Formal Total Syntheses of (−)- and (+)-Actinophyllic Acid - The Journal

Dec 28, 2017 - (−)-Actinophyllic acid (Figure 1, (−)-1), a monoterpernoid indole alkaloid, was isolated in 2005 by Carroll and co-workers from the...
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Cite This: J. Org. Chem. 2018, 83, 754−764

Formal Total Syntheses of (−)- and (+)-Actinophyllic Acid Fei Xue, Huifang Lu, Liping He, Wenfei Li, Dan Zhang, Xiao-Yu Liu, and Yong Qin* Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China S Supporting Information *

ABSTRACT: The formal total syntheses of (−)-actinophyllic acid and its enantiomer starting from the same chiral intermediate are reported. The synthesis features a photoredox organocatalytic asymmetric alkylation to generate the original C15 chirality, a photocatalytic C−H functionalization of 3-methylindole in flow for constructing the C16 all-carbon quaternary center, a regioselective 1,3-dipolar cycloaddition, and an intramolecular Henry reaction to assemble the pentacyclic core of the target molecule.

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with π-nucleophiles as a key reaction.3 In 2016, the Kwon group reported the asymmetric total synthesis of (−)-actinophyllic acid based on a chiral phosphine-catalyzed [3+2] annulation and a distinctive lactol formation.4 Very recently, Chen and co-workers reported an impressive synthesis of 1 featuring a desymmetrization-based strategy.5 Meanwhile, the groups of Wood, Taniguchi, Maldonado, and Coldham have reported their synthetic approaches toward actinophyllic acid in recent years.6 In continuation of our long-standing interest in the synthesis of complex alkaloid natural products, we embarked on a project targeting the hexacyclic actinophyllic acid.7 Herein, we describe our endeavors that led to the formal total syntheses of natural (−)-actinophyllic acid 1 and its enantiomer (+)-actinophyllic acid from the same chiral intermediate.

INTRODUCTION (−)-Actinophyllic acid (Figure 1, (−)-1), a monoterpernoid indole alkaloid, was isolated in 2005 by Carroll and co-workers

Figure 1. Structures of (−)- and (+)-actinophyllic acid 1.

from the leaves of Alstonia actinophylla.1 This compound was identified as a potent carboxypeptidase U inhibitor with an IC50 value of 0.84 μM through a coupled CPU/hippuricase assay. Structurally, actinophyllic acid is comprised of an unprecedented hexacyclic ring system, which features an azabicyclo[3.3.2]decanene scaffold (Figure 1, in blue), a pyrrolidine ring, a highly functionalized hemiketal moiety, five continuous stereogenic centers, and one all-carbon quaternary center. The aforementioned structural features and challenges, in combination with its intriguing bioactivity, have rendered actinophyllic acid an appealing target for synthetic chemists. The first milestone total syntheses of (±)-actinophyllic acid (2008)2a and (−)-actinophyllic acid (2010)2b were accomplished by the Overman group via an elegant aza-Cope/ Mannich reaction as a key step. In their systematic study, the absolute configuration of natural (−)-actinophyllic acid was assigned as 15R, 16S, 19S, 20S, 21R.2c In 2013, the Martin group disclosed a concise total synthesis of (±)-actinophyllic acid using a novel cascade reaction of N-stabilized carbocations © 2017 American Chemical Society

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RESULTS AND DISCUSSION During the past few years, our group has focused on the cyclopropane-based strategies to construct structurally intricate indole alkaloids.8 Concerning the present target molecule actinophyllic acid, we initially envisioned that the critical pyrrolidine unit could be assembled via a cyclopropane-based intramolecular [3+2] cycloaddition (via intermediate 7, Scheme 1), which would simultaneously facilitate construction of the core skeleton of actinophyllic acid (Scheme 1, 1, in red).7 Consequently, starting from the known chiral pyrrolidone 2, a 19-step synthesis was developed for the preparation of the azocino[4,3-b]indolyl intermediate 5.7 However, transformation of 5 into the key cyclopropane intermediate 6 was unsuccessful, which obstructed the implementation of the Received: October 30, 2017 Published: December 28, 2017 754

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

Article

The Journal of Organic Chemistry Scheme 1. Preliminary Studies toward the Total Synthesis of Actinophyllic Acid

Scheme 2. Retrosynthetic Analysis of Actinophyllic Acid (1)

nitrone 12 with nitroalkene 13.11 Nitrone 12 could be easily prepared from 14 by removal of both Bn and Cbz protecting groups, imine formation, and oxidation. In turn, the critical allcarbon quaternary center at C16 in 14 could be generated by direct coupling of 3-methylindole 15 with the chiral lactone 16; the latter could be further traced back to dimethyl bromomalonate 17 and aldehyde 18. A photoredox organocatalytic asymmetric alkylation method developed by MacMillan et al.12 was envisaged to secure the key C15 chirality in compound 16. As shown in Scheme 3, our synthesis commenced with the known alcohol 19.13 Swern oxidation of 19 gave aldehyde 18 in 95% yield. The pivotal asymmetric α-alkylation of 18 with dimethyl bromomalonate 17 was performed according to MacMillan’s photoredox organocatalytic protocol.12 In this

cyclopropane-based strategy. As a result, the inaccessibility of 6 along with the tedious synthetic procedure for preparing the azocino[4,3-b]indole 5 forced us to find an alternative access to actinophyllic acid. Outlined in Scheme 2 is our revised plan for the synthesis of (+)-actinophyllic acid 1. Given that the target molecule 1 has been synthesized from 8 by oxidation according to Martin’s report,3 we selected the latter as a starting point in our retrosynthetic analysis. Disconnection of the cyclic hemiketal in 8 would trace back to acetonide 9. We envisioned that the pyrrolidine ring of 9 could be formed through a one-pot reductive ring-opening/cyclization cascade from isoxazole 10.9 Construction of the D-ring in 10 could rely on C19−C20 bond formation via an intramolecular Henry reaction of 11, which could be generated from a 1,3-dipolar cycloaddition10 of 755

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

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The Journal of Organic Chemistry Scheme 3. Asymmetric Synthesis of Nitrone 12

Scheme 4. 1,3-Dipolar Cycloaddition of Nitrone 12 and Nitroalkene 13

in 65% yield. Lactone 23 was converted into 24 by two steps including reduction and selective protection of the two hydroxymethyl groups at C16 as an acetonide. Further protection of the free primary hydroxyl group in 24 with TBS, followed by a DDQ oxidation of the indole methyl group16 provided aldehyde 14 in 76% yield for two steps. Removal of both the Bn and Cbz groups in 14 through hydrogenation liberated a primary amine group, which intramolecularly condensed with the aldehyde group under anhydrous conditions to form an imine functionality. The resulting unstable imine intermediate was immediately subjected to oxidation with catalytic MeReO3 and using H2O2·urea as a co-oxidant17 to afford nitrone 12 in 56% yield for two steps, which set the synthetic stage ready for the planned 1,3-dipolar cycloaddition. With nitrone 12 available, we implemented the 1,3-dipolar cycloaddition of 12 with nitroalkene 13.11 The reaction proceeded smoothly in toluene at 40 °C via a regioselective endo-addition manner (Scheme 4, transition states 27a and

study, an improved yield was obtained using slightly modified conditions by switching the solvent and photocatalyst from DMF and Ru(bpy)3Cl2 to THF and Ir(ppy)3, respectively. Since the racemization of aldehyde 21 readily occurred, 21 was directly reduced with NaBH4 without purification to afford lactone 16 in 61% yield for two steps with 92% ee at C15. The ee value of 16 was determined by chiral chromatographic analysis after removing the ester group.14 This photocatalytic asymmetric α-alkylation was easily carried out on a 10 g scale without the loss of both enantioselectivity and yield. Our next task was to install an indole moiety at C16 in 16 to construct the sterically hindered all-carbon quaternary center. Although challenging, we found that a photocatalytic C−H functionalization method recently developed by Stephenson and co-workers provided us a good opportunity to realize this key transformation.15 After bromination of 16, the resultant bromolactone 22 and 3-methylindole 15 were subjected to irradiation by blue LEDs lights in a flow reactor in the presence of 4methoxy-N,N-diphenylaniline and Ru(bpy)3Cl2 to provide 23 756

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

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The Journal of Organic Chemistry Scheme 5. Synthesis of 10 and ent-10 via Intramolecular Henry Reaction

protecting group in 28a with TBAF, the resultant alcohol 29a was oxidized with TPAP/NMO18 to give aldehyde 11a as well as ca. 30% of the intramolecular Henry reaction product 30 (Scheme 5a). Without purification, the mixture of 11a and 30 was then treated with DBU in CH2Cl2 to completely convert 11a to 30.19 The overall yield of 30 from the corresponding alcohol 29a was 78% for two steps. During the Henry reaction of 11a, the stereochemistry at C15 was retained and the stereochemistry at C19 was inverted. Further oxidation of 30 afforded ketone 10 in 88% yield.19 The relative stereochemistry at C6, C15, C19, C20, and C21 in 30 and 10 was assigned by NOE experiments (Scheme 5a).14 When 28b was subjected to a similar consecutive process involving desilylation, oxidation, and Henry reaction, a product (ent-30) that had identical NMR spectra to 30 but opposite optical rotation was isolated in 55% yield over three steps (Scheme 5b). During oxidation of the primary alcohol 29b to aldehyde 11b, spontaneous formation of Henry adduct ent-30 was not observed because the C19 was spatially far away from the aldehyde group. Once 11b was

27b) to generate a pair of separable diastereomers 28a (35% yield) and 28b (47% yield), and 5% of starting material 12 was recovered. Both the pure 28a and 28b were observed to decompose slowly into nitrone 12 and nitroalkene 13 when stored at room temperature, indicating the above cycloaddtion was reversible. Attempts to improve the diastereoselectivity of the cycloaddition reaction by screening different solvents and temperatures, or adjusting the structures of the dipolarophile component, were unsuccessful.14 Presumably, the low diastereoselectivity of the 1,3-dipolar cycloaddition might be due to the relatively plane character of the dipole (compound 12, Scheme 4) involving an indole-fused unsaturated and flexible eight-membered ring and a remote C15 stereogenic center, which could not induce stereochemical control of the cycloaddition. At this point, it is more urgent for us to verify the feasibility of our synthetic strategy. Thus, both diastereomers of 1,3dipolar cycloaddtion were used for the subsequent transformations. As shown in Scheme 5a, after removal of the TBS 757

