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Cite This: J. Nat. Prod. 2019, 82, 59−65

Revision of the Structure of N,O‑Diacetylsolasodine. Unusual Epimerization at the Spiro Carbon Atom during Acetylation of Solasodine Dorota Czajkowska-Szczykowska,† Izabella Jastrzebska,† Joanna E. Rode,*,‡ and Jacek W. Morzycki*,† †

Institute of Chemistry, University of Białystok, ul. Ciołkowskiego 1K, 15-245 Białystok, Poland Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland

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S Supporting Information *

ABSTRACT: The steroidal alkaloid solasodine (1) undergoes inversion of configuration at the C-22 spiro atom when treated with acetic anhydride−pyridine at ambient temperature. The basic solvolysis of the N,O-diacetyl derivative (2) reverses the reaction, yielding the starting solasodine (1). The mechanisms of both processes (acetylation and deacetylation) were studied in terms of possible reaction pathways.

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either equatorial (25R) [e.g., in diosgenin (6)] or axial (25S) [e.g., in sarsasapogenin (7)]. The other group of Solanum alkaloids has an indolizidine (5) structure, as found in solanidine from S. tuberosum (potato). The configuration at C-20 in all natural spirostanes and spirosolanes is always S. In recent years several synthetic routes to steroidal alkaloids, especially solasodine (1), from a cheap and readily available steroidal sapogenin, diosgenin (6), have been developed (Scheme 1).18−22 In most methods the F-ring in 6 is opened under acidic conditions followed by substitution of an oxygen function in the intermediate pseudosapogenin with a nitrogen nucleophile. After deprotection of the primary amine in the side chain, it is subjected to cyclization, leading selectively to the 20S,22R diastereoisomer, solasodine (1), which is a thermodynamic product. During this transformation, the C25 stereocenter usually remains unaffected.

olasodine (1) occurs as the aglycone of glycoalkaloids that have been isolated mainly from plants belonging to the genus Solanum of the Solanaceae family.1−5 The genus Solanum consists of more than 1700 species distributed worldwide and is one of the largest genera among all flowering plants, found in the tropical and temperate zones. The genus includes major food plants, like potatoes, tomatoes, and eggplants, many tropical fruits, and curing herbs.6 A large number of Solanum species are used as traditional medicinal plants and have a very wide range of pharmacological activities.7 A literature survey reveals that solasodine (1) and related Solanum alkaloids, such as tomatidenol (3), tomatidine (4), and solanidine (5) (Figure 1), have diuretic, anticancer, antifungal, cardiotonic, antispermatogenic, antiandrogenic, immunomodulatory, and antipyretic activities and also various effects on the central nervous system.8−15 These Solanum alkaloids are essentially nitrogen analogues of steroidal sapogenins and are based on a C27 cholestane skeleton that may be categorized into two groups according to the structure of the side chain. One group has an oxa-aza spiro structure as exemplified by tomatidine (4) from S. lycopersicum (tomato) and solasodine (1) from S. melongena (eggplant). Unlike their oxygen counterparts, all these N-containing steroids (spirosolanes) may exhibit a different configuration at C-22 [22R in solasodine (1) and 22S in tomatidine (4)]. In naturally occurring spirostanes (with a few exceptions, e.g., isoplexigenins16 and hispigenins17) the configuration at C-22 is usually R as in diosgenin (6). The methyl group at C-25 in natural spirosolanes is equatorial, while in spirostanes it can be © 2019 American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION So far, no attempts have been undertaken to obtain the 22epimer of solasodine (1). However, formation of the (22S,25S) stereoisomer, tomatidenol (3), as a side product during the synthesis of solasodine (1) was recently reported.18 A few years ago we described the synthesis of 22-epidiosgenin acetate.23 This compound was fully characterized though it proved sensitive to acids and underwent rapid epimerization to diosgenin acetate in acid medium. Herein we report a simple Received: July 13, 2018 Published: January 7, 2019 59

DOI: 10.1021/acs.jnatprod.8b00573 J. Nat. Prod. 2019, 82, 59−65

Journal of Natural Products

Article

Figure 1. Common steroidal alkaloids of the Solanum family and related sapogenins.

