Go with the continuous flow: Asymmetric Synthesis of Bioactive Alkaloids by Multistep Continuous-Flow Processes

Project Information

AsymmFlow

Grant agreement ID: 890452

DOI

10.3030/890452

Project closed

EC signature date 11 March 2020

Start date 1 September 2020

End date 31 August 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 160 932,48

EU contribution

€ 160 932,48

Coordinated by

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

Periodic Reporting for period 1 - AsymmFlow (Go with the continuous flow: Asymmetric Synthesis of Bioactive Alkaloids by Multistep Continuous-Flow Processes)

Reporting period: 2020-09-01 to 2022-08-31

Summary of the context and overall objectives of the project

In the Realm of Chemistry, asymmetric synthesis has a prime importance as it allows creation of optically pure chemical entities. The synthesis of preferred enantiomer is highly desirable when seeking for specific biological activities owing to the importance of chirality. AsymmFlow delineates synthesis, characterization and application of novel asymmetric supported organocatalysts for enantioselective Pictet-Splengler cyclization in continuous flow/batch to produce tetrahydro-β-carboline (THβC) derivatives. The proposed immobilization strategy gives access to synthesize reusable, robust and stable catalytic systems for asymmetric continuous-flow processes.

The overall aim of AsymmFlow is to provide new sustainable tools for the synthesis of tetrahydro-β-carboline (THβC) derivatives, ranging from quaternary substituted and spiro compounds, which show potent anticancer and antimalarial activity. The advances provided through the project could be translated in future reduced cost and time production of such drugs. Thus, the results of the current project could be translated to an economic impact on human health. Furthermore, the explored synthetic route involves continuous flow chemistry and is in alignment with the principles of green chemistry; thus, the project also contributes with a positive impact on the environment.

AsymmFlow proposes the use of reusable immobilized organocatalysts by integrating them into continuous flow reactors to establish faster, safer, and a greener protocol for the enantioselective synthesis of THβC derivatives.
The specific objectives of the action have been:
1. Synthesis and characterization of asymmetric immobilized catalysts starting from proline and BINOL derivatives
2. Optimization of reaction conditions for the asymmetric synthesis of THβCs and Michael adducts under batch/continuous flow operation using immobilized catalysts
3. Synthesis of quaternary tryptolines, such as Spiroindolinones, and indoloquinolizidines in continuous flow.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

At the outset, polymer supported organocatalysts (Proline and BINOL based) have been synthesized to test them for enantioselective cyclisation reactions. Merging polymer-supported asymmetric organocatalysis with continuous flow in a packed bed reactor affords many advantages, thus it has been used as the key, enantiodetermining step in a short synthesis of indoloquinolizidines. Using this approach, first a highly enantioselective, solvent-free conjugate addition of dimethyl malonate to a diverse family of cinnamaldehydes in continuous flow, allowing the preparation of relevant oxodiesters in multigram amounts, has been developed. The obtained Michael adducts have been used to complete an expedient diastereoselective synthesis of indoloquinolizidine via cascade Pictet- Splengler cyclisation-lactamisation in continuous flow. Additionally, polymer-supported phosphoric acid (TRIP)-catalyzed first enantioselective Pictet-Spenlger reaction of tryptamines and diketo compounds has been accomplished in batch/continuous flow. Using the stated approach, a diverse library of quaternary tryptolines has been synthesized in good to excellent yields and enantiomeric excesses. Moreover, the scalability for the reaction has been attained utilizing an expedient continuous flow process with residence time of only 24 minutes. The robust immobilized catalyst has been recycled and reused multiple times in batch/flow. Additionally, the synthesis of the chiral precursor of Tadalafil and Iboga-type alkaloid (+)-Tabertinggine, as well as antimalarial spiroindolinones, has been achieved in batch/continuous-flow.

Exploitation and dissemination:
Talk/Oral communications/Poster presentation during MSCA-IF program:
1) Oral communication entitled “Immobilized organocatalyst for asymmetric Michael addition in batch/flow: Diastereoselective synthesis of diverse indoloquinolizidines in flow” at International Symposium on Green Chemistry (ISGC 2022), La Rochelle, France (16-20 May, 2022), in-person conference.
2) Poster presentation at “8th Conference on Frontiers in Organic Synthesis Technology” (FROST-8) by Flow Chemistry Society, Budapest, Hungary (24-26 November, 2021), in-person conference.
3) Invited talk entitled “Polymer supported asymmetric organocataylsis in continuous-flow: A powerful strategy for process intensification” international e-conference 2022 on current research in chemistry and nanosciences, India, virtual conference.
4) Invited talk in international e-conference on “Merging Continuous Flow Chemistry and Supported Catalysis for the Synthesis of Bioactive Molecules” at Department of Chemistry, A. S. & C. College, Manmad, Nashik, India (21/09/2021), virtual conference.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We were able to produce a highly sustainable route for the synthesis of precursor of Iboga-type alkaloid (+)-Tabertinggine as well as antimalarial spiroindolinones in batch/continuous-flow. In past decades, clinical trial studies revealed that spiroindolinones show potent antimalarial activity and thus will be a suitable alternative for existing antimalarial drug, Artemisinin. We believe our established route will provide future opportunities for sustainable, rapid, and enantioselective synthesis, using continuous production, of spiroindolinones. While pursuing the project the candidate has learned new techniques to synthesize polymer-supported organocatalysts and integrated them for asymmetric transformations. This experience will help the candidate to start his own research group and expand further the techniques learned during MSCA program. As expected, the candidate’s transition from experienced researcher to become independent/established researcher is on track.

Figure 1. An Enantio- and Diastereoselective Approach to Indoloquinolizidines in Continuous Flow

Figure 2. Enantioselective Pictet-Spengler cyclisation of diketo compounds with tryptamines