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

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The Journal of Organic Chemistry Scheme 6. Formal Total Syntheses of (−)-Actinophyllic Acid 1 and (+)-Actinophyllic Acid 1

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CONCLUSION In summary, we have accomplished formal total syntheses of (−)-actinophyllic acid 1 and its enantiomer (+)-actinophyllic acid. Key steps of the syntheses include: (1) an efficient photoredox organocatalytic alkylation of aldehyde to introduce the C15 chirality; (2) a photocatalytic C−H functionalization of 3-methyl indole to construct the congested C16 all-carbon quaternary center; (3) a regioselective 1,3-dipolar cycloaddition followed by a Henry reaction to generate 10 and ent-10 from the common chiral intermediate 12; and (4) an isoxazole ringopening/pyrrolidine ring formation cascade to construct the cage-like pentacyclic core. The here described synthetic approach to both enantiopodes of actinophyllic acid showcases the application of new synthetic technology of photoredox reactions in the assembly of complex natural products.22

treated with DBU in CH2Cl2, both the stereochemistry at C15 and C19 was inverted to force the aldehyde group at C20 into spatial proximity of C19. Thus, this process allowed a Henry reaction to take place to give ent-30. Subsequent oxidation of ent-30 provided ketone ent-10 in 90% yield. The generation of a pair of enantiomers (10 and ent-10) from the same chiral intermediate 12 via the 1,3-dipolar cycloaddition and the Henry reaction allowed us to synthesize both natural (−)-actinophyllic acid 1 and its enantiomer (+)-actinophyllic acid 1. As depicted in Scheme 6, removal of the nitro group at C19 in 10 was performed under the conditions of n-Bu3SnH and AIBN in toluene at 70 °C.20 This reaction afforded the debenzylated 31 (45% yield) as well as the nondebenzylated 32 (40% yield). We found that when compound 32 was resubjected to the conditions of n-Bu3SnH and AIBN, the anticipated debenzylation did not occur. We surmise that the nitro group might be involved in the debenzylation step, but the exact mechanism for the phenomenon remains unclear. After converting the free hydroxyl group in 31 into a mesylate, the resultant 33 was subjected to hydrogenation under reflux in the presence of AcONa in MeOH to give 34 via a cascade process of isoxazole ring-opening21 and pyrrolidine ring formation, thus constructing the pentacyclic core of actinophyllic acid. Ultimately, a onepot radical deoxygenation of 34, followed by formation of the hemiketal unit through heating the deoxygenated product with hydrochloric acid, afforded compound 35 in 74% overall yield as a salt. Similarly, ent-10 was elaborated into ent-35 through the same four-step synthetic sequence as that applied to 10.14 Compounds 35 and ent-35 showed opposite optical rotations and identical 1H and 13C NMR spectra, which were consistent with those of a racemic sample reported by the Martin group.3 Thus, the successful preparation of 35 and ent-35 constituted the formal total syntheses of both (−)-actinophyllic acid 1 and (+)-actinophyllic acid 1.

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EXPERIMENTAL SECTION

General Methods. All reactions that require anhydrous conditions were performed in flame-dried glassware under Ar atmosphere and all reagents were purchased from commercial suppliers without further purification. Solvent purification was conducted according to Purification of Laboratory Chemicals.23 The solvents for radical reactions were degassed in flame-dried glassware via syringe needle under Ar for 30 min. The products were purified by flash column chromatography on silica gel (200−300 meshes) from the Anhui Liangchen Silicon Material Company (China). Reverse phase chromatography was performed using reverse-phase C18 silica gel (200−300 meshes) from the Xi’an Jiaotong University Technologies Co. Ltd. (China). Reactions were monitored by thin layer chromatography (TLC, 0.2 mm, HSGF254) supplied by Yantai Chemicals (China). Visualization was accomplished with UV light, exposure to iodine, stained with ethanolic solution of phosphomolybdic acid or basic solution of KMnO4. 1H NMR and 13C NMR spectra were recorded on Varian INOVA-400/54, Agilent DD2-600/54 and calibrated by using residual undeuterated chloroform containing 0.03% v/v TMS (δ, 1H NMR = 7.260, 13C NMR = 77.00) unless otherwise 758

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

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The Journal of Organic Chemistry

3.08 (m, 3H), 2.92−2.79 (m, 1H), 1.78−1.60 (m, 2H). 13C NMR (150 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 171.5, 171.3, 167.8, 167.7, 156.3, 156.2, 137.3, 137.2, 136.3, 128.7, 128.6, 128.5, 128.3, 128.1, 127.9, 127.6, 127.3, 71.7, 71.4, 67.6, 67.4, 53.1, 52.1, 50.7, 50.4, 44.6, 43.8, 37.5, 31.0, 30.4. HRMS (ESI) m/z calcd for C23H25NNaO6 [M+Na]+ 434.1574; found 434.1571. Methyl (4R)-4-(2-(Benzyl((benzyloxy)carbonyl)amino)ethyl)-3bromo-2-oxotetrahydrofuran-3-carboxylate (22). To a solution of compound 16 (8.00 g, 19.4 mmol, 1.0 equiv) in anhydrous THF (200 mL) was added LHMDS (38.9 mL, 1 M in THF, 38.9 mmol, 2.0 equiv) dropwise under an argon atmosphere at −78 °C, and the resulting mixture was maintained at −78 °C for 1 h. Then a solution of NBS (5.19 g, 29.2 mmol, 1.5 equiv) in anhydrous THF (100 mL) was added dropwise through a dropping funnel. After being stirred for 10 h, the reaction was quenched with saturated aqueous NH4Cl (100 mL) at −78 °C and warmed to room temperature. This mixture was diluted with H2O (100 mL) and EtOAc (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was subjected to silica gel column chromatography (petroleum ether/EtOAc = 5:1) to give 22 (7.82 g, 82%) as pale yellow oil. [α]20 D = +1.2 (c 1.0, CHCl3). IR (neat) νmax = 1787, 1760, 1731, 1693, 1472, 1453, 1421, 1229, 1124, 1026, 731, 697 cm−1.1H NMR (600 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 7.37−7.16 (m, 10H), 5.21−5.16 (m, 2H), 4.56 (d, J = 15.6 Hz, 1H), 4.47−4.41 (m, 2H), 4.21 (m, 0.4H), 3.89−3.72 (m, 3.6 H), 3.26−3.18 (m, 2H), 2.89−2.80 (m, 1H), 1.89−1.85 (m, 1H), 1.76−1.62 (m, 1H).13C NMR (150 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 169.4, 169.2, 165.3, 156.2, 137.1, 136.2, 128.8, 128.7, 128.5, 128.3, 128.1, 127.9, 127.7, 127.4, 70.4, 70.1, 67.7, 67.6, 60.2, 59.9, 54.6, 50.6, 50.2, 43.9, 43.6, 43.3, 27.7, 27.3. HRMS (ESI) m/z calcd for C23H24BrNNaO6 [M+Na]+ 512.0679; found 512.0675 Methyl (4S)-4-(2-(Benzyl((benzyloxy)carbonyl)amino)ethyl)-3-(3methyl-1H-indol-2-yl)-2-oxotetrahydrofuran-3-carboxylate (23). 3Methylindole 15 (18.7 g, 143 mmol, 10.0 equiv), bromolactone 22 (7.00 g, 14.3 mmol, 1.0 equiv), tris(2,2′- bipyridyl)ruthenium(II) chloride hexahydrate (107 mg, 143 μmol, 0.01 equiv), and 4methoxytriphenylamine (7.85 g, 28.6 mmol, 2.0 equiv) were added to a 250 mL round-bottom flask wrapped with tinfoil. The flask was purged with Ar and anhydrous DMF (60 mL) was added. Then the reaction mixture was degassed. The resulting solution was pumped through the photoreactor14 at a flow rate to achieve a residence time of 40 min and then collected in a flask.15 Then the collected mixture was poured into EtOAc (100 mL) and H2O (100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over MgSO4, and concentrated in vacuo. Purification of the crude product through flash chromatography (petroleum ether/EtOAc = 10:1 to 4:1) gave compound 23 (5.01 g, 65%) as pale yellow foam. [α]20 D = +52.9 (c 0.7, CHCl3).IR (neat) νmax = 1781, 1736, 1692, 1454, 1421, 1260, 1239, 1209, 1085, 1020, 800, 732, 697, 583, 515 cm−1. 1H NMR (400 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 9.66 (brs, 0.6H), 9.56 (brs, 0.4H), 7.53 (d, J = 8.0 Hz, 1H), 7.31−7.17 (m, 11H), 7.13−7.07 (m, 2H), 6.98 (m, 1H), 5.14 (dd, J = 14.0, 12.4 Hz, 2H), 4.65 (m, 0.6 H), 4.37−4.22 (m, 3.4 H), 4.09−4.04 (m, 0.6H), 3.83−3.75 (m, 3.4H), 3.20−3.10 (m, 3.6 H), 2.90 (m, 0.4H), 2.15−2.11 (m, 3H), 1.74 (m, 1H), 1.57−1.45 (m, 1H).13C NMR (150 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 172.4, 168.4, 168.4, 156.3, 137.1, 136.2, 134.5, 129.0, 128.6, 128.5, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.2, 122.3, 119.4, 118.5, 110.1, 108.9, 108.8, 108.7, 70.8, 70.6, 67.5, 57.7, 57.6, 53.3, 50.8, 50.7, 46.8, 46.7, 44.9, 44.2, 27.8, 27.4, 9.4. HRMS (ESI) m/z calcd for C32H32N2NaO6 [M+Na]+ 563.2153; found 562.2147. Benzyl (S)-Benzyl(5-hydroxy-3,4-bis(hydroxymethyl)-4-(3-methyl1H-indol-2-yl)pentyl)carbamate (24). CaCl2 (12.3 g, 111 mmol, 10.0 equiv) was added in small portions to a solution of lactone 23 (6.00 g, 11.1 mmol, 1.0 equiv) in anhydrous ethanol (250 mL) at −10 °C. The

