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Cite This: J. Org. Chem. 2018, 83, 10948−10958

Enantioselective Radical Cyclization of Tryptamines by Visible LightExcited Nitroxides Kangjiang Liang,†,‡,∥ Xiaogang Tong,†,∥ Tao Li,† Bingfei Shi,† Haiyang Wang,† Pengcheng Yan,§ and Chengfeng Xia*,†

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†

Key Laboratory of Medicinal Chemistry for Natural Resource (Ministry of Education and Yunnan Province), School of Chemical Science and Technology, Yunnan University, Kunming 650091, China ‡ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Kunming 650201, China § School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China S Supporting Information *

ABSTRACT: Nitroxides can absorb both ultraviolet (UV) and visible light, and their electron can be excited from the π-bonding orbital to the antibonding π* orbital or the n-bonding orbital to the antibonding π* orbital, respectively. Despite the reported UVinduced hydrogen atom transfer (HAT) process, the potential of nitroxides for visible light-excited photosynthesis is underexplored. Here we demonstrate that nitroxide can convert indole to its radical through a visible light-induced HAT process. A chiral phosphoric acid-catalyzed cyclization of the in situ-formed imine radical, followed by trapping by another molecule of nitroxide, provides the product in high yield and enantioselectivity. To highlight the novelty and efficiency of this strategy, an asymmetric total synthesis of natural product (−)-verrupyrroloindoline was accomplished in 5 steps.

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INTRODUCTION Visible light-induced photochemical reactions are practical synthetic tools that are often compatible with various functional groups and have immense potential to enable unusual chemical transformations. These features have attracted considerable attention from synthetic chemists. Different types of colored chemicals, such as ruthenium or iridium complexes1 and organic dyes,2 have been investigated to catalyze a broad range of synthetically valuable reactions. However, the colored radicals were not documented for the visible light-induced photoreaction up to date. Nitroxides, especially the red-orange 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), are stable free radical species with a delocalized unpaired electron shared between the nitrogen and oxygen atoms. The N-O radical group of nitroxides can absorb in both the UV (at approximately 240 nm) and visible (at 410−460 nm) regions. The electron is excited from the π-bonding orbital to the antibonding π orbital* or the n-bonding orbital to the antibonding π orbital*, respectively (Figure 1a).3 However, the photochemical reactivities of nitroxides have received little attention and mainly involve the π−π* transition. There are a few examples, dating back to the 1970s, of the utilization of UV light-excited nitroxides to enable hydrogen atom transfer (HAT) of hydrocarbons, and the resultant C-centered radicals were rapidly trapped by ground state nitroxides (Figure 1b).3d,4 In addition, several other types of reactivities including photodegradation,5 and electron transfer3a,b have been reported. Most of the above researchers further demonstrated that nitroxides were inert in © 2018 American Chemical Society

Figure 1. Photochemical reactivity of nitroxides.

their reactions under visible light irradiation, except for the self-rearrangement of a special nitronyl nitroxide.6 Accordingly, the photochemical reactivity of visible light-excited nitroxides (n−π* transition) is a particularly underexplored area. We cogitated whether nitroxides could be excited by visible light and proceed with the downstream reactions. Our initial efforts focused on developing the visible light-induced Received: June 26, 2018 Published: August 9, 2018 10948

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

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The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditions

entry

sub.

cat.

additivea

conv. (%)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13d 14 15 16e

1 1 1 1 1 1 1 1 1 1 1 1 1 3 4 1

L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L2 L3 L1 L1 L1 L1

TEMPOH Ac2O CDI PhC2H4NCO CyNCO t-BuNCO p-TolNCO 4-Cl-PhNCO 4-CF3−PhNCO CyNCO CyNCO CyNCO CyNCO CyNCO CyNCO

23 0 100 92 >98 >98 >98 88 82 95 80 95 0 0 0 >98

20 0 91 80 91 94 93 72 65 84 63 88 0 0 0 95

eec (%) 98 73 83 97 98 97 98 96 97 −65 96

85

a

The TEMPOH was added with 0.5 equiv, other additives were added with 1.0 equiv. bYields were determined by isolation after chromatographic purification. cEnantiomeric excesses (ee) were determined by HPLC analysis using chiral stationary phases. dUnder dark. eWithout the base DMAP.

activation of indole N-H to indole radical by nitroxides through a HAT process (Figure 1c). The development of mild methods for direct conversion of strong amide N−H bonds into the N-centered radicals has been achieved with elegant protocols, including the photochemical conversions.7 Indole has a strong N−H bond-dissociation free energy (BDEF) of 91 kcal/mol and is energetically inaccessible as a direct HAT substrate for nitroxides (the BDEF of TEMPO-H ∼ 67 kcal/ mol).8 Normally the conversion of indole to indole radical required the deprotonation with strong bases (LDA, LHMDS, t-BuOK, etc.) following by an oxidant, such as copper(II),9 ferrous (III),10 or iodide.11 However, upon photochemical excitation by visible light, nitroxides are transformed into more reactive O-centered radical species, which would be able to abstract H atom from indole. During our submission, Knowles reported a very similar photochemistry of enantioselective cyclization of tryptamine catalyzed by an iridium photoredox catalyst in the presence of TEMPO.12 Knowles proposed that a photoexcited iridium catalyzed the oxidation of tryptamine through proton-coupled electron transfer (PCET) and the TEMPO served as recyclization of the iridium catalyst and

captured the tryptamine radical. Here we reported that the TEMPO could be directly excited by visible light and converted tryptamine to tryptamine radical though a HAT process without the catalyst of iridium.

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RESULTS AND DISCUSSION We initiated our studies by evaluating whether tryptamine 1 can be oxidized by TEMPO under visible light irradiation and followed by the chiral phosphoric acid-catalyzed enantioselective addition of the radical intermediate. Initially, by irradiating a mixture of TEMPO, tryptamine 1, and 4dimethylaminopyridine (DMAP)13 in toluene with blue LEDs (λmax at 455 nm) in the presence of a catalytic amount of chiral acid 8H-R-TRIP L1, the desired product 2a was obtained in 98% ee value but only with 20% yield (Table 1, entry 1). Screening the solvents, such as MTBE, THF, or DCM, did not improve the yields. We noticed that the product was merely generated in the first several hours and then the reaction did not move forward any more. Since the TEMPO was converted to TEMPOH by capturing a hydrogen atom from indole, we speculated that the indole radical might return 10949

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

Article

The Journal of Organic Chemistry Scheme 1. Controlled Mechanistic Experimentsa

a (a) The pre-prepared and in situ-generated oxoammonium species for enantioselective cyclization. (b) Direct photo-excited cyclization without the assistance of phosphoric acid catalyst and base.

optimized reaction conditions (Table 1, entries 14 and 15). Besides the proposed HAT process, it was possible that the reaction might undergo an oxoammonium-related pathway7d,14 or a PCET process.12 To verify whether the oxoammonium intermediate could react with tryptamine and get the similar outcomes, two controlled experiments were performed (Scheme 1a). We first prepared the chiral phosphoric oxoammonium salt according Toste’s procedures.15 When tryptamine 1 was treated with the pregenerated chiral phosphoric oxoammonium salt, we detected the formation of cyclized product 2a. However, the reaction was very slow and only 23% yield of product was isolated after 72 h. Moreover, the enantioselectivity of the product was also very low (5% ee). Furthermore, the in situ-generated chiral phosphoric acid oxoammonium salt was also evaluated by treatment of tryptamine 1 with TEMPO and phosphoric catalyst L1 without the presence of DMAP under dark.16 It was found that the product was only formed in trace amount (5%) with 18% ee value. These experimental results showed that the oxoammonium also could participate in the cyclization of tryptamine. However, the reaction rate was very slow along with quite poor enantioselectivity. In order to obtain the cyclization products with high enantioselectivities, the addition of base to suppress the competing reaction pathway was crucial. If the reaction was performed without base DMAP, both of the visible light-induced pathway and the oxoammonium pathway concurred during the cyclization and resulted in the decreasing of enantioselectivity to 85%. (Table 1, entry 16). As we proposed, the role of phosphoric L1 was to catalyze the cyclization of carbonyl amide to imine, while the base DMAP was to avoid the disproportionation of TEMPO under acid conditions. When the carbonyl amide was shifted to a

