Total Synthesis of (−)-Pavidolide B: A Ring Contraction Strategy | The

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Total Synthesis of (−)-Pavidolide B: A Ring Contraction Strategy Peirong Rao, Jialei Hu, Jun Xuan, and Hanfeng Ding* Department of Chemistry, Zhejiang University, Hangzhou 310058, China

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S Supporting Information *

ABSTRACT: A ring contraction approach for the total synthesis of (−)-pavidolide B was developed, which assembles this polycyclic natural product within 13 steps from known chiral alcohol 11. The key features of the strategy include (a) a double Mukaiyama−Michael addition/elimination, (b) a ringclosing metathesis, (c) a Wolff rearrangement, and (d) a latestage regioselective Schenck ene reaction.

C

syntheses of chatancin (2) have been successively described by Gössinger,3a Deslongchamps,3b and Maimone.3c Recently, Carreira and co-workers also accomplished an impressive total synthesis of (+)-sarcophytin (1).3d On the other hand, the biosynthetically related (−)-pavidolide B (4, Figure 1) was isolated together with (+)-sarcophytin (1) and (+)-chatancin (2) by Lin and co-workers from the marine soft coral Sinularia pavida in 2012.4 Preliminary investigations revealed that (−)-4 exhibits high selective inhibition against the human promyelocytic leukemia cell line HL-60 with an IC50 of 2.7 μg/mL. Structurally, (−)-4 contains a challenging [6,5,5,7] tetracyclic ring system embedded within fully functionalized cyclopentane and seven contiguous stereogenic centers. In 2017, Yang, Gong, and coworkers disclosed an enantioselective total synthesis of (−)-4 by employing a cascade radical annulation of vinylcyclopropane as the key step.5 Very recently, we also developed a divergent approach for the concise and efficient syntheses of four cembrane diterpenoids, including (+)-sarcophytin (1), (+)-chatancin (2), (−)-3-oxochatancin (3), and (−)-pavidolide B (4).6 In continuation of our interest in this area, we herein describe an alternative total synthesis of (−)-4 through a ring contraction strategy. Our retrosynthesis is depicted in Scheme 1. We rationalized that (−)-pavidolide B (4) could be synthesized from acid 5 through a late-stage functionalization, involving a lactonization, a site-selective allylic oxidation7 at C10, and epimerization at C11. For the construction of 5, a Wolff rearrangement8 induced ring contraction of α-diazoketone 6 was projected as the means to assemble the [6,5,7] tricyclic carbon framework of the molecule. We expected the latter intermediate would be accessible from bicyclic diene 7 through a ring-closing metathesis (RCM).9 Finally, we envisioned 7 could be prepared from cyclohexenone 9 and Rawal’s diene 10. In the forward sense, this would proceed through a double Mukaiyama−Michael addition/elimination process,10 followed

embrane diterpenoids constitute a large class of marine natural products featuring a 14-membered macrocyclic or polycyclic carbon skeleton.1 Among them, the sarcophytin family members were isolated from the Sarcophyton species (e.g., 1−3, Figure 1),2 whose primary biological function is

Figure 1. Structures of cembranoids 1−4.

believed to be chemical defense against predators.2d Of note, (+)-chatancin (2), bearing a ketone at C3, belongs to a new type of specific PAF antagonist.2c Initial studies indicate that it can inhibit both PAF induced platelet aggregation and PAF receptor binding with IC50 values of 0.22 μM and 0.32 μM, respectively, but has no effect on collagen, adenosine diphosphate, or arachidonic acid induced platelet aggregation. The above polycyclic cembranoids contain a common [6,6,6] tricyclic core structure, possessing six or seven stereogenic centers. In particular, the cis-decalin motif (A/B rings) is folded into a highly congested polycyclic arrangement via a transannularly bridged hemiketal between a tertiary alcohol at C10 and a ketone at either C3 or C14 position. Due to their intriguing structures and potentially important biological activities, these molecules have attracted tremendous attention from synthetic community. To date, three elegant total © XXXX American Chemical Society

Received: May 15, 2019 Published: June 21, 2019 A

DOI: 10.1021/acs.joc.9b01308 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 1. Retrosynthesis of (−)-Pavidolide B (4)

Scheme 2. Construction of Bicyclic Diene 7

at 70 °C in the absence of any Lewis acid promoters to give 12 with a greater than 20:1 dr at C13. It should be noted that the high temperature was identified as the key element for the observed excellent diastereoselectivity.6,13 Further addition of aqueous HF (49 wt %/wt) at −78 °C initiated a second Mukaiyama−Michael addition followed by elimination to afford the requisite cis-[6,6] bicyclic enone 8, with generation of the quaternary carbon at C4, in 84% yield as a single diastereomer. Iodination of 8 under Danishefsky’s conditions14 provided α-iodoenone 13 in 50% yield. In contrast, Johnson’s

by a Stille cross-coupling and an organocuprate 1,4-addition of the resultant bicyclic enone 8. Our synthesis began with the construction of bicyclic diene 7 (Scheme 2). Chiral alcohol 11 was readily prepared from commercially available (+)-carvone in two steps following the procedures developed by the groups of Guerra,11 and Yang and Gong.5 By treatment of 11 with Bz2O, Et3N, and 4-DMAP, 9 was obtained in 95% yield. After extensive optimization, we found that the expected Mukaiyama−Michael addition between benzoate 9 and Rawal’s diene 1012 occurred smoothly B

DOI: 10.1021/acs.joc.9b01308 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 3. Total Synthesis of (−)-Pavidolide B (4)

Table 1. Exploration of Conditions for the Site-Selective Allylic Oxidation of 19a

entry c

1 2 3 4 5 6e

conditions

yieldb (%; 20, 21)

Co(acac)2, NHPI, O2, MeCN, 50 °C CrO3, 3,5-DMP, CH2Cl2, 0 °C SeO2, TBHP, O2, CH2Cl2, 25 °C Ph2Se2, PhIO2, pyridine, C6H5Cl, 25−100 °C Mn(OAc)3, TBHP, O2, 3 Å MS, EtOAc, 25 °C Cl4NHPI, pyridine, TBHP, LiClO4, acetone or MeCN, 10 mA mmol−1

