Stereoselective Synthesis of (+)-Annuionone A and (−)-Annuionone B

Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People's Republic o...
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Stereoselective Synthesis of (+)-Annuionone A and (−)-Annuionone B Lizhen Jiang, Xiaojing Liu, Po Yuan, Yanli Zhang, and Xiaochuan Chen* Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China S Supporting Information *

ABSTRACT: A stereoselective synthetic approach was utilized to synthesize enantiopure annuionones A (1b) and B (2b), two ionone-type norsesquiterpenoids that both bear a 6oxabicyclo[3.2.1]octane framework and possess allelopathic activity. A stereoselective Diels−Alder reaction based on chiral trisubstituted dienophile 20 was employed to obtain the optically active polysubstituted cyclohexane core of both natural products. Using this approach, (+)-annuionone A (1b) and (−)-annuionone B (2b) were synthesized from lactol (+)-15 in 10% overall yield.

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he annuionones, a bioactive ionone subtype of norsesquiterpenoids and sesquiterpenoids, belong to a class of apocarotenoids that are produced mainly by the catabolism of carotenoids.1 In 1998, Macias and co-workers isolated annuionones A and B from Helianthus annuus L. (sunflower) var. SH-222 and VYP, respectively, and showed that both compounds possessed significant allelopathic activity and selectivity, suggesting that these compounds were good candidates as potential herbicide templates.2 The structures of annuionones A and B were initially proposed to be 5,11-exooxirane bisnorsesquiterpenoids 1a and 2a (Figure 1). Four years later, annuionone E (3a), the 9-hydroxy derivative of annuionone A, was also isolated from H. annuus L. cv. Peredovick by Macias and co-workers.3 Subsequently, the structural assignments for annuionones A, B, and E were corrected via a combination of total synthesis 4 and comprehensive spectroscopic studies 5 to the 6oxabicyclo[3.2.1]octanes 1b−3b, respectively. In 2005, annuionone H (4), possessing the same bicyclic core, was isolated from H. annuus L. cv. Suncross-42 by Anjum and co-workers.6 Bioassay results showed that 3b and 4 had potent plant growth inhibition activity and they could be used for developing new herbicides. The 6-oxabicyclo[3.2.1]octane skeleton of the annuionones was also present in related apocarotenoids and their glucosides, such as tanarifuranonol (5),7 ascleposides (6− 8),8 and macarangioside F (9).9 The unique structures and important bioactivity of these bicyclic apocarotenoids make them attractive targets for total synthesis. In 2003, Takikawa and co-workers achieved the first synthesis of (±)-annuionone A permitting the structural assignment revision from 1a to 1b.4 Their synthesis strategy featured the reductive alkylation of 3,5-dimethoxybenzoic acid and the stereoselective crotylation of cyclohexenone. Takikawa’s group also determined the absolute configuration of naturally occurring 1b as (1S,5R,6R) by optical resolution of a racemic secondary alcohol intermediate via the corresponding © 2017 American Chemical Society and American Society of Pharmacognosy

Figure 1. Ionone-type sesquiterpenoids containing the 6oxabicyclo[3.2.1]octane core.

diastereomeric Mosher’s ester.10 In 2005, Hsieh and Liao reported the syntheses of (±)-annuionone B and (±)-tanarifuranonol by employing an intramolecular Diels−Alder reaction between a masked o-benzoquinone and a pendant 2methallyl ether as the key step in constructing the critical 6Received: June 8, 2016 Published: March 24, 2017 805

DOI: 10.1021/acs.jnatprod.6b00522 J. Nat. Prod. 2017, 80, 805−812

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oxabicyclo[3.2.1]octane core.11 A stereoselective strategy for the synthesis of these enantiopure oxabicyclic apocarotenoids, however, has yet to be reported. As part of a continuing studies on the enantioselective synthesis of natural products via chiral dienophile-induced Diels−Alder reactions,12 we herein report the first stereoselective approach to synthesize optically active annuionones A and B. Both natural products were generated in 10% yield from L-erythrosedimethylketal [(+)-15].

Scheme 2. Preparation of Chiral Dienophile (−)-20

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RESULTS AND DISCUSSION The retrosynthetic analysis for 1b and 2b is illustrated in Scheme 1. It was envisioned that both natural products could Scheme 1. Retrosynthetic Analysis of Annuionones A and B

Scheme 3. Investigation of the Reaction of 20 with Dienes 21 and 24

be accessed from aldehyde 10. The critical 6-oxabicyclo[3.2.1]octane core of 10, could be constructed via an intramolecular oxy-Michael addition from cyclohexenone 11. A series of functional group conversions could generate cyclohexenone 11 from the polysubstituted cyclohexene 12. Synthesis of cyclohexene 12, which contains a stereogenic quaternary carbon, represented the key step in the synthetic strategy. Specifically, the plan relied on the stereoselective generation of 12 via an intermolecular Diels−Alder cycloaddition between appropriately substituted diene 13 and homochiral dienophile 14, the latter of which could be constructed readily from commercially available carbohydrates. Following this strategy, the synthesis began with the preparation of chiral dienophile from protected L-erythrose (+)-15.13 Wittig olefination of (+)-15 with (carboethoxyethylidene)triphenylphosphorane (16)14 in the presence of benzoic acid resulted in the target E-conjugated ester (−)-17 with excellent stereoselectivity. Subsequent hydrolysis of the 1,3-dioxolane moiety in (−)-17 afforded triol 18, the terminal 1,2-diol moiety of which was selectively protected to generate acetonide (−)-19. Oxidation of the secondary alcohol functionality with the Dess−Martin periodinane15 led to the α,β-unsaturated ketone (−)-20 (Scheme 2). With enone (−)-20 in hand, a series of diastereoselective intermolecular Diels−Alder reactions between this dienophile and several oxo-dienes were investigated (Scheme 3). 4Methoxy-2-trimethylsiloxypenta-1,3-diene (21)16 was first tested in the Diels−Alder reaction with (−)-20 aimed at generating cycloadduct 22. Various thermal and Lewis acidcatalyzed conditions were screened to achieve the cycloaddition, albeit without success. Unexpectedly, the Mukaiyama Michael addition adduct 23 was produced when ZnCl2 was utilized as a catalyst. The Diels−Alder reaction between 20 and

