Search

5-Hydroxymethyl-2-methoxyphenyl adamantane-1-acetate inhibits cell proliferation and stimulates depolymerization of microtubules of cancer cells to free tubulin. Its analogues were synthesized vi a the Steglich or Mitsunobu reactions to determine the role of structural subunits of the molecule in tubulin binding. Based on the structure–activity relationship studies, metabolically stable 1-[2-(5-hydroxymethyl-2-methoxyphenyl)ethyl]adamantane was invented, which exhibits a dual-target profile and retains in vitro activity observed for the lead compound. [ABSTRACT FROM AUTHOR]

Carbohydrates serve as versatile molecular scaffolds and platforms in organic chemistry, for example in combinatorial chemistry or for the multivalent presentation of ligands. Carbohydrate scaffolds are frequently employed in the synthesis of multivalent glycoconjugates and utilized for the study of fundamental parameters of carbohydrate recognition. However, facile procedures are required to achieve a useful variety of sugar platforms. Here, we report on the synthesis of a series of divalent und tetravalent hydroxypropylated mannosides, using an allylation‐hydroboration sequence. The hydroxypropyl‐linkers were further functionalized with thymine in a Mitsunobu reaction to achieve multivalent glycothymine scaffolds for intramolecular [2+2] photocyclization. This will be of importance to further investigate the influence of the 3D orientation in carbohydrate recognition. We discuss the scope of the allylation‐hydroboration sequence comparing 2,3‐, 2,6‐, and 4,6‐difunctionalization and 2,3,4,6‐tetrafunctionalization of protected 2‐aminoethyl α‐d‐mannopyranosides. Diverse carbohydrate scaffold molecules were achieved by an allylation‐hydroboration sequence and functionalized with thymine in a Mitsunobu reaction to allow intramolecular [2+2] photocyclization. These photosensitive glycoconjugate platforms can be employed to organize multivalency in carbohydrate recognition studies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • NPEC group is compatible with Ns and other protecting groups in polyamine synthesis. • Photoirradiation conditions for removal of N-NPEC group are optimized. • The precursor for marine natural product protoaculeine B is synthesized. Abstract Herein, we disclose an efficient combination of NPEC and Ns protecting groups in the synthesis of polyamine, by showing the orthogonal reactivity using N -NPEC- N -Ns alkylamines prepared from NPEC-NHNs. Selective photodeprotection of NPEC group in 12-mer polyamine and the complex conjugate has been further demonstrated toward the synthesis of novel polyamine natural product protoaculeine B. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Glycosylation of 7-OH flavonoids was achieved via the Mitsunobu reaction. • Various flavonoid 2-deoxyglucosides were generated. • Stereoselectivity was observed as mainly controlled by the sugar protecting groups. Abstract The Mitsunobu reaction of flavonoids and 3,4,6-tri- O -acetyl-2-deoxy- d -glucopyranose or 3,4,6-tri- O -benzyl-2-deoxy- d -glucopyranose is a very effective method for the stereoselective synthesis of flavonoid 2-deoxyglucosides. Since there is no C2 substituent on the sugar moieties, the observed α- or β-stereoselectivity was mainly controlled by the (acetyl or benzyl) protecting groups. Possible mechanistic insights are offered to explain the dual stereoselectivity. [ABSTRACT FROM AUTHOR]

Abstract A practical synthetic route to 7-formamidino-7-deazaguanosine (archaeosine), a hypermodified nucleoside observed in archaeal tRNA, has been developed, which involves the addition of hydroxylamine to the cyano group of 7-cyano-7-deazaguanosine (preQ 0 -nucleoside) and a subsequent Pd-catalyzed hydrogenation. PreQ 0 -nucleoside was obtained from an optimized β-selective glycosylation developed by Hocek et al. The corresponding archaeosine base was subsequently synthesized in high yield from its precursor 7-cyano-7-deazaguanine (preQ 0 ). Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

The Mitsunobu Reaction allows the conversion of primary and secondary alcohols to esters, phenyl ethers, thioethers and some other compounds. The nucleophile employed should be acidic, since one of the reagents, diethylazodicarboxylate (DEAD) must be protonated during the course of the reaction, preventing from the formation of unwanted side products. In this review, we try to focus on the scope and preparative synthetic applications of Mitsunobu reaction as a key step in the total synthesis of biologically active natural products. [ABSTRACT FROM AUTHOR]

