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A Protecting-Group-Free Total Synthesis of Chatenaytrienin-2 Rupesh A Kunkalkar, and Rodney Agustinho Fernandes J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01952 • Publication Date (Web): 01 Sep 2019 Downloaded from pubs.acs.org on September 2, 2019

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The Journal of Organic Chemistry

A Protecting-Group-Free Total Synthesis of Chatenaytrienin-2 Rupesh A. Kunkalkar and Rodney A. Fernandes* Department of Chemistry, Indian Institute of Technology Bombay, Powai Mumbai 400076, Maharashtra, India Supporting Information Placeholder

ABSTRACT: An efficient 7 step, protecting-group-free first total synthesis of chatenaytrienin-2 based on ring-closing metathesis and C(sp)-C(sp3) Sonogashira coupling with 36.5% overall yield has been described. The ready availability of starting materials and key Wittig olefination, ring-closing metathesis, Lindlar reduction and C(sp)-C(sp3) coupling makes this strategy applicable for the synthesis of various unbranched polyene-natural products having the 1,5,9,n-(Z)-configured double bonds. Annonaceous acetogenins solely found in the genera of the archaic plant family called as Annonaceae, are a group of fatty acid type natural products.1,2 Many natural products belonging to this group have been isolated, characterized and shown to possess interesting and important bioactivities,1,3 significantly the antitumor effects and growth inhibitory action against multidrug-resistant cancer cells.4 Structurally, acetogenins have a very long alkyl chain usually ranging from 32 to 34 carbon atoms substituted by oxygenated groups, usually tetrahydrofuran (THF) ring, epoxide or hydroxyl groups. These long chain compounds are mainly terminated by an α,β-unsaturated-γ-methyl-γ-lactone at one end and a methyl group on the other. The number of THF rings and the stereochemistry, both have a profound effect on the biological activities; e.g. adjacent bis-THF groups in membranacin,5,6 leads to a highly potent tumour growth inhibitor. The first acetogenin without a THF ring was isolated in 1990 containing epoxy-ene units, which gave the idea of natural occurrence of bis-unsaturated precursors, muricadienin, muridienins and chatenaytrienins.7 This led to the assumption of biosynthetic pathways for THF containing acetogenins, where these THF heterocycles originate from 1,5 and 1,5,9,n polyenes. The majority of these natural products feature exclusively (Z)-configured double bonds like in muricadienin, muridienins and chatenaytrienins.7b It is proposed that muricadienin might be a precursor for both the acetogenins cis- and trans-solamins.8 Many acyclic polyene acetogenins have been isolated from the same plant as their oxidized and cyclized THF forms.1b,9 In 1998, Cave et al. isolated chatenaytrienins, the polyenes (1,5,9 trienes) as a mixture of chatenaytrienin-1 (1a) and -2 (1b), and chatenaytrienin-3 (1c) and -4 (1d) (Figure 1).7b In 2016, Stark and Adrian executed the first total synthesis of chatenaytrienin-4 (1d) by an iterative strategy for the stereodivergent

synthesis of unbranched 1,5,9,n-polyenes.10 With our continued interest in the synthesis of γ-lactone and butenolide natural products11 and also our recent synthesis of (+)-muricadienin,11a we became interested in the synthesis of chatenaytrienin-2 (1b). Herein, we disclose an efficient protecting-group-free first total synthesis of chatenaytrienin-2 based on C(sp)-C(sp3) Sonogashira coupling and ring-closing metathesis (RCM) as key steps.

