Synthesis of Chiral cis-Cyclopropane Bearing Indole and Chromone

Jul 13, 2018 - Conformationally restricted analogues of SPD-304, the first small-molecule TNFα inhibitor, in which two heteroaryl groups, indole and ...
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Cite This: J. Org. Chem. 2018, 83, 7672−7682

Synthesis of Chiral cis-Cyclopropane Bearing Indole and Chromone as Potential TNFα Inhibitors Ryutaro Kanada, Makoto Tanabe, Ryuta Muromoto, Yukina Sato, Tomoki Kuwahara, Hayato Fukuda,† Mitsuhiro Arisawa,‡ Tadashi Matsuda, Mizuki Watanabe,* and Satoshi Shuto* Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060−0812, Japan

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S Supporting Information *

ABSTRACT: Conformationally restricted analogues of SPD304, the first small-molecule TNFα inhibitor, in which two heteroaryl groups, indole and chromone, are connected by chiral methyl- or ethyl-cis-cyclopropane, were designed. Synthesis of these molecules was achieved via Suzuki−Miyaura or Stille coupling reactions with chiral bromomethylenecyclopropane or iodovinyl-cis-cyclopropane as the substrate, both of which were prepared from chiral methylenecyclopropane as a common intermediate, constructing the heteroaryl-methyl or -ethyl-cis-cyclopropane structures as key steps. This study presents an efficient synthesis of a series of chiral cis-cyclopropane conjugates with two heteroaryl groups.

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INTRODUCTION Various drugs and biologically active compounds contain heteroaryl groups, such as indole, quinoline, and 1,4benzopyrone. These heteroaryl structures are biologically important scaffolds that effectively interact with proteins and are often referred to as “privileged structures”.1,2 The spatial arrangement of these structures is important for their interaction with the target biomolecules in a high-affinity manner.3 Thus, restricting conformation of the compounds to regulate the relative spatial position of heteroaryl components is an effective and traditional method used in medicinal chemistry research to increase the selectivity and affinity for the target biomolecule.4,5 To regulate the conformation of a compound, the cyclopropane ring is an attractive motif that is able to rigidly restrict the conformation to a “folded” or “extended” form with little steric repulsion in the target binding.6,7 In addition, although it is a saturated carbocyclic structure, the carbon shows sp2-carbon-like reactivity and properties; thus, this smallest ring is a key scaffold in drug design for not only creating a unique chemical space but also improving the pharmacological properties of the molecule.8 Construction of a chiral heteroaryl-cyclopropane is a current focus in medicinal and organic chemistry (Figure 1).8−10

SPD-304 (Figure 2), a small compound containing two heteroaryl groups, indole and chromone, linked via ethylene diamine, was identified as the first synthetic inhibitor of tumor necrosis factor α (TNFα) by He et al.11 TNFα is an established therapeutic target for the treatment of various autoimmune disorders,12 and all clinical drugs that directly target TNFα are biologics, such as monoclonal antibodies, that

Figure 2. Chemical structures of SPD-304 and a series of cyclopropane-based conformationally restricted analogues of SPD304 (1−4 and their enantiomers ent-1−ent-4). Figure 1. Examples of bioactive compounds with a heteroarylmethylcyclopropane structure. © 2018 American Chemical Society

Received: February 17, 2018 Published: July 13, 2018 7672

DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

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The Journal of Organic Chemistry suppress the function of TNFα.13 Biological therapies have drawbacks, however, including high cost and potential adverse side effects, such as the induction of an autoantibody immune response.14 As promising alternative drugs to biologics, several efforts have been made to develop small-molecule TNFα inhibitors, and SPD-304 is vitally important from this viewpoint. The inhibitory effect of SPD-304 on the TNFα function is due to its ability to directly bind to the TNFα dimer to prevent its trimerization.11 The X-ray structural crystallography to visualize the binding of SPD-304 to the TNFα dimer revealed that a hydrophobic and shape-driven interaction was likely a key factor, and the molecule was assumed a “folded” structure in which the indole and chromone moieties face each other.11,15 Thus, we considered that analogues of SPD-304 that were conformationally restricted to the folded form by replacing the ethylene diamine moiety with cis-cyclopropane might improve the binding affinity for TNFα. Herein, we report the synthesis of chiral cis-cyclopropanebased analogues of SPD-304, in which the indole and chromone moieties are connected with a conformationally restricted disubstituted cis-cyclopropane structure (1−4 and ent-1−ent-4, Figure 2). The key steps of the synthesis are Suzuki−Miyaura coupling reactions with a chiral methylene- or vinyl-cyclopropane and subsequent hydrogenation to provide chiral cis-arylmethylcyclopropane structures. This study presents an efficient synthesis of a series of chiral ciscyclopropane conjugates with two heteroaryl groups that are useful in medicinal chemical studies.

chiral cis-arylmethylcyclopropane structure in which an unusual heterocycle, i.e., N-3-(trifluoromethyl)phenylindole or 6,7-dimethylchromone, is connected to a chiral cyclopropane via a methylene unit. Fortunately, we recently developed an efficient procedure for producing chiral cisarylmethylcyclopropanes using a Suzuki−Miyaura coupling reaction with subsequent stereoselective hydrogenation, in which chiral bromomethylenecyclopropane 5 is used as an effective substrate.32 Although a great number of metalcatalyzed ring-opening reactions of methylenecyclopropanes have been reported,33−36 the introduction of a bromo substituent at the terminal carbon of methylenecyclopropane effectively provided a new entry for realizing the desired crosscoupling reaction without ring-opening. Thus, our method allowed us to synthesize the cyclopropane-based “folded” analogues of SPD-304 with unusual heteroaryl groups. The retrosynthetic analysis common for the desired conformationally restricted compounds (1−4) is outlined in Scheme 1. Our analysis revealed that 1−4 would be provided Scheme 1. Retrosynthetic Analysis of the Designed Cyclopropane-Based Analogues (1−4)

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RESULTS AND DISCUSSION Design. Since the report11 by He et al., several small inhibitors directly preventing TNFα trimerization have been reported. Most of the small inhibitors were discovered by highthroughput or virtual screening of a chemical library.16−20 As an alternative strategy to develop the inhibitors, we designed SPD-304 analogues 1−4 and ent-1−ent-4 (Figure 2), in which the ethylene diamine linker was replaced with cis-cyclopropane to restrict the spatial arrangement of the two heteroaryl groups to a “folded” position based on X-ray crystallographic analysis of the binding mode showing that the indole and chromone moieties face each other. X-ray analysis also showed that the two amino groups in SPD-304 are not involved in the interaction. Therefore, one amino group was removed in the designed structures to reduce the synthetic difficulty, and the other amino group was retained to improve the solubility in aqueous media. In the designed analogues, one heteroaryl group is connected with the cyclopropane ring via a one- or two-carbon linker and the other one is connected via an amino linker in a cis-arrangement. Chemistry. Although various optically active cis-cyclopropane derivatives have been synthesized,21−23 construction of arylmethylcyclopropane and arylcyclopropane structures, particularly those with the desired heteroaryl group, remains challenging.24−26 We are interested in the synthesis and application of these chiral structures as an rigid-core for medicinal chemical studies, and have developed efficient methods for synthesizing chiral di-, tri-, or tetrasubstituted cyclopropanes conjugated with an aryl or a heteroaryl group.27−31 The key step in the synthesis of the target cyclopropane derivatives of SPD-304 is the introduction of indole and chromone moieties to a chiral cyclopropane ring in a cisconfiguration. Particularly, it can be difficult to construct the

using reductive amination of amine 6, which may be converted by oxidation and Curtius rearrangement of 7 and 8. The cisheteroarylmethylcyclopropanes 7 (n = 1) with a methylene linker between a heteroaryl group and cyclopropane ring and the other cis-heteroarylethylcyclopropanes 8 (n = 2), which have an ethylene linker between a heteroaryl group and cyclopropane ring, could be provided through Suzuki−Miyaura couplings from optically active bromomethylenecyclopropane 5 and iodovinylcyclopropane 9, respectively. Both 5 and 9 would be prepared from chiral methylenecyclopropane 10 as a common intermediate. Indole units 11 and 12 were prepared from N-arylindole 1311 (Scheme 2). Iodine was introduced at the 3-position of 13 to give 14, which was converted to boronic acid pinacol ester 11, a substrate of the Suzuki−Miyaura coupling, by the lithium−halogen exchange protocol37 modified to an one-pot reaction. 3-Formylindole 12 was prepared from 13 according to a previous report.11 The synthesis of chromone units 15 and 16 is shown in Scheme 3. Treatment of 1738 with Me2NCH(OMe)2 at 90 °C 7673

DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

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The Journal of Organic Chemistry Scheme 2. Synthesis of Indole Units

Scheme 4. Synthesis of Chiral Cyclopropane Unit Substrates for the Suzuki−Miyaura Coupling

