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Mar 6, 2018 - ABSTRACT: The synthesis and antidiabetic evaluation of ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate. (TMPA) and its structural...
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Article Cite This: ACS Omega 2018, 3, 2661−2672

Synthesis of TMPA Derivatives through Sequential Ir(III)-Catalyzed C−H Alkylation and Their Antidiabetic Evaluation Suk Hun Lee,†,∥ Amit Kundu,†,∥ Sang Hoon Han,† Neeraj Kumar Mishra,† Kyeong Seok Kim,† Myung Hoon Choi,‡ Ashok Kumar Pandey,† Jung Su Park,*,§ Hyung Sik Kim,*,† and In Su Kim*,† †

School of Pharmacy, Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon 16419, Republic of Korea College of Pharmacy, Catholic University of Daegu, Hayang-ro, Hayang-eup, Gyeongsan 38430, Republic of Korea § Department of Chemistry, Sookmyung Women’s University, Cheongpa-ro, Yongsan-gu, Seoul 04310, Republic of Korea ‡

S Supporting Information *

ABSTRACT: The synthesis and antidiabetic evaluation of ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA) and its structural analogs are described. The construction of TMPA derivatives has been successfully achieved in only two steps, which involve the iridium(III)catalyzed α-alkylation of acetophenones with alcohols and the ketone-directed iridium(III)- or rhodium(III)-catalyzed redoxneutral C−H alkylation of α-alkylated acetophenones using Meldrum’s diazo compounds. This synthetic protocol efficiently provides a range of TMPA derivatives with site selectivity and functional group compatibility. In addition, the site-selective demethylation of TMPA derivative affords the naturally occurring phomopsin C in good yield. Moreover, all synthetic compounds were screened for in vitro adenosine 5′-monophosphateactivated protein kinase (AMPK) activation using HepG2 cells. Furthermore, TMPA (5ac) and 5cd showing the most potent AMPK activation were treated for the in vivo antidiabetic experiment. Notably, our synthetic compound 5cd was found to display the powerful antidiabetic effect, stronger than that of metformin and TMPA (5ac).

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INTRODUCTION

Additionally, unnatural ethyl 2-[2,3,4-trimethoxy-6-(1octanoyl)phenyl]acetate (TMPA) was also found to enhance the AMPK phosphorylation through blocking the Nur77− LKB1 interaction.6 Despite the potent antidiabetic activity and relatively simple structure of TMPA, two synthetic strategies have been reported for the preparation of TMPA.6 In 2012, Wu reported the multistep synthesis of TMPA in the longest linear 7 steps including Friedel−Craft intramolecular acylation, OsO4-mediated dihydroxylation, and Pinnick oxidation.6a Very recently, Seo demonstrated the short synthesis of TMPA based on the Lewis acid-mediated Friedel−Craft alkylation with ethyl chloro(methylthio)acetate followed by reductive desulfurization.6b Recently, the catalytic C−H functionalization has been recognized as a mild and economical route for the synthesis of biologically relevant organic molecules.7 Because of the pioneering work on the catalytic carbenoid insertion reaction toward the C−H functionalization reported by Yu,8 the directing group-assisted C(sp2)−H functionalization using diazo compounds has been intensively studied for C−H alkylation and heterocycle formation.9 Particularly, Meldrum’s diazo compounds were also utilized as a new class of α-diazo

Antidiabetic medication has revolutionized the treatment of metabolic disorders derived from high blood sugar level.1 For example, the use of antidiabetics such as glucagon-like peptide agonists, KATP channel inhibitors, adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling activators, αglucosidase inhibitors, and PPAR-γ inhibitors has received considerable attention as potential medicinal agents.2 In particular, metformin has become the most frequently prescribed agent for the treatment of decreasing insulin resistance via AMPK signaling enhancement.3 In 2000, natural octaketide metabolites, cytosporones A and B, were isolated from the broth of two endophytic fungi, Cytospora sp. CR200 and Diaporthe sp. CR146 (Figure 1).4 Notably, cytosporone B has been demonstrated to directly interact with ligand-binding domain of nuclear orphan receptor 77 (Nur77), which can stimulate the control of LKB1-mediated AMPK activation.5

Received: January 29, 2018 Accepted: February 22, 2018 Published: March 6, 2018

Figure 1. Structure of antidiabetic octaketide metabolites. © 2018 American Chemical Society

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temperature is highly important for the alkylation reaction to furnish 5aa in high yield (Table 1, entries 16 and 17). Finally, this reaction provided no formation of our desired product 5aa in the EtOH solvent (Table 1, entry 18). With the optimal reaction condition in hand, a variety of αalkylated acetophenones 3ab−3ed were coupled with Meldrum’s diazo ester 4a (Scheme 2). To our pleasure, ketides 3ab−3ad were found to display good reactivity, furnishing the ortho-alkylated TMPA derivatives 5ab−5ad. Notably, TMPA (5ac) was prepared from 1a in two steps in the overall 31% yield via the Ir(III)-catalyzed C(sp3)−H alkylation of 1a with primary alcohol 2c followed by subsequent Ir(III)-catalyzed ortho-C(sp2)−H alkylation using Meldrum’s diazo ester. However, in case of ortho-substituted acetophenone 3ba, the significantly decreased formation of our desired product 5ba was observed. Additionally, 2,4-dimethoxy-substituted acetophenone 3ca did not provide any coupling product under the current reaction conditions. Thus, we further screened the reaction conditions to achieve the site-selective alkylation between 3ba and 4a. Surprisingly, a cationic Rh(III) catalyst under the otherwise identical reaction conditions was found to be more effective to deliver our desired product 5ba in good yield (86%). The modified reaction conditions can be applied to ortho-substituted acetophenones 3bb−3bd and 3ca−3cd to generate the corresponding products in moderate to good yields. In addition, para-methoxy-substituted acetophenones 3da−3dd were found to be coupled with 4a under Ir(III) catalysis to provide the desired products 5da−5dd in moderate yields. Furthermore, meta-methoxy-substituted acetophenones 3ea−3ed afforded a mixture of regioisomers 5ea−5ed and 5ea′−5ed′ at the C-6 and C-2 positions with ab. 1:2 ratio. These results that suggest the formation of the cyclorhodated intermediate might be mainly dominated by the electronic effect instead of the steric effect. After successfully screening the substrate scope of α-alkylated acetophenones with Meldrum’s diazo ester, we envisioned that alcohols can be also used for the derivatization of ester moiety on TMPA. With this hypothesis, we performed the reaction of TMPA precursor 3ac with Meldrum’s diazo ester 4a in the presence of MeOH under the otherwise identical reaction conditions to give the methyl ester 6aa formed in 39% yield (Scheme 3). This protocol can be successfully applied to other alcohols to afford the corresponding ester derivatives 6ab−6ad in 56−65% yields. To demonstrate the utility of synthesized orthoalkylated acetophenones, we first performed the site-selective demethylation of 5cc using BBr3 (4 equiv) in CH2Cl2 at 0 °C, leading to access the phomopsin C (7a) in 76% yield, which was isolated from the mangrove endophytic fungus, Phomopsis sp. ZSU-H76 (Scheme 4).13 In the meanwhile, basic hydrolysis of ester moiety on 5cc was attempted to afford carboxylic acid 7b in high yield. Additionally, we also performed the construction of 3-isochromanone 7c, which is known to be a crucial synthetic intermediate in organic synthesis, via reduction of ketone using NaBH4, followed by subsequent intramolecular cyclization. To recognize the formation of ortho-substituted acetophenone using Meldrum’s diazo ester, the mechanistic investigations were subjected, as shown in Scheme 5. First, the treatment of 3ab with 4a in the absence of EtOH provided the C−H alkylated compound 8ab in 68% yield, which was further transformed into 5ab (88%) in EtOH solvent at 60 °C.14 These results support that compound 8ab is a crucial intermediate in this process.

agents to afford the corresponding alkylated and/or cyclized adducts.10 In continuation of our recent studies on the biologically active compounds based on catalytic C−H functionalization,11 we herein disclose the iridium(III)catalyzed α-alkylation of acetophenones with alcohols followed by the ketone-directed Ir(III)- and Rh(III)-catalyzed ortho-C− H alkylation of acetophenones with Meldrum’s diazo esters. As a result, this protocol may be beneficial to guide the design of a variety of antidiabetic TMPA derivatives and represents a catalytic alternative to transcend the barriers imposed by a previous multistep synthetic approach.

