Clavicipitic Acid Research Articles

Biomimetic Total Synthesis of Clavicipitic Acid: A DDQ-Mediated Intramolecular Cross-Dehydrogenative Coupling Approach

Clavicipitic acid, a communesin alkaloid precursor, has attracted significant attention due to its unique azepino[5,4,3-cd]indole framework. Herein, we report a novel biomimetic synthesis of clavicipitic acid diastereomers by utilizing a DDQ-mediated cross-dehydrogenative coupling (CDC) reaction. The synthesis involves Suzuki coupling for the prenylation of a 4-bromotryptophan derivative, followed by an intramolecular CDC reaction to construct the azepinoindole core. The trans isomer was obtained as the major product, and the two diastereomers were separable. The CDC reaction conditions, including temperature, solvent, and protecting groups, were investigated, and a plausible mechanism for the observed diastereoselectivity was proposed.

Total Synthesis of (−)-Clavicipitic Acid via γ,γ-Dimethylallyltryptophan (DMAT) and Chemoselective C–H Hydroxylation

The first total synthesis of natural (-)-clavicipitic acid from γ,γ-dimethylallyltryptophan (DMAT), its biosynthetic precursor, is described. This is done by regio- and chemoselective, remote, nondirected C(sp3)-H hydroxylation followed by aminocyclization. This study also features regio- and chemoselective Pd(0)-catalyzed linear prenylation at C4 of l-tryptophan boronic pinacol ester derivate, the latter obtained by a Lewis acid-promoted aziridine amino acid ring opening with 4-boronated indole. In addition, these results support the hypothesis that oxidative cyclization between amino acid nitrogen and the prenyl chain during clavicipitic acid biosynthesis can occur through the transient hydroxylated intermediate.

ChemInform Abstract: Strategies for the Total Synthesis of Clavicipitic Acid

AbstractReview: [30 refs.

Strategies for the Total Synthesis of Clavicipitic Acid.

Clavicipitic acid is an ergot alkaloid, which was isolated from Claviceps strain and Claviceps fusiformis. Its unique tricyclic azepinoindole skeleton has attracted synthetic chemists, and various strategies have been developed for its total synthesis. These strategies can be generally categorized into two types based on the synthetic intermediates, namely, 4-substituted gramine derivatives and 4-substituted tryptophan derivatives. This Minireview summarizes the reported total syntheses from the point of these two key intermediates.

Total Synthesis of cis-Clavicipitic Acid from Asparagine via Ir-Catalyzed C-H bond Activation as a Key Step.

4-Substituted tryptophan derivatives and the total synthesis of cis-clavicipitic acid were achieved in reactions in which Ir-catalyzed C-H bond activation was a key step. The starting material for these reactions is asparagine, which is a cheap natural amino acid. The reductive amination step from the 4-substituted tryptophan derivative gave cis-clavicipitic acid with perfect diastereoselectivity.

Synthesis of (±)-cis-Clavicipitic Acid by a Rh(I)-Catalyzed Intramolecular Imine Reaction

A new and short synthesis of racemic cis-clavicipitic acid was achieved by taking advantage of the double nucleophilic character of indole-4-pinacolboronic ester. Key to the success of the synthesis were an efficient and selective C-3 indole Friedel-Crafts alkylation and the development of an unprecedented intramolecular rhodium-catalyzed 1,2-addition of an aryl pinacolboronic ester to an unactivated imine.

ChemInform Abstract: Direct Olefination at the C‐4 Position of Tryptophan via C—H Activation: Application to Biomimetic Synthesis of Clavicipitic Acid.

AbstractThe reaction proceeds under mild conditions with various substituted olefins to give the corresponding 4‐substituted tryptophans.

Direct Olefination at the C-4 Position of Tryptophan via C–H Activation: Application to Biomimetic Synthesis of Clavicipitic Acid

The first Pd-catalyzed method for direct olefination at the C4 position of tryptophan derivatives has been developed via C-H activation to prepare 4-substituted tryptophans, which could be used for the synthesis of many hemiterpenoid indole alkaloids. This reaction proceeds under mild reaction conditions and with exceptional tolerance to a variety of functional groups. Furthermore, the efficiency of this method is demonstrated by the rapid and biomimetic synthesis of clavicipitic acid.

