Collective total synthesis of botryanes

Accepted Manuscript Collective total synthesis of botryanes Chuang Qiao, Wen Zhang, Jing-Chun Han, Wei-min Dai, Chuang-Chuang Li PII:

S0040-4020(18)31359-0

DOI:

https://doi.org/10.1016/j.tet.2018.11.019

Reference:

TET 29930

To appear in:

Tetrahedron

Received Date: 15 October 2018 Revised Date:

8 November 2018

Accepted Date: 9 November 2018

Please cite this article as: Qiao C, Zhang W, Han J-C, Dai W-m, Li C-C, Collective total synthesis of botryanes, Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.11.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Collective Total Synthesis of Botryanes ,

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Chuang Qiao,† # Wen Zhang,†,‡ # Jing-Chun Han,† Wei-min Dai‡ and Chuang-Chuang Li*,† †

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Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055, China ‡

Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China * Corresponding author: [email protected]

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# These authors contributed equally to this work.

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Graphical Abstract

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Abstract

Keywords

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The collective total synthesis of a series of botryanes, which are an important group of sesquiterpene antibiotics isolated from the metabolites of the fungus Botrytis cinerea, has been reported. The highly functionalized hydrindane skeleton of the botryanes was efficiently synthesized via an unusual intramolecular Diels-Alder reaction, which was promoted by TsOH as a protic acid. The concise total synthesis of (± ±)-hypocrolide A with a challenging hexacyclic skeleton was accomplished in 8 steps from the readily available starting materials.

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Intramolecular Diels-Alder reaction; botryanes; hypocrolide A; collective total synthesis

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ACCEPTED MANUSCRIPT 1. Introduction

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The botryanes (1–8) are a series of sesquiterpene antibiotics,1 which were originally derived from the metabolites of the fungus Botrytis cinerea.2 Most of the compounds belonging to this novel structural class are based on a unique hydrindane skeleton, which does not obey the simple isoprene rule.3,4 Hypocrolide A (9), an unusual botryane metabolite, was isolated by Che et al.5 in 2013. From a structural perspective, hypocrolide A possesses a sterically compact 5/6/6/5/6/6-fused hexacyclic skeleton, including a highly substituted 3,6dihydro-2H-pyran and a dihydrofuran unit. This compound also contains six stereocenters, including two quaternary centers, and therefore represents a significant synthetic challenge. The botryanes have been reported to show a variety of interesting biological activities.6 For example, botrydial (1) is the primary phytotoxic metabolite produced by Botrytis cinerea as a hypersensitive response (HR) inducer,7a and has been reported to shows significant antibiotic activity against Bacillus subtilis7b and Pythium debaryanum,4 as well as high levels of cytotoxicity against a series of human cancer cell lines.7c With only 2.7 mg (0.006 mmol) available, hypocrolide A has been reported to exhibit moderate cytotoxicity against human tumor cell lines compared with cisplatin.5 However, the relative scarcity of hypocrolide A from natural resources likely have been impediments to a more systematic evaluation of its biological activity. Taken together, the fascinating structural motifs and promising pharmacological properties of botryanes have attracted considerable interest from chemists working in a variety of different areas, which have resulted in many interesting investigations, including chemical transformations,7c structure-activity relationships,7b biosynthesis3,8 and synthetic studies.9 In 2016, we have reported the first and catalytic enantioselective total synthesis of hypocrolide A using an unusual rhodium-catalyzed intramolecular [4+2] cycloaddition.10 In our continuing efforts towards the synthesis of biologically active natural products,11 herein, we describe a concise total synthesis of (±)hypocrolide A and the collective synthesis of a series of other botryane compounds. The key synthetic strategy described in this study features an unusual intramolecular Diels-Alder reaction, which was promoted by TsOH as a protic acid.

Figure 1. Hypocrolide A and Other Botryanes.

