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Fifteen new isopimarane-type diterpenes, taichunins E-S (1-15), and a new 20-nor-isopimarane, taichunin T (16), together with four known compounds were isolated from Aspergillus taichungensis (IBT 19404). The structures of these new compounds were determined by NMR and mass spectroscopy, and their absolute configurations were analyzed by NOESY and TDDFT calculations of ECD spectra. Taichunins G, K, and N (3, 7, and 10) completely inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts in RAW264 cells at 5 μM, with 3 showing 92% inhibition at a concentration of 0.2 μM.

A new isoindolinone alkaloid, irpexine (1), was isolated as a racemate, along with a known green pigment, hypoxyxylerone (2), from the coculture of two endophytic fungi, Irpex lacteus and Phaeosphaeria oryzae. Compound 1 was found to be a newly produced metabolite of I. lacteus in the coculture with P. oryzae. Although 2 was produced in a monoculture of I. lacteus, its production was markedly enhanced by the coculture.

A new prenylated indoxyl alkaloid, Amoenamide B (1), was isolated from Aspergillus amoenus NRRL 35600 along with Asperochramide A (2). Although many prenylated oxyindole alkaloids, containing bicyclo[2.2.2]diazaoctane cores, have been isolated from the fungus of the genera Aspergillus and Penicillium to date, 1 is the fourth compound with the indoxyl unit containing the cores. During the structure elucidation of 1, we found that the planar structure matched to that of Speramide A (3), isolated from A. ochraceus KM007, but the reported structure of 3 was incorrect and turned out to be that of Taichunamide H (4), recently isolated from A. versicolor HDN11-84.

The marine-derived Aspergillus protuberus MF297-2 and the terrestrial A. amoenus NRRL 35600 produce enantiomeric prenylated indole alkaloids. Investigation of biological activities of the natural and synthetic derivatives revealed that (−)-enantiomers of notoamides A and B, 6-epi-notoamide T, and stephacidin A inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)–induced osteoclastogenic differentiation of murine RAW264 cells more strongly than their respective (+)-enantiomers. Among them, (−)-6-epi-notoamide T was the most potent inhibitor with an IC50 value of 1.7 μM.

A new prenylated alkaloid, Amoenamide A (6), was isolated from the fungus Aspergillus amoenus NRRL 35600. Previously, 6 was postulated to be a precursor of Notoamide E4 (21) converted from Notoamide E (16), which was a key precursor of the prenylated indole alkaloids in the fungi of the genus Aspergillus. We previously succeeded in the isolation of two pairs of antipodes, Stephacidin A (1) and Notoamide B (2), from A. amoenus and A. protuberus MF297-2 and expected the presence of other antipodes in the culture of A. amoenus. We here report five new antipodes (7–11) along with a new metabolite (12), which was isolated as a natural compound for the first time, from A. amoenus.

Four new norditerpenes, taichunins A-D (1-4), were isolated from the fungus Aspergillus taichungensis (IBT 19404). Compound 1 has a new carbon framework. The absolute configurations were determined by the calculated ECD spectral method. Compound 1 was cytotoxic against HeLa cells with an IC50 value of 4.5 μM, whereas 2-4 were nontoxic at 50 μM.

In the presence of pyridine, at −5 °C, lipase TL®-mediated kinetic resolution of (±)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)-propan-2-ol was found to proceed efficiently to give the corresponding (S)-alcohol and (R)-acetate, each with high enantiomeric excess and in quantitative yield. The alcohol (S)-1 and the acetate (R)-2-derived alcohol, (R)-1, could be converted to the 1-protected glycerols with either of the stereochemistry by the choice of the deprotection of the protective groups.

The marine-derived Aspergillus protuberus MF297-2 and the terrestrial A. amoenus NRRL 35600 produce enantiomeric prenylated indole alkaloids. Investigation of biological activities of the natural and synthetic derivatives revealed that (−)-enantiomers of notoamides A and B, 6-epi-notoamide T, and stephacidin A inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)–induced osteoclastogenic differentiation of murine RAW264 cells more strongly than their respective (+)-enantiomers. Among them, (−)-6-epi-notoamide T was the most potent inhibitor with an IC50 value of 1.7 μM.