A combination of the Mitsunobu reaction and Glaser coupling was used to achieve a new glycoazobenzene macrocycle. This photosensitive macrocycle can be efficiently and reversibly switched between two stable conformational isomers, which are characterized with photoswitchable shape, chiroptical and solubility behaviour. [ABSTRACT FROM AUTHOR]

The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors ( 11a – 17a ) as well as their dehydrate dihydrofuran derivatives ( 11b – 17b ), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC 50 values of 0.63 and 0.81 nM, respectively. However, all the dehydrate derivatives lose the SGLT2 inhibitory activity, with inhibition percentage no more than 66.5% at the concentration of 0.5 μM, which might because of the configuration inversion at C-2 of glucose. In conclusion, the present study improves understanding of the SAR of SGLT2 inhibitors, and provided more information that could be applied to design new molecules. [ABSTRACT FROM AUTHOR]

The Ph3P/ICH2CH2I system-promoted dehydroxylative substitution of alcohols was achieved to construct C–O, C–N, C–S and C–X (X = Cl, Br, and I) bonds. Compared with the previous approaches such as the Appel reaction and Mitsunobu reaction, this protocol offers some practical advantages such as safe operation and a convenient amination process. [ABSTRACT FROM AUTHOR]

3,3-Dimethoxypropylsulfonyl (Dimps) chloride was prepared and used as a new versatile sulfonating agent for ammonia, primary and secondary amines to afford corresponding Dimps-amides in excellent yields. The resulting N -nonsubstituted and N -monosubstituted Dimps-amides, activated amines, were alkylated satisfactorily under new Mitsunobu conditions. The Dimps group was removed by treatment in aqueous solution under acidic followed by basic conditions. Furthermore, epilachnene, the defensive droplets from the Mexican bean beetle, Epilachna varivestis , was synthesized utilizing this Dimps methodology in short steps. [ABSTRACT FROM AUTHOR]

Five chiral compounds were designed and synthesized using the Mitsunobu reaction to act as chiral inducers (i.e., chiral dopants) for the transformation of a nematic liquid crystal (LC) (4-n-octoxy-4′-cyanobiphenyl) into a cholesteric LC. These chiral inducers contain two types of chiral alkyl chains with different kinds of achiral mesogenic cores (biphenylcarboxylate, biphenoxy, and cyanobiphenoxy). We observed that the achiral mesogenic cores affected the helical twisting power in terms of both induction strength and helicity (left-/right-hand introduction). All the ester type inducers exhibited a positive Cotton effect and right-hand helical twisting power (HTP). However, ethers exhibited a negative Cotton effect and left-hand HTP. The microscopic HTPs (βM) of these inducers demonstrate a linear relation with their optical activities (ellipticity near the absorption maximum). Further, the time-dependent density functional theory (TD–DFT) calculation using the B3LYP/6-311++G (d, p) method has been used to predict the circular dichroism spectra of these inducers. The predicted optical activity was observed to be in accordance with that observed in the experimental result. This study proposes a method for predicting the HTP of chiral inducers that can be applied to achieve polymerization in the reaction fields of cholesteric LCs. [ABSTRACT FROM AUTHOR]

Abstract: 2‐Aminobenzenesulfonamide‐containing cyclononyne (ABSACN), which is a heterocycle that contains a sultam and strained alkyne group within the same ring, exhibits remarkable chemical reactivity in processes such as pyrrole transformations, Pauson–Khand cyclizations, click reactions, and Mitsunobu condensations. Herein, we introduce the synthesis and reactions of ABSACN, which focus on the sultam and alkyne functional groups, and study the unique characterization of prepared ABSACN derivatives by NMR and X‐ray crystallographic analyses. This work could lead to the efficient production of pharmaceutically relevant multiheterocyclic systems by using sequential cycloaddition reactions. ABSACN can also serve as a potential template for multifunctional clickable alkyne reagents. [ABSTRACT FROM AUTHOR]

Herein we disclose an efficient strategy for the convergent synthesis of 1',2'-cis-disubstituted carbocyclic ribo-nucleoside analogues. Starting from an enantiomerically pure cyclopentenol precursor, the key step for the preparation of the highly functionalized carbocyclic building block is an asymmetric dihydroxylation. Employing different variants of the Mitsunobu protocol, the condensation with allnatural nucleobases or their precursors affords a series of ribo-configured carbocyclic 1',2'-cis-disubstituted nucleoside analogues. [ABSTRACT FROM AUTHOR]

