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. 2019 Aug 16;4(9):14085–14091. doi: 10.1021/acsomega.9b01951

Ti-Catalyzed Cross-Cyclomagnesiation of 1,2-Dienes in the Total Z,Z,Z-Stereoselective Synthesis of Natural Acetogenin–Chatenaytrienin-1

Vladimir A D’yakonov 1,*, Regina A Tuktarova 1, Usein M Dzhemilev 1
PMCID: PMC6714518  PMID: 31497727

Abstract

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The first total synthesis of natural acetogenin, chatenaytrienin-1, was performed in 10 steps and in 41% overall yield using cross-cyclomagnesiation of (6Z)-heptadeca-1,2,6-triene and trideca-11,12-dien-1-ol tetrahydropyran acetal with EtMgBr in the presence of Mg metal and the Cp2TiCl2 catalyst (10 mol %) as the key step of the synthesis.

Introduction

Acetogenins, an abundant, structurally diverse group of natural compounds, are isolated from the Annonaceae plants, representing nonbranched fatty acids (C32–C34) with a γ-lactone moiety.1 In most cases, acetogenin molecules contain additional hydroxy, keto, epoxy, tetrahydrofuran, or tetrahydropyran groups as well as double and triple bonds. The enhanced interest in this class of compounds is due to a wide range of biological activities they exhibit such as antibacterial, immunosuppressive, antimalarial, anticancer, and antiprotozoal activities.2 Moreover, it has been shown that acetogenins, as well as compounds containing a 2,5-bis(hydroxymethyl)tetrahydrofuran moiety, are capable of exerting a cytotoxic effect on multidrug-resistant tumors due to inhibition of the ATP synthesis and are among the most active of currently known mitochondrial complex I inhibitors.3 In addition, acetogenins can interact with DNA polymerases and topoisomerases, thus affecting the synthesis of deoxyribonucleic acids in the cell.4 The possibility of affecting the regulation of cell cycle by relatively low concentrations of these substances, together with pronounced antitumor action and a relatively beneficial effect on healthy cells, makes this class of compounds promising for the development of new highly effective antitumor agents. Since plants produce exceptionally low (nanogram) quantities of acetogenins, a chemical synthesis is the only option for obtaining these compounds for practical use. It is important to ensure high stereoselectivity of the resulting compounds since the activity of these bioregulators is crucially affected by the geometry of the double bonds and asymmetric centers present in molecules.5

Currently, quite a number of examples of synthesizing of structurally diverse acetogenins and their analogues have been reported in the literature; in the vast majority of cases, these are representatives of the acetogenin family containing one to three furan moieties in the molecule, with the major synthetic strategy being successive assembly of the molecule from small blocks by known C–C bond formation protocols.6 Despite that an effective approach to cascade cyclization of the above-described unsaturated compounds has now been developed; at the same time, it has been shown that the crucial factor dictating the stereoselective formation of tetrahydrofurans and hydroxyl groups is a strict stereoconfiguration of substituents at the double bonds.

The Ru-catalyzed oxidative cyclization of 1Z,5Z-dienes yields only anti,anti-stereoisomers of 2,5-bis(hydroxymethyl)tetrahydrofurans, which exhibit the highest antitumor and antibacterial activities.7

Development of the strategy for the total synthesis of acetogenins containing tetrahydrofuran moieties via the oxidative cyclization of the appropriate bis-methylene-separated di- and polyenes is mainly hampered, in our opinion, by the lack of an efficient synthetic approach to the latter. A survey of literature indicates that methods used, most often, to generate the 1Z,5Z-diene moiety are based on the Wittig reaction, olefin metathesis, and stereoselective catalytic hydrogenation of acetylenes.8 The task becomes more challenging if the synthesis implies the formation of compounds containing three or more Z-double bonds.

The previously developed Ti-catalyzed homo- and cross-cyclomagnesiation of 1,2-dienes, which leads to strictly stereoselective formation of metal–carbon and carbon–carbon bonds, could be successfully utilized as a convenient and versatile tool in the stereoselective synthesis of various 1Z,5Z-diene derivatives (Scheme 1).9

Scheme 1. Ti-Catalyzed Homo- and Cross-Cyclomagnesiation of 1,2-Dienes.