Scheme 1. Common Synthetic Routes to Solasodine (1) from Diosgenin (6)

preparation of N,O-diacetyl-22-episolasodine (2). In contrast to 22-epispirostane, 22-epispirosolane (2) proved resistant to acid conditions and seems to be thermodynamically stable. Two isomeric N-formyl derivatives of solasodine have been obtained by treatment of the alkaloid with acetic−formic anhydride.24−26 However, physical data analyses (1H and 13C NMR, MS) of these compounds did not lead to consistent conclusions. The dominant view is that they are distinct rotamers resulting from a restricted rotation about the CN bond of the amide moiety [Figure 2(a)].24 The isomers were also suggested to result from nitrogen inversion (b),25 although it is difficult to understand how this could arise in view of the well-known partial double-bond character of the amide bond. There were also suggestions that the isomerism is due to a difference in configuration at C-22 (c).26 A nonchair conformation (twist boat) has been proposed for both epimers. The N,O-diacetyl derivative of solasodine has been described several times.27−35 Only one epimer (or rotamer)

has been reported. The melting points and physical data provided by different authors were consistent. However, analysis of the NMR data in a series of similar compounds led us to assume that the structural assignment for this compound could be wrong. Therefore, an X-ray diffraction data analysis of the N,O-diacetyl derivative of solasodine and computational studies were done that showed that the reported structure should be revised. Acetylation of solasodine (1) was carried out under basic (Ac2O, pyridine) or acidic (Ac2O, p-TsOH) conditions. The same product was obtained in both cases, which proved identical to the reported compound. A single crystal of the N,O-diacetyl derivative was obtained and subjected to the Xray diffraction study. The resulting structure showed the (22S) absolute configuration, opposite that in the starting solasodine (1). The configurations at C-20 and C-25 remained intact. The F-ring assumed a slightly distorted chair conformation, and the methyl group at C25 was axially oriented (Figure 3). 60



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Scheme 3. Formation of Pseudosolasodine (8)

previously established that this compound is formed when acetylated solasodine [apparently N,O-diacetyl-22-episolasodine (2)] is treated with acid or heated at elevated temperature.37 However, when compound 8 was subjected to acetic anhydride in pyridine, it did not cyclize to 2. The driving force for the epimerization reactions is formation of the lower energy product provided that the reaction is reversible and equilibrium can be reached (thermodynamic control). Therefore, different conformers of solasodine, 22-episolasodine, and their N-acyl derivatives have been calculated at the ωB97X-D/6-31G** level38,39 by using the Gaussian 0940 package of programs (for computational details see Supporting Information, Figure S1, Tables S1, S2). It should be noticed that the natural alkaloids solasodine (1) and tomatidenol (3) have lower energies than 22-episolasodine (Table 1). However, the situation changes when an acyl substituent is placed on nitrogen. This is partly caused by the change of the hybridization of the nitrogen atom, but also there is more space available for the acyl substituent in 22epispirosolanes. There is a short distance between the Nsubstituent and the 21-methyl group in the normal spirosolane. To avoid this interaction, the F-ring has a tendency to flip into a twist-boat conformation with the 27-methyl group located in a pseudoaxial position. Interestingly, N-formyl derivatives prefer the E configuration about the amide C−N partial double bond with a small hydrogen atom oriented toward the rest of the steroid molecule, while for N-acetylated alkaloids the Z configuration of the amide moiety prevails (Table 1, Figure S2, Table S3, Supporting Information). The difference in energies for the formamides (22R versus 22S) is small (0.32 kcal/mol), and for this reason both derivatives are formed. In contrast to that, acetamides exhibit a much larger difference (1.62 kcal/mol, Table 1), and, as a consequence, the N-acetyl derivative of 22episolasodine is formed exclusively. Calculations of the steric energies using the MM+ force field included in the package

Figure 2. Suggested isomeric forms of N,O-diformylsolasodine.

Figure 3. Molecular structure of N,O-diacetyl-22-episolasodine (2). Displacement ellipsoids are drawn at the 30% probability level. The figure was prepared with OLEX2.36

Interestingly, a basic hydrolysis of 2 afforded solasodine (1) as a consequence of a reversed epimerization at the C-22 spiro stereogenic center. A tentative mechanism of both processes (acetylation and solvolysis) that assumes inversion of configuration at C-22 is shown in Scheme 2. Pseudosolasodine (8) was also considered as an intermediate in the epimerization of solasodine (Scheme 3). It was

Scheme 2. Proposed Mechanism for Solasodine Acetylation and Deacetylation with Double Epimerization at C-22 Involving Rupture of the Carbon−Oxygen Bond