Danishefsky’s diene (24)17 also failed to produce the target cycloadduct 25 under all conditions explored. It is worth noting that the reaction between (−)-20 and 24 in the presence of ZnCl2 afforded 26 as a single isomer, presumably via a tandem hetero-Diels−Alder cycloaddition/elimination process instead of the Michael addition pathway observed in the formation of ketone 23. Gratifyingly, heating a mixture of 1-(trimethylsilyloxy)-1,3butadiene (27) and (−)-20 at 140 °C in toluene gave the target cycloadduct (+)-28 as the major product (32% yield) in addition to a complex mixture of several other unidentified cycloaddition adducts. Under these conditions, dienophile (−)-20 partially isomerized to the exo-methylene analogue 29. This isomerization product, also reacted with diene 27, resulting in the cycloaddition adduct 30 in 13% yield (Scheme 4). Although not important for the overall synthesis of 1b and 2b, the relative configuration of the silyloxy-bearing C-1 in 806

DOI: 10.1021/acs.jnatprod.6b00522 J. Nat. Prod. 2017, 80, 805−812

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(+)-28, albeit with the increased amounts of 30 and a complex mixture of other unidentified products (entry 2). Increased reaction times or higher temperatures both led to decreased yields, likely due to the deterioration of the starting materials and products (entries 3 and 4). The concentration of reactants also exerted a noticeable influence on the reaction, with better results being obtained upon increasing the concentration (entries 5 and 6). The best results were obtained when the reaction was performed in the absence of solvent for 20 h at 140 °C (entry 7). Either longer or shorter reaction times resulted in decreased yields (entries 8 and 9); under these various thermal conditions, although there was no significant change in the ratio of major product 28 and the concomitant byproducts. Conversely, utilizing Lewis acids commonly employed as catalysts for the Diels−Alder reaction failed to promote the cycloaddition between diene 27 and dienophile (−)-20 (entries 10−15). The only product observed in these cases was the occasional isomerization of 20 to the corresponding exo-methylene analogue 29 (entries 12−14). After identifying conditions to provide useful quantities of the cyclohexene (+)-28, advancing this key intermediate toward the synthesis of 1b and 2b was further investigated (Scheme 5). Simultaneous reduction of the keto- and ester carbonyl groups in (+)-28 with DIBAL afforded a 4:1 mixture of diastereoisomeric diols (+)-33a and (+)-33b, together with a small amount of the desilylated product 34. The absolute configurations of the secondary alcohol functionalities in (+)-33a and (+)-33b were not assigned as they were not important for the overall synthetic strategy. Only the pure major isomer (+)-33a was carried through in subsequent reactions. Concomitant removal of the TMS group, hydrolysis of the acetonide, and oxidative cleavage of the resulting glycol with periodic acid18 resulted in a mixture of aldehyde 35 and cyclic hemiacetals 36. Without further separation, this mixture was treated with NaBH4 to generate triol (+)-37 in 80% yield over the two steps. Alternatively, the monoacetate 38, available from selective acetylation of the primary alcohol moiety in (+)-33a, could be converted into triol (+)-37 in improved overall yield following a similar two-step oxidative cleavage/reduction process via intermediate aldehyde 39. Following the same procedures as applied to (+)-33a, diastereomer (+)-33b and triol 34 were also converted into (+)-37 in comparable yields. In order to simplify the process, triol (+)-37 was prepared in 71% overall yield from (+)-28 following a sequential three-step manipulation that used only one chromatographic purification. The two primary hydroxy groups in (+)-37 were selectively protected with TBSCl, and the resulting bis-silyl ether (+)-40 was oxidized to the corresponding α,β-unsaturated ketone (+)-41 using the Dess−Martin periodinane. Although enone (+)-41 was resistant to nucleophilic attack by MeMgBr, 1,2addition of MeLi to (+)-41 occurred smoothly with high stereoselectivity to give tertiary alcohol (+)-42. Even though the resulting tertiary alcohol was generated as a single diastereomer, the absolute configuration of this stereogenic center was not important to the overall synthetic plan and was thus not assigned. Dauben−Michno oxidative rearrangement19 of allylic alcohol (+)-42 with pyridinium chlorochromate afforded the transposed enone (+)-43 in 92% yield. After TBAF-mediated removal of both TBS protecting groups in (+)-43, concomitant intramolecular oxa-Michael addition established the target 6-oxabicyclo[3.2.1]octane framework. The reaction afforded a chromatographically inseparable mixture of ketone 44 and hemiketal 45 (ca. 2.7:1 ratio based

Scheme 4. Synthesis of (+)-28 and Determination of Relative Configuration

(+)-28 was assigned by NMR spectroscopic analysis of cyclohexane 31 generated via catalytic hydrogenation of the cyclohexene 28. In the 1H NMR spectrum of 31, the large H-3 coupling constant (dt, J = 10.4, 5.6 Hz) indicates its axial orientation in the chair conformation. The small J value (d, J = 5.6 Hz) resulting from the axial−equatorial coupling of H-4 with H-3 indicated that the substituted cyclohexane 31 had a 3,4-cis arrangement. It is assumed that the ketocarbonyl group of dienophile (−)-20 preferably occupied the endo position during cyclocondensation. This is consistent with the configuration of the known cycloadduct 32, an intermediate in the synthesis of infectocaryone that was also produced via a Diels−Alder reaction between diene 27 and a dienophile similar to 20.12 The absolute configuration of (+)-28 was assigned as (3S, 4R, 5R) on the basis of comparison with the related trisubstituted cyclohexene 32, and it was subsequently confirmed by the transformation of (+)-28 into the natural products. The formation of the major cycloadduct (+)-28 with the appropriate stereochemistry is shown in Figure 2.

Figure 2. Preferred steric approach in the cycloaddition of (−)-20 and 27.