Scheme 1

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The results reported in the papers mentioned above9 can be used for the synthesis of a broad range of natural biologically active compounds, higher 5Z,9Z-dienoic acids, insect pheromones, lembehynes, unique macrocarbocycles, and also acetogenins.4,10

In particular, previously, we developed an original five-step synthesis of a natural acetogenin, muricadienin 1, a bioprecursor of cis-solamin 2 (Figure 1), giving the product in ∼60% yield. The synthesis involved cross-cyclomagnesiation of functionally substituted allenes with EtMgBr in the presence of Mg metal (halogen ion acceptor) and catalyzed by Ti complexes as the key step. In addition, we previously found that muricadienin exhibits inhibitory activity in vitro against key cell cycle enzymes human topoisomerases I and IIα and has high cytotoxicity against human embryonic kidney cells HEK293 (IC50 = 0.39 μM).4

Figure 1.

Figure 1

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Structures of muricadienin, chatenaytrienin-l and 4,cis-solamin and membranacin.

Considering the practical value of research aimed at the search for new preparative approaches for the syntheses of natural biologically active compounds with a Z-polyunsaturated hydrocarbon chain and also to study the applicability of reactions we developed for the preparation of more structurally sophisticated acetogenins, here, we intended to synthesize chatenaytrienin-1 3 using the Ti-catalyzed cross-cyclomagnesiation of 1,2-dienes as the key step.

Chatenaytrienin-l 3, which was isolated in 1998 by Gleye and co-workers from Annona muricata, is a natural triene bioprecursor of Annonaceous acetogenin, membranacin 5, containing a bis-THF moiety (Figure 1).11

When our study was started, only a single example of synthesizing a structurally similar homologue of compound 3, chatenaytrienin-4 4, was available from the literature. Compound 4 was prepared in 15 steps in an overall yield of 6%.12

Results and Discussion

Initially, we carried out the retrosynthetic analysis of the chatenaytrienin-l 3, which implied the successive synthesis of (11Z,15Z,19Z)-triaconta-11,15,19-trienoic acid 6 by means of catalytic cross-cyclomagnesiation followed by the construction of α-substituted butenolide, with the Fries rearrangement being the final step of the synthesis of the target triene (Scheme 2).

Scheme 2. Retrosynthetic Analysis of Chatenaytrienin-1.

Scheme 2

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The initial monomer needed for the preparation of Z,Z,Z-trienoic acid 6, (6Z)-heptadec-1,2,6-triene 10, was synthesized in several steps using the alkylation of commercially available dodec-1-yne 8 with ethylene oxide (Scheme 3).13 The subsequent selective hydrogenation of alcohol 12 was carried out in the presence of Brown’s catalyst P2–Ni and afforded unsaturated alcohol 9 with Z-configuration of the double bond in ∼98% yield.14 Ethynylation of compound 13, obtained by bromination of alcohol 9 with LiBr,15 on treatment with lithium acetylenide yielded (5Z)-hexadec-5-en-1-yne 14 in a quantitative yield.16 Allene 10 was obtained from alkyne 14 by the Crabbé reaction that involves refluxing with paraformaldehyde, dicyclohexylamine, and copper iodide.17

Scheme 3. Synthesis of (6Z)-Heptadeca-1,2,6-triene.

Scheme 3

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According to the developed synthetic strategy, (11Z,15Z,19Z)-triaconta-11,15,19-trienoic acid 6 was prepared by the cross-cyclomagnesiation of (6Z)-heptadeca-1,2,6-triene 10 and trideca-11,12-dien-1-ol tetrahydropyran acetal 11 with EtMgBr in the presence of Mg metal and the Cp2TiCl2 catalyst (10 mol %) at room temperature (Scheme 4). The reaction proceeded via the intermediate magnesacyclopentane 15, which was hydrolyzed to give (11Z,15Z,19Z)-triaconta-11,15,19-trien-1-ol tetrahydropyran acetal 16 in 85% yield. The subsequent oxidation of tetrahydropyran acetal 16 with the Jones reagent gave the desired Z,Z,Z-trienoic acid 6.

