Constructing 24(23→22)-abeo-Cholestane from Tigogenin in a 20(22

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Constructing 24(23→22)-abeo-Cholestane from Tigogenin in a 20(22→23)-abeo-Way via a PhI(OAc)2‑mediated Favorskii Rearrangement Xiao-Ling Jiang, Yong Shi,* and Wei-Sheng Tian* CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China S Supporting Information *

ABSTRACT: Transforming tigogenin, a steroidal sapogenin, to a 24(23→22)-abeo-cholestane, which is an unusual structural feature shared by the aglycons of saundersiosides and candicanoside A, is described. The spiroketal of tigogenin was unfolded and the resulting C22-ketone was subjected to Favorskii rearrangement mediated by PhI(OAc)2/KOH/ MeOH to squeeze out the C22 from the side chain, thus reaching the 24(23→22)-abeo-cholestane structure.

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aundersiosides and candicanoside A are steroidal glycosides isolated from the genus Ornithogalum by Mimaki in 1990s.1 These glycosides show potent antitumor activities and their aglycons are closely related 24(23→22)-abeo-cholestanes containing a six-membered lactone ring E, which is a unique structural feature of these natural products (Figure 1a). The Yu group and our group have developed efficient methods to assemble these intriguing structures from dehydropiandrosterone (19C) and dehydropregnenolone (21C), respectively.2 Although both dehydropiandrosterone and dehydropregnenolone are derived from steroidal sapogenins (27C), synthesizing this six-membered ring E directly from the intact skeleton of a 27C starting material has not been reported yet. Herein, we communicate an example of this transformation. When omitting the oxygen atoms of 1−3 and comparing with the normal carbon skeleton of cholestanes (5), we found that the rearranged structure could be interpreted as either 24(23→22)-abeo-(6) or 20(22→23)-abeo-(7), as shown in Figure 1b. Accordingly, there could be two possible approaches to reach the target structure from the intact skeleton of cholestanes. For example, saundersioside J (4) has an unarranged ring E and might be considered a natural synthetic precursor of other saundersioside members. A pinacol rearrangement-like reaction could move the C24−C27 unit of 4 from C23 to C22, which could be considered biomimetic and matches the title 24(23 → 22)-abeo-. On the other hand, the rearrangement could go the opposite direction: moving the steroidal backbone (C1−C21) from C22 to C23, which supports the title 20(22→23)-abeo-. Both approaches are feasible, and the latter could start from relatively simple substrates and was thus preferred. We selected tigogenin (8), a steroidal sapogenin, which has suitable C16 and C22 functionalities, as the starting material of our study (Scheme 1). The C16- and C26-hydroxyl groups and the C22-ketone constitute the spiroketal (rings EF) of 8. We © 2017 American Chemical Society

Figure 1. (a) Aglycons of candicanoside A and saundersiosides. (b) Rearranging the carbon skeleton of cholestanes to the same structure in two different ways (the corresponding atom numbering in 5 was used in 6 and 7 to show their relationships).

Received: December 22, 2016 Published: March 27, 2017 4402

DOI: 10.1021/acs.joc.6b03043 J. Org. Chem. 2017, 82, 4402−4406

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The Journal of Organic Chemistry

Scheme 2. Favorskii Reaction of α-Bromo Ketone 19 Failed

Scheme 1. Possible Ways To Rearrange C20 from C22 to C23a

participation of the C16-OAc group, and 21 and 22 were plausibly derived from cyclopropanone 23, an intermediate that should be generated during Favorskii rearrangement. Without suitable nucleophiles in the reaction system, the cyclopropanone of 23 was opened through loss of a β-hydrogen to provide 21 and 22, presumably via a cyclopropanone-dienol rearrangement.7 As Favorskii method on α-bromo ketone 19 did not proceed smoothly, we explored another Favorskii variant. The electrophilic character and the ability as leaving group have made hypervalent iodine compounds useful tools in organic chemistry.8 It was reported that PhI(OAc)2/KOH/MeOH system could induce Favorskii-type ring-contraction, delivering methyl cyclopentanecarboxylates from cyclohexones in moderate yields.9 Although no successful example on acyclic ketones was reported,10 to our delight, after many attempts, treating 18 with PhI(OAc)2 (2.5 equiv) and KOH (70 equiv) in MeOH at ambient temperature for 2 h afforded methyl ester 24 in 52% yield as a ca. 3/1 mixture of C23 epimers whose C23configuration could not be assigned (Scheme 3).11 Deprotection of C26-OTBDPS, C3-OAc, and C16-OAc of 24, followed by treatment of the crude triol with HCl, delivered lactone 12 in 57% yield as one isomer.12 The NOESY analysis of 12 shows correlation between C16α-H and C22-H; the C22 was thus determined to be R-configured, which was in accordance with the natural products. One plausible explanation for the stereoselective outcome of the Favorskii reaction was illustrated in Scheme 4. The stereochemistry of C20 could influence the reaction on the other side of C22 ketone, thus the Favorskii reaction of 18 exhibited certain stereoselectivity. The enolate 27 approached PhI(OMe)2 from the less hindered Re face to give a C23Rconfigured intermediate 25. The migration of C20 to C23, from the back of −I(OMe)Ph group, reversed the stereochemistry of C23, delivering the C23R-configured 24. Two factors might cause the low stereoselectivity of this reaction: the substratecontrol of 27 was not strong or C23 of 25 was epimerizable in the reaction medium.