noted. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br = broad, td = triple doublet, dt = double triplet, m = multiplet, and coupling constants (J) are reported in Hertz (Hz). Infrared (IR) spectra were recorded on a PerkinElmer Spectrum Two FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded on Agilent LC-MSD TOF ESI mass spectrometers. The specific optical rotation was obtained from Rudolph Research Analytical Autopol VI automatic polarimeter. Chiral HPLC analysis was performed on HP Agilent 1260 apparatus (Chiralpak OJ-H Column, 4.6 × 250 mm, 5 μm). Benzyl Benzyl(2-oxoethyl)carbamate (18). A solution of DMSO (15.0 mL, 0.211 mol, 2.2 equiv) in anhydrous CH2Cl2 (100 mL) was added dropwise to a solution of oxalyl chloride (16.2 mL, 0.191 mol, 2.0 equiv) in anhydrous CH2Cl2 (100 mL) at −78 °C over 30 min. The resulting mixture was stirred at −78 °C for 30 min. A solution of benzyl benzyl(2-hydroxyethyl)carbamate 1914 (30.0 g, 0.0957 mol, 1.0 equiv) in anhydrous CH2Cl2 (200 mL) was slowly added over 20 min and the mixture was stirred for 5 h at −78 °C. Then Et3N (66.5 mL, 0.479 mol, 5.0 equiv) was added dropwise, and the reaction was allowed to warm to 25 °C slowly. After stirring for 1 h, the reaction was diluted with CH2Cl2 (100 mL) and H2O (200 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with water (200 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc = 6:1) to give compound 18 (28.32 g, 95%) as pale yellow oil. IR (neat) νmax = 1692, 1472, 1453, 1420, 1364, 1225, 1120, 1070, 979, 731, 696 cm−1. 1H NMR (600 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 9.69 (s, 0.5H), 9.57 (s, 0.5H), 7.38−7.17 (m, 10H), 5.17 (d, J = 12.6 Hz, 2H), 4.49 (d, J = 11.4 Hz, 2H), 3.30−3.21 (m, 2H), 2.43−2.29 (m, 2H), 1.95−1.76 (m, 2H). 13C NMR (100 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 201.4, 201.1, 156.4, 156.2, 137.5, 136.4, 128.4, 128.3, 127.8, 127.7, 127.3, 127.2, 67.2, 50.3, 50.1, 46.1, 45.1, 40.8, 40.6, 20.3, 20.0. HRMS (ESI) m/z calcd for C19H21NNaO3 [M+Na]+ 334.1414; found 334.1413. Methyl (4S)-4-(2-(Benzyl((benzyloxy)carbonyl)amino)ethyl)-2-oxotetrahydrofuran- 3-carboxylate (16). Aldehyde 18 (22.1 g, 71.1 mmol, 1.5 equiv), dimethyl bromomanolate 1724 (10.0 g, 47.4 mmol, 1.0 equiv), (2S,5R)-2-tert-butyl-3,5-dimethylimidazolidin-4-one trifluoromethanesulfonic acid salt 20 (3.04 g, 9.48 mmol, 0.2 equiv), and Ir(ppy)3 (154 mg, 237 μmol, 0.005 equiv) were added to an ovendried 250 mL round-bottom flask wrapped with tinfoil. Then the flask was purged with Ar, and anhydrous THF (100 mL) was added. The above mixture was cooled to 0 °C and 2,6-lutidine (10.9 mL, 94.8 mmol, 2.0 equiv) was added. After the resultant reaction mixture was degassed for 30 min by bubbling Ar, the tinfoil was removed and the reaction was irradiated by 15 W fluorescent light at 25 °C.12 After being stirred for ca. 8 h, the reaction was completed (identified by TLC analysis). The mixture was diluted with EtOAc (100 mL) and H2O (100 mL) at 0 °C. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was dissolved in MeOH (200 mL) and cooled to 0 °C. NaBH4 (3.58 g, 94.8 mmol, 2.0 equiv) was added in small portions. The reaction was allowed to stirred at 25 °C for 2 h and quenched with saturated aqueous NH4Cl (100 mL) at 0 °C. After removing MeOH under reduced pressure, EtOAc (200 mL) was added to the resultant residue. The aqueous layer was extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with water (200 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated. Purification of the residue by silica gel flash chromatography (petroleum ether/EtOAc = 4:1) afforded lactone 16 (11.90 g, 61% for two steps) as pale yellow oil. [α]20 D = −17.4 (c 0.62, CHCl3). IR (neat) νmax = 1778, 1737, 1692, 1421, 1357, 1231, 1213, 1147, 1128, 1018, 732, 696 cm−1. 1H NMR (400 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 7.36−7.15 (m, 10H), 5.21−5.14 (m, 2H), 4.54−4.39 (m, 2.6H), 4.32− 4.27 (m, 0.4 H), 3.95−3.87 (m, 0.6H), 3.76−3.65 (m, 3.4H), 3.34− 759

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

Article

The Journal of Organic Chemistry

0.15, CHCl3). IR (neat) νmax = 3354, 2928, 2856, 1697, 1463, 1422, 1371, 1254, 1222, 1198, 1092, 1029, 834, 736, 698, 523 cm−1. 1H NMR (400 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 9.44 (brs, 0.5H), 9.29 (brs, 0.5H), 7.50 (d, J = 8.0 Hz, 1H), 7.31−7.21 (m, 10H), 7.15−7.06 (m, 3H), 7.00 (m, 1H), 5.16−5.05 (m, 2H), 4.55−4.38 (m, 2H), 4.29 (d, J = 12.4 Hz, 0.5H), 4.22−4.11 (m, 2H), 4.05−4.83 (m, 3H), 3.62 (d, J = 12.4 Hz, 0.5H), 3.44−3.38 (m, 0.5H), 3.30−3.24 (m, 0.5H), 3.15−3.07 (m, 1H), 2.38 (m, 0.5H), 2.29−2.23 (m, 3.5 H), 1.42 (s, 3H), 1.42 (overlapped, 1H), 1.38 (s, 3H), 1.38 (overlapped, 1H), 0.96 (s, 4.5H), 0.92 (s, 4.5H), 0.12 (s, 3H), 0.03 (s, 3H). 13C NMR (150 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 156.5, 156.3, 137.5, 136.6, 135.1, 134.4, 134.3, 130.1, 128.5, 128.4, 128.1, 127.9, 127.8, 127.7, 127.3, 127.2, 127.1, 121.3, 118.7, 118.0, 110.5, 106.8, 98.1, 67.3, 67.2, 66.1, 66.0, 65.6, 61.8, 50.2, 49.6, 45.2, 44.9, 43.5, 43.4, 39.7, 39.4, 26.0, 25.6, 25.1, 24.6, 22.3, 18.4, 10.4, −5.4, −5.5, −5.6. HRMS (ESI) m/z calcd for C40H54N2NaO5Si [M+Na]+ 693.3694; found 693.3693. Benzyl (S)-Benzyl(4-((tert-butyldimethylsilyl)oxy) −3-(5-(3-formyl1H-indol-2-yl)-2,2-dimethyl-1,3-dioxan-5-yl)butyl)carbamate (14). DDQ (3.35 g, 14.8 mmol, 3.0 equiv) was added in small portions to a solution of compound 26 (3.30 g, 4.92 mmol, 1.0 equiv) in EtOAc (100 mL) at 0 °C. The resulting dark green mixture was stirred at reflux for 5 h. Then this reaction was cooled to 0 °C and quenched with saturated aqueous NaHCO3 (50 mL). The resulting mixture was filtered through Celite. The filtrate was separated into two layers, and the aqueous layer was extracted with EtOAc (3 × 100 mL). The organic extracts were combined, washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried, and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 5:1) to afford compound 14 (2.73 g, 81%) as pale yellow foam. [α]20 D = −5.3 (c 0.34, CHCl3). IR (neat) νmax = 3310, 2928, 2856, 1693, 1650, 1454, 1397, 1372, 1252, 1217, 1105, 1079, 833, 775, 733, 697 cm−1. 1H NMR (600 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 10.32 (s, 0.5H), 10.29 (s, 0.5H) 10.14 (brs, 0.5H), 9.99 (brs, 0.5H), 8.20−8.16 (m, 1H), 7.43−7.36 (m, 1H), 7.33−7.25 (m, 6 H), 7.22−7.18 (m, 4H), 7.10−7.08 (m, 1H), 6.99 (m, 1H), 5.15−5.11 (m, 1H), 5.08 (d, J = 12.0 Hz, 0.5 H), 4.99 (d, J = 12.6 Hz, 0.5H), 4.54−4.37 (m, 3H), 4.30 (d, J = 12.0 Hz, 0.5 H), 4.22−4.08 (m, 2.5 H), 3.88 (d, J = 10.8 Hz, 0.5 H), 3.80 (d, J = 11.4 Hz, 0.5 H), 3.70 (d, J = 11.4 Hz, 0.5H), 3.20−3.06 (m, 1.5 H), 2.63−2.59 (m, 1H), 1.68−1.67 (m, 0.5H), 1.57−1.53 (m, 1H), 1.48 (s, 1.5H), 1.45 (s, 1.5H), 1.40−1.38 (m, 0.5H), 1.31(s, 1.5H), 1.29 (s, 1.5H), 0.92 (s, 4.5H), 0.86 (s, 4.5 H), 0.08 (s, 1.5H), 0.06 (s, 1.5 H), − 0.06 (s, 3H). 13C NMR (150 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 184.6, 156.4, 156.2, 150.1, 137.5, 136.6, 134.5, 134.4, 128.7, 128.5, 128.4, 128.1, 128.0, 127.8, 127.4, 127.3, 127.2, 123.2, 122.6, 120.0, 119.5, 113.9, 113.4, 111.2, 98.7, 67.3, 65.4, 65.3, 65.0, 61.3, 50.6, 50.0, 45.0, 44.8, 44.7, 44.5, 40.1, 40.0, 26.8, 26.3, 25.9, 24.8, 24.3, 21.6, 21.0, 18.3, 18.2, − 5.6, − 5.7. HRMS (ESI) m/z calcd for C40H52N2NaO6Si [M+Na]+ 707.3487; found 707.3481. (S,E)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2′,2′-dimethyl3,4,5,7-tetrahydrospiro[azocino[4,3-b]indole-6,5′-[1,3]dioxane]2oxide (12). A mixture of compound 14 (0.50 g, 0.73 mmol, 1.0 equiv) and Pd/C (10% Pd on carbon, wet, 200 mg) in MeOH (100 mL) was stirred at reflux under 1.0 atm of H2 for 20 min. Then the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo, the resulting residue was then dissolved in anhydrous MeOH (100 mL), and 4 Å powdered molecular sieves (500 mg) was added. The reaction was heated to reflux overnight before it was cooled to room temperature and filtered. After concentration of the filtrate under reduced pressure, the crude imine was dissolved in MeOH (100 mL), urea hydrogen peroxide (206 mg, 2.19 mmol, 3.0 equiv) and methyltrioxorhenium (4.0 mg, 0.015 mmol, 0.02 equiv) were added sequentially. This reaction was stirred at 35 °C for 1 h. After evaporating off methanol under reduced pressure, the residue was suspended in CH2Cl2 (100 mL) and the insoluble urea was filtered off. The filtrate was concentrated in vacuo to afford the crude nitrone, which was purified by silica gel flash chromatography

