Biosynthesis-Inspired Total Synthesis of Bioactive Styryllactones (+

Aug 12, 2016 - A protecting-group-free total synthesis of (+)-goniodiol (1), (6S,7S,8S)-goniodiol (2), (−)-parvistone D (4), and (+)-parvistone E (6...
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Biosynthesis-Inspired Total Synthesis of Bioactive Styryllactones (+)-Goniodiol, (6S,7S,8S)‑Goniodiol, (−)-Parvistone D, and (+)-Parvistone E Perla Ramesh*,† and Tadikamalla P. Rao‡ †

Division of Natural Products Chemistry and ‡Centre for NMR and Structural Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500007, India S Supporting Information *

ABSTRACT: A protecting-group-free total synthesis of (+)-goniodiol (1), (6S,7S,8S)-goniodiol (2), (−)-parvistone D (4), and (+)-parvistone E (6) was efficiently achieved in five steps from commercially available trans-cinnamaldehyde with high overall yields (72−75%). The synthesis strategy was inspired from the proposed biosynthesis pathway of styryllactones. Key transformations of the strategy include a one-pot conversion of goniothalamin oxide to goniodiol or 9deoxygoniopypyrone in aqueous media, stereoselective epoxidation, ring-closing metathesis, and stereoselective Maruoka allylation. The route is amenable to synthesis of various analogues for biological evaluation.

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furfuryl alcohol as starting material in 18 steps. However, most of the synthesis strategies tend to use lengthy sequences and employ protection−deprotection strategies that cause low overall yields. As part of an interest in developing synthesis strategies for bioactive natural products,10 herein is reported a concise and nature-inspired stereoselective total synthesis of the bioactive styryllactones (+)-goniodiol (1), (6S,7S,8S)-goniodiol (2), (−)-parvistone D (4), and (+)-parvistone E (6) in five simple steps with high overall yields from commercially available transcinnamaldehyde using the concept of “protecting-group-free total synthesis”. The synthesis strategy is inspired by the biosynthesis pathway proposed by Chang and co-workers (Scheme 1).3 According to this pathway, the styryllactones occur via the shikimate pathway. The condensation of cinnamoyl-CoA with two molecules of malonyl-CoA followed by reduction, lactonization, and dehydration provides the lactone 7. Lactone 7 undergoes hydrogenation to goniothalamin (8), which upon further oxidation leads to the formation of goniothalamin oxides 9a and 9b. Epoxide ring opening of 9 followed by hydrolysis and subsequent rearrangement generates the diverse group of styryllactones.

ioactive styryllactone secondary metabolites isolated from several species of the genus Goniothalamus1 have been traditionally used for the treatment of edema and rheumatism, as painkillers, as abortive treatment, and as insect repellants.2 Recently, new 6S-styryllactones have been isolated from a methanolic extract of Polyalthia parvif lora leaves by Chang and co-workers.3 These styryllactones exhibit diverse biological activities that include pesticidal, embryotoxic, teratogenic, antibacterial, antifungal, antimalarial, and antitumor activities. Goniodiols and bicyclic 9-deoxygoniopypyrones possess three and four contiguous stereogenic centers, respectively, with excellent biological activity against various human tumor cell lines (Figure 1).1−5 For example, (+)-goniodiol (1) shows selective and potent cytotoxicity against human lung carcinoma A-549 and murine leukemia cell line P-388 with an ED50 value of 0.51 μM and an IC50 value of 19.48 μM, respectively.4 7-epiGoniodiol (3) displays selective activities in the test of the trypan blue dye exclusion method, shows strong inhibition against HL-60 cells in concentrations as low as 4.27 μM, and also displays cytotoxicity against Bel7470 (hepatocarcinoma), Bcap32 (breast cancer), and HeLa cell lines with IC50 values of 4.1, 54.7, and 12.82 μM, respectively.5 Owing to the broad spectrum of potent biological activities of this class of natural products as well as fascinating structural architecture, extensive efforts toward their total synthesis have been reported.6 For example, Honda and co-workers4,7 reported the stereoselective total syntheses of the majority of natural styryllactones starting from D-glyceraldehyde and employing NBS-mediated lactol formation. Vatele and Surivet8 employed (R)-mandelic acid as a chiral source for the synthesis of several styryllactones. Recently, Tong and co-workers9 reported the total synthesis of parvistones D and E from © XXXX American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION On the basis of the biosynthesis hypothesis, goniothalamin oxides 9a and 9b appear to be precursors to the styryllactone natural products. It was envisioned that the goniodiol or Received: April 30, 2016

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DOI: 10.1021/acs.jnatprod.6b00386 J. Nat. Prod. XXXX, XXX, XXX−XXX

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Figure 1. Representative styryllactone natural products.

