Hot off the press

Abstract

A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as psychotripine from leaves of Psychotria pilifera.

Sorbicillinoids are a class of polyketides with a range of intriguing structures. Sorbiterrin A 1, a metabolite of a marine-derived Penicillium terrestre, is the first example of a sorbicillinoid with a [3.3.1]bicyclic system.¹ A biosynthetic pathway to sorbiterrin A 1 from sorbicillin has been proposed. Myrolactones A 2 and B 3 are metabolites of an endophytic Myrothecium species isolated from roots of Vatica mangachapoi.² The biosynthetic origin of the myrolactones is not clear from their structures.

Garlicnin A 4 has been isolated from a fraction of the extract of garlic bulbs, Allium sativum that promotes macrophage activation.³ The authors propose a biosynthetic pathway to garlicnin A 4 from S-allyl L-cysteine. Roots of Echinops transiliensis are the source of echinopsacetylene A 5 that shows toxicity towards the subterranean termite Coptotermes formosanus.⁴Echinopsacetylene A 5 is the first natural example of an α-terthienyl moiety linked to another acetylenic thiophene moiety.

Feeding experiments have demonstrated that there are two pathways for pyrrole formation in the aminocoumarin antibiotic coumermycin A₁6 from Streptomyces rishiriensis.⁵ The terminal pyrrole units had previously been shown to be derived from L-proline and the origin of the central pyrrole unit has now been shown to be L-threonine. Erythrazole A 7, a metabolite of a marine-derived Erythrobacter species, is of mixed biosynthetic origin and a pathway to the benzothiazole has been proposed.⁶

A polyol, amdigenol A 8, with a linear C₉₈carbon chain, is produced by a marine dinoflagellate of the genus Amphidinium.⁷ Amdigenol 8 has some structural similarities to amphidonol. Mollenyne A 9, from the sponge Spirastrella mollis, is unusual as it contains both bromine and chlorine substituents.⁸ The sponge Halichondria okadai is the source of halichonine B 10 that has been shown to induce apoptosis in HL60 cells.⁹ The structure of halichonine B 10, confirmed by X-ray analysis, shows a diprenylated putrescine linked to a drimane sesquiterpenoid. The structure of biyoulactone A 11, from roots of Hypericum chinense, was also confirmed by X-ray analysis.¹⁰ A biogenetic pathway to biyoulactone A 11 from a prenylated acylphloroglucinol derivative is proposed.

The family Meliaceae has produced 1300 limonoids to date with rich structural diversity and interesting biological activities. Tan and Luo have produced an extensive review covering the structural diversity and biological activities of these limonoids.¹¹ Ten further examples, including munronoid A 12 whose structure was confirmed by X-ray analysis, have been reported from Munronia unifoliolata.¹² Canarene 13, from Canarium schweinfurthii, has a new triterpenoid skeleton that was also confirmed by X-ray analysis.¹³ A biosynthetic pathway to canarene 13 involving a series of 1,2-hydride and methyl migrations has been proposed. Nine isomalibaricane triterpenoids, such as globostelletin M 14, have been isolated from the sponge Rhabdastrella globostellata.¹⁴ The globostelletins have cyclised and rearranged side-chains whose biosynthetic relationships have been proposed.

Psychotripine 15, from leaves of Psychotria pilifera, has an unusual hendecacyclic system.¹⁵ A biosynthetic route to psychotripine 15 from three units of tryptamine has been postulated. The symmetrical indole alkaloid 16, a metabolite of an endophytic fungus Colletotricum species isolated from Cephalotaxus hainanensis, also appears to be derived from tryptamine.¹⁶

A web themed issue of Chemical Communications highlighting glycochemistry and glycobiology has been published.¹⁷ Edited by Seeberger and Werz, the issue covers various aspects of glycoscience including the total synthesis of complex glycans, carbohydrate mimetics as well as carbohydrate-based microarrays. A comprehensive series of reviews describing various aspects of lipid biochemistry, metabolism and signalling have been reported in an entire issue of Chemical Reviews.¹⁸

T. Eguchi and co-workers have characterised a series of enzymes responsible for converting L-glutamate to 3-amino-2-methylpropionate, the starter unit for polyketide chain elongation to antibiotics such as vicenistatin 17.¹⁹ Based on bioinformatics, the authors propose that such a pathway is common for carrying amino acids into the biosynthesis of other macrolactam antibiotics. One of the key enzymes in the methylerythritol phosphate pathway, IspH, a [4Fe–4S]-cluster-containing enzyme that catalyses the reductive dehydroxylation of 4-hydroxy-3-methyl-butenyl diphosphate (HMBPP) 18 (Scheme 1) has been studied using fluoro-substituted substrate analogues.²⁰ This work has generated insight into how this reaction proceeds, such as the regiochemistry of the protonation of the allylic anion intermediate as well as the involvement of the terminal phosphate group of HMBPP 18 in mediating the final protonation step.