a

Protecting groups of C16-OH and C26-OH are omitted for clarity, X = leaving group.

could open the spiroketal rings to reveal the hidden C22ketone and convert it to our target structure in a few steps through a Favorskii rearrangement or a Wolff rearrangement. After introducing a suitable leaving group at C23 of 9, Favorskii rearrangement of 10 could deliver 12 via cyclopropanone mechanism (CPM) or semibenzylic mechanism (SBM, quasi Favorskii rearrangement).3 On the other hand, Wolff rearrangement of α-diazo ketone 14 could also establish the desired sixmembered ring of 12.4 Favorskii method was preferred because it has many variants and wider substrate scope, and the substrate is easier to prepare. We first unfolded the spiroketal of tigogenin (8) to reveal the C22 ketone. Following the procedure reported by Sandovaĺ 5 ketone 16 was prepared from 8 and the exposed Ramirez, C26-OH was protected to give acetate 17 and TBDPS ether 18 (Scheme 2). Compound 17 was treated with phenyltrimethylammonium tribromide (PTAB, Jacques reagent)6 and the resultant α-bromo ketone 19 was subjected to various bases to trigger a Favorskii reaction. Unfortunately, we found that most of the reaction systems were complex and gave unidentifiable products. When the reaction was carried out in MeOH, the C26 acetate was cleaved and the exposed C26-OH attacked C22 and C23, thus making the wanted reaction impossible to proceed. We did not isolate identifiable product with the desired methyl ester or lactone unit that indicates the formation of cyclopropanone intermediate. When 19 was treated with DBU in toluene, a non-nucleophilic solvent, at 80 °C for 24 h, we isolated orthoacetate 20 in 26% yield, along with α,β-unsaturated ketones 21 and 22 in 3.6 and 8.9% yield, respectively. The formation of 20 was due to the intramolecular 4403