Covering: up to February 2017 Various fungi of the genera Aspergillus, Penicillium, and Malbranchea produce prenylated indole alkaloids possessing a bicyclo[2.2.2]diazaoctane ring system. After the discovery of distinct enantiomers of the natural alkaloids stephacidin A and notoamide B, from A. protuberus MF297-2 and A. amoenus NRRL 35660, another fungi, A. taichungensis, was found to produce their diastereomers, 6-epi-stephacidin A and versicolamide B, as major metabolites. Distinct enantiomers of stephacidin A and 6-epi-stephacidin A may be derived from a common precursor, notoamide S, by enzymes that form a bicyclo[2.2.2]diazaoctane core via a putative intramolecular hetero-Diels-Alder cycloaddition. This review provides our current understanding of the structural and stereochemical homologies and disparities of these alkaloids. Through the deployment of biomimetic syntheses, whole-genome sequencing, and biochemical studies, a unified biogenesis of both the dioxopiperazine and the monooxopiperazine families of prenylated indole alkaloids constituted of bicyclo[2.2.2]diazaoctane ring systems is presented.

We previously described the bioconversion of Notoamide T into (+)-Stephacidin A and (−)-Notoamide B, which suggested that Versicolamide B (8) is biosynthesized from 6-epi-Notoamide T (10) via 6-epi-Stephacidin A. Here we report that [13C]2-10 was incorporated into isotopically enriched 8 and seven new metabolites, which were not produced under normal culture conditions. The results suggest that the addition of excess precursor activated the expression of dormant tailoring genes giving rise to these structurally unprecedented metabolites.

Covering: 1936 to 2013 Epidithiodioxopiperazine alkaloids possess an astonishing array of molecular architecture and generally exhibit potent biological activity. Nearly twenty distinct families have been isolated and characterized since the seminal discovery of gliotoxin in 1936. Numerous biosynthetic investigations offer a glimpse at the relative ease with which Nature is able to assemble this class of molecules, while providing synthetic chemists inspiration for the development of more efficient syntheses. Herein, we discuss the isolation and characterization, proposed fungal biogeneses, and total syntheses of epidithiodioxopiperazines.

This paper describes the selective syntheses of two cis-isomer-enriched cyclopentanone fragrances: ( Z )-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (four steps, 62% overall yield, 67% cis) and Magnolione ® (five steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3a R ,7a S )-5-methyl-2,3,3a,4,7,7a-hexahydro-1 H -inden-1-one as well as (3a′ R ,7a′ S )-5′-methyl-2′,3′,3a′,4′,7′,7a′-hexahydrospiro[[1,3]dioxolane-2,1′-indene] has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2 S ,3 R -isomer-enriched 3 and 4 .

The enantiospecific synthesis of desthiochetomin, a putative biosynthetic intermediate of the epidithiodioxopiperazine natural product chetomin, is described. A diastereoselective N-alkylation was employed to form the key C3-N1’ bond of the heterodimeric indoline core, followed by peptide coupling and dioxopiperazine cyclization with the requisite N-methyl amino acids. A related sarcosine–derived dioxopiperazine was prepared in the same manner. The first proposed biosynthesis of chetomin is also detailed in the text.

A racemic synthesis of the ABCD ring core of the ambiguines that preserves the tertiary alcohol has been accomplished in a convergent synthesis in 10 synthetic steps, in an overall yield of 46% from commercially available 4-bromoindole and m -methylanisole.

A substituted 2R-allyl-3S-methylproline ethyl ester suitable for elaboration to paraherquamides E, F and related 13C-labeled putative biosynthesis intermediates have been prepared efficiently in six steps and 24% overall yield. The key steps are a 5-exo-trig cyclization of a zinc enolate on an unactivated alkene and a stereocontrolled alkylation of the enolate formed from 3S-methyl-pyrrolidine-1,2R-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester.

A biomimetic total synthesis of the fungal metabolite marcfortine C utilizing an intramolecular Diels–Alder reaction is described. In addition, a key stereoselective oxaziridine-mediated oxidation/pinacol rearrangement of indole 24 was used to complete the total synthesis.

The regiochemical outcome of Pictet-Spengler cyclization reactions directed toward the preparation of the pentacyclic core of the ecteinascidin class of antitumor antibiotics has been investigated on two different phenolic substrates. In one substrate, the assistance of an incipient benzylamine group at C-4 is postulated to direct the cyclization in favor of the pentacyclic framework of ET-743, which bears a hydroxyl group at C-18. Conversely, cyclization of an alternative substrate lacking a heteroatom at C-4 favors the opposite regiochemical outcome, primarily affording an unnatural pentacyclic core bearing a hydroxyl group at C-16.

The coupling of activated esters to gramine derivatives is described using ethyl propiolate. A series of substrates have been prepared using these mild conditions to provide a scope and limitations for this methodology.

