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Article Cite This: J. Org. Chem. 2019, 84, 831−839

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Synthesis of Javanicunines A and B, 9‑Deoxy-PF1233s A and B, and Absolute Configuration Establishment of Javanicunine B Ming-Zhong Wang,*,†,‡,⊥ Tong-Xu Si,†,⊥ Chuen-Fai Ku,‡ Hong-Jie Zhang,*,‡ Zheng-Ming Li,§ and Albert S. C. Chan*,† †

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, People’s Republic of China § State Key Laboratory of Elemento-organic Chemistry, Research Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China

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S Supporting Information *

ABSTRACT: Javanicunines A-B and 9-deoxy-PF1233s A-B belong to a family of natural diketomorpholines with a unique isopropenyl group at C-10b or C-5a and a hydroxyl group at C-11a or C-10b. We herein reported the first total synthesis of javanicunines A-B and 9-deoxy-PF1233s A-B. Pivotal features of the synthesis included a nucleophilic substitution reaction, followed by a Davis’ oxaziridine oxidation to assemble javanicunines A-B, and a chemoselective and stereoselective oxidation with Murray’s reagent to install the requisite C-10b hydroxyl group in 9-deoxy-PF1233s A-B. The present synthesis also established the absolute configuration of javanicunine B.

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INTRODUCTION Pyrrolidinoindoline natural products are a growing family of alkaloids that have exhibited a great variety of biological properties. Pyrrolidinoindolines consist mainly of the majority of diketopiperazines (DKPs) and the minority of diketomorpholines (DKMs). DKPs have attracted extensive attention, with much efforts on their biosynthetic pathways and their total synthesis. Nevertheless, a few investigations on the phytochemistry and medicinal chemistry of the DKMs have been reported.1,2 Javanicunines A (1) and B (2) (Figure 1) are the two unprecedented isoprenylated (C-10b) DKMs alkaloids isolated from the Eupenicillium javanicum (IFM 54704) by Nakadate et al.3 The absolute configuration of javanicunine A was determined by chemical degradation, and the absolute configuration of javanicunine B was proposed on the basis of its same biogenetic origin of javanicunine A. Because of the scarce amount of 1 and 2, their biological activity testing was only limited to fungicidal activities.3 The novel DKMs alkaloids 9-deoxy-PF1233 A (3) and B (4) with the rare isoprenylation at C-5a and the “S” configuration at C11a (Figure 1) were recently identified from Aspergillus species (MEXU 27854) by Aparicio-Cuevas et al.4 Their absolute configurations were determined on the basis of the comparison of the experimental and DFT calculated vibrational circular © 2018 American Chemical Society

dichroism spectra. Although the biological activities of 3 and 4 were not recorded in the literature,4 the C-7 hydroxylation derivative of 4 (shornephine A) and its analogue (nocardioazine A, Figure 1) had been both reported as strong inhibitors against P-glycoprotein-reversing multidrug resistance.1,5 Upon inspection, the installation of a single tertiary hydroxyl group at C-11a in 2 (DKM skeleton) was rare, while the dihydroxylated and tetrahydroxylated DKPs skeletons were developed well by Kim et al. using [Ag(py)2 ]MnO4 .6 To construct the configurations of 5aR, 10bS, and 11aS in 3 and 4 is also a challenging task for chemists. Intrigued by the diketomorpholine skeleton with a unique isopropenyl group in 1−4 and the potential biological activities of them, we designed the current study to accomplish the concise synthesis of javanicunines A (1) and B (2) and 9deoxy-PF1233s A (3) and B (4) that will provide sufficient amounts of the compounds for further pharmacological and structure−activity relationship studies in the future. Herein, we disclose the first total synthesis of 1−4 and the establishment of the absolute configuration of 2. Received: October 17, 2018 Published: December 18, 2018 831

DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839

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The Journal of Organic Chemistry

Figure 1. Structures of javanicunines A-B, 9-deoxy-PF1233s A-B, and nocardioazine A.

Figure 2. Retrosynthetic analysis of 1−4.

Scheme 1. Synthesis of Bromo-Substituted Diketomorpholine 6a

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RESULTS AND DISCUSSION The retrosynthetic route is outlined in Figure 2. Javanicunines A (1) and B (2) could be prepared from the intermediate 5 by an acetylation followed by a hydroxylation (for 2). The C(10b)-isoprenyl-substituted diketomorpholine 5 was anticipated to be furnished from 6a (R3 = β-H, R4 = β-Br, R5 = isopropyl) by reacting with prenyl tributylstannane through a nucleophilic substitution reaction developed by Wang et al.7

The C-(10b) brominated diketomorpholine 6a might be prepared from 7a by reacting with NBS in the presence of the PPTS catalysis. The preparation of diketomorpholine 7a could be accomplished by the L-tryptophan derivative 9a and the commercially available (S)-2-hydroxypropanoic acid unit 8a (Figure 2). 9-Deoxy-PF1233s A (3) and B (4) could be synthesized from the intermediate 6b (R3 = α-reverse prenyl, 832

DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839

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The Journal of Organic Chemistry Scheme 2. Synthesis of Diketomorpholine 5

Scheme 3. Total Synthesis of Javanicunine A (1)