Scheme 3. Synthesis of Chromone Units

Scheme 5 shows the synthesis of the heteroarylmethylcyclopropane derivatives. We previously reported that Suzuki− Scheme 5. Synthesis of cis-Heteroarylmethylcyclopropanes

afforded a β-enamino ketone intermediate without purification, and subsequent treatment of the ketone with iodine and pyridine produced 3-iodo chromone 1839 in high yield. The same reaction conditions as for providing 11 and Miyaura borylation reaction40 were attempted to convert 18 to chromone-3-boronic acid pinacol ester, but the desired boronate was not obtained. Next, stannylation of 18 with (Me3Sn)2 in the presence of a catalytic amount of Pd(0) gave 3-trimethylstannanyl chromone 15. Compound 16 was obtained from 17 using a general Vilsmeier−Haack reaction.41 The synthesis of the cis-cyclopropane substrates for the Suzuki−Miyaura coupling is outlined in Scheme 4. Chiral methylenecyclopropane 10, which was prepared from (R)epichlorohydrin (19) according to the method we reported previously,32,42 was subjected to a hydroboration reaction with 9-borabicyclo[3.3.1]nonane, followed by oxidation with H2O2 and phosphate buffer (0.05 M KH2PO4/NaOH, pH 10.0) to stereoselectively give cis-cyclopropane derivative 20.42,43 This one-pot hydroboration−oxidation of chiral methylenecyclopropane 10 is a useful procedure for preparing the chiral 1,2dicarbon-substituted cis-cyclopropane structure. Oxidation of alcohol 20 to the corresponding cis-cyclopropanealdehyde44 by Dess−Martin periodinane followed by Takai−Uchimoto olefination afforded iodovinylcyclopropane 9, which was converted to boronic acid pinacol ester 21 by the same protocol used for the above-described indole-unit synthesis. Both of 9 and 21 were obtained as an inseparable mixture of the two stereoisomers (E/Z = 5/1−3/1); thus, the E/Z mixtures were used for the Suzuki−Miyaura coupling with indole or chromone units, respectively. Methylenecyclopropane 10 was also converted to bromomethylenecyclopropane 5 as an inseparable mixture of two stereoisomers (E/Z = 1/0.8) in two steps.32

Miyaura coupling with chiral bromomethylenecyclopropane 5 effectively provides cis-arylmethylcyclopropane derivatives,32 which can be applied for the preparation of a cis-cyclopropane analogue-conjugated indole with a methylene linker. Thus, Suzuki−Miyaura coupling of 5 with boronic acid pinacol ester 11 was conducted using Ag2O (1 equiv) as an additive and TBAF (2.5 equiv) as a base and reagent for removing the TBDPS group under PdCl2(dppf)-catalyzed conditions (10 mol % catalyst, DMF/THF (4/1), room temperature) to afford the expected coupling product 22, which was immediately subjected to reduction conditions without 7674

DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

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The Journal of Organic Chemistry purification (Scheme 5A). When Cs2CO332 or other classical bases (K2CO3, Na2CO3, K3PO4) were used instead of TBAF, the desired coupling product possessing a silyl ether was not obtained. In our previous report,32 the unsaturated bond of the coupling products having a protected hydroxyl group could be stereoselectively reduced by catalytic hydrogenation to provide the corresponding cis-cyclopropane derivatives. However, in the present study, hydrogenation of compound 22 possessing an unprotected alcohol, in the presence of Pd/C or Rh/C45 as catalysts, failed to give the desired cyclopropane and led instead to a complex mixture of products. On the other hand, diimide reduction of 22 using o-nitrobenzenesulfonyl hydrazide46 with Et3N produced the desired saturated alcohol 23 as a diasteromixture (cis/trans = 1/0.8). For the synthesis of chromone-methylcyclopropane, we investigated Stille coupling of 5 with chromone-3-stannane 15 under various conditions. When the reaction was carried out using PdCl2(dppf) (9 mol %) and Ag2O (1 equiv) in DMF at room temperature, the expected coupling product 24 was obtained, although the yield of the crude product of 24 were low (∼30%) and there was room for improvement in the reaction conditions (Scheme 5B). Thus, chiral bromomethylenecyclopropane 5 was a useful substrate, not only for Suzuki−Miyaura coupling but also for Stille coupling. Catalytic hydrogenation of 24 and subsequent treatment with TBAF followed by silica gel column chromatography afforded cischromone-methylcyclopropane 25 as a single diastereomer.32 The Pd-catalyzed coupling reactions with chiral bromomethylenecyclopropane effectively provided the desired heteroaryl cis-cyclopropane, although the yield was insufficient in the case of chromone derivative 25. The heteroarylethylcyclopropane derivatives were also synthesized by Suzuki−Miyaura coupling using cis-iodovinylcyclopropane 7 as the substrate (Scheme 6). Treatment of 7 and indole unit 11 with PdCl2(dppf) and Cs2CO3 gave the corresponding coupling product 26 as a mixture of two

stereoisomers (E/Z = 5/1) (Scheme 6A). Catalytic hydrogenation of 26 with Pd/C followed by removal of a TBDPS group using TBAF afforded alcohol 27. Coupling of 21 with 3iodochromone 18 under conditions similar to those used for the synthesis of indole-ethylcyclopropane 26 gave coupling product 28 (Scheme 6B). The silyl-protecting group of 28 was removed by treatment with 3HF·Et3N to afford alcohol 29 as a mixture of two stereoisomers (E/Z = 5/1) in 89% yield in two steps. Indole-methyl or -ethylcyclopropane SPD-304 analogues 1 and 2 were synthesized through a common procedure (Scheme 7). The hydroxylmethyl group of the cis/transScheme 7. Synthesis of Indole-methyl or -ethyl-ciscyclopropane SPD-304 Analogues 1 and 2

mixture 23 was converted to a carboxylic group by Dess− Martin oxidation and subsequent Pinnick oxidation to give 32 in a pure cis-form after silica gel column chromatography. Compound 32 was treated with diphenylphosphoryl azide for conversion to an acyl azide which was heated and the resulting isocyanate was then treated with benzyl alcohol in a one-pot fashion to provide Cbz-protected amine 34. After removal of the Cbz group of 34 by hydrogenolysis, reductive amination of the product with 3-formyl chromone 16 using 2-methylpyridine borane complex47 produced the desired cyclopropane SPD-304 analogue 1 (n = 1), although the yield was insufficient. In the reductive amination reaction, the corresponding dialkylamine product as well as a 4-chromanone product were generated as byproducts. Attempts to improve the yield of the reaction by changing the reagents (NaBH(OAc)3, NaBH3CN) and reaction conditions (equiv of the reducing reagents, solvents, and temperature) were unsuccessful. The corresponding homologous analogue 2 with an ethylene linker (n = 2) was prepared from 27 using the same procedure. The chromone-methyl or -ethyl cyclopropane SPD-304 analogues 3 and 4 were synthesized from 25 and 29, respectively (Scheme 8). Compound 25 was subjected to oxidation conditions using excess MnO2 and subsequent Pinnick oxidation to give a corresponding carboxylic acid, which was converted to Fmoc-protected amine 36 by treatment with diphenylphosphoryl azide followed by Curtius rearrangement without any purification (Scheme 8A). In the

Scheme 6. Synthesis of cis-Heteroarylethylcyclopropanes

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DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

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cyclopropane 5 was a useful substrate for not only Suzuki− Miyaura coupling, but also Stille coupling to synthesize cisheteroarylmethylcyclopropane compounds, and intermediate 10 was stereoselectively converted to chiral cis-cyclopropane methyl alcohol to lead into cis-heteroarylethylcyclopropane compounds. Unfortunately, the synthesized analogues exhibited the little inhibitory activity against TNFα, but the synthetic study presents a practical procedure for preparing cisheteroarylcyclopropane-containing compounds useful in medicinal chemical studies.

Scheme 8. Synthesis of Chromone-methyl or -ethyl-ciscyclopropane SPD-304 Analogues 3 and 4

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EXPERIMENTAL SECTION

General Information. All commercially available materials were used as received unless otherwise noted. Column chromatography was performed using silica gel 60N (spherical, natural, 63-210 μm). All compounds were characterized by 1H NMR, 13C NMR, and mass spectra. Some compounds were analyzed by elemental analysis. Nuclear magnetic resonance spectra were recorded on a JEOL 400 or 500 MHz instrument. All 1H NMR spectra are reported in δ units, parts per million (ppm), and were measured relative to signals for tetramethylsilane (0.00 ppm) in the deuterated solvent. All 13C NMR spectra are reported in ppm relative to deuterochloroform (77.00 ppm), unless otherwise stated, and all were obtained with 1H decoupling. Low- and high-resolution mass analysis were performed on a double-focusing high-resolution magnetic sector mass-analyzer instrument. 3-Iodo-N-[3-(trifluoromethyl)phenyl]indole (14). To a solution of N-[3-(trifluoromethyl)phenyl]indole (13)11 (1.12 g, 4.29 mmol) in DMF (35 mL) was added N-iodosuccinimide (1.06 g, 4.72 mmol) at 0 °C, and the mixture was stirred at 0 °C for 4 h. To the mixture was added sodium bicarbonate (40 mg), the resulting mixture was stirred at room temperature for 10 min. The mixture was diluted with water (35 mL) and extracted with diethyl ether. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (hexane) to give 14 (1.63 g, 4.21 mmol, 98%) as a white solid. mp. 93−94 °C (recryst. from EtOH, white needle); 1H NMR (500 MHz, CDCl3) δ 7.26−7.33 (2 H, m), 7.45 (1 H, s), 7.48 (2 H, dd, J = 2.5, 7.5 Hz), 7.53 (2 H, dd, J = 2.5, 6.4 Hz), 7.64−7.70 (3 H, m), 7.75 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 60.2, 110.2, 121.1 (q, JC−F = 3.6 Hz), 121.7, 121.8, 123.5 (q, JC−F = 270.6 Hz), 123.6 (q, JC−F = 3.5 Hz), 124.0, 127.4, 130.5, 131.2, 131.4, 132.4 (q, JC−F = 32.1 Hz), 135.6, 139.5; LRMS (EI) m/z 386 (M+); HRMS (EI) calcd for C15H9F3IN: 386.9732, found 386.9731 (M+). 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[3(trifluoromethyl)phenyl]indole (11). To a mixture of 14 (1.21 g, 3.13 mmol) and triisopropyl borate (0.932 mL, 4.07 mmol) in toluene/ THF (3/1, 32 mL) was added dropwise n-butyl lithium (1.65 M solution in hexane, 2.47 mL, 4.07 mmol) at −78 °C, and the reaction mixture was stirred at −78 °C for 3 h. To the mixture was added pinacol (555 mg, 4.70 mmol) at −78 °C, and the resulting mixture was stirred at room temperature for 3 h. After addition of saturated aqueous NH4Cl, the resulting mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (2% AcOEt in hexane) to give 11 (1.15 g, 2.97 mmol, 95%) as a light yellow solid. mp. 88−89 °C (recryst. from hexane, yellow plate); 1H NMR (400 MHz, CDCl3) δ 1.39 (12 H, s), 7.24−7.28 (2 H, m), 7.52 (1 H, m), 7.62−7.66 (2 H, m), 7.73 (1 H, m), 7.79 (2 H, m), 8.11 (1 H, m); 13C NMR (125 MHz, CDCl3) δ 24.9, 83.1, 110.1, 121.1 (q, JC−F = 3.6 Hz), 121.5, 123.0, 123.1, 123.3 (q, JC−F = 3.6 Hz), 123.6 (q, JC−F = 270.7 Hz), 127.3, 130.3, 132.3 (q, JC−F = 32.5 Hz), 133.1, 136.7, 136.8, 140.0; LRMS (EI) m/z 387 (M+); HRMS (EI) calcd for C21H21BF3NO2: 387.1617, found 387.1616 (M+). 3-Formyl-6,7-dimethylchromone (16). The experimental conditions were similar to the report in the literature.41 To a solution of 17 (821 mg, 5.00 mmol) in DMF (5 mL) was added phosphoryl chloride

