Search

The Rho family of Ras superfamily small GTPases regulates a broad range of biological processes such as migration, differentiation, cell growth and cell survival. Therefore, the availability of small molecule modulators as tool compounds could greatly enhance research on these proteins and their biological function. To this end, we designed a biochemical, high throughput screening assay with complementary follow-up assays to identify small molecule compounds inhibiting MgcRacGAP, a Rho family GTPase activating protein involved in cytokinesis and transcriptionally upregulated in many cancers. We first performed an in-house screen of 20,480 compounds, and later we tested the assay against 342,046 compounds from the NIH Molecular Libraries Small Molecule Repository. Primary screening hit rates were about 1% with the majority of those affecting the primary readout, an enzyme-coupled GDP detection assay. After orthogonal and counter screens, we identified two hits with high selectivity towards MgcRacGAP, compared with other RhoGAPs, and potencies in the low micromolar range. The most promising hit, termed MINC1, was then examined with cell-based testing where it was observed to induce an increased rate of cytokinetic failure and multinucleation in addition to other cell division defects, suggesting that it may act as an MgcRacGAP inhibitor also in cells.

we reasoned that suitableactivation of the enone moiety could facilitate this ringclosure mode. We then realized that an allyl carbamate(Alloc) group would be ideal for this purpose. The maskednitrogen nucleophile can be liberated under neutral condi-tions, a very important factor considering the sensitive natureof the enone. A related 6-exo heterocyclization has beendemonstrated previously by Martin and co-workers, and a 5-exo cyclization by Tsuji et al.

Aldehydes may be dimerized to symmetric esters via the Tishchenko reaction. This process is traditionally catalyzed by aluminum alkoxides, but a wide variety of different metal catalysts has been explored and implemented, ranging from simple alkali metal compounds to actinoid complexes. The mechanistic key step is a hydride transfer from a hemiacetal intermediate to an aldehyde, both participants being coordinated to the metal catalyst in the transition state. Recent research on the Tishchenko reaction has especially focused on the controlled synthesis of unsymmetrical esters. In the aldol-Tishchenko variant, an aldol reaction takes place first between two aldehydes, or a ketone and an aldehyde. In the subsequent Tishchenko step, another aldehyde molecule coordinates to the aldol product, forming a hemiacetal intermediate. An intramolecular hydrogen transfer from the hemiacetal to the carbonyl group takes place, giving a 1,3-diol monoester product. With -hydroxy ketone substrates, the reaction is highly diastereoselective towards 1,3-anti-diols due to a highly organized six-membered transition state promoted by coordination of a metal catalyst to both the hemiacetal and carbonyl groups. Thus, recent research has strongly focused on the development of direct catalytic asymmetric aldol-Tishchenko reactions. The Evans-Tishchenko reaction is a further variant of the aldol-Tishchenko reaction, being used to reduce preformed -hydroxy ketones to anti-1,3-diols under relatively mild conditions. This method is applied to various total syntheses of natural products. Samarium iodide is commonly used as the catalyst, and nearly any aldehyde is suitable as the reducing agent. The reaction has also been exploited in a reverse fashion to oxidize complex aldehydes to carboxylic acids using a simple sacrificial -hydroxy ketone as the oxidant. This review covers the literature from the discovery of the Tishchenko reaction in 1887 up to early 2014. Different catalyst systems for both Tishchenko and aldol-Tishchenko reactions are discussed and compared in the “Scope and Limitations” section, and the state of the art in substrate complexity for the reaction is presented in the “Tabular Survey”.

The condensation reaction of 2-amino-3-hydroxypyridine with different carboxylic acids by microwave-assisted heating is a fast method for producing libraries based on fused 2-substituted oxazolo[4,5-b]pyridines in moderate to good yields.

Whereas starting compound (III) is already known, an efficient approach to the analogous amino acid derivatives (I) and (V) is investigated to prepare them in a reasonable yield.

Harmicine, a chiral tetrahydro-β-carboline with a rare tetracyclic pyrrolidine framework, was isolated from the plant Kopsia griffithii in 1998. Before that, harmicine had already appeared frequently in the chemical literature as a starting material for natural product synthesis and it had been used as a model substrate in various methodology studies. Herein we review the relevant information available on this heterocyclic natural product before and after its isolation and classification as a natural product.

