Compositions comprising triterpenoids

Example 1A—Preparation of Isolated Acidic Fraction of Mastic Gum

[0355]To a 50 gram amount of mastic gum, absolute ethanol (800 ML) was added, and the mixture was left to stand for 24 hours. The mixture was shaken for 30 minutes at 150 rpm and left to stand for two hours. The obtained ethanol solution was decanted from insoluble material into a 3 L round bottom flask. To the insoluble material 400 ML of fresh ethanol was added and the mixture was shaken again 30 minutes at 150 rpm and was left to stand for 30 minutes. The obtained ethanol solution was decanted and added to the first ethanol solution. This step was repeated once more using 200 ML absolute ethanol. This provided 1.4 L of ethanol solution. The ethanol was evaporated using a rotary evaporator, and n-hexane (1.2 Liter) was added to the remaining material, and the mixture was shaken at 150 rpm for 4 hours. It was then left to stand for 4 hours and the hexane solution was decanted from insoluble material into a 3 L Erlenmeyer. To the remaining insoluble material, 800 ML fresh hexane was added and the mixture was shaken for 6 hours at 150 rpm and left to stand for 12 hours. The hexane solution was decanted into the 3 L Erlenmeyer flask containing the first 1.2 L of hexane solution. The hexane was evaporated in a clean 3 L round bottom flask to give about 30 grams of extract. (Yields range typically from 50-70% depending on the age and particle size of the used Mastic gum.)

[0356]The obtained extracted material was subsequently dissolved in diethyl ether (500 ML) and extracted with a 5% aqueous sodium carbonate solution (4×100 ML), the basic aqueous layer and an oily/emulsion layer were carefully separated form the diethyl ether layer. The diethyl ether layer was then additionally extracted with 0.4 N aqueous sodium hydroxide (3×100 ML) and the basic aqueous layer and an oily/emulsion layer were again carefully separated from the diethyl ether layer. (This remaining diethyl ether layer is called diethyl ether layer Nr.I, and will be used herein below in Example 1B). The two basic aqueous extracts (including oily/emulsion layers) were separately acidified to pH 1-2 by slow addition of 10% aqueous hydrochloric acid and were subsequently extracted with fresh diethyl ether (3×200 ML). The thus obtained etheral fractions were combined and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate, the diethyl ether was removed using a rotary evaporator. This procedure gave ca. 15 gram of isolated acidic fraction of mastic gum as a white solid, corresponding to about 50% yield based on the intermediate extract obtained after the ethanol/hexane extraction. This particular isolated acidic fraction obtained from mastic gum as described hereinabove is termed “Acidic Mixture 1”.

[0357]Based on the starting 50 grams of Mastic gum, the yield for this acidic fraction is about 30%. Typical yields of this particular acidic fraction from mastic gum range from about 25% to about 35%. Without wishing to be bound to any theory or mechanism, these variations in yield can occur due to natural (e.g. seasonal) fluctuations in the composition of the Mastic gum and may also be influenced by age and storage conditions of the Mastic gum.

Example 1B: Isolation of the Neutral Fraction of Mastic Gum

[0358]The diethyl ether layer Nr.I obtained in Example 1A was transferred to a clean separatory funnel and washed with water (200 ML) and brine (150 ML). It was then dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the diethyl ether was evaporated using a rotary evaporator. This gave about 15 grams of isolated neutral fraction as a white to off-white sticky solid (which will become a very viscous liquid above 35-40° C.). This is about 50% yield based on the extract obtained after the ethanol/hexane extraction presented in Example 1A. This particular isolated neutral fraction obtained from mastic gum as described here is termed “Neutral Mixture 1”. Based on the starting 50 grams of Mastic gum, the yield for this neutral fraction (“Neutral Mixture 1”) is about 30%. Typical yields of this neutral fraction from mastic gum range from about 25 to about 35%.

[0359]The mass-balance of this particular acid-base extraction described here is typically over 90% and often more than 95% based on the intermediate extract obtained after the ethanol/hexane extraction procedure. The ratio of the thus isolated acidic fraction (“Acidic Mixture 1”) to isolated neutral fraction (“Neutral Mixture 1”) is usually approaching 1:1 (and nearly always within the 0.8:1.2 to 1.2:0.8 range).

[0360]Isolation of individual triterpenoic acids and neutral triterpenoids from isolated acidic fractions and isolated neutral fractions can be accomplished using standard column chromatography and HPLC-methods as known to a person skilled in the art.