DOI: 10.1021/acs.joc.6b03043 J. Org. Chem. 2017, 82, 4402−4406

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chromatography on silica gel (PE/EA: 6/1) to give 19 (945 mg, 74%, mixture of C23-epimers, unstable in solution and during purification, could be used in the next step without purification) as a white solid and 17 (213 mg, 19%) as white solid. Rf: 0.43 (hexane/ethyl acetate: 3/1); IR (KBr): 2974, 2938, 2846, 1739, 1443, 1370, 1243, 1155, 1028, 961 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.87−4.82 (m, 1H), 4.73−4.58 (m, 2H), 4.36 (dd, J = 11.6, 3.3 Hz, 1H), 3.99−3.83 (m, 2H), 3.37−3.27 (m, 1H), 2.04 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.35 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.86 (s, 3H), 0.81 (s, 3H), 0.67 (td, J = 11.3, 3.9 Hz, 1H); LRMS-ESI (m/z): 661.2 [M +Na]+; HRMS (ESI-TOF) (m/z): [M+H]+ calcd. for C33H52O7Br 639.2891, found: 639.2891. Compounds 20−22. A solution of 19 (0.32 g, 0.5 mmol) and DBU (0.38 mL, 2.5 mmol) in toluene (25 mL) was heated at 80 °C under argon atmosphere for 24 h. The mixture was then concentrated under reduced pressure and purified through flash column chromatography on silica gel (PE/EA: 10/1) to obtain three colorless oil products 20 (72 mg, 26%), 21 (10 mg, 3.6%), and 22 (25 mg, 8.9%). 3β,26-Diacetoxy-5α-cholest-20(22)-en-16β,22,23-orthoacetate (20). Rf: 0.53 (hexane/ethyl acetate: 3/1); [α]26 D + 1.1 (c 0.7, CHCl3); IR (KBr): 2933, 2851, 1733, 1450, 1340, 1366, 1243, 1028, 925, 737 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.70−4.62 (m, 1H), 4.27−4.23 (m, 1H), 4.20−4.14 (m, 1H), 3.95 (dd, J = 10.7, 5.3 Hz, 1H), 3.85 (dd, J = 10.9, 6.4 Hz, 1H), 2.04 (s, 3H), 2.00 (s, 3H), 1.65 (s, 3H), 1.54 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.91 (s, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.4 (C), 170.8 (C), 152.8 (C), 118.8 (C), 94.9 (CH), 81.7 (C), 73.7 (CH), 71.4 (CH), 69.0 (CH2), 63.4 (CH), 54.3 (CH), 54.2 (CH), 44.7 (CH), 41.5 (C), 39.6 (CH2), 36.9 (CH2), 35.6 (C), 34.4 (CH), 34.1 (CH2), 32.8 (CH), 32.0 (CH2), 28.9 (CH2), 28.5 (CH2), 27.5 (CH2), 25.6 (CH3), 22.7 (CH3), 21.6 (CH3), 21.1 (CH3), 20.5 (CH2), 17.4 (CH3), 14.8 (CH3), 12.4 (CH3); LRMS-ESI (m/z): 559.3 [M+H]+; HRMS (ESI-TOF) (m/z): [M+H]+ calcd. for C33H51O7 559.3629, found: 559.3623. 3β,16β,26-Triacetoxy-5α-cholest-20(21)-en-22-one (21). Rf: 0.35 (hexane/ethyl acetate: 3/1); [α]26 D + 32 (c 0.5, CHCl3); IR (KBr): 2933, 2852, 1736, 1682, 1450, 1366, 1243, 1170, 1028, 736 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.17 (s, 1H), 5.99 (s, 1H), 5.26−5.21 (m, 1H), 4.70−4.62 (m, 1H), 3.94−3.86 (m, 2H), 2.95 (d, J = 7.6 Hz, 1H), 2.81−2.59 (m, 2H), 2.51−2.28 (m, 1H), 2.04 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.85 (s, 3H), 0.81 (s, 3H), 0.69 (td, J = 11.6, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 202.0 (C), 171.3 (C), 170.7 (C), 170.1 (C), 144.9 (C), 126.7 (CH2), 75.2 (CH), 73.7 (CH), 69.0 (CH2), 54.4 (CH), 53.8 (CH), 51.6 (CH), 44.7 (CH), 43.5 (C), 37.8 (CH2), 36.7 (CH2), 35.7 (C), 35.2 (CH), 34.9 (CH2), 34.8 (CH2), 34.0 (CH2), 32.3 (CH), 31.9 (CH2), 28.5 (CH2), 28.1 (CH2), 27.5 (CH2), 21.6 (CH3), 21.5 (CH3), 21.1 (CH3), 20.7 (CH2), 16.9 (CH3), 14.3 (CH3), 12.3 (CH3); LRMS-ESI (m/z): 576.3 [M+NH4]+; HRMS (ESI-TOF) (m/z): [M+H]+ calcd. for C33H51O7 559.3629, found: 559.3629. 3β,16β,26-Triacetoxy-5α-cholest-17(20)-en-22-one (22). Rf: 0.28 (hexane/ethyl acetate: 3/1); [α]26 D + 15 (c 1.0, CHCl3); IR (KBr): 2935, 2854, 1736, 1693, 1450, 1369, 1241, 1175, 1029, 958 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.61−5.58 (m, 1H), 4.71−4.63 (m, 1H), 3.93−3.86 (m, 2H), 2.62−2.42 (m, 2H), 2.05 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H), 1.94 (d, J = 1.5 Hz, 3H), 1.03 (s, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.82 (s, 3H), 0.70 (td, J = 12.3, 3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 207.5 (C), 171.3 (C), 170.8 (C), 170.4 (C), 149.6 (C), 132.8 (C), 74.5 (CH), 73.7 (CH), 69.0 (CH2), 53.9 (CH), 51.1 (CH), 45.2 (C), 44.6 (CH), 38.5 (CH2), 37.0 (CH2), 36.7 (CH2), 35.6 (C), 34.5 (CH), 34.0 (CH2), 32.3 (CH), 32.2 (CH2), 31.7 (CH2), 28.4 (CH2), 27.5 (CH2), 27.3 (CH2), 21.6 (CH3), 21.3 (CH2), 21.1 (CH3), 21.0 (CH3), 16.8 (CH3), 16.5 (CH3), 15.2 (CH3), 12.3 (CH3); LRMS-ESI (m/z): 576.3 [M+NH4]+; HRMS (ESI-TOF) (m/ z): [M+H]+ calcd. for C33H54O7N 576.3895, found: 576.3883. 3β,16β-Diacetoxy-26-((tert-butyldiphenylsilyl)oxy)-5α-cholestan-22-one (18). To a solution of 16 (0.53 g, 1 mmol) and imidazole (0.14 g, 2 mmol) in DCM (10 mL) was added TBDPSCl (0.4 mL, 1.5 mmol) at 0 °C. The resulting solution was stirred for 3.5 h, quenched with saturated aqueous NH4Cl, diluted with water, and