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that are readily bridged at room temperature. Next, the E-ring closure is barrierless in the presence of, for example, AcO−, which is necessary for hydrogen capture (Figure S3a, Supporting Information). Otherwise, during ring closure the energy of the system increases (Figure S3b). The resulting Nacetyl-22-episolasodine is more stable than N-acetylsolasodine (i-ax) by ca. 1.6 kcal/mol. The rupture of the carbon−oxygen bond during the reaction is supported by previous studies on acetylation of solasodine (1) with Ac2O/HOAc/BF3·Et2O.41 The strongly acidic conditions prevented N-acetylation, and the reaction afforded (25R)-22,26-epiminocholesta-5,22(N)diene-3β,16β-diyl diacetate as a result of the E-ring cleavage. In an alternative mechanism of C-22 epimerization, the Fring opening with formation of the carboxonium ion [cat(→ RR)] was assumed (Scheme 4, Figure 5). However, it seems that computational results do not confirm this process. First, the cat(→SR) cation, which should yield (22S,25R)-N-acetyl22-episolasodine, is less stable by 3.37 kcal/mol than the cat(→RR) cation, leading to (22R,25R)-N-acetylsolasodine. In the next step, a rotation that transforms cat(→RR) into cat(→ SR) should occur about the C-23−C-24 bond (not about the C-22−C-23 one as expected; see the two structures superposed in Figure 6). This process goes through a small energy barrier (12.4 kcal/mol), which could be easily overcome. Finally, N-acetyl-22-episolasodine should be formed during Fring closure. However, forcing the F-ring closure by shortening the N−C-22 distance always resulted in an energy increase. Thus, we considered the AcO− group to abstract a proton from the NHAc moiety. Yet, due to the positive charge at C-22 (Figure S4, Supporting Information), the AcO− group binds to this position, forming a stable species and thus blocking this center. Again, structures leading to N-acetylsolasodine instead of N-acetyl-22-episolasodine are more stable. Moreover, in such a case closing the F-ring requires an energy barrier of ca. 100 kcal/mol to be overcome. Thus, based on the ωB97X-D/6-31G** calculations a mechanism via opening of the F-ring is both thermodynamically and kinetically unfavorable. On the other hand, the deacetylation mechanism of Nacetyl-22-episolasodine toward solasodine (1) with epimerization at C-22 is predicted to be both thermodynamically and

Table 1. Comparison of the Relative Energies of the Most Stable Conformers (ΔE, ΔG298; kcal/mol) Calculated at the ωB97X-D/6-31G** Level and Steric Energies (SE, kcal/ mol) Calculated Using the MM+ Force Field compound

ΔE

ΔG298

SE

ΔSE

solasodine (1) (22R,25R) tomatidenol (3) (22S,25S) 22-episolasodine (22S,25R) N-acetyl N-acetylsolasodine (Z)-t-boat N-acetylsolasodine (Z)-chair N-acetylsolasodine (E) N-acetyl-22-episolasodine (Z) N-acetyl-22-episolasodine (E) N-formyl N-formylsolasodine (E) N-formylsolasodine (Z) N-formyl-22-episolasodine (E) N-formyl- 22-episolasodine (Z)

0.00 0.50 1.34

0.00 0.97 1.88

54.25 56.15 57.83

0.00 1.90 3.58

1.62 1.96 10.91 0.00 5.45

1.04 0.84 9.51 0.00 4.98

n.d. 58.77 61.20 56.45 61.68

n.d. 2.32 4.75 0.00 5.23

0.00 1.21 0.32 0.48

0.00 1.28 0.92 1.21

52.13 54.20 51.60 52.43

0.53 2.60 0.00 0.83

HyperChem showed that the qualitative results of energetical stability of the considered structures are in accordance with the more sophisticated and time-consuming ab initio quantumchemical calculations (Table 1). For elucidation of the reaction mechanism both thermodynamic and kinetic controls must be investigated. Therefore, to confirm the proposed mechanism for solasodine acetylation and deacetylation with double epimerization at C-22 involving cleavage of the C-22−O bond, calculations at the ωB97X-D/631G** level were performed. At the beginning N-acetylation of solasodine (Scheme 2) occurs (of course, O-acetylation also occurs, but it was not considered in calculations for simplicity). Because there is a small energy difference between the two most stable i-ax and i-eq conformers (0.34 kcal/mol), both structures are shown in the energy diagram (Figure 4). As a result of the reaction with Ac+ or H+ (depending on the reaction conditions), the opening of the E-ring takes place. The N-acetyliminium cations, ii-eq and ii-ax, are formed, and rotation about the C-20−C-22 bond affords the more stable cations (iii). The rotations go through ca. 16 kcal/mol barriers

Figure 4. Mechanism via the E-ring opening for solasodine N-acetylation with epimerization at C-22 calculated at the ωB97X-D/6-31G** level (in calculations the O-acetylation was not considered). *Energies of TS structures were estimated from the scan procedures. The energy scales are approximate, and exact total energies of the mechanism species are collected in Table S4 (Supporting Information). 62