back to indole through a reversible HAT process by capturing a hydrogen atom from TEMPOH. To verify this hypothesis, 0.5 equiv of TEMPOH was added to the reaction, and we observed that the reaction was completely inhibited (Table 1, entry 2). These experimental results showed that the TEMPOH inhibited the reaction by quenching the indole radical. The Ac2O or N,N′-carbonyldiimidazole (CDI) was then added into the reaction mixture to get rid of the TEMPOH. We found that the yield was significantly improved, which confirmed the negative effects of TEMPOH in the reaction mixture (Table 1, entries 3 and 4). However, besides the increasing of yield, the ee value was apparently decreased. We conjectured that the AcOH or imidazole derived from Ac2O and CDI might disturb the phosphoric acid catalyzed enantioselective cyclization. After comparison with several procedures for removal of TEMPOH in situ, the isocyanates were proved to be the efficient and reliable approaches (Table 1, entries 5−10). The product 2a was obtained in 94% yield and 98% ee value when cyclohexyl isocyanate (CyNCO) was added (Table 1, entry 6). Further evaluation of chiral phosphoric acids with different substituents and backbones indicated that L1 was the most effective catalyst (Table 1, entries 11 and 12). Other bases, including organic bases (Et3N, pyridine, 2,2′-bipyridine, 2,6-lutidine, DBU, 1,1,3,3-tetramethylguanidine, etc.) and inorganic bases (Na2 CO 3 , NaHCO3, K2CO3, Cs2CO3, NaOH, tBuOK, etc.), were evaluated, and DMAP was discovered to be the optimum one. Importantly, the visible light irradiation was essential and no reactions occurred when the reaction was stirred in the dark (Table 1, entry 13). We found that the existence of N-H for the HAT process was critical and the N-methylated tryptamine 3 and Ncarboxylated tryptamine 4 did not give any products under the 10950

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

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The Journal of Organic Chemistry Scheme 2. Proposed Visible Light-Excited Pathway

Table 2. Substrate Scope for the Enantioselective Catalytic Photoreaction

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DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

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loindoline was not determined because only 1.5 mg of product was isolated from 1.2 kg of soft coral S. verruca. Recently, Huanng reported the first asymmetric total synthesis of (−)-verrupyrroloindoline through a DMDO triggered onepot four-step tandem reaction.21 Our synthesis of (−)-verrupyrroloindoline 9 commenced with the enantioselective catalytic photoreaction with 8H-S-TRIP as catalyst to afford (−)-2a in 94% yield and 98% ee (Scheme 3). Deprotecting the

more nucleophilic OH group (5), the visible light-excited reaction smoothly proceeded to give the corresponding product 6 (80%) without the assistance of phosphoric acid catalyst and base (Scheme 1b). Since no phosphoric acid catalyst and base were involved in the reaction conditions, this indicated that the hydrogen of N-H was directly abstracted by activated TEMPO in an HAT manner instead of the PCET pathway under the assistance of phosphoric acid and base. On the basis of the experimental results, a plausible mechanism is depicted in Scheme 2. The TEMPO is excited by blue light to provide the excited state TEMPO*, which engages in HAT with the tryptamine A to generate an indole radical B and TEMPOH. This HAT process is a reversible reaction and the TEMPOH must be gotten rid of. The in situgenerated imine radical intermediate B undergoes a chiral phosphoric acid-catalyzed asymmetric cyclization process.17 The observed stereoselectivity of the reaction resulted from the TEMPO trapping the radical intermediate18 from the less steric Re face of imine and catalyst complex (TS1) based on the Goodman’s model.19 With the optimized reaction conditions, we examined the scope for the enantioselective cyclization of tryptamines. Initially, we investigated the cyclization of tryptamines that bear a range of carbonyl protecting groups. Substrates with Ac, CO2Me, and Alloc groups provided the pyrroloindolines in good yields and excellent enantioselectivities (Table 2, compounds 2b−2d). Crystals of 2c were suitable for X-ray crystallographic analysis, which established the stereochemical outcome of the asymmetric catalytic process. To demonstrate that these reactions effectively proceeded under mild conditions, a base-labile Fmoc-protected substrate was successfully converted to the corresponding product 2e with 63% yield and 96% ee. Although good yield was also obtained when the tryptamine was protected with a Boc group (2f), the enantioselectivity was relatively lower, which demonstrated that the steric interaction with the phosphoric catalyst had some influence on the asymmetric induction. The substituted tryptamine derivatives were next explored for visible light-induced reaction. Electron-donating groups, such as methyl or methoxyl, substituted on the C-5 of tryptamine were tolerated, and the desired compounds 2g and 2h were obtained with high enantioselectivities. The derivatives 2i and 2j with chloro or bromo groups on the aryl ring enabled further conversions. Furthermore, a fluorosubstituted pyrroloindoline 2k was afforded in 97% enantioselectivity with the developed method. When the 2-methyl tryptamine was subjected to the reaction, the resulting cyclized product 2l was achieved with 63% yield and 88% ee. The commercially available para-functionalized TEMPO derivatives were also explored, and the related products were afforded in both high yields and ee values under the standard conditions (Table 2, compounds 2m−2p). Some other unstable nitroxides, such as di-tert-butyl nitroxide (DTBN), were also subjected to the visible light-induced cyclization. However, the nitroxides decomposed very quickly and no desired products were harvested. To highlight the utility and efficiency of this enantioselective catalytic photoreaction for the synthesis of pyrroloindoline natural products, we sought to complete the asymmetric total synthesis of (−)-verrupyrroloindoline 9. Verrupyrroloindoline, a rare 3-hydroxypyrroloindoline alkaloid with a 2a,5a-diazacyclopenta[jk]fluorene skeleton, was isolated from the soft coral Sinularia verruca.20 The absolute structure of verrupyrro-

Scheme 3. Total Synthesis of (−)-Verrupyrroloindoline 9

Cbz group under hydrogenolysis conditions, followed by Michael addition with propiolate, formed the vinylogous amide 7 in 87% yield over two steps. Acid-catalyzed condensation of 7 with acetaldehyde furnished 8 as a single diastereoisomer with 84% yield. Finally, removal of the TMP group with Zn and AcOH delivered (−)-verrupyrroloindoline 9 in 91% yield. The 1H and 13C NMR data for synthetic (−)-verrupyrroloindoline 9 were identical with those of the natural product. However, the optical rotation of synthetic (−)-verrupyrroloindoline ([α]25 D = −690 (c = 0.07, CHCl3)) was much larger than that of the isolated natural product ([α]25 D = −22 (c = 0.06, CHCl3)), while the optical rotation of synthetic (−)-verrupyrroloindoline by Huang was ([α]25 D = −631 (c = 1.0, CHCl3).21 By HPLC analysis using chiral stationary phases with the synthetically racemic verrupyrroloindoline as a standard sample, the isolated natural verrupyrroloindoline was discovered to contain a mixture of the (−)-verrupyrroloindoline and (+)-verrupyrroloindoline with only 5.6% ee value.22

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CONCLUSIONS In summary, we have established that the colored free radical species, nitroxide, could be directly activated upon irradiation by visible light. The excited nitroxide abstracted a hydrogen atom from tryptamine to generate tryptamine radical without any other photocatalysts through a HAT process. The enantioselective cyclization of the radical intermediate was achieved by catalysis with a chiral phosphoric acid. The efficiency and utility of the method was further demonstrated by the rapid asymmetric synthesis of the indole alkaloid (−)-verrupyrroloindoline. The direct irradiative excitation of nitroxides without other photocatalysts, together with the mild reaction conditions and excellent enantioselectivity, will provide the opportunities of other chemo-, regio-, and stereoselective reactions.