2. Results and discussion

Retrosynthetically, (±)-hypocrolide A (9) could be generated from coumarin 10 and (±)-10-oxodihydrobotry-1(9),4(5)-diendial (4) via a (3+2) oxidative cycloaddition reaction.10 Compound 4 could itself be synthesized from the substituted hydrindane 11 via a lactonization reaction and double bond migration process. In turn, compound 11 could be formed from 12 via an intramolecular Diels-Alder (IMDA) reaction.12 Last, dienyne 12 could be derived from the known compound 13.9b Synthetically, botrydial (1), 10-oxodehydrodihydrobotrydial (5) and several other botryanes could be constructed collectively from 11 according to a series of simple functional group transformations.

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Figure 2. Retrosynthetic Analysis of (±)-Hypocrolide A and Other Botryanes.

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Our synthesis began with the preparation of dienyne (±)-12 (Scheme 1). The known acetylene-aldehyde (±)-139b reacted cleanly with Wittig reagent 14 to give the desired Z,E-diene (±)-15 in 91% yield (6.0 g scale). The subsequent treatment of (±)-15 with lithium diisopropylamide (LDA, 16) and ClCO2Me (17) afforded the 1,3,8-dienyne (±)-12 in good yield (5.2 g scale). With (±)-12 in hand, we proceeded to investigate our proposed IMDA reaction to synthesize the 5-6 bicyclic system of the botryanes (Scheme 1). Unfortunately, this reaction did not occur in refluxing toluene. Interestingly, however, when the reaction was carried out in the presence of p-toluenesulfonic acid (TsOH) in toluene at 100 °C, compound 12 readily underwent tandem IMDA, deprotection and lactonization reactions to afford (±)-18 and (±)-19 in a 1:1 mixture of compounds, which could be readily separated by flash column chromatography (83% combined yield on 11.4 g scale). Interestingly, tricycle (±)-19, which is a C2-epimer of (±)-4, was observed as the product of a double bond migration reaction. The structure of (±)-18 was determined by 2D-NMR. In contrast, the expected product (±)-20 was not found, which indicated that the Z,E-diene (±)-12 had undergone an isomerization reaction to give the more stable E,E-diene prior to the cycloaddition reaction under acidic conditions with heating. These results showed that TsOH play a variety of different roles as a protic acid to catalyze the IMDA reaction,13 to remove of the benzyl group, to mediate the lactonization and to promote the double bond isomerization and migration steps. Using the route described above, we succeeded in the facile synthesis of 12.0 g of (±)-18, thereby highlighting the robust nature of the chemistry.

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Scheme 1. Synthesis of Compounds (±)-18 and (±)-19.

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Next, we proceeded to investigate the synthesis of a series of botryanes from (±)-18 and (±)-19 (Scheme 2). Compound (±)-18 underwent a chemoselective double bond migration in the presence of DBU to give (±)-10-oxodihydrobotry-1(9),4(5)-diendial (4)14a in 86% yield. The subsequent treatment of (±)-4 with LiAlH4, followed by the Swern oxidation of the resulting alcohol, gave (±)-botrydienal (3)14b,c in 67% overall yield. In meanwhile separate experiment, compound 19 underwent a dehydrogenation in the presence of DDQ to generate (±)-10-oxodehydrodihydro-botrydial (5)14b in 92% yield. The subsequent reduction and oxidation of (±)-5 gave (±)dehydrobotrydienol (6)6a and (±)-dehydrobotrydienal (7)14b in 85% and 87% yields, respectively. The 1H and 13C NMR spectra of 3–7 were identical to those of the natural products.

Scheme 2. Collective Synthesis of (±)-Botryanes 3–7.

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Having successfully prepared the α,β β ,γ,δ-unsaturated lactone ((±)--4), we continued towards the final stage of the total synthesis of (±)hypocrolide A according to previous procedure.10 The oxidative (3+2) cycloaddition reaction of (±)-4 and 10 with 3.0 equiv. of CAN was performed in acetic acid in the presence of 1.5 equiv. of Cu(OAc)2. These conditions provided the cycloaddition products (±)-22 and (±)21 as a 2.6:1 mixture in 65% yield. The sequential reduction and oxidation of (±)-22 provided dialdehyde (±)-23 in 78% overall yield. The subsequent treatment of (±)-23 with TFA in DCM/MeOH led to the removal of the PMB group and the formation of dimethoxy-dihydro2H-pyran moiety to give (±)-hypocrolide A (9) and (±)-C1,2-diepi-hypocrolide A (24) as a 1:1 mixture in an overall yield of 61%. The 1H and 13C NMR spectra for the newly synthesized (±)-hypocrolide A were identical to those of the natural product.5 Interestingly, the treatment of (±)-24 with TFA in DCM and MeOH led to (±)-9 in 84% brsm yield.