(Scheme 3). The analytical data of the synthesized product 9a are identical to those of the natural product.14

Scheme 1. Plausible Biosynthesis Pathway of Styryllactones

Scheme 3. Synthesis of Key Intermediate 9a

goniopyranopyrone styryllactones could be constructed via a one-pot stereo- and regioselective epoxide ring opening of goniothalamin oxides 9a and 9b, which could in turn be prepared by stereoselective epoxidation of goniothalamin 8. Finally, compound 8 could be obtained from commercially available trans-cinnamaldehyde (10) via stereoselective Marouka allylation, followed by acrylation and ring-closing metathesis (RCM) (Scheme 2). Accordingly, enantioselective allylation of trans-cinnamaldehyde 10 using allyltributyltin in the presence of Ti(i-PrO)4 and (S)-BINOL in CH2Cl2 at −15 °C furnished alcohol (S)-11 in 94% yield and 94% ee.11 Esterification of 11 with acryloyl chloride in the presence of Et3N in CH2Cl2 at 0 °C yielded the corresponding acrylate 12 in 95% yield. The acrylate 12 was subjected to RCM12 using 10 mol % Grubbs’s first-generation ruthenium catalyst, generating the target α-pyrone 8 in 95% yield. Epoxidation of δ-lactone 8 with m-CPBA in CH2Cl2 gave a mixture of diastereoisomers 9a and 9b (3:2) in 70% yield. Gratifyingly, treatment of 8 with Oxone in the presence of (+)-(R,R)-salen−Mn(III) catalyst under Han’s reaction conditions13 yielded the lactone epoxide 9a with the anticipated regio- and diastereoselectivity (dr, 98:2) in excellent yield

With the lactone key intermediate 9a in hand, the focus was shifted to the regio- and stereoselective epoxide ring-opening reaction to obtain the styryllactone natural products that would support the proposed biosynthesis pathway (Scheme 4). Various acid catalysts such as HClO4, TFA, AgOTf, Sn(OTf)2, Sc(OTf)3, and Eu(OTf)3 were screened for the epoxide opening reaction in aqueous media, and the results are illustrated in Table 1. The reaction of 9a with 1 equiv of HClO4 (entry 1) in H2O at room temperature proceeded well but afforded an inseparable mixture of diastereoisomers 13 and 2 in 4:6 ratio. Importantly, no 1,4-Michael addition product was observed, even when the reaction was continued for a further 24 h under acidic conditions at room temperature. Surprisingly, when the reaction was quenched with solid NaHCO3, only one diastereomer, (6S,7S,8S)-goniodiol (13), underwent intramolecular Michael addition and yielded the target bicyclic product parvistone D (4) (Scheme 4). Both (6S,7S,8S)goniodiol (2) and parvistone D (4) were readily separated by silica gel column chromatography. The analytical data of synthesized 2 and 4 were in complete agreement with the

Scheme 2. Biosynthetically Inspired Retrosynthesis of Styryllactones

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DOI: 10.1021/acs.jnatprod.6b00386 J. Nat. Prod. XXXX, XXX, XXX−XXX

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Scheme 4. Epoxide Ring Opening of 9a

natural product parvistone D (4) in 92% yield as the sole product (Scheme 5).

Table 1. Catalyst Screening for the Stereo- and Regioselective Epoxide Ring Opening of 9a with Watera entry

catalyst

time (h)

yield (%)b

2:4c

1 2 3 4 5 6 7 8

HClO4 TFA Sn(OTf)2 AgOTf Sc(OTf)3 Eu(OTf)3 catalyst-free catalyst-freee

3 3 12 3 24 24 24 24

96 94 95 60d trace trace NR 96

6:4 6:4 6:4 6:4 ND ND ND 97:3

Scheme 5. Synthesis of Parvistone D (4)

a

Unless otherwise indicated, the reactions were performed on a 0.23 mmol scale of 9a using 1 equiv of catalyst at room temperature in 6 mL of H2O; after completion of the reaction (time) 3 equiv of NaHCO3 was added. NR: no reaction. ND: not determined. bIsolated yields. cDetermined by 1H NMR spectroscopy of the crude mixture. d Compound 8 was formed in 35% yield along with compounds 2 and 4. eReaction performed at 60 °C.