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EXPERIMENTAL SECTION

General Information. 1H, 13C NMR and 19F NMR spectra were recorded on a Bruker Avance 400 MHz spectrophotometer. Chemical shifts (d) are expressed in ppm, and J-values are given in Hz. The residual solvent protons (1H) or the solvent carbons (13C) were used 10952

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

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The Journal of Organic Chemistry

Controlled Experiment To Prepare 2a with in SituGenerated Oxoammonium Catalyst Complex. To an ovendried 10 mL glass vial, containing benzyl (2-(1H-indol-3-yl)ethyl)carbamate (29.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), and TEMPO (39.3 mg, 0.25 mmol), was added toluene (1 mL). The reaction mixture was stirred in the dark at −15 °C under argon for 72h. Next, the crude mixture was directly purified by silica gel chromatography (acetone/petroleum ether 1:40) to afford the product 2a as a colorless oil (2.3 mg, 5% yield, 18% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 12.1 min, tminor = 13.8 min (18% ee); [α]21 D = +43 (c = 0.15, CHCl3). Controlled Experiment To Prepare 2a without Base DMAP. To an oven-dried 10 mL glass vial, containing benzyl (2-(1H-indol-3yl)ethyl)carbamate (29.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), and CyNCO (12.5 mg, 0.1 mmol), was added toluene (1 mL). The vial was placed ∼10 cm from two 18 W blue LED lamps (λmax at 455 nm), and the reaction mixture was irradiated at −15 °C under argon for 72 h. Next, the crude mixture was directly purified by silica gel chromatography (acetone/petroleum ether 1:40) to afford the product 2a as a colorless oil (42.7 mg, 95% yield, 85% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/min, λ = 254 nm: tmajor = 12.0 min, tminor = 13.5 min (85% ee); [α]21 D = +251 (c = 0.31, CHCl3). (3aS,8aR)-1-(3a-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-1(2H)-yl)ethan-1-one (2b). Prepared according to the general procedure using N-(2-(1H-indol-3yl)ethyl)acetamide (20.2 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 96 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:5) to afford the product 2b as a colorless oil (31.0 mg, 87% yield, 97% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak ADH column, 90:10 hexane/i-PrOH, flow rate 0.5 mL/min, λ = 254 nm: tmajor = 12.3 min, tminor = 14.0 min (97% ee); [α]21 D = +399 (c = 0.64, CHCl3). Inseparable rotamers (3.4:1): the spectra data of the major isomer are reported. 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 7.1, 1H), 7.11 (t, J = 7.8, 1H), 6.76 (t, J = 7.1, 1H), 6.52 (d, J = 7.8, 1H), 6.07 (s, 1H), 5.04 (s, 1H), 3.79−3.66 (m, 1H), 3.26 (td, J = 11.0, 6.7, 1H), 2.75 (td, J = 11.9, 8.7, 1H), 2.55−2.45 (m, 1H), 2.04 (s, 3H), 1.59−1.19 (m, 6H), 1.07 (s, 3H), 1.05 (s, 3H), 0.79 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 170.0, 150.7, 129.9, 129.6, 126.0, 118.4, 109.3, 96.1, 77.8, 60.0, 59.3, 47.0, 40.8, 40.4, 40.1, 33.1, 32.3, 22.2, 20.6, 20.5, 17.1; HR-ESI-MS (m/z): calcd. for C21H32N3O2 [M + H]+: 358.2489, found 358.2493. (3aS,8aR)-Methyl 3a-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2c). Prepared according to the general procedure using methyl (2-(1Hindol-3-yl)ethyl)carbamate (21.8 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:30) to afford the product 2c as white crystals (34.5 mg, 93% yield, 91% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 10.0 min, tminor = 8.7 min (91% ee); [α]21 D = +317 (c = 0.22, CHCl3). Inseparable rotamers (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 7.5, 1H), 7.11 (t, J = 7.6, 1H), 6.80−6.74 (m, 1H), 6.53 (d, J = 7.9, 1H), 6.00 (s, 0.56H), 5.92 (s, 0.44H), 4.92 (s, 0.56H), 4.60 (s, 0.44H), 3.93- 3.84 (m, 0.56H), 3.82−3.67 (m, 3.44H), 3.17−2.99 (m, 1H), 2.76−2.55 (m, 1H), 2.42−2.38 (m, 1H), 1.59−1.18 (m, 6H), 1.08 (s, 3H) 1.05 (s, 1.32H), 1.04 (s, 1.68H), 0.84 (s, 1.68H), 0.81 (s, 1.32H), 0.74 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 155.6, 154.9, 150.6, 150.4, 130.3, 130.2, 129.8, 129.7, 126.0, 125.9, 118.8, 118.6, 109.3, 97.9, 96.7, 78.3, 77.7, 60.0, 59.3, 52.6, 52.4, 45.6, 45.3, 40.8,

as internal standards. ESIMS and HRESIMS were taken on an Agilent 6540 Q-TOF spectrometer. Optical rotations were measured at the sodium D line with a 100 mm path length cell, and are reported as follows: [α]TD (c in g per 100 mL, solvent). Blue LED lamps (18 W) were used to irradiate the reaction mixtures. The emission spectra of the blue LED lamp were recorded on a Fluorescence Spectrophotometer F-4500. All reagents were used as received without further purification unless indicated otherwise. Thin layer chromatographies were carried out on GF254 plates. Flash chromatography was performed with 200−300 mesh silica gels. Visualization of the developed chromatogram was performed by fluorescence quenching or by ceric ammonium molybdate, or KMnO4 stain. Yields reported were for isolated, spectroscopically pure compounds. General Procedures for Visible Light-Excited Enantioselective Cyclization of Tryptamines. To an oven-dried 10 mL glass vial, containing the tryptamine derivative (0.1 mmol, 1 equiv), L1 (0.01 mmol, 10 mol %), the nitroxide (0.25 mmol, 2.5 equiv), DMAP (0.15 mmol, 1.5 equiv), and CyNCO (0.1 mmol, 1 equiv), was added solvent (1 mL). The pH value of the reaction mixture was around 8. The vial was placed ∼10 cm from two 18 W blue LED lamps (λmax at 455 nm), and the reaction mixture was irradiated at −15 °C under argon until TLC showed the complete consumption of tryptamine. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (acetone/petroleum ether) to afford the product (the racemic product was obtained by using (±)-1,1′-binaphthyl-2,2′-diylhydrogen phosphate as the catalyst). (3aS,8aR)-Benzyl 3a-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2a). Prepared according to the general procedure using benzyl (2-(1Hindol-3-yl)ethyl)carbamate (29.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:40) to afford the product 2a as a colorless oil (42.2 mg, 94% yield, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 12.2 min, tminor = 13.8 min (98% ee); [α]21 D = +290 (c = 0.49, CHCl3). Inseparable rotamers1 (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.45−7.27 (m, 6H), 7.14−7.06 (m, 1H), 6.79−6.75 (m, 1H), 6.53 (d, J = 7.9, 0.56H), 6.48 (d, J = 7.9, 0.44H), 6.04 (s, 0.56H), 5.96 (s, 0.44H), 5.28−5.07 (m, 2H), 4.94 (s, 0.56H), 4.54 (s, 0.44H), 3.94− 3.86 (m, 0.44H), 3.82 (t, J = 9.3, 0.56H), 3.14−3.09 (m, 1H), 2.70− 2.65 (m, 1H), 2.43−2.38 (m, 1H), 1.58−1.22 (m, 6H), 1.08 (s, 1.68H), 1.07 (s, 1.32H), 1.04 (s, 3H), 0.83 (s, 1.68H), 0.77 (s, 1.32H), 0.75 (s, 1.68H), 0.73 (s, 1.32H); 13C NMR (100 MHz, CDCl3): δ 155.0, 154.3, 150.6, 150.4, 136.8, 136.7, 130.3, 130.2, 129.8, 129.7, 128.6, 128.5, 128.2, 128.1, 128.0, 127.8, 126.0, 125.9, 118.8, 118.6, 109.4, 109.3, 97.9, 96.8, 78.5, 77.8, 67.0, 66.8, 60.0, 59.3, 45.6, 45.4, 40.8, 40.4, 40.1, 39.8, 33.0, 32.6, 32.5, 26.9, 20.6, 20.5, 20.4, 17.1; HR-ESI-MS (m/z): calcd. for C27H36N3O3 [M + H]+: 450.2751, found 450.2750. Controlled Experiment To Prepare 2a with Pregenerated Oxoammonium Salt. To an oven-dried 10 mL glass vial, containing benzyl (2-(1H-indol-3-yl)ethyl)carbamate (29.4 mg, 0.1 mmol), 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (29.2 mg, 0.12 mmol), Na3PO4 (24.6 mg, 0.15 mmol), and L1 (7.6 mg, 0.01 mmol), was added toluene (1 mL). The reaction mixture was stirred in the dark at −15 °C under argon for 72h. After this time, the reaction mixture was diluted with saturated aqueous Na2SO3 (2 mL) and the contents were shaken vigorously. The aqueous phase was extracted with EA (5 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was subjected to flash chromatography on silica gel (acetone/petroleum ether 1:40) to afford 2a as a colorless oil (10.3 mg, 23%, 5% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/min, λ = 254 nm: tmajor = 12.2 min, tminor = 13.7 min (5% ee); [α]21 D = +15 (c = 0.22, CHCl3). 10953