Figure 1. Chatenaytrienins-1, -2, -3 and -4 (1a-d). Retrosynthetically, C(sp)-C(sp3) Sonogashira coupling and Lindlar reduction were planned from precursors, enediyne 2 and bromobutenolide 3, to lead to 1b as shown in Scheme 1. The ene-diyne 2 can be easily prepared using aldehyde from 4 by Wittig olefination. Alkylation of 6 would give 4. Esterification of acid 5 with chiral homoallyl alcohol and ring-closing metathesis (RCM) will give 3. Compound 5 can be prepared from 10-bromodecan-1-ol (7) through oxidation and -methylenation. The chatenaytrienins 1a-d have the common (Z,Z,Z)-1,5,9-triene system and the terminal butenolide moiety. The difference lies in the spacers between the olefin bond and the butenolide unit and also the terminal alkyl chain. The synthetic strategy adopted here is quite flexible in that compound 7 could be of different carbon chain length. Also the alkylhalo compound for

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alkylation of 6 can be varied. Thus, the strategy can eventually lead to the synthesis of all chatenaytrienins. Scheme 1. Retrosynthesis of chatenaytrienin-2 (1b)

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-methelenic acid 5 in 73% yield over three steps. Acid 5

was then esterified with the chiral alcohol 9 under Steglich conditions,14 which afforded ester 11 in 91% yield. Compound 11 on ring-closing metathesis using the Grubbs-II catalyst (20 mol%) delivered 3 in 88% yield, similar to our earlier report.11a However, when Hoveyda−Grubbs-II catalyst was used, the bromobutenolide 3 was obtained in 93% yield, requiring 10 mol% of the catalyst. The ene-diyne 2 was prepared as shown in Scheme 3. Alkylation of commercially available compound 6 with 1-bromododecane provided the alkynol 4 in 84% yield. The Wittig salt 12 was prepared from the same compound 6, by first converting alcohol to iodide and then reaction with triphenylphosphine. Further oxidation of alcohol 4 to aldehyde and reaction with the ylide from 12 resulted in the ene-diyne 2 in 76% yield over two steps (E/Z = 5:95, by NMR). The strategy demonstrates the dual use of alkyne 6 to obtain both, the alcohol 4 and also the Wittig salt 12. Scheme 3. Synthesis of ene-diyne 2

The synthesis of 1b began with the preparation of bromobutenolide 3 as shown in Scheme 2. Styryl methyl ketone 8 was prepared on gram scale in 98% yield by Wittig olefination between benzaldehyde and 1-(triphenylphosphoranylidene)-2-propanone.12 Compound 8 was reduced following literature procedure reported by Corey to afford 9 in 95% yield and 97% ee.13 Oxidation of 10-bromodecan-1-ol (7) using Dess−Martin periodinane to the corresponding aldehyde and subsequent Mannich condensation with formaldehyde furnished -methelenic aldehyde 10. Further oxidation of aldehyde 10 under Pinnick conditions provided Scheme 2. Synthesis of bromobutenolide 3

The completion of the total synthesis of 1b was accomplished as shown in Scheme 4. The key C(sp)-C(sp3) Sonogashira coupling15 between ene-diyne 2 and bromobutenolide 3 was executed using previously optimized Sonogashira coupling conditions in our muricadienin synthesis.11a Thus, the reaction of 2 with 3 using [PdCl(allyl)]2 (2.5 mol%) and ligand 13 (5 mol%) in the presence of CuI (7.5 mol%) as additive and Cs2CO3 (1.4 equiv) as base in Et2O/DMF (2:1) as solvent at 45 C furnished the coupled product 14. Compound 14 however was not stable enough to be characterized. Surprisingly, we observed the presence of only one olefinic proton in the 1H NMR (excluding the butenolide proton). Similarly, the 13C NMR showed the presence of only three peaks for the olefinic carbons though there should be 4 carbons corresponding to two olefin bonds (including the butenolide bond).16 Hence we considered using the crude product for the next step of Lindlar reduction. Thus, after the coupling of compound 2 with 3, the reaction mixture was filtered through a small pad of Celitesilica gel and the pad washed with EtOAc/petroleum ether (19:1). The filtrate was concentrated and the residue was subjected to Lindlar reduction using Pd/CaCO3 and quinoline under H2 (3 atm) to provide cleanly chatenaytrienin-2 (1b) in 59% overall yield from 3. Chatenaytrienin-2 (1b)