(+)-Goniodiol (1) was prepared following the general sequence described in Scheme 6. Esterification of alcohol ent11 with acryloyl chloride afforded RCM precursor ent-12, which was subjected to ring-closing metathesis using Grubbs’s first-generation catalyst,12 to afford the unsaturated lactone ent8 in 95% yield. Asymmetric epoxidation of lactone ent-8 with Oxone in the presence of (−)-(S,S)-salen−Mn(III) catalyst furnished goniothalamin oxide ent-9a, which on further epoxide opening in water at 60 °C afforded the natural product (+)-goniodiol (1) in 72% overall yield with analytical data in agreement with those reported for the natural sample.1g Next, our efforts were diverted toward the synthesis of parvistone E (6), a structurally unique natural styryllactone with a pyranopyrone skeleton and four contiguous stereogenic centers. Toward this goal, the catalytic asymmetric epoxidation of known lactone 8 by using chiral (−)-(S,S)-salen−Mn(III) complex afforded the target goniothalamine oxide (9b) in 90% yield (98:2 dr). Surprisingly, when compound 9b was heated in aqueous media in the absence of catalyst, the reaction did not stop at the goniodiol 15 stage, but the reaction proceeded all the way to the bicyclic parvistone E (6) in one pot, in almost quantitative yield (Scheme 7). The physical data of synthetic 6 agree well with the literature data.3,9 The relative configuration of parvistone E (6) was confirmed by a detailed 2D NMR study (Figures S23−S28, Supporting Information). However, treatment of compound 9b with HClO4 in water at room temperature afforded an inseparable diastereomeric mixture of (6S,7R,8R)-goniodiol (16) and ent-3 in a 1:1 diastereomeric ratio, confirmed by crude 1H NMR data analysis (Scheme 8). In this reaction, interestingly, no 1,4-Michael addition product was observed in the presence of acid catalyst, even after the addition of excess NaHCO3 at room temperature.

literature data.3,9 Moreover, the relative configuration of parvistone D (4) was subsequently confirmed by detailed 2D NMR analysis (Figures S17−S22, Supporting Information). With this positive result in hand, the ring-opening reaction of 9a was attempted with different acid catalysts. Upon treatment with TFA (entry 2) and the Lewis acid Sn(OTf)2 (entry 3) similar results were obtained. Treatment of epoxide 9a with AgOTf (entry 4) gave goniothalamine (S)-8 (35% yield) along with 2 and 4 (6:4 ratio; 60% yield). In the presence of Sc(OTf)3 (entry 5) or Eu(OTf)3 (entry 6), only trace amounts of product were observed, even after 24 h at room temperature. However, when the reaction was carried out in the absence of catalyst (entry 7) in water at room temperature, no product was observed and the starting material was recovered. Interestingly, the stereoselectivity of the ring-opening reaction was dramatically improved by using hot water alone. Upon heating at 60 °C in the absence of any catalyst, 9a furnished (6S,7S,8S)goniodiol (2) in a highly stereo- and regioselective manner and in nearly quantitative yield (entry 8). The overall yield of (6S,7S,8S)-goniodiol (2) starting from trans-cinnamaldehyde was 72% (Scheme 4). Quenching of 2 with base does not lead to the formation of 14 probably due to the presence of the axial phenyl group in the anticipated bicyclic product 14. To improve the overall yield of parvistone D (4), the goniothalamine (S)-8 was subjected to Sharpless asymmetric dihydroxylation15 reaction with AD-mix-β at 0 °C to give the C

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Scheme 6. Synthesis of (+)-Goniodiol (1)

Scheme 7. Synthesis of Parvistone E (6)

