A novel asymmetric total synthesis route of (+)- and (−)-limaspermidine has been designed and reported, using Diels−Alder cycloadditions between 3,5-dibromo-2-pyrone and tert-butyl acrylate as starting materials. This route employs Pd-catalyzed intramolecular aromatic C−H amidation and imino-Diels−Alder reaction to construct the key indoline and indolizidine moieties on a central cyclohexane core, allowing for the facile, direct synthesis of both (+)- and (−)-limaspermidine.
Seven-membered cyclic β-keto esters to form the C-ring and the methoxycarbonyl group at C-16 of ervatamine molecule were successfully designed and synthesized via ring opening and α-hydroxymethylation of 1,4-dioxaspiro[4.5]decan-8-one. Their structures and properties were determined based on 1H NMR, 13C NMR, HSQC, HRMS spectra, and specific rotation measurements. These results provide the basis for us to continue to successfully synthesize ervatamine molecules.
A novel convenient method for the synthesis of bis(indolyl)methane derivatives from relatively cheap and commercially available chemicals such as indole and aldehydes in a one-pot process using a heterogeneous catalyst Ga-MCM-41-SO3H was presented. Notably, the use of this catalyst produced products in very high yields (up to 98%) under mild conditions and the catalyst was found to be stable and reusable, retaining high catalytic activity even after five cycles. Interestingly, two alkaloids Arsindoline A and Turbomycine B were successfully synthesized using this catalyst. These findings suggest that Ga-MCM-41-SO3H could be a promising alternative to conventional acid homogeneous catalysts in the synthesis of bis(indolyl)methane derivatives, offering several advantages including easy separation and reuse, high stability, and low toxicity.

We have reported a novel total asymmetric synthesis route to both (+)- and (−)-limaspermidine, starting from 3,5-dibromo-2-pyrone and tert-butyl acrylate as starting materials. Hydrolysis of the tert-butyl ester to a carboxylic acid and chiral separation via the formation of diastereomeric salts with quinine provided the necessary asymmetry for the synthesis. Further transformations, including Pd-catalyzed intramolecular aromatic C−H amidation and imino-Diels−Alder reactions to construct the indoline subunit and rings D and E, respectively, have successfully led to the total synthesis of the natural (+)-limaspermidine and its enantiomer (−)-limaspermidine.
We designed and synthesized seven-membered cyclic β-keto esters to form the C-ring and the methoxycarbonyl group at C-16 of ervatamine molecule through ring opening and α-hydroxymethylation of 1,4-dioxaspiro[4.5]decan-8-one. Their structures and properties were determined based on 1H NMR, 13C NMR, HSQC, HRMS, and specific rotation measurements. These results provide the basis for us to continue to successfully synthesize ervatamine molecules.
We are reporting a potential application of Ga-MCM-41-SO3H material as an efficient heterogeneous catalyst for the synthesis of bis(indolyl)methane derivatives in high yield under mild conditions. Interestingly, two alkaloids Arsindoline A and Turbomycine B were successfully synthesized in the employment of our catalyst. Notably, the catalyst was found to be air-stable and recyclable, retaining its catalytic activity even after six cycles. These results suggested that Ga-MCM-41-SO3H material could be a promising alternative catalyst to common acid homogeneous catalysts in the synthesis of bis(indolyl)methane derivatives, offering several advantages including ease of separation and reuse, high stability, and low toxicity. The packing of the Ga-MCM-41-SO3H catalyst in a flow system could also open new opportunities for the practical synthesis of drugs and bioactive compounds, making it a valuable tool in the development of more sustainable chemical and pharmaceutical processes.

- Publications:
1. Oh S-H, Oh J-Y, Vo NB, Ngo QA, Kovalenko V, Cho C-G. Asymmetric Formal Total Syntheses of (+)- and (−)-Limaspermidine from Chirally Resolved 2-Pyrone Diels–Alder Cycloadducts via Aromatic C–H Amidation and Imino-Diels–Alder Reaction. The Journal of Organic Chemistry. 2024. doi:10.1021/acs.joc.4c01696.
2. Dang V. Do, Van T. H. Nguyen, Nguyen Tuan Linh, Thanh Son Le, Vo Ngoc Binh, Hien Nguyen, Cheon-Gyu Cho, Tran Quang Hung, Tuan Thanh Dang, Quoc Anh Ngo. Efficient Synthesis of Bis(indolyl)methane Derivatives on Heterogeneous Ga-MCM-41-SO3H Catalyst under Mild Condition. ChemistrySelect. 2024. Doi: 10.1002/slct.202403150.  
3. Vo Ngoc Binh, Cho Cheon-Gyu and Ngo Quoc Anh. Synthesis and characterization of seven-membered β-keto esters as building blocks toward ervatamine synthesis. Hnue Journal of Science, Natural Sciences 2023, 68 (3), 75-81. doi: 10.18173/2354-1059.2023-0062.
- Training: Training 01 bachelor (successfully defended)
Student name: Trinh Thu Ha
Major: Chemical Engineering
Training institution: School of Chemistry and Life Sciences, Hanoi University of Science and Technology.
Thesis title: Synthesis and evaluation of biological activity of some novel pyrazolo[4,3-b] indole derivatives
Year of defense: 2024