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RESULTS AND DISCUSSION The synthesis of TMPA derivatives was initiated by the formation of α-alkylated acetophenones. Acetophenone 1a was first coupled with primary alcohols 2a−2d to provide the αalkylated acetophenones 3aa−3ad in moderate yields under Ir(III) catalysis (Scheme 1).12 Moreover, this method has been Scheme 1. Synthesis of α-Alkylated Acetophenones

further applied to a range of acetophenones 1b−1e containing methoxy groups at the ortho-, meta-, and para-positions, furnishing the corresponding products (3ba−3bd, 3ca−3cd, 3da−3dd, and 3ea−3ed) in moderate to high yields. Meanwhile, the ketone-directed iridium(III)-catalyzed orthoalkylation of acetophenone 3aa with Meldrum’s diazo ester 4a as a model substrate was performed, as shown in Table 1. No coupling reaction between 3aa and 4a under cationic Ir(III) catalysis in the presence of EtOH solvent was observed (Table 1, entry 1). Interestingly, when EtOH was subjected as an additive in DCE solvent, our desired orthoalkylated product 5aa was obtained in 22% yield (Table 1, entry 2). To our delight, the treatment of NaOAc as an acetate source was found to be more effective in this transformation (Table 1, entry 3). Notably, AgOAc additive was found to be very crucial for the high level of conversion in this reaction to afford our desired product 5aa in 71% yield (Table 1, entries 4−7). In addition, AgSbF6 and AgPF6 as counter anions were found to be less effective (Table 1, entries 8 and 9). Moreover, other cationic transition-metal catalysts such as Rh(III), Co(III), and Ru(II) were found to be ineffective in this coupling reaction (Table 1, entries 10−12). Solvent screening revealed that DCE is superior to other solvents such as THF, MeCN, and toluene (Table 1, entries 13−15). It should be noted that the reaction 2662

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entry

catalyst (mol %)

additive (mol %)

solvent

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c 17d 18

[IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [RhCp*Cl2]2 (2) [CoCp*(CO)I2] (5) [Ru(p-cymene)Cl2]2 (5) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2) [IrCp*Cl2]2 (2)

AgNTf2 (8) AgNTf2 (8), EtOH (2 equiv) AgNTf2 (8), NaOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), CsOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), LiOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), Cu(OAc)2 (8 mol %), EtOH (2 equiv) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv) AgSbF6 (8), AgOAc (8 mol %), EtOH (2 equiv) AgPF6 (8), AgOAc (8 mol %), EtOH (2 equiv) AgSbF6 (8), AgOAc (8 mol %), EtOH (2 equiv) AgNTf2 (10), AgOAc (8 mol %), EtOH (2 equiv) AgNTf2 (10), AgOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), AgOAc (8 mol %), EtOH (2 equiv) AgNTf2 (8), AgOAc (8 mol %)

EtOH DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE THF MeCN toluene DCE DCE EtOH

N.R. 22 42 59 N.R. 64 71 62 43 8 N.R. N.R. trace N.R. trace 53 N.R. N.R.

Reaction conditions: 3aa (0.2 mmol), 4a (0.24 mmol), catalyst (quantity noted), additive (quantity noted), and solvent (1 mL) under air at 60 °C for 20 h in pressure tubes. bIsolated yield by flash column chromatography. cThe reaction was carried out at 100 °C. dThe reaction was carried out at room temperature. a

Scheme 2. Synthesis of TMPA Derivatives

Scheme 4. Transformations of TMPA Derivative 5cc

Scheme 5. Mechanistic Investigation via the Isolation of Intermediate 8ab

Scheme 3. Derivatization of Ester Moiety on TMPA C−H alkylations using Meldrum’s diazo esters,9f,10b a plausible reaction mechanism is outlined in Scheme 6. Initially, acetophenones 3 can undergo C−H activation with a cationic Ir(III) or Rh(III) species to generate a metallacycle intermediate A. Subsequently, the coordination of Meldrum’s diazo ester 4a followed by the release of N2 gas affords a metal−carbenoid intermediate B. Migratory insertion can deliver a 6-membered metallacycle species C, which takes place at the protonation process to deliver the C−H alkylated

On the basis of the above mechanistic investigations and preceding literature studies on the Ir(III)- or Rh(III)-catalyzed 2663

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represented as the relative percent value, as shown in Figure 2. A well-known AMPK activator metformin was selected as a positive control. A range of compounds (5ac, 5bd, 5cd, 5dd, 6ac, and 6ad) exhibited comparable activity with metformin. In particular, TMPA (5ac) and 5cd were found to display the most potent AMPK activation, stronger than that of a positive control. Notably, compound 5cd was found to be a novel AMPK activator. The structure−activity relationship (SAR) between 5bd, 5cd, and 5dd indicates that the length of α-alkyl chain on acetophenone, and the position of aromatic OMesubstituents play an important role for the activation of AMPK. In addition, the ethyl carboxylate functionality on TMPA (5ac) is found to be very crucial for AMPK activation, which was observed by the comparison with compounds 6aa−6ad. On the basis of in vitro assay results on AMPK activation, we further performed in vivo antidiabetic evaluation of TMPA (5ac) and 5cd using streptozotocin (STZ)-induced diabetic animal models (Figure 3). Interestingly, TMPA (5ac) was

Scheme 6. Proposed Reaction Mechanism

compound 8 and an active catalyst. Finally, transesterification of 8 with EtOH provides our desired product 5. AMPK has been known as a major cellular regulator of glucose and lipid metabolism in eukaryotes, and AMPK can be automatically activated when intracellular ATP levels are lower.15 The effect of AMPK activation is related to the enhancement of insulin sensitivity through the increase of glucose uptake and lipid oxidation in skeletal muscle as well as inhibition of the formation of glucose and lipid in the liver.16 Therefore, AMPK is a key molecule in controlling metabolic diseases such as type 2 diabetes mellitus, obesity, and cancer. On the basis of the previously reported data on the indirect AMPK activation of cytosporones and TMPA,5,6 we have first evaluated the in vitro AMPK activation against our synthetic TMPA derivatives. In this experiment, HepG2 cells were treated with the synthesized compounds and the phosphorylated AMPK (p-AMPK) expression level was determined by the western blotting analysis. The potency of compounds on AMPK activation was compared with a vehicle control and

Figure 3. Antidiabetic evaluation of 5ac and 5cd using type 2 diabetesinduced animal models.

found to gradually reduce the blood glucose level, which showed a comparable effect with metformin. Moreover, our

Figure 2. Effect of synthetic compounds on AMPK activation in HepG2 cells. The bars represent the percentage of relative densitometric values compared with the vehicle control. 2664