Scheme 4. Titanium-Catalyzed Cross-Cyclomagnesiation of Allenes.

Scheme 4

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All that remains for the synthesis of chatenaytrienin-l 3 was the formation of the terminal butenolide moiety, which was effected by a method that proved useful,18 based on the Fries rearrangement catalyzed by DMAP (Scheme 5). Indeed, O-acylation of cyclic β-keto ether 7, which was obtained from (S)-ethyl lactate by a reported two-step procedure,19 with acid 6 followed by the DMAP-initiated rearrangement afforded triene 17, which was then undergo reduction by NaBH3CN in acetic acid to produce α-alkylated butenolide 18 in a yield of more than 97%.

Scheme 5. Fries Rearrangement: Introduction of the Terminal α-Substituted Butenolide.

Scheme 5

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The hydroxyl group in the C3-position of butenolide was eliminated by successive synthesis of triflate 19 and its reduction with Bu3SnH catalyzed by Pd2(dba)3; this gave the target chatenaytrienin-l 3 in ∼91% yield.8k

Conclusions

Thus, we have achieved the first stereoselective 10 step synthesis of chatenaytrienin-l using Ti-catalyzed cross-cyclomagnesiation of aliphatic and oxygenated 1,2-dienes with the Grignard reagent. This study demonstrates the enormous synthetic potential of the proposed method as a convenient tool for stereoselective preparation of 1Z,5Z-diene systems. Currently, our efforts are focused on the synthesis of a number of natural homologues of chatenaytrienin-l to obtain larger amounts of these products and conduct extensive studies of their antitumor, antibacterial, and antiparasitic activities.

Experimental Section

General Information

1-Dodecyne, lithium acetylide, ethylene diamine complex, nickel (II) acetate tetrahydrate (Ni(OAc)2·4H2O), dicyclohexylamine, copper (I) iodide (CuI), bis(cyclopentadienyl)titanium (IV) dichloride (Cp2TiCl2), 4-dimethylaminopyridine (DMAP), N,N′-dicyclohexylcarbodiimide (DCC), sodium cyanoborohydride (NaBH3CN), trifluoromethanesulfonic anhydride (Tf2O), and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) were obtained from Sigma-Aldrich and Acros organics. All reactions were carried out under an argon atmosphere. 1H and 13C NMR spectra were obtained using a Bruker Ascend 500 spectrometer in CDCl3 operating at 500 MHz for 1H and 125 MHz for 13C and a Bruker AVANCE 400 spectrometer in CDCl3 operating at 400 MHz for 1H and 100 MHz for 13C. IR spectra were recorded on a Bruker VERTEX 70V using KBr discs over the range of 400–4000 cm–1. Mass spectra of MALDI TOF/TOF positive ions (matrix of sinapic acid) are recorded on a mass spectrometer Bruker Autoflex III Smartbeam. Elemental analyses were measured on a 1106 Carlo Erba apparatus. Individuality and purity of the synthesized compounds were controlled using TLC on Sorbfil plates; anisic aldehyde in acetic acid was used as a developer. Column chromatography was carried out on Acrus silica gel (0.060–0.200 mM).

Cross-Cyclomagnesiation of (6Z)-Heptadeca-1,2,6-triene (10) and 2-(Trideca-11,12-dien-1-yloxy)tetrahydro-2H-pyran (11) by EtMgBr in the Presence of Mg Metal and Cp2TiCl2 Catalyst (General Procedure)

Diethyl ether (50 mL), (6Z)-heptadeca-1,2,6-triene 10 (2.3 g, 10.0 mmol), 2-(trideca-11,12-dien-1-yloxy)tetrahydro-2H-pyran 11 (2.3 g, 8.4 mmol), EtMgBr (66.8 mL, 100.2 mmol) (as 1.5 M solution in Et2O), Mg powder (3.0 g, 125.8 mmol), and Cp2TiCl2 (0.4 g, 1.8 mmol) were charged into a glass reactor with stirring under argon (∼0 °C). The reaction mixture was heated to 20–22 °C and stirred for 24 h. The reaction mixture was treated with a 5% solution of NH4Cl in H2O (30 mL) and extracted with diethyl ether (2 × 100 mL). The combined organic phases were dried over MgSO4 and filtrated. Then, the solvent was removed under reduced pressure. Silica gel column chromatography (hexane/EtOAc = 35:1) of the residue gave compound 16.

