Wieland-Miescher Ketone Research Articles

Divergent total synthesis of sesquiterpene (hydro)quinone meroterpenoids dysideanones A and E–G

The first total synthesis of marine sesquiterpene (hydro)quinone meroterpenoids dysideanones A and E–G (1 and 4–6) has been accomplished in an enantioselective and divergent way. The sesquiterpene fragment and the aromatic moiety were efficiently connected via a site-selective and diastereoselective intermolecular alkylation of Wieland–Miescher ketone derivative 9 and benzyl bromide 10. The core 6/6/6/6-fused backbone of dysideanones was efficiently constructed through an intramolecular radical cyclization reaction. Dysideanone G (6) was easily prepared on a gram-scale and dysideanones A, E, and F (1, 4, and 5) were divergently transformed from dysideanone G (6) in one or two steps

Enantioselective total synthesis of atisane diterpenoids: (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one.

Enantioselective total synthesis of (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one has been accomplished starting from enantiopure Wieland-Miescher ketone. Key features of the syntheses include a benzannulation step to construct the tricyclic core, an oxidative dearomatization step to generate the diene, and a Diels-Alder reaction with ethylene gas to establish the bicyclo[2.2.2]octane framework. Efficient late-stage functionalisation of the A-ring by aerobic oxidation and Baeyer-Villiger oxidation completed the atisane target molecules.

Synthetic studies toward Swinhoeisterol A: Synthesis of the 6/6/5/7 tetracyclic core

6/6/5/7 Tetracyclic core of Swinhoeisterol A was constructed starting from Wieland-Miescher ketone and silylated ethyl 5–hydroxyvalerate. After modification, the bicyclic and linear subunits were assembled by means of cross-metathesis reaction. Then, cyclopentane C ring was formed by the intramolecular aldol condensation. C17-stereocenter was constructed using Claisen rearrangement followed by the decarbonylation step. Finally, ene reaction was applied for the simultaneous formation of cycloheptane d-ring and tetrasubstituted double bond between rings B and C.

Regio- and stereoselective nucleophilic addition reactions of Swaminathan ketone and its methylated analog using organometallic reagents

Herein, we report the regio- and stereoselective nucleophilic addition reactions of Swaminathan ketone 2a and its methylated analog 2b, both of which contain a 6–7 fused carbocyclic enedione moiety. Nucleophilic additions to 2 using generic organometallic reagents, such as Grignard and organolithium reagents, preferentially occurs at the conjugated carbonyl group to afford a range of tert-alcohols with high stereoselectivity. The selectivity observed with 2 was notable when compared to that observed with Wieland–Miescher ketone 1a bearing a decalin framework. A variety of substituents, such as alkyl, alkenyl, alkynyl and aryl groups, can be introduced into 2 using this method. Exceptionally, the allylation reaction of 2 occurred at both the conjugated and non-conjugated carbonyl groups, but this regioselectivity problem was solved using organocopper reagents.

Practical and Scalable Total Syntheses of (+)-Dysidavarones A–C

AbstractA practical and scalable enantioselective total syntheses of the marine anticancer sesquiterpene quinone meroterpenoids (+)-dysidavarones A–C has been accomplished. The central bridged bicyclo[3.3.1]nonane structure of dysidavarones was efficiently established by a one-pot intermolecular diastereoselective alkylation and intramolecular α-arylation of a Wieland–Miescher ketone derivative with a substituted benzylic bromide, without protection of the more-reactive C(4) carbonyl group. (+)-Dysidavarones A and ‘E’ were prepared on a 150-mg scale, demonstrating the efficiency and reliability of our synthetic route and providing sufficient amounts of the dysidavarones for further bioactivity evaluation.

L-Proline: A Versatile Organo-Catalyst in Organic Chemistry.