resulting mixture was stirred until the white solids were entirely dissolved. Then NaBH4 (6.30 g, 166 mmol, 15.0 equiv) was added in small portions. After stirring at −10 °C for 48 h, the reaction mixture was poured into a solution of 1 M HCl (300 mL) at 0 °C. The resulting mixture was evaporated under reduce pressure to remove ethanol, and the residue was diluted with EtOAc (300 mL).The layers were separated and the aqueous layer was extracted with EtOAc (3 × 300 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc, 2:1 to 0:100) to yield compound 24 (2.87 g, 50%) as white foam and the dehydroxylmethyl byproduct.14 Data for compound 24: [α]20 D = −11.2 (c 0.4, CHCl3). IR (neat) νmax = 3363, 2932, 1675, 1454, 1424, 1331, 1238, 1120, 1028, 739, 698 cm−1. 1H NMR (600 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 9.95 (brs, 0.8H), 9.72 (brs, 0.2H), 7.51 (d, J = 7.8 Hz, 1H), 7.36−7.24 (m, 9H), 7.14 (t, J = 7.8 Hz, 1H), 7.10−7.06 (m, 3H), 5.20−5.10 (m, 2H), 4.41 (d, J = 16.2 Hz, 1H), 4.26 (d, J = 15.6 Hz, 2H), 4.12 (m, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.93 (d, J = 12.0 Hz, 1H), 3.78−3.76 (m, 1H), 3.61 (t, J = 9.6 Hz, 1H), 3.46−3.34 (m, 2H), 3.24−3.15 (m, 1H), 3.06−3.01 (m, 1H), 2.28−2.23 (m, 4H), 1.89−1.87 (m, 1H), 1.63−1.59 (m, 1H), 1.49−1.43 (m, 1H). 13C NMR (150 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 156.9, 137.1, 136.2, 135.2, 135.0, 129.2, 128.7, 128.6, 128.3, 128.0, 127.7, 127.5, 121.6, 119.0, 117.8, 127.5, 121.6, 119.0, 117.8, 111.0, 106.0, 67.7, 65.5, 64.6, 59.7, 44.7, 42.6, 23.5, 9.9. HRMS (ESI) m/z calcd for C31H36N2NaO5 [M+Na]+ 539.2516; found 539.2518. Benzyl (S)-Benzyl(3-(2,2-dimethyl-5-(3-methyl-1H-indol-2-yl)-1,3dioxan-5-yl)-4-hydroxybutyl)carbamate (25). 2-Metoxypropene (2.0 mL, 21.3 mmol, 2.2 equiv) and D-camphorsulfonic acid (0.450 g, 1.94 mmol, 0.2 equiv) were successively added to a stirred solution of compound 24 (5.00 g, 9.68 mmol, 1.0 equiv) in acetone (250 mL) at 0 °C. This reaction was stirred for 2 h before being quenched with saturated aqueous NaHCO3 (150 mL) at 0 °C. The resulting mixture was evaporated under reduced pressure to remove acetone, diluted with H2O (100 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL), dried over MgSO4, filtered, and concentrated. The residue was subjected to silica gel flash chromatography (CH2Cl2/EtOAc = 30:1) to give compound 25 (2.16 g, 40%) and byproduct.14 Data for compound 25: [α]20 D = −3.2 (c 0.4, CHCl3). IR (neat) νmax = 3355, 2989, 2935, 1674, 1454, 1423, 1372, 1219, 1198, 1117, 1089, 1028, 833, 735, 697, 455 cm−1. 1 H NMR (400 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 9.15 (brs, 0.6H), 8.61 (brs, 0.4H), 7.50 (d, J = 7.6 Hz, 1H), 7.33−7.25 (m, 5H), 7.21−7.19 (m, 3H), 7.15 (t, J = 7.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.04−6.99 (m, 2H), 5.16−5.06 (m, 2H), 4.35−4.24 (m, 3H), 4.19−3.99 (m, 5H), 3.88 (m, 0.6H), 3.68 (m, 0.4H), 3.34−3.29 (m, 1H), 3.22−3.14 (m, 1H), 2.27−2.12 (m, 5H), 1.69 (s, 1.2H), 1.43 (2.8 H), 1.39 (s, 3H). 13C NMR (150 MHz, CDCl3, some signals exist as a pair due to the presence of amide rotamers) δ 156.5, 156.4, 137.5, 137.3, 136.6, 136.4, 135.2, 135.0, 134.4, 134.0, 129.8, 129.7, 128.5, 128.2, 128.1, 127.9, 127.4, 121.7, 121.4, 119.1, 118.9, 118.0, 117.9, 110.7, 110.5, 107.2, 107.0, 98.4, 67.4, 65.9, 65.2, 64.8, 61.2, 60.8, 50.2, 45.2, 44.9, 43.0, 42.6, 41.5, 40.5, 26.4, 25.8, 25.1, 24.9, 21.1, 10.4. HRMS (ESI) m/z calcd for C34H40N2NaO5 [M+Na]+ 579.2829; found 579.2825. Benzyl (S)-Benzyl(4-((tert-butyldimethylsilyl)oxy)-3-(2,2-dimethyl5-(3-methyl-1H-indol-2-yl)-1,3-dioxan-5-yl)butyl)carbamate (26). Imidazole (0.810 g, 11.9 mmol, 2.2 equiv) and TBSCl (1.62 g, 10.8 mmol, 2.0 equiv) were successively added to a solution of compound 25 (3.00 g, 5.39 mmol, 1.0 equiv) in anhydrous DMF (50 mL) at 0 °C. This reaction was warmed to 25 °C and stirred for 2 h. Then the mixture was quenched with saturated aqueous NH4Cl (100 mL) at 0 °C and diluted with EtOAc (100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude material by silica gel flash chromatography (petroleum ether/EtOAc = 8:1) furnished compound 26 (3.40 g, 94%) as pale yellow foam. [α]20 D = −8.7 (c 760

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

Article

The Journal of Organic Chemistry

7.40−7.35 (m, 4H), 7.34−7.32 (m, 2H), 7.16 (t, J = 5.2 Hz, 1H), 7.22 (t, J = 5.2 Hz, 1H), 5.81 (dd, J = 5.6, 3.6 Hz, 1H), 4.92 (dd, J = 6.8, 3.2 Hz, 1H), 4.77 (d, J = 7.6 Hz, 1H), 4.64 (dd, J = 16.0, 8.0 Hz, 2H), 4.50−4.46 (m, 2H), 4.34 (d, J = 8.0 Hz, 1H), 4.20−4.17 (m, 1H), 4.01 (d, J = 8.0 Hz, 1H), 3.96−3.93 (m, 1H), 3.76−3.71 (m, 2H), 3.52− 3.47 (m, 1H), 2.64−2.61 (m, 1H), 2.11−2.06 (m, 1H), 1.80−1.76 (m, 1H), 1.73−1.60 (m, 2H), 1.51 (s, 3H), 1.28 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 138.6, 137.3, 134.5, 128.6 (×2), 128.0, 127.7 (×2), 126.9, 122.0, 119.8, 118.3, 111.1, 104.9, 99.5, 92.9, 80.3, 73.7, 70.6, 67.8, 67.1, 66.2, 61.9, 53.6, 42.4, 42.2, 27.2, 25.9, 20.7. HRMS (ESI) m/z calcd for C29H35N3NaO7 [M+Na]+ 560.2367; found 560.2371. (1’S,2’S,7’S,13c’R,14’R)-2′-((Benzyloxy)methyl)-2,2-dimethyl-1′nitro-1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-ol (30). Four Å powdered molecular sieves (100 mg) and 4-methylmorpholine Noxide (NMO, 40 mg, 0.34 mmol, 2.0 equiv) were added to a solution of compound 29a (90 mg, 0.17 mmol, 1.0 equiv) in anhydrous CH2Cl2 (8 mL) under an argon atmosphere at 0 °C. Tetrapropylammonium perruthenate (TPAP, 12 mg, 0.034 mmol, 0.2 equiv) was then added in one portion. The resulting black mixture was stirred at 25 °C for 30 min and then filtered through a short pad of silica using petroleum ether/EtOAc (1:1) as the eluent. The filtrate was concentrated in vacuo to give a crude mixture of the aldehyde intermediate 11a and 30, which was then dissolved in CH2Cl2 (5 mL) and stirred with DBU (13 μL, 0.085 mmol, 0.5 equiv) at 25 °C. The reaction was stirred for 2 h before removal of the solvent under reduced pressure. The resulting residue was purified by silica gel flash chromatography (petroleum ether/EtOAc = 1:1) to give compound 30 (70 mg, 78%) as yellow oil. [α]20 D = −35.0 (c 0.08, CHCl3). IR (neat) νmax = 3451, 2924, 2850, 1732, 1541, 1462, 1375, 1322, 1253, 1225, 1194, 1153, 1109, 1064, 832, 738, 699, 524, 487 cm−1. 1H NMR (600 MHz, CDCl3) δ 9.34 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.37− 7.29 (m, 6H), 7.23 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 6.02 (s, 1H), 5.47 (t, J = 4.8 Hz, 1H), 4.51, 4.48 (ABq, J = 11.4 Hz, each 1H), 4.38 (s, 1H), 4.15 (d, J = 12.0 Hz, 1H), 4.09 (d, J = 11.4 Hz, 1H), 4.03 (d, J = 11.4 Hz, 1H), 3.92 (d, J = 11.4 Hz, 1H), 3.75 (dd, J = 10.8, 4.8 Hz, 1H), 3.64 (dd, J = 10.2, 5.4 Hz, 1H), 3.27−3.24 (m, 2H), 2.97 (td, J = 15.6, 3.6 Hz, 1H), 2.47−2.40 (m, 1H), 2.37−2.36 (m, 1H), 1.70 (m, 1H), 1.66 (s, 3H), 1.57 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 139.0, 137.2, 134.9, 128.4 (× 2), 128.0 (× 3), 127.8, 122.7, 120.4, 118.0, 110.8, 104.5, 100.5, 99.1, 81.5, 73.9, 70.9, 69.8, 69.4, 66.4, 64.5, 49.5, 44.9, 38.5, 28.1, 21.3, 19.0. HRMS (ESI) m/z calcd for C29H33N3NaO7 [M+Na]+ 558.2211; found 558.2212. (1’R,2’S,7’S,13c’R)-2′-((Benzyloxy)methyl)-2,2-dimethyl-1′-nitro1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-one (10). Four Å powdered molecular sieves (60 mg) and 4-methylmorpholine Noxide (NMO, 26 mg, 0.22 mmol, 2.0 equiv) were added to a solution of compound 30 (60 mg, 0.11 mmol, 1.0 equiv) in anhydrous CH2Cl2 (5 mL) under an argon atmosphere at 0 °C. Tetrapropylammonium perruthenate (TPAP, 8.0 mg, 0.022 mmol, 0.2 equiv) was then added in one portion. The resulting mixture was stirred at 25 °C for 1 h, before the solvent was evaporated off. Purification of the crude material by silica gel flash chromatography (petroleum ether/EtOAc = 1:1) afforded compound 10 (53 mg, 88%) as pale yellow foam. [α]20 D = −55.0 (c 0.2, CHCl3). IR (neat) νmax = 3448, 2923, 1713, 1552, 1461, 1376, 1261, 1198, 1096, 1072, 830, 742, 698, 525 cm−1. 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 7.39−7.32 (m, 5H), 7.26−7.23 (m, 2H), 7.16 (t, J = 5.2 Hz, 1H), 6.00 (s, 1H), 4.92 (s, 1H), 4.54 (dd, J = 13.2, 7.6 Hz, 2H), 4.16 (d, J = 8.0 Hz, 1H), 4.04−4.02 (m, 3H), 3.89 (d, J = 7.2 Hz, 1H), 3.67 (d, J = 8.0 Hz, 1H), 3.36 (d, J = 10.0 Hz, 1H), 3.21 (td, J = 9.6, 1.6 Hz, 1H), 3.15−3.14 (brs, 1H), 2.41 (t, J = 13.8 Hz, 1H), 1.85 (d, J = 10.8 Hz, 1H), 1.65 (s, 3H), 1.57 (s, 3H).13C NMR (150 MHz, CDCl3) δ 195.8, 137.3, 137.2, 135.0, 128.4 (× 2), 127.8 (× 2), 127.7 (×2), 123.1, 120.5, 118.3, 110.9, 107.5, 103.2, 99.1, 84.5, 73.8, 70.0, 69.2, 66.5, 62.7, 53.1, 49.7, 38.3, 27.8, 22.6, 19.1. HRMS (ESI) m/z calcd for C29H31N3NaO7 [M+Na]+ 556.2054; found 556.2051. (1’R,2’R,7’R,13c’S,14’S)-2′-((Benzyloxy)methyl)-2,2-dimethyl-1′nitro-1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]-