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132.4, 105.5, 60.9, 56.3, 38.3, 31.7, 29.3, 29.1, 24.5, 22.6, 14.0; IR (KBr) ν: 2926, 2854, 1678, 1583, 1504, 1455, 1411, 1322, 1230, 1156, 1123, 1004, 859, 823 cm−1; HRMS (quadrupole, EI): calcd for C17H26O4 [M]+, 294.1831; found, 294.1833. 1-(3,4,5-Trimethoxyphenyl)nonan-1-one (3ad). 0.77 g (50%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 1.74−1.69 (m, 2H), 1.38−1.27 (m, 10H), 0.88 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.3, 153.0, 142.4, 132.4, 105.5, 60.9, 56.3, 38.4, 31.8, 29.4, 29.1, 24.5, 22.6, 14.1; IR (KBr) ν: 2925, 2853, 1679, 1583, 1504, 1455, 1411, 1322, 1230, 1155, 1124, 1004, 854, 829 cm−1; HRMS (quadrupole, EI): calcd for C18H28O4 [M]+, 308.1988; found, 308.1987. 1-(2-Methoxyphenyl)hexan-1-one (3ba). 0.54 g (52%); light brown oil; 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.95 (t, J = 7.2 Hz, 2H), 1.69−1.63 (m, 2H), 1.36−1.30 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.3, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.7, 31.6, 24.1, 22.5, 14.0; IR (KBr) ν: 2955, 2929, 2860, 1673, 1597, 1485, 1464, 1436, 1282, 1243, 1180, 1162, 1023, 754 cm−1; HRMS (quadrupole, EI): calcd for C13H18O2 [M]+, 206.1307; found, 206.1305. 1-(2-Methoxyphenyl)heptan-1-one (3bb). 0.72 g (65%); light brown oil; 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J = 7.6, 1.6 Hz, 1H), 7.45−7.41 (m, 1H), 6.99 (td, J = 8.4, 1.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.95 (t, J = 7.2 Hz, 2H), 1.70−1.62 (m, 2H), 1.37−1.27 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.4, 158.3, 133.0, 130.1, 128.9, 120.6, 111.4, 55.4, 43.8, 31.7, 29.1, 24.4, 22.5, 14.0; IR (KBr) ν: 2954, 2927, 2857, 1472, 1597, 1484, 1464, 1436, 1284, 1241, 1180, 1162, 1023, 753 cm−1; HRMS (quadrupole, EI): calcd for C14H20O2 [M]+, 220.1463; found, 220.1464. 1-(2-Methoxyphenyl)octan-1-one (3bc). 0.66 g (56%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.62 (dd, J = 7.6, 2.0 Hz, 1H), 7.45−7.41 (m, 1H), 6.98 (td, J = 8.4, 1.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.94 (t, J = 7.6 Hz, 2H), 1.70−1.62 (m, 2H), 1.35−1.26 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.4, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.7, 31.7, 29.3, 29.1, 24.4, 22.6, 14.0; IR (KBr) ν: 2953, 2925, 2854, 1673, 1597, 1484, 1464, 1436, 1283, 1242, 1179, 1161, 1024, 753 cm−1; HRMS (quadrupole, EI): calcd for C15H22O2 [M]+, 234.1620; found, 234.1621. 1-(2-Methoxyphenyl)nonan-1-one (3bd). 0.62 g (50%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J = 8.0, 2.0 Hz, 1H), 7.45−7.41 (m, 1H), 6.99 (td, J = 8.4, 1.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 1.70−1.62 (m, 2H), 1.35−1.26 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.4, 158.2, 133.0, 130.1, 128.8, 120.6, 111.4, 55.4, 43.8, 31.8, 29.5, 29.4, 29.2, 24.4, 22.6, 14.1; IR (KBr) ν: 2924, 2853, 1673, 1597, 1484, 1464, 1436, 1283, 1242, 1180, 1162, 1024, 753 cm−1; HRMS (quadrupole, EI): calcd for C16H24O2 [M]+, 248.1776; found, 248.1773. 1-(2,4-Dimethoxyphenyl)hexan-1-one (3ca). 0.58 g (49%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.8, 2.0 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H), 1.69− 1.62 (m, 2H), 1.36−1.30 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 201.0, 164.1, 160.5, 132.6, 121.5, 104.9, 98.4, 55.5, 55.4, 43.6, 31.7, 24.3, 22.5, 14.0;

synthetic derivative 5cd exhibited the most potent antidiabetic effect, which is about 13% stronger than that of metformin.

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CONCLUSIONS In conclusion, we described the efficient synthesis of TMPA derivatives via the iridium(III)-catalyzed α-alkylation of acetophenones with alcohols and the ketone-directed iridium(III)- or rhodium(III)-catalyzed redox-neutral C−H alkylation of acetophenones using Meldrum’s diazo compounds. This transformation efficiently provides an array of orthoalkylated acetophenones with site selectivity and functional group compatibility. In addition, all synthetic compounds were evaluated for in vitro AMPK activation using HepG2 cells. Notably, a novel synthetic compound 5cd was found to exhibit the stronger AMPK activation effect than metformin. The SAR indicates that the length of α-alkyl chain on acetophenone and the position of aromatic OMe substituents play an important role for the AMPK activation and antidiabetic effect. Furthermore, selected compounds TMPA (5ac) and 5cd showing the most potent AMPK activation were subjected for the in vivo antidiabetic experiment. Interestingly, our synthetic derivative 5cd exhibited the most potent antidiabetic effect, which is about 13% stronger than metformin.

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EXPERIMENTAL SECTION General Procedure for the Synthesis of α-Alkylated Acetophenones (3aa−3ed). To an oven-dried sealed tube charged with 1-(3,4,5-trimethoxyphenyl)ethan-1-one (1a) (1.1 g, 5 mmol, 100 mol %), [IrCp*Cl2]2 (39.8 mg, 0.05 mmol, 1 mol %), and NaOH pellets (0.2 g, 5 mmol, 100 mol %) were added n-butyl alcohol (2a) (0.41 g, 5.5 mmol, 110 mol %) and toluene (0.5 mL) under air at room temperature. The reaction mixture was allowed to stir for 17 h at 110 °C. The reaction mixture was cooled to room temperature and extracted with EtOAc (2 × 15 mL). The organic layer was washed with brine solution (2 × 60 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 20:1) to afford 3aa (0.67 g, 50%) as a yellowish oil. 1-(3,4,5-Trimethoxyphenyl)hexan-1-one (3aa). 0.67 g (50%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 1.76−1.70 (m, 2H), 1.38−1.34 (m, 4H), 0.91 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.3, 153.0, 142.4, 132.4, 105.6, 60.9, 56.3, 38.3, 31.5, 24.2, 22.5, 13.9; IR (KBr) ν: 2933, 2871, 1679, 1583, 1504, 1455, 1411, 1329, 1230, 1158, 1123, 1003, 865, 824 cm−1; HRMS (quadrupole, EI): calcd for C15H22O4 [M]+, 266.1518; found, 266.1516. 1-(3,4,5-Trimethoxyphenyl)heptan-1-one (3ab). 0.69 g (49%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.21 2 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 1.76−1.69 (m, 2H), 1.40−1.30 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.3, 153.0, 142.4, 132.4, 105.5, 60.9, 56.3, 38.4, 31.6, 29.0, 24.5, 22.5, 14.0; IR (KBr) ν: 2931, 2587, 1679, 1583, 1504, 1455, 1411, 1321, 1229, 1156, 1123, 1003, 854, 831 cm−1; HRMS (quadrupole, EI): calcd for C16H24O4 [M]+, 280.1675; found, 280.1678. 1-(3,4,5-Trimethoxyphenyl)octan-1-one (3ac). 0.76 g (52%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.21 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.92 (t, J = 7.2 Hz, 2H), 1.76−1.69 (m, 2H), 1.37−1.27 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.3, 153.0, 142.4, 2665

