Reactivity of sulfonylbutadienes. Synthesis of Ginsenol analogues

The reactivity of sulfonylbutadienes has been studied with enamines and the obtained products used as starting materials for the synthesis of Ginsenol analogues


Introduction
Ginsenol is a tricyclic sesquiterpene with a tertiary hydroxyl group that has been isolated from the roots of Panax ginseng bre 1 , figure 1.Its carbon framework appears in a large number of natural diterpenes and alkaloids 2 .Among Ginsenol biological properties include its antifungal activity in vitro against Botrytis cinerea 3 , pathogens of many crops and lettuce, tomatoes and grapes, producing diseases manifested by the appearance of spots on the leaves and the coating of the plant with a powdery gray mold, hence the name 4 .In our group, we have been interested in the reactivity of sulfonylbutadienes for many years in order to obtain biologically active compounds. 5Having studied the synthesis of bicyclic[3.3.1]systems 6 , we decided to use our knowledge to apply it to the synthesis of systems like Ginsenol.In this sense we study the reactivity of dienylsulfones with enamines derived from cyclohexanone to obtain bicyclic [3.3.1]systems and secondly, its application for the synthesis of Ginsenol analogues.

Results and Discussion
When a mixture of compounds 2E and 3Z (85/15), previously obtained by our group, was treated with enamine 4-(1-cyclohexenyl)morpholine a mixture of compounds 4a and 4b were obtained in a moderate yield of 36%.Scheme 1.

Scheme 1. Reaction of sulfonylbutadienes with 4-(1-cyclohexenyl)morpholine.
The structure of compound 4a was established unequivocally by mono and bidimensional NMR studies and double irradiation experiments. 13C-NMR spectrum of compound 4a shows the signal corresponding to C-7 (16.3 ppm), similar to analogue compounds described in literature with chair-boat conformation 7 .Indeed, signal corresponding to C-7 appears at a higher shift than 20 ppm in double-chair conformations.Moreover, differences at 1 H-NMR spectrum shifts for hydrogens at position 3 are also remarkable.In this compound, due to the carbonyl anisotropic effect, the axial hydrogen at C-3 (H-3β) appears at 1.25 ppm as a quartet of coupling constants 12.6 Hz, and the signal of the equatorial hydrogen at 1.70 ppm as a double triplet of constants 12.6 and 2.0 Hz.The hydrogen at 2.95 ppm, which appears as a double triplet of constants 12.6 and 2.0 Hz, corroborates the chair-boat conformation and the equatorial position of the morpholine group, Figure 2.
The spectroscopic properties of 4b were obtained from a fraction mixture of 4a/4b very enriched in 4b.The presence of a quartet for hydrogen at C-3 shows the same conformation (1.25 ppm, q, J= 12.6 Hz) and substitution than 4a.The methyl on the double bond (Me-C-1') shift, both at the 1 H-NMR and 13 C-NMR spectra, shows that 4b is the same compound than 4a but with a Z-geometry at the double bond (Figure 2).Studies made in these systems by other researching groups show that the 2,4-diaxial interaction at the chair-chair conformation of a bulky group (like morpholine) at position 2-exo, forces the bicyclo[3.3.1]nonane(hybridization sp2 at C-9) to adopt the chair-boat conformation. 8his fact is also observed at bicyclo[3.3.1]nonan-9-ones2-exo and 4-exo dicarboxylic 9 or 2,4disubstituted bicyclo[3.3.1]nonan-9-one. 10his bicyclo[3.3.1]nonan-9-one4a was possible to be crystallized, consequently X-ray diffraction experiments let corroborate the structure derived from resonance, see Figure 3. Next, the reactivity of sulfonylbutadiene 1 was studied with different enamines such as 4-(1cyclohexenyl)morpholine, 4-(1-cyclopentenyl)morpholine and 1-cyclohexen-1-enyl-pyrrolidine.

