Diversity-oriented Synthesis Of Oxacyclic Spirooxindole Derivatives: Useful DOS Strategy For Drug Discovery

In recent years, diversity-oriented synthesis (DOS) has drawn a huge interest from researchers in the vicinity of synthetic organic chemistry and medicinal chemistry because it is a powerful device to find the most structural variability from easy starting materials. Also, it is important to synthesize a variety of novel and biologically attractive small molecules in drug discovery.

The spirocyclic oxindole scaffolds are significant in nature because they occur in many natural products like horsfiline, gelsemine, gelseverine, and rhynchophylline. Especially, the construction of oxygen-containing spirooxindole frameworks has fascinated large attention of synthetic chemists because, they have various types of bioactivity such as anticancer, antimalarial, antitubercular, and anti-HIV. Therefore, the development of efficient methods to create substituted spirooxindole is of great impact. Recently, a lot of research has been done in the synthesis of spirooxindoles.

In this regard, we have developed an efficient approach for the synthesis of new complex oxacyclic spirooxindole scaffolds by using a diversity-oriented synthetic strategy (Adv. Synth. Catal. 2017, 359, 3444 – 3453). First, we synthesized required (1,6)/(1,7)/(1,8)–enynes from the simple substituted isatins as shown in Figure 1. These oxindole enynes are used as starting materials for the divergent synthesis of various functionalized oxacyclic spiroxindoles such as spirooxindole-5,6-bicyclic/5,5-bicyclic cyclopentenones and spirooxindole-vinyldihydropyran/tetrahydrooxepines by using Cobalt catalyzed intramolecular Pauson–Khand (2+2+1) cyclization reaction (IPKR) and Ruthenium-catalyzed Ring-closing Enyne Metathesis (RCEYM).

Under Intramolecular Pauson-Khand reaction optimized conditions by using Co2(CO)8 (1.1 eq.) in DCM at room temperature for 2 h, followed by cycloaddition promoted with NMO (6.0 eq.), we have explored a variety of spirooxindoles such as spirooxindole-5,6-bicyclic fused cyclopentenones (5) and spirooxindole-5,5-bicyclic fused cyclopentenones (7) by changing of R/R1 groups including electron-donating and electron-withdrawing groups on the oxindole moiety in good to excellent yields.

In 2016, Schreiber et al. (Org. Lett. 2016, 18, 6280–6283) used these classes of small molecules (fused cyclopentenone derivatives) in drug discovery, as well as those relying on fragment-based drug discovery (FBDD), high-throughput screening (HTS) and real-time biological annotation in cell morphological features.

On the other hand, After optimization of Ring-closing Enyne Metathesis (RCEYM), with  Grubbs-1 catalyst (5 mol%) in DCM at 40oC for 12 h, we have synthesized various spirooxindole-vinyl dihydropyrans (6) and spirooxindole-vinyl tetrahydrooxepines (10) in excellent yields and we were pleased to find that the reaction also accommodated several functional groups, such as 5-Me, 5-OMe, 5-OCF3, 5-F, 5-Cl, 6-Cl, 7-Cl, 4-Br, 5-Br on the oxindole moiety.

In summary, we have developed an efficient strategy for diversity-oriented synthesis (DOS) of novel oxygen-containing fused spirooxindole scaffolds from simple isatins via IPKR and RCEYM reactions. We hope that the elaborated DOS approach will find applications in drug discovery and the creation of bioactive compounds.

This study, Diversity-Oriented Synthesis of Oxacyclic Spirooxindole Derivatives through Ring-Closing Enyne Metathesis and Intramolecular Pauson–Khand (2+2+1) Cyclization of Oxindole Enynes was recently published by Satheeshkumar Reddy Kandimalla and Gowravaram Sabitha (Indian Institute of Chemical Technology) in the journal Advanced Synthesis & Catalysis.

About The Author

Satheeshkumar Reddy Kandimalla

Satheeshkumar is a research scientist at the Indian Institute of Chemical Technology.

Gowravaram Sabitha

Sabitha is a Senior Principal Scientist at Indian Institute of Chemical Technology.

Comment (1)

Speak Your Mind!

READ THIS NEXT

Adolescent Self-Efficacy Is Shaped By Family, School, And Peers

Adolescence is rife with changes and challenges in preparation for the demands of adulthood. Teens are busy learning how to drive, date, and navigate their first jobs, all while gaining independence from their parents. This combination of autonomy and new challenges makes self-efficacy, or belief in one’s ability to successfully accomplish goals, an especially important […]

Informal Urban Firewood Markets Persist Despite Large-Scale Socioeconomic Development

Almost three-quarters of Africa’s urban population uses firewood as their primary source of domestic energy, and the International Energy Agency projected that the absolute numbers will almost double by 2030. However, future projections of energy demand and specifically firewood use are complicated, uncertain and depend a great deal on the broader political and socio-economic trajectories […]

Types Of Cedar Trees: Eastern Red Vs. Western Red

There are a variety of types of cedar trees, from eastern red cedar to western red cedar, all of which can be identified once you know how. The eastern red cedar, a juniper, is common among wide swaths of the United States plains and east coast, with alternate leaves and double toothed. The western red […]

A Dangerous Antibiotic Has Traveled Around The World From China

Antibiotic resistance is a major problem that the world is facing as bacterial strains become adept at avoiding the drugs we have against them. As this resistance continues to grow, researchers around the globe have seen the spread of the mrc-1 gene, which grants resistance to colistin, a last resort antibiotic. What is Colistin? Colistin is […]

How To Write A Cursive Lowercase z

Have you ever wondered how to write a cursive lowercase “z”? Below you’ll learn some interesting facts about cursive, as well as how to write a cursive lowercase “z”. How To Write A Cursive Lowercase Z You can write a cursive lowercase “z” by picking a point that originates about a quarter of the way […]

Meiosis Anaphase 1

Meiosis is the process which creates sex cells, or gametes. During the process of meiosis, chromosomes are divided by half in order to create haploid cells. These parent cells that give birth to haploid cells are different from their haploid offspring, as the haploid cells have a genome which is distinct. The process of meiosis can […]

Late Paleogene To Neogene Paleogeography Of The Euxinian Part Of Paratethys With Focus On Crimean – Caucasian Junction

A major event of the Cenozoic history of the Earth was a collision of the African–Arabian and Indian plates with Eurasia. It led to the raising of the Alpine Fold Belt and, in the closure of the Tethyan Basin, connecting the Atlantic and Indian oceans. The region under consideration includes the central Crimean-Caucasian part of […]