DOI: 10.1021/acsomega.8b00179 ACS Omega 2018, 3, 2661−2672

Article

ACS Omega IR (KBr) ν: 2954, 2931, 2859, 1662, 1598, 1573, 1463, 1416, 1253, 1210, 1161, 1130, 1103, 1027, 826 cm−1; HRMS (quadrupole, EI): calcd for C14H20O3 [M]+, 236.1412; found, 236.1413. 1-(2,4-Dimethoxyphenyl)heptan-1-one (3cb). 0.71 g (57%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.0 Hz, 1H), 6.51 (dd, J = 8.0, 4.0 Hz, 1H), 6.44 (d, J = 4.0 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.91 (t, J = 8.0 Hz, 2H), 1.68−1.61 (m, 2H), 1.37−1.30 (m, 6H), 0.88 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.3, 55.5, 55.4, 43.6, 31.7, 29.2, 24.6, 22.5, 14.0; IR (KBr) ν: 2953, 2926, 2855, 1662, 1598, 1574, 1463, 1416, 1253, 1209, 1161, 1130, 1027, 834 cm−1; HRMS (quadrupole, EI): calcd for C15H22O3 [M]+, 250.1569; found, 250.1568. 1-(2,4-Dimethoxyphenyl)octan-1-one (3cc). 0.71 g (54%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.4, 2.0 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t, J = 7.2 Hz, 2H), 1.68− 1.61 (m, 2H), 1.33−1.26 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.4, 55.5, 55.4, 43.6, 31.7, 29.4, 29.2, 24.6, 22.6, 14.1; IR (KBr) ν: 2925, 2854, 1663, 1598, 1574, 1463, 1416, 1254, 1209, 1161, 1130, 1027, 834 cm−1; HRMS (quadrupole, EI): calcd for C16H24O3 [M]+, 264.1725; found, 264.1725. 1-(2,4-Dimethoxyphenyl)nonan-1-one (3cd). 0.74 g (53%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.0 Hz, 1H), 6.51 (dd, J = 8.8, 1.6 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H), 1.68−1.61 (m, 2H), 1.34−1.26 (m, 10H), 0.87 (t, J = 6.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 201.0, 164.1, 160.5, 132.5, 121.5, 104.9, 98.3, 55.5, 55.4, 43.6, 31.8, 29.5, 29.2, 24.6, 22.6, 14.1; IR (KBr) ν: 2924, 2853, 1663, 1598, 1574, 1463, 1416, 1254, 1209, 1161, 1028, 834 cm−1; HRMS (quadrupole, EI): calcd for C17H26O3 [M]+, 278.1882; found, 278.1881. 1-(4-Methoxyphenyl)hexan-1-one (3da). 0.57 g (55%); white solid; mp = 42.4−44.1 °C; 1H NMR (400 MHz, CDCl3): δ 7.95−7.92 (m, 2H), 6.94−6.91 (m, 2H), 3.86 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 1.76−1.68 (m, 2H), 1.37−1.33 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.2, 163.3, 130.3, 130.2, 113.6, 55.4, 38.3, 31.6, 24.3, 22.5, 13.9; IR (KBr) ν: 2955, 2931, 2860, 1674, 1597, 1509, 1461, 1417, 1308, 1252, 1168, 1030, 828 cm−1; HRMS (quadrupole, EI): calcd for C13H18O2 [M]+, 206.1307; found, 206.1305. 1-(4-Methoxyphenyl)heptan-1-one (3db). 0.90 g (82%); white solid; mp = 44.2−46.7 °C; 1H NMR (400 MHz, CDCl3): δ 7.96−7.92 (m, 2H), 6.95−6.90 (m, 2H), 3.86 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 1.75−1.67 (m, 2H), 1.40−1.29 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.2, 163.3, 130.3, 130.2, 113.6, 55.4, 38.3, 31.6, 29.1, 24.6, 22.5, 14.0; IR (KBr) ν: 2954, 2929, 2856, 1675, 1597, 1509, 1460, 1417, 1308, 1255, 1467, 1029, 835 cm−1; HRMS (quadrupole, EI): calcd for C14H20O2 [M]+, 220.1463; found, 220.1460. 1-(4-Methoxyphenyl)octan-1-one (3dc). 0.99 g (84%); white solid; mp = 53.2−55.9 °C; 1H NMR (400 MHz, CDCl3): δ 7.94 (dt, J = 10.0, 3.2 Hz, 2H), 6.92 (dt, J = 9.6, 2.8 Hz, 2H), 3.86 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 1.75−1.68 (m, 2H), 1.37−1.27 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.2, 163.2, 130.3, 130.2, 113.6, 55.4, 38.3, 31.7, 29.4, 29.1, 24.6, 22.6, 14.0; IR (KBr) ν: 2954,

2925, 2854, 1675, 1599, 1509, 1462, 1417, 1308, 1255, 1168, 1030, 829 cm−1; HRMS (quadrupole, EI): calcd for C15H22O2 [M]+, 234.1620; found, 234.1618. 1-(4-Methoxyphenyl)nonan-1-one (3dd). 0.96 g (77%); white solid; mp 53.8−55.2 °C; 1H NMR (400 MHz, CDCl3): δ 7.93 (dt, J = 9.6, 2.8 Hz, 2H), 6.92 (dt, J = 9.6, 2.8 Hz, 2H), 3.86 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H), 1.75−1.67 (m, 2H), 1.38−1.25 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 199.2, 163.2, 130.3, 130.2, 113.6, 55.4, 38.3, 31.8, 29.4, 29.1, 24.6, 22.6, 14.1; IR (KBr) ν: 2954, 2924, 2853, 1676, 1599, 1509, 1463, 1417, 1307, 1254, 1168, 1031, 833 cm−1; HRMS (quadrupole, EI): calcd for C16H24O2 [M]+, 248.1776; found, 248.1776. 1-(3-Methoxyphenyl)hexan-1-one (3ea). 0.61 g (59%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.0, 2.4 Hz, 1H), 3.85 (s, 3H), 2.94 (t, J = 7.6 Hz, 2H), 1.77− 1.70 (m, 2H), 1.37−1.34 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 200.5, 159.9, 138.6, 129.6, 120.8, 119.4, 112.4, 55.5, 38.8, 31.6, 24.2, 22.6, 14.1; IR (KBr) ν: 2955, 2930, 2860, 1683, 1597, 1582, 1485, 1463, 1428, 1287, 1266, 1169, 1040, 784 cm−1; HRMS (quadrupole, EI): calcd for C13H18O2 [M]+, 206.1307; found, 206.1308. 1-(3-Methoxyphenyl)heptan-1-one (3eb). 0.63 g (57%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.53 (dt, J = 7.6, 1.6 Hz, 1H), 7.49−7.48 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.09 (ddd, J = 8.4, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 1.76−1.68 (m, 2H), 1.41−1.29 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.6, 29.0, 24.4, 22.5, 14.0; IR (KBr) ν: 2954, 2928, 2857, 1684, 1597, 1582, 1486, 1463, 1428, 1254, 1167, 1044, 783 cm−1; HRMS (quadrupole, EI): calcd for C14H20O2 [M]+, 220.1463; found, 220.1460. 1-(3-Methoxyphenyl)octan-1-one (3ec). 0.65 g (55%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.54 (dt, J = 7.6, 1.2 Hz, 1H), 7.49−7.48 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.10 (ddd, J = 8.0, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 1.76−1.69 (m, 2H), 1.39−1.27 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.6, 29.3, 29.1, 24.4, 22.6, 14.1; IR (KBr) ν: 2954, 2925, 2855, 1683, 1597, 1582, 1485, 1463, 1428, 1252, 1167, 1040, 783 cm−1; HRMS (quadrupole, EI): calcd for C15H22O2 [M]+, 234.1620; found, 234.1619. 1-(3-Methoxyphenyl)nonan-1-one (3ed). 0.73 g (59%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.54 (dt, J = 7.6, 1.6 Hz, 1H), 7.49−7.48 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.10 (ddd, J = 8.4, 2.8, 1.0 Hz, 1H), 3.85 (s, 3H), 2.94 (t, J = 7.2 Hz, 2H), 1.76−1.68 (m, 2H), 1.39−1.27 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 200.4, 159.8, 138.5, 129.5, 120.7, 119.3, 112.3, 55.4, 38.7, 31.8, 29.4, 29.3, 29.2, 24.4, 22.6, 14.1; IR (KBr) ν: 2954, 2924, 2853, 1683, 1597, 1582, 1486, 1463, 1428, 1259, 1166, 1043, 783 cm−1; HRMS (quadrupole, EI): calcd for C16H24O2 [M]+, 248.1776; found, 248.1775. General Procedure for the Synthesis of orthoAlkylated Derivatives (5aa−5ed′ and 6aa−6ad). To an oven-dried sealed tube charged with 1-(3,4,5trimethoxyphenyl)hexan-1-one (3aa) (53.3 mg, 0.2 mmol, 100 mol %), [IrCp*Cl2]2 (3.2 mg, 0.004 mmol, 2 mol %) or [RhCp*Cl2]2 (2.5 mg, 0.004 mmol, 2 mol %), AgNTf2 (6.2 mg, 0.016 mmol, 8 mol %), AgOAc (2.6 mg, 0.016 mmol, 8 mol %), 2666

