ADVERTISEMENT

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.

ADVERTISEMENT

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.

ADVERTISEMENT

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.

Comment (1)

Comments

READ THIS NEXT

Atomic Radius Trend

The atomic radius trend describes how the atomic radius changes as you move across the periodic table of the elements. […]

Parts Of The Hand

The parts of the human hand are capable of many different tasks, able to carry out a wide variety of functions. […]

Biased And Crossmap Dropout Strategies For Convolutional Neural Networks

Over the last decade, deep learning models, particularly Convolutional Neural Networks (CNN), have shown outstanding results in various fields, including […]

Quitting Smoking Means Gaining Weight, But Why?

If you quit smoking, you often gain weight. Researchers have now investigated in twins how big the difference is and […]

GPAtlasRRT: Exploring What We Cannot See

When manipulating an unfamiliar object, we use the sense of touch to feel our way around it. We feel even […]

Community-Led Regeneration Initiatives Can Alleviate Fuel Poverty

In developed countries characterized by temperate climates, a household is regarded as experiencing “fuel poverty” when it cannot afford to […]

Synthetic Salinity Model: An Alternative To Expensive And Time-Consuming, Ground-Based Soil Salinity Measurements

Climate change and associated sea-level rise is an imminent and inevitable threat for low-lying countries like Bangladesh. Additionally, a new […]

Science Trends is a popular source of science news and education around the world. We cover everything from solar power cell technology to climate change to cancer research. We help hundreds of thousands of people every month learn about the world we live in and the latest scientific breakthroughs. Want to know more?