[0361]It is to be understood, and it is clear to a person skilled in the art, that other extraction protocols can be used to obtain different isolated acidic fractions and isolated neutral fractions from suitable plant materials that can subsequently be used for the isolation of triterpenoic acids and/or neutral triterpenoids.

Example 2—Synthesis of a Triterpenoic Acid and Some Neutral Triterpenoids

Synthesis A: Preparation of Oleanonic Acid

[0362]Oleanonic acid was obtained in three steps from oleanolic acid.

[0363]Oleanolic acid was first converted to the corresponding methyl ester by treatment with methyl iodide and potassium carbonate in dimethylformamide (DMF). Oxidation of oleanolic acid methyl ester to oleanonic acid methyl ester was performed using Dess-Martin periodane reagentin dichloromethane (DCM). Hydrolysis of oleanonic acid methyl ester with lithium hydroxide in aqueous THF gave upon acidification the desired oleanonic acid.

Oleanonic Acid Methyl Ester:

[0364]Oleanolic acid (3.66 g, 1.0 eq) was dissolved in DMF (20.0 vol.). K2CO3 (3.3 g, 3.0 eq) was added and mixture was stirred for 10 minutes, then methyl iodide (0.75 ml, 1.5 eq) was added. Reaction mixture was carried out at room temperature overnight (full conversion on TLC). K2CO3 was filtered off from reaction mixture and reaction was poured into ice water. White solid was filtered off, washed with water and dried under reduced pressure to give desired product (3.62 g, 96.0%).

Methyl Ester Hydrolysis:

[0365]To oleanonic acid methyl ester (1.0 g) in dry DMF (30 ml) dry LiCl (200 mg) was added and the mixture was stirred under nitrogen at 50° C. for 6 hrs. Upon cooling to room temperature the reaction mixture was quenched by addition of 5% Na2CO3 solution (20 ml) and stirred overnight. Then 3% aqueous HCl was added till pH=2 and the mixture was extracted with diethyl ether (3×50 ml). The combined ether layers were washed with 0.5% HCl, and dried over sodium sulfate. Evaporation of the diethyl ether gave oleanonic acid as a white solid (0.73 g).

Synthesis B: Preparation of NF-A (Betulone)

[0366]NF-A was synthesized from betulin-28-acetate in two steps.

[0367]First, the 3-hydroxyl-group was oxidized to the corresponding ketone with PCC in dichloromethane. This was followed by the hydrolysis of the C-28 acetate group to give the desired NF-A (Betulone).

Oxidation Step:

[0368]28-acetyl betuline (3.2 g, 1.0 eq) was dissolved in DCM (40.0 vol.). Mixture was cooled in ice bath, then PCC (2.13 g, 1.5 eq) was added. Reaction mixture was warmed to room temperature and stirred overnight. Mixture was concentrated on silica gel and purified via flash column chromatography eluted with hexane:EtOAc (95:5->90:10->85:15) to give desired product as white powder (2.85-3.15 g, 80.0-99%).

Acetate Hydrolysis:

[0369]Starting material (1.14 g, 1.0 eq) was dissolved in mixture of THF:H2O (2:1, 40.0 vol.) then LiOH monohydrate (0.57 g, 10.0 eq) was added. Reaction was carried out at room temperature for 3 days. THF was evaporated. Mixture was extracted with EtOAc (3×), organic layers were combined, dried over MgSO4 and then concentrated under reduced pressure. Crude product was purified via column chromatography eluted with hexane:EtOAc 9:1 to give white powder (80%). Recovered starting material was hydrolyzed once more time, total yield 1.04 g (91.0%).

Synthesis C: Preparation of NF-B (Oleanonic Alcohol; 28-Hydroxy-Beta-Amyrone)

[0370]NF-B was synthesized from oleanonic acid methyl ester in three steps.

[0371]First, the 3-oxo group of oleanonic acid methyl ester (see synthesis A above) was converted with ethylene glycol and catalytic p-TosOH (p-Toluenesulfonic acid) to the corresponding acetal using the standard Dean-Stark set-up with toluene as the solvent. Next the methyl ester group was reduced to the corresponding alcohol with lithium aluminium hydride in THF. Hydrolysis of the acetal with diluted aqueous HCl in acetone gave the desired NF-B (oleanonic alcohol).