DOI: 10.1021/acsomega.8b00179 ACS Omega 2018, 3, 2661−2672

Article

ACS Omega

60.9, 55.6, 44.4, 38.2, 31.4, 23.3, 22.5, 14.1, 13.9; IR (KBr) ν: 2955, 2927, 2856, 1734, 1691, 1597, 1581, 1469, 1438, 1367, 1336, 1259, 1181, 1159, 1073, 1030, 950, 768 cm−1; HRMS (quadrupole, EI): calcd for C17H24O4 [M]+, 292.1675; found, 292.1675. Ethyl 2-(2-Heptanoyl-3-methoxyphenyl)acetate (5bb). 54.1 mg (88%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.27 (t, J = 8.0 Hz, 1H), 6.87−6.83 (m, 2H), 4.12 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.58 (s, 2H), 2.84 (t, J = 7.2 Hz, 2H), 1.70−1.62 (m, 2H), 1.36−1.27 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 207.8, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.8, 55.5, 44.4, 38.2, 31.6, 28.9, 23.5, 22.5, 14.1, 14.0; IR (KBr) ν: 2955, 2928, 2856, 1735, 1691, 1598, 1582, 1469, 1438, 1367, 1297, 1262, 1181, 1160, 1074, 1030, 949, 760 cm−1; HRMS (quadrupole, EI): calcd for C18H26O4 [M]+, 306.1831; found, 306.1832. Ethyl 2-(3-Methoxy-2-octanoylphenyl)acetate (5bc). 58.9 mg (92%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.27 (t, J = 8.0 Hz, 1H), 6.87−6.83 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t, J = 7.6 Hz, 2H), 1.70−1.62 (m, 2H), 1.34−1.26 (m, 8H), 1.24 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 207.9, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.9, 55.6, 44.4, 38.2, 31.7, 29.2, 29.1, 23.6, 22.6, 14.1, 14.0; IR (KBr) ν: 2955, 2925, 2854, 1735, 1691, 1597, 1581, 1469, 1438, 1367, 1297, 1260, 1180, 1158, 1074, 1029, 952, 754 cm−1; HRMS (quadrupole, EI): calcd for C19H28O4 [M]+, 320.1988; found, 320.1987. Ethyl 2-(3-Methoxy-2-nonanoylphenyl)acetate (5bd). 47.5 mg (71%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.28 (t, J = 8.0 Hz, 1H), 6.87−6.83 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t, J = 7.2 Hz, 2H), 1.70−1.62 (m, 2H), 1.35−1.22 (m, 13H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 207.9, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 60.9, 55.6, 44.4, 38.2, 31.8, 29.4, 29.3, 29.2, 23.6, 22.6, 14.2, 14.1; IR (KBr) ν: 2954, 2925, 2853, 1735, 1691, 1597, 1581, 1468, 1438, 1367, 1297, 1259, 1180, 1158, 1075, 1030, 952 cm−1; HRMS (quadrupole, EI): calcd for C20H30O4 [M]+, 334.2144; found, 334.2143. Ethyl 2-(2-Hexanoyl-3,5-dimethoxyphenyl)acetate (5ca). 24.5 mg (38%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 6.38 (s, 1H), 6.37 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.61 (s, 2H), 2.81 (t, J = 7.2 Hz, 2H), 1.66− 1.60 (m, 2H), 1.32−1.30 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.4, 38.8, 31.5, 23.7, 22.5, 14.1, 13.9; IR (KBr) ν: 2955, 2929, 2857, 1734, 1682, 1601, 1580, 1457, 1423, 1315, 1290, 1254, 1202, 1152, 1084, 1029, 950, 834 cm−1; HRMS (quadrupole, EI): calcd for C18H26O5 [M]+, 322.1780; found, 322.1781. Ethyl 2-(2-Heptanoyl-3,5-dimethoxyphenyl)acetate (5cb). 30.4 mg (45%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 6.38 (s, 1H), 6.37 (s, 1H), 4.11 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.60 (s, 2H), 2.81 (t, J = 7.6 Hz, 2H), 1.67− 1.59 (m, 2H), 1.35−1.29 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.5, 38.8, 31.7, 29.0, 24.0, 22.5, 14.1, 14.0; IR (KBr) ν: 2955, 2930, 2856, 1734, 1682, 1601, 1580, 1457, 1423, 1367, 1315, 1254, 1202, 1151, 1085, 1029, 950, 834 cm−1; HRMS

and 5-diazo-2,2-dimethyl-1,3-dioxane-4,6-dione (4a) (40.8 mg, 0.24 mmol, 120 mol %) were added EtOH (18.4 mg, 0.4 mmol, 200 mol %) and DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir for 20 h at 60 °C. The reaction mixture was cooled to room temperature, diluted with EtOAc (3 mL), and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 12:1) to afford 5aa (50.2 mg, 71%) as a yellowish solid. Ethyl 2-(6-Hexanoyl-2,3,4-trimethoxyphenyl)acetate (5aa). 50.2 mg (71%); yellowish solid; mp 66.0−68.2 °C; 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.84 (t, J = 7.2 Hz, 2H), 1.70−1.62 (m, 2H), 1.33−1.28 (m, 4H), 1.25 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 202.9, 172.0, 152.7, 151.7, 145.0, 133.5, 121.7, 108.4, 61.0, 60.7, 60.5, 56.1, 40.9, 31.8, 31.4, 24.0, 22.4, 14.2, 13.8; IR (KBr) ν: 2939, 2871, 1733, 1682, 1595, 1568, 1495, 1453, 1403, 1331, 1172, 1137, 1113, 1028, 966, 918, 831 cm−1; HRMS (quadrupole, EI): calcd for C19H28O6 [M]+, 352.1886; found, 352.1884. Ethyl 2-(6-Heptanoyl-2,3,4-trimethoxyphenyl)acetate (5ab). 44.9 mg (61%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.88 (s, 2H), 3.82 (s, 3H), 2.85 (t, J = 7.6 Hz, 2H), 1.70−1.62 (m, 2H), 1.35−1.28 (m, 6H), 1.25 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.0, 172.0, 152.7, 151.8, 145.1, 133.6, 121.8, 108.4, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.6, 28.9, 24.3, 22.4, 14.2, 13.9; IR (KBr) ν: 2933, 2857, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1335, 1230, 1174, 1138, 1116, 1029, 966, 920, 841 cm−1; HRMS (quadrupole, EI): calcd for C20H30O6 [M]+, 366.2042; found, 366.2044. Ethyl 2-(2,3,4-Trimethoxy-6-octanoylphenyl)acetate (5ac). 45.1 mg (59%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 1.70− 1.62 (m, 2H), 1.31−1.23 (m, 11H), 0.86 (t, J = 6.4 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 203.0, 172.0, 152.7, 151.7, 145.0, 133.5, 121.7, 108.4, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.6, 29.2, 29.0, 24.3, 22.5, 14.2, 14.0; IR (KBr) ν: 2927, 2854, 1736, 1683, 1593, 1568, 1495, 1454, 1403, 1333, 1251, 1162, 1137, 1116, 1029, 1006, 966, 920, 838 cm−1; HRMS (quadrupole, EI): calcd for C21H32O6 [M]+, 380.2199; found, 380.2202. Ethyl 2-(2,3,4-Trimethoxy-6-nonanoylphenyl)acetate (5ad). 49.1 mg (62%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 2H), 3.82 (s, 3H), 2.84 (t, J = 7.6 Hz, 2H), 1.69−1.62 (m, 2H), 1.32−1.23 (m, 13H), 0.86 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.0, 172.0, 152.8, 151.8, 145.1, 133.6, 121.8, 108.5, 61.0, 60.7, 60.5, 56.2, 41.0, 31.8, 31.7, 29.4, 29.2, 29.1, 24.3, 22.6, 14.2, 14.0; IR (KBr) ν: 2925, 2853, 1735, 1663, 1593, 1568, 1495, 1454, 1403, 1367, 1333, 1229, 1161, 1136, 1115, 1028, 1007, 966, 917, 838 cm−1; HRMS (quadrupole, EI): calcd for C22H34O6 [M]+, 394.2355; found, 394.2358. Ethyl 2-(2-Hexanoyl-3-methoxyphenyl)acetate (5ba). 50.3 mg (86%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.27 (t, J = 8.0 Hz, 1H), 6.87−6.85 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.84 (t, J = 7.2 Hz, 2H), 1.71−1.63 (m, 2H), 1.34−1.30 (m, 4H), 1.24 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 207.8, 171.2, 156.7, 132.3, 131.5, 130.2, 123.2, 109.9, 2667

