An efficient synthesis towards the core of Crinipellin and Alliacol- B along with their docking studies

1College of Pharmacy, Seoul National University, Seoul 08826, South Korea. 2Department of Chemistry, Government College of Engineering, Keonjhar, Odisha-758002, India. 3Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia. 4Department of Chemistry, Sukanti Degree College, Subarnapur, Odisha-767017, India. 5Department of Chemistry, Fakir Mohan (F.M.) University, VyasaVihar, Nuapadhi, Balasore-756089, Odisha, India. 6Department of Synthesis of Bioactive Substances and Pharmaceutical Technologies, National Institute for Chemical & Pharmaceutical Research and Development, Bucharest, Romania.


Introduction
The polyquinane natural products have generated a sustained interest among synthetic chemists from the last three decades due to their complex molecular architecture and wideranging biological properties. 1a-d In 1979, the research group of Anke and Steglich reported the isolation of an antibiotic crinipellin A 1a from the submerged cultures of basidomycete Crinipellisstipitaria, strain 7612, which was found to be most active against Gram-positive bacteria. 2 Afterward, Steglich and co-workers have isolated some more crinipellins 1b, 1cand 1d( Figure 1). By further investigations on several strains of C. Stipitaria, which were found to exhibit antibiotic activity. 3 Crinipellins, are the first group of polyquinane diterpenoids to contain a tetraquinane framework which integrates together a linear cis:anti:cistriquinane along with angular triquinane ring systems. Hanson and Thallerl have reported a novel sesquiterpenealliacolide, from cultures of the basidiomycete Marasmius alliaceus. 4 These substrates show adequate antimicrobial activity and inhibit DNA synthesis in the ascetic form of Ehrlich carcinoma at concentrations less than 10 µg/mL. 2 Studies towards synthesis of architecturally more complex crinipellinsare limitedand there are only a few total syntheses of crinipellin B. 5 Recently, a total synthesis of crinipellin A has reported by Lee and co-workers. 6  approach for creating molecular complexity by engaging oxidative dearomatization of ohydroxymethyl phenols, cycloaddition, and photochemical reactions. 7 Taking into consideration of interest towards crinipellin1, as well as alliacol B2, we extended our previous approach towards angular triquinane 8 to tetraquinane and alliacol B. Herein, we wish to report a novel route for the synthesis of the tetracyclic ring systems 1e, which is a common core of crinipellin via oxidative dearomatization, cycloaddition and oxa-di-pimethane rearrangement.
We considered to exploring a route to tetraquinane1e which is core of Crinipellin through intermolecular diels alder reaction and photochemically 1,2 acyl shift (Scheme 1). It was contemplated that the angularly fused tetraquinane of type 1emay beobtained from compound 6 by cyclopropane ring cleavage followed by hydrogenation.
We envisioned that the key precursor 4would be obtained from keto epoxide 5 by manipulation of oxirane ring. The tricyclic keto epoxides 5wasconsidered to be prepared from aromatic precursor 10 via oxidative dearomatization to spiroepxycyclohexa-2-,4dienone 9 followed by cycloaddition with dienophilecyclopentadiene. The aromatic precursors 6 would be readily prepared from 5-methoxy indanone. 8 As we all know that the ongoing COVID-19 outbreak driven by highly infectious SARS-CoV-2 and causing the current pandemic and has turned on the most critical universal health disaster of this century [9,10]. So, after synthesizing the compounds, we have performed the molecular docking studies against some selected proteins/enzymes receptors by using CLC Drug Discovery Workbench Software.