0, 0 0, 25 0, 68 10, 0 16,d 0 0, 0

a

Reactions were carried out on a 0.03 mmol scale. bIsolated yields. cDecomposition of 19. dYield refers to (−)-4. eRecovery of 19. 3,5-DMP = 3,5dimethylpyrazole. MS = molecular sieves. NHPI = N-hydroxyphthalimide. TBHP = tert-butyl hydroperoxide.

protocol (I2, pyridine)15 only led to the recovery of the starting material. Iodoenone 13 underwent a Stille cross-coupling with

allyltributylstannane in the presence of Pd(PPh3)4 to give 14 in 81% yield. Subsequently, introduction of the isopentenyl side C

DOI: 10.1021/acs.joc.9b01308 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

enone 20 was produced in 48% yield. Finally, the DBUpromoted epimerization at C11 proceeded efficiently to furnish (−)-4 in 98% yield. Synthetic (−)-4 exhibited identical spectroscopic (1H and 13C NMR) data, satisfactory optical rotation, and mass spectrometric data to those reported for the natural product.4 In summary, we have developed a ring contraction strategy for the total synthesis of (−)-pavidolide B (4) in 13 steps from known chiral alcohol 11. The key features include a double Mukaiyama−Michael addition/elimination, a ring-closing metathesis, a Wolff rearrangement, and a late-stage regioselective Schenck ene reaction. With the high efficiency in building structural complexity, the described strategy and methodologies should find wide application in the total syntheses of other members of polycyclic cembranoids and permit further exploration of their biological properties.

chain was realized through the TMS-accelerated Michael addition of the corresponding organocuprate, derived from the Grignard reagent 15,16 to 14 by the method of Nakamura and Kuwajima.17 As expected, the Michael addition took place exclusively at the convex side of the C5−C6 double bond and afforded 7 in 62% yield as a single isomer upon acid-promoted desilylation. Having rapidly assembled 7, we turned our attention to the late-stage synthesis of (−)-pavidolide B (4, Scheme 3). In the presence of the Grubbs II catalyst (5 mol %), ring-closing metathesis of 7 afforded the anticipated tricyclic ketone 16 in 83% yield. The latter compound was converted to the corresponding α-diazoketone through treatment with 2,4,6triisopropylbenzenesulfonyl azide, KOH, TBAB, and 18crown-6.18 Concurrent cleavage of the benzoyl group under basic conditions led to the isolation of 6 in 52% yield. The structure of 6 was confirmed by X-ray crystallographic analysis (for details, see the Supporting Information).19 After being transformed into mesylate 17 in 95% yield, the devised Wolff rearrangement was then investigated. Preliminary attempts to initiate such rearrangement using silver salts8,20 proved to be fruitless. To our delight, upon irradiation of a solution of 17 in THF at 25 °C with a medium-pressure Hg lamp8,21 for 1 h, the desired acid 18 was generated as a single diastereomer in 72% yield. Probably due to the steric effect from the equatorial isopropyl group at C1, the following intramolecular SN2 cyclization of 18 was met with failures. Delightfully, after exhaustive trials, 19 was obtained in a moderate yield with the aid of K2CO3 and 18-crown-6 in MeCN at 90 °C, which set the stage for the site-selective allylic oxidation. To our disappointment, Ishii’s protocol [Co(acac)2, NHPI, O2, MeCN, 50 °C]22 resulted in decomposition of the starting material (Table 1, entry 1). Upon treatment with CrO3/3,5DMP or SeO2/TBHP/O2, aldehyde 21 was generated as the sole product in 25% and 68% yields, respectively (entries 2 and 3). Pleasingly, the combination of diselenide, iodoxybenzene, and pyridine23 gave the desired enone 20 successfully, albeit in a low yield (entry 4). By employing the conditions described by Shing and co-workers [Mn(OAc)3, TBHP, 3 Å MS, rt],24 (−)-pavidolide B (4) was formed directly in 16% yield (entry 5). However, further replacement of Mn(OAc)3 with MnO2, CuI, Pd(OH)2, Rh2(CAP)4, RuCl3, and PhI(OAc)2 did not provide better results. Furthermore, the electrochemical C−H oxidation strategy developed by Baran and co-workers25 was investigated, which unfortunately led to the recovery of 19 (entry 6). On the other hand, the carboxylic acid-directed C− H hydroxylation of 18 at C10 following the procedures of White [Fe(PDP), H2O2, MeCN, rt]26 and Brown [Cu(OAc)2, H2O2, MeCN, rt]27 also failed to deliver any amounts of the desired product. In view of the above outcomes, we sought to pursue a more efficient conversion of 19 to (−)-pavidolide B (4). Inspired by our findings during the total syntheses of ent-kaurenoids,28 the regioselective Schenck ene reaction29 of 19 was tried. After exhaustive experimentation, we found that, upon exposure of 19 to in situ generated singlet oxygen from triphenyl phosphite ozonide (TPPO)30 followed by reduction with PPh3, a 4.2:1 mixture of the desired allyl alcohol 22 and its regioisomer 23 was obtained in a 78% combined yield. Subsequently, among the numerous oxidants screened, the oxoammonium salt TEMPO+BF4− reported by Iwabuchi and co-workers31 turned out to be optimal for effecting the Dauben−Michno oxidative rearrangement of 22. After a one-pot Dess−Martin oxidation,