3. Conclusion

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Scheme 3. Total Synthesis of (±)-Hypocrolide A.

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In summary, we have achieved the collective total synthesis of a series of botryanes, which are an important family of sesquiterpenes derived from the metabolites of the fungus Botrytis cinerea. The highly functionalized hydrindane system of botryanes was constructed efficiently via an unusual IMDA reaction mediated by TsOH. The concise total synthesis of (±)-hypocrolide A proceeded in 8 steps from the readily available aldehyde (±)-13. We believe that this strategy will provide a platform for the straightforward and collective synthesis of other botryanes and their analogs to facilitate further biological research.

4. Experimental section General Information Unless otherwise mentioned, all reactions were carried out under a nitrogen atmosphere under anhydrous conditions and all reagents were purchased from commercial suppliers without further purification. Solvent purification was conducted according to Purification of Laboratory Chemicals (Peerrin, D. D.; Armarego, W. L. and Perrins, D. R., Pergamon Press: Oxford, 1980). Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise stated. Reactions were monitored by Thin Layer Chromatography on plates (GF254) supplied by Yantai Chemicals (China) using UV light as visualizing agent, an ethanolic solution of phosphomolybdic acid, or basic aqueous potassium permanganate (KMnO4), and heat as developing agents. If not specially mentioned,

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ACCEPTED MANUSCRIPT flash column chromatography uses silica gel (200-300 mesh) supplied by Tsingtao Haiyang Chemicals (China), Preparative thin layer chromatography (PTLC) separations were carried out 0.50 mm Yantai (China) silica gel plates. NMR spectra were recorded on Bruker AV500, Bruker ARX400 and Bruker AV300 instruments. and calibrated using residual undeuterated solvent as an internal reference (CHCl3, δ 7.26 ppm 1H NMR, δ 77.00 13C NMR). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, b = broad, m = multiplet. High-resolution mass spectra (HRMS) were recorded on a Bruker Apex IV FTMS mass spectrometer using ESI (electrospray ionization). Infrared spectra were recorded on a Shimadzu IR Prestige 21, using thin films of the sample on KBr plates. Optical rotations were measured with a Rudolph autopol I automatic polarimeter using 10 cm glass cells with a sodium 589 nm filter.

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Synthesis of 15

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To a suspension of (E)-but-2-en-1-yltriphenylphosphonium bromide 14 (28.0 g, 70.7 mmol, 3.0 equiv) in anhydrous THF (250 mL) at -78 °C was added dropwise n-butyllithium (2.5 M in hexane, 28.3 mL, 3.0 mmol, 3.0 equiv). The reaction mixture was stirred for 0.5 h at the same temperature, and then the reaction device was transferred into an ice-water bath and the reaction mixture was stirred for another 0.5 h. Aldehyde (±)-139b (6.0 g, 23.3 mmol, 1.0 equiv) was dissolved in anhydrous THF (40 mL) and injected dropwise into the reaction system. Finally, the reaction was gradually warmed to room temperature for 1h. A saturated aqueous solution of NH4Cl (50 mL) was added and the mixture was extracted with Et2O (3 × 200 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 100/1) to give (±)-15 (6.2 g, 91% yield) as a colorless oil. Rf = 0.3 (100% hexane); IR (film) λmax 3302, 2924, 2862, 2330, 1767, 1450, 1373, 1242, 1096, 949, 733, 694, 635; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.27 (m, 5H), 6.60 – 6.46 (m, 1H), 5.75 (t, J = 11.9 Hz, 1H), 5.58 (dq, J = 13.5, 6.7 Hz, 1H), 5.30 (d, J = 12.1 Hz, 1H), 4.56 (s, 2H), 3.35 (q, J = 8.7 Hz, 2H), 2.16 (s, 1H), 1.82 (d, J = 14.3 Hz, 1H), 1.77 – 1.73 (m, 3H), 1.67 (d, J = 14.3 Hz, 1H), 1.31 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 138.8, 138.5, 130.1, 128.3, 128.1, 127.5, 127.4, 126.8, 90.1, 78.3, 73.2, 70.5, 50.3, 37.9, 35.7, 31.2, 31.0, 26.3, 18.3; HRMS (ESI) calcd for C21H28NaO [M+Na]+ Exact Mass: 319.2032; found: 319.2032.