Scheme 1

Y. Ito and co-workers have developed an understanding of how pradimicin A 19, an actinomycete-derived antibiotic is able to recognise D-mannopyranoside in the presence of a Ca²⁺ ion.²¹ Investigating this phenomenon in the solid state, which overcomes problems with complex equilibrium in solution and, using two-dimensional dipolar-assisted rotational resonance, the 1 : 1 complex was clearly identified. The D-mannopyranoside binding site was shown to be the ABC rings of pradimicin A. A combination of imaging mass spectrometry and a short sequence tagging (SST)-based genome mining approach that connects phenotypes and chemotypes with genotypes have been used to identify anti-infective agents such as arylomycin A2 20 in Streptomyces roseosporus.²² The combination of SST with imaging mass spectrometry enables the correlation of molecules to their biosynthetic genes using only a minimal sequence tag.

Using engineered mutants impaired in post-translational protein modification, Hertweck and co-workers have reported a new approach to activate metabolite production in eukaryotes.²³ Deleting a gene that encodes the N-acetyltransferase, NnaB in the fungus Aspergillus nidulans induces a metabolite switch resulting in the formation of new compounds such as pheofungin D 21. A novel peroxidase from the basidomycetous fungus Agrocybe aegerita (AaeAPO) has been shown to be an active catalyst for enantiospecific hydroxylation and epoxidation reactions (Scheme 2).²⁴ Irradiation of the reaction mixture with visible light generates through a sequence of reactions, hydrogen peroxide which is used by AaeAPO for oxyfunctionalisation. In contrast to other peroxidases, AaeAPO can also hydroxylate non-activated C–H bonds.

Scheme 2

A new synthesis of (2R,3R)- and (2R,3S)-stenusine 22, piperidine alkaloids from Stenus species, has been achieved using a yeast mediated reduction of an enone (Scheme 3).²⁵ The enantiomeric excess and yield of the reaction could be optimised using a co-solvent system of DMSO and water and by slow addition of the sucrose solution. An artificial metalloenzyme containing a catalytically active Os^VIII centre within a protein has been created for enantioselective dihydroxylation.²⁶ Using K₂[OsO₂(OH)₄] and wild-type streptavidin (SAV), dihydroxylation of various alkenes was achieved in good to excellent enantioselectivity (Scheme 4). It was also shown that single point mutation of SAV could generate catalysts with much improved enantioselectivity.

Scheme 3

Scheme 4

Ward and co-workers have developed an artificial metalloenzyme capable of olefin metathesis.²⁷ A catalyst 23 generated from biotin and the Hoveyda–Grubbs 2nd generation catalyst was able to effect ring closing metathesis (RCM) of N-tosyl diallylamine in the presence of avidin (Scheme 5). The addition of magnesium chloride and more acidic conditions allowed optimal conversion. A Hoveyda–Grubbs type catalyst with a bromoacetamide group has been used to modify a cysteine-containing small heat shock protein from Methanocaldococcus jannaschii (MjHSP).²⁸ The resulting protein bound ruthenium complex was able to carry out RCM of N-tosyl diallylamine with similar turnover number as the free ruthenium catalyst 24 (Scheme 6). Both artificial metalloenzymes allow RCM to be done in water without aggregation of the ruthenium catalyst.

Scheme 5

Scheme 6

Multi-gram quantities of both enantiomers of orthogonally protected 4,4-difluoroglutamic acid have been prepared using an enzymatic kinetic resolution as the key step.²⁹ Using DMSO and phosphate buffer as co-solvents, the racemic 4,4-difluoroglutamic acid derivative was resolved with subtilisin Carlsberg in excellent yield and enantioselectivity (Scheme 7). A one-pot synthesis of tetrahydrochromene derivatives catalysed by lipase from Porcine pancreas (PPL) has been developed.³⁰ A series of aldehydes, 1,3-dicarbonyl compounds and either malononitrile or ethyl cyanoacetate could be reacted in the presence of PPL to give the tetrahydrochromenes in excellent yields (Scheme 8).

Scheme 7

Scheme 8

A new probe has been developed for the selective and simultaneous fluorescence detection of cysteine and homocysteine.³¹ The acrylate of 2-(2′-hydroxy-3′-methoxyphenyl)benzothiazole (HMBT) 25 undergoes a conjugate addition and cyclisation with cysteine, forming a seven-membered thiazepine and releasing HMBT for fluorescence detection. The corresponding reaction with homocysteine forming an eight-membered ring is significantly slower, allowing selective optical detection of the two amino acids. A novel intramolecular charge transfer (ICT)-based ratiometric probe 26 for detecting hypochlorite in living cells has been developed.³² The probe operates by a new hypochlorite anion promoted de-diaminomaleonitrile reaction.

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