Reactivity with 4-(1-cyclohexenyl)morpholine
The different conditions scoped for the reaction between 1 and 4-(1-cyclohexenyl)morpholine are shown in Table1.a All the experiments were carried out using 5 equivalents of enamine per each equivalent of 1.
The structure of 5 was established by comparison of the NMR spectra of 4a and 4b, as well as those bicyclo [3.3.3]nonanessynthesized previously in our laboratory. 6The 1 H-NMR spectrum, of 5, shows that only remains the double bond adjacent to the sulfonyl group, signals corresponding to H-1' (6.90 ppm, dd, J= 15.1 and 7.6 Hz) and H-2' (6.31 ppm, d, J= 15.1 Hz).The constant 15.1 Hz indicates that the double bond between C-1' and C-2' keeps the Egeometry from the double bond of the starting material, see figure 4. The axial hydrogen of C-3 in 5 resonates as a quartet at 1.25 ppm (J=12.0Hz) similarly to 4a.Its shielding indicates the chair-boat situation of the bicycle, which is corroborated by the C-7 shifting (16.5 ppm) in its 13 C-NMR spectrum, under 20 ppm.
After chromatography of the mixture obtained in entry 1, compound 7 was isolated as a pure compound although in low yield.The structure of 7 was established unequivocally by mono and bidimensional NMR studies.In its 1 H-NMR spectrum, the olefinic hydrogens corresponding to H-4' and H-3' appear at 5.65 ppm (H-4', dd, J= 11.4 and 5.7 Hz) and 5.90 ppm (H-3', d, J= 11.4 Hz) respectively, see Figure 6.The hydrogen H-5' appears at 3.58 ppm as a doublet of constant J= 5.7 Hz, showing that it forms an angle of 90º with H-11'.These facts clearly demonstrate the trans stereochemistry between both hydrogens.The geometry of the double bond between positions 1' and 2 is cis, since the hydrogen H-9'α, appears very shielded at 1.25 ppm in its 1 H-NMR spectrum, due to the carbonyl of cyclohexanone.If the double bond were trans, the carbonyl anisotropy cone would not affect to any hydrogen of the bicycle.Likewise, the hydrogen at 1' appears as a singlet at 6.75 ppm, which means that it is not affected by the carbonyl of the cyclohexanone.In case it was affected, it should appear over 7.00 ppm.In ether the reaction did not work at all, entry 2. In entry 3, we were able to see compound 6 as major compound in the mixture.The fractions of the chromatography enriched with compound 6 (bicyclo[3.3.1]nonan-9-one) were analyzed by 1 H-NMR.The more characteristic signals of 6 are: 7.00 ppm (1H, dd, J= 16.0 and 8.0 Hz, H-1'), 6.30 ppm (1H, d, J= 16.0 Hz, H-2'), 2.90 ppm (1H, m, H-4).The structure and stereochemistry are determined subsequently.
In order to establish the stereochemistry of 6, the mixture enriched in 6, was submitted to treatment with phenylchloroformate to obtain compound 8. Scheme 2. Scheme 2. Reaction of 6 with phenylchloroformate.
The structure of 8 was established unequivocally by NMR.The chair-boat conformation, with the C-4 axial substituent is confirmed by signal corresponding to H-5 as a doublet at 2.25 ppm of coupling constant J= 9.1 Hz, the same constant as H-4, hence the chair-boat conformation with the C-4 axial substituent.The hydrogen at C-2, being in the same plane than the phenylcarbonate substituent is shielded to 3.40 ppm.The formation of 8 involves two molecules of phenylchloroformate as it is shown in figure 7. 12 It is important to note the inversion of the configuration at C-4, which confirms the former structure proposed for 6.

Ginsenol analogues
Once obtained our desired compounds 5 and 8 we decided to do the cyclization in order to obtain Ginsenol analogues.

Scheme 3. Cyclization reaction of 5 for Ginsenol analogues.
The basic Ginsenol framework is easily accessible from the bicyclic compound 5, as there is a vinyl sulfone and a carbonyl group.The existing chair-boat conformation and the equatorial position of the substituent containing the sulfonyl group approach these two groups in space, which facilitate the reaction between them.Treating 5 with n-butyl lithium gives the tricyclic compound 9, scheme 3, which structure is unequivocally determined by 13 C-NMR.It was observed the signal of a tetrasubstituted oxygenated carbon at 79.1 ppm, and the disappearance of the conjugated olefinic system of the sulfonyl group, appearing only a signal corresponding to the olefinic methyl at 150.3 ppm.
Compound 9 shows a chair-boat conformation confirmed by the chemical shifting of its C-6 carbon (18.7 ppm) below 20 ppm, in its 13 C-NMR spectrum 7 .Compound 8 was chosen as starting material with the purpose of synthesizing analogues without nitrogen substituents.It has an axial carbonate at C-4.When 8 is treated with n-butyl lithium in the same former conditions, 10 is obtained, see Scheme 4.