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The Journal of Organic Chemistry and chatenaytrienin-4 (1d) have the same core units, (1,5,9)-triene and the butenolide. The difference lies in the chain lengths of the terminal alkyl group and the spacer between the double bond and the butenolide. Thus, the part spectra (both 1H and 13C NMR) of 1b completely coincides with that of 1d10 (see spectra in Supporting Information for comparison). The isolation paper7b for chatenaytrienins have not characterized these molecules fully as they were obtained as mixtures of 1a + 1b and then 1c + 1d. Thus, the total synthesis gains significance in these natural product synthesis and biological evaluation. Scheme 4. Completion of the total synthesis of chatenaytrienin-2 (1b)

In summary, in this paper we have executed an efficient, convergent and protecting-group-free first total synthesis of chatenaytrienin-2 (1b) using ring-closing metathesis, (Z)-selective Wittig olefination, C(sp)-C(sp3) Sonogashira coupling, and Lindlar reduction as key steps. The synthesis is completed in 7 linear steps from 7 with 36.5% overall yield. The strategy is flexible that the synthesis of other chatenaytrienins can be achieved by varying the alkyl chain carbons in the materials used.

EXPERIMENTAL SECTION General information. Solvents were dried by using standard procedures. Thin-layer chromatography was performed on EM 250 Kieselgel 60 F254 silica gel plates. The spots were visualized by staining with KMnO4 or by using a UV lamp. 1H-NMR and 13C-NMR were recorded with a spectrometer operating at 400 or 500 and 100 or 125 MHz for proton and carbon nuclei, respectively. The chemical shifts are based on the CHCl3 peak at  = 7.26 ppm for proton NMR

and the CDCl3 peak at  = 77.00 ppm (t) for carbon NMR. IR spectra were obtained on an FT-IR spectrometer by evaporating compounds dissolved in CHCl3 on CsCl pellete. HRMS (ESI-TOF) spectra were recorded using positive electrospray ionization by the TOF method. Optical rotations were measured with a Rudolph polarimeter using the sodium D line (589 nm). (S,E)-4-Phenylbut-3-en-2-ol (9).13 To a solution of (E)-4phenylbut-3-en-2-one 8 (50 mg, 0.342 mmol, azeotropically dried with toluene) in toluene (0.5 mL) was added (S)-(−)2-butyl-CBS-oxazaborolidine (CBS reagent, 0.2M in toluene, 0.26 mL, 0.052 mmol, 15 mol%) at –78 C and subsequently catecholborane (62.4 mg, 0.52 mmol) was then added directly into the rapidly stirred heterogeneous reaction mixture