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EXPERIMENTAL SECTION

General Information. All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Anhydrous acetonitrile (CH3CN), methylene chloride (CH2Cl2), and 1,2-dichloroethane (DCE) were distilled immediately before use from calcium hydride. Tetrahydrofuran (THF) was distilled immediately before use from sodiumbenzophenone ketyl. Ethyl acetate (EtOAc), ethyl ether (Et2O), pyridine, triethylamine (Et3N), methanol (MeOH), chloroform (CHCl3), and toluene were purchased at the highest commercial quality and used without further purification. Yields refer to chromatographically homogeneous materials. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as a visualizing agent and an ethanolic solution of ammonium molybdate, anisaldehyde, and heat as developing agents. E. Merck silica gel (60, particle size 0.040− 0.063 mm) was used for flash column chromatography. NMR spectra were recorded on a Bruker AV-400 instrumentand calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br = broad, dd = doublet of doublets, td = triplet of doublets, m = multiplet. Melting points (mp) are uncorrected and recorded on a Buchi B−540 melting point apparatus. High-resolution mass spectra (HRMS) were recorded by using a Waters MALDI SYNAPT G2-Si high-definition mass spectrometer (ESI-TOF). The following abbreviations are used below: Bz = benzoyl, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP = N,N′dimethylaminopyridine, DMP = Dess−Martin periodinane, HMPA = hexamethylphosphoric triamide, MsCl = methanesulfonyl chloride, TBAB = tetra-n-butylammonium bromide, TBHP = tert-butyl hydroperoxide, TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy, THF = tetrahydrofuran, TMS = trimethylsilyl, TPPO = triphenyl phosphite ozonide, trisyl = 2,4,6-triisopropylbenzenesulfonyl. (1S,6S)-6-Isopropyl-3-methyl-4-oxocyclohex-2-en-1-yl Benzoate (9). To a stirred solution of enone 115,11 (12.8 g, 76.14 mmol) in CH2Cl2 (120 mL) at 25 °C were sequentially added Et3N (31.7 mL, 0.23 mol, 3.0 equiv), 4-DMAP (9.3 g, 76.14 mmol, 1.0 equiv), and Bz2O (25.8 g, 0.11 mol, 1.5 equiv). The resulting mixture was stirred at 25 °C for 30 min before NaHCO3 (100 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 30:1) afforded 9 (19.7 g, 95%) as a colorless oil: Rf = 0.50 (silica gel, hexanes/EtOAc 5:1); [α]20 D −202.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 6.63 (s, 1H), 5.80 (d, J = 9.4 Hz, 1H), 2.60 (dd, J = 15.2, 3.0 Hz, 1H), 2.41−2.34 (m, 1H), 2.33−2.24 (m, 1H), 2.00−1.92 (m, 1H), 1.81 (s, 3H), 0.96 (d, J = 7.0 Hz, 3H), 0.91 ppm (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.2, 166.2, 143.7, 136.9, 133.5, 129.9 (3C), D

DOI: 10.1021/acs.joc.9b01308 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

(ESI-TOF) calcd for C24H28O4Na+ [M + Na]+ 403.1880, found 403.1880. (1S,2S,4aR,5S,6S,8aS)-6-Allyl-2-isopropyl-4a-methyl-5-(3-methylbut-3-en-1-yl)-4,7-dioxodecahydronaphthalen-1-yl Benzoate (7). To a stirred solution of magnesium turnings (1.7 g, 71.54 mmol, 2.0 equiv) in THF (40 mL) at 25 °C was added 1,2-dibromoethane (0.15 mL, 1.79 mmol, 0.05 equiv). The resulting mixture was warmed to 66 °C and stirred for 5 min before a solution of 4-bromo-2-methylbut-1ene (5.8 g, 35.77 mmol) in THF (5 mL) was added dropwise. The resulting mixture was stirred at 66 °C for 1 h before it was added to a solution of CuBr·SMe2 (7.3 g, 35.77 mmol, 1.0 equiv) in THF (50 mL) at −78 °C. The resulting mixture was stirred at −78 °C for an additional 15 min before HMPA (6.2 mL, 35.77 mmol, 1.0 equiv), a solution of alkene 14 (6.8 g, 17.88 mmol, 0.5 equiv) in THF (10 mL), and TMSCl (4.5 mL, 35.77 mmol, 1.0 equiv) were sequentially added. The reaction was stirred at −78 °C for further 1.5 h before NH4Cl (50 mL, sat. aq) was added. The layers were separated, and the organic layer was acidified with AcOH (5.1 mL, 89.43 mmol, 2.5 equiv) and stirred at 25 °C for 1 h before NaHCO3 (50 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with Et2O (3 × 50 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 10:1) afforded 7 (4.8 g, 62%) as a colorless oil: Rf = 0.55 (silica gel, hexanes/EtOAc 5:1); 1 [α]20 D −36.6 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.3 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 6.03−5.89 (m, 1H), 5.42 (t, J = 10.9 Hz, 1H), 5.17−5.09 (m, 2H), 4.70 (d, J = 20.1 Hz, 2H), 2.77 (d, J = 14.0 Hz, 1H), 2.66 (t, J = 14.1 Hz, 1H), 2.51 (dd, J = 16.3, 6.2 Hz, 1H), 2.44−2.35 (m, 4H), 2.33− 2.28 (m, 1H), 2.22 (dd, J = 10.9, 4.6 Hz, 1H), 2.05−1.96 (m, 2H), 1.92−1.79 (m, 2H), 1.67 (s, 3H), 1.55−1.46 (m, 1H), 1.45−1.38 (m, 1H), 1.34 (s, 3H), 0.87 ppm (t, J = 6.5 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 212.9, 208.5, 165.7, 145.2, 136.0, 133.4, 130.0 (2C), 129.6, 128.6 (2C), 117.7, 111.2, 71.1, 52.8, 52.7, 50.1, 48.8, 42.1, 38.8, 36.9, 35.7, 31.6, 29.1, 26.8, 22.4, 20.7, 16.7, 15.7 ppm; HRMS (ESITOF) calcd for C29H38O4Na+ [M + Na]+ 473.2662, found 473.2670. (3S,4S,4aS,6aS,11aS,11bR)-3-Isopropyl-9,11b-dimethyl-1,6dioxo-2,3,4,4a,5,6,6a,7,10, 11,11a,11b-dodecahydro-1Hcyclohepta[a]naphthalen-4-yl Benzoate (16). To a stirred solution of bicyclic diene 7 (4.1 g, 9.11 mmol) in CH2Cl2 (100 mL) was added Grubbs II catalyst (0.39 g, 0.45 mmol, 5.0 mol %). The resulting mixture was warmed to 40 °C and stirred for 2 h before cooling to 25 °C and was concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 10:1) afforded 16 (3.2 g, 83%) as a colorless oil: Rf = 0.55 (silica gel, hexanes/EtOAc 5:1); [α]20 D −105.0 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.4 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 5.52 (s, 1H), 5.41 (t, J = 10.9 Hz, 1H), 2.90 (dd, J = 15.4, 8.6 Hz, 1H), 2.58−2.49 (m, 2H), 2.41−2.33 (m, 3H), 2.30−2.23 (m, 1H), 2.23−2.14 (m, 2H), 2.06−1.93 (m, 3H), 1.87−1.80 (m, 1H), 1.70 (s, 3H), 1.37 (s, 3H), 1.31−1.25 (m, 2H), 0.91 (d, J = 6.8 Hz, 3H), 0.87 ppm (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 212.6, 208.1, 165.5, 142.2, 133.4, 130.0 (2C), 129.6, 128.6 (2C), 123.3, 71.0, 53.8, 51.0, 50.5, 50.4, 48.8, 39.2, 35.3, 32.3, 27.5, 26.7, 26.0, 25.3, 20.9, 16.5, 15.8 ppm; HRMS (ESI-TOF) calcd for C27H34O4Na+ [M + Na]+ 445.2349, found 445.2359. (3S,4S,4aR,6aS,11aS,11bR)-5-Diazo-4-hydroxy-3-isopropyl9,11b-dimethyl-3,4,4a,5, 6a,7,10,11,11a,11b-decahydro-1Hcyclohepta[a]naphthalene-1,6(2H)-dione (6). To a stirred solution of tricyclic ketone 16 (1.3 g, 3.17 mmol) in toluene (15 mL) at 25 °C were sequentially added TBAB (1.0 g, 3.17 mmol, 1.0 equiv), 18crown-6 ether (0.84 g, 3.17 mmol, 1.0 equiv), and a solution of KOH (1.8 g, 31.70 mmol, 10.0 equiv) in H2O (5 mL). The resulting mixture was stirred at 25 °C for 30 min before trisylN3 (2.0 g, 6.35 mmol, 2.0 equiv) was added. The resulting mixture was warmed to 40 °C and stirred for an additional 4 h before KOH (1.8 g, 31.70 mmol, 10.0 equiv) and MeOH (20 mL) were added. The reaction was stirred at 40 °C for a further 2 h before cooling to 0 °C, and NH4Cl (50 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined

128.7 (2C), 71.4, 46.9, 36.8, 27.2, 20.5, 17.2, 15.5 ppm; HRMS (ESITOF) calcd for C17H20O3Na+ [M + Na]+ 295.1305, found 295.1303. (1S,2S,4aR,8aS)-2-Isopropyl-4a-methyl-4,7-dioxo1,2,3,4,4a,7,8,8a-octahydro-naphthalen-1-yl Benzoate (8). To benzoate 9 (8.0 g, 29.40 mmol) was added Rawal diene 10 (15.5 mL, 58.79 mmol, 2.0 equiv). The resulting mixture was stirred at 70 °C for 24 h before cooling to −78 °C and CH2Cl2 (100 mL) was added, followed by HF (40 wt %/wt aq, 29.4 mL, 0.59 mol, 20.0 equiv). The resulting mixture was warmed to 25 °C and stirred for an additional 24 h before NaHCO3 (100 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 5:1) afforded 8 (8.4 g, 84%) as a white solid: mp 127−129 °C (CH2Cl2/hexanes); Rf = 0.40 (silica gel, 1 hexanes/EtOAc 3:1); [α]20 D −274.0 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 8.3, 1.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 6.54 (dd, J = 10.1, 1.7 Hz, 1H), 6.16 (d, J = 10.1 Hz, 1H), 5.42 (t, J = 10.3 Hz, 1H), 2.70−2.63 (m, 1H), 2.53−2.46 (m, 3H), 2.34 (t, J = 13.5 Hz, 1H), 2.13−2.05 (m, 1H), 1.90−1.80 (m, 1H), 1.44 (s, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.80 ppm (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 209.8, 195.3, 165.8, 149.3, 133.5, 130.0 (2C), 129.9, 129.5, 128.6 (2C), 71.5, 50.4, 47.7, 47.2, 37.3, 36.4, 27.1, 21.9, 20.6, 15.9 ppm; HRMS (ESITOF) calcd for C21H24O4Na+ [M + Na]+ 363.1567, found 363.1567. (1S,2S,4aS,8aS)-6-Iodo-2-isopropyl-4a-methyl-4,7-dioxo1,2,3,4,4a,7,8,8a-octahydro-naphthalen-1-yl Benzoate (13). To a stirred solution of bicyclic diketone 8 (9.0 g, 26.46 mmol) in CH2Cl2 (50 mL) at 0 °C was added TMSN3 (7.0 mL, 52.91 mmol, 2.0 equiv). The resulting mixture was stirred at 0 °C for 2 h before iodine (13.4 g, 52.91 mmol, 2.0 equiv) and pyridine (21.3 mL, 0.26 mol, 5.0 equiv) were added. The resulting mixture was slowly warmed to 25 °C and stirred for an additional 12 h before Na2S2O3 (80 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 10:1) afforded 13 (6.2 g, 50%) as a yellow oil: Rf = 0.35 (silica gel, hexanes/EtOAc 5:1); [α]20 D −90.5 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.1 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.33 (d, J = 1.5 Hz, 1H), 5.34 (t, J = 10.3 Hz, 1H), 2.87−2.73 (m, 2H), 2.56 (dd, J = 14.3, 4.4 Hz, 2H), 2.39−2.31 (m, 1H), 2.15−2.07 (m, 1H), 1.91−1.82 (m, 1H), 1.47 (s, 3H), 0.89 (d, J = 7.0 Hz, 3H), 0.82 ppm (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 208.0, 188.4, 165.7, 157.1, 133.6, 130.0 (2C), 129.3, 128.7 (2C), 104.8, 71.4, 54.5, 47.9, 46.9, 37.5, 35.6, 27.2, 21.8, 20.6, 16.0 ppm; HRMS (ESI-TOF) calcd for C21H23IO4Na+ [M + Na]+ 489.0533, found 489.0536. (1S,2S,4aR,8aS)-6-Allyl-2-isopropyl-4a-methyl-4,7-dioxo1,2,3,4,4a,7,8,8a-octahydro-naphthalen-1-yl Benzoate (14). To a stirred solution of α-iodoenone 13 (11.6 g, 24.89 mmol) in THF (100 mL) at 25 °C were sequentially added Pd(PPh3)4 (2.2 g, 1.87 mmol, 7.5 mol %) and allyltributyltin (11.6 mL, 37.33 mmol, 1.5 equiv). The resulting mixture was warmed to 66 °C and stirred for 5 h before cooling to 25 °C and NH4Cl (70 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL, sat. aq), dried (Na2SO4), and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 10:1) afforded 14 (8.0 g, 81%) as a colorless oil: Rf = 0.45 (silica gel, hexanes/EtOAc 1 5:1); [α]20 D −141.4 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.1 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 6.25 (d, J = 1.7 Hz, 1H), 5.87−5.77 (m, 1H), 5.42 (t, J = 10.4 Hz, 1H), 5.12 (t, J = 1.2 Hz, 1H), 5.10−5.06 (m, 1H), 3.15−3.08 (m, 1H), 2.99−2.92 (m, 1H), 2.68 (dd, J = 17.9, 5.0 Hz, 1H), 2.54−2.43 (m, 3H), 2.34 (t, J = 13.5 Hz, 1H), 2.11−2.04 (m, 1H), 1.89−1.82 (m, 1H), 1.42 (s, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.80 ppm (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 210.2, 194.8, 165.9, 144.6, 139.0, 135.0, 133.5, 130.0 (2C), 129.5, 128.6 (2C), 117.3, 71.6, 50.6, 47.7, 47.2, 37.3, 36.6, 33.2, 27.0, 21.9, 20.7, 15.8 ppm; HRMS E

