Synthesis of naturally occurring polyynes

Over the past fifty years, hundreds of polyyne compounds have been isolated from nature. These often unstable molecules are found in sources as common as garden vegetables and as obscure as bacterial cultures. Naturally occurring polyynes feature a wide range of structural diversity and display an equally broad array of biological properties. Early synthetic efforts relied primarily on Cu-catalyzed, oxidative acetylenic homo- and heterocoupling reactions to assemble the polyyne framework. The past 25 years, however, have witnessed a renaissance in the field of polyyne natural product synthesis: transition-metal-catalyzed alkynylation reactions and asymmetric transformations have combined to substantially expand access to natural polyynes. This Review recounts these synthetic achievements and also highlights both the natural source(s) and biological relevance for many of these compounds.     

Total synthesis of naturally occurring 5,6,7- and 5,7,8-trioxygenated coumarins

The synthesis of five naturally occurring polyoxygenated coumarins is described. It concerns two 5,6,7-trioxygenated coumarins, i.e., 6-hydroxy-5,7-dimethoxycoumarin (fraxinol) 1 and 5,6,7-trimethoxycoumarin 2, and three 5,7,8-trioxygenated coumarins, i.e., 8-hydroxy-5,7-dimethoxycoumarin (leptodactylone) 3, 5,7,8-trimethoxycoumarin 4 and 8-(3-methyl-2-butenyloxy)-5,7-dimethoxycoumarin (artanin) 5. Key feature of the synthetic pathway is the synthesis of suitable tetraoxygenated benzaldehydes, which are then converted to the corresponding coumarins via a Wittig reaction.     

Synthesis of naturally occurring polyacetylenes via a bis-silylated diyne

A straightforward synthesis of a series of naturally occurring polyacetylenes has been developed, including the montiporynes A and C, possessing cytotoxic activity against several human solid tumor cells, the atractylodin, with antibiotic activity against Escherichia coli, and triynes, which display insecticidal activities, starting from the readily available 1,4-bis(trimethylsilyl)-1,3-butadiyne.     

Synthesis and structural revision of naturally occurring ayapin derivatives

The synthesis of three highly oxygenated naturally occurring coumarins, 8-methoxy-6,7-methylenedioxycoumarin, 5-methoxy-6,7-methylenedioxycoumarin and 5,8-dimethoxy-6,7-methylenedioxycoumarin is described for the first time, together with a new method for the preparation of ayapin (6,7-methylenedioxycoumarin). Comparison of the spectroscopic data of the synthetic tetraoxygenated coumarin 5,8-dimethoxy-6,7-methylenedioxycoumarin with literature reports resulted in the structural revision of several natural coumarins. Two coumarins, both identified as 5,8-dimethoxy-6,7-methylenedioxycoumarin must have other structures, while the structure of another coumarin, described as the isomeric 7,8-dimethoxy-5,6-methylenedioxycoumarin has to be revised to 5,8-dimethoxy-6,7-methylenedioxycoumarin.     

Total synthesis of four naturally occurring 2-azaanthraquinone antibiotics, 6-deoxy-8-methylbostrycoidin, 6-deoxybostrycoidin, 7-O-demethyl-6-deoxybostrycoidin and scorpinone

A total synthesis of four natural 2-azaanthraquinones, 6-deoxy-8-methylbostrycoidin, 6-deoxybostrycoidin, 7-O-demethyl-6-deoxybostrycoidin and scorpinone was accomplished using an optimized procedure for 2-azaanthraquinone synthesis, involving a [4+2]-cycloaddition protocol, of a polyoxygenated diene with a suitably functionalized benzoquinone, acetonylation with pyridinium ylids, cyclisation with ammonia and O-demethylation with boron(III) bromide. 2-Azaanthraquinones are rarely found in nature and reveal interesting physiological properties.     

