Dr. Subhash Ghosh
Laboratory of Total Synthesis
Total Synthesis of Bioactive Natural Products
The art of constructing complex natural products is the centerpiece of organic chemistry, which has played an important role in providing new molecules for drug discovery and development. Further it gives an opportunity to develop new strategy and chemistry that may find important application in other fields. In addition total syntheses play important role in structural elucidation of the natural products and provide their adequate quantities for further biological evaluation. Our group actively works on the total synthesis of bioactive natural products having important biological activity. Cytotoxic marine natural product bitungolides A-F were isolated from marine sponge and their structures were established by detailed NMR study. To confirm their absolute stereochemistry their total synthesis was attempted. Our group was the first to achieve the total synthesis of bitungolide F (J. Org. Chem. 2008, 75, 1582–1585) and confirmed its absolute stereochemistry. The strategy developed was utilized further for the synthesis of bitungolides E and B (Tetrahedron Lett., 2011, 52, 3106–3109; Org. Biomol. Chem., 2014, 12, 4002-4012). Our group used extensively sugars as chiral pool synthons for the synthesis of important natural products and the most notable one is the total synthesis of cytotoxic marine natural product (+)-varitriol and its analogues from D-mannitol by utilizing Heck reaction as a key step (J. Org. Chem. 2010, 75, 2107–2110). This work was highlighted in Organic Chemistry Portal (https://www.organic-chemistry.org/Highlights/2011/10January.shtm).
A unique strategy for the synthesis of (+)-Neopeltolide, a marine natural product with cytotoxic activity in the nanomolar range, was developed, using a Pd-catalyze oxa-Michel reaction for the construction of the tetrahydrofuran unit of the molecule (J. Org. Chem., 2012, 77, 9840–9845). Mandelalide A is a highly complex cytotoxic marine natural product isolated minute quantity from natural source. From literature precedence our group realized that the structure was assigned wrongly. An elegant strategy for the aglycon of the molecule was developed (Org. Lett., 2014, 16, 2658–2660) that later helped others to synthesize the maldelalide A (with corrected structure) in large scale for performing detailed biology. Our group also reported the total synthesis of the proposed structure of cytotoxic marine natural product maltepolide C by using intramolecular Heck-reaction as a key step and proved that the structure of the natural product was reported wrongly (Org. Lett., 2016, 18, 4092–4095). We also synthesized various poly hydroxylated natural products and mycalol one of them which shows excellent cytotoxic activity. For its synthesis Zipper reaction and Noyori asymmetric reduction were extensively used to build the molecule (Eur. J. Org. Chem.2018, 398-412). Callyspongiolide is an anticancer marine natural product was isolated in minute quantity from marine sponge. We developed an efficient strategy by which the natural product can be obtained in larger quantity [Org. Biomol. Chem., 2016, 14, 6769 – 6779; ACS Omega, 2018, 3, 16563–16575 (invited)]. Very recently our group achieved the total synthesis of the proposed structure metacridamide B and confirmed that the structure was reported wrongly (Tetrahedron Lett. doi.org/10.1016/j.tetlet.2021.153374).
Functionalization of 1-alkene-1,2-diboronic esters
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Dr. Ghosh’s group has made important contributions on the functionalization of 1-alkene-1,2-diboronic esters for the synthesis of heterocyclic as well as crbocyclic compounds. They showed that 1-Alkene-1,2-diboronic esters on azidation followed by click reaction produced either bistriazoles or unreported fused bis-(1,2,3-triazolo) pyrazines (J. Org. Chem. 2020, 85, 15104-15115), depending on the reaction conditions. Further, his group also observed that cyclopropanation of 1-alkene-1,2-diboronic esters followed by cross coupling would be an attractive option for the synthesis of highly substituted cyclopropane (J. Org. Chem. 2022, 87, 7649-7657) and this work has been highlighted in Organic Chemistry portal (https://www.organic-chemistry.org/abstracts/lit8/467.shtm). This functionalization of 1-alkene-1,2-diboronic esters chemistry was also used further for the synthesis of indolo[1,2-a]quinoline as well as isoquinolone fused tetracyclic (J. Org. Chem. 2023, 88, 5772–5779) and other heterocyclic compounds.
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Technologies developed:
Dr. Ghosh’s research groups, along with others, are also actively engaged in the process development of important APIs. Eribulin mesylate is a very complex synthetic anticancer medication used to treat breast cancer and liposarcoma. His group played an important role for the bench scale process development of eribulin meslate (Org. Process Res. Dev. 2020, 24, 2657-2664. U.S patent application no: 17621052). Under antiviral mission his group was actively engaged in the process development of two important antiviral drugs, daclatasvir (US Patent 11,344,858) and ledipasvir (patent filed). During COVID-19, his group aggressively worked with other groups at IICT for the process development of remdesivir (Tetrahedron Lett. 2022, 88, 153590).