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Synthesis of 12

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A solution of LDA (2.0 M in THF, 11.2 mL, 22.3 mmol, 1.3 equiv) was added dropwise to a stirred solution of (±)-15 (5.2 g, 17.6 mmol, 1.0 equiv) in dry THF (300 mL) at -78 °C and the reaction mixture was stirred for 30 min. Then the reaction device was transferred into an ice-water bath and the reaction mixture was stirred for another 0.5 h. Methyl carbonochloridate (2.7 mL, 35.2 mmol, 2.0 equiv) was added, and the mixture was allowed to warm to ambient temperature in 1 h. A saturated aqueous solution of NH4Cl (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 15/1) to give (±)-12 (5.4 g, 88% yield) as a light-yellow oil. Rf = 0.7 (hexane/ethyl acetate = 10/1); IR (film) λmax 3803, 3726, 3626, 2924, 2862, 2322, 2229, 1721, 1589, 1450, 1250, 1103; 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.28 (m, 5H), 6.59 – 6.47 (m, 1H), 5.79 (t, J = 11.9 Hz, 1H), 5.60 (dq, J = 16.7, 6.7 Hz, 1H), 5.26 (d, J = 12.1 Hz, 1H), 4.56 (d, J = 1.9 Hz, 2H), 3.75 (s, 3H), 3.40 (q, J = 8.8 Hz, 2H), 1.90 (d, J = 14.3 Hz, 1H), 1.77 (dd, J = 6.7, 1.4 Hz, 3H), 1.72 (d, J = 14.3 Hz, 1H), 1.34 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.2, 138.1, 137.8, 130.4, 128.3, 128.1, 127.8, 127.5, 127.2, 94.4, 77.1, 75.0, 73.1, 52.4, 49.8, 37.7, 36.0, 31.1, 30.9, 25.3, 18.3; HRMS (ESI) calcd for C23H30NaO3 [M+Na]+ Exact Mass: 377.2087; found: 377.2088. Synthesis of 18 and 19