Subsequently, the reaction conditions for the Diels−Alder cycloaddition between (−)-20 and 27 were further examined in order to improve the yield of (+)-28 (Table 1). When the reagents were combined in toluene and heated to 110 °C, the cycloaddition proceeded sluggishly, resulting in significant double bond migration and low yields of the target cycloadduct (+)-28 (entry 1). Incrementally increasing the temperature by 30 °C facilitated the reactions and improved the yield of 807

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Table 1. Reaction Conditions for the Cycloaddition Between (−)-20 and 27a

entry

concentration of 20 (M)

27 (equiv)

solvent

time (h)

catalyst

x (equiv)

temperature (°C)

yield of (+)-28 (%)

yield of 30 (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0.1 0.1 0.1 0.1 0.5 1 ---0.1 0.1 0.1 0.1 0.1 0.1

5 5 5 5 5 5 3 3 3 5 5 5 5 5 5

PhCH3 PhCH3 PhCH3 Ph(CH3)2 PhCH3 PhCH3 --d --d --d CH2Cl2 CH2Cl2 PhCH3 CH2Cl2 PhCH3 Et2O

36 22 32 20 20 20 20 26 15 10 10 6 18 18 10

---------Yb(OTf)3 Sc(OTf)3 Eu(fod)3 Et2AlCl Et2AlCl ZnCl2

---------0.05 0.05 0.03 2 2 2

110 140 140 160 140 140 140 140 140 10 10 110 10 10 10

20 (14b) 32 (7b) 30 25 37 43 52 43 40 (6b) 0 (82b) 0 (71b) 0 (50b) 0 (45b) 0 (48b) 0

10 (10c) 14 (5c) 13 11 15 16 15 14 13 (5c) 0 0 0 (22c) 0 (29c) 0 (23) 0

a The reactions were heated in sealed tubes, and the heating temperature refers to the bath temperature. bRecovered (−)-20. cRecovered 29. dThe reaction was performed with neat (−)-20 and 27.

All spectroscopic and spectrometric data ([α]D, NMR, IR, and MS) for the synthesized products 1b and 2b were in good accord with the data reported for natural annuionones A and B, respectively.2,10,11 The specific rotation data confirmed the absolute configuration of the 3,4,5,5-tetrasubstituted cyclohexene core in the major Diels−Alder product (+)-28 as (3S, 4R, 5R). Given that the enantiomer of the starting hemiacetal (−)-15 is readily available and inexpensive,22 the enantiomers of the naturally occurring annuionones, ent-1b and ent-2b, may also be synthesized by employing this practical synthetic route. In summary, we have developed the first stereoselective approach to synthesize several enantiopure ionone-type norsesquiterpenoids bearing a 6-oxabicyclo[3.2.1]octane framework. The key stereoselective Diels−Alder cycloaddition was achieved by employing the homochiral trisubstituted dienophile (−)-20 to afford the optically active polysubstituted cyclohexene (+)-28. The stereogenic isopropylidene-protected diol unit in (−)-20, which is readily converted into the requisite functionality later in the synthesis, induces stereoselectivity in the critical cycloaddition. Using this approach, natural (+)-annuionone A (1b) and (−)-annuionone B (2b) were synthesized from lactol (+)-15 in 10.2% and 10.7% overall yields, respectively. This simple and practical process is amenable to synthesizing both enantiomeric series of the bicyclic annuionones, depending on which enantiomer of lactol 15 is employed, thus allowing for subsequent structure−activity relationship studies.

Scheme 5. Transformation of 28 to Triol 37

on the 1H NMR spectrum). Dess−Martin periodinane oxidation of the mixture afforded the oxo-aldehyde 10. Given the relative instability of oxo-aldehyde 10, it was subjected to the olefination procedure without purification. The Horner− Wadsworth−Emmons olefination of 10 with diethyl (2oxopropyl)phosphonate,11,20 however, failed. A chemoselective Wittig olefination of aldehyde 10 with 1(triphenylphosphanylidene)propan-2-one21 resulted in the formation of annuionone B (2b) in 79% over two steps. Conversion of 2b into annuionone A (1b) was accomplished nearly quantitatively via catalytic hydrogenation of the alkene moiety (Scheme 6).

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured on a Rudolph AUTOPOL V polarimeter, and they are reported as follows: [α]TD (c: g/100 mL, in solvent). IR spectra were recorded on a Thermo NEXUS 670 spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker DRX-400 MHz NMR spectrometer with TMS as the internal standard and were calibrated using residual undeuterated solvent as an internal reference (CHCl3: 808

DOI: 10.1021/acs.jnatprod.6b00522 J. Nat. Prod. 2017, 80, 805−812

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Scheme 6. Syntheses of (+)-Annuionone A and (−)-Annuionone B