The discovery, isolation, elucidation of structure, and synthesis of antamanide

Antamanide is the name we have given to a constituent of the fungus Amanita phalloides. This substance counteracts the lethal action of the Amanita toxins phalloidine and α-amanatine if administered to the white mouse before, or simultaneously with, the poisons. Its concentration in the fungus is, however, so low that the toxic action of the latter predominates. Antamanide is a cyclic decapeptide formed from the L -amino acids alanine, phenylalanine, proline, and valine in the molar ratio 1:4:4:1. The amino-acid sequence was determined by a combination of gas chromatography and mass spectrometry. The structural formula assigned was confirmed by synthesis according to a classic route of peptide chemistry.     

Synthesis of naturally occurring phloroglucinol derivatives

Starting with isobutyryl phloroglucinol nine naturally occurring compounds from $\text{Helichrysum}$ species were synthesized.     

Synthesis of erythrinin A,a naturally occurring pyranoisoflavone

Erythrinin A ($\text{10}$) has been synthesised by the oxidative rearrangement of dihydropyranochalcone $\text{1}$ with thallium(III) nitrate (TTN) in trimethyl orthoformate (TMOF) to the dimethyl acetal $\text{2}$, followed by cyclisation to $\text{3}$, demethylation to $\text{6}$ and dehydrogenation. Compound $\text{10}$ could also be obtained from chalcone $\text{4}$ on similar rearrangement followed by cyclisation, demethoxymethylation and dehydrogenation. In another route, chalcone $\text{7}$ was oxidatively rearranged with TTN in TMOF, to $\text{8}$ which on treatment with HCl yielded $\text{10}$.     

Confirmation of the stereochemistry of two naturally occurring epimeric phenylpropanoids via synthesis: Elucidation of hitherto unknown full stereostructures

Herein we report our efforts toward unequivocal assignment of the hitherto unknown absolute configurations of two naturally occurring phenylpropanoids from Abies delavayi and Abies fabri via a combination of chiral pool synthesis and single crystal X-ray analysis which also confirmed their previously reported gross structures with relative stereochemistry. Toward this end we have achieved the first stereodivergent syntheses of threo-(1R,2R)-(−)- and erythro-(1S,2R)-(+)-1-(4-hydroxyphenyl)-1-methoxy-2,3-propanediol. The synthetic threo-isomer was found to be identical to the naturally occurring threo-isomer, while the natural erythro-isomer was postulated to be the enantiomer of the synthetic erythro-isomer.     

Synthesis of some naturally occurring prenylated juglone derivatives

Synthesis of -caryopterone (I), -dihydrocaryopterone )II), 9-methoxy--lapachone (III) and 4,9-dihydroxy--lapachone (IV) has been carried out starting from juglone via 2,8-dihydroxy-1,4-naphthoquinone.     

Synthesis of balsaminone A, a naturally occurring pentacyclic dinaphthofuran quinone

A short synthesis of the natural product balsaminone A, a dinaphthofuran quinone, is described. The key steps of the synthesis are base-induced coupling of 1,4-dihydroxy-2-naphthaldehyde with 2,3-dichloronaphthoquinone to give a pentacyclic dinaphthofuran directly, followed by conversion of the aldehyde into the desired methoxy group via the corresponding phenol. The synthesis, in which the structure of a key pentacyclic intermediate is corroborated by X-ray crystallography, confirms the original structural assignment of the natural product.     

The chemistry of recently isolated naturally occurring quinazolinone alkaloids

The present review portrays a concise account of the isolation, bioactivity, and synthesis of bioactive quinazolinone-based natural products for the period 1983-2005 and the recent developments in the area of complex quinazolinone natural products with a special emphasis on new synthetic routes and strategies.     

Genetic Fusion of Thermoresponsive Polypeptides with UCST-type Behavior Mediates 1D Assembly of Coiled-Coil Bundlemers

Thermoresponsive resilin-like polypeptides (RLPs) of various lengths were genetically fused to two different computationally designed coiled coil-forming peptides with distinct thermal stability, to develop new strategies to assemble coiled coil peptides via temperature-triggered phase separation of the RLP units. Their successful production in bacterial expression hosts was verified via gel electrophoresis, mass spectrometry, and amino acid analysis. Circular dichroism (CD) spectroscopy, ultraviolet-visible (UV/Vis) turbidimetry, and dynamic light scattering (DLS) measurements confirmed the stability of the coiled coils and showed that the thermosensitive phase behavior of the RLPs was preserved in the genetically fused hybrid polypeptides. Cryogenic-transmission electron microscopy and coarse-grained modeling revealed that functionalizing the coiled coils with thermoresponsive RLPs leads to their thermally triggered noncovalent assembly into nanofibrillar assemblies.     