R4 = α-Br, R5 = phenyl) by a nucleophilic substitution reaction with a hydroxyl group (for 3) followed by an acetylation (for 4). Meanwhile, the 6b might be prepared from 7b with H3PO4 followed by a radical reaction with NBS, which was inspired by Movassaghi et al.’s work for the synthesis of dimeric diketopiperazines.8 Similar to the synthesis of 7a, the diketomorpholines 7b could be also obtained from the Ltryptophan derivative 9b and the (S)-2-hydroxypropanoic acid unit 8b (Figure 2). We commenced the synthesis of the amide 10 by condensation of the L-tryptophan methyl ester 9a with the (S)-2-hydroxy-4-methylpentanoic acid (8a) through an amidation reaction in 62% yield. Diketomorpholine 7a was smoothly prepared from the amide 10 by a lactonization procedure under the ptoluenesulfonic acid (PTSA) catalysis. Unfortunately, the C(10b)-bromo-substituted diketomorpholine 6a could not be produced from 7a or 7c by the modifications on the literature methods (NBS/PPTS/CH2Cl2, Scheme 1).8,9 We then switched to an alternative approach to synthesize the

diketomorpholine 5 by starting from bromohexahydropyrroloindole 119 using a conventional procedure outlined in Scheme 2. The isoprenyl-substituted pyrroloindole 12 was obtained from 11 by reacting with prenyl tributylstannane through a nucleophilic substitution reaction in 90% yield. Removal of the N-Boc group in 12 with iodotrimethylsilane (TMSI) produced the corresponding free amine 13 which was added to a mixture solution of 8a, BOP-Cl, and collidine in THF to provide amide 14 in a trace yield (condition a, 5%). The amide 14 was able to be converted into the intermediate 5 under PTSA catalysis in 57% yield (following condition a, Scheme 2). After screening several amidation conditions, it was found that a mixture of 8a, 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-hydroxy-7-azabenzotriazole (HOAT), N,Ndiisopropylethylamine (DIPEA) 13 in DMF was heated at 80 °C for 10 h to give 5 in 52% yield in one pot (condition b, Scheme 2). 833

DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839

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The Journal of Organic Chemistry Scheme 4. Synthesis of C-11a-Hydroxyl-pyrroloindole 15

surprisingly found that the synthesized 2 and the reported javanicunine B were the same compound, which thus determined the absolute configuration (3S, 5aS, 10bR, 11aR) of javanicunine B as shown in Scheme 5. In our attempt to optimize the conditions for converting 1 to 2, we further noticed that the more equivalent of potassium bis(trimethylsilyl)amide (KHMDS) was added (n = 2) to the reaction, and the lower yield of 2 was obtained, which might be affected by the hydrolysis effect (the lactone and the amide bonds sensitive to KHMDS). After the successful synthesis of javanicunines A and B, we then switched our efforts to the preparation for 6b to synthesize PF1233s A and B. As outlined in Scheme 6, the precursor (7b) of 6b could be obtained from 16 under the same procedure for 7a. Additionally, the amide 16 could be only prepared from (S)methyl 2-amino-3-(2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl)propanoate (9b)13 and (S)-2-hydroxy-3-phenylpropanoic acid (8b) by a condensation reaction with the HATU and the HOAT in a heated condition (the BOP-Cl/collidine condition failed). Unsurprisingly, 6b was also not obtained from 7b (NBS/PPTS/CH2Cl2, etc., Scheme 6), which had the same result as that for converting 7a to 6a. Subsequently, we tried to treat 7b with H3PO4 followed by a radical reaction with NBS, a modified condition based on Movassaghi et al.’s method.8 However, 7b was hydrolyzed to afford 18 in the presence of H3PO4 rather than the desired product 17 (Scheme 7). We then conceived an alternative approach to synthesize 9deoxy-PF1233s A (3) and B (4) from 7b by an oxidation procedure outlined in Scheme 8, which was inspired by Schkeryantz et al. to synthesize gypsetin (DKP skeleton).14 As a result, a mixture of the epoxy intermediate 19a (unstable at 25 °C) and the undesired product 20 was unexpectedly obtained when 7b was treated with dioxiranes at −78 °C for 1 h (TLC detected, Scheme 8). During the separation of the mixture of 19a and 20, we found that the epoxy intermediate 19a was unstable and spontaneously transformed to 4

The diketomorpholine 5 was acetylated with acetic anhydride to give the javanicunine A (1), which displayed the identical NMR data and comparable optical rotation ([α]22 D = −93.5, c 2.0, CH2Cl2) to those reported by Nakadate et al. 3 ([α]22 D = −152.3, c 1.0, CH2Cl2). In our attempt to synthesize javanicunine B (2) directly from 1, we found that it was difficult to install a hydroxyl group at C-11a in 1 by using many conventional approaches ([Ag(py)2]MnO4/CH3CN,6 BPO/ O2,10a NBS/AIBN,10b etc.) (Scheme 3). Then, we tried a model reaction of treating the intermediate 12 with Davis’ oxaziridine.11 It was exciting to find that C-11a-hydroxylpyrroloindole 15 was a chemo-selective and stereoselective oxidation product of 12. The absolute configuration of C-11a was also testified by the chemical shift of the methoxy group in 15 (β-OCH3, δH 3.79, Scheme 4).12a,b However, the “R” (C-11a) configuration in 15 was not desired in the proposed natural product, and the yield was only 35% (Scheme 4).12c Treating 1 with the same condition for converting 12 to 15, we got the C-11a-epi-javanicunine B in 50% yield (Scheme 5). On the basis of the comparisons of the NMR (Table 1) and optical rotation data of the synthesized 2 ([α]22 D = −127.0, c 2.0, CH2Cl2) with those of the reported 3 javanicunine B ([α]22 D = −118.5, c 0.2, CH2Cl2), it was Scheme 5. Total Synthesis of Javanicunine B (2)

834

DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839

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The Journal of Organic Chemistry Table 1.

