Our Research
Total synthesis of complex natural products: Total synthesis of structurally challenging and intriguing biologically active natural products through a strategy driven approach is one of the central theme of our research activity. When choosing the probable target biological profile comes first, and then comes structural complexity. A solid chemical logic (power of retrosynthesis) was in full action to design the synthetic pathway. Streochemical issues are dealt with utmost care. Novel synthetic transformations and classical functional group interconversions (FGIs) are then employed to access the target molecules. Some of the core research programme in that direction is provided below.
Isocoumarin based Natural Products
Isocoumarins and dihydroisocoumarins (DHICs) possess a close relation with isochromans, they are known as isochromen-1-one and isochroman-1-ones, respectively, since the C-1 active methylene in isochromans can be easily oxidized to the related isocoumarins derivatives. Most of the natural isocoumarins and DHICs are given trivial names, which are derived mainly from the name of the species or genus of the host organisms. Isocoumarins are considered as important intermediates in the synthesis of a wide range of carbo- and heterocyclic compounds such as isoquinolines, isochromenes, and different aromatic compounds. We aim to achieve asymmetric total synthesis of naturally occurring isocoumarins through our in-house developed Cu(I) catalysed 6-endo-dig cyclization method for accessing the isocoumarin core present in those natural products.
Synthesis of topologically distinct γ-alkylidenebutenolide Natural Products
γ-Alkylideneutenolides are very important frameworks found in many natural products, and they also display promising biological activities. γ-Alkylidenebutenolides were isolated from various strains of fungi and different marine sources and till now more than 500 such natural products are known. These are also very useful synthetic intermediates in the total synthesis of natural compounds. Over the years many γ-alkylidenebutenolides natural products were isolated from natural sources having exocyclic γ-δ unsaturation. A close structural inspection revealed that structural variations arise from the C6 appendage in the general class of γ-Z or E alkylidenebutenolides. Other structural variations arise from the incorporation of various ring structures (cyclic connectivity related to topologically distinct fashion) as shown below.
Total synthesis of such complex natural products through a strategy-driven approach should be of paramount importance, as it will allow us to access those molecules in reasonable quantity for further biological study. In this current proposal, our main focus will be to develop efficient, sustainable, and atom-economical strategies for the total synthesis of topologically distinct γ-alkylidenebutenolides.
Core methodology
Topologically distinct alkylidene butenolides as synthetic targets
Synthetic Studies towards RALs
Resorcylic acid lactones (RALs) are naturally occurring 14-membered macrolactones constitutes a class of polyketide derived fungal metabolites and possess significant and promising biological activity. Their core structural feature consists of β-resorcylic acid framework (2,4-dihydroxybenzoic acid) fused with alicyclic side unit decorated with numerous functional groups in stereodefined fashion.From a structural perspective, they possess a relatively simple architectural pattern consisting of substituted aromatic part fused with acyclic side chain bearing certain functionality in proper stereochemical fashion. Their biogenesis seems to be interesting as it involved intriguing PKS pathway and a late stage macrolatonization was repponsible for the construction of the lactone framework. We are actively pursuing our efforts towards the total synthesis of several naturally occurring RALs by strategic exploration of several unique transformation. Few of our accomplishments in that direction in recent past is presented herein.
Synthetic Studies towards small macrolides
The main highlight of this part of the research is the synthetic studies directed towards total synthesis of naturally occurring small ring macrolides. The main highlight of our synthetic strategy is chemoenzymatic kinetic resolution coupled with Mitsunobu inversion and chemoenzymatic dynamic kinetic resolution to access some valuable chiral secondary alcohol intermediates. These intermediates are then employed successively to gain access of more advanced intermediates, which has close resemblance of the target molecule. In the final step of synthesis we often planned to adopt RCM/CM reaction by Ru-based metathesis catalyst as well as Yamaguchhi/Shinia macrolactonization protocol. The success of our synthetic strategy depends on the optimization of RCM/CM reaction and macrolactonization protocol.
Biocatalytic Process Development
Biocatalysis using enzymes play a pivotal role in the area of asymmetric organic synthesis for the production of numerous biologically active natural products, APIs, food ingredients, flavor chemicals and so on. And demand for the above process is (white biotechnology, the industrial application of biocatalysis) continuously increasing with the advancement of microbiology and molecular biological tools that allowed the researchers to produce a suitable biocatalyst in large excess within a short span of time.
Biocatalysis with ketoreductases: 2-Substituted-β-ketoesters act as very good substrates for several ketoreductase enzymes, and numerous reports are well known in the literature which demonstrates the successful application of those class of enzymes to yield β-hydroxy ketoesters in stereocontrolled way. As the substrate spectrum of the ketoreductase from Klebsiella pneumoniae have not explored at all, we have set our target to use different 2-substituted β-ketoesters as potential substrates for the enzyme to synthesize several β-hydroxy ketoesters in enantiopure fashion. At a later stage we intend to use the enzymatically synthesized β-hydroxy ketoesters for effective construction of many useful molecules such as oxetanes, β-lactones, azetidines, carbohydrate mimic, functionalized cyclopentane and cyclohexane frameworks.
Scaffold Oriented Synthesis (SOS)
This research theme focused on the design and synthesis of various small molecular multifunctional scaffolds which will lead us to natural product and related molecules after biocatalytic and chemical modification. These libraries are mainly based on core scaffold from individual natural products or specific substructures found across a class of natural products or a new chemotype together. The following hydroxymethylated cycloalkenone based scaffolds have been designed, synthesized and further synthetically elaborated to many natural products and related molecules.