Curtius rearrangement reaction, treatment with benzyl alcohol failed to afford the corresponding Cbz-protected amine, while treatment with 9-fluorenylmethanol successfully afforded the corresponding Fmoc-protected amine product 36. The Fmoc group of 36 was removed using Cs2CO3, and a similar reductive amination with 3-formyl indole 12 as described above provided the desired cyclopropane analogue 3. As for the synthesis of 4 (Scheme 8B), catalytic hydrogenation of 29 and subsequent conversion to Fmoc-protected amine 37 were conducted using the procedure described above. Deprotection of 37 using K2CO3 and subsequent reductive amination with 12 afforded the desired analogue 4. All the corresponding enantiomers of analogues (ent-1−ent4) were synthesized from (S)-epichlorohydrin using the same protocol as described above. The inhibitory activities against TNFα of the synthesized analogues (1−4 and ent-1−ent-4) were evaluated by an NFκB-responsive luciferase reporter gene assay with HEK-293T cells. All of the analogues exhibited weaker inhibitory activities than SPD-304 (Figures S3 and S4 and Table S1 in the Supporting Information).

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CONCLUSION In summary, we stereoselectively synthesized cis-cyclopropanebased conformationally restricted analogues of SPD-304 as potential TNFα inhibitors, in which two heteroaryl groups, indole and chromone moieties, were connected by chiral methyl- or ethyl-cis-cyclopropane. In the synthesis, we used chiral methylenecyclopropane 6 as a common intermediate to construct both methyl- and ethyl-cis-cyclopropane structures. We also demonstrated that optically active bromomethylene7676

DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

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The Journal of Organic Chemistry (927 μL, 10.0 mmol) at 0 °C, and the mixture was stirred at 80 °C for 15 h. After cooling to room temperature, to the mixture was added ice−water (20 mL). and then the precipitate was collected by filtration and washed with water and ethanol. The solid was dried over P2O5 under reduced pressure to give 16 (807 mg, 80%), used in the next reaction without any further purification. HRMS (ESI) calcd for C12H11O3: 203.0703 [(M + H)+], found 203.0700. The NMR spectra agree with those previously reported.48 3-Iodo-6,7-dimethylchromone (18). A mixture of 17 (164 mg, 1.00 mmol) and N,N-dimethylformamide dimethyl acetal (267 μL, 2.00 mmol) was heated to 90 °C for 4 h. After cooled to room temperature, excess MeOH and N,N-dimethylformamide dimethyl acetal were removed under reduced pressure to give a crude product of β-enamino ketone (220 mg). To a solution of the crude product in dichloromethane (2.0 mL) were added pyridine (80.7 μL, 1.00 mmol) and then iodine (508 mg, 2.00 mmol) portionwise at room temperature. The reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by addition of saturated aqueous Na2S2O3, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (20% AcOEt in hexane) to give 18 (277 mg, 0.923 mmol, 92% for 2 steps) as a light yellow solid. HRMS (ESI) calcd for C11H9O2I: 299.9647 (M+), found 299.9658. The NMR spectra agree with those previously reported.39 3-Trimethylstannyl-6,7-dimethylchromone (15). To a solution of 18 (2.44 g, 8.13 mmol) in 1,4-dioxane (273 mL) were added hexamethylditin (3.49 mL, 16.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (474 mg, 0.410 mmol) at room temperature, and the mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (10% AcOEt in hexane) to give 15 (2.41 g, 7.15 mmol, 88%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 0.33 (9 H, s), 2.33 (3 H, s), 2.36 (3 H, s), 7.17 (1 H, s), 7.54 (1 H, s), 7.86 (1 H, s); 13C NMR (125 MHz, CDCl3) δ −9.3, 19.3, 20.4, 118.0, 121.6, 122.5, 125.5, 134.1, 143.7, 155.3, 156.9, 181.1; LRMS (ESI) m/z 361 [(M + Na)+]; HRMS (ESI) calcd for C14H18NaO2Sn: 361.0221 [(M + Na)+], found 361.0229. (1S,2R)-2-(t-Butyldiphenylsilyloxy)methyl-1-hydroxymethylcyclopropane (20). To a solution of 6 (3.23 g, 10.0 mmol) in dry THF (40 mL) was added dropwise 9-borabicyclo[3.3.1]nonane (0.5 M solution in THF, 60.0 mL, 30.0 mmol) at −5 °C, and the resulting mixture was stirred at 0 °C for 4 h. To the reaction solution were added EtOH/ THF/H2O (1/1/1, 30 mL), phosphate buffer (0.05 M KH2PO4/ NaOH, pH 10.0, 20 mL) and aqueous H2O2 (35%, 20 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 24 h. After addition of saturated aqueous NH4Cl, the resulting mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by flash silica gel column chromatography (3−5% AcOEt in hexane) to give 20 (2.62 g, 77%) as a colorless oil. The ratio of diastereomer was determined by 1H NMR spectrum of the crude product. LRMS (EI) m/z 283 [(M − tBu)+]. The NMR spectra agree with those previously reported.42 (1S,2R)-2-(t-Butyldiphenylsilyloxy)methyl-1-(2′-iodovinyl)cyclopropane (9). To a suspension of chromium(II) chloride (1.17 g, 9.50 mmol) in THF (9.5 mL) was added dropwise a solution of 20 (495 mg, 1.46 mmol) and iodoform (1.21 g, 3.07 mmol) in THF (5.0 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 4 h. After addition of water, the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (0−1% AcOEt in hexane) to give a mixture of E/Z-isomer 9 (501 mg, 1.08 mmol, 74%, E/Z = 5/1) as a colorless oil. 1H NMR (500 MHz, CDCl3) (E-isomer) δ 0.45 (1 H, m), 0.89 (1 H, m), 1.05 (9 H, s), 1.35 (1 H, m), 1.62 (1 H, m), 3.50 (1 H, dd, J = 11.3, 8.2 Hz), 3.80 (1 H, dd, J = 11.3, 5.4 Hz), 6.00 (1 H, d, J = 14.5 Hz), 6.30 (1 H, dd, J = 14.5, 9.1 Hz), 7.37−7.45 (6 H, m), 7.66−7.69 (4 H, m); (Z-isomer) δ 0.51 (1 H, m), 0.90 (1 H, m), 1.04 (9 H, m),