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

Article

The Journal of Organic Chemistry

min, λ = 254 nm: tmajor = 7.6 min, tminor = 6.4 min (72% ee); [α]21 D = +220 (c = 0.22, CHCl3). Inseparable rotamers (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.33−7.29 (m, 1H), 7.12−7.07 (m, 1H), 6.78−6.72 (m, 1H), 6.52 (d, J = 7.9, 1H), 5.99 (s, 0.56H), 5.81 (s, 0.44H), 4.88 (s, 0.56H), 4.52 (s, 0.44H), 3.90−3.78 (m, 0.44H), 3.71 (t, J = 9.3, 0.56H), 3.94−3.65 (m, 1H), 3.15−2.95 (m, 1H), 2.72−2.55 (m, 1H), 2.44−2.29 (m, 1H), 1.64−1.18 (m, 15H), 1.09 (s, 1.32H), 1.08 (s, 1.68H), 1.06 (s, 1.32H), 1.04 (s, 1.68H), 0.83 (s, 1.68H), 0.81 (s, 1.32H), 0.79 (s, 1.32H), 0.75 (s, 1.68H); 13C NMR (100 MHz, CDCl3): δ 154.6, 150.7, 150.6, 139.1, 130.4, 130.1, 129.7, 129.6, 126.2, 125.9, 118.6, 118.3, 109.1, 97.8, 96.9, 80.0, 79.7, 78.2, 59.9, 59.2, 45.5, 45.0, 40.9, 40.8, 40.6, 40.4, 40.2, 39.8, 33.2, 32.9, 32.5, 32.3, 28.7, 28.5, 26.9, 20.6, 20.5, 20.4, 17.1; HR-ESI-MS (m/z): calcd. for C24H38N3O3 [M + H]+: 416.2908, found 416.2909. (3aS,8aR)-Benzyl 5-Methyl-3a-((2,2,6,6-tetramethylpiperidin-1yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2g). Prepared according to the general procedure using benzyl (2-(5methyl-1H-indol-3-yl)ethyl)carbamate (30.8 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:40) to afford the product 2g as a colorless oil (42.1 mg, 91% yield, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 10.1 min, tminor = 13.8 min (98% ee); [α]21 D = +276 (c = 0.31, CHCl3). Inseparable rotamers (1.2:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.48−7.28 (m, 5H), 7.12 (s, 1H), 6.93−6.90 (m, 1H), 6.45 (d, J = 8.0, 0.55H), 6.41 (d, J = 8.0, 0.45H), 6.09 (s, 0.55H), 6.01 (s, 0.45H), 5.33−5.06 (m, 2H), 4.78 (s, 0.55H), 4.41 (s, 0.45H), 3.96−3.86 (m, 0.45H), 3.85−3.76 (m, 0.55H), 3.15−3.09 (m, 1H), 2.70−2.65 (m, 1H), 2.40−2.36 (m, 1H), 2.28 (s, 3H), 1.58−1.20 (m, 6H), 1.12− 1.00 (m, 6H), 0.87 (s, 1.65H), 0.81 (s, 1.35H), 0.70 (s, 1.65H), 0.69 (s, 1.35H); 13C NMR (100 MHz, CDCl3): δ 155.0, 154.3, 148.3, 148.0, 136.9, 136.7, 130.9, 130.7, 130.3, 128.6, 128.5, 128.3, 128.1, 128.0, 127.8, 126.2, 126.1, 109.4, 109.3, 98.0, 96.9, 78.5, 77.8, 67.0, 66.8, 60.0, 59.2, 45.5, 45.3, 40.8, 40.5, 40.4, 40.1, 39.7, 33.0, 32.9, 32.7, 21.0, 20.6, 20.4, 17.1; HR-ESI-MS (m/z): calcd. for C28H38N3O3 [M + H]+: 464.2908, found 464.2902. (3aS,8aR)-Benzyl 5-Methoxy-3a-((2,2,6,6-tetramethylpiperidin1-yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2h). Prepared according to the general procedure using benzyl (2-(5-methoxy-1H-indol-3-yl)ethyl)carbamate (32.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 48 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:30) to afford the product 2h as a colorless oil (35.0 mg, 73% yield, 96% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 14.0 min, tminor = 20.5 min (96% ee); [α]21 D = +282 (c = 0.31, CHCl3). Inseparable rotamers (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.45−7.28 (m, 5H), 6.92 (t, J = 2.4, 1H), 6.77−6.68 (m, 1H), 6.50 (d, J = 8.5, 0.56H), 6.45 (d, J = 8.5, 0.44H), 6.10 (s, 0.56H), 6.01 (s, 0.44H), 5.34−5.04 (m, 2H), 4.67 (s, 0.56H), 4.30 (s, 0.44H), 3.94− 3.87 (m, 0.44H), 3.83 (t, J = 9.4, 0.56H), 3.77 (s, 3H), 3.22−3.05 (m, 1H), 2.69−2.61 (m, 1H), 2.41−2.36 (m, 1H), 1.61−1.18 (m, 6H), 1.09 (s, 1.68H), 1.08 (s, 1.32H), 1.04 (s, 3H), 0.87 (s, 1.68H), 0.80 (s, 1.32H), 0.71 (s, 1.68H), 0.70 (s, 1.32H); 13C NMR (100 MHz, CDCl3): δ 154.9, 154.3, 153.8, 153.6, 144.5, 144.3, 136.9, 136.7, 132.0, 131.8, 128.6, 128.5, 128.1, 128.0, 127.8, 116.0, 115.9, 111.4, 110.5, 110.4, 98.3, 97.2, 79.0, 78.3, 67.0, 66.8, 60.0, 59.3, 56.1, 45.5, 45.2, 40.9, 40.5, 40.4, 40.2, 39.7, 33.0, 32.9, 32.7, 32.6, 20.6, 20.4, 17.1; HR-ESI-MS (m/z): calcd. for C28H38N3O4 [M + H]+: 480.2857, found 480.2854. (3aS,8aR)-Benzyl 5-Chloro-3a-((2,2,6,6-tetramethylpiperidin-1yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate

40.4, 40.1, 39.8, 33.0, 32.9, 32.6, 32.5, 20.6, 20.4, 17.1; HR-ESI-MS (m/z): calcd. for C21H32N3O3 [M + H]+: 374.2438, found 374.2442. (3aS,8aR)-Allyl 3a-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2d). Prepared according to the general procedure using allyl (2-(1Hindol-3-yl)ethyl)carbamate (24.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:30) to afford the product 2d as a colorless oil (34.0 mg, 85% yield, 95% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 10.7 min, tminor = 9.0 min (95% ee); [α]21 D = +365 (c = 1.05, CHCl3). Inseparable rotamers (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 7.5, 1H), 7.10 (t, J = 7.6, 1H), 6.80−6.74 (m, 1H), 6.52 (d, J = 7.9, 1H), 6.08−5.85 (m, 2H), 5.39−5.18 (m, 2H), 4.93 (s, 0.56H), 4.75−4.54 (m, 2.44H), 3.93−3.85 (m, 0.44H), 3.81 (t, J = 9.7, 0.56H), 3.22−2.99 (m, 1H), 2.71−2.63 (m, 1H), 2.43−2.39 (m, 1H), 1.62−1.19 (m, 6H), 1.09 (s, 3H), 1.05 (s, 1.32H), 1.04 (s, 1.68H), 0.84 (s, 1.68H), 0.81 (s, 1.32H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 154.8, 154.1, 150.6, 150.4, 133.1, 132.9, 130.3, 130.1, 129.8, 129.7, 126.0, 125.9, 118.8, 118.6, 117.7, 117.3, 109.3, 97.9, 96.8, 78.4, 77.8, 65.9, 65.8, 60.0, 59.3, 45.5, 45.3, 40.8, 40.4, 40.3, 40.1, 39.8, 33.0, 32.9, 32.7, 32.5, 20.6, 20.5, 20.4, 17.1; HR-ESI-MS (m/z): calcd. for C23H34N3O3 [M + H]+: 400.2595, found 400.2598. (3aS,8aR)-(9H-Fluoren-9-yl)methyl 3a-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)carboxylate (2e). Prepared according to the general procedure using (9H-fluoren-9-yl)methyl (2-(1H-indol-3-yl)ethyl)carbamate (38.2 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and DCM (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:30) to afford the product 2e as a colorless oil (34.0 mg, 63% yield, 96% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/min, λ = 254 nm: tmajor = 15.2 min, tminor = 11.2 min (96% ee); [α]21 D = +236 (c = 0.26, CHCl3). Inseparable rotamers (1.5:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.80−7.74 (m, 2H), 7.71−7.65 (m, 0.6H), 7.62 (d, J = 7.1, 0.6H), 7.58−7.55 (m, 0.6H), 7.50−7.28 (m, 4.6H), 7.20 (d, J = 7.4, 0.6H), 7.15−7.10 (m, 0.4H), 7.08−7.03 (m, 0.6H), 6.78 (t, J = 7.4, 0.4H), 6.71 (t, J = 7.4, 0.6H), 6.54 (d, J = 7.8, 0.4H), 6.29 (d, J = 7.8, 0.6H), 6.06 (d, J = 2.1, 0.4H), 5.56 (d, J = 2.7, 0.6H), 4.90 (s, 0.4H), 4.76−4.54 (m, 1.2H), 4.49−4.18 (m, 2H), 3.85 (t, J = 9.3, 0.4H), 3.75−3.63 (m, 0.6H), 3.49 (s, 0.6H), 3.19 (td, J = 11.1, 6.6, 0.4H), 3.00 (td, J = 11.1, 6.9, 0.6H), 2.75 (td, J = 11.9, 8.8, 0.4H), 2.61−2.49 (m, 0.6H), 2.46 (dd, J = 12.2, 6.2, 0.4H), 2.31−2.22 (m, 0.6H), 1.53− 1.16 (m, 6H), 1.10 (s, 1.2H), 1.05 (s, 1.2H), 1.03 (s, 1.8H), 0.96 (s, 1.8H), 0.87 (s, 1.2H), 0.74 (s, 1.2H), 0.67 (s, 1.8H), 0.48 (s, 1.8H); 13 C NMR (100 MHz, CDCl3): δ 155.0, 154.2, 150.5, 150.0, 144.4, 144.3, 144.0, 143.9, 141.8, 141.5, 130.7, 130.3, 129.8, 129.6, 127.7, 127.3, 127.2, 127.0, 125.8, 125.2, 125.1, 124.9, 124.5, 120.1, 120.0, 118.6, 118.5, 109.4, 108.7, 97.3, 96.7, 78.3, 67.2, 66.2, 60.0, 59.7, 59.3, 59.1, 47.4, 47.3, 45.4, 44.9, 40.9, 40.4, 40.3, 40.2, 39.6, 32.9, 32.8, 32.6, 32.5, 20.6, 20.5, 20.4, 20.3, 17.0; HR-ESI-MS (m/z): calcd. for C34H40N3O3 [M + H]+: 538.3064, found 538.3061. (3aS,8aR)-tert-Butyl 3a-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2f). Prepared according to the general procedure using tert-butyl (2(1H-indol-3-yl)ethyl)carbamate (26 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:40) to afford the product 2f as a colorless oil (37.0 mg, 89% yield, 72% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ 10954

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

Article

The Journal of Organic Chemistry (2i). Prepared according to the general procedure using benzyl (2-(5chloro-1H-indol-3-yl)ethyl)carbamate (32.8 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:30) to afford the product 2i as a colorless oil (39.1 mg, 81% yield, 97% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 10.4 min, tminor = 14.9 min (97% ee); [α]21 D = +258 (c = 0.21, CHCl3). Inseparable rotamers (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.44−7.29 (m, 5H), 7.27 (s, 1H), 7.07−7.03 (m, 1H), 6.45 (d, J = 8.4, 0.56H), 6.40 (d, J = 8.4, 0.44H), 6.05 (s, 0.56H), 5.97 (s, 0.44H), 5.24−5.04 (m, 2H), 4.95 (s, 0.56H), 4.55 (s, 0.44H), 3.95−3.87 (m, 0.44H), 3.86−3.75 (m, 0.56H), 3.13−3.09 (m, 1H), 2.78−2.53 (m, 1H), 2.40−3.24 (m, 1H), 1.59−1.20 (m, 6H), 1.08 (s, 1.68H), 1.07 (s, 1.32H), 1.05 (s, 3H), 0.83 (s, 1.68H), 0.77 (s, 3H), 0.75 (s, 1.32H); 13C NMR (100 MHz, CDCl3): δ 154.9, 154.1, 149.0, 148.8, 136.7, 136.5, 132.0, 131.9, 129.7, 129.6, 128.7, 128.5, 128.2, 128.1, 127.8, 126.0, 125.9, 123.4, 123.1, 110.1, 97.6, 96.5, 78.8, 78.1, 67.1, 67.0, 60.1, 59.4, 45.5, 45.3, 40.8, 40.4, 40.3, 40.2, 39.8, 33.1, 33.0, 32.7, 32.5, 20.6, 20.5, 17.0; HR-ESI-MS (m/z): calcd. for C27H35ClN3O3 [M + H]+: 484.2361, found 484.2351. (3aS,8aR)-Benzyl 5-Bromo-3a-((2,2,6,6-tetramethylpiperidin-1yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2j). Prepared according to the general procedure using benzyl (2-(5bromo-1H-indol-3-yl)ethyl)carbamate (37.2 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:30) to afford the product 2j as a colorless oil (38.0 mg, 72% yield, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 10.4 min, tminor = 15.9 min (98% ee); [α]21 D = +278 (c = 0.30, CHCl3). Inseparable rotamers (1.5:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.46−7.27 (m, 6H), 7.19 (dt, J = 8.3, 2.2, 1H), 6.41 (d, J = 8.4, 0.6H), 6.36 (d, J = 8.4, 0.4H), 6.05 (s, 0.6H), 5.97 (s, 0.4H), 5.27−5.04 (m, 2H), 4.96 (s, 0.6H), 4.55 (s, 0.4H), 3.95−3.87 (m, 0.4H), 3.83 (t, J = 9.4, 0.6H), 3.13−3.09 (m, 1H), 2.69−2.64 (m, 1H), 2.40−2.35 (m, 1H), 1.60−1.20 (m, 6H), 1.08 (s, 3H), 1.05 (s, 3H), 0.82 (s, 1.8H), 0.77 (s, 3H), 0.75 (s, 1.2H); 13C NMR (100 MHz, CDCl3): δ 154.9, 154.1, 149.5, 149.3, 136.7, 136.5, 132.5, 132.4, 128.9, 128.8, 128.7, 128.5, 128.2, 128.1, 127.8, 110.7, 110.6, 110.3, 110.0, 97.6, 96.5, 78.7, 78.0, 67.1, 67.0, 60.1, 59.4, 59.3, 45.5, 45.3, 40.8, 40.4, 40.2, 39.8, 33.1, 32.7, 32.5, 20.6, 20.5, 17.0; HR-ESI-MS (m/z): calcd. for C27H35BrN3O3 [M + H]+: 528.1856, found 528.1848. (3aS,8aR)-Benzyl 6-Fluoro-3a-((2,2,6,6-tetramethylpiperidin-1yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2k). Prepared according to the general procedure using benzyl (2-(6fluoro-1H-indol-3-yl)ethyl)carbamate (31.2 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:30) to afford the product 2k as a colorless oil (39.3 mg, 84% yield, 97% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 12.9 min, tminor = 14.6 min (97% ee); [α]21 D = +335 (c = 1.33, CHCl3). Inseparable rotamers (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.45−7.28 (m, 5H), 7.25−7.20 (m, 1H), 6.51−6.38 (m, 1H), 6.21 (dd, J = 9.8, 2.2, 0.56H), 6.16 (dd, J = 9.8, 2.2, 0.44H), 6.00 (s, 0.56H), 5.91 (s, 0.44H), 5.27−5.10 (m, 2H), 5.05 (s, 0.56H), 4.63 (s, 0.44H), 3.94−3.86 (m, 0.44H), 3.86−3.78 (m, 0.56H), 3.13−3.08 (m, 1H), 2.72−2.55 (m, 1H), 2.40−2.35 (m, 1H), 1.70−1.15 (m, 6H), 1.06 (s, 3H), 1.04 (s, 3H), 0.81 (s, 1.68H), 0.79 (s, 3H), 0.73 (s, 1.32H); 13C NMR (100 MHz, CDCl3): δ 164.7 (d, J = 244.1), 154.9,