Result and discussion
In continuation of our theme towards synthesis of angular triquinanes, we had also thought of exploring a synthetic route to angular tetraquinanes along the similar lines as presented earlier. The tetracyclic chromophoric system 4 was readily synthesized from the aromatic precursor 6 as described below. Interestingly, oxidative dearomatization of 6 in the presence of cyclopentadiene directly gave the adduct 5 in reasonably good yield along with some unreacted spiroepoxycyclohexa-2,5-dienone 9 (Scheme 2). This is presumably due to high reactivity of cyclopentadiene which could intercept the cyclohexadienone9 formed in situ even under ambient conditions. The structure of adduct 5 was confirmed from its spectral features.
Further, it may be worth noting that adduct 5 is formed in a highly regio-and stereoselectivecycloaddition wherein the cyclohexadienone behaves as 4-partner and cyclopentadiene as a 2-partner (dienophile) and that other products arising from alternate pericyclic modes [such as  4 s(cyclopentadiene) +  2 s (cyclohexadienone)] was not formed.
The adduct 5 was converted into the desired chromophoric system 4 as shown in Scheme 3.
Thus, the keto-epoxide5was reduced with activated zinc in aqueous methanol (protic solvent) in the presence of ammonium chloride which gave the keto-alcohol 10 asthe major product (mixture of syn-anti isomers) along with ketone 9 as a minor product. Oxidation of the keto alcohol 10 with Jones reagent followed by decarboxylation of the resulting -keto-acid furnished the desired tricyclic compound 4 endowed with a -enonechromophore in good yield. The structures of all the compounds were supported from their spectral features.
After having obtained the tetracyclic compound 4, it was subjected to sensitized irradiation in acetone. Chromatography of the photolysate gave both products, the compound 11 containing cyclobutanone ring formed due to 1,3-acyl shift and pentacyclic compound 12 (formed due to oxa-di--methane rearrangement) in almost equal yields (Scheme 4).
The 1 H NMR and 13 C NMR spectra of the more nonpolar product 12 indicated that it is contaminated with some inseparable hydrocarbon (which could not be separated even after repeated column chromatography). Therefore, the product 12 was subjected to dihydroxylation with OsO4 which gave the pentacyclicdiol13 (Scheme 3.14) in excellent yield as a single diastereoisomer ( 1 H NMR and 13 C NMR spectra) whose structure was fully corroborated with its spectral characteristics. However, stereochemical orientation of the hydroxyl groups was not easily discernible from spectral features.
The behaviour of tetracyclic compound 4is same with previous tricyclic chromophoric systems 14 under photochemical transformation. 8 As, the 1,3-acyl shift product 15 was formed as a major amount in both direct irradiation as well as sensitized irradiationof compound 14, It was converted to its tricyclic lactone 16which is a core ofAlliacol B. and cyclooxygenase-2 (Prostaglandin Synthase-2) (PDB ID: 1CX2 [17]. In the docking simulation, the ligands (compounds 13 and 16) (Figure 1) are placed into apredictable binding site on the surface of a protein target. CLC Drug Discovery Workbench utilizes also MMFF94 (MMFF) force field when generate 3D structure on import. Different conformations are generated by rotation about rotatable bonds and conformation changes. Thus, the ligand optimizer was realized by geometry minimization using MMFF94 force field. Also, the minimization of the ligand is conforming to the binding pocket geometry.The protein-ligand interaction is scored, and the best scoring binding mode is returned for individually ligand, collected with the score. The ligand binding mode search is effectuated inside in the binding site (green sphere with a radius large enough to comprise all ligands docked to the receptor protein). After the import of the protein receptor from PDB bank, the next step is the setup binding site and the setup binding pockets; binding pockets are necessary to guide the docking simulation. After the setup the binding site and the binding pocket, the co-crystallized-natural ligand was extracted and was redocking in the active binding site of the protein receptor, for the validation of the method and of the docking parameters obtained from the molecular docking studies. interacting with the amino acids residues is presented in Figure S1b, 2b and S2b. The amino acids residues that formed the interacting group of each ligand are listed in Table S1. After analyzing the data obtained from the docking study, it was observed that the two studied compounds were placed in the same binding site of 1T9U as the cocrystallized one ( Figure   2c).  Table S2. After analyzing the data obtained from the docking study, it was observed that the two studied compounds were placed in the same binding site of 1T9U as the cocrystallized one (Figure 3c). interacting with the amino acids residues is presented in Figure S5b, 4b and S6b. The amino acids residues that formed the interacting group of each ligand are listed in Table S3. After analyzing the data obtained from the docking study, it was observed that the two studied compounds were placed in the same binding site of 4Z2C as the cocrystallized one ( Figure   4c). and 13 interacting with the amino acids residues is presented in Figure S7b, 5b and S8b. The amino acids residues that formed the interacting group of each ligand are listed in Table S4.
After analyzing the data obtained from the docking study, it was observed that the two studied compounds were placed in the same binding site of 3ERT as the cocrystallized one ( Figure   5c).  Figure S9b, 6b and S10b. The amino acids residues that formed the interacting group of each ligand are listed in Table S5. After analyzing the data obtained from the docking study, it was observed that the two studied compounds were placed in the same binding site of 3ERT as the cocrystallized one (Figure 6c). ( Figure S12a). The docking pose of the co-crystallized and of the compounds 16 and 13 interacting with the amino acids residues is presented in Figure S11b, 7b and S12b. The amino acids residues that formed the interacting group of each ligand are listed in Table S6.
After analyzing the data obtained from the docking study, it was observed that the two studied compounds were placed in the same binding site of 3ERT as the cocrystallized one ( Figure 7c). It has been calculated the parameters who can predict if a molecule possesses properties that might turn it into an active drug, according to the Lipinski's rule of five [18], the number of hydrogen donors < 5), the number of acceptors hydrogen < 10), molecular weight < 500 Da, the octanol-water partition coefficient (log P) < 5. (Table 1)  After analyzing the results of the molecular docking study, it is observed that the two compounds 16 and 13 possess properties that can turn them into future oral drugs (Lipinski violation is 0) ( Table 1). It was also found that compound 16 could be a drug with antimicrobial, antiviral, anticancer, antifungal or anti-inflammatory activity. For all molecular docking studies against the studied targets, it was also observed that compound 16 has a higher docking score than compound 13 and is close to each co-crystallized ligand taken as reference ( Figure 8). possess properties that can turn them into future oral drugs. It was also found that compound 16 could be a drug with antimicrobial, antiviral, anticancer, antifungal or anti-inflammatory activity. In addition, compound 16 has a higher docking score than compound 13 and is close to each co-crystallized ligand taken as reference.