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Scheme 4. An Alternative Mechanism for Solasodine Acetylation and Deacetylation with Double Epimerization at C-22 Involving Rupture of the Carbon−Nitrogen Bond

Figure 5. Alternative mechanism via the F-ring opening for solasodine N-acetylation with epimerization at C-22 calculated at the ωB97X-D/631G** level (in calculations the O-acetylation was not considered). *Energies of TS structures were estimated from the scan procedures. The energy scales are approximate, and exact total energies of the mechanism species are collected in Table S4 (Supporting Information).

process is somehow accompanied by changing the methyl group position from axial to equatorial. In conclusion, N-acetylation of a common Solanum alkaloid solasodine (1) proceeds with inversion of configuration at the spiro carbon atom. This phenomenon can also be expected for other N-acyl groups, e.g., N-propionyl, N-isobutyryl, and Npivaloyl, as is evident from calculation results shown in Table S5, Supporting Information. N,O-Diacetyl-22-episolasodine (2), when subjected to basic solvolysis, yielded the starting alkaloid (1) with an original configuration at C-22. The mechanisms of both epimerization reactions were confirmed by quantum-chemical DFT calculations.

Figure 6. Superposition of the cat(→RR) and cat(→SR) structures showing that rotation about the C 23−C-24 bond and not, as expected, about the C-22−C-23 bond, transforms one form into the other.

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kinetically favorable (Scheme 2, Figure 7). Simulations in the presence of EtOH instead of BuOH were considered. In the first step, the E-ring of 2 is opened, forming 22-episolasodinederived alkoxy anion (iv). Next, rotation along the C-20−C-22 bond (with 10.5 kcal/mol barrier) affords anion (v) with an axial position of the 27-methyl group. The E-ring closure is needed for recovery of solasodine, but it is possible only in the presence of an alcohol. In such a case, the process is barrierless (Figure S5a, Supporting Information); otherwise calculations show an increase of energy (Figure S5b). Moreover, this

EXPERIMENTAL SECTION

General Methods. Reagent-grade chemicals were purchased and used as received. CH2Cl2 was freshly distilled. Flash column chromatography and dry flash chromatography were performed with silica gel, pore size 40A (70−230 mesh), unless otherwise stated. All reactions were monitored by TLC on silica gel plates 60 F254. 1H (400 MHz) and 13C NMR (100 MHz) spectra were recorded at ambient temperature and are referenced to tetramethylsilane (0.0 ppm) and CDCl3 (77.0 ppm), respectively, unless otherwise noted. NMR resonance multiplicities are reported using the following abbreviations: b = broad, s = singlet, d = doublet, t = triplet, q = quartet, and 63



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Figure 7. Mechanism of N-deacetylation with epimerization at C-22 calculated at the ωB97X-D/6-31G** level (in calculations N-acetylsolasodine rather than the N,O-diacetyl derivative was considered). The energy scales are approximate, and exact total energies of the mechanism species are collated in Table S4, Supporting Information. m = multiplet; coupling constants J are reported in Hz. IR spectra were obtained in a CHCl3 solution with an FT-IR spectrometer, and data are reported in cm−1. Melting points were determined by a Kofler bench (Boetius type) apparatus and are uncorrected. Optical rotations were measured on a Jasco P-2000 polarimeter in MeOH. Acetylation of Solasodine (1). Procedure with pyridine/ Ac2O. Solasodine (1) (200 mg; 0.48 mmol) was dissolved in dry pyridine (5 mL) and Ac2O (3 mL) was added. The mixture was stirred at room temperature overnight and then was poured into water and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. Silica gel column chromatography with n-hexane/EtOAc (4:1) elution afforded N,O-diacetyl-22-episolasodine (2) in 55% yield (132 mg). Compound 2 proved identical in all respects with the reported compound.24 Mp 163−164 °C (CH2Cl2/n-hexane); lit. mp 162−164 °C; 1H NMR δ 5.31 (m, 1H), 4.54 (m, 1H), 4.13 (q, J = 7.1 Hz, 1H), 3.95 (bd, J = 11.5 Hz, 1H), 3.05 (m, 1H), 2.80 (dd, J = 13.0, 6.6 Hz, 1H), 2.14 (s, 3H), 1.98 (s, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.98 (s, 3H), 0.88 (d, J = 6.5 Hz, 3H), 0.86 (s, 3H); 13C NMR δ 170.7 (C), 170.3 (C), 139.6 (C), 122.1 (CH), 101.0 (C), 78.6 (CH), 73.6 (CH), 61.9 (CH), 55.6 (CH), 49.9 (CH), 48.9 (CH2), 40.8 (C), 39.9 (CH2), 38.0 (CH), 37.9 (CH2), 36.8 (CH2), 36.6 (C), 31.9 (CH2 × 2), 30.9 (CH), 27.8 (CH), 27.6 (CH2), 25.1 (CH3), 24.1 (CH2), 23.8 (CH2), 21.2 (CH3), 20.7 (CH2), 19.1 (CH3), 18.4 (CH3), 16.2 (CH3), 16.0 (CH3). Acetylation of Solasodine (1). Procedure with p-TsOH/Ac2O. Solasodine (1) (50 mg; 0.12 mmol) was added to a mixture of Ac2O (3 mL) and p-TsOH (5 mg). The mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and its pH adjusted to 8 by adding NaHCO3. The product was extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaCl solution, dried over Na2SO4, and evaporated in vacuo. Silica gel column chromatography with nhexane/EtOAc (4:1) elution afforded N,O-diacetyl-22-episolasodine (2) in 25% yield (15 mg). Deacetylation of N,O-Diacetyl-22-episolasodine (2). Metallic sodium was reacted with n-BuOH42 (25 mL); then N,O-diacetyl-22episolasodine (2) (50 mg; 0.1 mmol) was added. The mixture was stirred at reflux for 24 h. The n-BuOH was evaporated via a benzene azeotrope in vacuo, and then water was added. The products were extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated in vacuo. Silica gel column chromatography