154.1, 152.1 (d, JC‑F = 12.1), 151.9 (d, JC‑F = 12.1), 136.7, 136.5, 128.7, 128.5, 128.3, 128.2, 128.1, 127.8, 127.1, 127.0, 126.9, 125.5 (d, JC‑F = 2.1), 125.4 (d, JC‑F = 2.1), 105.3 (d, JC‑F = 23.0), 105.0 (d, JC‑F = 23.0), 97.1, 96.6, 96.4, 95.9, 79.3, 78.6, 67.1, 66.9, 60.1, 59.3, 45.7, 45.4, 40.8, 40.4, 40.3, 40.2, 39.8, 33.2, 33.1, 32.5, 32.4, 20.6, 20.5, 20.4, 17.1; 19F NMR (376 MHz, CDCl3): δ −112.47 (s, 0.44F), −112.62 (s, 0.56F); HR-ESI-MS (m/z): calcd. for C27H35FN3O3 [M + H]+: 468.2657, found 468.2651. (3aS,8aR)-Benzyl 8a-Methyl-3a-((2,2,6,6-tetramethylpiperidin-1yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2l). Prepared according to the general procedure using benzyl (2-(2methyl-1H-indol-3-yl)ethyl)carbamate (30.8 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:50) to afford the product 2l as a colorless oil (29.2 mg, 63% yield, 88% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 7.3 min, tminor = 7.8 min (88% ee); [α]21 D = +384 (c = 0.37, CHCl3). Inseparable rotamers (3.2:1): the spectra data of the major isomer are reported. 1H NMR (400 MHz, CDCl3): δ7.41−7.27 (m, 6H), 7.15−7.04 (m, 1H), 6.74 (t, J = 7.4, 1H), 6.53 (d, J = 7.8, 1H), 5.85 (s, 1H), 5.13 (d, J = 12.4, 1H), 5.01 (d, J = 12.4, 1H), 3.65−3.53 (m, 1H), 2.96−2.82 (m, 1H), 2.65 (m, 1H), 2.28 (m, 1H), 1.77 (s, 3H), 1.54−1.43 (m, 3H), 1.37 (s, 3H), 1.22 (m, 3H), 1.17 (s, 3H), 1.04 (s, 3H), 0.23 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 154.2, 151.6, 136.6, 129.7, 128.9, 128.8, 128.5, 128.3, 127.9, 127.6, 127.3, 117.8, 109.8, 93.1, 87.4, 66.3, 60.2, 59.5, 45.2, 41.2, 40.6, 37.4, 35.2, 30.4, 21.3, 20.8, 19.4, 17.2; HR-ESI-MS (m/z): calcd. for C28H38N3O3 [M + H]+: 464.2908, found 464.2911. (3aS,8aR)-Benzyl 3a-((2,2,6,6-Tetramethyl-4-oxopiperidin-1-yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2m). Prepared according to the general procedure using benzyl (2(1H-indol-3-yl)ethyl)carbamate (29.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), 4-oxo-TEMPO (42.5 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 96 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:20) to afford the product 2m as a colorless oil (37.0 mg, 80% yield, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 60:40 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 10.8 min, tminor = 13.0 min (98% ee); [α]21 D = +335 (c = 0.34, CHCl3). Inseparable rotamers (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.49−7.29 (m, 6H), 7.16−7.12 (m, 1H), 6.81−6.76 (m, 1H), 6.57 (d, J = 7.9, 0.56H), 6.52 (d, J = 7.9, 0.44H), 5.93 (s, 0.56H), 5.82 (s, 0.44H), 5.23−5.08 (m, 2H), 5.04 (s, 0.56H), 4.62 (s, 0.44H), 3.98− 3.90 (m, 0.44H), 3.88−3.81 (m, 0.56H), 3.21−3.02 (m, 1H), 2.79− 2.31 (m, 4H), 2.31−2.03 (m, 2H), 1.17−1.10 (m, 6H), 1.03 (s, 3H), 0.89 (s, 1.68H), 0.80 (s, 1.32H); 13C NMR (100 MHz, CDCl3): δ 208.2, 208.1, 155.0, 154.1, 150.9, 150.7, 136.6, 136.5, 130.4, 130.3, 128.7, 128.5, 128.4, 128.3, 128.1, 127.9, 126.5, 126.4, 118.9, 118.6, 109.6, 109.5, 98.3, 97.2, 78.9, 78.3, 67.2, 67.0, 62.9, 62.8, 62.3, 54.0, 53.6, 45.9, 45.6, 39.7, 39.4, 33.0, 31.9, 22.8, 22.7, 22.6; HR-ESI-MS (m/z): calcd. for C27H34N3O4 [M + H]+: 464.2544, found 464.2537. (3aS,8aR)-Benzyl 3a-((4-Methoxy-2,2,6,6-tetramethylpiperidin1-yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2n). Prepared according to the general procedure using benzyl (2-(1H-indol-3-yl)ethyl)carbamate (29.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), 4-methoxy-TEMPO (46.5 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:30) to afford the product 2n as a colorless oil (45.0 mg, 94% yield, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 1.0 mL/ min, λ = 254 nm: tmajor = 17.7 min, tminor = 14.1 min (98% ee); [α]21 D = +320 (c = 1.91, CHCl3). Inseparable rotamers (1.2:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 10955