Scheme 4. Cyclization reaction of 9 for Ginsenol analogues.
The structure of 10 is established by NMR.Its conformation is the same as 9, since its C-6 carbon appears at 18.2 ppm in its 13 C-NMR spectrum. 7

Conclusions
In this communication, we have described that sulfonylbutadienes are good starting materials for the of bicyclo[3.3.1]systems.These compounds have been used for the synthesis of Ginsenol analogues.

Experimental Section
General.Unless otherwise stated, all chemicals were purchased as the highest purity commercially available and were used without further purification.IR spectra were recorded on a BOMEM 100 FT-IR or an AVATAR 370 FT-IR Thermo Nicolet spectrophotometers. 1 H and 13 C-NMR spectra were performed in CDCl3 and referenced to the residual peak of CHCl3 at  7.26 ppm and  77.0 ppm, for 1 H and 13 C, respectively, using Varian 200 VX and Bruker DRX 400 instruments.Chemical shifts are reported in  ppm and coupling constants (J) are given in hertz.MS were performed at a VG-TS 250 spectrometer at 70 eV ionizing voltage.Mass spectra are presented as m/z (% rel int.).HRMS were recorded on a VG Platform (Fisons) spectrometer using chemical ionization (ammonia as gas) or Fast Atom Bombardment (FAB) technique.For some of the samples, QSTAR XL spectrometer was employed for electrospray ionization (ESI).Optical rotations were determined on a Perkin-Elmer 241 polarimeter in 1 dm cells.Diethyl ether and THF were distilled from sodium, and dichloromethane was distilled from calcium hydride under argon atmosphere.

Reactivity of 1 with different enamines Reactivity with 4-(1-cyclohexenyl)morpholine: (2R*,4S*)-2-(2'-phenylsulfonyl-E-vinyl)-4morpholinylbicyclo[3.3.1]nonan-9-one (5). General procedure
To a solution of the aldehyde 1 in the proper solvent, a catalytic amount of 2,6-di-tert-butyl-4methylphenol is added.The temperature of the mixture is then lowered to 0ºC and 4-(cyclohexenyl)morpholine (5 equivalents) is added.The mixture is stirred at room temperature under Argon during the specified time.Next, the solvent is removed under vacuum, and the product is extracted with ethyl acetate.The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated.The resulting crude is purified by flash chromatography (silica gel, CHCl3/MeOH mixtures).Depending on the solvent used, entries table 1: 1.

Reactivity with 4-(1-cyclopentenyl)morpholine
To a solution of aldehyde 1 (24.2 mg, 0.11 mmol) in dry 1,4-Dioxane (1.5 mL), a catalytic amount of 2,6-di-tert-butyl-4-methylphenol is added.The temperature is then lowered to 0ºC and 4-(1-cyclopentenyl)morpholine (0.1 mL, 0.54 mmol) is added.The mixture is stirred at room temperature under Argon for 3 days.Then, the solvent is removed under vacuum and the product is extracted with ethyl acetate.The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated.The resulting crude is purified by flash chromatography (silica gel, CHCl3/MeOH).7).General procedure To a solution of the aldehyde 1 in the proper solvent, a catalytic amount of 2,6-di-tert-butyl-4methylphenol is added.The temperature is then lowered to 0ºC and 1-cyclohexenylpyrrolidine is added.The mixture is stirred at room temperature under Argon during the specified time.Then, the solvent is removed under vacuum and the product is extracted with ethyl acetate.The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated.The resulting crude is purified by flash chromatography (silica gel, n-Hexane/ EtOAc mixtures).Detailed experiments, entries table 2: 1.

Figure 3 .
Figure 3.The molecular structure of one (B) of the three crystallographically independent molecules present in the crystals of 4b.See experimental part and supporting information.

Figure 7 .
Figure 7. Mechanism for the reaction of 6 to 8.