The formation of a series of analogs containing a pyridine moiety in place of the natural thiazole heterocycle, based on the potent, naturally occurring HDAC inhibitor Largazole has been accomplished. The synthetic strategy was designed modularly to access multiple inhibitors with different aryl functionalities containing both the natural depsipeptide and peptide isostere variant of the macrocycle. The cytotoxicity and biochemical activity of the library of HDAC inhibitors is described herein.

An intramolecular 1,3-dipolar cycloaddition has efficiently constructed the A-ring portions of the cylindrospermopsin alkaloids. A nitro-aldol addition of an elaborated nitroalkane to a pyrimidine aldehyde followed by an intramolecular reductive guanidinylation has enabled the syntheses of all three alkaloids in this family in 18–19 steps. We report the first asymmetric synthesis of cylindrospermopsin, unambiguously assigning its absolute configuration.

Three approaches towards the synthesis of the 1,7-dihydropyrano[2,3- g ]indole ring system of the stephacidins, paraherquamides and norgeamides have been investigated. The first involves a tandem nitrene insertion/aromatic Claisen rearrangement. The second consists of a more conventional approach from commercially available 6-benzyloxyindole. The third approach is a revised synthesis of the 2-prenylated pyrano indole necessary for a biomimetic Diels–Alder approach towards the stephacidins, aspergamides and the norgeamides.

[structure: see text] The structurally intriguing cell-cycle inhibitor spirotryprostatin A has been synthesized utilizing an azomethine ylide dipolar cycloaddition reaction as the key step. This pentacyclic alkaloid contains a prenylated tryptophan-derived oxindole moiety that has been created in a regiocontrolled and stereocontrolled manner in a single step.

A versatile synthesis of the bicyclo[2.2.2]diazaoctane core structure of asperparaline, brevianamide, paraherquamide, and stephacidin natural products is demonstrated. This convergent synthesis relies on an intramolecular hetero Diels–Alder reaction to construct the key tetracycle from a diketopiperazine derived azadiene; which in turn was formed from prolinamide and a pyruvic acid derivative. The stereochemical outcome of the Diels–Alder reaction was found to favor the brevianamide stereochemistry.

The asymmetric synthesis of the modified tyrosine derivative as a basic building block for the ecteinascidin and safracin family of antitumor alkaloids has been achieved in nine steps and 39% overall yield.

The putative metabolite, 5α-acetoxytaxa-4(20),11-dien-2α,10β-diol (7), which is a promising candidate as a biosynthetic pathway triol in taxol biosynthesis, has been prepared by Barton deoxygenation of the C-14-hydroxyl group of a differentially protected derivative of natural 2α,5α,10β-triacetoxy-14β-(2-methyl)-butyryloxytaxa-4(20),11-diene (8), a major taxoid metabolite isolated from Japanese Yew heart wood. The synthetic protocol devised, is amenable for the preparation of isotopically labeled congeners that will be useful to probe further intermediate steps in the biosynthesis of taxol.

A procedure for the asymmetric synthesis of a novel β-hydroxy-α-amino acid deriverative to be used in the preparation of the natural product MPC1001 and analogs has been developed. The amino acid was efficiently prepared in six steps via a Mukaiyama aldol reaction via a diphenyloxazinone and 3-bromo-4-methoxybenzaldehyde.

The asymmetric, stereocontrolled total syntheses of (+) and (−)-spirotryprostatin B ( 2 ) are described. Formation of the core pyrrolidine ring was accomplished via a diastereoselective asymmetric [1,3]-dipolar cycloaddition reaction. Addition of 3-methoxy-3-methylbutanal to (5R,6S)-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one generated an azomethine ylide that reacted with ethyl oxindolylidene acetate to furnish the desired cycloadduct ( 11 ) that possessed the correct relative and absolute stereochemistry of natural spirotryprostatin B. The key dipolar cycloaddition reaction sets four contiguous stereogenic centers. Reductive cleavage of the oxazinone generated the spiro-oxindole pyrrolidine ( 19 ) that was coupled to d -proline benzyl ester and cyclized to the pentacyclic diketopiperazine 22 . A Barton-modified Hunsdiecker protocol effected oxidative decarboxylation to yield 12-epi-spirotryprostatin B ( 30 ). Thermodynamic epimerization of the d -proline stereogenic center with sodium methoxide yielded spirotryprostatin B as the major product. The antipode of the natural product, ent-spirotryprostatin B, was prepared from (5S,6R)-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one. Several synthetic intermediates and spirotryprostatin analogs were tested for their activity as G2/M phase cell cycle inhibitors and microtuble assembly against 3Y1 and tsFT210 mammalian cells.