13

C and 1H NMR Comparisons of Synthesized 2a with Literature Values of 2b (CDCl3, δ in ppm, J in Hz) 2a

no 1 3 4 5a 6a 7 8 9 10 10a 10b 11 11a 12 13 14 15 16 17 18 19 20 21 22

13

C

167.3 77.0 165.3 80.5 142.1 120.7 130.0 overlap 125.0 124.4 130.0 59.3 42.0 87.4 37.6 23.9 21.2 23.3 40.4 142.5 115.3 22.3 22.9 169.9 23.5

2b 13

C

167.3 77.0 165.3 80.5 142.1 120.7 130.0 125.0 124.4 130.0 59.2 42.0 87.4 37.6 23.8 21.2 23.3 40.4 142.5 115.3 22.3 22.9 169.8 23.5

Δδ1

2a

2b

1

1

H

Δδ2

H

5.00, d (10.4)

5.00, dd (10.4, 3.1)

5.91, brs

5.92, brs

0.01

8.07, 7.42, 7.22, 7.37,

8.06, 7.42, 7.22, 7.37,

0.01

brs t (7.7) t (7.4) brd (7.5)

brs td (7.7, 1.2) td (7.4, 1.1) brd (7.5)

0.1

0.1

2.94, d (14.5) 2.69, d (14.5)

2.94, d (14.5) 2.69, d (14.5)

1.76, 1.90, 0.89, 0.97,

m 1.88, m m d (6.0) d (6.0)

1.76, 1.91, 0.89, 0.97,

m 1.87, m m d (6.0) d (6.0)

5.75, 5.12, 1.13, 0.96,

dd (17.2, 10.8) d (17.2) 5.16, d (10.8) s s

5.75, 5.12, 1.13, 0.96,

dd (17.2, 10.8) d (17.2) 5.16, d (10.8) s s

0.01 −0.01

0.1 2.61, brs

2.61, brs

Scheme 6. First Try of Synthesis of 6b

Scheme 7. Second Try of Synthesis of 6b

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DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839

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The Journal of Organic Chemistry Scheme 8. Total Synthesis of 9-Deoxy-PF1233 B (4)

Figure 3. 1H NMR (CDCl3, 25 °C) comparisons of 7b, 19a, 4, and 20.

completely at room temperature in 12 h (Figure 3). The transformed 4 displayed the identical NMR spectroscopic data to those reported by Aparicio-Cuevas et al.4 The optical rotation of the synthetic 4 ([α]22 D = +64.8, c 2.3, CH3OH) was comparable with that reported for the natural 4 product ([α]22 D = +93.0, c 0.1, CH3OH). A possible reaction mechanism was then proposed for producing 20 and 4 from 7b: First, the diketomorpholine 7b was oxidized by the dioxirane to form 19a and 19b (ratio = 4:1, on the basis of the yields of 4 and 20) at −78 °C; second, the 19a was stable and could be isolated while the 19b was unstable and instantly converted to the epimer 20 at −78 °C (Scheme 8), and some transformation processes also emerged from the 1H NMR comparisons (Figure 3). At last, the 9-deoxy-PF1233 A (3) was obtained from 4 by an acetylation reaction in 68% yield after several conditions were screened (Scheme 9). The synthesized 3 also displayed the identical NMR spectroscopic data to those reported by literature,4 and the optical rotation of the synthetic 3 ([α]22 D = +91.1, c 1.7, CH3OH) was comparable with that reported for 4 the natural product ([α]22 D = +160.0, c 0.1, CH3OH), which

Scheme 9. Total Synthesis of 9-Deoxy-PF1233 A (3)

further confirmed the absolute configuration of 9-deoxyPF1233 A (3) as shown in Scheme 9.

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CONCLUSIONS In summary, we have accomplished the first total synthesis of javanicunines A (1, 21.9% overall yield) and B (2, 10.8% overall yield) and 9-deoxy-PF1233s A (3, 8.1% overall yield) and B (4, 12.0% overall yield) through 9−10 steps by starting from L-tryptophan and two hydroxypropanoic acids (8a and 8b). These syntheses established the absolute configuration of the javanicunine B and further confirmed the absolute configurations of 9-deoxy-PF1233s A and B. The current 836

DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839

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The Journal of Organic Chemistry