A scalable synthesis of (−)- trans -2-(hydroxymethyl)-1,2,3,6-tetrahydropyridin-3-ol, a versatile chiral building block is described along with its transformation to (−)- trans -3-hydroxypipecolic acid.

Since its introduction to the synthetic community in 1984, Garner’s aldehyde has gained substantial attention as a chiral intermediate for the synthesis of numerous amino alcohol derivatives. This review presents some of the most successful carbon chain elongation reactions, namely carbonyl alkylations and olefinations. The literature is reviewed with particular attention on understanding how to avoid the deleterious epimerization of the existing stereocenter in Garner’s aldehyde.

In 1976 Mukaiyama published a paper that was to make a major impact on the development of the aldol reaction in the future. Mild enolate formation by treatment of a ketone with dibutylboron triflate in the presence of a tertiary amine generates a relatively stable boron enolate, which can subsequently react with an aldehyde to give the cross-aldol product in good yields. This reaction has become a reliable tool for the practicing synthetic chemist. Nearly 10000 polyketides are known, and of these about 600 contain the tripropionate unit with a stereotetrad, four contiguous stereocenters with alternating methyl and hydroxyl substituents in the main chain. The versatility of the boron enolate aldol reaction is showcased with selected applications in the synthesis of these structural motifs.

Stereoselective routes towards both isomers of 2-substituted 3-piperidinols are developed, exploiting the I2/P(O—Et)3-cyclodehydration for synthesis of cis-piperidinols (II).

A short and convenient synthesis of a carboxy functionalized PyOX-core is presented. The carboxy functionality offers a wide variety of possibilities for further modification. In this paper, the core is functionalized with a mercapto tail.

Knoevenagel condensation of substrates (I) or (IX) with aromatic aldehydes followed by diastereoselective cyclization yields an unseparable mixture of highly functionalized pyrrolidin-3-ones in a one-pot fashion.

The vicinal amino alcohol is a common motif in natural products and pharmaceuticals. Amino acids constitute a natural, inexpensive, and enantiopure choice of starting material for the synthesis of such functionalities. However, the matters concerning diastereoselectivity are not obvious. This Perspective takes a look in the field of diastereoselective synthesis of vicinal amino alcohols starting from amino acids using various methods.

Nature provides us with a wonderful pool of enantiopure starting materials for syn- thesis: amino acids, sugars, and many (but not all!) terpenes can be isolated even in large quantities in an uncompromised 100 % ee. Vicinal amino alcohols constitute a versatile group of organic structures; they are, in principle, available in enantiopure form from the chi- ral pool compounds or through chiral catalysis; they are potent intermediates for the synthe- sis of natural products and medicinally/biologically active compounds, and they provide a highly desirable scaffold for the construction of ligands for metals as well as organocatalysts. These new techniques will open up valuable new possibilities for the invention of new tech- nologies for chemical synthesis, the desired course of chemical discoveries for the future. A robust entry to enantiopure vicinal amino alcohols from inexpensive naturally occurring amino acids has therefore become a key challenge for our endeavors in the development of methodology.

The preparation of alkynes from carbonyl compounds via a one-carbon homologation has become a very useful pathway for the synthesis of acetylenic compounds, both internal and terminal. This tutorial review provides an overview of the different methods available for this transformation, including their scope and limitations, recent developments and applications in total syntheses.

A rapid high yielding synthesis of N-t-butoxycarbonyl-1-amino-2-oxo-3-oxabicyclo[3.1.0]hexane is described; the synthesis relies on an intramolecular carbenoid reaction of an appropriate malonate derivative followed by Curtius degradation to give the unprotected amino group.