Pyrrolizidine alkaloids (PAs) are potent hepatotoxins and carcinogens isolated from a wide variety of plants. The hepatotoxicity of these agents is a manifestation of the initial production and release of the reactive dehydropyrrolizidine, which is the DNA-cross-linking species, generated in the liver by the mixed function cytochrome P450 oxidases. A separate class of DNA cross-linkers, including the clinically significant mitomycins and the related FR900482 and congeners are reductively activated in vivo forming a very similar pyrrolic-type intermediate responsible for the DNA cross-linking reactivity of these substances. We report here the synthesis and DNA cross-linking studies of a reductively activated dehydromonocrotaline progentior and its dicarbamate derivative.

A substituted 1,7-dihydropyrano[2,3-g]indole suitable for elaboration to paraherquamide F has been prepared in eight steps and 6% overall yield. The key steps are a Fischer indolization and a Claisen rearrangement.

The syntheses and biosyntheses of the paraherquamide and brevianamide families of prenylated indole-derived alkaloids are reviewed. It has been proposed that the unique bicyclo[2.2.2]diazaoctan ring system that is common to this family of natural products, arises by a biological intramolecular Diels-Alder cycloaddition reaction. Both synthetic approaches and total syntheses of several members of this family of natural products are reviewed. The biosynthesis of these alkaloids has also constituted an active area of research and the current state of knowledge on the biosynthesis of these natural products are reviewed.

A substrate-induced stereocontrol strategy was used to gain access to the tetracyclic core of (-)-lemonomycin. An advanced intermediate was prepared from a known substituted tyrosinol through a 16-step sequence, which involved a Pictet-Spengler reaction, a [3+2] dipolar cycloaddition and an enamide hydrogenation.

A general asymmetric route to enantiomerically pure (S)-(+)-carnitine and analogs has been investigated that involves monoaddition of organometallic reagents to the lactone carbonyl group of ( 5R,6S )-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4 H -1,4-oxazin-2-one and Lewis acid promoted stereoselective allylation of the resulting hemiacetals. The diastereomerically pure allyl oxazines thus obtained were readily converted into enantiomerically pure ( S )-(+)-carnitine and two substituted analogs.

A TiCl4-promoted Mukaiyama-type aldol reaction of the ketenesilyl acetal of ethyl acetate with the lactone carbonyl of (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one ( 1 ) proceeds with a high degree of diastereoselectivity. The TBDMS-protected hemiketal thus obtained was efficiently converted into highly enantiomerically enriched (R)-(−)-carnitine by following an elimination–reduction protocol. This approach further demonstrates the utility of commercially available glycine template 1 as a potential substrate for the asymmetric synthesis of both enantiomers of carnitine.

It has been previously established in this laboratory that the β-methyl-β-hydroxyproline moiety of the potent anthelmintic agent paraherquamide A, is biosynthetically derived from l -isoleucine. The downstream events from l -Ile to paraherquamide A have now been investigated. The synthesis of [1- 13 C]-labeled l -β-methylproline is described by means of a Hoffman–Loeffler–Freytag reaction sequence from [1- 13 C]- l -Ile. This amino acid is shown to be a direct biosynthetic precursor to paraherquamide A by feeding and incorporation experiments in growing cultures of Penicillium fellutanum . Three tryptophan-containing dipeptides of l -β-methylproline have been constructed: [ 13 C 2 ]-2-(1,1-dimethyl-2-propenyl)- l -tryptophanyl-3( S )-methyl- l -proline; [ 13 C 2 ]-3( S )-methyl- l -prolyl-2-(1,1-dimethyl-2-propenyl)- l -tryptophan and [ 13 C 2 ]- cyclo -2-(1,1-dimethyl-2-propenyl)- l -tryptophan-3( S )-methyl- l -proline. [α- 15 N, 1- 13 C]-2-(1,1-Dimethyl-2-propenyl)- l -tryptophan was also prepared but none of these substances were found to serve as biosynthetic precursors to paraherquamide A.

An improved asymmetric synthesis of the guanidine-containing amino acid (2 S ,3 R )-capreomycidine has been achieved in seven steps and 28% overall yield. The key synthetic step involved a Mannich-type reaction between a chiral glycine aluminum enolate and the benzyl-imine of 3- tert -butyldimethylsiloxy-propionaldehyde.

The use of the Staudinger ketene–imine β-lactam-forming cycloaddition reaction and the Pictet–Spengler cyclization reaction in sequence, has been used to prepare highly functionalized tetrahydroisoquinolines relevant to the bioxalomycin and ecteinascidin family of antitumor alkaloids.