and the mixture was allowed to stir for 20 h at –78 C. It was then quenched with MeOH (1 mL) and the solution was warmed gradually to 25 C. Volatiles were evaporated and the residue was dissolved in EtOAc (10 mL). The organic layer was washed with brine (2 × 5 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography with petroleum ether/EtOAc (4:1) as an eluent to provide alcohol 9 (48.1 mg, 95%, 97% ee) as colorless oil. [α]D25 = −30.1 (c = 2.0, CHCl3), lit.17 [α]D25 = −29.2 (c = 2, CHCl3); IR (CHCl3) υmax = 3389, 3371, 3023, 2967, 2926, 2890, 1657, 1493, 1448, 1410, 1360, 1304, 1142, 1061, 1029, 966, 937, 876, 753, 692 cm–1; 1H NMR (400 MHz, CDCl3) δ = 7.41−7.36 (m, 2H), 7.32 (td, J = 6.2, 1.5 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 16.0 Hz, 1H), 6.27 (dd, J = 15.9, 6.4 Hz, 1H), 4.50 (quint., J = 6.4 Hz, 1H), 1.70 (br s, 1H), 1.38 (d, J = 6.3 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 136.6, 133.5, 129.4, 128.6, 127.6, 126.4, 68.9, 23.4 ppm. HRMS (ESI-TOF) m/z: [M + K]+ Calcd for C10H12OK 187.0520; Found: 187.0519. 10-Bromo-2-methylenedecanoic acid (5). To a solution of 10-bromodecan-1-ol 7 (237.2 mg, 1.0 mmol) in dry CH2Cl2 (15 mL) was added Dess–Martin periodinane (636.2 mg, 1.5 mmol, 1.5 equiv) in portions at 0 C and the reaction mixture allowed to stir for 2 h at room temperature. It was then treated with sat. aq. solutions of Na2S2O3·5H2O (3 mL) and NaHCO3 (3 mL) and stirred for 20 min. The solution was extracted with CH2Cl2 (3  20 mL). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated to afford the desired aldehyde (253 mg) that was taken for the next step without further purification. To the solution of the crude aldehyde (253 mg) in CH2Cl2 (8 mL) were added pyrrolidine (14.2 mg, 0.2 mmol, 0.20 equiv) and propionic acid (14.8 mg, 0.2 mmol, 0.20 equiv). The mixture was stirred for 5 min at 0 °C and then 37% aq. formaldehyde (0.24 mL, 3.0 mmol, 3.0 equiv) was added dropwise and the mixture stirred for 6 h at room temperature. CH2Cl2 (20 mL) was added and the organic layer separated and washed with water, brine, dried (Na2SO4) and concentrated to afford 10-bromo-2-methylenedecanal 10 (269 mg), which was directly taken for the next step. To a solution of crude 10 (269 mg) in t-BuOH (6 mL) was sequentially added cyclohexene (411 mg, 5.0 mmol, 5 equiv), a solution of NaClO2 (136 mg, 1.5 mmol, 1.5 equiv) and NaH2PO4·2H2O (214 mg, 1.2 mmol, 1.2 equiv) in H2O (6 mL) at 10 C. The pale-yellow reaction mixture was stirred