Development of Unprotected Syntheses in Aqueous Media

Introduction of carbon side chain at C(3)-position of indole ring was accomplished by using Pd-catalyzed allylation and vinylation. The selective vinylation at C(3)-position of 4-bromoindole was applied to the synthesis of optically active 4-bromotryptophan derivatives, which was used as a starting material for the synthesis of several optically active ergot alkaloids, which were clavicipitic acids, chanoclavine-I, costacalvine, and 1,1-dimethylallyltryptophan (DMAT). The three-step synthesis of optically active clavicipitic acids were accomplished without using a protecting group starting from 4-bromoindole and dl-serine. Some new synthetic reactions using unprotected amino acids were developed. Those were the biomimetic synthesis of tryptophan, the bromination of free aromatic amino acids, and the Pd-catalyzed N-allylation of free amino acids with allylic alcohol in aqueous media. Unique reactivity of π-allyl palladium complex or η3-(benzyl)palladium complex in aqueous media was found through Pd-catalyzed reaction of anthranilic acid, 2-aminobenzamide, and indole with allylic alcohols or benzyl alcohols, respectively.

Total Synthesis of Clavicipitic Acid and Aurantioclavine: Stereochemistry of Clavicipitic Acid Revisited

The stereocontrolled total synthesis of clavicipitic acid and aurantioclavine from a common azepino[5,4,3-cd]-indole intermediate is reported. This key azepinoindole nucleus was constructed via a one-pot Heck/Boc-deprotection/aminocyclization process from the 4-iodotryptophan derivative, which was assembled by a Pd-catalyzed indole synthesis procedure. After two or three additional deprotection steps from the azepinoindole intermediates, (-)-trans- and (-)-cis-clavicipitic acid were prepared. The syntheses of both (-)- and (+)-aurantioclavine were achieved with the same azepinoindole intermediates utilizing the Barton decarboxylation reaction as the key step to remove the stereohindered carboxylic acid. During the course of our synthesis, mis-assigned configurations of the synthesized clavicipitic acids and their derivatives in the literature were identified. Extensive studies including 2D-NMR study, X-ray diffraction analysis, titration experiment, and Rf value comparison unambiguously confirmed the new configuration assignment. The trans and cis configuration assignments of the synthesized clavicipitic acids and their derivatives in the past literature should be switched.

The five bromotryptophans

The five regioisomeric bromotryptophans (BrTrps) play an important role in the life of sponges and lower marine invertebrates. These bromo-amino acids, which are formed by post-translational modifications, are not found in nature in their free state, but rather are involved in more complex structures. Any of the BrTrps can be part of a peptide, a cyclic peptide, an indole alkaloid, an ergot alkaloid, a macrocycle and others. The present review covers the synthesis, physical and spectroscopic properties of the five BrTrps. It also describes the many exiting pharmacological and biological activities played by the BrTrps and by various secondary metabolites containing brominated tryptophan moieties. Of special interest are cyclic peptides containing the 2-BrTrp unit, which were isolated from marine sponges e.g. konbamide, orbiculamide A, the various keramamides, jaspamide eusynstyelamide and more. Important families of non-cyclic peptides containing the 6-BrTrp, include the styelins, the conotoxins, the cathelicidins and several constrained macrocyclic peptides. Many marine secondary BrTrp-containing, non-peptidic metabolites also display a remarkable spectrum of bioactivities, which can be harnessed for therapeutic and other purposes. Examples are: barettin, bromotryptanthrin, tetraacetyl clionamide, cyclocinamide A, clavicipitic acid, various brominated beta-carbolines. In this review we have presented the various synthetic routes leading to the preparation of the five BrTrps and many of its derivatives. Also, we have introduced the reader to many synthetic routes leading to BrTrp-containing non-peptidic natural products. Although the functional role of the various compounds in the human body is only poorly understood, its effects were extensively studied. Almost all of these compounds exhibit important therapeutic properties e.g. antifungal, antimicrobial, antihelmintic, insecticidal ichthyotoxic and anticancer activity. In the present review attempts have been made to provide synopsis, synthesis and symbiosis of chemical and biological actions, which may provide future guidance and facilitate further research in this area.