A new synthesis of entecavir from d -glucose in an average total yield of 3.5% was achieved via an intramolecular nitrile oxide cycloaddition (INOC) reaction and a Peterson olefination as key-steps. The present process was designed for industrial application, using widely available raw materials, simple and cheap reagents and avoiding low reaction temperatures, which are very common in the synthetic approaches towards similarly complex structures. [ABSTRACT FROM AUTHOR]

During our search for novel CGRP antagonists, we had great difficulty in accessing one of our key motifs. Herein, we communicate how we solved the problem by an unprecedented Mitsunobu alkylation using unprotected amino alcohols. [ABSTRACT FROM AUTHOR]

The scope of an unexpected Mitsunobu cyclisation to prepare N -arylated F sp 3 -enriched azacycles was investigated. In the current study, we have identified whether a p Ka-dependent Mitsunobu cyclodehydration or a p Ka-independent Mitsunobu intra molecular reaction was in operation. A Mitsunobu reaction, creating a leaving group, followed by intra molecular nucleophilic displacement was determined to be the dominant pathway. [ABSTRACT FROM AUTHOR]

Two mild and efficient strategies have been developed for the O-functionalisation of 4-hydroxy-6-alkyl-2-pyrones, by using them as nucleophilic partners in oxa-Michael additions and the Mitsunobu reaction. The reactions proceed in moderate to excellent yields on a range of substrates containing useful functionality. The reactions serve as practical and valuable synthetic methods to construct complex 2-pyronyl ethers, which are found embedded in a number of natural products.

A highly regioselective SN2' Mitsunobu reaction between Morita–Baylis–Hillman (MBH) alcohols, azodicarboxylates, and triphenylphosphine is developed, which provides an easy access to α-alkylidene-β-hydrazino acid derivatives in high yields and good stereoselectivity. This reaction represents the first direct transformation of MBH alcohols into hydrazines.

Synthetic routes to 5'-azidoribonucleosides are reported for adenosine, cytidine, guanosine, and uridine, resulting in a widely applicable one-pot methodology for the synthesis of these and related compounds. The target compounds are appropriate as precursors in a variety of purposive syntheses, as the synthetic and therapeutic relevance of azido- and amino-modified nucleosides is expansive. Furthermore, in the conversion of alcohols to azides, these methods offer a tractable alternative to the Mitsunobu and other more difficult reactions.

An operationally simple protocol for the synthesis of 2,3-dihydrobenzo[f][1,4]oxazepin-3-ones, based on an Ugi reaction of an ortho-(benzyloxy)benzylamine, glycolic acid, an isocyanide and an aldehyde, followed by an intramolecular Mitsunobu substitution was developed. The required ortho-(benzyloxy)benzylamines have been in situ generated from the corresponding azides, in turn prepared in high yields from salicylic derivatives.

Nucleosides with a norbornane fragment as sugar moiety (Figure 1) were found to have antiviral and anticancer activity [1]. [...]

Iodoarene catalysts can be applied in versatile reactions, for instance in the construction of complex chiral molecules via dearomatization of simple aromatic compounds. Recently, we reported the synthesis of the first carbohydrate-based chiral iodoarene catalysts and their application in asymmetric catalysis. Here we describe the synthesis of some new and improved catalysts. An account on how we got to the improved catalyst design, as well as the X-ray structure of one of the carbohydrate-based iodoarenes, is given.

Isonucleosides are rather stable regioisomeric analogs of nucleosides with broad therapeutic potential. We have previously demonstrated the ability of 5′ and 6′-isonucleosides to inhibit the activity of acetylcholinesterase, a major target for Alzheimer’s disease therapy. Continuing with our research on this topic, we report herein on the synthesis and biological evaluation of a variety of novel terminal isonucleosides and theobromine isonucleotide analogs. Xylofuranose-based purine or uracil 5′-isonucleosides and xylofuranos-5′-yl or glucos-6′-yl theobromine derivatives were accessed via Mitsunobu coupling between partially protected xylofuranose or glucofuranose derivatives with a nucleobase using conventional or microwave-assisted heating conditions. Theobromine-containing N-isonucleosidyl sulfonamide and phosphoramidate derivatives were synthesized from isonucleosidyl acetate precursors. The most active compounds in the cholinesterase inhibition assays were a glucopyranose-based theobromine isonucleosidyl acetate, acting as a dual inhibitor of acetylcholinesterase (AChE, Ki = 3.1 µM) and butyrylcholinesterase (BChE, Ki = 5.4 µM), and a 2-O,4-O-bis-xylofuranos-5′-yl uracil derivative, which displayed moderate inhibition of AChE (Ki = 17.5 µM). Docking studies revealed that the active molecules are positioned at the gorge entrance and at the active site of AChE. None of the compounds revealed cytoxic activity to cancer cells as well as to non-malignant mouse fibroblasts.