DOI: 10.1021/acsomega.8b00179 ACS Omega 2018, 3, 2661−2672

Article

ACS Omega (quadrupole, EI): calcd for C19H28O5 [M]+, 336.1937; found, 336.1939. Ethyl 2-(3,5-Dimethoxy-2-octanoylphenyl)acetate (5cc). 33.7 mg (48%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 6.39 (br s, 1H), 6.37 (br s, 1H), 4.13 (q, J = 8.0 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.61 (s, 2H), 2.82 (t, J = 8.0 Hz, 2H), 1.67−1.60 (m, 2H), 1.32−1.23 (m, 11H), 0.87 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 207.0, 171.3, 161.2, 158.7, 134.4, 124.3, 107.7, 97.5, 60.8, 55.5, 55.4, 44.5, 38.9, 31.7, 29.3, 29.1, 24.0, 22.6, 14.2, 14.1; IR (KBr) ν: 2954, 2927, 2854, 1734, 1682, 1601, 1580, 1457, 1423, 1366, 1315, 1260, 1201, 1151, 1086, 1030, 951, 833 cm−1; HRMS (quadrupole, EI): calcd for C20H30O5 [M]+, 350.2093; found, 350.2096. Ethyl 2-(3,5-Dimethoxy-2-nonanoylphenyl)acetate (5cd). 38.1 mg (52%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 6.38 (s, 1H), 6.37 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.60 (s, 2H), 2.81 (t, J = 7.2 Hz, 2H), 1.65− 1.59 (m, 2H), 1.29−1.22 (m, 13H), 0.87 (t, J = 6.4 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 207.0, 171.2, 161.2, 158.7, 134.4, 124.2, 107.7, 97.5, 60.8, 55.5, 55.3, 44.5, 38.8, 31.7, 29.4, 29.3, 29.1, 24.0, 22.6, 14.1, 14.0; IR (KBr) ν: 2925, 2853, 1735, 1682, 1602, 1580, 1457, 1423, 1367, 1315, 1256, 1201, 1151, 1087, 1030, 952, 834 cm−1; HRMS (quadrupole, EI): calcd for C21H32O5 [M]+, 364.2250; found, 364.2247. Ethyl 2-(2-Hexanoyl-5-methoxyphenyl)acetate (5da). 24.1 mg (41%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.85 (s, 3H), 2.88 (t, J = 7.2 Hz, 2H), 1.71−1.63 (m, 2H), 1.34−1.31 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 6.4 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.2, 31.5, 24.3, 22.5, 14.2, 13.9; IR (KBr) ν: 2956, 2928, 2858, 1733, 1673, 1603, 1569, 1464, 1428, 1367, 1336, 1315, 1291, 1244, 1211, 1159, 1131, 1031, 977, 877 cm−1; HRMS (quadrupole, EI): calcd for C17H24O4 [M]+, 292.1675; found, 292.1674. Ethyl 2-(2-Heptanoyl-5-methoxyphenyl)acetate (5db). 24.5 mg (40%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.85 (s, 3H), 2.88 (t, J = 7.2 Hz, 2H), 1.70−1.63 (m, 2H), 1.38− 1.30 (m, 6H), 1.26 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.3, 31.6, 29.0, 24.6, 22.5, 14.2, 14.0; IR (KBr) ν: 2955, 2929, 2856, 1734, 1673, 1603, 1569, 1464, 1367, 1336, 1315, 1291, 1255, 1230, 1208, 1159, 1131, 1031, 980, 877, 814 cm−1; HRMS (quadrupole, EI): calcd for C18H26O4 [M]+, 306.1831; found, 306.1831. Ethyl 2-(5-Methoxy-2-octanoylphenyl)acetate (5dc). 25.1 mg (39%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.84 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 1.68−1.62 (m, 2H), 1.33−1.24 (m, 11H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.3, 31.7, 29.3, 29.1, 24.6, 22.6, 14.2, 14.1; IR (KBr) ν: 2954, 2925, 2853, 1735, 1674, 1604, 1569, 1464, 1367, 1315, 1254, 1225, 1159, 1131, 1031, 983, 877, 815 cm−1; HRMS (quadrupole, EI): calcd for C19H28O4 [M]+, 320.1988; found, 320.1987.

Ethyl 2-(5-Methoxy-2-nonanoylphenyl)acetate (5dd). 26.8 mg (40%); white solid; mp 51.2−53.8 °C; 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.91 (s, 2H), 3.84 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 1.70−1.63 (m, 2H), 1.33−1.24 (m, 13H), 0.87 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 201.8, 171.5, 161.9, 137.5, 131.9, 129.7, 118.5, 111.8, 60.6, 55.3, 40.9, 40.2, 31.8, 29.4, 29.3, 29.2, 24.6, 22.6, 14.2, 14.0; IR (KBr) ν: 2925, 2854, 1736, 1675, 1604, 1569, 1463, 1367, 1315, 1254, 1160, 1132, 1032, 877, 816 cm−1; HRMS (quadrupole, EI): calcd for C20H30O4 [M]+, 334.2144; found, 334.2147. Ethyl 2-(2-Hexanoyl-4-methoxyphenyl)acetate (5ea). 8.9 mg (15%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.8 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t, J = 7.6 Hz, 2H), 1.72−1.64 (m, 2H), 1.35−1.31 (m, 4H), 1.25 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.5, 23.9, 22.5, 14.2, 13.9; IR (KBr) ν: 2955, 2929, 2857, 1734, 1686, 1607, 1573, 1502, 1463, 1418, 1368, 1338, 1288, 1256, 1160, 1032, 984, 928, 875 cm−1; HRMS (quadrupole, EI): calcd for C17H24O4 [M]+, 292.1675; found, 292.1673. Ethyl 2-(2-Hexanoyl-6-methoxyphenyl)acetate (5ea′). 22.3 mg (38%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 1.71−1.64 (m, 2H), 1.34−1.30 (m, 4H), 1.25 (t, J = 6.8 Hz, 3H), 0.89 (t, J = 6.8 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 204.8, 171.8, 158.2, 139.9, 127.8, 122.5, 120.3, 113.4, 60.5, 55.9, 41.6, 31.5, 31.4, 23.9, 22.5, 14.2, 13.9; IR (KBr) ν: 2955, 2932, 2871, 1734, 1685, 1580, 1459, 1439, 1409, 1367, 1335, 1265, 1205, 1158, 1030, 930, 883 cm−1; HRMS (quadrupole, EI): calcd for C17H24O4 [M]+, 292.1675; found, 292.1674. Ethyl 2-(2-Heptanoyl-4-methoxyphenyl)acetate (5eb). 8.7 mg (14%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t, J = 7.2 Hz, 2H), 1.71−1.64 (m, 2H), 1.38−1.28 (m, 6H), 1.25 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.6, 28.9, 24.1, 22.5, 14.2, 14.0; IR (KBr) ν: 2955, 2930, 2857, 1734, 1685, 1608, 1574, 1501, 1463, 1418, 1367, 1337, 1254, 1213, 1159, 1031, 984, 929, 873 cm−1; HRMS (quadrupole, EI): calcd for C18H26O4 [M]+, 306.1831; found, 306.1828. Ethyl 2-(2-Heptanoyl-6-methoxyphenyl)acetate (5eb′). 21.7 mg (35%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 1.70−1.63 (m, 2H), 1.37−1.30 (m, 6H), 1.25 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 204.8, 171.8, 158.1, 139.9, 127.8, 122.5, 120.3, 113.4, 60.5, 55.9, 41.6, 31.6, 31.5, 28.9, 24.2, 22.5, 14.2, 14.0; IR (KBr) ν: 2954, 2930, 2857, 1734, 1685, 1580, 1459, 1439, 1367, 1335, 1265, 1238, 1205, 1159, 1030, 931 cm−1; HRMS (quadrupole, EI): calcd for C18H26O4 [M]+, 306.1831; found, 306.1834. Ethyl 2-(4-Methoxy-2-octanoylphenyl)acetate (5ec). 8.4 mg (13%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.26 (br s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0, 4.0 2668