for 4 h at room temperature. The solution was extracted with EtOAc (3  25 mL). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography with petroleum ether/EtOAc (7:3) as an eluent to afford 5 (192.1 mg, 73% over three steps) as a sticky solid. IR (CHCl3) υmax = 2928, 2855, 1696, 1627, 1439, 1282, 1212, 1161, 949, 917, 758, 733, 648, 566 cm-1. 1H NMR (400 MHz, CDCl3) δ = 6.28 (d, J = 1.1 Hz, 1H), 5.64 (d, J = 2.0 Hz, 1H), 3.40 (t, J = 6.9 Hz, 2H), 2.29 (t, J = 7.7 Hz, 2H), 1.85 (quint., J = 6.9 Hz, 2H), 1.55–1.37 (m, 4H), 1.35–1.26 (m, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 172.6, 140.2, 126.9, 34.0, 32.8, 31.4, 29.2, 29.0, 28.6, 28.3, 28.1 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H20 BrO2 263.0641; Found 263.0643. (S,E)-4-Phenylbut-3-en-2-yl 10-bromo-2-methylenedecanoate (11). To a stirred solution of 5 (40 mg, 0.152 mmol, 1.0 equiv) in dry CH2Cl2 (2 mL) were added N,N’-dicyclohexylcarbodiimide (DCC, 37.6 mg, 0.182 mmol, 1.2 equiv) and DMAP (5.6 mg, 0.046 mmol, 0.3 equiv) at 0 C. The mixture was stirred for 10 min and then a solution of (S,E)-4-phenylbut-3-en-2-ol 9 (45 mg, 0.304 mmol, 2.0 equiv) in dry CH2Cl2 (1 mL) was added dropwise at 0 C. The reaction mixture was stirred for an additional 5 h at room temperature. It was then filtered through a cotton plug and the plug washed with CH2Cl2 (5 mL). The filtrate was washed with water, brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (20:1) as an eluent to afford 11 (54.4 mg, 91%) as colorless oil. [α]D25 = –25.1 (c = 1.3, CHCl3); IR (CHCl3) υmax = 2930, 2856, 1715, 1627, 1449, 1303, 1170, 1144, 1041, 965, 946, 812, 749, 693, 648 cm-1; 1H NMR (500 MHz, CDCl3) δ = 7.38 (d, J = 7.2 Hz, 2H), 7.31 (d, J = 7.3 Hz, 2H ), 7.26−7.22 (m, 1H), 6.62 (d, J = 16.0 Hz, 1H), 6.22 (dd, J = 6.7, 16.0 Hz, 1H), 6.16 (d, J = 1.3 Hz, 1H), 5.64–5.55 (m, 1H), 5.52 (d, J = 1.3 Hz, 1H), 3.39 (t, J = 6.9 Hz, 2H), 2.31 (t, J = 7.7 Hz, 2H), 1.83 (quint, J = 7.1 Hz, 2H), 1.51– 1.38 (m, 7H), 1.35–1.28 (m, 6H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ = 166.6, 141.3, 136.4, 131.4, 128.9, 128.6, 127.9, 126.6, 124.3, 71.1, 34.0, 32.8, 31.8, 29.2, 29.1, 28.7, 28.4, 28.1, 20.4 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H29BrO2Na 415.1243; Found 415.1248. (S)-3-(3-Bromooctyl)-5-methylfuran-2(5H)-one (3). To a stirred and degassed solution of ester 11 (50 mg, 0.127 mmol) in dry CH2Cl2 (10 mL) was added Hoveyda−Grubbs second-generation catalyst (8.0 mg, 0.0127 mmol, 10 mol%) at room temperature and the mixture was refluxed for 30 h. The mixture was then cooled and filtered through a small pad of silica gel and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using petroleum ether/EtOAc (5:1) as an eluent to provide bromobutenolide 3 (34.2 mg, 93%) as colorless semi-solid. [α]D25 = +16.3 (c = 0.7, CHCl3); IR (CHCl3) νmax = 2926, 2857, 1756, 1456, 1320, 1202, 1122, 1076, 1025, 953, 861, 760 cm−1; 1H NMR (500 MHz, CDCl3) δ = 6.98 (d, J = 1.4 Hz, 1H), 4.99 (qd, J = 6.8, 1.7 Hz, 1H), 3.40 (t, J = 6.9 Hz, 2H), 2.28–2.22 (m, 2H), 1.84 (quint., J = 6.9 Hz, 2H), 1.54 (quint., J = 7.7 Hz, 2H), 1.44–1.38 (m, 5H), 1.36–1.29 (m, 6H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ = 173.9, 148.9, 134.2, 77.4, 34.0, 32.7, 29.04, 29.00, 28.6, 28.0, 27.3,