1.43 (1 H, m), 1.79 (1 H, m), 3.60 (1 H, dd, J = 11.3, 7.4 Hz), 3.80 (1 H, dd, J = 11.3, 5.4 Hz), 5.86 (1 H, dd, J = 8.6, 7.5 Hz), 6.09 (1 H, d, J = 7.5 Hz), 7.37−7.45 (6 H, m), 7.66−7.69 (4 H, m); 13C NMR (125 MHz, CDCl3, E/Z mixture) δ 10.2, 11.8, 19.2, 20.7, 21.1, 22.0, 22.1, 26.8, 63.5, 63.9, 72.9, 80.3, 127.6, 127.7, 127.7, 129.6, 129.6, 133.6, 133.7, 135.6, 135.6, 140.6, 145.4; LRMS (ESI) m/z 485 [(M + Na)+]; HRMS (ESI) calcd for C22H27INaOSi: 485.0768, found 485.0772 [(M + Na)+]. (1R,2R)-2-(t-Butyldiphenylsilyloxy)methyl-1-[2′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]cyclopropane (21). A mixture of E/Z-isomer 21 (0.22 g, 0.48 mmol, 84%, E/Z = 3/1, colorless oil) was prepared from 9 (0.26 g, 0.57 mmol) as described for the preparation of 11. 1H NMR (400 MHz, CDCl3) (E isomer) δ 0.56 (1 H, m), 0.97 (1 H, m), 1.03 (9 H, s), 1.24 (6 H, s), 1.25 (6 H, s), 1.42 (1 H, m), 1.69 (1 H, m), 3.61 (1 H, dd, J = 10.9, 7.7 Hz), 3.82 (1 H, dd, J = 10.9, 5.9 Hz), 5.57 (1 H, d, J = 22 Hz), 6.40 (1 H, dd, J = 22, 12 Hz), 7.36−7.44 (6 H, m), 7.66−7.70 (4 H, m); (Z isomer) δ 0.44 (1 H, m), 0.97 (1 H, m), 1.04 (9 H, s), 1.27 (12 H, s), 1.42 (1 H, m), 2.43 (1 H, m), 3.69−3.79 (2 H, m), 5.27 (1 H, d, J = 17 Hz), 5.98 (1 H, dd, J = 17, 14 Hz), 7.36−7.44 (6 H, m), 7.66−7.70 (4 H, m); 13C NMR (125 MHz, CDCl3, E/Z mixture) δ 12.3, 19.2, 22.2, 22.4, 24.7, 24.8, 24.8, 24.9, 26.8, 26.8, 63.8, 82.9, 127.5, 127.6, 129.5, 129.5, 133.8, 134.0, 135.6, 135.7, 154.2; LRMS (ESI) m/z 485 [(M + Na)+]; HRMS (ESI) calcd for C28H39BNaO3Si: 485.2654, found 485.2648 [(M + Na)+]. {(1R,2RS)-2-[((3-Trifluoromethylphenyl)-1H-indol-3-yl)methyl]cyclopropyl}methanol (23, diastereomixture). To a solution of 532 (928 mg, 2.31 mmol) in DMF (23 mL) were added 11 (1.34 g, 3.47 mmol), silver(I) oxide (536 mg, 2.31 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (189 mg, 0.231 mmol) and tetrabutylammonium fluoride (1 M solution in THF, 5.78 mL, 5.78 mmol) at room temperature, and the mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with AcOEt and filtered through a short silica gel pad. The filtrate was evaporated, and the residue was partitioned between AcOEt and saturated aqueous NH4Cl. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was passed through short silica gel column (50% AcOEt in hexane) to give a crude coupling-product (585 mg). To a solution of the crude product in CH2Cl2 (17 mL) were added o-nitrobenzenesulfonyl hydrazide46 (2.96 g, 13.6 mmol) and triethylamine (2.36 mL, 17.0 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between AcOEt and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (33% AcOEt in hexane) to give a diastereomixture (23) (389 mg, 1.13 mmol, 49% for 2 steps, cis/trans = 1/0.8) as a yellow oil. 1H NMR (400 MHz, CDCl3) (cis-isomer) δ 0.26 (1 H, q, J = 5.1 Hz, H-3a), 0.91 (1 H, m, H-3b), 1.32 (1 H, m, H-1), 1.42 (1 H, m, H-2), 1.70 (1 H, br, OH), 2.86 (1 H, dd, J = 15.0, 7.0 Hz, Ar−CHaHb−), 2.95 (1 H, dd, J = 16.0, 7.0 Hz, Ar− CHaHb−), 3.64 (1 H, dd, J = 11.4, 9.2 Hz, −CHaHb−OH), 3.85 (1 H, dd, J = 11.4, 6.3 Hz, −CHaHb−OH), 7.19−7.30 (3 H, m, aromatic), 7.54−7.76 (6 H, m, aromatic); (trans-isomer) δ 0.55 (2 H, m, H-3), 1.07−1.13 (2 H, m, H-1 and H-2), 1.57 (1 H, br, OH), 2.75 (1 H, dd, J = 16.0, 6.0 Hz, Ar−CHaHb−), 2.83 (1 H, dd, J = 15.6, 5.5 Hz, Ar−CHaHb−), 3.47 (1 H, dd, J = 11.5, 6.8 Hz, −CHaHb−OH), 3.56 (1 H, dd, J = 11.5, 6.4 Hz, −CHaHb−OH), 7.19−7.33 (3 H, m, aromatic), 7.54−7.76 (6 H, m, aromatic); 13C NMR (125 MHz, CDCl3, diastereomixture) δ 9.8, 10.2, 15.6, 17.1, 18.4, 21.5, 24.0, 28.8, 63.2, 67.0, 110.2, 118.3, 118.8, 119.46, 119.51, 120.4, 120.5 (q, JC−F = 3.5 Hz), 120.7 (q, JC−F = 3.5 Hz), 122.4 (q, JC−F = 3.5 Hz), 122.6 (q, JC−F = 3.5 Hz), 122.9, 123.1, 123.68 (q, JC−F = 271 Hz), 123.69 (q, JC−F = 271 Hz), 124.4, 124.7, 126.9, 127.1, 129.1, 129.3, 130.2, 130.3, 132.13 (q, JC−F = 32.1 Hz), 132.16 (q, JC−F = 32.8 Hz), 135.8, 135.9, 140.35, 140.45; LRMS (ESI) m/z 368 [(M + Na)+]; HRMS (ESI) calcd for C20H18OF3NNa: 368.1233, found 368.1242 [(M + Na)+]. {(1R,2R)-2-[(6,7-Dimethylchromon-3-yl)methyl]cyclopropyl}methanol (25). To a solution of 5 (1.04 g, 2.59 mmol) in DMF (23 7677

DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

Article

The Journal of Organic Chemistry mL) were added 15 (960 mg, 2.85 mmol), silver(I) oxide (600 mg, 2.59 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (189 mg, 0.231 mmol) at room temperature, and the mixture was stirred at room temperature for 10 h. The reaction mixture was diluted with AcOEt and filtered through silica gel pad. The filtrate was evaporated, and the residue was partitioned between AcOEt and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was passed through a short silica gel column (50% AcOEt in hexane) to give crude coupling-product 24 (436 mg). To a solution of the crude product in AcOEt (9 mL) were added 5% palladium on carbon (131 mg) at room temperature, and the mixture was stirred at 0 °C for 1 h under an H2 atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated to give a crude residue (466 mg). To a solution of the crude residue in THF (8 mL) was added tetrabutylammonium fluoride (1 M solution in THF, 1.06 mL, 1.06 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was purified by silica gel column chromatography (33−50% AcOEt in hexane) to give 25 (105 mg, 0.406 mmol, 16% for 3 steps) as a colorless oil. [α]D17 = −25.6 (c 0.20, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.06 (1 H, m), 0.77 (1 H, m), 0.94 (1 H, m), 1.29 (1 H, m), 2.35 (3 H, s), 2.38 (3 H, s), 2.50 (1 H, dd, J = 15.5, 4.0 Hz), 2.61 (1 H, dd, J = 15.5, 4.0 Hz), 3.51 (1 H, m), 3.96 (1 H, m), 7.22 (1 H, s), 7.91 (1 H, s), 7.98 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 8.5, 15.8, 19.3, 19.4, 20.4, 24.1, 62.5, 118.0, 121.6, 124.3, 125.5, 134.4, 144.1, 152.8, 155.1, 178.3; LRMS (ESI) m/z 281 [(M + Na)+]; HRMS (ESI) calcd for C16H18O3Na: 281.1148, found 281.1146 [(M + Na)+]. {(1R,2S)-2-[2-(1-(3-Trifluoromethylphenyl)-1H-indol-3-yl)ethyl]cyclopropyl}methanol (27). To a solution of 7 (38.4 mg, 83.0 μmol) in DMF (0.83 mL) were added 11 (38.6 mg, 99.6 μmol), cesium carbonate (54.1 mg, 0.166 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (6.8 mg, 8.3 μmol) at room temperature, and the mixture was stirred at room temperature for 5 h. The reaction mixture was filtered through Celite, and the filtrate was partitioned between AcOEt and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was passed through silica gel (3% AcOEt in hexane) to give crude coupling-product 26 (42 mg). To a solution of the crude product in AcOEt (0.6 mL) was added 10% palladium on carbon (4.2 mg) at room temperature, and the mixture was stirred at room temperature for 1 h under an H2 atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated to give a crude residue (44 mg). To a solution of the crude residue in THF (0.5 mL) was added tetrabutylammonium fluoride (1 M solution in THF, 0.11 mL, 0.11 mmol) at room temperature, and the mixture was stirred at room temperature for 7 h. The solvent was evaporated, and the residue was purified by silica gel column chromatography (20% AcOEt in hexane) to give 27 (18.1 mg, 50.4 μmol, 61% for 3 steps) as a colorless oil. [α]D21 = +12.7 (c 0.73, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.07 (1 H, m), 0.78 (1 H, m), 1.04 (1 H, m), 1.14−1.22 (2 H, m), 1.73 (1 H, m), 1.92 (1 H, m), 2.91−2.96 (2 H, m), 3.59 (1 H, dd, J = 10.3, 9.2 Hz), 3.73 (1 H, dd, J = 10.3, 6.9 Hz), 7.15−7.28 (3 H, m), 7.54−7.75 (6 H, m); 13C NMR (125 MHz, CDCl3) δ 9.4, 16.2, 18.4, 25.4, 29.2, 63.3, 110.1, 118.8, 119.5, 120.4, 120.6 (q, JC−F = 3.6 Hz), 122.5 (q, JC−F = 3.6 Hz), 122.9, 123.6 (q, JC−F = 273 Hz), 124.5, 126.9, 129.3, 130.2, 132.2 (q, JC−F = 30 Hz), 135.8, 140.4; LRMS (ESI) m/z 382 [(M + Na)+]; HRMS (ESI) calcd for C21H20ONF3Na: 382.1389, found 382.1392 [(M + Na)+]. {(1R,2R)-2-[2-(6,7-Dimethylchromon-3-yl)ethenyl]cyclopropyl}methanol (29). To a solution of 21 (283 mg, 0.612 mmol) in DMF (6.1 mL) were added 18 (239 mg, 0.795 mmol), cesium carbonate (399 mg, 1.22 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (50 mg, 60 μmol) at room temperature, and the mixture was stirred at 80 °C for 45 min. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was partitioned between AcOEt and water. The organic layer was washed with brine, dried over anhydrous