tert-Butyl 3-(((3S,6S)-6-Isobutyl-2,5-dioxomorpholin-3-yl)methyl)-1H-indole-1-carboxylate (7c). To a solution of 7a (110.0 mg, 0.36 mmol) and DMAP (4.0 mg, 0.03 mmol) in CH2Cl2 (20.0 mL), di-tert-butyl dicarbonate ((Boc)2O, 80.0 mg, 0.36 mmol) was added, and the mixture was stirred for 30 min and extracted with CH2Cl2/H2O (100.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:9 to produce 7c (28.0 mg, 20% yield) as an 1 orange oil. [α]20 D = −116.7 (c 2.1, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 11.2, 4.0 Hz, 1H), 7.02 (dd, J = 7.2 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 5.12 (t, J = 4.8 Hz, 1H), 4.55 (dd, J = 11.2, 3.6 Hz, 1H), 3.48 (dd, J = 15.0, 4.8 Hz, 1H), 3.38 (dd, J = 15.0, 4.8 Hz, 1H), 1.38 (s, 9H), 1.33−1.20 (m, 1H), 1.01−0.89 (m, 1H), 0.58 (d, J = 6.8 Hz, 3H), 0.40 (d, J = 6.8 Hz, 3H), 0.00 (ddd, J = 14.8, 11.2, 4.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.6, 166.5, 149.7, 136.2, 127.2, 124.8, 122.6, 120.3, 118.8, 111.5, 107.9, 85.2, 78.0, 57.9, 41.9, 29.8, 27.8 (3C), 24.1, 22.5, 20.7; HRESIMS m/z 423.1880 [M + Na]+, calcd for C22H28N2O5Na, 423.1890. (2S,3aR,8aR)-1,8-ditert-butyl 2-Methyl 3a-(2-Methylbut-3-en-2yl)-3,3a-dihydropyrrolo[2,3-b]indole-1,2,8(2H,8aH)-tricarboxylate (12). To a solution of 119 (2.1 g, 4.2 mmol) and Cs2CO3 (2.1 g, 6.4 mmol) in CH2Cl2 (50.0 mL) at −78 °C, tributyl(3-methylbut-2-en-1yl)stannane (2.3 g, 6.4 mmol) and AgClO4 (1.74 g, 8.4 mmol) were added, and the mixture was stirred for 5 h under N2 protection. The reaction was quenched with saturated NH4Cl (aq), and was extracted with CH2Cl2/H2O (200.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:19) to produce 12 (1.83 g, 90% 1 yield) as a colorless oil. [α]20 D = −56.5 (c 2.6, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.33 (brs, 1H), 7.24 (d, J = 7.0 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.05 (dd, J = 7.5, 7.0 Hz, 1H), 6.16 (s, 1H), 5.86 (dd, J = 17.5, 10.5 Hz, 1H), 5.08 (d, J = 10.5 Hz, 1H), 5.00 (d, J = 17.5 Hz, 1H), 3.80 (dd, J = 10.5, 6.5 Hz, 1H), 3.71 (s, 3H), 2.38 (dd, J = 12.5, 6.5 Hz, 1H), 2.31−2.24 (m, 1H), 1.55 (s, 9H), 1.42 (s, 9H), 1.02 (s, 3H), 0.94 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 173.2, 150.9 (2C), 144.5, 132.4, 129.3, 125.5, 120.4, 117.4, 114.5, 111.3, 82.2 (2C), 63.8, 62.4, 52.7, 41.9, 39.3, 35.8, 27.3 (3C), 23.9, 22.8, 14.2 (3C); HRESIMS m/z 487.2803 [M + H]+, calcd for C27H39N2O6, 487.2803. (2S,3aR,8aR)-Methyl 3a-(2-Methylbut-3-en-2-yl)-1,2,3,3a,8,8ahexahydropyrrolo[2,3-b]indole-2-carboxylate (13). To a solution of 12 (1.26 g, 2.59 mmol) in CH3CN (35.0 mL) at 0 °C, iodotrimethylsilane (1.8 mL, 12.6 mmol) was added, and the mixture was stirred for 1 h at 0 °C. The reaction was quenched with DIPEA (2.6 mL, 14.8 mmol) and was kept stirring overnight at 25 °C. The solvent was removed in vacuum, and the residue was extracted with EtOAc/H2O (200.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:3) to produce 13 (0.65 g, 88% yield) as an 1 orange oil. [α]20 D = −56.7 (c 3.0, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.13 (d, J = 7.5 Hz, 1H), 7.05 (dd, J = 8.0, 7.5 Hz, 1H), 6.71 (dd, J = 8.0, 7.5 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.00 (dd, J = 17.0, 10.5 Hz, 1H), 5.12−5.02 (m, 2H), 5.01 (s, 1H), 3.70 (s, 3H), 3.62−3.54 (m, 2H), 2.27 (dd, J = 11.5, 5.0 Hz, 1H), 2.15 (t, J = 11.5 Hz, 1H), 1.11 (s, 3H), 1.00 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 174.1, 151.0, 144.5, 130.8, 128.4, 125.3, 118.3, 113.7, 108.9, 79.9, 65.7, 59.8, 52.1, 41.4, 41.0, 23.3, 22.9; HRESIMS m/z 287.1750 [M + H]+, calcd for C17H23N2O2, 287.1754. (3S,5aS,10bR,11aS)-3-Isobutyl-10b-(2-methylbut-3-en-2-yl)5a,6,11,11a-tetrahydro-[1,4]oxazino[4′,3′:1,5]pyrrolo[2,3-b]indole1,4(3H,10bH)-dione (5). To a solution of 13 (0.55 g, 1.9 mmol) and (S)-2-hydroxy-4-methylpentanoic acid (8a, 0.3 g, 2.3 mmol) in DMF (10.0 mL), HATU (1.0 g, 2.6 mmol), HOAT (8.0 mg, 0.06 mmol), and DIPEA (1.9 mL, 10.8 mmol) were added, and the mixture was stirred and heated for 14 h at 80 °C. The solvent was removed in vacuum, and the residue was extracted with CH2Cl2/H2O (200.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:7) to produce 5 (0.36 g, 52% yield) as an orange oil. [α]20 D = −360.5 (c 2.0,

study also established efficient methods that could be extended toward the synthesis of a pool of other complicated diketomorpholine derivatives for further drug discovery. This prospective research is under way and will be reported in due course.

