Synthesis of the Isodityrosine Moiety of Seongsanamide A–D and Its Derivatives

Abstract

The concise and highly convergent synthesis of the isodityrosine unit of seongsanamide A–D and its derivatives bearing a diaryl ether moiety is described. In this work, the synthetic strategy features palladium-catalyzed C(sp³)–H functionalization and a Cu/ligand-catalyzed coupling reaction. We report a practical protocol for the palladium-catalyzed mono-arylation of β-methyl C(sp³)–H of an alanine derivative bearing a 2-thiomethylaniline auxiliary. The reaction is compatible with a variety of functional groups, providing practical access to numerous β-aryl-α-amino acids; these acids can be converted into various tyrosine and dihydroxyphenylalanine (DOPA) derivatives. Then, a CuI/N,N-dimethylglycine-catalyzed arylation of the already synthesized DOPA derivatives with aryl iodides is described for the synthesis of isodityrosine derivatives.

1. Introduction

In 2018, Choi and coworkers [1] reported the isolation of seongsanamide A–D from a bacterial culture broth of Bacillus safensis KCTC 12796BP, obtained from a marine sponge collected in water samples of Seongsan on Jeju Island. Seongsanamides are bicyclic depsipeptides with an isodityrosine residue and exhibit antiallergenic properties (Figure 1). Furthermore, isodityrosine is a tyrosine dimer containing oxidatively coupled aromatic nuclei, and the tyrosine units are linked through a diaryl ether moiety [2]. A large class of biological cyclopeptides containing this structural unit exists in nature, with a wide range of pharmaceutical activities, such as seongsanamidesA–D, K-13 [3], OF4949-Ⅲ [3], rubiyunnanin D [4], and bouvardin [5].

In addition, diaryl ether (DE) is a functional scaffold that exists widely in both natural products and new drugs approved for the market [6]. Moreover, DE is always considered the fundamental fragment of a wide variety of medicinal and agrochemical agents as well as their bioisosteres (Figure 2). Over the years, medicinal chemists have exploited the use of privileged structures inspired by natural products in drug discovery. The introduction of functional groups, such as α-keto [7] amide and gem-dimethyl [8] moieties, into biologically active small molecules has emerged as an efficient way to obtain clinically useful drugs.

Due to their potential structural diversity, pharmaceutical value, and good druggability, isodityrosines and cyclopeptide derivatives have attracted increasing attention in the synthetic community. Numerous research laboratories have engaged in the total synthesis of these natural products or analogs, including Dötz benzannulation [9], S_NAr reactions [10], and the Ullman [11,12,13,14,15,16] and Evans–Chan–Lam [3,17,18] coupling reactions. However, the synthesis of isodityrosines and their derivatives usually begins with available natural amino acids, limiting the diversity of the synthesis of their derivatives and their applications in drug design.

To address these challenges, we aimed to establish a convenient and convergent synthetic route. In recent years, transition-metal-catalyzed C–H functionalization has provided general and practical access to various natural and unnatural aromatic amino acids [19,20,21,22,23]. Our retrosynthetic analysis of the isodityrosine moiety of seongsanamides is outlined in Scheme 1. We selected a strategy based on palladium-catalyzed C(sp³)–H functionalization and copper-catalyzed Ullmann coupling reactions. The iodityrosine moiety was prepared from key precursor 1 and 4-iodophenylalaninederivatives via a C–O coupling reaction. The DOPA derivative 1 was derived from intermediate 2 by removing hydroxyl protecting groups, Dakin oxidation of aldehyde, or Baeyer–Villiger oxidation of acetyl group. Compound 2 was prepared by removing the directing group of 3, which resulted from the palladium-catalyzed monoarylation of β-methyl C(sp³)–H of an alanine derivative with aryl iodides using a directing group. The structural diversity of aryl iodides could facilitate the synthesis of more isodityrosine derivatives.

2. Results

Our study began with the synthesis of N-phthaloylalanine derivatives 4a–c to examine potential amide directing groups (phthaloyl = Phth). Several commercially available aniline-based auxiliary groups, including 8-aminoquinoline [24,25,26], 2-thiomethylaniline (ArS) [27], and O-methylhydroxylamine [28], were selected for the palladium-catalyzed arylation. Subsequently, the treatment of 2-methoxybenzaldehyde with N-iodosuccinimide(NIS) and FeCl₃ produced the corresponding aryl iodide5a,with a yield of 89%.

Initially, the selectivity for mono- versus diarylation needed to be controlled. We initiated our investigation with the selective methyl C(sp³)–H monoarylation of alanine derivative with aryl iodide (5a) as the model system (Scheme 2). In 2012, Daugulis reported that the selective β-monoarylation of alanine derivatives occurred under solvent-free conditions in high yield using a 2-thiomethylaniline auxiliary [27]. In 2014, Bull reported that the 3-monoarylation of proline derivatives under solvent-free conditions with 8-aminoquinoline directing groups was also successful [26]. Previously, Shi reported that the use of coordinating solvents, such as dimethylamine (DMA) and dimethylpropyleneurea(DMPU), improved the selectivity in the arylation of alanine derivatives with aryl iodides [29].

Due to these studies, we selected solvent-free conditions using palladium (II) acetate (Pd(OAc)₂, 20 mol%), silver acetate (AgOAc, 1.5 equiv), and DMPU (5.0 equiv) as additives. In accordance with reported results, the arylation of 4b bearing an 8-aminoquinoline auxiliary mainly produced diarylated product 3ab when the reaction was conducted at 150 °C, and 4a bearing a 2-thiomethylaniline auxiliary mainly produced monoarylated product 3a (

Table 1. Palladium-catalyzed arylation of 4a–c with 5a.