with EtOAc elution afforded solasodine (1) in 40% yield (16 mg). Compound 1 was proved identical in all respects with an original sample of solasodine (1). Mp 197−199 °C (MeOH); [α]D −91 (c 0.15 in MeOH); lit.43 mp 198−200 °C (EtOH); [α]D −98 (c 0.35 in MeOH); 1H NMR δ 5.35 (m, 1H), 4.29 (m, 1H), 3.54 (m, 1H), 2.67 (dd, J = 4.2, 11.1 Hz, 1H), 2.60 (t, J = 10.6 Hz, 1H), 1.03 (s, 3H), 0.95 (t, J = 7.2 Hz, 1H), 0.85 (t, J = 6.3 Hz, 1H), 0.82 (s, 3H). X-ray Diffraction Analysis of N,O-Diacetyl-22-episolasodine (2). Crystals suitable for X-ray diffraction study were obtained at room temperature by slow evaporation from a CH2Cl2/n-hexane solution. The X-ray diffraction data were collected at 100(2) K on a SuperNova diffractometer (Rigaku) with a CCD detector and Cu Kα radiation. The crystal structure was solved using direct methods with SHELXS and refined with SHELXL.44 All hydrogen atoms were initially located in electron-density difference maps and were constrained to idealized positions, with C−H = 0.95−1.00 Å and with Uiso(H) = 1.5Ueq(C) for methyl hydrogen atoms and Uiso(H) = 1.2Ueq(C) for others, and the PLATON software45 was used to validate the crystallographic data. Crystal data for N,O-diacetyl-22-episolasodine (2): C31H47NO4, Mr = 497.69, colorless needle, 0.52 × 0.04 × 0.04 mm3, monoclinic space group P21, a = 10.1293(1) Å, b = 7.3868(1) Å, c = 18.5718(2) Å, β = 99.008(1)°, V = 1372.46(3) Å3, Z = 2, ρcalcd = 1.204 g·cm−3, μ = 0.61 mm−1, F(000) = 544, R1 = 0.033, wR2 = 0.085, 4236 independent reflections, θmax = 76.5°, θmin = 4.4°, 331 parameters. Flack x (based on all intensities) = 0.024(18); Hooft y = −0.05(7). CCDC 1832310 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.8b00573. Calculations, calculated structures (PDF) X-ray structure (CIF) 64



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AUTHOR INFORMATION

Corresponding Authors

*Tel: +48-22-343-2214. E-mail: [email protected]. *Tel: +48-85-738-8260. E-mail: [email protected]. ORCID

Dorota Czajkowska-Szczykowska: 0000-0002-7297-7422 Jacek W. Morzycki: 0000-0002-9049-5670 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge financial support from the National Science Centre, Poland (grant no. 2015/17/B/ST5/ 02892). The authors would like to thank Dr. K. Brzezinski from the Institute of Chemistry, University of Białystok, for generating the X-ray data. PL-Grid Infrastructure is acknowledged for generous allotment of the computing time (JER).

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DEDICATION Dedicated to Professor Janusz Zakrzewski on the occasion of his 70th birthday. REFERENCES

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