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

Article

The Journal of Organic Chemistry 7.42−7.29 (m, 6H), 7.16−7.05 (m, 1H), 6.79−6.74 (m, 1H), 6.53 (d, J = 7.9, 0.55H), 6.48 (d, J = 7.9, 0.45H), 5.95 (s, 0.55H), 5.92 (s, 0.45H), 5.23−5.12 (m, 2H), 4.97 (s, 0.55H), 4.56 (s, 0.45H), 3.94− 3.86 (m, 0.45H), 3.86−3.78 (m, 0.55H), 3.47−3.33 (m, 1H), 3.29 (s, 3H), 3.29−3.08 (m, 1H), 2.71−2.55 (m, 1H), 2.46−2.40 (m, 1H), 1.90−1.74 (m, 2H), 1.39−1.20 (m, 2H), 1.13 (s, 3H), 1.11 (s, 1.65H), 1.10 (s, 1.35H), 0.86 (s, 1.65H), 0.82 (s, 1.65H), 0.80 (s, 1.35H), 0.78 (s, 1.35H); 13C NMR (100 MHz, CDCl3): δ 155.0, 154.2, 150.7, 150.4, 136.7, 136.6, 130.0, 129.9, 129.7, 129.5, 128.7, 128.5, 128.2, 128.0, 127.8, 126.1, 118.9, 118.6, 109.4, 109.3, 98.1, 96.9, 78.7, 77.8, 71.5, 67.1, 66.9, 60.4, 59.6, 55.7, 45.6, 45.5, 45.4, 45.1, 45.0, 40.1, 39.8, 33.2, 32.6, 32.4, 21.6, 21.5; HR-ESI-MS (m/z): calcd. for C28H38N3O4 [M + H]+: 480.2857, found 480.2852. (3aS,8aR)-Benzyl 3a-((4-(Benzoyloxy)-2,2,6,6-tetramethylpiperidin-1-yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2o). Prepared according to the general procedure using benzyl (2-(1H-indol-3-yl)ethyl)carbamate (29.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), 4-hydroxy-TEMPO benzoate (69 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:20) to afford the product 2o as a colorless oil (51.8 mg, 91% yield, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 60:40 hexane/i-PrOH, flow rate 0.5 mL/min, λ = 254 nm: tmajor = 14.8 min, tminor = 32.1 min (98% ee); [α]21 D = +286 (c = 0.33, CHCl3). Inseparable rotamers (1.3:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 7.2, 2H), 7.54 (t, J = 7.3, 1H), 7.51−7.27 (m, 8H), 7.15−7.10 (m, 1H), 6.81−6.76 (m, 1H), 6.55 (d, J = 7.9, 0.56H), 6.50 (d, J = 7.9, 0.44H), 5.99 (s, 0.56H), 5.90 (s, 0.44H), 5.35−5.08 (m, 3H), 4.98 (s, 0.56H), 4.58 (s, 0.44H), 3.96−3.88 (m, 0.44H), 3.88−3.79 (m, 0.56H), 3.22−3.02 (m, 1H), 2.82−2.56 (m, 1H), 2.47−2.41 (m, 1H), 2.03−1.87 (m, 2H), 1.71−1.55 (m, 2H), 1.31−1.17 (m, 6H), 0.94−0.75 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 166.2, 166.1, 155.0, 154.2, 150.7, 150.5, 136.8, 136.6, 132.9, 130.5, 130.1, 130.0, 129.5, 129.4, 128.7, 128.5, 128.3, 128.2, 128.1, 127.9, 126.2, 126.1, 118.9, 118.6, 109.4, 98.1, 97.0, 78.6, 78.0, 67.2, 67.1, 66.9, 60.6, 59.9, 53.5, 45.7, 45.5, 45.1, 44.7, 40.2, 39.8, 33.1, 33.0, 32.4, 32.3, 21.5, 21.4, 21.3; HR-ESI-MS (m/z): calcd. for C34H40N3O5 [M + H]+: 570.2962, found 570.2951. (3aS,8aR)-Benzyl 3a-((4-Cyano-2,2,6,6-tetramethylpiperidin-1yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2p). Prepared according to the general procedure using benzyl (2(1H-indol-3-yl)ethyl)carbamate (29.4 mg, 0.1 mmol), L1 (7.6 mg, 0.01 mmol), 4-cyano-TEMPO (45.2 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), CyNCO (12.5 mg, 0.1 mmol), and toluene (1 mL). Time of irradiation: 72 h. The crude mixture was purified by silica gel chromatography (acetone/petroleum ether 1:20) to afford the product 2p as a colorless oil (40.8 mg, 86% yield, 97% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 60:40 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 12.2 min, tminor = 15.6 min (97% ee); [α]21 D = +327 (c = 0.53, CHCl3). Inseparable rotamers (1.2:1): the spectra data of the mixture are reported. 1H NMR (400 MHz, CDCl3): δ 7.51−7.26 (m, 6H), 7.19−7.07 (m, 1H), 6.85−6.75 (m, 1H), 6.54 (d, J = 7.9, 0.55H), 6.49 (d, J = 7.9, 0.45H), 5.87 (s, 0.55H), 5.80 (s, 0.45H), 5.27−5.04 (m, 2H), 4.98 (s, 0.55H), 4.56 (s, 0.45H), 3.96− 3.86 (m, 0.45H), 3.86−3.77 (m, 0.55H), 3.18−3.05 (m, 1H), 2.83− 2.50 (m, 2H), 2.46−2.40 (m, 1H), 1.97−1.51 (m, 4H), 1.07 (s, 6H), 0.91 (s, 1.65H), 0.85 (s, 1.35H), 0.79 (s, 1.65H), 0.74 (s, 1.35H); 13C NMR (100 MHz, CDCl3): δ 154.9, 154.1, 150.8, 150.5, 136.7, 136.5, 130.3, 130.2, 128.9, 128.7, 128.5, 128.4, 128.3, 128.1, 127.9, 126.2, 126.1, 121.9, 118.9, 118.6, 109.5, 109.4, 98.2, 97.1, 78.8, 78.0, 67.2, 67.0, 59.6, 59.5, 58.9, 45.7, 45.5, 43.1, 42.8, 42.7, 40.1, 39.7, 32.6, 31.7, 31.6, 20.8, 20.6, 20.5; HR-ESI-MS (m/z): calcd. for C28H35N4O3 [M + H]+: 475.2704, found 475.2709. 3a-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)-3,3a,8,8a-tetrahydro-2H-furo[2,3-b]indole (6). Prepared according to the general procedure without L1 catalyst and DMAP. Time of irradiation: 12 h. The crude mixture was purified by silica gel chromatography