DOI: 10.1021/acs.joc.9b01308 J. Org. Chem. XXXX, XXX, XXX−XXX

Note

The Journal of Organic Chemistry

1.71 (s, 3H), 1.69−1.56 (m, 2H), 1.53 (t, J = 10.3 Hz, 2H), 1.02 (d, J = 7.0 Hz, 6H), 0.98 ppm (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.7, 177.3, 141.8, 123.4, 77.4, 56.2, 56.0, 51.9, 49.7, 46.5, 44.1, 35.1, 31.4, 30.2, 28.1, 26.1, 25.3, 20.8, 20.6, 20.5 ppm; HRMS (ESI-TOF) calcd for C20H28O3Na+ [M + Na]+ 339.1931, found 339.1928. (2aR,2a1S,3S,5aR,5bS,10aS,10bS)-8-Hydroxy-3-isopropyl-5a,8dimethyl-2a1,3,4,5a,5b, 6,7,8,10a,10b-decahydro-1H-cyclohepta[2,3]indeno[7,1-bc]furan-1,5(2aH)-dione (22) and (2aR,2a1S,3S,5aR,5bS,10aS,10bS)-9-Hydroxy-3-isopropyl-5a,8-dimethyl-2a1,3,4,5a,5b,6,9, 10,10a,10b-decahydro-1H-cyclohepta[2,3]indeno[7,1-bc]furan-1,5(2aH)-dione (23). To a stirred solution of alkene 19 (42 mg, 0.13 mmol) in CH2Cl2 (4.0 mL) at −20 °C was added TPPO (0.25 M in CH2Cl2, 5.3 mL, 1.33 mmol, 10.0 equiv). The resulting mixture was stirred at −20 °C for 1 h before warming to 25 °C and PPh3 (104 mg, 0.40 mmol, 3.0 equiv) was added. The reaction was stirred at 25 °C for an additional 30 min before NaHCO3 (20 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 3:1) afforded 22 (28 mg, 63%) as a white amorphous solid, along with 23 (6.6 mg, 15%) as a white amorphous solid. Compound 22: Rf = 0.45 1 (silica gel, hexanes/EtOAc 1:1); [α]20 D −336.2 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 6.20 (dd, J = 12.6, 2.2 Hz, 1H), 5.84− 5.76 (m, 1H), 4.79 (d, J = 6.8 Hz, 1H), 3.23 (t, J = 8.0 Hz, 1H), 2.92−2.84 (m, 1H), 2.79−2.73 (m, 1H), 2.60 (t, J = 14.4 Hz, 1H), 2.35−2.29 (m, 1H), 1.84 (dd, J = 14.8, 6.8 Hz, 1H), 1.77 (dd, J = 10.6, 4.1 Hz, 2H), 1.69−1.64 (m, 1H), 1.60−1.55 (m, 3H), 1.47− 1.39 (m, 1H), 1.27 (s, 3H), 1.10 (s, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.98 ppm (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.2, 177.3, 140.7, 123.5, 77.1, 74.7, 55.2, 51.8, 50.8, 48.3, 46.3, 46.2, 41.2, 35.0, 30.1, 26.9, 24.0, 20.8, 20.5 ppm (2C); HRMS (ESI-TOF) calcd for C20H28O4Na+ [M + Na]+ 355.1880, found 355.1884. Compound 23: Rf = 0.38 (silica gel, hexanes/EtOAc 1:1); [α]20 D −267.5 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.37 (s, 1H), 4.78 (d, J = 6.9 Hz, 1H), 4.38 (d, J = 5.3 Hz, 1H), 3.19 (t, J = 7.9 Hz, 1H), 2.78−2.70 (m, 1H), 2.58 (t, J = 14.3 Hz, 1H), 2.43−2.26 (m, 2H), 2.19−2.07 (m, 2H), 2.01−1.93 (m, 1H), 1.81 (dd, J = 14.3, 6.9 Hz, 1H), 1.75 (s, 3H), 1.69−1.49 (m, 4H), 1.04 (s, 3H), 1.01 (d, J = 6.7 Hz, 3H), 0.97 ppm (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.6, 177.1, 144.9, 120.7, 77.3, 72.2, 54.9, 51.2, 49.5, 47.5, 47.4, 46.3, 37.1, 34.9, 30.2, 25.4, 20.8, 20.5, 20.0, 19.1 ppm; HRMS (ESI-TOF) calcd for C20H28O4Na+ [M + Na]+ 355.1880, found 355.1884. (2aR,2a1S,3S,5aR,5bS,10aR,10bR)-3-Isopropyl-5a,8-dimethyl2a,2a 1 ,3,4,5a,5b,6,7,10a,10b-decahydro-1H-cyclohepta[2,3]indeno[7,1-bc]furan-1,5,10-trione (20). To a stirred solution of allyl alcohol 22 (26 mg, 0.08 mmol) in CH2Cl2 (5.0 mL) at 25 °C was added TEMPO+BF4− (38 mg, 0.16 mmol, 2.0 equiv). The resulting mixture was stirred for 4 h before NaHCO3 (33 mg, 0.39 mmol, 2.5 equiv) and DMP (66 mg, 0.16 mmol, 1.0 equiv) were added. The reaction was stirred at 25 °C for an additional 20 min before Na2S2O3 (20 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 2:1) afforded 20 (12.7 mg, 48%) as a white amorphous solid. Please note the alternative preparation of 20 from 19: To a stirred solution of alkene 19 (9.5 mg, 0.03 mmol) in chlorobenzene (2.0 mL) at 25 °C were added pyridine (24 μL, 0.30 mmol, 10.0 equiv), Ph2Se2 (3.1 mg, 0.01 mmol, 0.3 equiv), and PhIO2 (21 mg, 0.09 mmol, 3.0 equiv). The resulting mixture was slowly warmed to 100 °C, stirred for 6 h before cooling to 25 °C, filtered through a short pad of Celite, and washed with EtOAc. The filtrate was collected and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 2:1) afforded 20 (1.0 mg, 10%): Rf = 0.40 (silica gel, hexanes/EtOAc 1 1:1); [α]20 D −228.4 (c 0.1, CHCl3); H NMR (400 MHz, CDCl3) δ 6.10 (s, 1H), 4.85 (d, J = 6.5 Hz, 1H), 3.79 (dd, J = 8.2, 6.5 Hz, 1H), 2.94 (dd, J = 12.8, 6.5 Hz, 1H), 2.76 (dd, J = 8.2, 6.5 Hz, 1H), 2.66−

organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 5:1) afforded 6 (0.57 g, 52%) as a yellow solid: mp 132−133 °C (CH2Cl2/hexanes); Rf = 0.55 (silica gel, hexanes/EtOAc 2:1); [α]20 D −230.2 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.62 (d, J = 6.9 Hz, 1H), 4.11−4.01 (m, 1H), 3.03 (dd, J = 12.8, 8.5 Hz, 1H), 2.88 (s, 1H), 2.50 (d, J = 9.8 Hz, 1H), 2.32 (s, 1H), 2.29 (d, J = 5.2 Hz, 1H), 2.23 (dd, J = 14.0, 2.7 Hz, 1H), 2.19−2.09 (m, 2H), 1.99 (dd, J = 15.1, 6.9 Hz, 1H), 1.96−1.87 (m, 2H), 1.76−1.70 (m, 1H), 1.70 (s, 3H), 1.30−1.13 (m, 2H), 1.12 (s, 3H), 0.96 (d, J = 7.0 Hz, 3H), 0.92 ppm (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 212.0, 193.5, 141.7, 124.1, 74.8, 68.3, 52.1, 50.5, 48.8 (2C), 47.6, 36.1, 33.0, 30.1, 27.6, 26.3, 25.8, 20.7, 16.2, 15.6 ppm; HRMS (ESI-TOF) calcd for C20H28N2O3Na+ [M + Na]+ 367.1992, found 367.2007. (3S,4S,4aR,6aS,11aS,11bR)-5-Diazo-3-isopropyl-9,11b-dimethyl1,6-dioxo-2,3,4,4a,5,6,6a,7,10,11,11a,11b-dodecahydro-1Hcyclohepta[a]naphthalen-4-yl Methanesulfonate (17). To a stirred solution of α-diazoketone 6 (1.3 g, 3.86 mmol) in CH2Cl2 (20 mL) at 0 °C were sequentially added Et3N (1.6 mL, 11.59 mmol, 3.0 equiv), 4-DMAP (0.47 g, 3.86 mmol, 1.0 equiv), and MsCl (0.60 mL, 7.73 mol, 2.5 equiv). The resulting mixture was stirred at 0 °C for 15 min before NaHCO3 (20 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 4:1) afforded 17 (1.6 g, 95%) as a colorless oil: Rf = 0.56 (silica gel, hexanes/EtOAc 2:1); [α]20 D −182.3 (c 0.5, CHCl3); 1 H NMR (400 MHz, CDCl3) δ 5.64 (d, J = 6.2 Hz, 1H), 5.16 (t, J = 10.6 Hz, 1H), 3.11 (s, 3H), 3.00 (dd, J = 13.4, 8.3 Hz, 1H), 2.75 (d, J = 10.2 Hz, 1H), 2.45 (dd, J = 14.0, 4.3 Hz, 1H), 2.36 (t, J = 13.9 Hz, 1H), 2.32−2.25 (m, 1H), 2.21 (td, J = 10.4, 3.3 Hz, 1H), 2.12−2.00 (m, 4H), 1.97−1.89 (m, 1H), 1.70 (s, 3H), 1.21 (td, J = 7.7, 7.1, 3.7 Hz, 2H), 1.16 (s, 3H), 0.97 (s, 3H), 0.95 ppm (d, J = 7.3 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 209.8, 192.9, 140.5, 124.2, 82.8, 65.7, 52.7, 49.4, 49.3, 47.4, 47.3, 38.9, 35.6, 33.0, 30.8, 27.7, 26.2, 26.1, 21.1, 16.1, 15.3 ppm; HRMS (ESI-TOF) calcd for C21H30N2O5SNa+ [M + Na]+ 445.1768, found 445.1775. (1S,2S,4aR,4bS,9aS,10S,10aS)-2-Isopropyl-4a,7-dimethyl-1((methylsulfonyl)oxy)-4-oxo-1,2,3,4,4a,4b,5,6,9,9a,10,10adodecahydrobenzo[a]azulene-10-carboxylic Acid (18). A solution of α-diazoketone 17 (0.54 g, 1.28 mmol) in THF (20 mL) at 25 °C was irradiated with a 500 W medium-pressure Hg lamp for 1 h before concentrating in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 2:1 → 1:2) afforded 18 (0.38 g, 72%) as a colorless 1 oil: Rf = 0.4 (silica gel, EtOAc); [α]20 D −31.9 (c 0.5, MeOH); H NMR (400 MHz, CD3OD) δ 5.60 (s, 1H), 4.95 (s, 1H), 3.17 (s, 3H), 2.74 (dd, J = 9.3, 5.7 Hz, 1H), 2.70−2.60 (m, 1H), 2.50 (dd, J = 10.3, 7.8 Hz, 3H), 2.21−2.12 (m, 2H), 2.08 (dt, J = 12.6, 6.5 Hz, 3H), 2.03−1.88 (m, 2H), 1.82 (d, J = 9.7 Hz, 1H), 1.77 (s, 3H), 1.64 (dd, J = 13.2, 6.1 Hz, 1H), 1.13 (s, 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.93 ppm (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 212.9, 176.5, 141.1, 123.0, 84.0, 57.4, 56.6, 56.2, 54.4, 46.4 (2C), 37.9, 35.1, 32.2, 32.0, 26.5, 25.8, 25.6, 19.6, 18.7, 14.9 ppm; HRMS (ESI-TOF) calcd for C21H32O6SNa+ [M + Na]+ 435.1812, found 435.1815. (2aR,2a1S,3S,5aR,5bS,10aS,10bS)-3-Isopropyl-5a,8-dimethyl2a 1 ,3,4,5a,5b,6,7,10,10a,10b-decahydro-1H-cyclohepta[2,3]indeno[7,1-bc]furan-1,5(2aH)-dione (19). To a stirred solution of acid 18 (0.42 g, 1.02 mmol) in MeCN (8 mL) were sequentially added 18-crown-6 ether (0.27 g, 1.02 mmol, 1.0 equiv) and K2CO3 (0.70 g, 5.09 mmol, 5.0 equiv). The resulting mixture was warmed to 90 °C and stirred for 14 h before cooling to 25 °C and NH4Cl (20 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 10:1) afforded 19 (0.15 g, 45%) as a white amorphous solid: Rf = 0.55 (silica gel, hexanes/ 1 EtOAc 5:1); [α]20 D −123.4 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 5.53 (s, 1H), 4.77 (d, J = 7.0 Hz, 1H), 3.13 (t, J = 8.1 Hz, 1H), 2.73−2.61 (m, 2H), 2.56 (dd, J = 14.4, 9.0 Hz, 1H), 2.30 (d, J = 11.9 Hz, 2H), 2.03−1.89 (m, 2H), 1.85 (dt, J = 14.6, 7.1 Hz, 2H), F