A stereocontrolled route for α′-amino allylic alcohols has been realised using L-serine as starting material. The title compounds are versatile synthons in a variety of natural product syntheses.

tert-Butyl-substituted allyl malonates, prepared in two steps from malonic acid, are diazotized in high yields. The diazomalonates 7 undergo a stereospecific copper(I)-catalyzed cyclopropanation to give 1-(tert-butoxycarbonyl)-3-oxa-2-oxobicyclo[3.1.0]hexanes 8 which can be converted to the protected (E)- or (Z)-1-aminocyclopropane-1-carboxylic acids 10 or 16 via Curtius- or Hoffman-type rearrangements, respectively. The sequences are short (six steps from malonic acid) and proceed with good overall yields (20-40% overall from malonic acid)

An efficient and highly stereocontrolled method for the construction of the natural syn stereochemistry at C30 and C32 in the calyculin C oxazole fragment has been devised starting from alanine. The title fragment itself is accessible in seven steps from N-BOC-alaninal.

A short synthesis of the taxol A-ring building block starting from an inexpensive mixture of E- and Z- citrals is described.

Careful A-ring substructure analysis for taxol has been carried out and a practical synthesis to all emergent substructures, viable as A-ring building blocks, has been developed. The synthesis starts from 2-methyl-l,3-cyclohexanedione and enters via ketalized trimethylvinyltrit1ate and ketalized trimethylester to trimethylketoalcohol(s) with the hydroxyl group protected. give a clear and camprehensive survey af the feasibility af aur ap

L-serine derived enoates 8 and 9 were subjected to catalytic dihydroxylation and hydrogenation reactions. The observed selectivities can be explained to arise from 1,3-allylic strain. © 1997 Elsevier Science Ltd.

New efficient synthetic routes have been developed starting from the fully protected L-threonine derivative 1 for some deoxy-4-aminohexoses: methyl 4-amino-4,6-dideoxy gulopyranoside 2 and epi-tolyposamine 3 . The title compounds were synthesized using an improved Horner-Emmons reaction of the threonine derived aldehyde 7 . A new method for selective removal of the aminal protection is also reported.

Treatment of the 9-phenylfluoren-9-yl (Pf) protected 4-oxo-proline-ethyl ester ( 6 ) with NaHMDS and N -(5-chloro-2-pyridyl)triflimide gives the corresponding enoltriflate in good yield. Pd mediated coupling of the triflate with trimethylalkyltin, trimethylaryltin, trimethylalkenyltin and carbon monoxide proceeds to give the 4-substituted-3,4-didehydroprolines.

A highly diastereoselective dihydroxylation protocol has been developed for acyclic allylic alcohol derivatives leading to triol derivatives with diastereoselectivity reversed to the classical osmylation (anti-Kishi). Selectivities are acceptable for E -allylic derivatives 1 , and high for those derived from Z -derivatives 4 .

All cells of higher organisms are covered with surface carbohydrates, which are linked to peptides or fatty acids to form glycoconjugates (1). These cell surface glycoconjugates (glycoproteins, proteoglycans, glycosphingolipids, and glycosyl phosphatidyl inositols) play an important role in biological recognition, carrying encoded biological information that is recognized by other cells, viruses, bacteria, and toxins (2). This is another example of the lock and key mechanism, which was first used by Emil Fischer in 1897 to explain the interactions between enzymes and substrates. The recognition event is important for the regulation of cell-substratum adhesion and cell proliferation, for the binding and uptake of extracellular components, and for the regulation of extracellular matrix formation (3).

Pyridylmethylphenols 2 can mimic the geometry of γ-turns. Hydrogen bonding in 2 has been characterized by X-ray crystallography, IR and NMR spectroscopy, and molecular modeling.

Two routes were evaluated for the preparation of multiply functionalized cyclohexane derivatives in a stereocontrolled fashion from readily available Hajos–Parrish ketone 1. Reduction (catalytic or dissolving metal) led to the cis-isomer 8, in stark contrast to previous literature. Finally, modification of earlier steroid chemistry allowed the synthesis of the trans-isomer 14. The latter is a useful intermediate for the synthesis of 7-deoxytaxol derivatives.

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein–ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)- and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.

A series of carbamimidates and carbamimidothioates structurally related to chlorhexidine were prepared and tested for their antibacterial activity. The most effective compounds showed activities very similar to chlorhexidine, although, lacking in the width of the antibacterial spectrum.