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25.1, 19.2 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H21BrO2Na 311.0617; Found 311.0613. Heptadec-4-yn-1-ol (4). To a stirred solution of 4-pentyn1-ol 6 (841 mg, 10 mmol, 2.0 equiv) in dry THF (20 mL) and HMPA (6 mL) was added dropwise n-BuLi (13.8 ml, 1.6M, 22 mmol, 4.4 equiv) at −78 C. The reaction mixture was then stirred for 30 min at same temperature. To this mixture was added dropwise 1-bromododecane (1.246 g, 5 mmol, 1.0 equiv) dissolved in THF (5 mL). The reaction mixture was then stirred for 12 h and then quenched with sat. aq. solution of NH4Cl (20 mL). The solution was extracted with Et2O (3  30 mL). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography with petroleum ether/EtOAc (9:1) as an eluent to give heptadec-4-yn-1-ol 48 (1.060 g, 84%) as sticky white solid. IR (CHCl3) υmax = 3428, 2982, 2211, 1613, 1510, 1497, 1467, 1370, 1315, 1229, 1152, 1123, 1025, 909, 821, 783, 750, 631 cm-1; 1H NMR (400 MHz, CDCl3) δ = 3.73 (t, J = 6.1 Hz, 2H), 2.26 (tt, J = 6.9, 2.5 Hz, 2H), 2.11 (tt, J = 7.1, 2.9 Hz, 2H), 1.72 (quint., J = 6.4 Hz, 2H), 1.45 (quint., J = 7.7 Hz, 2H), 1.37–1.20 (m, 18H), 0.86 (t, J = 6.7 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 81.1, 79.2, 62.0, 31.9, 31.6, 29.63, 29.60, 29.5, 29.3, 29.1, 29.0, 28.9, 22.6, 18.7, 15.4, 14.1 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H33O 253.2526; Found 253.2527. Pent-4-yn-1-yltriphenylphosphonium iodide (12). To a solution of 4-pentyn-1-ol 6 (1.0 g, 11.89 mmol) in dry CH2Cl2 (20 mL) were added sequentially PPh3 (3.743 g, 14.27 mmol, 1.2 equiv), imidazole (0.971 g, 14.27 mmol, 1.2 equiv) and iodine (3.622 g, 14.27 mmol, 1.2 equiv) at 0 C. The reaction mixture was stirred for 4 h at room temperature. It was then treated with sat. aq. solution of Na2S2O3.5H2O (15 mL) and stirred for further 10 min. The organic layer was separated and the aqueous layer extracted with CH2Cl2 (2  20 mL). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated to half its volume and then passed through a small silica gel column (10 cm) and washed with petroleum ether (50 mL). The filtrate was concentrated until 5-10 mL of petroleum ether remained (concentrations of fractions was done at low temperature and pressure considering the volatility of iodoalkyne). To this was added PPh 3 (3.743 g, 14.27 mmol, 1.2 equiv) and benzene (20 mL). The mixture was refluxed for 10 h. The phosphonium salt 12 precipitated out as white solid. The mixture was concentrated and the phosphonium salt formed was washed with dry THF (3  10 mL) under nitrogen atmosphere (to remove excess PPh3), vacuum dried and was used directly for next reaction (5.42 g). (Z)-Docosa-5-en-1,9-diyne (2). To a solution of heptadec-4yn-1-ol 4 (252.4 mg, 1 mmol, 1.0 equiv) in CH2Cl2 (5 mL) was added Dess–Martin periodinane (636.2 mg, 1.5 mmol, 1.5 equiv) in portions at 0 C and the reaction mixture was allowed to stir for 4 h at room temperature. It was then treated with sat. aq. solution of Na2S2O3·5H2O (3 mL) and NaHCO3 (3 mL) and stirred for 20 min. The solution was extracted with CH2Cl2 (3  20 mL). The combined organic layers were washed with water, brine, dried (Na2SO4) and