Acetal Formation:

[0372]Oleanonic acid methyl ester (1.4 g, 1.0 eq) was dissolved in toluene (20.0 vol.) then TsOH (0.006 g, 0.01 eq) and ethylene glycol (0.46 g, 2.5 eq) were added. Reaction was refluxed for 3 hours under Dean-Stark condenser. TLC indicated full conversion of starting material. Reaction was cooled to RT and quenched with NaHCO3 sat. sol., then extraction to EtOAc was done (3×). Organic layers were washed with water, dried over MgSO4 and concentrated. The crude product was obtained as a grey solid and was used in the next step without any further purification (1.42 g).

Ester Reduction:

[0373]LAH (0.86 g, 2.5 eq) was suspended in THF anh. (20.0 vol.) and was cooled to 0° C. Starting material (3.85 g, 1.0 eq) was dissolved in THF anh. (25.0 vol.) and was added to suspension dropwise. After addition mixture was warmed to room temperature and stirred for 2 hours (full conversion on TLC). Reaction mixture was quenched by “1-2-3 method”. The resulting slurry was filtered through Celite. The filtrate was concentrated and used in the next step without further purification (3.5 g).

“1-2-3 method”: [0374] 1. Add H2O to reaction mixture. The same quantity (mL) of water as quantity (g) of LAH [0375] 2. Add 15% NaOH to mixture. Double quantity (mL) of 15% NaOH as quantity (g) of LAH [0376] 3. Add H2O to mixture. Triple quantity (mL) of water as quantity (g) of LAH

Acetal Hydrolysis:

[0377]Starting material (3.5 g, 1.0 eq) was suspended in mixture of acetone (12.0 vol.) and 1M HCl (10.0 vol.). Reaction mixture was refluxed for 3 hours (full conversion on TLC). Reaction mixture was quenched with NaHCO3 sat. solution to pH 8, extracted with EtOAc (3×), dried over MgSO4 and concentrated. The crude product was purified via column chromatography, eluted with hexane:EtOAc (98:2495:5493:7) and triturated with MeOH (1 g crude product/5 mL MeOH). The precipitate was filtered off and dried in vacuo to give desired product as white solid (2.63 g).

Synthesis D and E: Preparation of Oleanolic Alcohol (Aka Erythrodiol; 28-Hydroxy-Beta-Amyrin) and NF-3 (Oleanonic Aldehyde)

[0378]It was found that oleanolic alcohol (aka erythrodiol) was most easily synthesized by reduction of oleanolic acid methyl ester (see synthesis A) with lithium aluminium hydride in THF. (Attempts to prepare this compound by direct reduction of oleanolic acid gave very low yields even after prolonged reaction times and using large excess of lithium aluminium hydride.)

[0379]Oleanonic aldehyde (NF-3) was subsequently synthesized from oleanolic alcohol by oxidation using the Dess-Martin periodane reagent.

28-Hydroxy-Beta-Amyrin (Erythrodiol):

[0380]LAH (1.2 g, 3.0 eq) was suspended in anhydrous THF (10.0 vol.) and was cooled to 0° C. Starting material (5.0 g, 1.0 eq) was dissolved in anhydrous THF (15.0 vol.) and was added to suspension dropwise. After addition, the mixture was allowed to reach room temperature and was further stirred for 2 hours (full conversion on TLC). The reaction was quenched by the “1-2-3 method” (see synthesis C). The resulting slurry was filtered through Celite. Filtrate was concentrated and the crude product was used in the next step without further purification (4.60 g).

Oleanonic Aldehyde (NF-3):

[0381]28-hydroxy-beta-amyrin (2.8 g, 1.0 eq) was dissolved in DCM (20.0 vol.) then was added DMP (5.36 g, 2.0 eq). Reaction was carried out for 1 hour. Crude product was concentrated on silica gel and purified via column chromatography eluted with hexane, then hexane:EtOAc (99:1→9:1) to give oleanonic aldehyde as a white solid (0.60 g).

Synthesis F: Preparation of Masticadienonic Aldehyde

[0382]Masticadienonic aldehyde was prepared from masticadienonic acid in three steps. The methyl ester of masticadienonic acid was prepared using diazomethane in diethyl ether or by using trimethylsilyldiazomethane in dichloromethane (DCM)/methanol. Reduction of the methyl ester with lithium aluminium hydride gave masticadienediol. The diol was then converted into masticadienonic aldehyde by oxidation with Dess-Martin Periodane reagent.

