Editorial to the Special Issue "Total Synthesis of Natural Products: A Themed Issue Dedicated to Professor Dr. Dieter Schinzer for His 65th Birthday".

Natural products have intrigued humans throughout history [...

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines - development of a phosphite-driven cyclodehydration.

A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing simple triethylphosphite as a substitute for triphenylphosphine is developed.

Pharmacological importance of optically active tetrahydro-β-carbolines and synthetic approaches to create the C1 stereocenter.

1,2,3,4-Tetrahydro-β-carbolines (THβCs) are a pharmacologically important group of compounds belonging to the indole alkaloids. C1-Substituted optically active THβCs have been the target of extensive synthetic efforts due to the presence of the scaffold in numerous natural products and synthetic targets. This review briefly summarizes the methods to obtain the C1 stereocenter and concentrates on evaluating the pharmacological importance of optically active C1-substituted THβCs, including their PDE5-inhibitory, antimalarial, antiviral and antitumor activities.

Boron enolate chemistry toward the syntheses of polyketide stereotetrads.

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.

Efficient, stereodivergent access to 3-piperidinols by traceless P(OEt)3 cyclodehydration.

A stereodivergent and highly diastereoselective (dr up to >19:1 for both isomers), step economic (5-6 steps), and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, the core motif of numerous bioactive compounds, providing efficient access to the NK-1 inhibitor L-733,060 is presented. Additionally, a "traceless" (referring to the simplified byproduct separation) cyclodehydration realizing simple P(OEt)3 as a substitute for PPh3 is developed.

Diastereoselective intramolecular allyl transfer from allyl carbamate accompanied by 5-endo-trig ring closure.

To All(oc) involved: A palladium-catalyzed formal 5-endo-trig heteroannulation of enones generated in situ from amino acid derived β-keto nitriles has been realized (see scheme; Alloc=allyl carbamate). The reaction proceeds with allyl-group transfer from the carbamate protecting group to generate two new contiguous stereocenters, including one quaternary center, with high selectivity.

Diastereoselective synthesis of vicinal amino alcohols.

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.

Asymmetric synthesis of Pachastrissamine (Jaspine B) and its diastereomers via η3-allylpalladium intermediates.

A short route for the synthesis of Pachastrissamine (Jaspine B), an anhydrosphingosine derivative, and all three of its diastereomers is presented. The route consists of only 9 steps from the commercially available Garner's aldehyde. The furan framework is formed via an η(3)-allylpalladium intermediate.

Rapid and practical synthesis of (-)-1-deoxyaltronojirimycin.

Herein a practical and scalable route to 1-deoxyaltronojirimycin is presented. The target is achieved in 9 steps and 43% yield featuring only two chromatographic purifications.

The 9-phenyl-9-fluorenyl group for nitrogen protection in enantiospecific synthesis.

One of the biggest challenges in asymmetric synthesis is to prevent racemization of enantiopure starting materials. However, at least some of the enantiopurity is lost in most of the existing reactions used in synthetic organic chemistry. This translates into unnecessary material losses.

Towards the total synthesis of calyculin C: preparation of the C(9)-C(25) spiroketal-dipropionate unit.

An asymmetric synthesis of the C(9)-C(25) spiroketal fragment of calyculin C is described. Key steps include two crotylation reactions using successively Brown's reagent and (Z)-crotyltrifluorosilane for the formation of the anti, anti, anti stereotetrad, ynone formation by a Pd-catalyzed coupling of a thiol ester with a terminal alkyne and a double intramolecular hetero-Michael addition for the stereoselective construction of the spiroketal framework.

Conversion of carbonyl compounds to alkynes: general overview and recent developments.

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.

Conformational ensembles of flexible beta-turn mimetics in DMSO-d6.

Beta-turns play an important role in peptide and protein chemistry, biophysics, and bioinformatics. The aim of this research was to study short linear peptides that have a high propensity to form beta-turn structures in solution. In particular, we examined conformational ensembles of beta-turn forming peptides with a general sequence CBz-L-Ala-L-Xaa-Gly-L-Ala-OtBu.

Short and straightforward synthesis of (-)-1-deoxygalactonojirimycin.

The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to alpha-chiral aldehydes is characterized by lack of epimerization of the vulnerable stereogenic center. This is demonstrated by a highly diastereoselective synthesis of 1-deoxygalactonojirimycin in eight steps from commercial starting materials with overall yield of 35%.