Na2SO4, and evaporated. The residue was passed through silica gel (9% AcOEt in hexane) to give crude coupling-product 28 (285 mg, yellow oil). To a solution of a part of the crude product (133 mg) in THF (3.3 mL) was added triethylamine trihydrofluoride (255 μL, 1.57 mmol) at room temperature, and the mixture was stirred at room temperature for 20 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (50% AcOEt in hexane) to give a mixture of E/Z isomer (29) (73 mg, 0.27 mmol, 89% for 2 steps, E/Z = 5/1) as a yellow oil. 1H NMR (500 MHz, CDCl3) (E isomer) δ 0.61 (1 H, m), 1.07 (1 H, m), 1.47 (1 H, m), 1.76 (1 H, m), 1.82 (1 H, br), 2.35 (3 H, s), 2.37 (3 H, s), 3.59 (1 H, dd, J = 11.5, 8.5 Hz), 3.87 (1 H, dd, J = 11.5, 6.5 Hz), 6.38 (1 H, d, J = 16.0 Hz), 6.53 (1 H, dd, J = 16.0, 9.0 Hz), 7.19 (1 H, s), 7.86 (1 H, s), 7.95 (1 H, s); (Z isomer) δ 0.54 (1 H, m), 1.07 (1 H, m), 1.47 (1 H, m), 1.70 (1 H, m), 2.35 (3 H, s), 2.38 (3 H, s), 3.46 (1 H, dd, J = 11.5, 11.5 Hz), 3.91 (1 H, dd, J = 11.5, 5.0 Hz), 5.63 (1 H, dd, J = 11.5, 9.5 Hz), 6.36 (1 H, d, J = 11.5 Hz), 7.22 (1 H, s), 7.99 (1 H, s), 8.11 (1 H, s); 13C NMR (125 MHz, CDCl3, E/Z mixture) δ 11.8, 19.4, 19.8, 20.4, 21.7, 63.3, 118.0, 120.9, 121.4, 121.9, 125.6, 133.0, 134.4, 143.8, 151.9, 154.4, 176.7; LRMS (ESI) m/z 293 [(M + Na)+]; HRMS (ESI) calcd for C17H18NaO3: 293.1148, found 293.1148 [(M + Na)+]. {(1R,2RS)-2-[((3-Trifluoromethylphenyl)-1H-indol-3-yl)methyl]cyclopropane}-1-carboaldehyde (30). To a solution of 23 (382 mg, 1.11 mmol) in CH2Cl2/pyridine (5/1, 13.3 mL) was added Dess− Martin periodinane (938 mg, 2.21 mmol) at room temperature, and the mixture was stirred at room temperature for 3 h. To the reaction mixture was added saturated aqueous Na2S2O3 (35 mL) at room temperature, and the resulting mixture was vigorously stirred at room temperature for 10 min. The resulting solution was extracted with AcOEt, and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (20% AcOEt in hexane) to give 30 (312 mg, 0.909 mmol, 82%, diastereomixture, cis/trans = 1/0.8) as a yellow oil. 1H NMR (500 MHz, CDCl3) (cis-isomer) δ 1.36−1.48 (2 H, m), 2.00 (1 H, m), 2.09 (1 H, m), 2.97 (1 H, m), 3.18 (1 H, m), 7.17−7.29 (3 H, m), 7.53− 7.75 (6 H, m), 9.58 (1 H, d, J = 4.6 Hz); 1H NMR (500 MHz, CDCl3) (trans-isomer) δ 1.14 (1 H, m), 1.36−1.48 (1 H, m), 1.86 (1 H, m), 1.94 (1 H, m), 2.84 (1 H, m), 2.89 (1 H, m), 7.17−7.29 (3 H, m), 7.53−7.75 (6 H, m), 9.09 (1 H, d, J = 5.7 Hz); 13C NMR (125 MHz, CDCl3, diastereomixture) δ 15.1, 15.3, 22.3, 23.6, 24.7, 27.7, 27.8, 30.5, 110.2, 110.3, 116.3, 117.6, 119.27, 119.34, 120.5, 120.6, 120.7 (q, JC−F = 3.5 Hz), 122.7 (q, JC−F = 3.5 Hz), 123.1, 123.2, 123.7 (q, JC−F = 271 Hz), 124.7, 124.9, 127.1, 128.8, 129.0, 130.28, 130.31, 132.16 (q, JC−F = 32.1 Hz), 132.20 (q, JC−F = 32.3 Hz), 135.8, 135.9, 140.19, 140.24, 200.8, 201.4; LRMS (ESI) m/z 366 [(M + Na)+]; HRMS (ESI) calcd for C20H16OF3NNa: 366.1076, found 366.1082 [(M + Na)+]. {(1R,2R)-2-[((3-Trifluoromethylphenyl)-1H-indol-3-yl)methyl]cyclopropane}-1-carboxylic acid (32). To a solution of 30 (310 mg, 0.903 mmol) in acetone (14 mL) were added 2-methyl-2-butene (1.92 mL, 18.1 mmol) and a solution of sodium dihydrogen phosphate dihydrate (986 mg, 6.32 mmol) and sodium chlorite (80%, 817 mg, 7.22 mmol) in water (9.0 mL) at room temperature, and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0 °C and acidified with aqueous HCl (0.5 M), where the pH of the resulting solution was about 3. The solution was extracted with AcOEt, and the organic layer was washed with aqueous HCl (0.5 M), water (two times) and brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (20% AcOEt in hexane) to give 32 (161 mg, 0.488 mmol, 50%) as a light-yellow oil. [α]D20 = −22.3 (c 1.00, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.23−1.26 (2 H, m), 1.79− 1.84 (2 H, m), 3.03 (1 H, dd, J = 15.3, 6.8 Hz), 3.13 (1 H, dd, J = 15.3, 6.8 Hz), 7.18−7.20 (2 H, m), 7.25 (1 H, t, J = 7.5 Hz), 7.52− 7.55 (2 H, m), 7.58 (1 H, t, J = 7.5 Hz), 7.64−7.65 (2 H, m), 7.74 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 15.0, 18.5, 22.6, 22.9, 110.1, 117.8, 119.5, 120.4, 120.6 (q, JC−F = 3.6 Hz), 122.5 (q, JC−F = 3.6 Hz), 123.0, 123.7 (q, JC−F = 271 Hz), 124.7, 127.0, 129.1, 130.2, 132.1 (q, 7678

DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

Article

The Journal of Organic Chemistry JC−F = 32 Hz), 135.8, 140.4, 179.5; LRMS (ESI) m/z 358 [(M − H)−]; HRMS (ESI) calcd for C20H15O2NF3: 358.1060, found 358.1066 [(M − H)−]. Benzyl {(1R,2S)-2-[((3-trifluoromethylphenyl)-1H-indol-3-yl)methyl]cyclopropyl}carbamate (34). To a solution of 32 (41 mg, 0.11 mmol) in CH2Cl2 (1.1 mL) were added diphenylphosphoryl azide (36 μL, 0.17 mmol) and triethylamine (23 μL, 0.17 mmol) at 0 °C, and the mixture was stirred at room temperature for 11 h. To the mixture was added toluene (2.3 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 12 h. To the reaction mixture was added benzyl alcohol (116 μL, 1.13 mmol) at room temperature, and the mixture was stirred for 36 h under reflux conditions. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH 2 Cl 2 (2.3 mL), and to the mixture were added tertbutyldiphenylsilyl chloride (293 μL, 1.13 mmol), triethylamine (157 μL, 1.13 mmol) and DMAP (13.8 mg, 0.113 mmol) at room temperature for the silylation of excess benzyl alcohol to facilitate the isolation of the product. The resulting mixture was stirred at the same temperature for 1 h. After addition of MeOH, the mixture was partitioned between AcOEt and aqueous HCl (1 M). The organic layer was neutralized with saturated aqueous NaHCO3, washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (15−20% AcOEt in hexane) to give 34 (37 mg, 0.080 mmol, 71%) as a yellow oil. [α]D20 = −10.1 (c 0.12, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.45 (1 H, m), 1.08 (1 H, m), 1.39 (1 H, m), 2.86 (3 H, m), 5.04 (1 H, d, J = 12 Hz), 5.08 (1 H, s, NH), 5.12 (1 H, d, J = 12 Hz), 7.17−7.33 (8 H, m), 7.52−7.66 (5 H, m), 7.76 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 12.6, 16.9, 23.3, 27.8, 66.7, 110.1, 117.8, 119.4, 120.4, 120.6 (q, JC−F = 4.1 Hz), 122.4 (q, JC−F = 3.6 Hz), 123.0, 123.7 (q, JC−F = 271 Hz), 124.6, 126.9, 128.0, 128.4, 129.1, 130.2, 132.1 (q, JC−F = 32 Hz), 135.8, 136.4, 140.4, 157.3; LRMS (ESI) m/z 487 [(M + Na)+]; HRMS (ESI) calcd for C27H23O2N2F3Na: 487.1604, found 487.1600 [(M + Na)+]. 6,7-Dimethyl-3-{[(1R,2S)-2-((1-(3-trifluoromethylphenyl)-1Hindol-3-yl)methyl)cyclopropylamino]methyl}-4H-chromen-4-one (1). A mixture of 34 (13 mg, 28 μmol) and 10% palladium on carbon (8 mg) in EtOH (1.3 mL) was stirred at room temperature for 2 h under an H2 atmosphere. The mixture was filtered through Celite, and the filtrate was evaporated to give a crude product of primary amine (9.0 mg, a light-yellow oil). To a solution of the crude product in MeOH/THF (3/1, 0.27 mL) were added acetic acid (3.1 μL, 55 μmol) and 3-formyl-6,7-dimethylchromone (16) (5.5 mg, 27 μmol) at room temperature, and the mixture was stirred at room temperature for 0.5 h. To the reaction mixture was added 2methylpyridine borane complex (3.5 mg, 33 μmol) at room temperature, and the resulting mixture was stirred at room temperature for 1 h. After addition of saturated aqueous NaHCO3, the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (10−33% AcOEt in hexane) to give 1 (3.2 mg, 6.2 μmol, 23% for 2 steps) as a yellow oil. [α]D21 = −1.4 (c 0.16, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.31 (1 H, m), 0.79 (1 H, m), 1.23 (1 H, m), 2.33 (1 H, m), 2.38 (3 H, s), 2.39 (3 H, s), 2.95 (1 H, dd, J = 15.9, 6.9 Hz), 3.05 (1 H, dd, J = 15.9, 6.9 Hz), 3.63 (1 H, d, J = 13.7 Hz), 3.80 (1 H, d, J = 13.7 Hz), 7.17−7.26 (4 H, m), 7.53−7.57 (2 H, m), 7.63 (1 H, t, J = 8 Hz), 7.68−7.73 (2 H, m), 7.78−7.80 (2 H, m), 7.94 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 12.4, 17.9, 19.3, 20.4, 22.8, 34.3, 45.9, 110.0, 118.2, 119.5, 119.7, 120.3, 120.6 (q, JC−F = 3.6 Hz), 121.8, 122.1, 123.3 (q, JC−F = 3.6 Hz), 122.8, 123.7 (q, JC−F = 271 Hz), 124.4, 125.2, 127.0, 129.5, 132.1 (q, JC−F = 32 Hz), 134.3, 135.8, 140.6, 144.0, 152.7, 155.1, 178.1; LRMS (ESI) m/z 517 [(M + H)+]; HRMS (ESI) calcd for C31H28O2N2F3: 517.2097, found 517.2103 [(M + H)+]. {(1R,2S)-2-[2-((3-Trifluoromethylphenyl)-1H-indol-3-yl)ethyl]cyclopropane}-1-carboaldehyde (31). 31 (114 mg, 0.318 mmol, 85%, colorless oil) was prepared from 23 (135 mg, 0.376 mmol) as described for the preparation of 30. [α]D23 = −4.2 (c 0.80, CHCl3);

H NMR (500 MHz, CDCl3) δ 1.25−1.29 (2 H, m), 1.61 (1 H, m), 1.90−1.99 (2 H, m), 2.10 (1 H, m), 2.82−2.95 (2 H, m), 7.15−7.28 (3 H, m), 7.53−7.70 (5 H, m), 7.75 (1 H, s), 9.41 (1 H, d, J = 5.2 Hz); 13C NMR (125 MHz, CDCl3) δ 14.6, 24.7, 25.2, 27.7, 28.6, 110.2, 117.8, 119.4, 120.4, 120.6 (q, JC−F = 3.5 Hz), 122.6 (q, JC−F = 3.5 Hz), 123.0, 123.6 (q, JC−F = 279 Hz), 124.7, 127.0, 129.1, 130.2, 132.2 (q, JC−F = 32 Hz), 135.8, 140.3, 201.4; LRMS (ESI) m/z 380 [(M + Na)+]; HRMS (ESI) calcd for C21H18ONF3Na: 380.1233, found 380.1230 [(M + Na)+]; Anal. Calcd for C21H18F3NO: C, 70.58; H, 5.08; N, 3.92. Found: C, 70.30; H, 5.06; N, 3.87. {(1R,2S)-2-[2-((3-Trifluoromethylphenyl)-1H-indol-3-yl)ethyl]cyclopropane}-1-carboxylic acid (33). 33 (79.0 mg, 0.211 mmol, 81%, light yellow amorphous solid) was prepared from 31 (93.6 mg, 0.262 mmol) as described for the preparation of 32. [α]D21 = −28.7 (c 1.10, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.05 (1 H, m), 1.13 (1 H, m), 1.45 (1 H, m), 1.72 (1 H, m), 1.97−2.09 (2 H, m), 2.80−2.90 (2 H, m), 7.11 (1 H, s), 7.17 (1 H, t, J = 8 Hz), 7.22 (1 H, m), 7.50 (1 H, d, J = 8 Hz), 7.53−7.60 (2 H, m), 7.63−7.64 (2 H, m), 7.73 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 14.5, 18.1, 23.0, 24.8, 27.6, 110.1, 118.2, 119.5, 120.3, 120.5 (q, JC−F = 3.6 Hz), 122.4 (q, JC−F = 3.6 Hz), 122.8, 123.7 (q, JC−F = 271 Hz), 124.6, 126.9, 129.3, 130.2, 132.1 (q, JC−F = 32 Hz), 135.7, 140.4, 179.8; LRMS (ESI) m/z 372 [(M − H)−]; HRMS (ESI) calcd for C21H17O2NF3: 372.1217, found 372.1217 [(M − H)−]. Benzyl {(1R,2S)-2-[2-((3-trifluoromethylphenyl)-1H-indol-3-yl)ethyl]cyclopropyl}carbamate (35). 35 (59 mg, 0.12 mmol, 83%, yellow oil) was prepared from 33 (55 mg, 0.15 mmol) as described for the preparation of 34 excluding the silylation step. [α]D20 = +7.0 (c 1.07, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.22 (1 H, m), 0.95 (1 H, m), 1.03 (1 H, m), 1.72 (1 H, m), 1.85 (1 H, m), 2.68 (1 H, m), 2.92 (2 H, m), 4.77 (1 H, br), 5.03−5.10 (2 H, m), 7.14−7.19 (2 H, m), 7.22−7.36 (6 H, m), 7.51−7.67 (5 H, m), 7.37 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 12.1, 17.6, 24.8, 27.7, 28.4, 66.7, 110.1, 118.6, 119.5, 120.4, 120.6 (q, JC−F = 4.7 Hz), 122.5 (q, JC−F = 4.7 Hz), 122.9, 123.7 (q, JC−F = 272 Hz), 124.6, 127.0, 128.06, 128.12, 128.4, 129.2, 129.7, 130.2, 132.1 (q, JC−F = 33.4 Hz), 135.8, 136.4, 140.4, 157.2; LRMS (ESI) m/z 501 [(M + Na)+]; HRMS (ESI) calcd for C28H25O2N2F3Na: 501.1760, found 501.1757 [(M + Na)+]. 6,7-Dimethyl-3-{[(1R,2S)-2-(2-(1-(3-trifluoromethylphenyl)-1Hindol-3-yl)ethyl)cyclopropylamino]methyl}-4H-chromen-4-one (2). 2 (11 mg, 0.020 mmol, 25% for 2 steps, light-yellow oil) was prepared from 35 (38 mg, 0.078 mmol) as described for the preparation of compound 1. [α]D19 = +3.6 (c 0.34, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.13 (1 H, m), 0.67 (1 H, m), 0.85 (1 H, m), 1.86 (1 H, m), 2.03 (1 H, m), 2.23 (1 H, m), 2.33 (3 H, s), 2.37 (3 H, s), 2.91 (2 H, m), 3.60 (1 H, d, J = 13.7 Hz), 3.73 (1 H, d, J = 13.7 Hz), 7.16− 7.19 (3 H, m), 7.23 (1 H, t, J = 7.5 Hz), 7.52−7.56 (2 H, m), 7.61 (1 H, t, J = 7.5 Hz), 7.68−7.69 (2 H, m), 7.75−7.77 (2 H, m), 7.92 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 11.8, 18.2, 19.3, 20.4, 25.4, 27.6, 34.4, 45.8, 110.0, 118.1, 119.2, 119.7, 120.3, 120.5 (q, JC−F = 3.5 Hz), 121.8, 122.2, 122.3 (q, JC−F = 3.5 Hz), 122.8, 124.5, 125.2, 126.9, 129.5, 130.2, 134.3, 135.7, 140.5, 144.0, 152.7, 155.1, 178.0; LRMS (ESI) m/z 531 [(M + H)+]; HRMS (ESI) calcd for C32H30O2N2F3: 531.2254, found 531.2251 [(M + H)+]. (9H-Fluoren-9-yl)methyl {(1R,2S)-2-[(6,7-dimethylchromon-3-yl)methyl]cyclopropyl}carbamate (36). To a solution of 25 (105 mg, 0.406 mmol) in CH2Cl2 (4.1 mL) was added excess amount of manganese(IV) oxide (1.05 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through Celite, and the filtrate was evaporated to give a crude product of aldehyde (64 mg). To a solution of the crude product in acetone (8.0 mL) were added 2-methyl-2-butene (863 μL, 8.12 mmol) and a solution of sodium dihydrogen phosphate dihydrate (114 mg, 0.731 mmol) and sodium chlorite (80%, 92 mg, 0.81 mmol) in water (2.2 mL) at room temperature, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C and acidified with aqueous HCl (0.5 M), where the pH of the resulting solution was about 3. The solution was extracted with AcOEt, and the organic layer was washed with aqueous HCl (0.5 M), water (two times) and brine, dried over anhydrous Na2SO4, and 1