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toluene 100oC, 24h 83%

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Compound (±)-12 (11.4 g, 32.2 mmol, 1.0 equiv) and TsOH-H2O (5.5 g, 32.2 mmol, 1.0 equiv) were dissolved in toluene (600 mL) under nitrogen atmosphere and the solution was heated to 100 °C for 24 h. When the reaction was cooled to room temperature, the mixture was neutralized with a saturated aqueous solution of NaHCO3 (100 mL), extracted with ethyl acetate (3 × 200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1) to give (±)-18 (3.02 g, 40.7% yield) as a light-yellow oil and (±)-19 (3.14 g, 42.3%) as a light-yellow solid. Note: Using the described route, a total of 12.0 g of 18 was prepared readily after four simple parallel operations. Compound 18 Rf = 0.5 (hexane/ethyl acetate = 5/1); IR (film) λmax 3742, 3626, 2955, 2870, 1721, 1573, 1458, 1366, 1242, 1049; 1H NMR (400 MHz, CDCl3) δ 5.79 – 5.67 (m, 1H), 5.60 – 5.50 (m, 1H), 4.04 (dd, J = 26.9, 10.4 Hz, 2H), 3.16 (ddd, J = 10.0, 4.8, 2.5 Hz, 1H), 3.05 – 2.86 (m, 1H), 1.52 (dd, J = 43.1, 13.8 Hz, 2H), 1.25 (s, 3H), 1.19 (s, 3H), 1.16 (d, J = 7.1 Hz, 3H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.6, 162.1, 133.7, 121.4, 119.7, 76.9, 49.7, 48.3, 41.2, 37.6, 29.2, 28.6, 25.0, 23.5, 20.7. HRMS (ESI) calcd for C15H21O2 [M+H]+ Exact Mass: 233.1536; found: 233.1535. Compound 19 Rf = 0.35 (hexane/ethyl acetate = 5/1); IR (film) λmax 3742, 3618, 2924, 1712, 1574, 1381, 1381, 1242, 1157, 1040; 1H NMR (400 MHz, CDCl3) δ 5.73 (t, J = 4.2 Hz, 1H), 4.19 (d, J = 10.1 Hz, 1H), 4.00 (d, J = 10.2 Hz, 1H), 2.72 – 2.60 (m, 1H), 2.55 (ddd, J = 19.1, 9.3, 3.8 Hz, 1H), 2.24 (dt, J = 19.1, 4.4 Hz, 1H), 1.68 (d, J = 12.8 Hz, 1H), 1.44 (d, J = 12.9 Hz, 1H), 1.39 (s, 3H), 1.25 (s, 3H), 1.16 (s, 3H), 1.15 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.0, 160.3, 144.8, 124.0, 118.3, 78.5, 50.2, 42.9, 38.4, 33.2, 30.5, 29.9, 25.2, 23.7, 21.3; HRMS (ESI) calcd for C15H21O2 [M+H]+ Exact Mass: 233.1536; found: 233.1535.

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Synthesis of 4

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Compound (±)-18 (2.8 g, 12.1 mmol, 1.0 equiv) and DBU (5.4 mL, 36.3 mmol, 3.0 equiv) were added in anhydrous toluene (250 mL) under nitrogen atmosphere and the solution was heated to 120 °C for 20 h. The reaction mixture was cooled to room temperature, and neutralized with a saturated aqueous solution of NH4Cl (50 mL), extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 15/1) to give (±)-10-oxodihydrobotry-1(9),4(5)-diendial 4 (2.4 g, 86% yield) as a lightyellow solid. Rf = 0.45 (hexane/ethyl acetate = 5/1); IR (film) λmax 2924, 2862, 1712, 1458, 1381, 1203, 1003; 1H NMR (300 MHz, CDCl3) δ 5.73 (dd, J = 6.4, 2.6 Hz, 1H), 4.22 (d, J = 10.3 Hz, 1H), 3.99 (d, J = 10.3 Hz, 1H), 2.90 – 2.71 (m, 1H), 2.61 (ddd, J = 17.5, 9.8, 2.6 Hz, 1H), 2.25 (dd, J = 17.6, 6.4 Hz, 1H), 1.73 (d, J = 13.1 Hz, 1H), 1.52 (d, 1H), 1.36 (s, 3H), 1.28 (s, 3H), 1.18 (s, 3H), 0.88 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.2, 158.8, 145.8, 121.4, 119.8, 78.6, 51.0, 41.7, 38.9, 31.7, 31.0, 31.0, 23.1, 23.0, 17.9; HRMS (ESI) calcd for C15H21O2 [M+H]+ Exact Mass: 233.1536; found: 233.1539. Synthesis of 3a

To a solution of (±)-10-oxodihydrobotry-1(9), 4(5)-diendial 4 (140 mg, 0.60 mmol, 1.0 equiv) in Et2O (60 mL) at 0 °C was added LiAlH4 (34mg, 0.90 mmol, 1.5 equiv). After being stirred at 0 °C for 2h, the reaction was quenched by dropwise addition of a sodium hydroxide solution (3M, 6 mL). The mixture was filtered through a celite pad and wash with Et2O (2 x 50 mL). The organic layers were dried over

