Salvia species show gastrointestinal, urinary, antinflammatory, antidiabetic, ipolipidemic and antiaggregating effects. In the last decade, several clinical trials have been developed in order to investigate the real value of Salvia extracts treatment; results obtained are promising and confer scientific basis in the use of medicinal plants from folk medicine.     

Solid-phase synthesis of heterocyclic aromates: applicability towards combinatorial chemistry; a review

Because of their biological activity, stability in vivo, the rigid spatial positioning of their substituents, and their synthetic challenges, heterocyclic aromates continue to be of interest to both academic and industrial medicinal chemists. Currently, many drug-like heterocyclic aromates are prepared via solid-phase organic chemistry methods. This review examines the applicability of those methods towards combinatorial chemistry with respect to the basic demands of such an approach: 1) synthesis, work-up and subsequent purification should be easily automated enabling the efficient simultaneous synthesis of large numbers of highly pure compounds in a minimum amount of time, 2) large diversity among the ligands to be synthesized, 3) high conversion rates of the individual reaction steps, and 4) the use of commercially available starting materials. Although many methods have been developed for the synthesis of heterocyclic aromates, very few of the available methods enable the synthesis of highly diverse heteroaromatic libraries.     

Enantiospecific total synthesis of the sarpagine related indole alkaloids talpinine and talcarpine as well as the improved total synthesis of alstonerine and anhydromacrosalhine-methine via the asymmetric Pictet-Spengler reaction

The enantiospecific total synthesis of talpinine 1 and talcarpine 2 has been accomplished from D-(+)-tryptophan in 13 steps (11 reaction vessels) in 10% and 9.5% overall yields, respectively. Moreover, this synthetic approach has been employed for the improved synthesis of alstonerine 3and anhydromacrosalhine-methine 4 in 12% and 14% overall yield, respectively. A convenient synthetic route for the enantiospecific, stereospecific preparation of the key intermediate (-)-N(a)-H, N(b)-benzyl tetracyclic ketone 15a via the asymmetric Pictet-Spengler reaction on a multihundred-gram scale has been developed. A diastereocontrolled (>30:1) anionic oxy-Cope rearrangement and the intramolecular rearrangement to form ring-E and an N(b)-benzyl/N(b)-methyl transfer reaction also served as key steps. This general approach can now be utilized for the synthesis of macroline/sarpagine related indole alkaloids and their antipodes for biological screening.