The lipase TL®-mediated kinetic resolution of (±)-benzoin ( 1 ) proceeded to give the corresponding optically pure benzoin ( R )- 1 . On the other hand, ( S )-benzoin- O -acetate ( 5 ) could be hydrolyzed without epimerization to give ( S )-benzoin ( S )- 1 , under alkaline conditions. Further, ( R )- 1 was converted to (1 R ,2 S )-2-amino-1,2-diphenylethanol (99:1 er) according to the procedure reported previously.

The synthesis of three isoprenylated derivatives of cyclo-L-Trp-L-Pro is described. These substances have been evaluated for cytotoxic activity in rat normal fibroblast 3Y1 cells and have also been evaluated in vitro for the inhibition of microtubule assembly.

An efficient enzymatic resolution of racemic cis -β-hydroxypipecolic acid is described affording both the (2 S ,3 R ) and (2 R ,3 S ) protected amino acids in good yield and high enantiomeric ratios.

The reactivity of model systems for the proposed [4+2] cycloaddition in the biosynthesis of the brevianamides, paraherquamides, and marcfortines is explored. The model for the intermolecular reaction reveals that the cycloaddition takes place under mild conditions only if activated, very reactive dienophiles are used. When relatively unreactive dienophiles such as cyclopentene and cyclohexene are used, harsh reaction conditions and/or a Lewis acid catalyst are necessary for the reaction. In contrast, the model for the intramolecular reaction demonstrates that the cycloaddition takes place within a few hours at room temperature, even in the absence of a Lewis acid catalyst. Conclusions drawn from these results are discussed in relation to the biosynthesis of the aforementioned metabolites.

FR66979, a drug closely related to the mitomycin C class of antitumor antibiotics, is shown to covalently cross-link DNA to the DNA-binding domain of the High Mobility Group I/Y (HMG I/Y) DNA-binding proteins in the minor groove.

The synthesis of [20-C2H3]-Taxa-4(5), 11(12)-diene (3b), [20-C2H2]-Taxa-4(20), 11(12)-diene (7b), [20-3H3]-Taxa-4(5), 11(12)-diene (3c), [20-3H2]-Taxa-4(20), 11(12)-diene, (7c), [20-C3H2]-Taxa-4(20), 11(12)-diene-5-α-ol (4b ), [20-13CH2]-Taxa-4(20), 11(12)-diene (7d) and [20-13CH3]-taxa-4(5), 11(12)-diene (3d) from the previously reported ketone 6 is described. Grignard addition to ketone provides the tertiary carbinols 8 which were dehydrated to a mixture of 3 and 7. Alternatively, 7 can be prepared directly from ketone 6 by Wittig olefination. Copyright © 2000 John Wiley & Sons, Ltd.

The efficient synthesis of a water-soluble C11a-epi-analogue (6b) of quinocarcin is described. This substance, and a netropsin amide conjugate (8) lack the capacity to inflict oxidative damage on DNA due to the stereoelectronic geometry of their oxazolidine nitrogen atoms. The capacity of these substances to alkylate DNA through the generation of an iminium species has been examined. Both compounds were found to be unreactive as DNA alkylating agents. The results of this study are discussed in the context of previous proposals on the mode of action of this family of antitumor alkaloids.

A stereocontrolled synthesis of an eight-membered ring precursor to a photo-triggered mitosene is described.

We report a stereoselective synthesis of the five consecutive stereocenters of AMPTD in seven steps. Highlights include an Evans glycolate aldol reaction, the use of a Weinreb amide as an aldehyde masking group, and a Mannich reaction with an Ellman-type chiral sulfimine.

The tetracyclic core of the mitomycin family of natural products has been formed in one step from an acyclic precursor via a reductive aminocyclization reaction. Additionally, the eight-membered benzazocine can be prepared without the need for prior activation of the aniline. Construction of a mitomycin K analogue lacking the C9a methoxy moiety is also reported herein.

A photooxygenation reaction of 2′,2′,4′,4′-tetramethyl tetrahydroindole (9) followed by a pinacoltype rearrangement furnished 2′,2′,4′,4′-tetramethyl-3-spirocyclopentylsuccinimide (11). This transformation constitutes a model study for the synthesis of the spirosuccinimide ring system of asperparaline A.

Lewis Acid-mediated coupling reactions of (5R, 6S)-2-acetoxy-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazine (2a) with allylsilanes (3a-d) proceeded to give the coupling products (4a-b) with moderate to good stereoselectivity. The coupling products (4a-b) were effectively converted into 1-Boc-3- and 4-hydroxypyrrolidines (8a, syn-b, and c).