mixture was stirred for a further 2 h. The in situ generated solution of catalyst was cooled to −15 °C and treated sequentially with transcinnamaldehyde (10) (0.80 g, 6.1 mmol) and allyltributyltin (2.06 mL, 6.6 mmol), and the reaction mixture was stirred for 48 h at the same temperature. The reaction mixture was quenched with saturated NaHCO3 (10 mL) solution and extracted with Et2O (3 × 10 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified by flash column chromatography (n-hexane/EtOAc, 9:1) to give homoallyl alcohol 11 (1.0 g, 94%, >95% ee) as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.36− 7.15 (5H, m), 6.57 (1H, d, J = 16.0 Hz), 6.19 (1H, dd, J = 16.0, 6.2 Hz), 5.90−5.76 (1H, m), 5.20−5.07 (2H, m), 4.36−4.27 (1H, m), 2.47−2.30 (2H, m), 1.64 (1H, d, J = 3.5 Hz); 13C NMR (75 MHz, CDCl3) δ 136.5, 133.9, 131.4, 130.2, 128.5, 127.5, 126.4, 118.3, 71.6, 41.9; ESIMS m/z 175 [M + H]+; HRESIMS m/z [M + H]+ calcd for C12H15O 175.112 29, found 175.112 41. (S,E)-1-Phenylhexa-1,5-dien-3-yl Acrylate (12). Et3N (0.99 mL, 7.0 mmol) and acryloyl chloride (0.30 mL, 3.5 mmol) were added to a stirred solution of 11 (0.34 g, 2.0 mmol) in CH2Cl2 (5 mL) at 0 °C, and the reaction mixture was stirred for 2 h. The reaction was quenched with H2O (1 mL), and the product was extracted with CH2Cl2 (2 × 3 mL). The organic layer was dried over MgSO4, evaporated under reduced pressure, and purified by column chromatography (n-hexane/EtOAc, 9.5:0.5) to obtain acryl ester 12 (423 mg, 95%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.38−7.22 (5H, m), 6.64 (1H, d, J = 15.8 Hz), 6.43 (1H, dd, J = 17.3, 1.3 Hz), 6.20−6.11 (2H, m), 5.84 (1H, dd, J = 10.5, 1.5 Hz), 5.83− 5.76 (1H, m), 5.58−5.53 (1H, m), 5.16−5.09 (2H, m), 2.55−2.51 (2H, m); 13C NMR (75 MHz, CDCl3) δ 165.3, 136.2, 132.9, 132.7, 130.7, 128.6, 128.5 (2C), 127.9, 126.8, 126.5 (2C), 118.1, 73.9, 39.0; ESIMS m/z 229 [M + H]+, 251 [M + Na]+; HRESIMS m/z [M + H]+ calcd for C15H17O2 229.122 31, found 229.122 17. (S,E)-6-Styryl-5,6-dihydro-2H-pyran-2-one (8). Grubbs (I) catalyst (0.054 g, 10 mol %) was added to a solution of 12 (0.15 g, 0.66 mmol) in CH2Cl2 (10 mL) at room temperature. After stirring for 6 h at reflux, the mixture was concentrated and purified by flash column chromatography (n-hexane/EtOAc, 7:3) to obtain (S)goniothalamin (8) (125 mg, 95%) as a white solid: {[α]25D −165 (c 1, CHCl3), for ent-8 [α]25D +167 (c 1.1, CHCl3)}; 1H NMR (300 MHz, CDCl3) δ 7.40−7.28 (5H, m), 6.94−6.90 (1H, m), 6.73 (1H, d, J = 15.8 Hz), 6.28 (1H, dd, J = 15.8, 6.2 Hz), 6.09 (1H, dt, J = 9.9, 1.8 Hz), 5.12−5.08 (1H, m), 2.56−2.53 (2H, m); 13C NMR (75 MHz, CDCl3) δ 163.8, 144.6, 135.6, 133.0, 128.6 (2C), 128.2, 126.6 (2C), 125.5, 121.5, 77.8, 29.8; ESIMS m/z 201 [M + H]+, 223 [M + Na]+;

Scheme 8. HClO4-Catalyzed Epoxide Opening of 9b

In conclusion, unique stereoselective total synthesis of cytotoxic styryllactone natural products, namely, (+)-goniodiol (1), (6S,7S,8S)-goniodiol (2), (−)-parvistone D (4), and (+)-parvistone E (6), has been achieved in a highly atom- and step-economical, protecting-group-free manner and in only five simple steps from readily available trans-cinnamaldehyde, with high overall yields (72−75%). Importantly, the product 9a (or ent-9a) could be hydrated to furnish (6S,7S,8S)-goniodiol (2) [or (+)-goniodiol (1)] in the absence of catalyst. Similarly, compound 9b was converted into parvistone E (6) via a onepot regioselective epoxide opening and intramolecular 1,4Michael addition process under catalyst-free conditions in aqueous media. Eventually, the proposed biosynthesis pathway was supported by converting goniothalamin oxides into different styryllactone natural products.