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EXPERIMENTAL SECTION

General Experimental Procedures. Unless otherwise noted, commercially available reagents were used without further purification. All reactions were conducted in oven-dried (120 °C) or flamedried glassware under a N2 atmosphere and at ambient temperature (20−25 °C) unless otherwise stated. All solvents were distilled prior to use: Toluene, THF, and benzene were distilled from Na/ benzophenone, and CH2Cl2, DMF, and Et3N from CaH2. All nonaqueous reactions were performed under an atmosphere of nitrogen or argon using oven-dried glassware and standard syringe in septa techniques. Evaporation and concentration under reduced pressure was performed at 10−500 mbar. 1H NMR spectra were recorded in CDCl3 (unless stated otherwise) on a Bruker Avance 400 or 500 at 400 or 500 MHz (13C NMR spectra at 100 or 125 MHz). Chemical shifts are reported as δ values referenced to either TMS or to the solvent residual. High-resolution mass spectra (HRMS) were measured on a Shimadzu LCMS-IT-TOF mass spectrometer. The reaction progress was checked on precoated TLC plates. TLC was carried out using precoated sheets (Qingdao silica gel 60-F250, 0.2 mm) which, after development, were visualized under UV light at 254 nm. Flash column chromatography was performed using the indicated solvents on Qingdao silica gel 60 (230−400 mesh ASTM). Yields refer to chromatographically purified compounds, unless otherwise stated. (S)-Methyl 2-((S)-2-Hydroxy-4-methylpentanamido)-3-(1Hindol-3-yl) Propanoate (10). To a solution of 8a (6.17 g, 46.7 mmol) and BOP-Cl (23.4 g, 92.0 mmol) in THF (100.0 mL) that was stirred for 10 min at 0 °C, the 9a (10.2 g, 46.7 mmol) solution in THF (50.0 mL) and collidine (20.0 mL) was added, and the mixture was stirred overnight. The solvent was removed under vacuum, and the residue was extracted with EtOAc/H2O (200.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:3) to produce 10 (9.5 g, 62% yield) as an orange oil. [α]20 D = +28.3 (c 2.3, CH2Cl2); 1 H NMR (500 MHz, CDCl3) δ 8.61 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 4.88 (dt, J = 7.5, 6.0 Hz, 1H), 4.06−3.97 (m, 1H), 3.61 (s, 3H), 3.28 (d, J = 6.0 Hz, 2H), 1.76−1.67 (m, 1H), 1.50 (ddd, J = 13.0, 9.5, 3.5 Hz, 1H), 1.39−1.28 (m, 1H), 0.86 (d, J = 7.0 Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 174.9, 172.8, 136.2, 127.5, 123.0, 122.2, 119.5, 118.5, 111.5, 109.5, 70.7, 52.5, 43.4, 27.6, 24.4, 23.4, 21.3 (2C); HRESIMS m/z 333.1810 [M + H]+, calcd for C18H25N2O4, 333.1809. (3S,6S)-3-((1H-Indol-3-yl)methyl)-6-isobutylmorpholine-2,5dione (7a). To a solution of 10 (6.94 g, 20.0 mmol) in toluene (100.0 mL), PTSA·H2O (5.7 g, 30.0 mmol) was added, and the mixture was stirred and heated at 120 °C for 1 h, which was then poured into ice water (200.0 mL) and extracted with CH2Cl2 (150.0 mL × 2). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:2) to produce 7a (3.9 g, 65% yield) as an orange viscosity. [α]20 D = −94.3 (c 2.2, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.15 (dd, J = 8.0, 7.2 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.13 (s, 1H), 4.72 (dd, J = 10.0, 3.2 Hz, 1H), 4.48 (dd, J = 9.2, 3.6 Hz, 1H), 3.60 (dd, J = 14.8, 4.0 Hz, 1H), 3.20 (dd, J = 14.8, 9.2 Hz, 1H), 1.89−1.79 (m, 1H), 1.77−1.67 (m, 1H), 1.42 (ddd, J = 14.8, 10.0, 4.0 Hz, 1H), 0.90 (d, J = 5.6 Hz, 3H), 0.87 (d, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.0, 167.6, 136.5, 126.7, 123.7, 122.9, 120.3, 118.4, 111.6, 108.7, 53.4, 39.9, 28.7, 23.9, 23.0, 21.1 (2C); HRESIMS m/z 301.1542 [M + H]+, calcd for C17H21N2O3, 301.1547. 837

DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839

Article

The Journal of Organic Chemistry

concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:5) to produce 16 (420 mg, 63% 1 yield) as a light-yellow oil. [α]20 D = −23.5 (c 2.3, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.30 (dd, J = 6.8, 1.3 Hz, 1H), 7.27−7.20 (m, 2H), 7.20−7.09 (m, 5H), 6.17 (dd, J = 17.2, 10.4 Hz, 1H), 5.27−5.18 (m, 2H), 4.97−4.86 (m, 1H), 4.16 (dt, J = 8.4, 4.0 Hz, 1H), 3.62 (s, 3H), 3.36 (dd, J = 14.4, 6.8 Hz, 1H), 3.20 (dd, J = 14.4, 8.8 Hz, 1H), 2.93 (dd, J = 14.0, 4.0 Hz, 1H), 2.72 (d, J = 4.8 Hz, 1H), 2.29 (dd, J = 14.0, 8.8 Hz, 1H), 1.61 (s, 3H), 1.59 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 172.6, 145.8, 140.6, 137.0, 134.2, 129.9, 129.5 (2C), 128.5 (2C), 126.8, 121.6, 119.5, 118.2, 112.3, 110.6, 105.4, 72.8, 53.1, 52.4, 40.2, 39.1, 28.1, 27.7, 27.6; HRESIMS m/z 435.2272 [M + H]+, calcd for C26H31N2O4, 435.2278. (3S,6S)-6-Benzyl-3-((2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl)methyl)morpholine-2,5-dione (7b). A solution of 16 (460.0 mg, 1.0 mmol) and p-toluenesulfonic acid (218.0 mg, 1.2 mmol) in toluene (50.0 mL) was heated for 1.5 h at 120 °C. After the starting materials were all consumed, the mixture was poured into ice water (100.0 mL) rapidly and was extracted with CH2Cl2 (50.0 mL × 2). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:7) to produce 7b (260.0 mg, 65% yield) as an orange viscosity. [α]20 D = −74.4 (c 1.8, CH2Cl2); 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.36 (brs, 4H), 7.27 (dd, J = 8.8, 7.6 Hz, 3H), 7.16 (dd, J = 7.6, 7.2 Hz, 1H), 7.10 (dd, J = 7.6, 7.2 Hz, 1H), 6.05 (dd, J = 17.2, 10.4 Hz, 1H), 5.70 (s, 1H), 5.13 (dd, J = 14.0, 8.4 Hz, 2H), 5.06−5.01 (m, 1H), 4.36 (dd, J = 11.2, 2.8 Hz, 1H), 3.50 (dd, J = 14.0, 3.6 Hz, 1H), 3.39 (dd, J = 14.0, 3.6 Hz, 1H), 3.27 (dd, J = 14.4, 6.0 Hz, 1H), 2.62 (dd, J = 14.4, 11.2 Hz, 1H), 1.48 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 165.6, 145.4, 141.5, 135.2, 134.2, 130.4 (2C), 128.9, 128.8 (2C), 127.5, 122.2, 120.3, 117.9, 112.9, 110.9, 103.9, 78.9, 54.0, 38.9, 37.5, 28.5, 27.8, 27.8; HRESIMS m/z 401.1874 [M-H]−, calcd for C25H25N2O3, 401.1871. (3S,5aR,10bS,11aS)-3-Benzyl-10b-hydroxy-5a-(2-methylbut-3en-2-yl)-5a,6,11,11a-tetrahydro-[1,4]oxazino[4′,3′:1,5]pyrrolo[2,3b]indole-1,4(3H,10bH)-dione (9-Deoxy-PF1233 B, 4). To a solution of 7b (60.0 mg, 0.15 mmol) in THF (10.0 mL) at −78 °C, the precooled dimethyldioxirane (0.08 mmol/L in acetone, 3.0 mL) was added, and the mixture was stirred for 1 h at −78 °C. The starting materials were detected by TLC when it was finished, and the reaction was quenched with saturated Na2S2O3 (aq). The solvent was removed in vacuum, and the residue was extracted with CH2Cl2/H2O (100.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:9) to produce 19a (32.0 mg, 52% yield, unstable), 20 (11.0 mg, 18% yield), and 4 (13.0 mg, 20% yield) as colorless oil. The unstable compound 19a (25.0 mg, 0.06 mmol) was dissolved in CH2Cl2 (5.0 mL) and was stirred for 12 h at room temperature to give 4 completely (25.0 mg, 100% yield) as a light-yellow oil. [α]25 D = +64.8 (c 2.3, CH3OH); 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 7.6 Hz, 1H), 7.25−7.14 (m, 6H), 6.83 (dd, J = 8.0, 7.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.37 (dd, J = 17.6, 10.8 Hz, 1H), 6.29 (s, 1H), 5.24− 5.09 (m, 2H), 4.77 (dd, J = 8.8, 3.6 Hz, 1H), 4.34 (dd, J = 10.4, 2.0 Hz, 1H), 3.31 (ddd, J = 16.0, 14.4, 2.8 Hz, 2H), 2.86 (ddd, J = 18.4, 14.4, 9.6 Hz, 2H), 2.07 (s, 1H), 1.38 (s, 3H), 1.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 166.1, 147.7, 143.9, 136.1, 130.9, 129.5 (2C), 129.4, 128.5 (2C), 126.9, 124.7, 120.6, 113.8, 111.0, 94.7, 87.9, 78.5, 57.1, 44.9, 36.8, 34.8, 25.8, 23.3; HRESIMS m/z 419.1964 [M + H]+, calcd for C25H27N2O4, 419.1965. (3S,5aS,10bR,11aS)-3-Benzyl-10b-hydroxy-5a-(2-methylbut-3en-2-yl)-5a,6,11,11a-tetrahydro-[1,4]oxazino[4′,3′:1,5]pyrrolo[2,3b]indole-1,4(3H,10bH)-dione (20). Colorless oil. [α]20 D = −202.3 (c 1.3, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.35−7.25 (m, 5H), 7.24−7.18 (m, 2H), 6.85 (dd, J = 8.0, 7.5 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 6.22 (dd, J = 14.5, 6.5 Hz, 1H), 5.05 (dd, J = 14.5, 6.5 Hz, 2H), 4.72 (dd, J = 7.5, 3.5 Hz, 1H), 3.77 (dd, J = 11.0, 7.5 Hz, 1H), 3.42 (dd, J = 15.0, 3.5 Hz, 1H), 3.11 (dd, J = 15.0, 7.5 Hz, 1H), 2.85 (dd, J = 13.0, 11.0 Hz, 1H), 2.70 (dd, J = 13.0, 7.5 Hz, 1H), 2.32 (s, 1H), 1.17 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ

CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 7.6 Hz, 1H), 7.11 (td, J = 7.6, 1.2 Hz, 1H), 6.77 (td, J = 7.2, 2.0 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.97 (dd, J = 17.2, 10.8 Hz, 1H), 5.49 (s, 1H), 5.16− 5.05 (m, 3H), 4.69 (dd, J = 9.6, 2.4 Hz, 1H), 4.06 (dd, J = 10.0, 7.2 Hz, 1H), 2.66−2.53 (m, 2H), 1.97−1.88 (m, 2H), 1.79 (t, J = 9.6 Hz, 1H), 1.12 (s, 3H), 1.00 (s, 3H), 0.97 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 168.9, 165.9, 149.6, 143.2, 129.1, 128.6, 124.9, 119.1, 114.9, 109.6, 77.8, 77.6, 61.8, 57.6, 40.8, 37.8, 36.0, 23.9, 23.3, 22.8, 22.5, 21.2; HRESIMS m/z 369.2174 [M + H]+, calcd for C22H29N2O3, 369.2173. (3S,5aR,10bR,11aS)-6-Acetyl-3-isobutyl-10b-(2-methylbut-3-en2-yl)-5a,6,11,11a-tetrahydro-[1,4]oxazino[4′,3′:1,5]pyrrolo[2,3-b]indole-1,4(3H,10bH)-dione (1). To a solution of 5 (0.3 g, 0.8 mmol) in Ac2O (5.0 mL, 50.0 mmol), N,N-diisopropyl-ethylamin (0.4 mL, 2.4 mmol) was added, and the mixture was stirred for 12 h at 60 °C. The reaction was quenched with saturated NaHCO3 (aq) and was extracted with CH2Cl2/H2O (200.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:6) to produce 1 (0.25 g, 76% 1 yield) as a colorless viscosity. [α]22 D = −93.5 (c 2.0, CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.99 (brs, 1H), 7.36−7.31 (m, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.16 (dd, J = 9.6, 5.6 Hz, 1H), 5.92 (s, 1H), 5.79 (dd, J = 17.2, 10.8 Hz, 1H), 5.14 (dd, J = 14.0, 10.8 Hz, 2H), 4.69− 4.63 (m, 1H), 4.00 (dd, J = 10.8, 6.4 Hz, 1H), 2.70 (dd, J = 12.8, 6.0 Hz, 1H), 2.63 (s, 3H), 2.53 (dd, J = 12.8, 10.8 Hz, 1H), 1.96−1.87 (m, 2H), 1.79 (t, J = 10.0 Hz, 1H), 1.16 (s, 3H), 0.97 (s, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 168.5, 165.2, 142.9, 142.8, 131.7, 129.4, 124.7, 124.3, 119.7, 114.9, 79.5, 77.3, 60.9, 57.7, 40.4, 37.8, 35.2, 23.9, 23.5, 23.3, 23.0, 22.4, 21.1; HRESIMS m/z 411.2279 [M + H]+, calcd for C24H31N2O4, 411.2278. (2R,3aR,8aS)-1,8-Ditert-butyl 2-Methyl 2-Hydroxy-3a-(2-methylbut-3-en-2-yl)-3,3a-dihydropyrrolo[2,3-b]indole-1,2,8(2H,8aH)-tricarboxylate (15). To a solution of KHMDS (1.0 mol/L in THF, 0.15 mL) in THF (4.0 mL) at −78 °C, 12 (50.0 mg, 0.1 mmol) was dissolved in THF (4.0 mL) and was added dropwise, and the mixture was stirred for 20 min at −78 °C under N2 protection. The N(phenylsulfonyl)phenyloxaziridine (80.0 mg, 0.3 mmol) was dissolved in THF and was precooled, and the solution was added to the earlier mixture rapidly. The reaction was stirred for 3 h at −78 °C and was quenched with saturated NH4Cl (aq). The solvent was removed in vacuum, and the residue was extracted with EtOAc/H2O (100.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:14) to produce 15 (18.0 mg, 35% yield) as a colorless viscosity. [α]20 D = −63.2 (c 1.9, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.45 (brs, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.07 (dd, J = 7.6, 7.4 Hz, 1H), 6.21 (s, 1H), 5.86 (dd, J = 17.2, 10.8 Hz, 1H), 5.05 (dd, J = 17.2, 10.8 Hz, 2H), 3.79 (s, 3H), 2.70 (d, J = 13.2 Hz, 1H), 2.31 (d, J = 13.2 Hz, 1H), 1.54 (s, 9H), 1.42 (s, 9H), 1.02 (s, 3H), 0.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.6, 152.2 (2C), 143.3, 142.9, 133.6, 128.5, 124.7, 123.2, 118.6, 114.3, 81.4 (2C), 78.7, 77.2, 59.4, 52.0, 40.3, 34.6, 28.4 (6C), 23.0, 22.2; HRESIMS m/z 525.2575 [M + Na]+, calcd for C27H38N2O7Na, 525.2571. (3S,5aS,10bR,11aR)-6-Acetyl-11a-hydroxy-3-isobutyl-10b-(2methylbut-3-en-2-yl)-5a,6,11,11a-tetrahydro-[1,4]oxazino[4′,3′:1,5]pyrrolo[2,3-b]indole-1,4(3H,10bH)-dione (2). The synthesis procedure of 2 (21.0 mg, 50% yield) from 1 (40.0 mg, 0.1 mmol) was the same as that for 15. Colorless viscosity. [α]22 D = −127.0 (c 2, CH2Cl2); 1H NMR (500 MHz, CDCl3, Table 1); 13 C{1H} NMR (125 MHz, CDCl3, Table 1); HRESIMS m/z 427.2225 [M + H]+, calcd for C24H31N2O5, 427.2227. (S)-Methyl 2-((S)-2-hydroxy-3-phenylpropanamido)-3-(2-(2methylbut-3-en-2-yl)-1H-indol-3-yl)propanoate (16). To a solution of 9b13 (440.0 mg, 1.54 mmol) and (S)-2-hydroxy-3-phenylpropanoic acid (8b, 260.0 mg, 1.57 mmol) in DMF (10.0 mL), HATU (1.0 g, 2.6 mmol), HOAT (10.0 mg, 0.08 mmol), and DIPEA (1.5 mL, 8.5 mmol) were added, and the mixture was stirred and heated for 3 h at 80 °C. The solvent was removed in vacuum, and the residue was extracted with CH2Cl2/H2O (200.0 mL, 1:1). The organic phase was 838

DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839

Article

The Journal of Organic Chemistry 170.1, 167.6, 148.7, 143.6, 135.8, 131.1, 129.9 (2C), 129.5, 128.4 (2C), 127.1, 123.7, 120.3, 113.9, 111.4, 91.9, 88.8, 80.4, 56.9, 44.8, 35.9, 35.5, 26.4, 22.9; HRESIMS m/z 419.1969 [M + H]+, calcd for C25H27N2O4, 419.1965. (3S,5aR,10bS,11aS)-3-Benzyl-5a-(2-methylbut-3-en-2-yl)-1,4dioxo-1,3,4,5a,6,10b,11,11a-octahydro-[1,4]oxazino[4′,3′:1,5]pyrrolo[2,3-b]indol-10b-yl Acetate (9-Deoxy-PF1233 A, 3). To a solution of 4 (15.0 mg, 0.04 mmol) and DMAP (5.0 mg, 0.04 mmol) in pyridine (2.5 mL, 27.0 mmol), Ac2O (0.15 mL, 1.5 mmol) was added, and the mixture was stirred for 12 h at 80 °C. The reaction was quenched with saturated NaHCO3 (aq) and was extracted with CH2Cl2/H2O (100.0 mL, 1:1). The organic phase was concentrated in vacuum, and the residue was purified by flash chromatography (EtOAc:hexanes = 1:9) to produce 3 (11.0 mg, 68% yield) as a light1 yellow oil. [α]25 D = +91.1 (c 1.7, CH3OH); H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.6 Hz, 1H), 7.25−7.11 (m, 6H), 6.78 (dd, J = 8.0, 7.6 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.32 (dd, J = 8.0, 7.6 Hz, 1H), 6.28 (d, J = 12.0 Hz, 1H), 5.14 (dd, J = 20.0, 12.0 Hz, 2H), 4.74 (dd, J = 8.8, 3.2 Hz, 1H), 4.37 (d, J = 9.6 Hz, 1H), 4.20 (d, J = 14.0 Hz, 1H), 3.32 (dd, J = 14.0, 3.2 Hz, 1H), 2.83 (ddd, J = 24.0, 14.0, 9.6 Hz, 2H), 1.99 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.7, 167.0, 166.0, 148.6, 144.0, 136.0, 131.2, 129.5 (2C), 128.6, 128.5 (2C), 126.9, 125.6, 120.4, 112.8, 110.9, 98.3, 91.1, 78.4, 58.4, 45.3, 34.9, 34.6, 25.5, 24.9, 21.6; HRESIMS m/z 461.2077 [M + H]+, calcd for C27H29N2O5, 461.2071.