DOI: 10.1021/acsomega.8b00179 ACS Omega 2018, 3, 2661−2672

Article

ACS Omega

CDCl3): δ 203.6, 171.5, 152.8, 151.7, 144.9, 133.7, 121.8, 108.4, 67.8, 61.0, 60.7, 56.2, 41.1, 32.1, 31.6, 29.2, 29.1, 24.3, 22.5, 21.8, 14.0; IR (KBr) ν: 2929, 2854, 1731, 1683, 1593, 1568, 1495, 1454, 1403, 1325, 1289, 1229, 1173, 1136, 1108, 1047, 1005, 970, 919, 830 cm−1; HRMS (quadrupole, EI): calcd for C22H34O6 [M]+, 394.2355; found, 394.2358. Butyl 2-(2,3,4-Trimethoxy-6-octanoylphenyl)acetate (6ac). 53.1 mg (65%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 4.08 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.88 (s, 2H), 3.82 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 1.68− 1.57 (m, 4H), 1.41−1.24 (m, 10H), 0.91 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.0, 172.1, 152.8, 151.8, 145.0, 133.6, 121.8, 108.4, 64.5, 61.0, 60.7, 56.2, 41.1, 31.8, 31.6, 30.6, 29.2, 29.1, 24.3, 22.5, 19.1, 14.0, 13.6; IR (KBr) ν: 2955, 2930, 2855, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1332, 1289, 1164, 1136, 1115, 1047, 1005, 967, 918, 837 cm−1; HRMS (quadrupole, EI): calcd for C23H36O6 [M]+, 408.2512; found, 408.2509. Benzyl 2-(2,3,4-Trimethoxy-6-octanoylphenyl)acetate (6ad). 45.1 mg (51%); light yellow solid; mp = 64.8−66.7 °C; 1H NMR (400 MHz, CDCl3): δ 7.37−7.29 (m, 5H), 7.04 (s, 1H), 5.15 (s, 2H), 3.97 (s, 2H), 3.91 (s, 6H), 3.79 (s, 3H), 2.84 (t, J = 7.2 Hz, 2H), 1.69−1.61 (m, 2H), 1.31−1.25 (m, 8H), 0.88 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 202.9, 171.9, 152.8, 151.7, 145.1, 136.2, 133.5, 128.3, 128.1, 127.9, 121.6, 108.4, 66.3, 61.0, 60.7, 56.2, 41.0, 31.8, 31.6, 29.2, 29.1, 24.3, 22.6, 14.0; IR (KBr) ν: 2955, 2930, 2855, 1735, 1683, 1593, 1568, 1495, 1454, 1403, 1333, 1165, 1136, 1115, 1048, 1006, 968, 919, 834 cm−1; HRMS (quadrupole, EI): calcd for C26H34O6 [M]+, 442.2355; found, 442.2354. Experimental Procedure and Characterization Data for the Synthesis of Phomopsin C (7a). To an oven-dried sealed tube charged with ethyl 2-(3,5-dimethoxy-2octanoylphenyl)acetate (5cc) (70.1 mg, 0.2 mmol, 100 mol %) in CH2Cl2 (1 mL) was added boron tribromide (1 M solution in dichloromethane, 0.8 mL, 0.8 mmol, 400 mol %) under argon at −78 °C. The reaction mixture was allowed to stir for 2 h at 0 °C. The reaction mixture was cooled to room temperature, quenched with H2O and saturated NaHCO3 solution to make pH 7 of the reaction mixture, and then extracted with EtOAc (3 × 20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/ EtOAc = 5:1) to afford 7a (51.1 mg) in 76% yield. Ethyl 2-(3-Hydroxy-5-methoxy-2-octanoylphenyl)acetate (7a). 51.1 mg (76%); brown solid; mp 75.6−77.8 °C; 1H NMR (400 MHz, CDCl3): δ 12.4 (s, 1H), 6.36 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.84 (s, 2H), 3.79 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 1.72−1.65 (m, 2H), 1.30−1.23 (m, 8H), 1.25 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.5, 170.8, 165.1, 163.6, 136.2, 115.9, 112.5, 100.4, 61.3, 55.3, 43.2, 41.9, 31.6, 29.1, 29.0, 24.9, 22.5, 14.1, 14.0; IR (KBr) ν: 3228, 2954, 2925, 2854, 1736, 1710, 1608, 1588, 1464, 1438, 1368, 1305, 1197, 1153, 1022, 962, 844 cm−1; HRMS (orbitrap, ESI): calcd for C19H28O5 [M + H]+, 336.1937; found, 336.1939. Experimental Procedure and Characterization Data for the Synthesis of Carboxylic Acid (7b). To an ovendried sealed tube charged with 2-(3,5-dimethoxy-2octanoylphenyl)acetate (5cc) (70.1 mg, 0.2 mmol, 100 mol %) were added 1 M NaOH (1 mL) and THF (1 mL) under air at room temperature. The reaction mixture was allowed to stir for 14 h at room temperature. The reaction mixture was

Hz, 1H), 4.12 (q, J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t, J = 8.0 Hz, 2H), 1.69−1.64 (m, 2H), 1.33−1.23 (m, 11H), 0.87 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.4, 60.6, 55.5, 40.8, 39.1, 31.7, 29.2, 29.1, 24.2, 22.6, 14.2, 14.0; IR (KBr) ν: 2954, 2925, 2854, 1735, 1686, 1608, 1574, 1501, 1464, 1418, 1368, 1252, 1213, 1159, 1032, 987, 928, 874 cm−1; HRMS (quadrupole, EI): calcd for C19H28O4 [M]+, 320.1988; found, 320.1990. Ethyl 2-(2-Methoxy-6-octanoylphenyl)acetate (5ec′). 21.9 mg (34%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.14 (q, J = 8.0 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t, J = 8.0 Hz, 2H), 1.70−1.63 (m, 2H), 1.33−1.23 (m, 11H), 0.87 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 204.9, 171.8, 158.2, 139.9, 127.8, 122.6, 120.3, 113.3, 60.5, 55.9, 41.7, 31.7, 31.5, 29.2, 29.1, 24.3, 22.6, 14.2, 14.0; IR (KBr) ν: 2953, 2926, 2855, 1735, 1686, 1580, 1459, 1439, 1367, 1335, 1266, 1236, 1204, 1158, 1031, 1009, 930, 833 cm−1; HRMS (quadrupole, EI): calcd for C19H28O4 [M]+, 320.1988; found, 320.1989. Ethyl 2-(4-Methoxy-2-nonanoylphenyl)acetate (5ed). 8.7 mg (13%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.26 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.8 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 2.89 (t, J = 7.6 Hz, 2H), 1.71−1.64 (m, 2H), 1.34−1.23 (m, 13H), 0.87 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 203.8, 171.9, 158.5, 138.8, 133.4, 126.0, 115.9, 115.5, 60.6, 55.5, 40.8, 39.1, 31.8, 29.4, 29.3, 29.1, 24.2, 22.6, 14.2, 14.1; IR (KBr) ν: 2954, 2925, 2854, 1735, 1686, 1608, 1574, 1501, 1463, 1418, 1368, 1258, 1213, 1159, 1031, 985, 928, 874 cm−1; HRMS (quadrupole, EI): calcd for C20H30O4 [M]+, 334.2144; found, 334.2144. Ethyl 2-(2-Methoxy-6-nonanoylphenyl)acetate (5ed′). 22.2 mg (33%); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.14 (q, J = 8.0 Hz, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.88 (t, J = 8.0 Hz, 2H), 1.70−1.63 (m, 2H), 1.35−1.23 (m, 13H), 0.87 (t, J = 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 204.9, 171.8, 158.2, 139.9, 127.8, 122.5, 120.3, 113.3, 60.5, 55.9, 41.7, 31.8, 31.5, 29.4, 29.2, 29.1, 24.2, 22.6, 14.2, 14.0; IR (KBr) ν: 2952, 2926, 2853, 1737, 1606, 1596, 1489, 1462, 1425, 1340, 1304, 1262, 1207, 1148, 1098, 1053, 950, 827 cm−1; HRMS (quadrupole, EI): calcd for C20H30O4 [M]+, 334.2144; found, 334.2144. Methyl 2-(2,3,4-Trimethoxy-6-octanoylphenyl)acetate (6aa). 29.7 mg (39%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 7.04 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.89 (s, 2H), 3.83 (s, 3H), 3.68 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 1.70− 1.63 (m, 2H), 1.32−1.24 (m, 8H), 0.86 (t, J = 6.8 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3): δ 202.9, 172.5, 152.8, 151.8, 145.1, 133.4, 121.7, 108.5, 61.0, 60.7, 56.2, 51.8, 40.9, 31.7, 31.6, 29.2, 29.1, 24.3, 22.5, 14.0; IR (KBr) ν: 2929, 2854, 1738, 1682, 1593, 1568, 1495, 1454, 1403, 1333, 1290, 1194, 1164, 1136, 1115, 1048, 1004, 962, 919, 841 cm−1; HRMS (quadrupole, EI): calcd for C20H30O6 [M]+, 366.2042; found, 366.2045. Isopropyl 2-(2,3,4-Trimethoxy-6-octanoylphenyl)acetate (6ab). 44.3 mg (56%); yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.04 (s, 1H), 5.05−4.99 (m, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.88 (s, 2H), 3.85 (s, 3H), 2.87 (t, J = 7.6 Hz, 2H), 1.72−1.65 (m, 2H), 1.35−1.25 (m, 8H), 1.27 (s, 3H), 1.25 (s, 3H), 0.89 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, 2669