H NMR = δH 7.26, 13C NMR = δC 77.16). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling constants (J) are reported in Hz. HRMS spectra were recorded using a Shimadzu LCMS-IT-TOF spectrometer, and MeOH or CH2Cl2 was used to dissolve the samples. Flash chromatography was performed using silica gel (200−300 mesh). Reactions were monitored by TLC. Visualization was achieved under a UV lamp at 254 nm. Solvents were distilled prior to use: CH2Cl2, xylene, and toluene from CaH2, THF and Et2O from Na. MeOH was distilled from Mg and acetone from K2CO3. Other reagents were obtained from commercial suppliers unless otherwise stated. α,β-Unsaturated Ester (−)-17. To a solution of compound (+)-15 (17.37 g, 0.109 mol) in dry PhCH 3 (543 mL), (carboethoxyethylidene)triphenylphosphorane (16) (59 g, 0.164 mol) and benzoic acid (437.5 mg, 3.6 mmol) were added sequentially at room temperature (rt). The resulting mixture was refluxed for 10 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc = 5:1) to give (E)-α,β-unsaturated ester(−)-17 (23.58 g, 89%) as a colorless oil; [α]22D − 30 (c 0.7, CHCl3); IR (neat) νmax 3448, 2985, 2935, 1712, 1652, 1455, 1376, 1318, 1247, 1217, 1046 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.69 (1H, dd, J = 8.4, 1.6 Hz), 4.98 (1H, t, J = 7.6 Hz), 4.34 (1H, td, J = 6.8, 4.4 Hz), 4.26−4.10 (2H, m), 3.60−3.45 (2H, m), 2.24 (1H, brs), 1.87 (3H, d, J = 1.2 Hz), 1.51 (3H, s), 1.39 (3H, s), 1.27 (3H, t, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 167.1, 135.9, 131.2, 109.4, 78.5, 73.9, 61.9, 61.0, 27.8, 25.2, 14.2, 13.2; HRMS (ESITOF) m/z 267.1208 [M + Na]+ (calcd for C12H20O5Na, 267.1207). Alcohol (−)-19. E-Conjugated ester (−)-17 (2.44 g, 10 mmol) was dissolved in a mixture of MeOH (100 mL), H2O (15 mL), and HCl (5 mL), and the resulting solution was stirred for 1 h at rt. The mixture was neutralized with anhydrous NaHCO3, and the solvents were removed by evaporation under reduced pressure. The residue was purified by chromatography (CH2Cl2/MeOH = 10:1) to afford the corresponding triol 18 as a colorless oil. Triol 18 was dissolved in anhydrous acetone (100 mL), then 2,2-dimethoxypropane (2.5 mL, 20 mmol) and p-toluenesulfonic acid (86.1 mg, 0.5 mmol) were added. The solution was stirred for 40 min at rt, and the solvents were removed by evaporation under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aq NaHCO3. The organic phase was separated, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography (petroleum ether/EtOAc = 5:1) to afford acetonide (−)-19 (1.95 g, 80%, for 2 steps) as a colorless oil; [α]20D − 2 (c 1.1, CHCl3); IR (neat) νmax 3445, 2986, 2923, 1713, 1375, 1247, 1112, 1067, 1023, 851, 755 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.56 (1H, dq, J = 8.6, 1.2 Hz), 4.57−4.49 (1H, m), 4.22−4.11 (2H, m), 4.08 (1H, m), 3.98 1

(1H, dd, J = 8.2, 6.8 Hz), 3.92 (1H, dd, J = 8.2, 6.4 Hz), 2.66−2.53 (1H, m), 1.88 (3H, d, J = 1.2 Hz), 1.40 (3H, s), 1.32 (3H, s), 1.26 (3H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 167.5, 138.0, 131.3, 109.5, 77.5, 68.5, 65.1, 60.9, 26.3, 25.0, 14.2, 13.3; HRMS (ESITOF) m/z 267.1208 [M + Na]+ (calcd for C12H20O5Na, 267.1207). Enone (−)-20. Dess−Martin periodinane (19.1 g, 45 mmol) was added to a solution of acetonide (−)-19 (10 g, 41 mmol) in CH2Cl2 (410 mL), and the resulting white suspension was stirred for 1 h at rt. Saturated aq NaHCO3 was added until the solids were dissolved. The aqueous phase was separated and extracted with CH2Cl2 (3 × 400 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to flash column chromatography (petroleum ether/EtOAc = 10:1) to yield unsaturated ketone (−)-20 (8.9 g, 90%) as a bright-yellow oil; [α]21D − 45 (c 0.7, CHCl3); IR (neat) νmax 3381, 2987, 1720, 1685, 1377, 1259, 1110, 1059, 837 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38 (1H, q, J = 1.6 Hz), 4.50 (1H, dd, J = 7.6, 5.0 Hz), 4.27−4.17 (3H, m), 4.04 (1H, dd, J = 8.8, 5.0 Hz), 2.22 (3H, d, J = 1.6 Hz), 1.46 (3H, s), 1.37 (3H, s), 1.30 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 200.7, 167.3, 144.1, 127.7, 111.3, 80.7, 66.5, 61.7, 26.0, 25.2, 14.7, 14.1; HRMS (ESI-TOF) m/z 265.1052 [M + Na]+ (calcd for C12H18O5Na, found 265.1050). Diels−Alder Adduct (+)-28. In a sealed tube, ketone (−)-20 (2.00 g, 8.26 mmol) and diene 27 (4.3 mL, 24.5 mmol) were stirred at 140 °C for 20 h. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/EtOAc = 25:1) to yield (+)-28 (1.64 g, 52%) as a pale-yellow oil; [α]20D + 53 (c 0.8, CHCl3); IR (neat) νmax 2986, 2956, 1720, 1382, 1375, 1251, 1085, 943, 883, 842, 750, 666 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.81−5.72 (1H, m), 5.69−5.58 (1H, m), 4.94− 4.84 (1H, m), 4.44 (1H, t, J = 6.8 Hz), 4.18−4.06 (4H, m), 3.91 (1H, d, J = 6.0 Hz), 2.34 (1H, brd, J = 17.6 Hz), 2.22 (1H, dm, J = 17.6 Hz), 1.46 (3H, s), 1.40 (3H, s), 1.32 (3H, s), 1.22 (3H, t, J = 7.2 Hz), 0.11 (9H, s); 13C NMR (100 MHz, CDCl3) δ 208.9, 176.8, 127.5, 126.8, 110.4, 80.7, 65.8, 65.6, 60.6, 52.2, 42.6, 35.2, 25.8, 25.2, 20.1, 13.9, 0.0; HRMS (ESI-TOF) m/z 407.1866 [M + Na] + (calcd for C19H32O6SiNa, 407.1863). Compounds 33a/b and 34. Compound (+)-28 (256 mg, 0.67 mmol) was dissolved in CH2Cl2 (7 mL) under an Ar atmosphere, cooled to −78 °C, and DIBAL-H (1 M in hexanes, 2.7 mL, 2.7 mmol) was added slowly. The reaction mixture was stirred for 1 h at −78 °C and then quenched with MeOH (1 mL) at −78 °C. Next a saturated aqueous sodium potassium tartrate solution (7 mL) was added, and the mixture was stirred for 6 h at rt. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column 809