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured with a JASCO P-1020 digital polarimeter at 25 °C. 1H and 13C NMR and 2D NMR spectra were recorded on a Varian 300 or 400 or Bruker Avance 500 MHz spectrometer. The 1H NMR chemical shifts are referenced to internal TMS (δH 0.0); 13C NMR chemical shifts are referenced to internal CDCl3 (δC 77.0). HRESIMS data were recorded on a Bruker micrOTOF-Q mass spectrometer. All column chromatographic separations were performed over silica gel of 60−120 mesh. HRESIMS data were recorded on an ESI-QTOF mass spectrometer. (S,E)-1-Phenylhexa-1,5-dien-3-ol (11). Ti(i-PrO)4 (0.26 mL, 0.90 mmol) was added to a stirred solution of TiCl4 (33 μL, 0.30 mmol) in CH2Cl2 (10 mL) at 0 °C under a nitrogen atmosphere. After 1 h, Ag2O (0.14 g, 0.60 mmol) was added at room temperature, and the reaction mixture was stirred in the dark for 5 h. (S)-Binaphthol (0.35 g, 1.2 mmol) was added at room temperature, and the reaction D

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(51 mg, 95%) as a white solid: {[α]21D +95 (c 0.4, CHCl3), lit.9 [α]20D +101.3 (c 0.4, CHCl3), lit.3 [α]20D −280 (c 0.18, CH2Cl2)}; 1H NMR (400 MHz, CDCl3) δ 7.44−7.34 (5H, m), 4.96 (1H, m), 4.49 (1H, m), 4.43 (1H, d, J = 9.6 Hz), 3.63 (1H, m), 3.01 (1H, dd, J = 19.3, 1.5 Hz), 2.89 (1H, dd, J = 19.3, 5.1 Hz), 2.25 (2H, m); 13C NMR (100 MHz, CDCl3) δ 168.7, 137.7, 128.7, 128.6 (2C), 127.3 (2C), 76.6, 74.4, 72.6, 65.8, 36.6, 29.9; ESIMS m/z 235 [M + H]+, 257 [M + Na]+; HRESIMS m/z [M + Na]+ calcd for C13H14NaO4 257.078 43, found 257.077 66.