L-proline is a natural amino acid having secondary amine functionality and acts as a bifunctional catalyst (organo-catalyst). The amino-functional group acts as Lewis base type while carboxylic acids act as Brønsted acid type catalysts. It catalyzed different asymmetric syntheses, including known reactions such as Aldol condensation, Mannich reaction, Michael Addition, Knoevenagel condensation, Hantzsch synthesis, OXA-Michael Henry tandem, Ullmann reactions, Wieland-Miescher ketone synthesis, Robinson annulation, Biginelli reaction, α- amination. It is also an essential catalyst for synthesizing heterocyclic skeletons such as coumarin, spiro-oxindoles, imidazoles, benzimidazoles, quinoxalines, podophyllotoxin, benzothiazoles, isoxazolidines, phenothiazines, aziridine, indole, 1,5-benzodiazepines, pyridine, and quinazolines. In this review, we had the objective to critically summarize the use of proline and proline derivatives as catalysts of multicomponent reactions performed in various media and leading to synthetically and biologically relevant heterocycles, a very important class of compounds that constitutes over 60% of drugs and agrochemicals. All scholarly articles for L-Proline catalyzed reactions were retrieved from ScienceDirect, Google Scholar , PubMed, etc. Results and Conclusion: Given the importance of L-Proline based reactions, it has been observed to have tremendous applications in organic chemistry. It can also act as a 'Green catalyst'.

Divergent total synthesis of marine meroterpenoids (+)-dysidavarones A–C

Here, we report a concise and divergent enantioselective total synthesis of marine sesquiterpene quinone meroterpenoids (+)-dysidavarones A–C (1–3) using predysidavarone 6 as a key common intermediate. The highly strained and bridged eight-membered carbocycle of predysidavarone 6 was constructed by a one-pot intermolecular alkylation and intramolecular arylation of Wieland–Miescher ketone derivative 11 and benzyl bromide 12. The total synthesis of (+)-dysidavarones A–C (1–3) was achieved from predysidavarone 6 in a divergent manner by a late-stage introduction of the ethoxy group, which reveals the possible source of the ethoxy group within (+)-dysidavarones A–C (1–3) and provides a late-stage modifiable route for the synthesis of dysidavarone analogs for further anti-cancer activity evaluation.

Preparation of Ionic Liquid Supported Organocatalysts for the Synthesis of Stereoselective (R)-9-Methyl-5(10)-Octaline-1,6-Dione

: The synthesis of Proline-2-triethyl-ethylamide hexafluorophosphate (ILPA-PF6) (with 96% yield) and further the application during the synthesis of (R)-9-Methyl-5(10)-octaline-1,6-dione (Wieland-Miescher ketone molecule) are defined in this manuscript. The suggested protocol signifies one of the most efficient methods for the synthesis of these flexible chiral building blocks in good yield. The evident solubility of ionic liquids allows straightforward isolation of the (R)-9-Methyl- 5(10)-octaline-1,6-dione product from reaction mass. Additionally, six times catalyst recycling was considered the main conclusion of this proposed procedure. Background: The synthesis of WMK starts with the Michael Addition step, where the α, β- unsaturated ketone reacts with 2-methyl-1,3-cyclohexanedione followed by the nucleophilic attack and produces the triketone. Further, the isolated triketone goes to intramolecular Aldol Condensation, (in the Robinson Annulation reaction cascade) to get an enolate. Later, followed by the dehydrogenation reaction of enolate (to expel hydroxide ion) the desired product Wieland Miescher Ketone was isolated in good yield. The above conventional method suffers from several drawbacks like a slow reaction rate, the requirement of high boiling point solvent systems, and low reaction yield. Objective:: To prepare ionic liquid-supported organocatalysts for the synthesis of stereoselective (R)- 9-Methyl-5(10)-octaline-1,6-dione Method: This report summarizes the synthesis and its application of triethyl salt-supported prolinebased organocatalysts as recyclable and highly efficient for the asymmetric Wieland-Miescher ketone ((R)-9-Methyl-5(10)-octaline-1,6-dione). An ionic liquid-supported proline (as a catalyst) is equipped with basic proline and a significantly acidic amide moiety to promote the reaction rate, and synchronously having a specialty of ionic liquid could be easy to separate and recycle. Results:: The report simply defined the WMK molecule in good yield and enantioselectivity followed by minimal ether washing. During the reaction, low catalyst loading i.e., 0.5 g of catalyst was found enough to attain the maximum yield and enantioselectivity in 2 hours. Furthermore, catalyst recycling was observed 6 times as a significant element of the suggested catalytic method. Conclusion:: The synthesis of an extremely dynamic and enantioselective ILPA-PF6 catalytic approach is demonstrated in the report. The ILPA-PF6 catalyst was further modified after its characterization for use in the synthesis of the WMK molecule and the subsequent intramolecular aldol reaction of triketone. The WMK molecule was isolated with good yield and enantioselectivity followed by minimal ether washing. During the reaction, low catalyst loading i.e., 0.5 g of catalyst was found enough to get the maximum yield and enantioselectivity in 2 hours. Additionally, catalyst recycling was observed 6 times as a significant element of the suggested catalytic method.