2-[(11Z,15Z,19Z)-Triaconta-11,15,19-trien-1-yloxy]tetrahydro-2H-pyran (16)

Yield 8.1 g (85%), pale yellow oily liquid. 1H NMR (500 MHz, CDCl3, δ): 5.45–5.35 (m, 6H), 4.59 (m, 1H), 3.89 (m, 1H), 3.75 (m, 1H), 3.52 (m, 1H), 3.40 (m, 1H), 2.10 (m, 6H), 2.04 (m, 6H), 1.85 (m, 1H), 1.73 (m, 1H), 1.63–1.52 (m, 6H), 1.40–1.25 (m, 30H), 0.90 (t, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3, δ): 130.4 (signals of 2C), 129.6 (signals of 2C), 129.1 (signals of 2C), 98.8, 67.7, 62.3, 31.9, 30.8, 29.8–29.3 (signals of 13C), 27.5 (signals of 2C), 27.4 (signals of 2C), 27.3 (signals of 2C), 26.3, 25.5, 22.7, 19.7, 14.1. IR (film): 3008, 2956, 2924, 1644, 1612, 1466, 1404, 1302, 1261, 996, 902, 841, 783, 721, 655, 611 cm–1. Anal. Calcd for C35H64O2: C, 81.33; H, 12.48. Found: C, 81.19; H, 12.46. MALDI TOF: m/z 539.538 ([M + Na]+, calcd 539.480).

Oxidation of 2-[(11Z,15Z,19Z)-Triaconta-11,15,19-trien-1-yloxy]tetrahydro-2H-pyran 16 with Jones Reagent

To a solution of 2-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yloxy]tetrahydro-2H-pyran 16 (8.0 g, 15.3 mmol) in acetone (100 mL) and CH2Cl2 (25 mL) at room temperature, Jones reagent (18.7 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, quenched with water (50 mL), and concentrated to remove the excess of acetone and CH2Cl2. Then, the aqueous layer was extracted with diethyl ether (3 × 100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography using hexane/EtOAc = 30:1 as the elution solvent to afford (11Z,15Z,19Z)-triaconta-11,15,19-trienoic acid 6.

(11Z,15Z,19Z)-Triaconta-11,15,19-trienoic Acid (6)

Yield 5.3 g (78%), colorless oil. 1H NMR (500 MHz, CDCl3, δ): 5.45–5.35 (m, 6H), 2.36 (t, J = 7.5 Hz, 2H), 2.11 (m, 6H), 2.05 (m, 6H), 1.65 (m, 2H), 1.40–1.25 (m, 28H), 0.90 (t, J = 6.4 Hz, 3H). 13C NMR (125 MHz, CDCl3, δ): 180.1, 130.4, 130.3, 129.6 (signals of 2C), 129.1 (signals of 2C), 34.1, 31.9, 29.8–29.1 (signals of 12C), 27.5 (signals of 2C), 27.4 (signals of 2C), 27.3 (signals of 2C), 24.7, 22.7, 14.1; IR (film): 2926, 2851, 1712, 1466, 1374, 1309, 1283, 1260, 1230, 1206, 1183, 965, 935, 723, 722 cm–1. Anal. Calcd for C30H54O2: C, 80.65; H, 12.18. Found: C, 80.49; H, 12.16. MALDI TOF: m/z 469.508 ([M + Na]+, calcd 469.402), 485.398 ([M + K]+, calcd 485.376).

