Total Synthesis of Biologically Important Pyrrolidinone Natural Products and Analogues Thereof.

Informazioni relative al progetto

SYNOX

ID dell’accordo di sovvenzione: 708354

DOI

10.3030/708354

Progetto chiuso

Data della firma CE 16 Febbraio 2016

Data di avvio 1 Settembre 2016

Data di completamento 31 Agosto 2018

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 183 454,80

Contributo UE

€ 183 454,80

Coordinato da

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 1 - SYNOX (Total Synthesis of Biologically Important Pyrrolidinone Natural Products and Analogues Thereof.)

Periodo di rendicontazione: 2016-09-01 al 2018-08-31

Sintesi del contesto e degli obiettivi generali del progetto

Natural products are the active components of many traditional medicines. A large number of currently prescribed drugs are either directly derived from or inspired by natural products. However, the availability of natural products from natural sources can be limited mkaing the full study their properties very challenging. Hence, there is always a need for greener, economic synthetic methodologies for the synthesis of natural products and analogues for the better understanding of their bioactivities with the future prospect of developing novel drugs. Considering the huge importance of natural products in drug discovery, in the proposal, we developed the synthesis of all three members of Inthomycins and C-16 substituted core of the oxazolomycins. These natural products display a wide variety of biological properties, including antibiotic activity, anti-tumour activity and anti-viral activity, thus developing a route has the potential for to benefitfor society in the future. Apart from this, our strategy offers an advancement over the previous literature in terms of sustainability and environment-friendly chemical process that avoids the use of highly toxic chemicals as well as potentially hazardous materials.
The synthesis of the inthomycins has been executed from simple and readily available starting materials to obtain the final core of these natural products efficiently, and should allow the futuer synthesis of the further biologically active natural products the oxazolomycins.
The work conducted during the fellowship will facilitate Dr Kumar to obtain an independent academic research position because during these 2 years he has been able to develop and widen his competences, particularly in terms of multi/interdisciplinary and inter-sectoral experience and transferable skills.
The novel strategies and reactions developed during this fellowship will advance the field of total synthesis of complex biologically active natural products and natural products fragments, which will be useful for both academic and pharmaceutical industries. In addition, the avoidance of toxic material is an advancement to the previous work and a further step towards the environmentally friendly protocols. Also, these natural products have already shown wide range of biological activities. Thus, the developed synthetic strategies will contribute to the social and economic benefit in the Horizon 2020 Programme. Furthermore, the research carried out during the tenure of this fellowship has definitely enhanced the innovation capacity, and helped the candidate develop these critical skills, which are valuable for his career.
The work conducted during these two years of fellowship has been published in a high-ranked journal and one more document will be forthcoming published. Also, work has been presented at many places including academic meetings and industrial symposiums, in which a high interest has been shown from other researchers.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

In this project, we developed an efficient and flexible route to the synthesis of Inthomycins and related triene fragments of the Oxazolomycins. In addition, efforts were made towards the synthesis of the C-16 substituted core of the Oxazolomycins.
In phase 1 of the project, we developed a route for the synthesis of all three Inthomycins. Direct alkylation of a substituted oxazole with a conjugated enyne bromide via a deprotonation /metallation provided the left-hand fragment in sufficient quantities to start the synthesis. For the right-hand fragment, we used an enantioselective Kiyoka cross-aldol reaction between the methyl trimethylsilyl dimethylketene acetal and the known (E)- or (Z)-vinyl iodide substrate, readily prepared from propargyl alcohol. Next, we attempted the Zr(IV)-catalysed syn-selective hydroboration of the enyne fragment followed by the Suzuki cross coupling with the iodide fragment to accomplish the required triene geometry of Inthomycin B and C. For Inthomycin A, we faced some issues with anti-selective hydroboration of enyne fragement, then we altered our synthetic strategy and investigated a Sonogashira/semi-hydrogenation sequence. Pleasingly, the Sonogashira reaction of the enyne with (Z)-vinyl iodide substrate using Pd(0) gave the coupled product in satisfactory yields. Then, several catalytic systems were tried to access the semi-hydrogenation of alkyne, where the use of Zn(Cu/Ag) couple in methanol gave the desired triene geometry in excellent yield and complete stereoselectivity. Next, hydrolysis and aminolysis of the corresponding pentaflurorophenyl ester gave Inthomycin A in total 14 steps.
In phase 2 of the project, attempts were made towards the synthesis of right-hand fragment of the Oxazolomyins. We expanded on and further developed an efficient and operationally straightforward synthesis of the pyrrolidinone core of Oxazolomycin A using Mn(III) and Cu(II)-mediated oxidative radical cyclisation of a chiral amidomalonate. The key oxidative radical cyclisation delivered the required [3.3.0]-bicyclic lactone-lactam in high yield and with good diastereoselectivity. The pyrrolidinone is readily transformed into a key aldehyde using 8-step sequence in good yield. The ext important step involved the addition of organometallic derived 5-carbon unit to this key aldehyde. Synthesis of the 5-carbon unit involveed the catalytic enantioselective SN2’ methodology using Cu(I) and Taniphos ligand, followed by Hoveyda-Grubbs II catalysed alkene cross-coupling. We then exposed the key aldehyde to the synthesised Grignard reagent to give required alcohol in good yield and high diastereoselectivity. Due to the time constraint, we did not finish the synthesis of Oxazolomycin, but the successful addition of the organometallic reagent to the key aldehyde is a huge step forward. Now, the only remaining step in the synthesis of Oxazolomycin A is the diene-amine installation followed by amide bond formation of the carboxylic acid equivalent of Inthomycin A of which numerous syntheses exist in the literature.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

After this two-year fellowship, the information in the original proposal regarding the impact is still relevant. This Fellowship has allowed a great improvement in the state-of-the-art in the construction of complex biologically active natural products and natural products fragments through a powerful and impacting synthetic methodology, raising the standing of EU Chemistry within this field at a global level. The reactions developed will be applicable to a broader substrate range and thus useful for the preparation of other natural products as well as drug target molecules. Therefore, this Fellowship has constituted a significant contribution to the field, and may benefit synthetic organic chemists, pharmaceutical, agrochemical and the fine-chemicals industries.
A significant part of the results obtained during the project concerning the synthesis of Inthomycins has been published in Chemistry–A European Journal.
The further development in the synthesis of Oxazolomycin A will be followed and will likely result in further publications.
The nature of the research, namely basic scientific research, means that no patent applications have been made.
The total publication output is likely to be two or three publications from the 24-month grant.

Stucture of the inthomycins