Despite the great importance of β-lactam antibiotics, there is still a limited number of synthetic approaches for the formation of β-lactam–containing dipeptides. In this study, we report upon the stereoselective preparation of β-lactam–containing pseudopeptides, where different reaction conditions and NH2 protective groups were tested to obtain compounds that contain 3-amino-azetidin-2-one. We demonstrate that the protective group is essential for the outcome of the reaction. Successful implementation of dibenzyl-protected serine-containing dipeptides through the Mitsunobu reaction can provide the desired products at high yields and stereoselectivity.

In vivo imaging of biological processes is an important asset of modern cell biology. Selectively reacting fluorophores herein are an important tool and click chemistry reactions take a large share in these events. 5-Ethynyl-2′-deoxyuridine (EdU) is well known for visualizing DNA replication, but does not show any selectivity for incorporation into DNA. Striving for specific visualization of virus replication, in particular HIV replication, a series of propargylated purine deoxynucleosides were prepared aiming for selective incorporation by HIV reverse transcriptase (RT). We here report on the synthesis and preliminary biological effects (cellular toxicity, HIV inhibitory effects, and feasibility of the click reaction) of these nucleoside analogues.

We described a synthetic approach to bisphenol-based monocyanate esters based on mono-O-methylation of parental bisphenols followed by cyanation of the residual phenolic hydroxyl. Structures of the synthesized compounds were determined by the application of IR, NMR 1H and 13C spectroscopies, EI and MALDI mass spectrometry, and purity of the final product was controlled by HPLC. We showed that stability of the cyanate esters depends on the nature of the bridging group. Temperature range of thermally initiated cyclotrimerization of synthesized monocyanate ester, as well as reaction enthalpy, was determined by differential scanning calorimetry (DSC).

An efficient approach to a variety of chiral silacyclopentanes having silicon stereogenic center based on the stereospecific transformations of C4 carbon stereogenic center of silacyclopentenols by Mitsunobu reaction or Tsuji–Trost reaction has been developed. The thus obtained substitution products can be converted into novel silacyclopentane triols, amines, and carboxylic acids in stereospecific manner. [ABSTRACT FROM AUTHOR]

The cyclization of N6-(ω-hydroxyalkyl)adenines with a N6H-group leads to N6,N1 ring closure regardless of the method of the cyclization that was used. Five-membered to eight-membered rings were obtained using NBS/PPh3; however, under Mitsunobu conditions, the eight-membered fused purine was not formed. Surprisingly, the cyclization of N6-methyl- N6-(4-hydroxybutyl)adenine only leads to N6,N7 ring closure using both methods. [ABSTRACT FROM AUTHOR]

Based on the features of its crystallization, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 2 , the synthetic precursor of the chiral drug xibenolol 1 , was resolved into pure enantiomers by the direct method of entrainment. The enantiomers of diol 2 through a Mitsunobu reaction were converted into the nonracemic 1,2-epoxy-3-(2,3-dimethylphenoxy)propanes ( S )- and ( R )- 3 , and then into the xibenolol enantiomers. Single crystals of (+)- and (−)- 1 ·HCl were studied by X-ray diffraction. On the basis of the Flack parameter, the absolute ( R )- and ( S )-configurations were assigned to these compounds and to the other intermediate chiral substances. [ABSTRACT FROM AUTHOR]

As part of a collaborative research project aimed at designing new chemicals active on mosquito larvae, we sought accessible raw materials and an efficient synthesis method for preparing large amounts of active substances. For this we selected retinoic acid, which has functionality close to that of juvenile hormones. From this molecule we developed ester and trifluoromethyl ketone synthesis that was fast and led to good yields. [ABSTRACT FROM AUTHOR]