Synthesis of (5S)-4-Hydroxy-5-methyl-3-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]furan-2(5H)-one (18)

DIPEA (2.3 mL, 13.3 mmol) was added to a suspension of butenolide 7 (1.5 g, 13.3 mmol), fatty acid 6 (5.2 g, 11.7 mmol), 4-DMAP (0.4 g, 3.3 mmol), and DCC (2.7 g, 13.3 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was stirred overnight with warming to room temperature. The yellow solution was filtered, and the solid was washed with diethyl ether. The filtrate was concentrated, and the residue was dissolved in ethyl acetate. The organic phase was washed with a solution of 1 N HCl and brine, dried over MgSO4, filtrated, and concentrated under reduced pressure. To remove residual urea derivative, the mixture was dissolved in diethyl ether, filtrated, and concentrated in vacuo to yield a brownish solid that was directly used in the subsequent reduction step. To this end, the crude product was dissolved in acetic acid (30 mL), and NaBH3CN (5.3 g, 23.4 mmol) was slowly added at 10 °C. The reaction mixture was stirred overnight with warming to room temperature and then poured into a solution of 1 N HCl (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with H2O and brine, dried over MgSO4, filtrated, and concentrated in vacuo (3 × codestillation with toluene to remove acetic acid). The title compound 18 was obtained in analytically pure product.

(5S)-4-Hydroxy-5-methyl-3-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]furan-2(5H)-one (18)

Yield 5.6 g (90%), colorless waxy solid. [α]D21 + 1.0 (c 0.71, CHCl3). 1H NMR (500 MHz, CDCl3, δ): 5.46–5.37 (m, 6H), 4.84 (q, J = 6.5 Hz, 1H), 2.22 (t, J = 7.5 Hz, 2H), 2.10 (m, 6H), 2.05 (m, 6H), 1.52 (d, J = 6.5 Hz, 3H), 1.48 (m, 2H), 1.40–1.25 (m, 30H), 0.89 (t, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3, δ): 177.7, 177.4, 130.4 (signals of 2C), 129.6 (signals of 2C), 129.1 (signals of 2C), 100.9, 75.3, 31.9, 29.7–29.4 (signals of 13C), 28.1, 27.5 (signals of 2C), 27.4 (signals of 2C), 27.3 (signals of 2C), 22.7, 21.1, 17.8, 14.1. IR (film): 3005, 2924, 2853, 1751, 1730, 1654, 1457, 1376, 1313, 1267, 1249, 1180, 1142, 1081, 1078, 777, 722 cm–1. Anal. Calcd for C35H60O3: C, 79.49; H, 11.44 Found: C, 79.39; H, 11.41. MALDI TOF: m/z 551.518 ([M + Na]+, calcd 551.444), 567.481 ([M + K]+, calcd 567.418).

Synthesis of (2S)-2-Methyl-5-oxo-4-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]-2,5-dihydrofuran-3-yl Trifluoromethanesulfonate (19)

DIPEA (2.5 mL, 14.1 mmol) was added to a stirred solution of compound 18 (5.0 g, 9.4 mmol) in DCM (100 mL) at room temperature. The solution was cooled to −78 °C and Tf2O (3.1 g, 1.9 mL, 10.9 mmol) was slowly added. The mixture was stirred at −78 °C for 2 h. After complete conversion, DCM (20 mL) was added, and the reaction mixture was extracted with a solution of 1 N HCl (100 mL). The combined organic phases were washed with H2O, brine, dried over MgSO4, and filtrated. The solvents were removed under reduced pressure. Silica gel column chromatography (hexane/EtOAc = 30:1) of the residue gave triflate 19.