Masticadienonic Acid Methyl Ester:

[0383]MDA (1 g, 1.0 eq) was dissolved in mixture of DCM (10.0 ml) and MeOH (10.0 ml) and 2M solution of TMS-diazomethane in DCM (4.4 ml, 4.0 eq) was added dropwise within 30 minutes. Color of the solution turned to light yellow, reaction mixture was stirred for 30 minutes. Reaction progress was monitored on TLC (hexane:EA 4:1, visualized in pAA stain solution).

[0384]The reaction was quenched by addition of few drops of AcOH until the yellowish color disappeared. The mixture was concentrated, dissolved in EA and washed with sat. NaHCO3 and sat. brine. Organic layer was dried and concentrated to give desired MDA-methyl ester (1.02 g). Product was used in subsequent step without further purification.

Masticadienediol:

[0385]LAH (0.21 g, 10.0 eq) was suspended in THF anh. (20.0 vol.) and was cooled to 0° C. MDA (0.25 g, 1.0 eq) was dissolved in THF anh. (25.0 vol.) and was added to suspension dropwise within 15 minutes. After addition mixture was warmed to room temperature and stirred for 2 hours (full conversion on TLC). Reaction mixture was quenched by “1-2-3 method”. Resulted slurry was filtrated through Celite. Filtrate was concentrated and was purified via column chromatography eluted with appropriate eluent mixture (DCM:MeOH) to give masticadienediol (110 mg). The same reaction on 2.5 g scale gave 1.7 gr product. A mixture of isomers was obtained, with the 3-beta-isomer as the main product (alpha/beta ratio ca. 5:1). The isomers can be further separated by preparative HPLC.

Masticadienonic Aldehyde:

[0386]masticadienediol (0.45 g, 1.0 eq) was dissolved in DCM (20.0 vol.) then was added DMP (0.95 g, 2.2 eq). Reaction was carried out for 2 hours. Crude product was concentrated on silica gel and purified via column chromatography eluted with hexane, then hexane:EtOAc (99:1→9:1) to give desired product as white solid (0.3 g).

Synthesis G: Preparation of Isomasticadienonic Aldehyde

[0387]Isomasticadienonic aldehyde was synthesized from isomasticadienonic acid using the same sequence of reactions as used for masticadienonic aldehyde in Synthesis E described above.

Isomasticadienonic Acid Methyl Ester:

[0388]IMDA (1 g, 1.0 eq) was dissolved in mixture of DCM (10.0 ml) and MeOH (10.0 ml) and 2M solution of TMS diazomethane (4.4 ml, 4.0 eq) was added dropwise within 30 minutes. Color of the solution turned to light yellow, reaction mixture was stirred for 30 minutes. Reaction progress was monitored on TLC (hexane:EA 4:1, visualized in pAA stain solution).

[0389]The reaction was quenched by addition of few drops of AcOH until the yellowish color disappeared. The mixture was concentrated, dissolved in EA and washed with sat. NaHCO3 and sat. brine. Organic layer was dried and concentrated to give desired IMDA methyl ester (1.02 g). Product was used in subsequent step without further purification.

Isomasticadienediol:

[0390]LAH (0.21 g, 10.0 eq) was suspended in THF anh. (20.0 vol.) and was cooled to 0° C. MDA (0.25 g, 1.0 eq) was dissolved in THF anh. (25.0 vol.) and was added to suspension dropwise within 15 minutes. After addition mixture was warmed to room temperature and stirred for 2 hours (full conversion on TLC). Reaction mixture was quenched by “1-2-3 method”. Resulted slurry was filtrated through Celite. Filtrate was concentrated and was purified via column chromatography eluted with appropriate eluent mixture (DCM:MeOH) to give isomasticadienediol (0.16 g, 65.0%). The same reaction on 2.5 g scale gave 1.55 gr product (61%). A mixture of isomers was obtained, with the 3-beta-isomer as the main product (alpha/beta ratio ca. 5:1). The isomers can be further separated by preparative HPLC.

Isomasticadienonic Aldehyde:

[0391]isomasticadienediol (0.45 g, 1.0 eq) was dissolved in DCM (20.0 vol.) then was added DMP (0.95 g, 2.2 eq). Reaction was carried out for 2 hours. Crude product was concentrated on silica gel and purified via column chromatography eluted with hexane, then hexane:EtOAc (99:1→9:1) to give desired product as white solid (0.4 g).