DOI: 10.1021/acs.jnatprod.6b00522 J. Nat. Prod. 2017, 80, 805−812

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CDCl3) δ 5.80 (1H, dd, J = 10.0, 5.2 Hz), 5.73 (1H, br.d, J = 10.0 Hz), 4.76 (1H, br.s), 4.20−4.06 (3H, m), 4.05−3.94 (3H, m), 3.72 (1H, br.t, J = 10.0 Hz), 2.20 (1H, d, J = 17.6 Hz), 2.09 (1H, br.s), 2.02 (3H, d, J = 1.2 Hz), 1.76 (1H, dd, J = 17.6, 5.2 Hz), 1.37 (3H, s), 1.34 (3H, s), 1.25 (3H, s), 0.18 (9H, d, J = 1.2 Hz); 13C NMR (100 MHz, CDCl3) δ 170.3, 127.8, 126.3, 108.6, 75.9, 72.9, 69.3, 67.9, 67.7, 39.9, 36.8, 34.4, 26.3, 24.7, 20.2, 19.1, 0.0; HRMS (ESI-TOF) m/z 409.2022 [M + Na]+ (calcd for C19H34O6SiNa, 409.2020). Preparation of Triol (+)-37 from Monoacetate (+)-38. To a stirred solution of (+)-38 (93 mg, 0.24 mmol) in EtOAc (2.5 mL), was added H5IO6 (164 mg, 0.72 mmol), and the resulting suspension was stirred for 30 min at rt. The reaction mixture was filtered through Celite, and the filter cake was washed with EtOAc. The filtrate was washed with H2O, and the organic phase was separated. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with H2O and brine, and dried over anhydrous Na2SO4. Removal of the solvent in vacuo afforded the aldehyde 39 as a yellow oil, which was used in the next step without purification. To a solution of 39 in THF (2.4 mL) at 0 °C was added LiBH4 (2.0 M in THF, 0.5 mL, 1 mmol). The resulting mixture was stirred overnight at rt, followed by addition of MeOH (0.2 mL). The mixture was concentrated, and the residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH = 8:1) to yield triol (+)-37 (37.3 mg, 90%, for 2 steps) as a yellow oil. Bissilyl Ether (+)-40. To a solution of triol (+)-37 (26.3 mg, 0.15 mmol) and imidazole (31.2 mg, 0.45 mmol) in CH2Cl2 (0.8 mL), was added TBSCl (56.5 mg, 0.375 mmol) in one portion, and the resulting solution was stirred at rt for 5 h. Water (1 mL) was added, and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were dried and concentrated. The residue was purified by flash column chromatography (petroleum ether/EtOAc = 25:1) to yield silyl ether (+)-40 (55.1 mg, 90%) as a colorless oil; [α]20D + 59 (c 0.6, CHCl3); IR (neat) νmax 3473, 2955, 2929, 2887, 2857, 1620, 1471, 1463, 1389, 1361, 1256, 1094, 1071, 1006, 963, 939, 837, 775, 734, 666 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.87−5.76 (1H, m), 5.76−5.65 (1H, m), 4.45 (1H, s), 4.00−3.83 (2H, m), 3.41 (1H, d, J = 4.8 Hz), 3.27 (2H, dd, J = 22.0, 10.0 Hz), 2.10−1.99 (2H, m), 1.66 (1H, s), 1.63−1.53 (1H, m), 0.96 (3H, s), 0.89 (18H, d, J = 2.8 Hz), 0.08 (6H, d, J = 1.6 Hz), 0.03 (6H, s); 13C NMR (100 MHz, CDCl3) δ 128.7, 127.1, 69.4, 66.9, 61.5, 43.2, 36.3, 35.1, 25.9, 25.8, 19.9, 18.3, 18.1, −5.4, −5.5, −5.6, −5.6; HRMS (ESI-TOF) m/z 423.2727 [M + Na]+ (calcd for C21H44O3Si2Na, 423.2726). Cyclohexenone(+)-41. Dess−Martin periodinane (664 mg, 1.5 mmol) was added to a solution of silyl ether 40 (417.8 mg, 1 mmol) in CH2Cl2 (10 mL), and the resulting white suspension was stirred for 1 h at rt. Saturated aq NaHCO3 was added until the solids were dissolved. The aqueous phase was separated and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to flash column chromatography (petroleum ether/ EtOAc = 30:1) to yield α,β-unsaturated ketone (+)-41 (403.2 mg, 97%) as a yellow oil; [α]20D + 7 (c 0.7, CHCl3); IR (neat) νmax 3394, 2955, 2929, 2885, 2857, 1674, 1472, 1389, 1361, 1253, 1102, 1005, 837, 776, 666 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.79 (1H, dt, J = 10.0, 4.0 Hz), 5.99 (1H, dt, J = 10.0, 2.0 Hz), 3.97 (1H, dd, J = 10.4, 4.0 Hz), 3.91 (1H, dd, J = 10.8, 4.0 Hz), 3.45 (1H, d, J = 10.0 Hz), 3.31 (1H, d, J = 9.6 Hz), 2.41 (1H, ddd, J = 19.2, 4.4, 2.0 Hz), 2.34 (1H, dd, J = 3.6, 2.4 Hz), 2.28 (1H, t, J = 4 Hz), 1.03 (3H, s), 0.86 (9H, s), 0.84 (9H, s), 0.01 (3H, s), 0.00 (3H, s), −0.01 (6H, d, J = 1.6 Hz); 13C NMR (100 MHz, CDCl3) δ 201.3, 148.3, 129.2, 69.4, 61.6, 54.6, 40.4, 35.0, 25.9, 25.8, 20.4, 18.2, 18.1, −5.6, −5.7, −5.7; HRMS (ESI-TOF) m/z 421.2570 [M + Na]+ (calcd for C21H42O3Si2Na, 421.2569). Tertiary Alcohol(+)-42. MeLi (1.6 M in THF, 63 μL, 0.1 mmol) was added dropwise to a stirred solution of ketone (+)-41 (20.1 mg, 0.05 mmol) in THF (1 mL) at −78 °C under Ar. The resulting mixture was stirred at −78 °C for 1 h, saturated NH4Cl (1 mL) was added, and the resulting mixture was allowed to warm to rt. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×