(CH2Cl2/MeOH, 30:1 to 20:1) to give compound 12 (187 mg, 56% from compound 14) as yellow foam. [α]20 D = −431.4 (c 0.7, CHCl3). IR (neat) νmax = 2991, 2929, 2856, 1448, 1371, 1255, 1219, 1198, 1164, 1096, 1075, 833, 776, 736, 524, 494 cm−1. 1H NMR (400 MHz, CDCl3) δ 10.36 (brs, 1H), 8.18 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 4.60 (m, 2H), 4.24 (m, 1H), 4.07−3.82 (m, 4H), 3.69 (d, J = 10.8 Hz, 1H), 2.31−2.19 (m, 3H), 1.63−1.58 (m, 6H), 0.92 (s, 9H), 0.08 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 142.6, 135.5, 132.5, 126.2, 123.2, 121.0, 118.1, 111.2, 103.6, 99.1, 67.3, 66.0, 64.6, 58.8, 38.7, 28.6, 27.1, 25.8 (× 4), 19.1, 18.3, −5.6 (× 2). HRMS (ESI) m/z calcd for C25H38N2NaO4Si [M+Na]+ 481.2493; found 481.2490. 1,3-Dipolar Cycloaddition of Nitrone 12 with Nitroalkene 13. A round-bottom flask was charged with nitrone 12 (0.200 g, 0.436 mmol, 1.0 equiv). Under argon, a solution of compound 1325 (0.425 g, 2.20 mmol, 5.0 equiv) in anhydrous toluene (10 mL) was added through syringe. The reaction was stirred at 40 °C for 15 h. After removal of toluene under reduced pressure, the residue was subjected to silica gel flash chromatography (petroleum ether/EtOAc, 15:1 to 10:1) to give compound 28a (99 mg, 35%) and 28b (134 mg, 47%) as yellow foam, respectively. Data for (1S,2S,7S,13cR)-2-((benzyloxy)methyl)-7(((tert-butyldimethylsilyl)oxy)methyl)-2′,2′-dimethyl-1-nitro1,2,6,7,9,13c-hexahydro-5H-spiro[isoxazolo[2′,3′:1,2]azocino[4,3-b]indole-8,5′-[1,3]dioxane] (28a): IR (neat) νmax = 3404, 2926, 2855, 1726, 1556, 1461, 1371, 1257, 1222, 1200, 1077, 1027, 836, 777, 740, 698 cm−1. 1H NMR (400 MHz, CDCl3) δ 9.08 (brs, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.41−7.32 (m, 6H), 7.18−7.10 (m, 2H), 5.81 (dd, J = 8.0, 6.0 Hz, 1H), 4.99−4.92 (m, 2H), 4.67, 4.62 (Abq, J = 12.0 Hz, each 1H), 4.47 (d, J = 8.0 Hz, 1H), 4.40 (dd, J = 11.6, 4.0 Hz, 2H), 4.07−4.04 (m, 1H), 3.97 (dd, J = 12.4, 2.4 Hz, 1H), 3.84 (dd, J = 10.4, 6.8 Hz, 1H), 3.75−3.74 (m, 2H), 3.49−3.41 (m, 1H), 2.62−2.58 (m, 1H), 1.79−1.65 (m, 1H), 1.53 (s, 3H), 1.42−1.40 (m, 1H), 1.28 (s, 3H), 1.26 (overlapped, 1H), 0.93 (s, 9H), 0.13 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 139.0, 134.6, 128.6 (×2), 127.9, 127.7 (×2), 126.9, 121.8, 119.6, 118.3, 111.0, 104.7, 98.8, 92.9, 80.4, 73.7, 70.8, 67.8, 67.4, 66.3, 65.3, 62.1, 53.6, 42.7, 41.6, 28.4, 26.1, 25.9 (×4), 19.9, −5.3, −5.4. HRMS (ESI) m/z calcd for C35H49N3NaO7Si [M+Na]+ 674.3232; found 674.3235. Data for (1R,2R,7S,13cS)-2-((benzyloxy)methyl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2′,2′-dimethyl-1nitro-1,2,6,7,9,13c-hexahydro-5H-spiro[isoxazolo[2′,3′:1,2]azocino[4,3-b]indole-8,5′-[1,3]dioxane] (28b): IR (neat) νmax = 3404, 2926, 2855, 1726, 1556, 1461, 1371, 1257, 1222, 1201, 1077, 836, 777, 740, 698 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.45 (brs, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.42−7.38 (m, 4H), 7.36−7.32 (m, 1H), 7.27 (d, J = 5.2 Hz, 1H), 7.18 (t, J = 5.2 Hz, 1H), 7.13 (t, J = 5.2 Hz, 1H), 5.81 (dd, J = 4.8, 2.8 Hz, 1H), 4.89 (dd, J = 5.6, 2.8 Hz, 1H), 4.82 (m, 1H), 4.69, 4.64 (ABq, J = 8.0 Hz, each 1H), 4.56 (d, J = 4.8 Hz, 1H), 4.46−4.44 (m, 2H), 4.29 (m, 1H), 3.78−3.73 (m, 2H), 3.52−3.47 (m, 1H), 3.37 (m, 1H), 2.82−2.78 (m, 1H), 2.35 (m, 1H), 2.01 (overlapped, 1H), 1.85−1.81 (m, 1H), 1.49 (s, 3H), 1.49 (overlapped, 1H), 1.39 (s, 3H), 0.77 (s, 9H), −0.09 (s, 3H), −0.15 (s, 3H).13C NMR (150 MHz, CDCl3) δ 139.0, 136.1, 134.4, 128.5(2), 127.9, 127.7 (2), 127.3, 122.1, 119.8, 118.1, 110.9, 104.0, 98.1, 92.8, 79.9, 73.7, 70.9, 68.4, 67.9, 41.8, 40.2, 26.7, 25.9, 25.7 (3), 23.9, 18.0, −5.6 (2). HRMS (ESI) m/z calcd for C35H49N3NaO7Si [M+Na]+ 674.3232; found 674.3233. ((1S,2S,7S,13cR)-2-((Benzyloxy)methyl)-2′,2′-dimethyl-1-nitro1,2,6,7,9,13c-hexahydro-5H-spiro[isoxazolo[2′,3′:1,2]azocino[4,3b]indole-8,5′-[1,3]dioxan]-7-yl)methanol (29a). Tetrabutylammonium fluoride (1 M in THF, 0.69 mL, 0.69 mmol, 3.0 equiv) was added to a solution of compound 28a (150 mg, 0.23 mmol, 1.0 equiv) in THF (15 mL) at 0 °C. The reaction was stirred at 25 °C for 1 h before being quenched with saturated aqueous NH4Cl (10 mL) at 0 °C. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (petroleum ether/EtOAc = 1:1) gave compound 29a (103 mg, 83%) as yellow foam. IR (neat) νmax = 3404, 2927, 1721, 1555, 1460, 1371, 1315, 1260, 1199, 1096, 1076, 1027, 832, 734, 698, 525 cm−1. 1H NMR (600 MHz, CDCl3) δ 8.94 (brs, 1H), 7.47 (d, J = 5.2 Hz, 1H), 761