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ACCEPTED MANUSCRIPT anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to give (±)-3a (129 mg, 93% yield) as a colorless oil. Rf = 0.2 (hexane/ethyl acetate = 3/1); IR (film) λmax 3618, 2924, 2855, 1751, 1458, 1373, 1242, 1041; 1H NMR (400 MHz, CDCl3) δ 5.35 (dd, J = 5.3, 3.2 Hz, 1H), 4.32 (d, J = 11.4 Hz, 1H), 4.17 (d, J = 11.4 Hz, 1H), 3.63 (d, J = 11.2 Hz, 1H), 3.51 (d, J = 11.2 Hz, 1H), 2.41 – 2.29 (m, 2H), 2.04 – 1.95 (m, 1H), 1.93 (d, J = 13.2 Hz, 1H), 1.44 (d, J = 13.2 Hz, 1H), 1.23 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H), 1.05 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.3, 141.1, 134.1, 114.0, 70.2, 61.9, 53.0, 46.9, 38.7, 32.7, 31.6, 31.0, 30.7, 25.7, 18.8; HRMS (ESI) calcd for C15H22NaO2 [M+Na]+ Exact Mass: 257.1512; found: 257.1521. Synthesis of botrydienal 3 O

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Oxalyl chloride (0.15 mL, 1.8 mmol, 2.3 equiv) was added to a flask containing dichloromethane (20 mL) at -78 oC. Then methyl sulfoxide (0.21 mL, 3.0 mmol, 3.8 equiv) was added. After the reaction mixture was stirred at the same temperature for 0.5 h, the diol (±)3a (190 mg, 0.8 mmol, 1.0 equiv) in dichloromethane (10 mL) was slowly added. After stirring at -78oC for another 0.5 h, the mixture was treated with triethylamine (0.75 mL, 5.3 mmol, 6.6 equiv). The solution was stirred at -78 oC for 0.5 h, and then was allowed to warm to room temperature. This reaction was quenched with an aqueous solution of HCl (3 M, 10 mL), extracted with dichloromethane (3 x 30 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 15/1) to give (±)-botrydienal 3 (89 mg, 72% yield) as a colorless oil. Rf = 0.6 (hexane/ethyl acetate =10/1); IR (film) λmax 1766, 1573, 1348, 1242, 1049, 748; 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 9.66 (s, 1H), 5.87 (dd, J = 6.3, 2.8 Hz, 1H), 2.94 – 3.01 (m, 1H), 2.45 (ddd, J = 18.5, 8.7, 2.8 Hz, 1H), 2.24 (d, J = 13.6 Hz, 1H), 2.16 – 2.22 (m, 1H), 1.64 (d, J = 13.6 Hz, 1H), 1.52 (s, 3H), 1.25 (s, 3H), 1.05 (s, 3H), 0.91 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 199.9, 189.8, 155.3, 149.5, 135.9, 123.78, 56.4, 50.5, 40.4, 3.58, 30.6, 28.7, 25.3, 24.2, 18.3; HRMS (ESI) calcd for C15H20NaO2 [M+Na]+ Exact Mass: 255.1356; found: 255.1354.

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Synthesis of 5

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(±)-19 (50 mg, 0.21 mmol, 1.0 equiv) and DDQ (95 mg, 0.42 mmol, 2.0 equiv) were dissolved in anhydrous toluene (30 mL) under nitrogen atmosphere and the solution was heated to 120 °C for 12 h. When it was cooled to room temperature, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1) to give (±)-10-oxodehydro-dihydro-botrydial 5 (46 mg, 92% yield) as a light-yellow solid. Rf = 0.45 (hexane/ethyl acetate = 10/1); IR (film) λmax 2963, 1759, 1728, 1581, 1458, 1373, 1242, 1064; 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 4.36 (d, J = 10.1 Hz, 1H), 4.13 (d, J = 10.1 Hz, 1H), 2.62 (s, 3H), 2.08 (s, 2H), 1.98 (d, J = 12.9 Hz, 1H), 1.86 (d, J = 12.9 Hz, 1H), 1.51 (s, 3H), 1.45 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.0, 151.4, 147.0, 139.6, 131.7, 127.4, 119.6, 79.2, 52.0, 45.1, 40.8, 30.8, 30.7, 24.7, 20.3; HRMS (ESI) calcd for C15H19O2 [M+H]+ Exact Mass: 231.1380; found: 231.1378. Synthesis of 6