The Mitsunobu reaction has emerged as an important alternative for the preparation of synthetic 2'-deoxynucleosides, which have various biological and biotechnological applications. In this work, the Mitsunobu-based synthesis of 2'-deoxynucleosides was systematically studied. The effect of phosphine, azodicarbonyl reagent, and solvent on the product yield and α/β ratio was investigated, and the highest yield and β-selectivity were obtained using (n-Bu)2P and 1,1'-(azodicarbonyl) dipiperidine in DMF. The reaction was successfully applied to various nucleobase analogues. [ABSTRACT FROM AUTHOR]

Nonenzymatic posttranslational modifications (nPTMs) of proteins are involved in age-related, metabolic and other diseases and need to be investigated at the molecular level. Here, we describe how we used organic synthesis to enable the study of the effect of argpyrimidine (Apy), an nPTM that forms at arginine residues, on one of its target proteins. We developed an efficient approach to Apy as a universal building block for Fmoc-based solid-phase peptide synthesis that allows for the construction of peptides containing this nPTM in predetermined positions. Moreover, a straight forward one-step synthesis of protecting-group-free Apy was achieved, which enabled the preparation of gram-quantities of this noncanonical amino acid that can serve as a biomarker or a feedstock in construction of Apy-containing proteins via the expanded genetic code methods. [ABSTRACT FROM AUTHOR]

A series of novel asymmetric azo reagents, 1-( tert -butyl)-2-(4-substituted benzyl) azodicarboxylate, were prepared. The synthetic process has the advantage of simpleness, easy operation, mild reaction condition and high yield. The 1-( tert -butyl)-2-(4-chlorobenzyl) azodicarboxylate (tBCAD) was selected for its stability and convenience to handle, and its precursor can be recycled by recrystallization with toluene. The t BCAD and DIAD were applied to a wide variety of Mitsunobu reactions. The experimental results showed that the performance of tBCAD in Mitsunobu reaction was comparable to that of DIAD, while the stability of tBCAD was much better than DIAD. Thus, tBCAD can be a novel, stable, effective azo-reagent for the Mitsunobu reaction. [ABSTRACT FROM AUTHOR]

The first total synthesis of greensporone C, a cytotoxic 14-membered resorcylic acid lactone, has been accomplished via a longest linear sequence of 16 steps in 3.3% overall yield. The key features of the synthesis include Mitsunobu esterification and ring-closing metathesis to construct the macrocycle and establish the ( E )-olefin geometry, respectively. Our synthesis also confirmed the absolute stereochemistry of the natural product. [ABSTRACT FROM AUTHOR]

The bacterial metabolite and potent innate immune modulator d - glycero -β- d - manno -heptose-1,7-bisphosphate (HBP) and its α-configured counterpart d - glycero -α- d - manno -heptose-1,7-bisphosphate were synthesized via stereoselective anomeric phosphorylation of the peracetylated d , d -heptose 7-dibenzylphosphate by exploiting different nucleophilicity of equatorial and axial lactols in the d - manno -series. We also report a novel approach for anomeric phosphorylation using modified Mitsunobu reaction conditions and provide the first full structural characterization of HBP. The first chemical synthesis of HBP offers access to an anomerically pure structurally defined probe for biological studies and to a lead compound operating as a powerful stimulator of intracellular signaling for possible therapeutic immunomodulation. [ABSTRACT FROM AUTHOR]

The chiral pool amino acids have been utilized for the construction of steroidal and non-steroidal architectures in the quest for steroidomimetics. Chirality derived from amino acid-based architectures provides new and easy to incorporate chiral chemical space, which is otherwise very difficult to introduce and comprised of several synthetic steps for asymmetric steroids. The different and exciting ligand-receptor interactions may arise from the use of each amino acid enantiomer that was introduced into the chiral steroidal backbone. The A and D rings of steroidal architectures can be mimicked by the phenyl group of the amino acid tyrosine. The Mitsunobu reaction, nucleophilic substitution and elimination, etc. were utilized for constructing diverse tri- and tetracyclic steroidal skeletons as well as benzofused seco-steroids from amino acids. These benzofused, amino acid-derived steroidal and nonsteroidal molecules had promising biological activity in hormonal related disorders. [ABSTRACT FROM AUTHOR]