Formal Total Synthesis of Salvinorin A.

The generation of the quaternary stereocenter at the C9 position of salvinorin A precursors by the Claisen rearrangement was investigated. The required allyl alcohol was prepared from a Wieland‐Miescher ketone using a known γ‐hydroxylation, reduction of the enone double bond, cyanohydrin formation, and elimination, yielding an unsaturated nitrile. A two‐step reduction led to the required allyl alcohol. The subsequent Johnson‐Claisen rearrangement provided a mixture of two diastereomeric 1,4‐unsaturated esters in a ratio of around 2.6 : 1. The major isomer could be converted to a key intermediate of the Hagiwara synthesis of salvinorin A.

Organocatalyst Design for the Stereoselective Annulation towards Bicyclic Diketones and Analogues

The Wieland–Miescher ketone, Hajos–Parrish–Eder–Sauer–Wiechert ketone, and their analogues are bicyclic diketones essential as building blocks for the synthesis of several natural and bioactive molecules. For this reason, since 1971, when Hajos and Parrish and Eder, Sauer, and Wiechert reported the stereoselective synthesis of these compounds promoted by L-proline, numerous methodologies and organocatalysts have been studied over the years with the aim of identifying increasingly efficient asymmetrical syntheses of these bicyclic ketones. This review will outline the methodological and stereochemical features of the organocatalytic stereoselective synthesis of these bicyclic scaffolds based on the different organocatalysts employed from 1971 until today. Particular emphasis will be given to the structural features of the catalysts and to the reaction conditions.

Total syntheses of wentilactones A and B, and related norditerpene dilactones.

Wentilactones A and B, two representative tetranorditerpenoid dilactones with promising antitumor activities, are synthesized for the first time. The synthesis employs 3β-hydroxydilactone 6 as a common precursor, which is derived from (S)-Wieland-Miescher ketone, and leads easily to derivatives with various modifications on the A-ring, such as CJ-1445, asperolide B, and the unnamed natural congener 4.

Asymmetric Intramolecular Aldol Reactions Mediated by Chiral Triamines Bearing a Pyrrolidine Scaffold to Provide a Wieland–Miescher Ketone

Asymmetric Intramolecular Aldol Reactions Mediated by Chiral Triamines Bearing a Pyrrolidine Scaffold to Provide a Wieland–Miescher Ketone

Bioinspired Total Synthesis of Marine Anticancer Meroterpenoids Dysideanone B and Dysiherbol A and Structure Revision of Dysiherbol A

AbstractOur recent progress on the total synthesis of marine anticancer sesquiterpene quinone/hydroquinone dysideanone B and dysiherbol A is briefly highlighted. This success relied on some key transformations. The union of the terpene and quinone/hydroquinone moieties was realized through a site and stereoselective α-position alkylation of Wieland–Miescher ketone derivative with a bulky benzyl bromide. The 6/6/6/6-tetracycle of dysideanone B was constructed using an intramolecular radical cyclization and the 6/6/5/6-fused core structure of dysiherbol A was forged by an intramolecular Heck reaction, respectively. The possible origin of ethoxy group in dysideanone B was revealed by mimicking the isolation conditions at a late stage. The structure of dysiherbol A was revised through the total synthesis of this natural product. Schmalz’s synthesis of dysiherbol A was also included.

Total Synthesis of Anti‐Cancer Meroterpenoids Dysideanone B and Dysiherbol A and Structural Reassignment of Dysiherbol A

AbstractThe first total synthesis of marine anti‐cancer meroterpenoids dysideanone B and dysiherbol A have been accomplished in a divergent way. The synthetic route features: 1) a site and stereoselective α‐position alkylation of a Wieland–Miescher ketone derivative with a bulky benzyl bromide to join the terpene and aromatic moieties together and set the stage for subsequent cyclization reactions; 2) an intramolecular radical cyclization to construct the 6/6/6/6‐tetracycle of dysideanone B and an intramolecular Heck reaction to forge the 6/6/5/6‐fused core structure of dysiherbol A. A late‐stage introduction of the ethoxy group in dysideanone B reveals that this group might come from the solvent ethanol. The structure of dysiherbol A has been revised based on our chemical total synthesis.

