C-H activation of SP3 carbon using oxime as directing group
Late stage functionalization was used to synthesize several sulfonamide derivatives taking 18β-glycyrrhetinic acid as a lead molecule (Scheme 1) and hence followed by the analysis of their anticancer profiles.
Tosyl azide (6a) was used as amine source for Ir-catalyzed C-H amidation of ketooxime (Scheme 3). Amidation takes place at equatorial methyl group of compound 6 in a selective manner.
Preparation of Jone’s reagent
Jone’s reagent, diluted chromium trioxide in sulphuric acid, acts as an oxidant for organic compounds diluted in acetone 2.5M reagent can be prepared by dissolving chromiumtrioxide (25g, 25mol) in water (75 ml) which was taken in a 500 ml beaker, followed by the addition of concentrated sulphuric acid (25 ml), which was kept in an ice-bath, slow addition with constant stirring is appreciated, keeping temperature in a range of 0°C–5°C.
Preparation of ketone
Followed by the dilution of 18β-Glycyrrhetinic acid in Tetra hydro furan the mixture was kept in ice bath along with slow, drop wise addition of Jone’s reagent maintaining a temperature of 0°C for nearly for a time period of one hour.
Preparation of ketoester
Followed by the dissolution of the ketone compound (302g, 645 mmol) in acetone, potassium carbonate (134g, 968 mmol) was added which was then followed by the slow addition of methyl iodide (60 mL, 968 mmol). And an overnight stirring was carried at room temperature. The solution obtained was then poured into water (10 mL), and chloroform (8 mL) was added, the obtained solution is then stirred and separated. Obtained organic layer was then dried over anhydrous sodium sulfate, which was then filtered and concentrated under reduced pressure to obtain the desired compound.
Synthesis of ketoxime
Methoxylamine hydrochloride (677mg, 8.1 mmol), NaOAc (1.08g, 13.2 mmol) were placed in a RB flask and 10 ml water was added continuously stirring the mixture for 5h, keeping temperature at 80°C. Once the reaction is completed, TLC was checked to confirm the completion of the reaction. Followed by the dilution of reaction mixture with 10ml of CH2Cl2, aqueous layer was extracted with 10 ml of CH2Cl2. Obtained organic layers was combined and dried over Na2SO4, followed by filtration and concentration under vacuum, which promises an environment of reduced pressure. Purification of the residue was done by column chromatography aiding silica as the stationary phase and 10 o/o of EtOAc in hexane as the eluent, which gives a colorless solid (5).
General procedure for the Ir-Catalyzed amidation of ketoximes with azides
Ketoxime (1.0 eqiv), azide (2.0 eqiv), [IrCp*Cl2]2 (5mol o/o), AgNTf2 (20 mol o/o), AgOAc (0.02 mmol, 10 mol o/o) and 1,2-DCE (0.5mL) was added into a screw capped vile with magnetic stirrer in N2 atmosphere. The reaction mixture was stirred at 60°C for 24h. Concentration of solvent was done under the reduced pressure on completion of the reaction. Obtained residue was then purified by column chromatography on silica gel (EtOAc/hexne), which further gives the desired product. Preparation of the compound 6 was done using the general procedure discussed above, which was then purified by flash chromatography (20 o/o EtOAc/hexane) which furnishes a white solid.
RESULTS AND DISCUSSION
Melting point: 308–310°C
1H NMR (300MHz, CDCl3) : δ 75(s,1H), 2.97(m, 1H), 2.64(m,
1H), 2.41(s, 1H), 2.41-0.87(m,
13C NMR(75MHz, CDCl3) : δ217.3, 199.7, 181.2, 169.8, 128.4
, 76.6, 61.0, 55.4, 48.2, 47.8,
45.3, 43.8, 43.3, 40.9, 39.7, 37.7,
36.7, 34.2, 32.1, 31.9, 30.9, 28.6,
2 8.4, 26.5, 26.3, 23.3, 21.4, 18.8,
Melting point: 248–250°C
1H NMR (300MHz, CDCl3) : δ 68(s, 1H), 3.69(s, 3H), 2.97(m,
1H), 2.62(m, 1H), 2.40(s, 1H),
13C NMR (75MHz, CDCl3) : δ 215.6, 198.4, 176.1, 168.7,
128.3, 60.9, 55.3, 51.5, 48.2,
47.5, 45.1, 43.8, 43.2, 41.1
39.6, 37.7, 36.6, 33.9, 32.1,
31.7, 31.0, 28.5, 28.2, 26.5,
26.4, 26.3, 23.3, 21.3, 18.7,
Melting point: 256–258°C
[α]20D : +108.6(c=0.79,CHCl3).