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ACCEPTED MANUSCRIPT To a solution of (±)-10-oxodehydro-dihydro-botrydial 5 (30 mg, 0.13 mmol, 1.0 equiv) in Et2O (20 mL) at 0 °C was added LiAlH4 (10 mg, 0.23 mmol, 2.0 equiv). After being stirred at 0 °C for 1 h, the reaction was quenched by dropwise addition of of an aqueous sodium hydroxide solution (3 M, 3 mL). The mixture was filtered through a Celite pad and wash with Et2O (2 x 10 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to give (±)-dehydrobotrydienol 6 (25 mg, 85% yield) as a colorless oil. Rf = 0.3 (hexane/ethyl acetate = 3/1); IR (film) λmax 3302, 2924, 2862, 1759, 1581, 1373, 1458, 1250, 980, 756. 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 4.76 (q, J = 11.5 Hz, 2H), 3.94 (d, J = 11.4 Hz, 1H), 3.64 (d, J = 11.4 Hz, 1H), 2.43 (s, 3H), 2.21 (d, J = 13.1 Hz, 1H), 2.08 (s, 2H), 1.79 (d, J = 13.1 Hz, 1H), 1.39 (s, 3H), 1.30 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 152.3, 144.07, 136.37, 134.4, 130.5, 123.0, 71.0, 58.7, 54.0, 50.3, 40.8, 32.2, 31.1, 26.3, 18.9; HRMS (ESI) calcd for C15H22NaO2 [M+Na]+ Exact Mass: 257.1512; found: 257.1512.

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Synthesis of 7

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Oxalyl chloride (21 µl, 0.25 mmol, 2.3 equiv) was added to a flask containing dichloromethane (20 mL) at -78 oC. Then methyl sulfoxide (30 µl, 0.42 mmol, 3.8 equiv) was added to this solution. After stirring at the same temperature for 0.5 h, the (±)-dehydrobotrydienol 6 (25 mg, 0.11 mmol, 1.0 equiv) in dichloromethane (8 mL) was slowly added. After stirring at -78oC for another 0.5 h, the mixture was treated with triethylamine (0.10 ml, 0.73 mmol, 6.6 equiv). The solution was stirred at -78 oC for 0.5 h, and then was allowed to warm to room temperature. This reaction was quenched with an aqueous solution of HCl (3 M, 10 mL), extracted with dichloromethane (3 x 30 mL). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 15/1) to give (±)-dehydrobotrydienal 7 (22 mg, 87% yield) as a colorless oil. Rf = 0.6 (hexane/ethyl acetate =10/1); IR (film) λmax 1759, 1705, 1581, 1249, 756; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.60 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.8, 0.5 Hz, 1H), 2.68 (s, 3H), 2.20 (d, J = 13.5 Hz, 1H), 1.87 (d, J = 13.5 Hz, 1H), 1.55 (s, 3H), 1.34 (s, 3H), 1.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.9, 191.7, 153.4, 144.6, 141.2, 132.5, 129.7, 128.7, 57.9, 51.3, 42.4, 31.4, 30.6, 22.0, 19.2; HRMS (ESI) calcd for C15H19O2 [M+H]+ Exact Mass: 231.1380; found: 231.1376. Acknowledgments

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This work was supported by the Natural Science Foundation of China (Grant nos. 21472081, 21522204, and 21672095), Guangdong Science and Technology Department (2016A050503011), the Shenzhen Science and Technology Innovation Committee (Grant nos. JCYJ20170412152454807 and JSGG20160301103446375), the Shenzhen Nobel Prize Scientists Laboratory Project (C17783101) and Project KQTD2016053117035204 supported by Shenzhen Peacock Plan.

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