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DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

Article

The Journal of Organic Chemistry

(ESI) calcd for C31H29NO4Na: 502.1989, found 502.1987 [(M + Na)+]. 6,7-Dimethyl-3-{2-[(1S,2R)-2-(((1-(3-trifluoromethylphenyl)-1Hindol-3-yl)methyl)amino)cyclopropyl]ethyl}-4H-chromen-4-one (4). 4 (4.4 mg, 0.0083 mmol, 31% for 2 steps, yellow oil) was prepared from compound 37 (13 mg, 0.027 mmol) as described for the preparation of 3. [α]D20 = +7.3 (c 0.36, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.16 (1 H, m), 0.70 (1 H, m), 0.81 (1 H, m), 1.66− 1.74 (3 H, m), 1.94 (1 H, m), 2.33 (3 H, s), 2.36 (3 H, s), 2.53−2.64 (2 H, m), 4.04 (1 H, d, J = 14.3 Hz), 4.08 (1 H, d, J = 14.3 Hz), 7.17−7.26 (3 H, m), 7.33 (1 H, s), 7.52 (1 H, d, J = 8.5 Hz), 7.58 (1 H, d, J = 7.5 Hz), 7.63 (1 H, t, J = 8.0 Hz), 7.69−7.72 (3 H, m), 7.76 (1 H, s), 7.93 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 11.9, 18.1, 19.3, 20.4, 26.1, 26.2, 34.9, 44.7, 110.2, 117.8, 118.1, 119.7, 120.6, 120.7 (q, JC−F = 3.6 Hz), 121.8, 122.7 (q, JC−F = 3.6 Hz), 123.0, 123.7 (q, JC−F = 271 Hz), 124.3, 125.4, 125.6, 127.1, 128.9, 130.3, 132.2 (q, JC−F = 32.1 Hz), 134.0, 136.0, 140.4, 143.6, 151.7, 155.1, 177.8; LRMS (ESI) m/z 531 [(M + H)+]; HRMS (ESI) calcd for C32H30O2F3N2: 531.2254, found 531.2256 [(M + H)+]. (1R,2S)-2-(t-Butyldiphenylsilyloxy)methyl-1-(2′-iodovinyl)cyclopropane (ent-9). ent-9 (438 mg, 0.947 mmol, 70%, colorless oil, E/Z = 5/1) was prepared from ent-2042 (459 mg, 1.36 mmol) as described for the preparation of 7. LRMS (ESI) m/z 485 [(M + Na)+]; HRMS (ESI) calcd for C22H27INaOSi: 485.0768, found 485.0762 [(M + Na)+]. (1S,2S)-2-(t-Butyldiphenylsilyloxy)methyl-1-[2′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]cyclopropane (ent-21). ent21 (221 mg, 0.478 mmol, 81%, colorless oil, E/Z = 5/1) was prepared from ent-9 (272 mg, 0.588 mmol) as described for the preparation of 21. LRMS (ESI) m/z 485 [(M + Na)+]; HRMS (ESI) calcd for C28H39BNaO3Si: 485.2654, found 485.2658 [(M + Na)+]. {(1S,2SR)-2-[((3-Trifluoromethylphenyl)-1H-indol-3-yl)methyl]cyclopropyl}methanol (ent-23). ent-23 (869 mg, 2.50 mmol, 63% for 2 steps, yellow oil, diasteromixture) was prepared from ent-5 (1.60 g, 4.00 mmol) as described for the preparation of 23. LRMS (ESI) m/z 368 [(M + Na)+]; HRMS (ESI) calcd for C20H18OF3NNa: 368.1233, found 368.1240 [(M + Na)+]. {(1S,2S)-2-[(6,7-Dimethylchromon-3-yl)methyl]cyclopropyl}methanol (ent-25). ent-25 (135 mg, 0.523 mmol, 10% for 3 steps, colorless oil) was prepared from ent-5 (2.21 g, 5.50 mmol) as described for the preparation of 25. [α]D21 = +20.5 (c 0.63, CHCl3); LRMS (ESI) m/z 281 [(M + Na)+]; HRMS (ESI) calcd for C16H18O3Na: 281.1148, found 281.1147 [(M + Na)+]. {(1S,2R)-2-[2-(1-(3-Trifluoromethylphenyl)-1H-indol-3-yl)ethyl]cyclopropyl}methanol (ent-27). ent-27 (75 mg, 0.21 mmol, 60% for 3 steps, colorless oil) was prepared from ent-7 (162 mg, 0.350 mmol) as described for the preparation of 27. [α]D20 = −11.0 (c 0.20, CHCl3); LRMS (EI) m/z 359 (M+); HRMS (ESI) calcd for C21H20OF3N; 359.1497 (M+), found 359.1490. {(1S,2S)-2-[2-(6,7-Dimethylchromon-3-yl)ethenyl]cyclopropyl}methanol (ent-29). ent-29 (76 mg, 0.28 mmol, 77% for 2 steps, yellow oil, E/Z mixture) was prepared from ent-21 (169 mg, 0.365 mmol) as described for the preparation of 29. LRMS (ESI) m/z 293 [(M + Na)+]; HRMS (ESI) calcd for C17H18O3Na: 293.1151, found 293.1148 [(M + Na)+]. {(1S,2SR)-2-[((3-Trifluoromethylphenyl)-1H-indol-3-yl)methyl]cyclopropane}-1-carboaldehyde (ent-30). ent-30 (760 mg, 2.20 mmol, 88%, yellow oil, diasteromixture) was prepared from ent-23 (869 mg, 2.50 mmol) as described for the preparation of 30. LRMS (APCI) m/z 344 [(M + H)+]; HRMS (APCI) calcd for C20H17OF3N: 344.1257, found 344.1253 [(M + H)+]. {(1S,2S)-2-[((3-Trifluoromethylphenyl)-1H-indol-3-yl)methyl]cyclopropane}-1-carboxylic acid (ent-32). ent-32 (395 mg, 1.10 mmol, 50%, light yellow oil) was prepared from ent-30 (760 mg, 2.20 mmol) as described for the preparation of 32. [α]D21 = +25.4 (c 1.01, CHCl3); LRMS (APCI) m/z 360 [(M + H)+]; HRMS (APCI) calcd for C20H17O2F3N: 360.1204, found 360.1206 [(M + H)+]. Benzyl {(1S,2R)-2-[((3-trifluoromethylphenyl)-1H-indol-3-yl)methyl]cyclopropyl}carbamate (ent-34). ent-34 (363 mg, 0.780 mmol, 71%, yellow oil) was prepared from ent-32 (395 mg, 1.10 mmol) as described for the preparation of 34. [α]D21 = +3.1 (c 1.30,