Synthesis H: Preparation of NF-2 ((8R)-3-Oxo-8-hydroxypolypoda-13E,17E,21-triene)

[0392]NF-2 was prepared from NF-1 by oxidation of the secondary hydroxyl group to the ketone using Dess-Martin periodane reagent.

[0393]NF-2 ((8R)-3-Oxo-8-hydroxypolypoda-13E,17E,21-triene): NF-1 (0.90 g, 1.0 eq) was dissolved in DCM (20.0 vol.) then was added DMP (1.90 g, 2.2 eq). Reaction was carried out for 2 hours. Crude product was concentrated on silica gel and purified via column chromatography eluted with hexane, then hexane:EtOAc (9:1→3:1) to give desired product as white solid (0.72 g).

[0394]Other suitable oxidation methods for this reaction are the Swern-oxidation, pyridinium chlorochromate in DCM and the Oppenauer oxidation.

Synthesis I: Preparation of Beta-Amyrin

[0395]Beta-amyrin was prepared in five steps from oleanolic acid.

[0396]First, the 3-hydroxyl group was protected as TES-ether using TES-triflate (TES=triethylsilyl). This was followed by reduction of the methyl ester to the corresponding alcohol using lithium aluminium hydride, giving the monoprotected diol. The free hydroxyl group was oxidized to the aldehyde using PCC (pyridinium chlorochromate). The aldehyde group was converted to beta-amyrin in a three-step one-pot sequence. First step was formation of the tosylhydrazide. Upon changing the solvent system, the hydrazide was reduced by refluxing with sodiumborohydride which simultaneously removed the TES-protecting group resulting in direct formation of the desired beta-amyrin.

Oleanolic Acid Methyl Ester:

[0397]Oleanolic acid (5.0 g, 1.0 eq) was dissolved in DMF (20.0 vol.). K2CO3 (4.54 g, 3.0 eq) was added and mixture was stirred for 5-10 min, then CH3I (2.0 eq) was added. Reaction mixture was carried out at room temperature overnight (full conversion on TLC). K2CO3 was filtered off from reaction mixture and reaction was poured into ice water. White solid was filtered off, washed with water and dried under reduced pressure. Crude product was used in the next step without any purification (5.1 g).

TES Protection of 3-Hydroxyl Group:

[0398]Oleanolic acid methyl ester (5.1 g, 1.0 eq) was dissolved in DCM (20.0 vol.) containing TEA (9.9 ml, 6.6 eq). The mixture was stirred for 15 minutes and TESOTf (8.0 ml, 3.3 eq) was added dropwise. The reaction mixture was stirred overnight at RT until completion. (TLC hexane:EA; 4:1). The mixture was diluted with 1M HCl and extracted with DCM (2×). Combined organic layers were dried and concentrated. The crude mixture was purified by column chromatography (hexane:EA 98:2) to give desired product as white solid. (6.6 g).

Ester Reduction:

[0399]LAH (1.29 g, 2.5 eq) was suspended in THF anh. (20.0 vol.) and was cooled to 0° C. Starting material (6.61 g, 1.0 eq) was dissolved in THF anh. (25.0 vol.) and was added to suspension dropwise. After addition, mixture was warmed to room temperature and stirred for 2 hours (full conversion on TLC). Reaction was quenched by “1-2-3 method” (see Synthesis C). The resulting slurry was filtered through Celite. The filtrate was concentrated and used in the next step without further purification (4.55 g).

Alcohol Oxidation:

[0400]Mono-protected diol (1.0 g, 1.0 eq) was dissolved in DCM (20.0 vol.) and cooled to 0° C. To that was added PCC (0.58 g, 1.5 eq) and mixture was stirred for 2 h at RT. Reaction progress was monitored on TLC (hexane:EA 9:1). Reaction was concentrated on SiO2 and purified via column chromatography eluted with hexane:EA to give pure product (0.76 g).

One-Pot Conversion of TES-Aldehyde Intermediate into Beta-Amyrin (Hydrazide Formation; Reduction; TES Cleavage):

[0401]Starting material (0.62 g, 1.0 eq) was suspended in EtOH (26.0 vol.), p-toluenesulfonyl hydrazide (0.25 g, 1.2 eq) was added and mixture was refluxed overnight. Reaction progress was monitored on TLC (hexane:EA 7:3). EtOH was concentrated and residue was dissolved in THF (33.0 vol.) and water (5.0 vol.) and NaBH4 (0.42 g, 10.0 eq). Reaction was continued at RT overnight and then 2 hours at reflux. Reaction was cooled down and portioned between water and EA, layers were separated, water layer was extracted 2× with EA. Combined organic layers were dried and concentrated to give crude residue. Crude reaction mixture purified via column chromatography eluted with hexane:EA to give beta-amyrin as a white solid (100 mg).