HRESIMS m/z [M + Na]+ calcd for C13H12NaO2 223.073 50, found 223.073 12. (S)-6-((2R,3R)-3-Phenyloxiran-2-yl)-5,6-dihydro-2H-pyran-2one (9a). A buffer solution of 50 mM Na2B4O7·10H2O in 0.4 mM aqueous Na2EDTA (11 mL) was added to a solution of (S)goniothalamin (8) (0.30 g, 1.5 mmol), (R,R)-(+)-N,N′-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (Jacobsen’s (R,R)-salen−Mn(III) catalyst, 0.040 g, 0.063 mmol) and n-Bu4NHSO4 (0.018 g, 0.053 mmol) in CH3CN (16 mL), and the reaction mixture was cooled to 0 °C. 1,1,1-Trifluoroacetone (0.2 mL) was added, followed by portionwise addition of two solutions of Oxone (3.40 g, 5.5 mmol) in 0.4 mM aqueous Na2EDTA (17 mL) and aqueous NaHCO3 (1.1 g in 17 mL of H2O, 13 mmol) with stirring over a period of 1.5 h. The mixture was treated with H2O (1 mL) and extracted with Et2O (2 × 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (n-hexane/EtOAc, 1:2) to give epoxide lactone 9a (289 mg, 89%, dr 98:2) as a white solid: {[α]25D −97 (c 0.7, CHCl3), for ent-9a [α]25D +95 (c 0.7, CHCl3)}; 1H NMR (500 MHz, CDCl3) δ 7.38−7.28 (5H, m), 6.93 (1H, ddd, J = 9.7, 5.4, 2.8 Hz), 6.07 (1H, ddd, J = 9.7, 2.4, 1.0 Hz), 4.68 (1H, ddd, J = 10.6, 4.5, 3.6 Hz), 4.08 (1H, d, J = 1.8 Hz), 3.24 (1H, dd, J = 3.6, 2.1 Hz), 2.69−2.63 (1H, m), 2.58−2.52 (1H, m); 13C NMR (125 MHz, CDCl3) δ 162.8, 144.0, 135.9, 128.6 (3C), 125.7 (2C), 121.6, 75.1, 62.1, 55.0, 26.2; ESIMS m/z 239 [M + Na]+; HRESIMS m/z [M + Na]+ calcd for C13H12NaO3 239.067 87, found 239.066 81. (6S,7S,8S)-Goniodiol (2). A suspension of compound 9a (0.050 g, 0.23 mmol) in distilled H2O (6 mL) was stirred at 60 °C for 24 h. The mixture was extracted with EtOAc (2 × 5 mL), and the organic phase was washed with brine (1 mL), dried over MgSO4, concentrated, and purified by silica gel flash column chromatography (n-hexane/EtOAc, 4:6) to afford (6S,7S,8S)-goniodiol (2) (52 mg, 96%, dr 97:3) as a white solid: {[α]25D −64 (c 0.7, CHCl3), for (+)-goniodiol (1) [α]25D +76 (c 1, CHCl3)}; 1H NMR (500 MHz, CDCl3) δ 7.43−7.32 (5H, m), 6.93 (1H, ddd, J = 9.7, 6.4, 2.1 Hz), 6.01 (1H, ddd, J = 9.7, 2.8, 0.7 Hz), 4.95 (1H, d, J = 7.3 Hz), 4.80 (1H, ddd, J = 12.8, 3.8, 2.2 Hz), 3.73 (1H, br t, J = 5.6 Hz), 2.80 (1H, ddt, J = 18.4, 10.9, 2.4 Hz), 2.58 (1H, br s), 2.28 (1H, br d, J = 7.6 Hz), 2.22−2.16 (1H, m); 13C NMR (100 MHz, CDCl3) δ 163.5, 146.0, 140.6, 128.8 (2C), 128.3, 126.5 (2C), 120.6, 76.7, 75.0, 63.7, 26.0; ESIMS m/z 257 [M + Na]+; HRESIMS m/z [M + Na]+ calcd for C13H14O4Na 257.078 43, found 257.078 58. (S)-6-((2S,3S)-3-Phenyloxiran-2-yl)-5,6-dihydro-2H-pyran-2one (9b). A buffer solution of 50 mM Na2B4O7·10H2O in 0.4 mM aqueous Na2EDTA (11 mL) was added to a solution of (S)goniothalamin (8) (0.30 g, 1.5 mmol), (S,S)-(+)-N,N′-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (0.040 g, 0.063 mmol), and n-Bu4NHSO4 (0.018 g, 0.053 mmol) in CH3CN (16 mL), and the reaction mixture was cooled to 0 °C. 1,1,1Trifluoroacetone (0.2 mL) was added, followed by portionwise addition of two portions of Oxone (3.4 g, 5.5 mmol) in 0.4 mM aqueous Na2EDTA (17 mL) and aqueous NaHCO3 (1.1 g in 17 mL of H2O, 13 mmol) with stirring for 2 h. The mixture was treated with H2O (1 mL) and extracted with Et2O (2 × 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (n-hexane/ EtOAc, 1:2) to give lactone epoxide 9b (291 mg, 90%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.39−7.26 (5H, m), 6.95 (1H, ddd, J = 9.7, 5.1, 3.4 Hz), 6.08 (1H, dt, J = 9.7, 2.0 Hz), 4.45 (1H, dt, J = 9.7, 5.5 Hz), 3.90 (1H, d, J = 1.9 Hz), 3.28 (1H, dd, J = 5.5, 1.9 Hz), 2.62−2.57 (2H, m); 13C NMR (100 MHz, CDCl3) δ 162.8, 144.3, 135.6, 128.7, 128.6 (2C), 125.7 (2C), 121.5, 77.1, 61.5, 57.2, 25.9; ESIMS m/z 239 [M + Na]+; HRESIMS m/z [M + Na]+ calcd for C13H12NaO3 239.067 87, found 239.066 81. Parvistone E (Leiocarpin A) (6). A suspension of compound 9b (0.050 g, 0.23 mmol) in distilled H2O (6 mL) was stirred at 60 °C for 24 h. The mixture was subsequently extracted with EtOAc (2 × 5 mL), and the organic phase was washed with brine (1 mL), dried over MgSO4, concentrated, and purified by silica gel flash column chromatography (n-hexane/EtOAc, 4:6), providing parvistone E (6)

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b00386. 1D and 2D NMR spectra of all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: 91-40-27191625. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Council of Scientific and Industrial Research, Ministry of Science and Technology, New Delhi, for funding the project ORIGIN (CSC-0108).

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REFERENCES

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DOI: 10.1021/acs.jnatprod.6b00386 J. Nat. Prod. XXXX, XXX, XXX−XXX