DOI: 10.1021/acs.joc.9b01308 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry 2.58 (m, 1H), 2.42 (dt, J = 19.7, 3.7 Hz, 1H), 2.35 (dd, J = 15.0, 1.8 Hz, 1H), 2.20 (td, J = 13.1, 12.6, 6.0 Hz, 1H), 2.03−1.90 (m, 2H), 1.89 (s, 3H), 1.82 (dt, J = 13.4, 6.7 Hz, 1H), 1.71−1.65 (m, 1H), 1.55−1.50 (m, 1H), 1.08 (s, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.98 ppm (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 209.9, 197.0, 175.5, 154.6, 128.3, 76.1, 56.9, 52.7, 49.8, 47.7, 44.8, 44.6, 35.0, 33.8, 29.0, 27.2, 23.3, 19.5, 19.3, 18.4 ppm; HRMS (ESI-TOF) calcd for C20H27O4+ [M + H]+ 331.1904, found 331.1901. (2aR,2a1S,3S,5aR,5bS,10aS,10bS)-3-Isopropyl-5a-methyl-1,5dioxo-2a,2a 1 ,3,4,5,5a,5b, 6,7,10,10a,10b-dodecahydro-1Hcyclohepta[2,3]indeno[7,1-bc]furan-8-carbaldehyde (21). To a stirred solution of alkene 19 (9.5 mg, 0.03 mmol) in toluene (2.0 mL) at 25 °C was added SeO2 (17.5 mg, 0.16 mmol, 5.3 equiv). The resulting mixture was warmed to 90 °C and stirred for 30 min before cooling to 25 °C, and NaHCO3 (5.0 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 2:1) afforded 21 (6.7 mg, 68%) as a white amorphous solid: Rf = 0.58 (silica gel, hexanes/EtOAc 1:1); [α]20 D −146.7 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 6.88 (s, 1H), 4.82 (d, J = 6.8 Hz, 1H), 3.27−3.17 (m, 1H), 3.10−3.02 (m, 1H), 2.97 (dd, J = 15.1, 6.5 Hz, 1H), 2.79−2.70 (m, 2H), 2.65 (t, J = 14.4 Hz, 1H), 2.35 (dd, J = 14.6, 1.6 Hz, 1H), 2.04−1.92 (m, 1H), 1.90−1.78 (m, 1H), 1.71 (dd, J = 8.6, 5.8 Hz, 2H), 1.68−1.61 (m, 2H), 1.04 (d, J = 6.7 Hz, 3H), 1.02 (s, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.88 ppm (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.0, 193.6, 177.0, 153.5, 147.8, 77.2, 55.8, 55.2, 51.6, 49.6, 46.2, 42.4, 35.0, 30.2, 29.4, 25.2, 21.2, 20.8 (2C), 20.5 ppm; HRMS (ESI-TOF) calcd for C20H27O4+ [M + H]+ 331.1904, found 331.1901. (2aR,2a1S,3S,5aR,5bS,10aR,10bR)-3-Isopropyl-5a,8-dimethyl2a,2a 1 ,3,4,5a,5b,6,7,10a,10b-decahydro-1H-cyclohepta[2,3]indeno[7,1-bc]furan-1,5,10-trione (4). To a stirred solution of enone 20 (11.3 mg, 0.035 mmol) in toluene (5.0 mL) at 25 °C was added DBU (26 μL, 0.18 mmol, 5.0 equiv). The resulting mixture was warmed to 40 °C and stirred for 12 h before cooling to 25 °C, and NH4Cl (10 mL, sat. aq) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 4:1) afforded (−)-4 (11.1 mg, 98%) as a white solid. Please note the alternative preparation of (−)-4 from 19: To a solution of alkene 19 (9.5 mg, 0.03 mmol) in EtOAc (3.0 mL) at 25 °C were added TBHP in decane (5.5 M, 24 μL, 0.13 mmol, 4.0 equiv) and 4 Å molecular sieves (20 mg). The resulting mixture was stirred for 30 min before Mn(OAc)·2H2O (0.8 mg, 3.20 μmol, 0.1 equiv) was added. The reaction was stirred at 25 °C for an additional 72 h before filtering through a short pad of Celite and washing with EtOAc. The filtrate was collected and concentrated in vacuo. Flash column chromatography (silica gel, hexanes/EtOAc 4:1) afforded (−)-pavidolide B (4, 1.6 mg, 16%). Compound (−)-4: mp 176−178 °C (CH2Cl2/hexanes); Rf = 0.45 (silica gel, hexanes/EtOAc 2:1); [α]20 D −134.8 (c 0.4, MeOH); 1H NMR (400 MHz, CDCl3) δ 5.98 (dd, J = 2.6, 1.4 Hz, 1H), 4.94 (dt, J = 6.7, 1.7 Hz, 1H), 3.80 (dd, J = 8.9, 0.9 Hz, 1H), 3.62 (d, J = 9.3 Hz, 1H), 3.04 (dd, J = 8.9, 6.6 Hz, 1H), 2.55−2.47 (m, 1H), 2.45−2.40 (m, 2H), 2.39−2.37 (m, 1H), 2.00 (t, J = 1.1 Hz, 3H), 1.92−1.81 (m, 2H), 1.76−1.70 (m, 1H), 1.63−1.48 (m, 2H), 1.05 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H), 0.97 ppm (s, 3H); 1H NMR (400 MHz, DMSO-d6) δ 5.90 (s, 1H), 4.99 (d, J = 6.8 Hz, 1H), 3.71 (d, J = 9.0 Hz, 1H), 3.41 (d, J = 9.4 Hz, 1H), 2.95 (dd, J = 8.9, 6.9 Hz, 1H), 2.57 (ddd, J = 9.9, 9.4, 3.9 Hz, 1H), 2.49 (dd, J = 15.1, 11.0 Hz, 1H), 2.47−2.44 (m, 1H), 2.32 (dd, J = 17.8, 6.3 Hz, 1H), 2.16 (dd, J = 15.2, 2.7 Hz, 1H), 1.97 (s, 3H), 1.91−1.84 (m, 1H), 1.70−1.61 (m, 2H), 1.33 (dd, 24.5, 12.1 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.81 ppm (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 211.7, 199.2, 179.9, 163.5, 129.1, 78.0, 59.1, 54.5, 54.0, 48.9, 47.2, 45.1, 34.8, 34.0, 30.3, 27.9, 26.6, 21.8, 20.7, 20.4 ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ 211.5, 199.3, 179.9, 164.4, 128.4, 78.2, 59.2, 54.4, 53.8, 48.2, 46.9, 44.3, 34.7, 33.8,