Control of the cytotoxicity of dansylated polytheonamide mimic,an artificial peptide ion channel,by modification of the N-terminal structure

We demonstrate that the cytotoxicity of dansylated polytheonamide mimic (2) is controlled by chemical modification of its N-terminal structure. Dansylated polytheonamide mimic (2) is an ion channel peptide which displays potent cytotoxicity against P388 mouse leukemia cells (IC₅₀ = 12 nM). To modulate its cytotoxicity, three analogues of 2, possessing distinct N-terminal structures with different hydrophobicities, were synthesized and their cytotoxicities were evaluated. This focused structure–activity relationship study unveiled that the cytotoxicity of 2 is enhanced 10-fold by simply changing its N-terminal 5,5-dimethyl-2-oxohexanamide to the more hydrophobic palmitamide. The data obtained here provide new understanding for the functional control of the artificial ion channel peptide 2.     

First total synthesis of hormaomycin, a naturally occurring depsipeptide with interesting biological activities

Some unique features were disclosed during the structure elucidation of the cyclic depsipeptide hormaomycin (1), first isolated in 1989 from a Streptomyces griseoflavus strain and found to have quite an interesting spectrum of biological activities. Besides one residue of the proteinogenic amino acid isoleucine [(S)-Ile], it contains two units of 3-methylphenylalanine [(betaMe)Phe], one of (2R)-allo-threonine [a-Thr] as well as two moieties of 3-(trans-2-nitrocyclopropyl)alanine [(3-Ncp)Ala] and one of 4-(Z)-propenylproline [(4-PE)Pro]. The latter two have never been found in any natural product before. The side chain of 1 is terminated with the residue of 5-chloro-1-hydroxypyrrole-2-carboxylic acid [Chpca]. This first synthetic access to hormaomycin 1 will make it possible to prepare structural analogues of this interesting natural depsipeptide in order to elucidate structure-activity relationships and the biologically active minimal unit.     

Lipoxins and Related Eicosanoids: Biosynthesis,Biological Properties,and Chemical Synthesis

Among the various enzymes found in human tissues that act on arachidonic acid, there are three major types of lipoxygenases (LO), operating at the 5-, 12-, and 15-positions. The 5-LO is a key enzyme and plays a central role in the biosynthesis of leukotrienes, which are potent arachidonate-derived mediators of allergy and inflammation. Because of the importance of the 5-LO-derived products in human pathophysiology, studies were initiated to examine the consequences of initial lipoxygenation at C15 of arachidonic acid as well as to probe interactions between the major LO pathways. These studies led to the identification of a new series of biologically active tetraene-containing eicosanoids termed lipoxins. This article summarizes the isolation, biosynthesis, and chemical synthesis of lipoxins and related systems, and reviews recent results concerning their formation and biological activities. The total synthesis of these molecules based on a new and general synthetic strategy involving palladium catalysis is reviewed. This synthetic approach has allowed the preparation of several types of acyclic eicosanoids in their naturally occurring forms which, in turn, allowed comparisons with naturally derived materials and enabled detailed studies of the biological actions of these biomolecules. Structure–activity relationships were also derived by combining chemical synthesis and biological investigations.     

Stereoselective Synthesis of Enantiomerically Pure Natural Products—Estrone as Example

Natural products have been synthesized for billions of years in animals, plants, and microorganisms. As a rule they occur enantiomerically pure. Their chiral character corroborates their use in metabolism or as biologically active agents. Natural products may be insufficient in quality or quantity. They have recently begun to become accessible, either unchanged or modified, by biological synthesis; here, too, they are obtained enantiomerically pure. In the last twenty years chemical synthesis has become a major concern of organic chemists. Their target compounds are primarily enantiomerically pure natural products or biologically active variants thereof.