(2S)-2-Methyl-5-oxo-4-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]-2,5-dihydrofuran-3-yl Trifluoromethanesulfonate (19)

Yield 5.6 g (91%), pale yellow oil. [α]D21 + 17.0 (c 0.71, CHCl3). 1H NMR (500 MHz, CDCl3, δ): 5.46–5.37 (m, 6H), 5.13 (q, J = 6.8 Hz, 1H), 2.33 (t, J = 7.2 Hz, 2H), 2.11 (m, 6H), 2.04 (m, 6H), 1.61 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H), 1.40–1.23 (m, 30H), 0.90 (t, J = 6.4 Hz, 3H). 13C NMR (125 MHz, CDCl3, δ): 169.1, 163.4, 130.4 (signals of 2C), 129.6 (signals of 2C), 129.1 (signals of 2C), 121.9, 118.4 (J = 319 Hz), 74.4, 31.9, 29.7–29.1 (signals of 13C), 27.5 (signals of 2C), 27.4 (signals of 2C), 27.3 (signals of 2C), 26.7, 22.7 (signals of 2C), 17.7, 14.1. IR (film): 3005, 2924, 2853, 1751, 1730, 1654, 1457, 1376, 1313, 1267, 1249, 1180, 1142, 1081, 1078, 777, 722 cm–1. Anal. Calcd for C36H59F3O5S: C, 65.42; H, 9.00 Found: C, 65.36; H, 8.97. MALDI TOF: m/z 683.418 ([M + Na]+, calcd 683.404).

Synthesis of (5S)-5-Methyl-3-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]furan-2(5H)-one (Chatenaytrienin-l 3)

Pd2(dba)3 (13.7 mg, 0.015 mmol, 1.5 mol %) and PPh3 (39.3 mg, 0.15 mmol, 15.0 mol %) were dissolved in dry THF (10 mL). After stirring for 5 min at room temperature, triflate 19 (0.7 g, 1.0 mmol) and Bu3SnH (0.8 mL, 3.0 mmol) were added to the orange solution. The mixture was heated to 50 °C and stirred at this temperature for 5 h. After complete conversion of the starting material, the reaction was cooled to room temperature, diluted with H2O (10 mL), and extracted with diethyl ether (3 × 30 mL). The combined organic phases were dried over MgSO4 and filtrated. Then, the solvents were removed under reduced pressure. Silica gel column chromatography (hexane/EtOAc = 20:1) of the residue gave chatenaytrienin-l 3.

(5S)-5-Methyl-3-[(11Z,15Z,19Z)-triaconta-11,15,19-trien-1-yl]furan-2(5H)-one (3)

Yield 0.4 g (88%), colorless waxy solid. [α]D21 + 12.8 (c 0.64, CHCl3). 1H NMR (500 MHz, CDCl3, δ): 6.99 (d, 3J = 1.0 Hz, 1H), 5.45–5.33 (m, 6H), 5.00 (qd, 3J = 6.5, 3J = 1.5 Hz, 1H), 2.28 (t, J = 7.5 Hz, 2H), 2.09 (m, 6H), 2.04 (m, 6H), 1.56 (m, 2H), 1.42 (d, J = 6.5 Hz, 3H), 1.38–1.25 (m, 30H), 0.89 (t, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3, δ): 173.9, 148.8, 134.3, 130.4 (signals of 2C), 129.6 (signals of 2C), 129.1 (signals of 2C), 77.4, 31.9, 29.8–29.2 (signals of 13C), 27.5 (signals of 3C), 27.4 (signals of 3C), 27.3, 25.2, 22.7, 19.2, 14.1. IR (film): 2924, 2853, 1759, 1654, 1619, 1458, 1375, 1318, 1261, 1198, 1075, 1027, 968, 875, 722 cm–1; Anal. Calcd for C35H60O2: C, 81.97; H, 11.79 Found: C, 81.81; H, 11.76. MALDI TOF: m/z 535.521 ([M + Na]+, calcd 535.449), 551.469 ([M + K]+, calcd 551.423).

Acknowledgments

This work was supported by the Russian Science Foundation (grant no. 18-73-10030). The structural studies of the synthesized compounds were performed with the use of Collective Usage Centre “Agidel” at the Institute of Petrochemistry and Catalysis of RAS.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b01951.

  • Methods of synthesis and characterization data of the products 3, 6, 9–14, 18, and 19 as well as copies of 1H and 13C NMR spectra of final products (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao9b01951_si_001.pdf (1.8MB, pdf)

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