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

Article

The Journal of Organic Chemistry

an argon atmosphere. After being stirred at 70 °C for 5 h, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether/EtOAc 1:1 to 1:2) to give compounds 31 (17 mg, 45%) as colorless oil and 32 (18 mg, 40%) as colorless oil. Data for (1’S,2’S,7’S,13c’S)-2′-(hydroxymethyl)-2, 2dimethyl-1′, 2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-one (31): [α]20 D = +68.7 (c 0.08, CHCl3). IR (neat) νmax = 3456, 2924, 1692, 1460, 1375, 1260, 1192, 1097, 1073, 1030, 829, 747 cm−1. 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 5.18 (d, J = 6.4 Hz, 1H), 4.66−4.63 (m, 1H), 4.20 (d, J = 12.4 Hz, 1H), 4.06−3.99 (m, 2H), 3.92−3.87 (m, 1H), 3.77−3.71 (m, 2H), 3.55 (dd, J = 6.4, 2.8 Hz, 1H), 3.36−3.31 (m, 1H), 3.23−3.15 (m, 1H), 2.86−2.84 (m, 1H), 2.43−2.29 (m, 2H), 1.77−1.73 (m, 1H), 1.66 (s, 3H), 1.58 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 208.7, 138.8, 134.8, 127.5, 122.8, 120.3, 118.0, 111.0, 103.5, 99.0, 85.6, 69.4, 67.1, 65.1, 64.4, 59.5, 55.1, 50.6, 37.0, 28.5, 22.9, 18.7. HRMS (ESI) m/z calcd for C22H27N2O5 [M+H]+ 399.1914; found 399.1915. Data for (1’S,2’S,7’S,13c’S)-2′-((benzyloxy)methyl)-2, 2-dimethyl-1′, 2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-one (32): [α]20 D = +64.0 (c 0.05, CHCl3). IR (neat): νmax = 3448, 2922, 2852, 1694, 1668, 1461, 1375, 1262, 1194, 1098, 830, 736, 699 cm−1. 1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.40− 7.35 (m, 5 H), 7.31 (t, J = 6.6 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 5.22 (d, J = 6.0 Hz, 1H), 4.72 (m, 1H), 4.69, 4.63 (Abq, J = 12.0 Hz, each 1H), 4.19 (d, J = 12.0 Hz, 1H), 4.02 (dd, J = 12.0 Hz, 18.0 Hz, 2H), 3.73−3.67 (m, 3H), 3.60−3.57 (m, 1H), 3.32 (d, J = 15.6 Hz, 1H), 3.17 (t, J = 13.2 Hz, 1H), 2.83 (s, 1H), 2.36 (t, J = 14.4 Hz, 1H), 1.74−1.71 (m, 1H), 1.65 (s, 3H), 1.57 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 209.0, 138.8, 137.9, 134.8, 128.4 (× 2), 127.7, 127.6 (× 2), 127.5, 122.7, 120.1, 118.1, 110.9, 103.7, 99.0, 84.5, 73.7, 72.3, 69.5, 67.0, 64.6, 58.9, 55.2, 50.5, 37.0, 28.5, 22.8, 18.7. HRMS (ESI) m/z calcd for C29H33N2O5 [M+H]+ 489.2384; found 489.2385. ((1’S,2’S,7’S,13c’S)-2,2-Dimethyl-14′-oxo-1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-2′-yl)methylmethanesulfonate (33). Triethylamine (26 μL, 0.19 mmol, 5.0 equiv) and methanesulfonyl chloride (13 μL, 0.17 mmol, 4.5 equiv) were added successively to a solution of compound 31 (15 mg, 0.038 mmol, 1.0 equiv) in anhydrous CH2Cl2 (2 mL) under an argon atmosphere at 0 °C. After being stirred at 25 °C for 1 h, the reaction was diluted with CH2Cl2 (2 mL) and quenched with saturated aqueous NH4Cl (2 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The organic layers were washed with brine (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue through silica gel flash chromatography (petroleum ether/EtOAc = 1:1) provided compound 33 (17 mg, 95%) as pale yellow oil. [α]20 D = +27.0 (c 0.1, CHCl3). IR (neat) νmax = 2956, 2924, 2856, 1695, 1461, 1351, 1260, 1172, 1097, 1020, 813, 746 cm−1. 1H NMR (600 MHz, CDCl3) δ 9.47 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 5.16 (d, J = 6.0 Hz, 1H), 4.79 (brs, 1H), 4.44 (dd, J = 10.8, 3.6 Hz, 1H), 4.37 (dd, J = 10.8, 4.8 Hz, 1H), 4.18 (d, J = 12.0 Hz, 1H), 4.02, 4.01 (ABq, J = 12.0 Hz, each 1H), 3.71 (d, J = 12.6 Hz, 1H), 3.58−3.55 (m, 1H), 3.34 (d, J = 15.0 Hz, 1H), 3.21−3.15 (m, 4H), 2.87 (brs, 1H), 2.34−2.29 (m, 1H), 1.78−1.75 (m, 1H), 1.66 (s, 3H), 1.58 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 207.7, 138.8, 134.9, 127.4, 122.9, 120.4, 117.8, 111.0, 102.9, 99.1, 82.3, 70.2, 69.4, 67.0, 64.2, 59.0, 55.0, 50.5, 38.0, 37.1, 28.4, 22.7, 18.7. HRMS (ESI) m/z calcd for C23H28N2NaO7S [M +Na]+ 499.1509; found 499.1508. (1’S,2’R,7’S,13c’S)-2′-Hydroxy-2,2-dimethyl-2′,3′,6′,7′,9′,13c’-hexahydro-1’H,5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanopyrrolo[1′,2’:1,2]azocino[4,3-b]indol]-14′-one (34). A mixture of compound 33 (15 mg, 0.031 mmol, 1.0 equiv), NaOAc (21 mg, 0.16 mmol, 5 equiv) and Pd(OH)2/C (10% Pd on carbon, wet, 5 mg) in MeOH (3 mL) was stirred at reflux under 1.0 atm pressure of H2 for 20 min. Then the mixture was cooled to room temperature and filtered

methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-ol (ent-30). A mixture of compound 28b (0.30 g, 0.46 mmol, 1.0 equiv) and tetrabutylammonium fluoride (1 M in THF, 1.4 mL, 1.4 mmol, 3.0 equiv) in THF (30 mL) was stirred at 0 °C for 2 h before being quenched with saturated aqueous NH4Cl (30 mL) at 0 °C. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. Compared with compound 29a, the desilylated product 29b of compound 28b was unstable, which was partially decomposed during workup. Therefore, the residue was filtered through a short pad of silica using petroleum ether/EtOAc (1:1 v/v) as the eluent. The filtrate was concentrated in vacuo and used immediately. The resulting crude product was dissolved in anhydrous CH2Cl2 (15 mL), 4 Å powdered molecular sieves (200 mg), 4-methylmorpholine N-oxide (NMO, 108 mg, 0.920 mmol, 2.0 equiv), tetrapropylammonium perruthenate (32 mg, 0.092 mmol, 0.2 equiv) were added sequentially under an argon atmosphere at 0 °C. The resulting black mixture was stirred at 25 °C for 30 min and then filtered through a short pad of silica using petroleum ether/ EtOAc (1:1 v/v) as the eluent. The filtrate was concentrated in vacuo to give the crude aldehyde intermediate, which was then dissolved in CH2Cl2 (10 mL) under argon and treated with DBU (34 μL, 0.23 mmol, 0.5 equiv) at 25 °C. The reaction was stirred for 2 h before evaporation of the solvent under reduced pressure. The residue was purified by silica gel flash chromatography (petroleum ether/EtOAc = 1:1) to give compound ent-30 (136 mg, 55% from compound 28b) as yellow oil. [α]20 D = +31.0 (c 0.2, CHCl3). IR (neat) νmax = 3451, 2925, 2851, 1542, 1462, 1375, 1323, 1253, 1194, 1154, 1109, 1064, 832, 738, 699, 524 cm−1. 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.38−7.28 (m, 6H), 7.23 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 6.02 (s, 1H), 5.47 (t, J = 4.8 Hz, 1H), 4.50 (dd, J = 16.0 Hz, 11.6 Hz, 2H), 4.37 (s, 1H), 4.15, 4.08 (ABq, J = 12.0 Hz, each 1H), 4.03 (d, J = 11.6 Hz, 1H), 3.91 (d, J = 11.2 Hz, 1H), 3.75 (dd, J = 10.0, 4.0 Hz, 1H), 3.64 (dd, J = 10.0, 5.2 Hz, 1H), 3.25 (m, 2H), 2.96 (td, J = 14.0, 3.2 Hz, 1H), 2.47−2.39 (m, 1H), 2.37− 2.36 (m, 1H), 1.70 (m, 1H), 1.66 (s, 3H), 1.57 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 139.0, 137.2, 134.9, 128.4 (× 2), 127.8 (× 4), 122.7, 120.4, 118.0, 104.5, 100.5, 99.1, 81.5, 73.9, 70.9, 69.8, 69.4, 66.4, 64.5, 49.5, 44.9, 38.4, 28.1, 21.3, 19.0. HRMS (ESI) m/z calcd for C29H33N3NaO7 [M+Na]+ 558.2211; found 558.2213. (1’S,2’R,7’R,13c’S)-2′-((Benzyloxy)methyl)-2,2-dimethyl-1′-nitro1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-one (ent-10). Alcohol ent-30 (0.100 g, 0.187 mmol, 1.0 equiv) was subjected to oxidation in the presence of 4 Å powdered molecular sieves (100 mg), 4-methylmorpholine N-oxide (NMO, 44 mg, 0.37 mmol, 2.0 equiv), and tetrapropylammonium perruthenate (13 mg, 0.037 mmol, 0.2 equiv), as that applied to compound 30. Purification of the crude product via column chromatography on silica gel (petroleum ether/ EtOAc = 1:1) yielded compound ent-10 (90 mg, 90%) as yellow oil. [α]20 D = +52.4 (c 0.25, CHCl3). IR (neat) νmax = 3448, 2924, 1714, 1553, 1461, 1376, 1261, 1199, 1097, 1072, 943, 830, 742, 699, 526 cm−1. 1H NMR (600 MHz, CDCl3) δ 9.31 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.39−7.32 (m, 5H), 7.26−7.23 (m, 2H), 7.16 (t, J = 7.8 Hz, 1H), 5.99 (s, 1H), 4.91 (s, 1H), 4.55, 4.52 (ABq, J = 11.4 Hz, each 1H), 4.15 (d, J = 12.6 Hz, 1H), 4.03−4.02 (m, 3H), 3.88 (d, J = 10.8 Hz, 1H), 3.67 (d, J = 12.0 Hz, 1H), 3.36−3.34 (d, J = 15.6 Hz, 1H), 3.202 (td, J = 14.4, 3.0 Hz, 1H), 3.14−3.13 (m, 1H), 2.40 (t, J = 13.8 Hz, 1H), 1.84 (d, J = 16.2 Hz, 1H), 1.64 (s, 3H), 1.56 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 195.8, 137.3, 137.2, 135.0, 128.3 (× 2), 127.8 (× 2), 127.7 (× 2), 123.1, 120.5, 118.3, 110.9, 107.5, 103.2, 99.1, 84.5, 73.8, 30.0, 69.2, 66.5, 62.7, 53.1, 49.7, 38.3, 27.9, 22.6, 19.1. HRMS (ESI) m/z calcd for C29H31N3NaO7 [M+Na]+ 556.2054; found 556.2057. (1’S,2’S,7’S,13c’S)-2′-(Hydroxymethyl)-2,2-dimethyl1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-one (31). nBu3SnH (126 μL, 0.470 mmol, 5.0 equiv) was added to a solution of compound 10 (50 mg, 0.094 mmol, 1.0 equiv) and AIBN (15 mg, 0.094 mmol, 1.0 equiv) in degassed anhydrous toluene (10 mL) under 762