DOI: 10.1021/acsomega.8b00179 ACS Omega 2018, 3, 2661−2672

Article

ACS Omega

HepG2 cells were collected and washed with cold PBS. The harvested cells were then lysed on ice for 30 min in 100 μL lysis buffer [120 mM NaCl, 40 mM Tris (pH 8.0), 0.1% Nonidet P40] and centrifuged at 10 000g for 30 min. The supernatants were collected from the lysates and the protein concentrations were determined using the protein assay kit (Pierce, Rockford, IL). Aliquots of the lysates (20 μg protein) were boiled for 5 min and electrophoresed on 10% SDS-polyacrylamide gels. Proteins in the gels were transferred to nitrocellulose membranes, which were then incubated with p-AMPK antibody (Cell Signaling Technology, Beverly, MA) or mouse monoclonal β-actin antibody (Sigma-Aldrich, St. Louis, MO). The membranes were further incubated with secondary antimouse or antirabbit antibodies. Finally, protein bands were detected using an enhanced chemiluminescence western blotting detection kit (Pierce Biotechnology, Rockford, IL). Antidiabetic Evaluation of 5ac and 5cd Using Type 2 Diabete-Induced Animal Models. Rats were fasted overnight and were administered with a single intraperitoneal injection with STZ (25 mg/kg/body weight) in 0.1 M citrate buffer (pH 4.5). TMPA (5ac) and 5cd were, respectively, dissolved in DMSO into a final concentration of 1 M and then dissolved in 5.0% (v/v) Tween-80 in 0.9% (w/v) saline. One group of rat was injected intraperitoneally with TMPA (5ac) daily at a dose of 25 mg/kg/body weight for 7 days. One group of rat was injected intraperitoneally with 5cd daily at a dose of 25 mg/kg/body weight for 7 days. The other group was injected with metformin as a positive control (250 mg/kg/body weight dissolved in normal saline). Before the blood glucose measurement, rats were fasted for 12 h. The blood glucose level of rat was analyzed in every alternative days using OneTouch Ultra glucometer.

quenched with 1 M HCl (1 mL) to make pH 7 and extracted with CH2Cl2 (3 × 20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 1:2) to afford 7b (46.3 mg) in 72% yield. 2-(3,5-Dimethoxy-2-octanoylphenyl)acetic Acid (7b). 46.3 mg (72%); light brown solid; mp 80.8−82.3 °C; 1H NMR (400 MHz, CDCl3): δ 6.48 (d, J = 1.6 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.51 (s, 2H), 2.91 (t, J = 7.6 Hz, 2H), 1.68−1.61 (m, 2H), 1.28−1.26 (m, 8H), 0.86 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 210.1, 172.1, 162.6, 159.9, 135.4, 122.6, 107.5, 98.2, 55.7, 55.6, 44.2, 41.4, 31.6, 29.3, 29.0, 24.7, 22.5, 14.0; IR (KBr) ν: 2925, 2853, 1738, 1711, 1600, 1580, 1457, 1423, 1324, 1290, 1203, 1153, 1084, 1059, 950, 835 cm−1; HRMS (orbitrap, ESI): calcd for C18H26O5 [M + H]+, 322.1780; found, 322.1779. Experimental Procedure and Characterization Data for the Synthesis of 1-Heptyl-6,8-dimethoxyisochroman (7c). To an oven-dried sealed tube charged with 2-(3,5dimethoxy-2-octanoylphenyl)acetate (5cc) (70.1 mg, 0.2 mmol, 100 mol %) were added NaBH4 (15.1 mg, 0.4 mmol, 200 mol %) and EtOH (1 mL) under air at room temperature. The reaction mixture was allowed to stir for 4 h at 60 °C. The reaction mixture was cooled to room temperature, quenched with H2O and saturated NH4Cl solution to make pH 7 of reaction mixture, and then extracted with CH2Cl2 (3 × 20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 15:1) to afford 7c (23.4 mg) in 40% yield. 1-Heptyl-6,8-dimethoxyisochroman (7c). 23.4 mg (40%); yellowish oil; 1H NMR (400 MHz, CD3OD): δ 6.29 (s, 1H), 6.24 (s, 1H), 4.80 (dd, J = 8.8, 2.0 Hz, 1H), 4.02−3.96 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.76−3.72 (m, 1H), 2.84−2.76 (m, 1H), 2.69 (dt, J = 16.4, 4.8 Hz, 1H), 1.86−1.69 (m, 2H), 1.46−1.43 (m, 2H), 1.35−1.26 (m, 8H), 0.88 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 158.7, 156.7, 135.6, 120.1, 104.1, 96.5, 72.0, 59.5, 55.2, 55.1, 33.2, 31.9, 29.5, 29.4, 29.3, 25.8, 22.7, 14.1; IR (KBr) ν: 2952, 2923, 2853, 1736, 1605, 1595, 1489, 1463, 1425, 1340, 1304, 1261, 1207, 1148, 1098, 1054, 951, 827 cm−1; HRMS (orbitrap, ESI): calcd for C18H28O3 [M + H]+, 292.2038; found, 292.2040. 5-(6-Heptanoyl-2,3,4-trimethoxyphenyl)-2,2-dimethyl-1,3dioxane-4,6-dione (8ab). 57.4 mg (68%); yellowish oil; 1H NMR (400 MHz, CDCl3): δ 6.73 (s, 1H), 5.24 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 2.40−2.34 (m, 2H), 1.82 (s, 3H), 1.79 (s, 3H), 1.55 (m, 2H), 1.46 (m, 2H), 1.33 (m, 4H), 0.94−0.86 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 207.7, 164.9, 161.3, 159.4, 154.6, 145.6, 124.6, 113.3, 106.1, 102.2, 67.1, 61.2, 60.9, 56.1, 46.5, 31.5, 28.8, 28.2, 27.3, 24.9, 22.5, 14.0; IR (KBr) ν: 2922, 2851, 1734, 1603, 1596, 1490, 1462, 1341, 1303, 1260, 1208, 1149, 1099, 951, 830 cm−1; HRMS (quadrupole, EI): calcd for C20H30O8 [M]+, 422.1941; found, 422.1939. In Vitro Assay of Synthetic Compounds on p-AMPK Activation. HepG2 cells were treated with the compounds for 4 h, and the p-AMPK expression was determined by the western blotting analysis. The HepG2 hepatocytes were obtained from the American Type Culture Collection (ATCC, USA). The HepG2 cells were cultured in Dulbecco’s modified Eagle’s medium containing glucose (Invitrogen, USA), supplemented with 10% (v/v) fetal bovine serum (Gibco BRL, USA). After treatment with compounds for 4 h,

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b00179. Immunoblot assay of synthetic compounds on AMPK activation, and 1H and 13C NMR copies of all products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (J.S.P.). *E-mail: [email protected] (H.S.K.). *E-mail: [email protected] (I.S.K.). ORCID

In Su Kim: 0000-0002-2665-9431 Author Contributions ∥

S.H.L. and A.K. equally contributed.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (nos. 2016R1A4A1011189, 2016R1C1B2014895, and 2017R1A2B2004786). 2670

DOI: 10.1021/acsomega.8b00179 ACS Omega 2018, 3, 2661−2672

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