Scheme 3. PhI(OAc)2-Induced Favorskii Reaction Enabled the Formation of 24(23→22)-abeo-Cholestane Skeleton

Scheme 4. Plausible Explanation for the C23-Configuration of 24

In summary, we have accomplished a transformation of tigogenin, a 27C starting material, to 24(23→22)-abeocholestane, a unique structural unit which exists in saundersiosides and candicanoside and is unprecedented in natural products. The reagent system PhI(OAc)2/KOH/MeOH was used to trigger a Favorskii rearrangement of C22-ketone, moving the steroidal backbone from C22 to C23. This 20(22→ 23)-abeo-approach allows facile preparation of 24(23→22)abeo-cholestane from cholestane with simple transformation.

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EXPERIMENTAL SECTION

3β,16β,26-Triacetoxy-23-bromo-5α-cholestan-22-one (19). To a solution of 17 (1.12 g, 2 mmol) in THF (40 mL) at 0 °C was slowly added a precooled solution of PhMe3NBr (0.84 g, 2.2 mmol) in THF (10 mL) via cannula. The mixture was stirred at room temperature for 24 h, quenched with saturated aqueous Na2S2O3 solution and brine, and extracted with ethyl acetate (3 × 50 mL). The combined organic portions were dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified through column 4404

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extracted with ethyl acetate (3 × 50 mL). The combined organic portions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified through column chromatograph on silica gel (PE/EA: 8/1) to give 18 (0.73 g, 96%) as colorless oil. Rf: 0.53 (hexane/ethyl acetate: 3/1); [α]26 D + 31 (c 0.5, CHCl3); IR (KBr): 2956, 2933, 2857, 1735, 1710, 1378, 1244, 1111, 1078, 1029, 704 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.70−7.60 (m, 4H), 7.46−7.33 (m, 6H), 4.97−4.92 (m, 1H), 4.72−4.64 (m, 1H), 3.59−3.38 (m, 2H), 2.95−2.87 (m, 1H), 2.60−2.51 (m, 1H), 2.01 (s, 3H), 1.90 (s, 3H), 1.09 (d, J = 7.1 Hz, 3H), 1.05 (s, 9H), 0.91 (d, J = 6.6 Hz, 3H), 0.83 (s, 3H), 0.82 (s, 3H), 0.68 (td, J = 11.3, 4.1 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 213.3, 170.8, 169.8, 135.7, 134.0, 134.0, 129.7, 127.7, 75.9, 73.7, 68.8, 55.3, 54.1, 53.8, 44.6, 43.6, 42.3, 40.0, 39.1, 36.7, 35.6, 35.6, 35.0, 34.9, 34.1, 31.8, 28.5, 27.5, 27.1, 27.0, 21.6, 21.2, 21.0, 19.4, 16.9, 16.8, 13.6, 12.3; LRMS-MALDI (m/z): 757.5 [M+H]+; HRMS (MALDI-TOF) (m/z): [M+H]+ calcd. for C47H69O6Si 757.4858, found: 757.4858. Methyl 3β-Hydroxy-16-acetoxy-26-((tert-butyldiphenylsilyl)oxy)-5α-24(23→22)-abeo-cholestan-23-oic-ate 24. To the mixture of 18 (76 mg, 0.1 mmol), PhI(OAc)2 (80 mg, 0.25 mmol), and KOH (0.39 g, 7.0 mmol) was added dry MeOH (5.0 mL) at room temperature, then exothermal phenomena was observed. The resulting solution was stirred at room temperature for 2 h, and quenched with saturated aqueous NH4Cl. The mixture was diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic portions were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified through column chromatograph on silica gel (PE/EA: 4/1) to give 24 (39 mg, 52%) as colorless oil and a ca. 3/1 mixture of isomers. Rf: 0.47 (hexane/ethyl acetate: 2/1); IR (KBr): 2928, 2855, 1735, 1463, 1243, 1112, 1029, 739, 703, 505 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.74−7.59 (m, 4H), 7.44−7.35 (m, 6H), 5.21−5.16 (m, 1H), 3.62 (s, 3H), 3.60−3.55 (m, 1H), 3.55−3.49 (m, 1H), 3.45−3.40 (m, 1H), 2.07 (s, 3H), 1.05 (s, 9H), 0.91−0.83 (m, 9H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.1, 171.0, 135.8, 135.8, 134.2, 129.6, 127.7, 127.7, 74.2, 71.4, 69.6, 56.8, 54.5, 54.4, 51.5, 44.9, 43.9, 42.9, 39.8, 38.2, 37.0, 35.6, 35.1, 34.8, 34.2, 32.7, 31.9, 31.6, 29.9, 28.7, 27.8, 27.0, 21.4, 21.1, 19.5, 16.2, 13.9, 12.9, 12.4; LRMS-MALDI (m/z): 762.5 [M+NH4]+; HRMS (MALDI-TOF) (m/ z): [M+NH4]+ calcd. for C46H72O6NSi 762.5123, found: 762.5113. 