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

Article

The Journal of Organic Chemistry through Celite. After concentration of the filtrate, the residue was purified by silica gel flash chromatography (CH2Cl2/MeOH/NH4OH = 90:10:0.5) to give compound 34 (12 mg, 97%) as colorless oil. [α]20 D = +12.0 (c 0.05, CHCl3). IR (neat) νmax = 3372, 2920, 2347, 1560, 1408, 1261, 1197, 749 cm−1. 1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.13 (t, J = 7. Two Hz, 1H), 4.90 (t, J = 8.4 Hz, 1H), 4.60 (d, J = 5.4 Hz, 1H), 4.18 (d, J = 12.0 Hz, 1H), 4.09 (d, J = 11.4 Hz, 1H), 4.04 (d, J = 11.4 Hz, 1H), 3.74 (dd, J = 13.8, 8.4 Hz, 1H), 3.68 (d, J = 12.0 Hz, 1H), 3.36−3.33 (m, 1H), 3.16−3.11 (m, 2H), 2.73−2.68 (m, 2H), 2.62 (t, J = 15.0 Hz, 1H), 2.23 (br, 1H), 1.66 (s, 3H), 1.66 (overlapped, 1H), 1.58 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 211.6, 139.5, 134.9, 127.2, 122.3, 119.9, 117.9, 110.8, 106.0, 98.9, 75.1, 69.7, 67.8, 65.1, 60.3, 57.7, 57.0, 47.6, 36.8, 28.7, 23.7, 18.5. HRMS (ESI) m/z calcd for C22H27N2O4 [M+H]+ 383.1965; found 383.1961. (1R,4S,7S,8S,13cS,16R)-16-Hydroxy-8-(hydroxymethyl)1,2,3,4,5,6,7,8,9,13c-decahydro-1,7,8-(epimethanetriyloxymethano)pyrrolo[1′,2’:1,2]azocino[4,3-b]indol-4-ium Chloride (35). To a solution of compound 34 (10 mg, 0.026 mmol, 1.0 equiv) in anhydrous toluene were added 1,1′-thiocarbonyldiimidazole (TCDI, 23 mg, 0.13 mmol, 5.0 equiv) and DMAP (10 mg, 0.078 mmol, 3.0 equiv). After being stirred at reflux for 2 h, the reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in degassed anhydrous toluene (2 mL), to which were added with AIBN (4.0 mg, 0.026 mmol, 1.0 equiv) and n-Bu3SnH (21 μL, 0.078 mmol, 3.0 equiv) under an argon atmosphere. The mixture was heated to reflux for 30 min, before it was cooled to room temperature and concentrated. The residue was treated with a mixture of 6 M HCl (1 mL) and MeOH (1 mL), and stirred at reflux for 1 h. Then it was cooled and concentrated under reduced pressure. Purification of the crude product through reverse phase chromatography (MeOH: H2O, 0:100 to 20:80, containg 0.1% TFA) gave compound 35 (7 mg, 74%). [α]20 D = +46.0 (c 0.05, MeOH). IR (neat) νmax = 3379, 1676, 1453, 1206, 1141, 846, 802, 725 cm−1. 1H NMR (600 MHz, CD3OD) δ 7.60 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 5.46 (d, J = 7.2 Hz, 1H), 4.17 (d, J = 11.4 Hz, 1H), 4.14 (d, J = 11.4 Hz, 1H), 3.97 (d, J = 7.8 Hz, 1H), 3.70 (td, J = 12.6, 7.8 Hz, 1H), 3.61−3.56 (m, 1H), 3.57 (d, J = 7.8 Hz, 1H), 3.22− 3.15 (m, 2H), 2.96 (d, J = 13.8 Hz, 1H), 2.78−2.72 (m, 1H), 2.65− 2.64 (m, 1H), 2.53−2.47 (m, 1H), 2.40−2.35 (m, 1H), 2.24−2.22 (m, 1H). 13C NMR (150 MHz, CD3OD) δ 143.0, 137.1, 128.4, 123.3, 121.1, 117.9, 112.5, 108.3, 102.5, 75.3, 64.3, 62.8, 55.3, 53.4, 53.1, 50.5, 47.3, 26.2, 19.7. (The 1H and 13C NMR data were consistent with those of racemic 35 reported by the Matin group,3 see Supporting Information.) HRMS (ESI) m/z calcd for C19H23N2O3 [M+H]+ 327.1703; found 327.1701. ( 1 ’ R , 2’ R , 7 ’ R , 1 3 c ’ R ) - 2 ′ - ( H y d r o x y m e t h y l )- 2 , 2 - d i m e t h y l 1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-one (ent-31). A mixture of compound ent-10 (60.0 mg, 112 μmol, 1.0 equiv), nBu3SnH (0.15 mL, 0.56 mmol, 5.0 equiv), and AIBN (18.0 mg, 112 μmol, 1.0 equiv) in degassed anhydrous toluene (10 mL) was heated at 70 °C for 5 h. After concentration of the mixture in vacuo, the residue was purified by flash chromatography (petroleum ether/EtOAc 1:1 to 1:2) to give compound ent-31 (19 mg, 43%) as colorless oil and ent-32 (23 mg, 42%) as colorless oil. Data for (1’R,2’R,7’R,13c’R)-2′(hydroxymethyl)-2,2-dimethyl-1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-one (ent-31): [α]20 D = −63.0 (c 0.1, CHCl3). IR (neat): νmax = 3456, 2924, 1693, 1461, 1376, 1260, 1192, 1098, 1073, 1031, 829, 747 cm−1. 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 5.19 (d, J = 6.4 Hz, 1H), 4.66−4.63 (m, 1H), 4.20 (d, J = 12.4 Hz, 1H), 4.06−3.99 (m, 2H), 3.90−3.87 (m, 1H), 3.76− 3.71 (m, 2H), 3.55 (dd, J = 6.4, 2.8 Hz, 1H), 3.35−3.31 (m, 1H), 3.23−3.15 (m, 1H), 2.85−2.84 (m, 1H), 2.44−2.33 (m, 2H), 1.77− 1.73 (m, 1H), 1.66 (s, 3H), 1.58 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 208.7, 138.8, 134.9, 127.5, 122.8, 120.3, 118.0, 111.0, 103.5, 99.0, 85.6, 69.4, 67.1, 65.1, 64.4, 59.5, 55.1, 50.6, 37.1, 28.5, 22.9, 18.7.

HRMS (ESI) m/z calcd for C22H27N2O5 [M+H]+ 399.1914; found 399.1913. Data for (1’R,2’R,7’R,13c’R)-2′-((benzyloxy)methyl)-2,2dimethyl-1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-14′-one (ent32): [α]20 D = −59.0 (c 0.1, CHCl3). IR (neat) νmax = 3448, 2922, 2853, 1695, 1668, 1461, 1376, 1263, 1194, 1098, 831, 737, 699 cm−1. 1 H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.40−7.35 (m, 5 H), 7.31 (t, J = 6.6 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 5.22 (d, J = 6.0 Hz, 1H), 4.72 (m, 1H), 4.69, 4.63 (ABq, J = 12.0 Hz, each 1H), 4.19 (d, J = 12.6 Hz, 1H), 4.04, 4.01 (ABq, J = 12.0 Hz, each 1H), 3.73−3.67 (m, 3H), 3.59−3.58 (m, 1H), 3.32 (d, J = 15.6 Hz, 1H), 3.17 (t, J = 13.2 Hz, 1H), 2.83 (s, 1H), 2.36 (t, J = 14.4 Hz, 1H), 1.73 (d, J = 15.6 Hz, 1H), 1.65 (s, 3H), 1.57 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 209.0, 138.8, 137.9, 134.8, 128.4, 127.7, 127.6, 127.5, 122.7, 120.1, 118.1, 110.9, 103.7, 99.0, 84.5, 73.7, 72.3, 69.5, 67.0, 64.6, 58.9, 55.2, 50.5, 37.1, 28.5, 22.8, 18.7. HRMS (ESI) m/z calcd for C29H33N2O5 [M+H]+ 489.2384; found 489.2386. ((1’R,2’R,7’R,13c’R)-2,2-Dimethyl-14′-oxo-1′,2′,6′,7′,9′,13c’-hexahydro-5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanoisoxazolo[2′,3′:1,2]azocino[4,3-b]indol]-2′-yl)methylmethanesulfonate (ent33). A mixture of alcohol ent-31 (18 mg, 0.045 mmol, 1.0 equiv), triethylamine (32 μL, 0.23 mmol, 5.0 equiv), and methanesulfonyl chloride (16 μL, 0.20 mmol, 4.5 equiv) in anhydrous CH2Cl2 (2 mL) was stirred at 25 °C for 2 h. Workup of the reaction according to the procedure described for the preparation of 33 was performed. The obtained crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc = 1:1) to give compound ent-33 (20 mg, 93%) as pale yellow oil. [α]20 D = −27.5 (c 0.08, CHCl3). IR (neat): νmax = 2956, 2925, 2856, 1696, 1461, 1351, 1260, 1173, 1097, 1021, 814, 746 cm−1. 1H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.16 (d, J = 6.0 Hz, 1H), 4.79−4.77 (m, 1H), 4.43 (dd, J = 11.4, 3.6 Hz, 1H), 4.36 (dd, J = 11.2, 4.8 Hz, 1H), 4.16 (d, J = 12.4 Hz, 1H), 4.05−3.99 (m, 2H), 3.71 (d, J = 12.4 Hz, 1H), 3.55 (dd, J = 6.0, 3.2 Hz, 1H), 3.35−3.31 (m, 1H), 3.21−3.13 (m, 4H), 2.87 (m, 1H), 2.35−2.28 (m, 1H), 1.78−1.75 (m, 1H), 1.66 (s, 3H), 1.58 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 207.7, 138.8, 134.9, 127.4, 122.9, 120.4, 117.8, 111.0, 102.9, 99.1, 82.3, 70.2, 69.3, 66.9, 64.2, 59.0, 55.0, 50.5, 38.0, 37.1, 28.3, 22.7, 18.8. HRMS (ESI) m/z calcd for C23H28N2NaO7S [M+Na]+ 499.1509; found 499.1510. (1’R,2’R,7’R,13c’R)-2′-Hydroxy-2,2-dimethyl-2′,3′,6′,7′,9′,13c’-hexahydro-1’H,5′H-spiro[[1,3]dioxane-5,8′-[1,7]methanopyrrolo[1′,2’:1,2]azocino[4,3-b]indol]-14′-one (ent-34). A mixture of compound ent-33 (18 mg, 0.038 mmol, 1.0 equiv), NaOAc (26 mg, 0.19 mmol, 5 equiv) and Pd(OH)2/C (10% Pd on carbon, wet, 6 mg) in MeOH (3 mL) was stirred at reflux under 1.0 atm of H2 for 20 min. Then the mixture was cooled to room temperature and filtered through Celite. After concentration of the filtrate, the residue was purified by silica gel flash chromatography (CH2Cl2/MeOH/NH4OH = 90:10:0.5) to give compound ent-34 (14 mg, 96%) as colorless oil.19 [α]20 D = −16.2 (c 0.08, CHCl3). IR (neat) νmax = 3372, 2921, 2348, 1560, 1409, 1261, 1197, 1052, 750 cm−1. 1H NMR (600 MHz, CDCl3) δ 9.44 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 4.88 (t, J = 8.4 Hz, 1H), 4.58 (d, J = 5.4 Hz, 1H), 4.18 (d, J = 12.6 Hz, 1H), 4.09 (d, J = 11.4 Hz, 1H), 4.04 (d, J = 11.4 Hz, 1H), 3.72 (dd, J = 14.4 Hz, 8.4 Hz, 1H), 3.68 (d, J = 12.0 Hz, 1H), 3.35−3.32 (m, 1H), 3.15−3.10 (m, 2H), 2.73−2.68 (m, 2H), 2.64−2.59 (m, 1H), 2.43 (br, 1H), 1.65 (s, 3H), 1.65 (overlapped, 1H), 1.58 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 211.61, 139.47, 134.91, 127.22, 122.32, 119.86, 117.90, 110.83, 105.97, 98.91, 75.11, 69.75, 67.75, 65.09, 60.35, 57.65, 57.01, 47.64, 36.78, 28.71, 23.63, 18.55. HRMS (ESI) m/z calcd for C22H27N2O4 [M+H]+ 383.1965; found 383.1965. (1S,4R,7R,8R,13cR,16S)-16-Hydroxy-8-(hydroxymethyl)1,2,3,4,5,6,7,8,9,13c-decahydro-1,7,8-(epimethanetriyloxymethano)pyrrolo[1′,2’:1,2]azocino[4,3-b]indol-4-ium Chloride (ent35). According to the procedure described for the preparation of 35, alcohol ent-34 (10 mg, 0.026 mmol, 1.0 equiv) was first converted to corresponding thioxoester in the presence of 1,1′-thiocarbonyldiimidazole (TCDI, 23 mg, 0.13 mmol, 5.0 equiv) and DMAP (10 mg, 0.078 mmol, 3.0 equiv) in anhydrous toluene, which was followed by 763

DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764

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The Journal of Organic Chemistry

Lett. 2013, 54, 2180−2182. (d) Mortimer, D.; Whiting, M.; Harrity, J. P. A.; Jones, S.; Coldham, I. Tetrahedron Lett. 2014, 55, 1255−1257. (7) For a preliminary study, see: Xue, F.; Xiao, T.; Li, M.; Zhang, K.F.; He, L.-P.; Qin, Y.; Liu, X.-Y.; Zhang, D. Tetrahedron 2017, 73, 2109−2115. (8) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447−457. (9) For selected examples on the construction of pyrrolidine ring via nitrone-olefin [3+2] cycloaddition/ring-opening/ring-closure sequence, see: (a) Lahiri, R.; Palanivel, A.; Kulkarni, S. A.; Vankar, Y. D. J. Org. Chem. 2014, 79, 10786−10800. (b) Beňadiková, D.; Medvecký, M.; Filipová, A.; Moncol, J.; Gembický, M.; Prónayová, N.; Fischer, R. Synlett 2014, 25, 1616−1620. (c) Martella, D.; Cardona, F.; Parmeggiani, C.; Franco, F.; Tamayo, J. A.; Robina, I.; Moreno-Clavijo, E.; Moreno-Vargas, A. J.; Goti, A. Eur. J. Org. Chem. 2013, 2013, 4047−4056. (d) Tamayo, J. A.; Franco, F.; Re, D. L.; SánchezCantalejo, F. J. Org. Chem. 2009, 74, 5679−5682. (e) Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. Org. Lett. 2007, 9, 207−209. (10) For selected reviews on 1,3-dipolar cycloaddition of nitrone and olefin, see: Nájera, C.; Sansano, J. M. Org. Biomol. Chem. 2009, 7, 4567−4581. (b) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. - Eur. J. 2009, 15, 7808−7821. (c) Rück-Braun, K.; Freysoldt, T. H. E.; Wierschem, F. Chem. Soc. Rev. 2005, 34, 507−516. (d) Confalone, P. N.; Huie, E. M. In Organic Reactions; Kende, A. S., et al., Eds.; John Wiely & Sons, Inc., 1988; Vol. 36, pp 1−173. (11) For selected examples on 1,3-dipolar cycloaddition of nitrone and nitroalkene, see: (a) Shinohara, R.; Akimoto, T.; Iwamoto, O.; Hirokawa, T.; Yotsu-Yamashita, M.; Yamaoka, K.; Nagasawa, K. Chem. - Eur. J. 2011, 17, 12144−12152. (b) Iwamoto, O.; Nagasawa, K. Org. Lett. 2010, 12, 2150−2153. (c) Iwamoto, O.; Shinohara, R.; Nagasawa, K. Chem. - Asian J. 2009, 4, 277−285. (12) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77−80. (13) Kadota, I.; Yamagami, Y.; Fujita, N.; Takamura, H. Tetrahedron Lett. 2009, 50, 4552−4553 . For the preparation of 19, see the Supporting Information for details.. (14) See the Supporting Information for details. (15) (a) Furst, L.; Matsuura, B. S.; Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. Org. Lett. 2010, 12, 3104−3107. (b) Swift, E. C.; Williams, T. M.; Stephenson, C. R. J. Synlett 2016, 27, 754−758. (16) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213−1216. (17) Soldaini, G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473−476. (18) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 1994, 639−666. (19) The structures of 30, 10, and ent-34 were confirmed by 2D NMR experiments, see Supporting Information. (20) For selected examples on the removal of nitro group using nBu3SnH and AIBN, see: (a) Rivinoja, D. J.; Gee, Y. S.; Gardiner, M. G.; Ryan, J. H.; Hyland, C. J. T. ACS Catal. 2017, 7, 1053−1056. (b) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462−10465. (c) Davis, T. A.; Danneman, M. W.; Johnston, J. N. Chem. Commun. 2012, 48, 5578−5580. (21) Kim, J. H.; Seo, W. D.; Lee, J. H.; Lee, B. W.; Park, K. H. Synthesis 2003, 16, 2473−2478. (22) For selected reviews, see: (a) Kärkäs, M. D.; Porco, J. A., Jr.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683−9747. (b) Nicholls, T. P.; Leonori, D.; Bissember, A. C. Nat. Prod. Rep. 2016, 33, 1248− 1254. (23) Purification of Laboratory Chemicals, Second ed.; Perrin, D. D., Armarego, W. L. F., Perrin, D. R. Pergamon Press: Oxford, 1980. (24) Habeeb, J. J.; Bogovic, C. N.; PCT Int. Appl. WO2011009025A1, 20 Jan. 2011. (25) Lucet, D.; Sabelle, S.; Kostelitz, O.; Le Gall, T.; Mioskowski, C. Eur. J. Org. Chem. 1999, 1999, 2583−2591.

radical deoxygenation using AIBN (4.0 mg, 0.026 mmol, 1.0 equiv) and n-Bu3SnH (21 μL, 0.078 mmol, 3.0 equiv) in degassed anhydrous toluene (2 mL). The resulting ketone was treated with a mixture of 6 M HCl (1 mL) and MeOH (1 mL) at reflux for 1 h. Purification of the crude product via reverse phase chromatography (MeOH: H2O, 0:100 to 20:80 v/v, containg 0.1% TFA) furnished compound ent-35 (6 mg, 63%). [α]20 D = −50.0 (c 0.08, MeOH). IR (neat) νmax = 3379, 1675, 1451, 1202, 1139, 845, 801, 725 cm−1. 1H NMR (600 MHz, CD3OD) δ 7.60 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 5.46 (d, J = 7.2 Hz, 1H), 4.18 (d, J = 11.4 Hz, 1H), 4.15 (d, J = 11.4 Hz, 1H), 3.97 (d, J = 7.8 Hz, 1H), 3.70 (td, J = 7.8 Hz, 12.6 Hz, 1H), 3.61−3.56 (m, 1H), 3.58 (d, J = 7.8 Hz, 1H), 3.22−3.16 (m, 2H), 2.96 (d, J = 13.8 Hz, 1H), 2.78−2.72 (m, 1H), 2.65−2.64 (m, 1H), 2.53−2.46 (m, 1H), 2.40−2.35 (m, 1H), 2.25−2.22 (m, 1H). 13C NMR (150 MHz, CD3OD) δ 143.0, 137.1, 128.4, 123.3, 121.1, 117.9, 112.5, 108.4, 102.5, 75.3, 64.3, 62.8, 55.3, 53.4, 53.1, 50.5, 47.3, 26.2, 19.7. (The 1H and 13C NMR data were consistent with those of racemic 35 reported by the Matin group,3 see Supporting Information.) HRMS (ESI) m/z calcd for C19H23N2O3 [M +H]+ 327.1703; found 327.1702.

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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.7b02747. The flow reactor for the synthesis of compound 23, determination of the ee value of compound 16 and HPLC data, and copies of 1H and 13C NMR spectra for all new compounds and tables listing the NMR chemical shifts of 35 and ent-35 in comparison with literature values (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Yong Qin: 0000-0003-3434-5747 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NSFC (21732005 and 21702140) and the China Postdoctoral Science Foundation (2017M610608).

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REFERENCES

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DOI: 10.1021/acs.joc.7b02747 J. Org. Chem. 2018, 83, 754−764