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The Journal of Organic Chemistry concentrated to afford the corresponding aldehyde (231 mg) that was used for next step directly. To a solution of pent-4-yn-1-yltriphenylphosphonium iodide 12 (502 mg, 1.1 mmol, 1.1 equiv) in dry THF (10 mL) under nitrogen atmosphere was added NaHMDS (1.1 mL, 1M solution in THF, 1.1 mmol, 1.1 equiv) drop wise at –78 °C and stirred for 1 h. To the orange colored suspension, pre-dissolved solution of crude heptadec-4-ynal (231 mg) in THF (10 mL) was added drop wise. After 12 h, the reaction mixture was quenched with sat. aq. solution of NH4Cl. The solution was extracted with EtOAc (3  20 mL). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography with petroleum ether as an eluent to afford (Z)-docosa-5-en-1,9-diyne 2 (228.4 mg, 76%) as colorless oil. IR (CHCl3) υmax = 3010, 2926, 2854, 2318, 2253, 1464, 1380, 1319, 1122, 1087, 1027, 910, 766, 732, 649 cm-1; 1H NMR (500 MHz, CDCl3) δ = 5.56−5.44 (m, 2H), 2.34−2.17 (m, 8H), 2.13 (tt, J = 7.1, 2.2 Hz, 2H), 1.95 (t, J = 2.6 Hz, 1H), 1.47 (quint., J = 6.9 Hz, 2H), 1.37−1.23 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ = 129.8, 128.6, 84.1, 80.7, 79.5, 68.4, 31.9, 29.7, 29.6, 29.55, 29.3, 29.2, 29.1, 28.9, 27.1, 26.4, 22.7, 19.1, 18.8, 18.7, 14.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H37O 317.2839; Found 317.2842. Chatenaytrienin-2 (1b). To a solution of 1,3-bis(1-adamanthyl)benzimidazolium chloride 13 (2.3 mg, 0.0055 mmol, 5 mol%), CuI (1.57 mg, 0.0083 mmol, 7.5 mol%), [PdCl(π-allyl)]2 (1.0 mg, 0.0028 mmol, 2.5 mol %), and Cs2CO3 (50.5 mg, 0.1548 mmol, 1.4 equiv) in a mixture of dry Et2O/DMF (2:1, 1.0 mL) in a sealed tube was added a solution of enediyne 2 (59.8 mg, 0.199 mmol, 1.8 equiv) in a mixture of dry Et2O and DMF (0.5 mL) followed by the solution of bromolactone 3 (32 mg, 0.1106 mmol, 1.0 equiv) in a mixture of dry Et2O and DMF (0.5 mL). The tube was then sealed with a teflon lined cap and the reaction mixture was stirred vigorously at 45 °C for 20 h. The crude reaction mixture was filtered through a small pad of Celite-silica gel and the pad washed using petroleum ether/EtOAc (19:1) as an eluent. The filtrate was concentrated under vacuum to afford 14 (78 mg) that was used in next reaction. To the solution of 14 (78 mg) in absolute MeOH (2 mL) was added Lindlar catalyst Pd/CaCO3 (26.1 mg of 5% Pd on CaCO3 poisoned with lead) and quinoline (21.4 mg, 0.166 mmol, 1.5 equiv). The reaction mixture was stirred under H2 (3 atm) for 3 h at 40 C. After complete consumption of the starting material, the crude reaction mixture was filtered through a small pad of Celite-silica gel and the filtrate concentrated. The residue was purified by silica gel column chromatography with petroleum ether/EtOAc (19:1) as an eluent to afford 1b (33.5 mg, 59% over two steps) as a colorless waxy solid. []D25 = +15.8 (c = 0.5, CHCl3); IR (CHCl3) νmax = 3007, 2925, 2853, 1759, 1654, 1464, 1376, 1318, 1217, 1200, 1119, 1073, 1027, 968, 858, 757, 722, 665 cm1; 1H NMR (500 MHz, CDCl3) δ = 6.97 (d, J = 1.4 Hz, 1H), 5.44– 5.33 (m, 6H), 4.99 (qd, J = 6.8, 1.6 Hz, 1H), 2.26 (t, J= 7.9 Hz, 2H), 2.14–2.05 (m, 8H), 2.05–1.97 (m, 4H), 1.54 (quint., J = 7.5 Hz, 2H), 1.40 (d, J = 6.8 Hz, 3H), 1.34–1.24 (m, 30H), 0.88 (t, J = 6.9 Hz, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) δ = 173.9, 148.8, 134.3, 130.4, 130.3, 129.63, 129.6, 129.1,

129.06, 77.4, 31.9, 29.7, 29.68, 29.6, 29.56, 29.4, 29.35, 29.32, 29.3, 29.25, 29.2, 27.4, 27.39, 27.36, 27.3, 27.2, 25.2, 22.7 ppm. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C35H61O2 513.4666; Found 513.4666.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: 1H and 13C NMR spectra (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ORCID Rodney A. Fernandes: 0000-0001-8888-0927

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank SERB New Delhi, Grant No. EMR/2017/000499 for financial support. RAK thank the University Grants Commission of India (UGC) for research fellowship.

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A Protecting-Group-Free Total Synthesis of Chatenaytrienin-2 | The

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