Total Synthesis Without Protection: Three‐Step Synthesis of Optically Active Clavicipitic Acids by a Biomimetic Route.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total Synthesis without Protection: Three‐Step Synthesis of Optically Active Clavicipitic Acids by a Biomimetic Route

AbstractA three‐step synthesis of a mixture of optically active cis‐ and trans‐clavicipitic acids 6, which are ergot alkaloids, was achieved, starting from 4‐bromoindole (7) and dl‐serine (dl‐2). This short synthesis was made possible by omitting the protection and deprotection steps from the synthetic route. The key step was the spontaneous cyclization of 4‐vinyltryptophan (10) formed from the Heck reaction of 4‐bromotryptophan (8) with 2‐methyl‐3‐buten‐2‐ol (9) in aqueous media. During this investigation, we also found that the palladium‐catalyzed reaction of 8 with 9 showed an interesting pH dependence; under strongly basic conditions, the Heck reaction occurred to give a C4‐vinylated product 10, whereas an N‐allylated product 19b was formed under neutral or weakly basic conditions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Syntheses without protection: a three-step synthesis of optically active clavicipitic acid by utilizing biomimetic synthesis of 4-bromotryptophan

The optically active clavicipitic acid ( 4), an ergot alkaloid, was synthesized by a three-step sequence from 4-bromoindole ( 1). The reaction of 1 with dl-serine ( 2) in the presence of Ac 2O followed by enzymatic kinetic resolution gave ( S)-4-bromotryptophan ( 3). The Heck reaction of 3 with 1,1-dimethylallylalcohol in aqueous media gave clavicipitic acid in one-pot.

A concise total synthesis of (±)- cis-and (±)- trans-clavicipitic acids by combinational use of directed lithiation and flouride ion-induced elimination-addition reaction of 1-(triisopropylsilyl)gramine derivatives

A six-step total synthesis of (±)-clavicipitic acid ( 1) from 1-(triisopropylsilyl)gramine ( 2) was achieved by combinational use of 4-selective lithiation of 2 and flouride ion-induced elimination-addition reaction of 4-[( E)-3-hydroxy-3-methyl-1-butenyl]-1-(triisopropylsilyl)gramine ( 7) as key reactions. Separation of cis- and trans-diastereomers ( 1a and 1b) were easily accomplished by simple fractional crystallization and column chromatography. The overall yields of 1a and 1b from 2 were 21% and 17%, respectively.

11 光学活性Clavicipitic Acidの全合成(口頭発表の部)

11 光学活性Clavicipitic Acidの全合成(口頭発表の部)

ChemInform Abstract: Synthetic Studies on Indoles and Related Compounds. Part 36. Optically Active Total Synthesis of Clavicipitic Acid (XI).

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Optically Active Total Synthesis of Clavicipitic Acid

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOptically Active Total Synthesis of Clavicipitic AcidYuusaku Yokoyama, Toshifumi Matsumoto, and Yasuoki MurakamiCite this: J. Org. Chem. 1995, 60, 6, 1486–1487Publication Date (Print):March 1, 1995Publication History Published online1 May 2002Published inissue 1 March 1995https://doi.org/10.1021/jo00111a004RIGHTS & PERMISSIONSArticle Views2113Altmetric-Citations124LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (272 KB) Get e-AlertsSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts

Synthesis of (±)-Clavicipitic Acid and Its Derivatives

A formal total synthesis of (±)-clavicipitic acid was achieved in five steps from indole-3-carboxaldehyde. Syntheses of (±)-4-cyano-, (±)-4-methyl-, and (±)-4-hydroxymethyl-6-(2-methyl-1-propen-1-yl)- 3,4,5,6-tetrahydro-1H-azepino [5,4,3-cd] indoles are also reported

パラジウムを利用したインドール骨格への選択的炭素鎖導入法の開発とその応用

Two new methods for the introduction of a carbon side chain at the C3-position of indoles are presented. The first one is the palladium-catalyzed allylation of 3-bromoindoles with various allyl esters in the presence of hexa-n-butylditin. This is a new type of cross-coupling reaction which does not involve an organometallic reagent as a coupling partner. The second one is the vinylation of bromoindole in the presence of stoichiometric amount of Pd (II) salt. The reaction occurs selectively at the C3-position without affecting the carbon-bromine bond. The first total synthesis of optically acive clavicipitic acid is accomplished by a biomimetic route starting from 4-bromodehydrotryptophan which was prepared in one-step from 4-bromoindole by applying the above selective vinylation.