3β,26-Dihydroxy-5α-24(23→22)-abeo-cholestan-23-oic-16ate (12). To a solution of 24 (370 mg, 0.5 mmol, mixture of isomers) in THF (50 mL) was added TBAF (2.5 mL, 1.0 M in THF, 2.5 mmol) at room temperature. The resulting solution was stirred for 12 h, quenched with MeOH, and concentrated under reduced pressure. The crude product was dissolved in THF/H2O (50 mL/1.0 mL), and to the resulting solution was added KOH (0.14 g, 2.5 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 h and at reflux for another 2.5 h. The mixture was neutralized by adding 1.2 N HCl, diluted with water, and extracted with ethyl acetate (3 × 25 mL). The combined organic portions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified through column chromatograph on silica gel (PE/EA: 1/1) to give 12 (120 mg, 57%) as a white solid. Rf: 0.31 (hexane/ethyl acetate: 1/3); [α]26 D −45 (c 0.75, CHCl3); mp 143−145 °C; IR (KBr): 3323, 2923, 2850, 1732, 1450, 1379, 1254, 1186, 1076, 1043 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.72−4.67 (m, 1H), 3.63−3.56 (m, 1H), 3.56− 3.48 (m, 1H), 3.45−3.41 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.82 (s, 3H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 177.1 (C), 78.7 (CH), 71.2 (CH), 68.0 (CH2), 59.5 (CH), 54.5 (CH), 53.6 (CH), 44.9 (CH), 44.2 (CH), 42.0 (C), 39.3 (CH2), 38.1 (CH2), 37.0 (CH2), 35.6 (C), 35.0 (CH), 34.9 (CH), 33.3 (CH2), 32.1 (CH2), 31.5 (CH2), 30.9 (CH), 30.0 (CH2), 28.5 (CH2), 20.8 (CH2), 20.7 (CH3), 17.0 (CH3), 14.9 (CH3), 12.4 (CH3); LRMS-ESI (m/z): 433.2 [M+H]+; HRMS (ESI-TOF) (m/z): [M +H]+ calcd. for C27H45O4 433.3312, found: 433.3310.

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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.joc.6b03043. 1 H and 13C NMR spectra of all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] *E-mail: [email protected] ORCID

Yong Shi: 0000-0002-7887-3050 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21272258, 21572248) for financial support. REFERENCES

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DOI: 10.1021/acs.joc.6b03043 J. Org. Chem. 2017, 82, 4402−4406

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The Journal of Organic Chemistry R.; White, K. B. J. Am. Chem. Soc. 1981, 103, 686−688. (c) Moriarty, R. M.; Hu, H.; Gupta, S. C. Tetrahedron Lett. 1981, 22, 1283−1286. (11) It should be noted that the Favorskii reaction transforming 18 to 24 could proceed via either cyclopropanone mechanism (CPM) or semibenzylic mechanism (SBM). Although the SBM pathway was given in Scheme 3 to explain the generation of 24, there was no evidence in favor of one mechanism over another. (12) Since 24 was used as a ca. 3/1 diastereomeric mixture, it was not clear whether lactone 12 was formed from solely the major isomer of 24 or from both isomers via epimerization of C22 (α position of carbonyl group) in basic medium. As we did not obtain 24 in pure form, no further investigation was performed.

4406

DOI: 10.1021/acs.joc.6b03043 J. Org. Chem. 2017, 82, 4402−4406