chromatography (petroleum ether/EtOAc = 5:1 to 2:1) to yield diols (+)-33a (132 mg, 58%) and (+)-33b (32 mg, 14%), together with triol (+)-34 (30.2 mg, 15%); (+)-33a [α]20D + 73 (c 0.5, CHCl3); IR (neat) νmax 3463, 2984, 2955, 2927, 1621, 1382, 1371, 1254, 1217, 1152, 1071, 1052, 943, 880, 843, 753 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.83 (1H, ddd, J = 10.0, 5.2, 1.6 Hz), 5.60 (1H, br.d, J = 10.0 Hz), 4.77 (1H, brs), 4.37 (1H, d, J = 9.2 Hz), 4.17 (1H, dd, J = 8.2, 6.0 Hz), 4.11 (1H, m), 4.02 (1H, dd, J = 8.2, 4.8 Hz), 3.84 (1H, dt, J = 9.2, 2.0 Hz), 3.73 (1H, d, J = 11.2 Hz), 3.34 (1H, d, J = 11.2 Hz), 2.31 (1H, br.d, J = 17.6 Hz), 2.06 (1H, dd, J = 4.0, 2.4 Hz), 1.71 (1H, dd, J = 17.6, 4.8 Hz), 1.38 (3H, s), 1.34 (3H, s), 1.18 (3H, s), 0.17 (9H, s); 13C NMR (100 MHz, CDCl3) δ 128.5, 126.1, 108.7, 76.2, 72.8, 68.9, 67.7(x2), 40.0, 36.4, 35.6, 26.1, 24.7, 19.0, 0.0; HRMS (ESI-TOF) m/z 367.1917 [M + Na]+ (calcd for C17H32O5SiNa, 367.1915); (+)-33b [α]21D + 107 (c 0.8, CHCl3); IR (neat) νmax 3416, 3028, 2958, 1417, 1375, 1253, 1215, 1157, 1125, 1059, 869, 843, 801, 753, 703 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.81 (1H, ddd, J = 10.0, 5.2, 2.4 Hz), 5.63−5.56 (1H, m), 4.55 (1H, d, J = 5.2 Hz), 4.13 (2H, ddd, J = 11.2, 8.0, 1.2 Hz), 4.06 (1H, t, J = 7.4 Hz), 3.96 (1H, t, J = 7.2 Hz), 3.75 (1H, d, J = 4.8 Hz), 3.66 (1H, s), 3.51 (1H, dd, J = 6.8, 5.2 Hz), 2.49−2.30 (2H, m), 1.78−1.71 (1H, m), 1.43 (3H, s), 1.36 (3H, s), 0.67 (3H, s), 0.15 (9H, s); 13C NMR (100 MHz, CDCl3) δ 129.6, 125.8, 108.5, 76.8, 75.9, 70.6, 68.7, 65.4, 39.6, 35.0, 25.7, 25.6, 25.2, 14.4, 0.0; HRMS (ESI-TOF) m/z 367.1917 [M + Na]+ (calcd for C17H32O5SiNa, 367.1913); (+)-34 [α]21D + 28 (c 0.4, CHCl3); IR (neat) νmax 3395, 2986, 2929, 2885, 1653, 1456, 1429, 1378, 1256, 1217, 1154, 1068, 1036, 966, 848, 756, 564 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.86 (1H, ddd, J = 9.6, 5.2, 1.2 Hz), 5.78 (1H, dt, J = 10.0, 3.2 Hz), 4.68 (1H, s), 4.30 (1H, s), 4.26−4.20 (1H, m), 4.17 (1H, dd, J = 8.4, 6.4 Hz), 4.04 (1H, dd, J = 8.4, 4.8 Hz), 3.93 (1H, d, J = 6.0 Hz), 3.70 (1H, d, J = 10.8 Hz), 3.32 (1H, d, J = 11.2 Hz), 2.55 (1H, s), 2.32 (1H, dd, J = 17.6, 1.6 Hz), 2.12 (1H, s), 2.07 (1H, dd, J = 4.4, 2.4 Hz), 1.72 (1H, dd, J = 17.6, 5.2 Hz), 1.40 (3H, s), 1.34 (3H, s), 1.17 (3H, s); 13 CNMR (100 MHz, CDCl3) δ 129.4, 127.2, 109.5, 77.1, 73.3, 69.5, 68.0, 67.2, 41.0, 36.9, 36.2, 26.8, 25.3, 19.8; HRMS (ESI-TOF) m/z 295.1521 [M + Na]+ (calcd for C14H24O5Na, 295.1520). Triol (+)-37. H5IO6 (37 mg, 0.18 mmol) was added to a stirred solution of diol (+)-33a (19 mg, 0.06 mmol) in EtOAc (1.2 mL), and the resulting suspension was stirred for 30 min at rt. The reaction mixture was filtered through Celite, and the filter cake was washed with EtOAc. The filtrate was washed with H2O, and the organic phase was separated. The aqueous layer was extracted with EtOAc (3 × 10 mL); the combined organic extracts were washed with H2O and brine, and dried over anhydrous Na2SO4. Removal of the solvent in vacuo resulted in a mixture of aldehyde 35 and cyclic hemiacetals 36 as a yellow oil, which was carried on to the next step without further purification. The mixture of 35 and 36 was suspended in MeOH (1 mL), then NaBH4 (3.4 mg, 0.09 mmol) was added. The mixture was stirred at rt for 20 min and concentrated under reduced pressure. The residue was subjected to column chromatography (CH2Cl2/MeOH = 8:1) to yield triol (+)-37 (7.6 mg, 80%, for 2 steps) as a yellow oil; [α]20D + 105 (c 0.7, MeOH); IR (film) νmax 3381, 2917, 1592, 1473, 1423, 1116, 1043, 663 cm−1; 1H NMR (400 MHz, CD3OD) δ 5.76− 5.68 (2H, m), 4.37 (1H, m), 3.81 (2H, d, J = 6.4 Hz), 3.34 (1H, d, J = 11.2 Hz), 3.27 (1H, d, J = 11.2 Hz), 2.04−1.90 (2H, m), 1.67 (1H, dm, J = 17.2 Hz), 0.97 (3H, s); 13C NMR (100 MHz, CD3OD) δ 129.6, 128.5, 70.4, 67.5, 61.3, 46.2, 37.4, 36.0, 20.2; HRMS (ESI-TOF) m/z 195.0997 [M + Na]+ (calcd for C9H16O3Na, 195.0995). Monoacetate (+)-38. To a stirred solution of (+)-33a (328 mg, 1 mmol) in anhydrous CH2Cl2 (10 mL), Ac2O (0.14 mL, 1.5 mmol), pyridine (0.16 mL, 2 mmol), and DMAP (5 mg, 0.05 mmol) were added. When TLC showed complete conversion of the starting material, the reaction mixture was quenched with saturated aq NaHCO3 solution and extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc = 10:1) to yield (+)-38 (378 mg, 98%) as a colorless oil; [α]D 20 + 80 (c 0.7, CHCl3); IR (neat) νmax 3476, 2986, 2953, 2941, 1889, 1743, 1372, 1250, 1232, 1156, 1077, 1035, 977, 940, 879, 840, 667 cm−1; 1H NMR (400 MHz, 810