Total Synthesis of Anti-Cancer Meroterpenoids Dysideanone B and Dysiherbol A and Structural Reassignment of Dysiherbol A.

The first total synthesis of marine anti-cancer meroterpenoids dysideanone B and dysiherbol A have been accomplished in a divergent way. The synthetic route features: 1) a site and stereoselective α-position alkylation of a Wieland-Miescher ketone derivative with a bulky benzyl bromide to join the terpene and aromatic moieties together and set the stage for subsequent cyclization reactions; 2) an intramolecular radical cyclization to construct the 6/6/6/6-tetracycle of dysideanone B and an intramolecular Heck reaction to forge the 6/6/5/6-fused core structure of dysiherbol A. A late-stage introduction of the ethoxy group in dysideanone B reveals that this group might come from the solvent ethanol. The structure of dysiherbol A has been revised based on our chemical total synthesis.

Discovery of New Carbonyl Reductases Using Functional Metagenomics and Applications in Biocatalysis.

Enzyme discovery for use in the manufacture of chemicals, requiring high stereoselectivities, continues to be an important avenue of research. Here, a sequence directed metagenomics approach is described to identify short chain carbonyl reductases. PCR from a metagenomic template generated 37 enzymes, with an average 25% sequence identity, twelve of which showed interesting activities in initial screens. Six of the most productive enzymes were then tested against a panel of 21 substrates, including bulkier substrates that have been noted as challenging in biocatalytic reductions. Two enzymes were selected for further studies with the Wieland Miescher ketone. Notably, enzyme SDR‐17, when co‐expressed with a co‐factor recycling system produced the anti‐(4aR,5S) isomer in excellent isolated yields of 89% and 99% e.e. These results demonstrate the viability of a sequence directed metagenomics approach for the identification of multiple homologous sequences with low similarity, that can yield highly stereoselective enzymes with applicability in industrial biocatalysis.

Biocatalytic Approaches to the Enantiomers of Wieland–Miescher Ketone and its Derivatives

AbstractBiocatalytic approaches have been investigated in order to isolate the enantiomers of Wieland–Miescher ketone (1) and of its alcoholic derivatives (cis‐2 and trans‐3). Specifically, two enzymes from our in‐house metagenomic collection of oxidoreductases, IS2‐SDR and Dm7α‐HSDH, catalyzed the kinetic resolution of the starting racemic ketone 1 or its complete conversion into two diastereomeric products, respectively. Moreover, the kinetic resolution of the racemic cis‐alcohol (2) was very efficiently obtained (E≅2.000) by lipase PS catalyzed acetylation in dry acetone. All the products were isolated with ee≥95 %. Simple chemical elaborations of some of them allowed to isolate the missing enantiomers.

Screening of Biocatalysts for Synthesis of the Wieland–Miescher Ketone

Lipases, a versatile class of biocatalysts, have been shown to function in non-aqueous media/organic solvents and to possess “promiscuous” catalytic activity for a wide range of organic transformations. In this study, we explored the biocatalytic properties of a library of commercially available lipases by screening them for catalysis of a one-pot synthesis of Wieland–Miescher ketone, an important intermediate in the synthesis of biologically active compounds such as steroids and terpenoids, from methyl vinyl ketone and 2-methyl-1,3-cyclohexanedione. As a direct outgrowth of this screen, we created an optimized procedure for Wieland–Miescher ketone (WMK) synthesis using crude lipase preparations, characterizing both reaction yield and enantiomeric excess. We also identified principal components of the crude lipase mixture through proteomics and present evidence for a non-lipolytic origin of the observed catalysis. Finally, using the optimized conditions developed in this study, we propose a general absorbance-based screening methodology for assessing biocatalytic potential of crude enzyme preparations for synthesis of WMK.

Aspects in the Total Syntheses of Higher Terpenoids Starting From Wieland–Miescher Ketone and Its Derivative: A Review

Synthetic studies of higher terpenoids starting from Wieland–Miescher ketone since 2012 have been compiled.

A Synthetic Approach Toward a Brominated Oxocane Labdane Diterpenoid Isolated From Laurencia obtusa

The synthesis of a labdane oxocane epoxy-alcohol is described starting from the Wieland–Miescher ketone derivative via ring closing olefin metathesis of a diene derivative, targeting the total synthesis of a brominated oxocane labdane diterpenoid isolated from Laurencia obtusa.