Synthesis J: Preparation of Beta-Amyrone

[0402]Beta-amyrone was prepared from beta-amyrin by oxidation of the hydroxyl group to the corresponding ketone using pyridinium chlorochromate (PCC). Other suitable methods are the Dess-Martin reagent or Swern oxidation.

Via PCC-Oxidation:

[0403]Beta-amyrin (100 mg, 1.0 eq) was dissolved in DCM (20.0 vol.) and cooled to 0° C. To that was added PCC (76 mg, 1.5 eq) and mixture was stirred for 1 h at RT. Reaction progress was monitored on TLC (hexane:EA 6:1). Reaction was concentrated on SiO2 and purified via column chromatography eluted with hexane:EA (60:1→20:1) to give pure product (63 mg).

Via Dess-Martin Reagent:

[0404]Starting material (100 mg, 1.0 eq) was dissolved in DCM (20.0 vol.) then was added DMP (0.95 g, 2.2 eq). Reaction was carried out for 2 hours. Crude product was concentrated on silica gel and purified via column chromatography eluted with hexane:EA (60:1→20:1) to give pure product to give desired product as white solid (0.67 g).

Synthesis K: Preparation of 28-oxo-lupen-3-one

[0405]28-oxo-lupen-3-one was synthesized from NF-A (betulone, see Synthesis B), by oxidation of the 28-hydroxyl group to the corresponding aldehyde with Dess-Martin periodane.

[0406]Starting material (1.0 g, 1.0 eq) was dissolved in DCM (20.0 vol.) then was added DMP (2.20 g, 2.2 eq). Reaction was carried out for 2 hours. Crude product was concentrated on silica gel and purified via column chromatography eluted with hexane, then hexane:EtOAc (99:1→9:1) to give desired product as white solid (0.74 g).

[0407]Other suitable oxidation methods for this reaction where the Swern-oxidation, pyridinium chlorochromate in DCM.

Synthesis L: Preparation of Oleanolic Aldehyde

[0408]Oleanolic aldehyde was prepared in two steps from the mono-protected diol intermediate from beta-amyrin Synthesis I.

[0409]The free hydroxyl group was oxidized to the corresponding aldehyde using PCC or Dess-Martin Periodane. This was followed by removal of the TES-group with TBAF in aqueous THF to give the desired oleanolic aldehyde.

Via PCC-Oxidation:

[0410]The mono-protected diol (1.0 g, 1.0 eq) was dissolved in DCM (20.0 vol.) and cooled to 0° C. To that was added PCC (0.58 g, 1.5 eq) and mixture was stirred for 2 h at RT. Reaction progress was monitored on TLC (hexane:EA 9:1). Reaction was concentrated on SiO2 and purified via column chromatography eluted with hexane:EA to give pure product (0.76 g).

Via Dess-Martin Oxidation:

[0411]The mono-protected diol (1.0 g, 1.0 eq) was dissolved in DCM (20.0 vol.) then was added DMP (2.20 g, 2.2 eq). Reaction was carried out for 2 hours. Reaction progress was monitored on TLC (hexane:EA 9:1). The reaction mixture was concentrated on SiO2 and purified via column chromatography eluted with hexane:EA to give pure product (0.69 g).

Removal of TES-Group:

[0412](150 mg, 1.0 eq) was dissolved in THF (15.0 vol.) and cooled to 0° C.

[0413]To that was added TBAF (113 mg, 2.0 eq) and mixture was stirred overnight at RT. Reaction progress was monitored on TLC (hexane:EA 4:1). Reaction was concentrated on SiO2 and purified via column chromatography eluted with hexane:EA (9:1→6:1) to give pure product (86 mg).

[0414]Some suitable references for synthesis of several triterpenoids encountered in the current application are: [0415] D. Barton et al. J. Chem. Soc. 1956, 4150, [0416] V. Domingo et al. J. Org. Chem. 74, 6151, 2009. [0417] V. Domingo et al. Org. Biomol. Chem. 11, 559, 2013. [0418] J. Justicia et al. Eur. J. Org. Chem. 10, 1778, 2004.