DOI: 10.1021/acs.jnatprod.6b00522 J. Nat. Prod. 2017, 80, 805−812

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2 day at rt and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 3:1) to give (−)-2b2,11 (25 mg, 79%, for 2 steps) as a colorless oil; [α]21D − 14 (c 0.3, CHCl3), {lit.2 [α]25D − 13.5 (c 0.1, CHCl3)}; IR (neat) νmax 3500, 2937, 2871, 1716, 1674, 1627, 1454, 1418, 1373, 1328, 1259, 1180, 1013, 818, 734, 634 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.71 (1H, dd, J = 15.2, 10.0 Hz), 6.39 (1H, d, J = 15.6 Hz), 3.78 (1H, d, J = 8.0 Hz), 3.67 (1H, dd, J = 8.4, 2.8 Hz), 2.55−2.32 (5H, m), 2.29 (3H, s), 1.28 (3H, s), 1.04 (3H, s); 13C NMR (100 MHz, CDCl3) δ 207.9, 196.8, 139.1, 135.8, 83.5, 79.1, 58.5, 49.9, 49.0, 45.1, 28.3, 24.3, 20.6; HRMS (ESI-TOF) m/z 245.1154 [M + Na]+ (calcd for C13H18O3Na, 245.1155). (+)-Annuionone A (1b). 10% Palladium on carbon (7.5 mg) was added to a solution of (−)-2b (7.5 mg, 0.034 mmol) in MeOH (0.7 mL), and the mixture was stirred for 2 h under hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filter cake was washed with MeOH. The organic layer was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether/EtOAc = 2:1) to give (+)-1b2,4,10 (7.2 mg, 95%) as a colorless oil; [α]21D + 13 (c 0.3, CHCl3), {lit.2 [α]25D + 12.3 (c 0.4, CHCl3)}; IR (neat) νmax 3419, 2935, 1714, 1457, 1378, 1273, 1227, 1169, 1019, 813 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.63 (1H, d, J = 8.0 Hz), 3.56 (1H, dd, J = 8.0, 2.8 Hz), 2.68−2.64 (2H, m), 2.44−2.35 (3H, m), 2.25(1H, s), 2.19 (3H, s), 1.84 (1H, m), 1.68−1.62 (2H, m), 1.32 (3H, s), 1.08 (3H, s); 13C NMR (100 MHz, CDCl3) δ 209.1, 207.5, 83.4, 78.3, 53.0, 49.4, 48.6, 43.5, 42.6, 30.1, 24.9, 20.8, 18.6; HRMS (ESI-TOF) m/z 247.1310 [M + Na]+ (calcd for C13H20O3Na, found 247.1309).

