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.

Gelsemine flower (Credit: Wikipedia)

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.

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