30.3, 27.7, 26.4, 21.7, 20.7, 20.5 ppm; HRMS (ESI-TOF) calcd for C20H26NaO4+ [M + Na]+ 353.1723, found 353.1725.

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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.joc.9b01308. Copies of 1H and 13C NMR spectra for all new compounds and crystal data of compound 6 (PDF) X-ray crystallographic data of compound 6 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hanfeng Ding: 0000-0002-1781-4604 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Zhejiang Natural Science Fund for Distinguished Young Scholars (LR16B020001) and the National Natural Science Foundation of China (21871230 and 21622205). We thank Ms. Yaqin Liu (Zhejiang University) for NMR spectroscopic assistance.

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REFERENCES

(1) (a) Roethle, P. A.; Trauner, D. The chemistry of marine furanocembranoids, pseudopteranes, gersolanes, and related natural products. Nat. Prod. Rep. 2008, 25, 298−317. (b) Li, Y.; Pattenden, G. Perspectives on the structural and biosynthetic interrelationships between oxygenated furanocembranoids and their polycyclic congeners found in corals. Nat. Prod. Rep. 2011, 28, 1269−1310. (c) Aratake, S.; Tomura, T.; Saitoh, S.; Yokokura, R.; Kawanishi, Y.; Shinjo, R.; Reimer, J. D.; Tanaka, J.; Maekawa, H. Soft Coral Sarcophyton (Cnidaria: Anthozoa: Octocorallia) Species Diversity and Chemotypes. PLoS One 2012, 7, e30410. (2) (a) Anjaneyulu, A. S. R.; Venugopal, M. J. R. V.; Sarada, P.; Rao, G. V.; Clardy, J.; Lobkovsky, E. Sarcophytin. A Novel Tetracyclic Diterpenoid From The Indian Ocean Soft Coral Sarcophyton elegans. Tetrahedron Lett. 1998, 39, 135−138. (b) Anjaneyulu, A. S. R.; Gowri, P. M.; Venugopal, M. J. R. V.; Sarada, P.; Murthy, M. V. R. K.; Rao, G. V.; Murthy, P. S. N.; Rao, C. V.; Kumar, G. Novel diterpenoids from the Indian Ocean soft coral Sarcophyton elegans. J. Indian Chem. Soc. 1999, 76, 651−659. (c) Sugano, M.; Shindo, T.; Sato, A.; Iijima, Y.; Oshima, T.; Kuwano, H.; Hata, T. Chatancin, a PAF antagonist from a soft coral, Sarcophyton sp. J. Org. Chem. 1990, 55, 5803−5805. (d) Bogdanov, A.; Hertzer, C.; Kehraus, S.; Nietzer, S.; Rohde, S.; Schupp, P. J.; Wagele, H.; Konig, G. M. Defensive Diterpene from the Aeolidoidean Phyllodesmium longicirrum. J. Nat. Prod. 2016, 79, 611− 615. (e) Anjaneyulu, A. S. R.; Gowri, P. M.; Krishna Murthy, M. V. R. 7-Dehydrosarcophytin, another Novel Diterpenoid from the Soft Coral Sarcophyton elegans of the Indian Ocean. J. Chem. Res. 1999, 0, 140−141. (f) Anjaneyulu, V.; Makarieva, T. N.; Ilyin, S. G.; Dmitrenok, A. S.; Radhika, P.; Subbarao, P. V.; Nesterov, V. V.; Antipin, M. Y.; Stonik, V. A. Two New Diterpenoids, Sarcophytins B and C, from the Indian Ocean Soft Coral Sarcophyton Species. J. Nat. Prod. 2000, 63, 109−111. (3) For total syntheses, see: (a) Aigner, J.; Gössinger, E.; Kählig, H.; Menz, G.; Pflugseder, K. Total Synthesis of Chatancin. Angew. Chem., Int. Ed. 1998, 37, 2226−2228. (b) Soucy, P.; L’Heureux, A.; Toró, A.; Deslongchamps, P. Pyranophane Transannular Diels−Alder Approach to (+)-Chatancin: A Biomimetic Asymmetric Total Synthesis. J. Org. Chem. 2003, 68, 9983−9987. (c) Zhao, Y.; Maimone, T. J. Short, Enantioselective Total Synthesis of Chatancin. Angew. Chem., Int. Ed. G

DOI: 10.1021/acs.joc.9b01308 J. Org. Chem. XXXX, XXX, XXX−XXX

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H

DOI: 10.1021/acs.joc.9b01308 J. Org. Chem. XXXX, XXX, XXX−XXX