Calyculins and related marine natural products as serine-threonine protein phosphatase PP1 and PP2A inhibitors and total syntheses of calyculin A, B, and C.

Calyculins, highly cytotoxic polyketides, originally isolated from the marine sponge Discodermia calyx by Fusetani and co-workers, belong to the lithistid sponges group. These molecules have become interesting targets for cell biologists and synthetic organic chemists. The serine/threonine protein phosphatases play an essential role in the cellular signalling, metabolism, and cell cycle control.

3-Heterocycle-phenyl N-alkylcarbamates as FAAH inhibitors: design, synthesis and 3D-QSAR studies.

Carbamates are a well-established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta-substituted phenolic N-alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3-(oxazol-2yl)phenyl cyclohexylcarbamate (2 a), inhibited FAAH with a sub-nanomolar IC(50) value (IC(50)=0.

Catalytic activity dependency on catalyst components in aerobic copper-TEMPO oxidation.

The influence of catalyst components in the copper-TEMPO (2,2,6,6-tetramethylpiperidine N-oxide) catalysed aerobic oxidation of alcohols was investigated. The type and amount of base greatly influences reactivity. The bipyridyl ligand concentration had no major influence on catalysis, but excessive amounts led to a decrease in activity for longer reaction times.

Highly chemoselective copper-catalyzed conjugate reduction of stereochemically labile alpha,beta-unsaturated amino ketones.

Highly chemoselective conjugate reduction of chiral alpha,beta-unsaturated amino ketones has been developed by using triisopropyl phosphite ligated copper hydride complex. The highlights of the method are wide substrate compatibility and exceptional chemoselectivity.

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields.

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.

Synthesis of quinolinyl and isoquinolinyl phenyl ketones as novel agonists for the cannabinoid CB2 receptor.

A series of quinolinyl and isoquinolinyl phenyl ketones was synthesized and their CB(2) receptor-dependent G-protein activities were determined using the [(35)S]GTPgammaS binding assay. Both quinoline and isoquinoline derivatives exhibited similar CB(2) receptor agonist activity, the most potent ligands being the 2-(Me(2)N)-phenyl substituted derivatives, which were also full agonists at the CB(2)-receptor.

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors.

A series of para-substituted phenolic N-alkyl carbamates were evaluated for their FAAH and MGL inhibitory activities. The compounds were generally selective for FAAH, with IC(50) values in the nM range, whereas inhibition of MGL required concentrations three orders of magnitude higher. The most potent compounds, dodecylcarbamic acid 4-(4,5-dihydrothiazol-2-yl)phenyl (12) and 4-(1,2,3-thiadiazol-4-yl)phenyl (26) esters, inhibited FAAH and MGL with IC(50) values at the low-nanomolar (IC(50)s; 0.

Total synthesis of amaminol A: establishment of the absolute stereochemistry.

The first synthetic route to amaminol A with use of an organocatalytic intramolecular Diels-Alder reaction is reported. The absolute stereochemistry is proven with a crystallographic image of a cyclic carbamate of amaminol A.

Design, synthesis, and in vitro evaluation of carbamate derivatives of 2-benzoxazolyl- and 2-benzothiazolyl-(3-hydroxyphenyl)-methanones as novel fatty acid amide hydrolase inhibitors.

Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme.

Cleavage of recombinant proteins at poly-His sequences by Co(II) and Cu(II).

Improved ways to cleave peptide chains at engineered sites easily and specifically would form useful tools for biochemical research. Uses of such methods include the activation or inactivation of enzymes or the removal of tags for enhancement of recombinant protein expression or tags used for purification of recombinant proteins. In this work we show by gel electrophoresis and mass spectroscopy that salts of Co(II) and Cu(II) can be used to cleave fusion proteins specifically at sites where sequences of His residues have been introduced by protein engineering.

Highly enantioselective conjugate addition of thiols using mild scandium triflate catalysis.

A Sc complex of (4S,5S)-diphenyl PYBOX 1 was found to serve as a catalyst for the asymmetric conjugate addition reactions between various thiols and 3-crotonoyl-2-oxazolidinone, affording the corresponding adducts in good yields and high enantioselectivies (up to 92% ee). A new improved method for making (4S,5S)-diphenyl PYBOX is presented.