evaporated to give a crude product of carboxylic acid. To a solution of the crude product in toluene (4.1 mL) were added diphenylphosphoryl azide (175 μL, 0.812 mmol) and triethylamine (113 μL, 0.812 mmol) at 0 °C, and the mixture was stirred at room temperature for 12 h, followed by at 100 °C for 12 h. To the reaction mixture was added 9-fluorenylmethanol (1.59 g, 8.12 mmol) at room temperature, and the mixture was stirred for 36 h under reflux conditions. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was partitioned between AcOEt and aqueous HCl (1 M). The organic layer was neutralized with saturated aqueous NaHCO3, washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (20−33% AcOEt in hexane) to give 36 (98 mg, 0.211 mmol, 52% for 3 steps) as a yellow oil. [α]D20 = −18.5 (c 0.63, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.46 (1 H, m), 0.97 (1 H, m), 1.05 (1 H, m), 2.37 (3 H, s), 2.39 (3 H, s), 2.54 (1 H, m), 2.64− 2.66 (2 H, m), 4.29 (1 H, m), 4.33−4.42 (2 H, m), 7.24−7.41 (6 H, m), 7.76−7.77 (3 H, m), 7.90 (1 H, s), 8.03 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 13.0, 17.0, 19.2, 20.4, 26.4, 27.4, 47.3, 66.7, 118.1, 119.8, 121.7, 123.7, 125.4, 127.0, 127.5, 134.3, 141.3, 143.9, 144.2, 144.2, 151.7, 155.2, 157.8, 178.1; LRMS (ESI) m/z 488 [(M + Na)+]; HRMS (ESI) calcd for C30H27O4NNa: 488.1832, found 488.1835 [(M + Na)+]. 6,7-Dimethyl-3-{[(1S,2R)-2-(((1-(3-trifluoromethylphenyl)-1Hindol-3-yl)methyl)amino)cyclopropyl]methyl}-4H-chromen-4-one (3). To a solution of 36 (19.7 mg, 0.0423 mmol) in MeOH/THF (3/ 1, 850 μL) were added cesium carbonate (16.5 mg, 0.0508 mmol) at room temperature, and the mixture was stirred at room temperature for 1 h. To the mixture were added THF (420 μL), acetic acid (20.6 μL, 0.360 mmol), and 3-formylindole 12 (12 mg, 0.042 mmol) at room temperature, and the mixture was stirred at room temperature for 0.5 h. To the mixture was added 2-methylpyridine borane complex (5.4 mg, 0.051 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After addition of saturated aqueous NaHCO3, the resulting mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (33−50% AcOEt in hexane) to give 3 (7.3 mg, 0.014 mmol, 33% for 2 steps) as a yellow oil. [α]D23 = +4.6 (c 0.33, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.28 (1 H, m), 0.76 (1 H, m), 1.14 (1 H, m), 2.34 (3 H, s), 2.37 (3 H, s), 2.41 (1 H, m), 2.60 (1 H, dd, J = 7.5, 15.5 Hz), 2.89 (1 H, dd, J = 7.0, 15.5 Hz), 4.08 (1 H, d, J = 14 Hz), 4.12 (1 H, d, J = 14 Hz), 7.18−7.28 (3 H, m), 7.33 (1 H, s), 7.53 (1 H, d, J = 8.0 Hz), 7.59 (1 H, d, J = 7.5 Hz), 7.64 (1 H, t, J = 8.0 Hz), 7.71 (1 H, d, J = 8.0 Hz), 7.75−7.77 (2 H, m), 7.83 (1 H, s), 7.96 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 12.1, 16.7, 19.3, 20.4, 23.7, 35.1, 44.8, 110.2, 118.0, 119.7, 120.7, 120.8 (q, JC−F = 3.5 Hz), 121.8, 122.7 (q, JC−F = 4.1 Hz), 123.1, 123.7 (q, JC−F = 271 Hz), 124.7, 125.4, 125.7, 127.1, 128.9, 130.3, 132.2 (q, JC−F = 32.8 Hz), 134.0, 136.0, 140.3, 143.6, 151.8, 155.1, 178.1; LRMS (ESI) m/z 517 [(M + H)+]; HRMS (ESI) calcd for C31H28O2F3N2: 517.2097, found 517.2096 [(M + H)+]. (9H-Fluoren-9-yl)methyl {(1R,2S)-2-[2-(6,7-dimethylchromon-3yl)ethyl]cyclopropyl}carbamate (37). To a solution of 29 (61 mg, 0.22 mmol) in AcOEt (2.2 mL) was added 10% palladium on carbon (18 mg) at room temperature, and the mixture was stirred at 0 °C for 1 h under an H2 atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated to give a crude residue (58 mg). 37 (27 mg, 0.056 mmol, 25% for 4 steps, yellow oil) was prepared from the crude residue (58 mg) as described for the preparation of 36. [α]D23 = −13.0 (c 0.78, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.27 (1 H, m), 0.92−1.01 (2 H, m), 1.54 (1 H, m), 1.80 (1 H, m), 2.30 (3 H, s), 2.37 (3 H, s), 2.49 (1 H, m), 2.65 (1 H, m), 2.76 (1 H, m), 4.27 (1 H, t, J = 7.5 Hz), 4.39 (2 H, d, J = 7.5 Hz), 6.26 (1 H, br), 7.21 (1 H, s), 7.26−7.31 (2 H, m), 7.36−7.39 (2 H, m), 7.75−7.79 (5 H, m), 8.01 (1 H, s); 13C NMR (125 MHz, CDCl3) δ 12.8, 17.4, 19.3, 20.4, 24.4, 27.4, 29.7, 47.2, 66.7, 118.0, 119.8, 121.5, 123.6, 125.4, 127.0, 127.5, 134.4, 141.2, 144.1, 144.2, 153.0, 155.1, 157.9, 178.5; LRMS (ESI) m/z 502 [(M + Na)+]; HRMS 7680

DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

Article

The Journal of Organic Chemistry CHCl3); LRMS (APCI) m/z 465 [(M + H)+]; HRMS (APCI) calcd for C27H24O2F3N2: 465.1784, found 465.1777 [(M + H)+]. 6,7-Dimethyl-3-{[(1S,2R)-2-((1-(3-trifluoromethylphenyl)-1Hindol-3-yl)methyl)cyclopropylamino]methyl}-4H-chromen-4-one (ent-1). ent-1 (36 mg, 0.069 mmol, 22%, yellow oil) was prepared from ent-34 (147 mg, 0.316 mmol) as described for the preparation of 1. [α]D21 = +5.2 (c 1.20, CHCl3); LRMS (ESI) m/z 517 [(M + H)+]; HRMS (ESI) calcd for C31H28O2F3N2: 517.2097, found 517.2089 [(M + H)+]. {(1S,2R)-2-[2-((3-Trifluoromethylphenyl)-1H-indol-3-yl)ethyl]cyclopropane}-1-carboxylic acid (ent-33). ent-33 (33 mg, 0.089 mmol, 56% for 2 steps, light yellow oil) was prepared from ent-27 (56 mg, 0.16 mmol) via ent-31 as described for the preparation of 30 and 32. [α]D21 = +21.4 (c 0.88, CHCl3); LRMS (ESI) m/z 372 [(M − H)−]; HRMS (ESI) calcd for C21H17O2F3N: 372.1217 [(M − H)−], found 372.1218. Benzyl {(1S,2R)-2-[2-((3-trifluoromethylphenyl)-1H-indol-3-yl)ethyl]cyclopropyl}carbamate (ent-35). ent-35 (34 mg, 0.070 mmol, 80%, yellow oil) was prepared from ent-33 (33 mg, 0.088 mmol) as described for the preparation of 35. [α]D24 = −3.7 (c 1.20, CHCl3); LRMS (ESI) m/z 501 [(M + Na)+]; HRMS (ESI) calcd for C28H25O2F3N2Na: 501.1760 [(M + H)+], found 501.1756. 6,7-Dimethyl-3-{[(1S,2R)-2-(2-(1-(3-trifluoromethylphenyl)-1Hindol-3-yl)ethyl)cyclopropylamino]methyl}-4H-chromen-4-one (ent-2). ent-2 (7.2 mg, 0.014 mmol, 21% for 2 steps, light yellow oil) was prepared from ent-35 (33 mg, 0.068 mmol) as described for the preparation of 1. [α]D21 = −1.1 (c 1.00, CHCl3); LRMS (ESI) m/z 531 [(M + H)+]; HRMS (ESI) calcd for C32H30O2F3N2: 531.2254, found 531.2248 [(M + H)+]. (9H-Fluoren-9-yl)methyl {(1S,2R)-2-[(6,7-dimethylchromon-3-yl)methyl]cyclopropyl}carbamate (ent-36). ent-36 (80 mg, 0.17 mmol, 48% for 3 steps, yellow oil) was prepared from ent-25 (92 mg, 0.36 mmol) as described for the preparation of 36. [α]D22 = +37.1 (c 1.02, CHCl3); LRMS (ESI) m/z 488 [(M + Na)+]; HRMS (ESI) calcd for C30H27O4NNa: 488.1832, found 488.1827 [(M + Na)+]. 6,7-Dimethyl-3-{[(1R,2S)-2-(((1-(3-trifluoromethylphenyl)-1Hindol-3-yl)methyl)amino)cyclopropyl]methyl}-4H-chromen-4-one (ent-3). ent-3 (28 mg, 0.054 mmol, 39% for 2 steps, yellow oil) was prepared from ent-36 (67 mg, 0.14 mmol) as described for the preparation of 3. [α]D22 = −10.5 (c 0.15, CHCl3); LRMS (ESI) m/z 517 [(M + H)+]; HRMS (ESI) calcd for C31H28O2F3N2: 517.2097, found 517.2091 [(M + H)+]. (9H-Fluoren-9-yl)methyl {(1S,2R)-2-[2-(6,7-dimethylchromon-3yl)ethyl]cyclopropyl}carbamate (ent-37). ent-37 (32 mg, 0.068 mmol, 24% for 4 steps, yellow oil) was prepared from ent-29 (76 mg, 0.28 mmol) as described for the preparation of 37. [α]D21 = +8.1 (c 1.10, CHCl3); LRMS (ESI) m/z 502 [(M + Na)+]; HRMS (ESI) calcd for C31H29O4NNa: 502.1989, found 502.1991 [(M + H)+]. 6,7-Dimethyl-3-{2-[(1R,2S)-2-(((1-(3-trifluoromethylphenyl)-1Hindol-3-yl)methyl)amino)cyclopropyl]ethyl}-4H-chromen-4-one (ent-4). ent-4 (13 mg, 0.024 mmol, 35% for 2 steps, yellow oil) was prepared from ent-37 (32 mg, 0.068 mmol) as described for the preparation of 4. [α]D21 = −7.9 (c 0.36, CHCl3); LRMS (ESI) m/z 531 [(M + H)+]; HRMS (ESI) calcd for C32H30O2F3N2: 531.2254, found 531.2255 [(M + H)+].

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ORCID

Mizuki Watanabe: 0000-0001-7209-5713 Satoshi Shuto: 0000-0001-7850-8064 Present Addresses †

Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. ‡ Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by MEXT/JSPS KAKENHI Grant Numbers JP2310550201, JP20890002, JP21390028, and a research grant from Takeda Science Foundation (MW). We are grateful to Sanyo Fine Co., Ltd. for the gift of the chiral epichlorohydrins. We are also grateful to Sumitomo Dainippon Pharma Co., Ltd. for the gift of rhTNFα.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00466.

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REFERENCES

Determination of the configuration of 32, the protocol and results of the inhibitory activity tests, and copies of HPLC chart and NMR spectra (PDF)

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*E-mail: [email protected]. *E-mail: [email protected]. 7681

DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682

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DOI: 10.1021/acs.joc.8b00466 J. Org. Chem. 2018, 83, 7672−7682