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(2) Borthwick, A. D. 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem. Rev. 2012, 112, 3641−3716. (3) Nakadate, S.; Nozawa, K.; Horie, H.; Fujii, Y.; Nagai, M.; Komai, S.; Hosoe, T.; Kawai, K.; Yaguchi, T.; Fukushima, K. New dioxomorpholine derivatives, javanicunine A and B, from Eupenicillium javanicum. Heterocycles 2006, 68, 1969−1972. (4) Aparicio-Cuevas, M. A.; Rivero-Cruz, I.; Sanchez-Castellanos, M.; Menendez, D.; Raja, H. A.; Joseph-Nathan, P.; Gonzalez, M. D. C.; Figueroa, M. Dioxomorpholines and derivatives from a marinefacultative Aspergillus Species. J. Nat. Prod. 2017, 80, 2311−2318. (5) Raju, R.; Piggott, A. M.; Huang, X. C.; Capon, R. J. Nocardioazines: A novel bridged diketopiperazine scaffold from a marine-derived bacterium inhibits p-glycoprotein. Org. Lett. 2011, 13, 2770−2773. (6) Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Total synthesis of (+)-11,11’-dideoxyverticillin A. Science 2009, 324, 238−241. (7) Wang, Y.; Kong, C.; Du, Y.; Song, H.; Zhang, D.; Qin, Y. Silverpromoted friedel-crafts reaction: concise total synthesis of (−)-ardeemin, (−)-acetylardeemin and (−)-formylardeemin. Org. Biomol. Chem. 2012, 10, 2793−2797. (8) Movassaghi, M.; Ahmad, O. K.; Lathrop, S. P. Directed heterodimerization: stereocontrolled assembly via solvent-caged unsymmetrical diazene fragmentation. J. Am. Chem. Soc. 2011, 133, 13002−13005. (9) (a) Espejo, V. R.; Li, X. B.; Rainier, J. D. Cyclopropylazetoindolines as precursors to C(3)-quaternary-substituted indolines. J. Am. Chem. Soc. 2010, 132, 8282−8284. (b) López, S. C.; Pérez-Balado, C.; Rodríguez-Graña, P.; Lera, Á . R. Mechanistic insights into the stereocontrolled synthesis of hexahydropyrrolo[2,3-b]indoles by electrophilic activation of tryptophan derivatives. Org. Lett. 2008, 10, 77−80. (10) (a) Baran, P. S.; Corey, E. J. A short synthetic route to (+)-austamide, (+)-deoxyisoaustamide, and (+)-hydratoaustamide from a common precursor by a novel Palladium-mediated indole dihydroindoloazocine cyclization. J. Am. Chem. Soc. 2002, 124, 7904− 7905. (b) Iwasa, E.; Hamashima, Y.; Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. Total synthesis of (+)-shaetocin and its analogues: Their histone methyltransferase G9a inhibitory activity. J. Am. Chem. Soc. 2010, 132, 4078−4079. (11) Davis, F. A.; Abdul-Malik, N. F.; Awad, S. B.; Harakal, M. E. Epoxidation of olefins by oxaziridines. Tetrahedron Lett. 1981, 22, 917−920. (12) (a) The δH (3.09−3.13) οf α-OCH3 in epi-11, epi-11a, and epi12 is smaller than the δH (3.71−3.79) of β-OCH3 in 11, 11a, and 12 owing to the shielding effect of benzene ring. The δH of 11, 11a, epi11, and epi-11a is cited from ref b and the 1H NMR of epi-12 is provided in the Supporting Information. (b) Wada, M.; Murata, T.; Oikawa, H.; Oguri, H. Nickel-catalyzed dimerization of pyrrolidinoindoline scaffolds: systematic access to chimonanthines, folicanthines and (+)-win 64821. Org. Biomol. Chem. 2014, 12, 298−306. (c) Most of 12 was decomposed, and no “S” (C-11a) configuration of epi-15 was isolated. (13) Zhao, L.; May, J. P.; Huang, J.; Perrin, D. M. Stereoselective synthesis of brevianamide E. Org. Lett. 2012, 14, 90−93. (14) Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.; Danishefsky, S. J. Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: Novel constructions of 2,3disubstituted indoles. J. Am. Chem. Soc. 1999, 21, 11964−11975.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02650. 1 H and 13C NMR spectra for compounds 1−5, 7a−7c, 9b, 10−13, 15, 16, and 20. The comparison of 1H and 13 C NMR data of 3 and 4 (provided and synthesized) (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]; tel: +86-(0)20-39943043; fax: +86-(0)20-39943043. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ming-Zhong Wang: 0000-0003-2498-5222 Hong-Jie Zhang: 0000-0002-7175-5166 Albert S. C. Chan: 0000-0002-4193-4702 Author Contributions ⊥

M.-Z. Wang and T.-X. Si contributed equally to this work

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the Research Foundation for Advanced Talents (36000-18821101), China; Guangdong Natural Science Foundation (2017A030313751), China; the Science and Technology Planning Project of Guangzhou City (201707010189), China; and the Interdisciplinary Research Matching Scheme (RC-IRMS/15-16/02) of Hong Kong Baptist University, Hong Kong SAR, China.

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REFERENCES

(1) Khalil, Z. G.; Huang, X. C.; Raju, R.; Piggott, A. M.; Capon, R. J. Shornephine A: Structure, chemical stability, and p-glycoprotein inhibitory properties of a rare diketomorpholine from an Australian marine-derived Aspergillus sp. J. Org. Chem. 2014, 79, 8700−8705. 839

DOI: 10.1021/acs.joc.8b02650 J. Org. Chem. 2019, 84, 831−839