1H NMR(400 MHz,CDCl3) : δ 5.67(s,1H),3.81(s,3H),3.68(s,3H),2.93
(ddd, J=15.6,5.0,3.8Hz,1H),2.81(ddd, J=
13.3, 5.7, 3.7 Hz, 1H), 2.11-1.76(m,5H)
1.72-1.37(m,6H), 1.34(s, 3H), 1.30(d
J= 9.6Hz, 2H),1.21-1.18(m, 1H), 1.23(s,
3H), 1.14 (s, 6H), 1.06 (s, 3H), 1.05-0.98
13C NMR(101 MHz, CDCl3) : δ 200.0, 177.0, 169.5, 165.9, 128.6, 61.5,
61.2, 55.8, 51.9, 48.5, 45.5, 44.2, 43.4,
41.2, 40.3, 39.2, 37.9, 37.1, 32.6, 32.0,
31.3, 28.7, 28.5, 27.4, 26.6, 26.5, 23.6,
23.4, 18.8, 18.3, 17.9, 15.8
HRMS (ESI) : m/zcalcd for C32H50NO4[M+H]+ :512.3740;
Compound 6 (Sulfonamide Derivative)
Melting point: 210–212°C
[α]20 D : +69.15(= 0.98, CHCl3)
1H NMR (500MHz, CDCl3) : δ 7.74(d, J = 8.2 Hz, 2H), 7.32 (d, J =
8.1Hz, 2H), 5.67(s, 1H), 5.21 (dd, J =
9.8, 4.4Hz, 1H), 3.74 (s, 3H), 3.69 (s,
3H), 3.05-2.82(m, 4H), 2.44(s, 3H)
2.41(S, 1H), 2.12-1.69 (m, 8H),
1.55-1.38(m, 5H), 1.36 (s, 3H), 1.34-
1.30(m, 2H), 1.26(s, 3H), 1.15 (s, 3H),
1.14(s, 3H), 1.60-1.00(m, 1H), 0.96(s,
3H), 0.91-0.84(m, 2H), 0.80(s, 3H)
13C NMR (101Hz, CDCl3) : δ 200.0, 177.1, 170.1, 164.0, 143.3,
137.3, 129.9, 128.4, 127.0, 61.6,
61.4, 51.9, 49.1, 48.6, 48.2, 45.6,
44.2, 43.5, 41.2, 38.7, 37.9, 36.9,
32.1, 32.0, 31.3, 28.7, 28.5, 26.5,
23.6, 21.7, 20.8, 19.0, 18.1, 17.9,
HRMS (ESI) : m/z calcd for C39H57N2O6S[M+H]+:
681.3937; found 681.3932
NMR and Mass Data's
CONCLUSION AND RECOMMENDATIONS
Need of modernistic and innovative strategies for the synthesis of efficient anticancer drugs are seemed to have a greater escalation day by day. On the basis of the potent anticancer profiles which were observed in 18β-Glycyrrhetinic acid, but were not expressed in an efficient extent in its natural form, a study was done by preparation of sulfonamide moieties on the basis of their known anticancer profiles, taking GA as lead molecule. Oxime directed C-H amidation was done to reach the target. Ability of oximes to act as a sophisticated directing group and its ability to act as an internal oxidant which in turn diminishes the need of an external oxidant makes oxime unique as a directing group compared to others with the same mechanistic property. Initially 18-βGlycyrrhetinic acid was oxidized in to corresponding ketone (Jone’s oxidation). Obtained ketone was then subjected to esterification which in turn lead to the formation of keto ester (3.1.3) followed by this the synthesis of ketoxime was carried out as per the procedure discussed above (3.1.4). Further Ir-catalyzed C-H amidation was done by considering Chang’s protocol as the reference. A general procedure was followed for this (3.1.5). Obtained GA- sulfonamide derivative is expected to show advanced anticancer properties compared to its starting material. Structural conformation of each compounds was done using spectrometric and spectroscopic techniques such as 13C and 1H NMR along with mass spectrometry. Column chromatography along with thin layer chromatography was used as the main aid for the purification of the compounds.
1. (a) Thornber C W.; Chem. soc. Rev. 1979, 8, 563. (b) Colinas, P. A. Expert Opin Ther. Patents 2013, 23, 761;
(c) Casini, A; Scozzafava A.; Mastrolorenzo, A.; Supuran C. T Current Cancer Drug Targets 2002, 2, 55.
2. Owa, T.; Nagasu. T. Exp. Opin. Ther. Patents 2000, 10, 1725.
3. Gao, Cheng.; Dai, F-J.; Cui, H-W.; Peng, S-H.; He, Y.; Wang X; Yi; Z-F.; Qiu W-W. Chem. Biol. Drug Des. 2014, 84, 223.
4. Kang, T.; Kim, Y.; Lee, D.; Wang, Z.;Chang, S.; J. Am. Chem. Soc. 2014, 136, 4141.
5. Gao, Cheng.; Dai, F-J.; Cui, H-W.; Peng, S-H.; He, Y.; Wang X; Yi; Z-F.; Qiu W-W. Chem. Biol. Drug Des. 2014, 84, 223.
I would have immense pleasure to offer my thanks and regards to Indian Academy of Sciences, BANGALORE for endowing me such a great opportunity to work in an illustrious institution like IICT Hyderabad, and to boost up my knowledge along with the gain of a wonderful research experience which would be a mile stone and helpful in the construction of my research career. I would also like to thank Dr. S. Chandrasekhar for his guidance and support.