(acetone/petroleum ether 1:50) to afford the product 6 as a colorless oil (25.2 mg, 80% yield). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 6.9, 1H), 7.10 (td, J = 7.8, 1.1, 1H), 6.78 (t, J = 7.2, 1H), 6.55 (d, J = 7.8, 1H), 6.14 (s, 1H), 4.51 (s, 1H), 4.10 (t, J = 8.3, 1H), 3.66−3.60 (m, 1H), 2.70 (td, J = 12.0, 7.8, 1H), 2.32 (dd, J = 11.7, 4.8, 1H), 1.65−1.21 (m, 6H), 1.12 (s, 3H), 1.08 (s, 3H), 0.88 (s, 3H), 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 150.6, 131.0, 129.4, 126.3, 118.7, 108.7, 98.6, 96.0, 67.3, 59.9, 59.3, 43.5, 40.8, 40.4, 33.0, 32.9, 20.6, 20.4, 17.1; HR-ESI-MS (m/z): calcd. for C19H29N2O2 [M + H]+: 317.2229, found 317.2223. (3aR,8aS)-Benzyl 3a-((2,2,6,6-Tetramethylpiperidin-1-yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate ((−)-2a). To an oven-dried 10 mL glass vial, containing benzyl (2-(1H-indol-3-yl)ethyl)carbamate (29.4 mg, 0.1 mmol), 8H-S-TRIP (7.6 mg, 0.01 mmol), TEMPO (39.3 mg, 0.25 mmol), DMAP (18.3 mg, 0.15 mmol), and CyNCO (12.5 mg, 0.1 mmol), was added toluene (1 mL). The vial was placed ∼10 cm from two 18 W blue LED lamps, and the reaction mixture was irradiated at −15 °C for 72 h under argon. Next, the mixture was directly purified by silica gel chromatography (acetone/petroleum ether 1:40) to afford the product (−)-2a as a colorless oil (42.2 mg, 94% yield, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/min, λ = 254 nm: tmajor = 13.5 min, tminor = 12.0 min (98% ee); = −296 (c = 0.39, CHCl3). The spectroscopic data are in [α]21.4 D agreement with (+)-2a. (E)-3-((3aR,8aS)-Ethyl 3a-((2,2,6,6-Tetramethylpiperidin-1yl)oxy)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-1(2H)-yl)acrylate (7). To a solution of (−)-2a (22.5 mg, 0.05 mmol) in a MeOH:EA = 1:1 (2.5 mL) was added 10% Pd(OH)2 (10 mg), and the vessel was purged several times with H2. The mixture was stirred under 1 atm of H2 for 30 min and then filtered over a pad of Celite. After washing the solids with a 1:1 MeOH/EA mixture (15 mL), the collected filtrates were concentrated in vacuo. Without any further purification, ethyl propiolate (5.4 mg, 0.055 mmol) was added to the CH3CN solution (1 mL) of the crude product. The mixture was stirred at room temperature for 1 h. CH3CN was evaporated, and the residue was subjected to flash chromatography on silica gel (acetone/ petroleum ether 1:20) to afford 7 as a colorless oil (18.4 mg, 87% yield for two steps, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/min, λ = 254 nm: tmajor = 9.0 min, 1 tminor = 7.3 min (98% ee); [α]21 D = −492 (c = 0.21, CHCl3). H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 12.7, 1H), 7.32 (d, J = 7.5, 1H), 7.12 (td, J = 7.9, 1.2, 1H), 6.91−6.75 (m, 1H), 6.55 (d, J = 7.9, 1H), 5.96 (s, 1H), 4.68 (d, J = 13.1, 1H), 4.57 (s, 1H), 4.15 (q, J = 7.1, 2H), 3.50 (t, J = 9.5, 1H), 3.20−3.05 (m, 1H), 2.79−2.68 (m, 1H), 2.44 (dd, J = 12.2, 6.5, 1H), 1.59−1.31 (m, 6H), 1.27 (t, J = 7.1, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 0.88 (s, 3H), 0.60 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 169.3, 150.0, 147.4, 129.8, 125.3, 119.6, 110.0, 60.1, 59.3, 59.1, 40.8, 40.4, 33.1, 32.7, 20.6, 20.3, 17.0, 14.6; HR-ESI-MS (m/z): calcd. for C24H36N3O3 [M + H]+: 414.2751, found 414.2744. (2a1R,5R,9bR)-Ethyl 5-Methyl-9b-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)-1,2,2a,19b-tetrahydro-5H-2a,5adiazacyclopenta[jk]fluorene-4-carboxylate (8). To a solution of 9 (16.5 mg, 0.04 mmol) in CH3CN (0.5 mL) was added 40% aqueous CH3CHO (16 μL, 0.4 mmol). The mixture was then adjusted to pH ∼ 6 with 1% aqueous HCl. After being stirred at 40 °C for 1 h, saturated NaHCO3 aqueous solution was added to quench the reaction. The aqueous phase was extracted with EA (10 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was subjected to flash chromatography on silica gel (acetone/petroleum ether 1:40) to afford 8 as a colorless oil (14.8 mg, 84%, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak ADH column, 95:5 hexane/i-PrOH, flow rate 0.5 mL/min, λ = 254 nm: tmajor = 8.9 min, tminor = 8.4 min (98% ee); [α]21 D = −650 (c = 0.48, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 7.4, 1H), 7.22− 7.12 (m, 2H), 6.76 (t, J = 7.4, 1H), 6.56 (d, J = 8.0, 1H), 5.11 (s, 1H), 4.51 (q, J = 6.7, 1H), 4.21−4.06 (m, 2H), 3.78−3.64 (m, 1H), 2.93− 10956

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

Article

The Journal of Organic Chemistry

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2.71 (m, 2H), 2.65−2.55 (m, 1H), 1.54−1.17 (m, 12H), 1.10 (s, 6H), 1.05 (s, 3H), 0.79 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 167.4, 151.7, 142.9, 130.5, 130.0, 126.9, 118.7, 109.7, 102.2, 92.6, 60.2, 59.5, 59.1, 50.6, 45.8, 41.0, 40.6, 36.6, 34.0, 32.5, 21.7, 20.6, 17.2, 14.6; HRESI-MS (m/z): calcd. for C26H38N3O3 [M + H]+: 440.2908, found 440.2910. (−)-Verrupyrroloindoline 9. To a solution of compound 8 (13.2 mg, 0.03 mmol) in THF/H2O/HOAc (0.5 mL:0.5 mL:0.2 mL) under argon was added activated zinc dust (20 mg, 0.3 mmol) in one portion. The mixture was stirred at room temperature for 2 h until no starting material was detected by TLC. Then saturated NaHCO3 aqueous solution was added to quench the reaction. The aqueous phase was extracted with DCM (10 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was subjected to flash chromatography on silica gel (acetone/petroleum ether 1:5) to afford (−)-verrupyrroloindoline 9 as a colorless oil (8.2 mg, 91%, 98% ee). The enantiomeric excess was determined by HPLC analysis on a Daicel ChiralPak AD-H column, 80:20 hexane/i-PrOH, flow rate 0.5 mL/ min, λ = 254 nm: tmajor = 12.1 min, tminor = 12.6 min (98% ee); [α]25 D = −690 (c = 0.07, CHCl3). 1H NMR (400 MHz, CDCl3) δ = 7.31 (dd, J = 7.2, 1.2, 1H), 7.24 (td, J = 7.8, 1.2, 1H), 7.13 (s, 1H), 6.85 (t, J = 7.2, 1H), 6.69 (d, J = 7.8, 1H), 4.73 (s, 1H), 4.53 (q, J = 6.6, 1H), 4.13 (q, J = 7.2, 2H), 3.81−3.67 (m, 1H), 2.88 (dd, J = 18.6, 9.6, 1H), 2.75 (s, 1H), 2.62−2.58 (m, 2H), 1.41 (d, J = 6.6, 3H), 1.26 (t, J = 7.2, 3H); 13C NMR (100 MHz, CDCl3): δ 167.3, 150.8, 142.6, 131.1, 130.9, 124.1, 120.3, 111.1, 101.6, 84.0, 78.4, 59.2, 49.8, 46.3, 33.9, 21.7, 14.5; HR-ESI-MS (m/z): calcd. for C17H21N2O3 [M + H]+: 301.1547, found 301.1547.

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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.8b01597. X-ray crystallographic data for compound 2c (CIF) HPLC traces of chiral compounds, 1H and 13C spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Pengcheng Yan: 0000-0002-9114-2244 Chengfeng Xia: 0000-0001-5617-5430 Author Contributions ∥

K.L. and X.T. 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 National Natural Science Foundation of China (21572236 and 21602194), and the Program for Changjiang Scholars and Innovative Research Team in University (IRT_17R94).

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REFERENCES

(1) (a) Xuan, J.; Xiao, W.-J. Visible-Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2012, 51, 6828−6838. (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (2) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075−10166. (3) (a) Keute, J. S.; Anderson, D. R.; Koch, T. H. Photochemical reactivity of the di-tert-butyl nitroxide.pi.,.pi.* state and di-tert-butyl 10957

DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958

Article

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DOI: 10.1021/acs.joc.8b01597 J. Org. Chem. 2018, 83, 10948−10958