10 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/EtOAc = 20:1) to yield tertiary alcohol (+)-42 (20.7 mg, 99%) as a colorless oil; [α]20D + 14 (c 0.5, CHCl3); IR (neat) νmax 3447, 2955, 2931, 2891, 1858, 1594, 1467, 1388, 1254, 1093, 1005, 839, 776, 665 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.65 (1H, ddd, J = 10.0, 5.6, 1.6 Hz), 5.58 (1H, dd, J = 10.4, 2.4 Hz), 4.15 (1H, dd, J = 11.2, 3.6 Hz), 4.05 (1H, dd, J = 11.2, 3.6 Hz), 3.99 (1H, s), 3.57 (1H, d, J = 10.0 Hz), 3.24 (1H, d, J = 10.0 Hz), 2.25 (1H, d, J = 17.2 Hz), 1.70 (1H, t, J = 3.6 Hz), 1.59 (1H, dd, J = 17.2, 5.6 Hz), 1.25 (1H, s), 1.08 (3H, s), 0.90 (9H, s), 0.88 (9H, s), 0.10 (6H, d, J = 4.4 Hz), 0.04 (6H, s); 13C NMR (100 MHz, CDCl3) δ 133.7, 125.1, 71.1, 70.0, 60.8, 46.5, 37.2, 37.0, 31.1, 25.9, 25.8, 19.1, 18.3, 17.9, −5.5, −5.6, −5.7, −5.8; HRMS (ESI-TOF) m/z 437.2833 [M + Na]+ (calcd for C22H46O3Si2Na, 437.2835). Cyclohexenone (+)-43. Tertiary alcohol (+)-42 (57 mg, 0.14 mmol) was added to a flame-dried flask, followed by CH2Cl2 (1.4 mL, 0.1 M), and NaOAc (50.8 mg, 0.62 mmol). The mixture was cooled to 0 °C, and PCC (89 mg, 0.41 mmol) was added in portions over 2 min. After 15 min, the mixture was warmed to rt and stirred for 10 h. The yellow precipitate was filtered through a pad of silica gel and concentrated under reduced pressure. The residue was subjected to column chromatography (petroleum ether/EtOAc = 20:1) to yield enone (+)-43 (52.2 mg, 92%) as a colorless oil; [α]20D + 75 (c 0.5, CHCl3); IR (neat) νmax 3439, 2955, 2930, 2857, 1669, 1467, 1383, 1254, 1100, 896, 838, 777, 674, 541 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.93 (1H, s), 3.95 (1H, dd, J = 10.8, 3.6 Hz), 3.83 (1H, dd, J = 10.8, 3.2 Hz), 3.40 (1H, d, J = 9.6 Hz), 3.17 (, 1H, d, J = 9.6 Hz), 2.60 (1H, d, J = 17.2 Hz), 2.29 (1H, t, J = 3.2 Hz), 2.04 (1H, d, J = 17.6 Hz), 1.97 (3H, d, J = 1.2 Hz), 1.09 (3H, s), 0.86 (9H, s), 0.83 (9H, s), 0.01 (3H, s), −0.02 (6H, d, J = 2.0 Hz), −0.03 (3H, s); 13C NMR (100 MHz, CDCl3) δ 199.7, 160.7, 127.6, 69.7, 61.7, 46.9, 44.8, 40.1, 25.8, 25.7, 23.6, 22.1, 18.2, 18.1, −5.6, −5.7, −5.7; HRMS (ESITOF) m/z 435.2727 [M + Na]+ (calcd for C22H44O3Si2Na, 435.2725). Cyclic Ethers 44 and 45. TBAF (1.0 M in THF, 0.19 mL, 0.19 mmol) was added to a solution of enone (+)-43 (31.4 mg, 0.08 mmol) in THF (1 mL) in an ice bath. The mixture was warmed to rt and stirred for 5 h. The reaction mixture was quenched with saturated aq NH4Cl and extracted with EtOAc (3 × 10 mL). The organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 2:1) to give an inseparable mixture of ketone 44 and hemiketal 45 (12.3 mg, 88%) as a colorless oil; [α]21D + 19 (c 0.3, CHCl3); IR (neat) νmax 3423, 2899, 1710, 1454, 1381, 1271, 1228, 1175, 1093, 1014, 911, 807 cm−1; 44: 1 H NMR (400 MHz, CDCl3) δ 3.99 (1H, dd, J = 10.0, 1.2 Hz), 3.87 (1H, dd, J = 10.8, 6.8 Hz), 3.66 (1H, d, J = 8.0 Hz), 3.63 (1H, dd, J = 8.0, 2.4 Hz), 2.44 (2H, s), 2.43 (1H, dd, J = 18.0, 2.4 Hz), 2.29 (1H, dd, J = 18.0, 1.6 Hz), 2.00 (1H, t, J = 6.4 Hz), 1.80 (1H, br s), 1.41 (3H, s), 1.16 (3H, s); 13C NMR (100 MHz, CDCl3) δ 209.6, 82.5, 78.9, 59.4, 55.1, 50.1, 49.3, 42.6, 25.1, 20.7; 45: 1H NMR (400 MHz, CDCl3) δ 4.15 (1H, dd, J = 10.4, 2.4 Hz), 4.00−3.98 (1H, m), 3.57 (2H, s), 3.06 (1H, s), 1.93 (1H, dd, J = 13.6, 1.2 Hz), 1.87 (1H, d, J = 12.8 Hz), 1.83 (1H, d, J = 3.2 Hz), 1.80 (1H, d, J = 3.6 Hz), 1.74 (1H, dd, J = 12.8, 3.2 Hz), 1.39 (3H, s), 1.17 (3H, s); 13C NMR (100 MHz, CDCl3) δ 95.9, 81.2, 80.5, 60.4, 49.8, 48.0, 47.8, 40.6, 24.3, 20.9; HRMS (ESI-TOF) m/z 207.0997 [M + Na]+ (calcd for C10H16O3Na, 207.0992). (−)-Annuionone B (2b). The mixture of 44 and 45 (26.7 mg, 0.15 mmol) was dissolved in dry CH2Cl2 (1.5 mL), followed by successive addition of NaHCO3 (18.3 mg, 0.22 mmol) and Dess−Martin periodinane (92.3 mg, 0.22 mmol) in an ice bath. The resulting white suspension was stirred for 1 h at rt, and saturated aq NaHCO3 was added until the solids were dissolved. The aqueous phase was separated and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to flash column chromatography to yield oxo-aldehyde 10 as a yellow oil. 1-(Triphenylphosphoranylidene)-2-propanone (55 mg, 0.17 mmol) was added to a solution of oxo-aldehyde 10 in CH2Cl2 (1.5 mL) at rt. The mixture was stirred for

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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.6b00522. 1 H and 13C NMR spectra of compounds 17, 19, 20, 28, 33a, 33b, 34, 37, 38, 40−44, 1b, and 2b (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: (+86) 28-8541-2095. ORCID

Xiaochuan Chen: 0000-0003-3901-0524 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National Natural Science Foundation of China (21172153, 21321061). We thank Prof. J. J. Chruma of Sichuan University for valuable document revisions. Compound characterization was performed by the Comprehensive Specialized Laboratory Training Platform, College of Chemistry, Sichuan University, as well as Prof. Xiaoming Feng’s group.

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REFERENCES

(1) Parry, A. D.; Horgan, R. Phytochemistry 1991, 30, 815−821. (2) Macías, F. A.; Varela, R. M.; Torres, A.; Oliva, R. M.; Molinillo, J. M. G. Phytochemistry 1998, 48, 631−636. (3) Macías, F. A.; Torres, A.; Galindo, J. L. G.; Varela, R. M.; Á lvarez, J. A.; Molinillo, J. M. G. Phytochemistry 2002, 61, 687−692. (4) Takikawa, H.; Isono, K.; Sasaki, M.; Macías, F. A. Tetrahedron Lett. 2003, 44, 7023−7025. (5) Macías, F. A.; López, A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G. Phytochemistry 2004, 65, 3057−3063. (6) Anjum, T.; Bajwa, R. Phytochemistry 2005, 66, 1919−1921.

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DOI: 10.1021/acs.jnatprod.6b00522 J. Nat. Prod. 2017, 80, 805−812

Journal of Natural Products

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DOI: 10.1021/acs.jnatprod.6b00522 J. Nat. Prod. 2017, 80, 805−812