Entry	Substrate	Temp.	Time	Yield (%)	Ratio (mono/di) g
1 a	4a	150 °C	24 h	38 e	2.2:1 h
2 a	4b	150 °C	24 h	12 e	1:3.1 h
3 b	4a	100 °C	48 h	48 e	12:1
4 b	4a	80 °C	48 h	62 e	mono
5 b	4a	60 °C	60 h	42 f	mono
6 c	4b	80 °C	48 h	26 f	1:1.7
7 d	4c	80 °C	48 h	36 e	mono
8 i	4a	80 °C	48 h	65 e	–
9 j	4a	80 °C	48 h	51 e	–

^a 4 (0.6 mmol) was used. ^b 4a (1.5 mmol) was used. ^c 4b (1.5 mmol) was used. ^d 4c (4.0 mmol) was used. ^e Isolated yields. ^f Yields are based on ¹H-NMR analysis. ^g The ratio of the mono- to the diarylated product was determined via ¹HNMR spectroscopy of the crude reaction mixture. ^h The ratio of the mono- to the diarylated product was determined via isolated yield. ⁱ 4a (4.4 mmol) was used. ^j 4a (18.5 mmol) was used.

, entries 1 and 2). The optimization of this transformation continued with 4a. We aimed to maximize the yield of 3a and the selectivity of monoarylation. We found that lowering the reaction temperature to 100 °C improved both the yield and selectivity of the reaction (48% yield, mono/di 12:1; Table 1, entry 3). Further screening showed that running the reaction at 80 °C increased both mono-selectivity and yield (62% yield, Table 1, entry 4). However, no satisfactory result was obtained when the reaction was run at 60 °C (42% yield, Table 1, entry 5).

Additional optimization experiments showed that the more strongly coordinating 8-aminoquinoline auxiliary still provided a predominantly diarylated product at 80 °C (mono/di 1:1.7; Table 1, entry 6). Interestingly, the palladium-catalyzed C(sp³)–H arylation of Weinreb amides 4c bearing an N-methoxyamide auxiliary was also successful, with a 36% yield(Table 1, entry 7). Notably, the reaction was also successful on a larger scale, and the yields were similar to those obtained on a smaller scale (Table 1, entries 8 and 9).

With the optimized the reaction conditions for the β-monoarylation of alanine-derived amide 4a, we next investigated the scope of alkyl iodides that were compatible in the reaction (Scheme 3). A wide range of aryl iodides with different electron-withdrawing functional groups, such as formyl (3b, 53%; 3c, 51%), acetyl (3e, 54%; 3f, 57%), bromo (3n, 60%), and methoxycarbonyl (3j, 71%) groups underwent efficient monoarylation to produce the corresponding substituted phenylalanines in moderate yields (see Supplementary Materials). Moreover, aryl iodide bearing a nitro (3p) substituent was less reactive and successful, affording a 36% yield. Additionally, aryl iodides bearing alkoxy (3g, 76%; 3h, 60%; 3i, 56%) substituents were compatible with this protocol to produce their desired products in moderate to good yields.

Importantly, 3,4-disubstituted aryl iodides bearing one alkoxy group and an electron-withdrawing functional group also reacted smoothly under the standard conditions to produce the β-monoarylation products in moderate yields (3d, 55%; 3k, 57%; 3l, 60%; 3m, 57%). In general, aryl iodides carrying electron-donating groups are more reactive than aryl iodides bearing electron-withdrawing groups. Also proving to be compatible were 3,4-Disubstituted aryl iodides, albeit with reduced yields (3r, 33%; 3s, 36%).

However, an unfavorable steric effect was also apparent in 2-substituted aryl iodides, and decreased reactivity was also evident; sterically hindered immediately adjacent to the iodide decreased reactivity. Notably, steric aryl iodides were also compatible with the reaction conditions, although they were less reactive (3t, 36%; 3u, 46%; 3v, 33%). Interestingly, the 4-tert-butoxycarbonylamino- and 4-iodo-aryl derivatives were also successful, providing handles for potential further functionalization (3o, 46%; 3q, 40%).

Based on our access to a wide range of phenylalanine derivatives, we subsequently examined the removal of the directing group. The sequential transformation of formyl, acetyl, and alkoxy groups to hydroxyl groups provided various tyrosine and DOPA derivatives that could be used to produce more isodityrosine derivatives via the Ullmann coupling reaction. The directing group of 3a was easily removed by treatment with H₂SO₄ in methanol (MeOH) to produce the corresponding methyl ester 2a with a 77% yield (Scheme 4). The treatment of aldehyde 2a with m-CPBA produced the formate ester, which was immediately converted into the corresponding phenol 1 (74% yield for two steps).

Subsequently, we focused on the second key step, the copper-catalyzed Ullmann coupling reaction of DOPA derivative 1 (Scheme 5, see Supplementary Materials). The development of useful methods via the Cu/ligand-catalyzed arylation of phenols for assembling diaryl ethers was accomplished [30,31,32,33,34]. Initially, we selected the coupling of phenylalanine-derived aryl iodides (1.5 equiv), with 1 as a model reaction to optimize the reaction conditions. The coupling reaction was tested in the presence of CuI (1.0 equiv) and Cs₂CO₃ (4.5 equiv) when the reaction was carried out in 1,4-dioxane (0.1 M) under N₂ at 90 °C for 20 h. We tested several ligands that are known to promote copper-catalyzed coupling reactions. Interestingly, we found that using commercially available N,N-dimethylglycine as a ligand produced the corresponding products. Moreover, several phenylalanine-derived aryl iodides with different protecting groups at the C-terminus were compatible with the reaction conditions (6a, 49%; 6b, 50%; 6c, 44%). Notably, in isodityrosine derivatives 6a–d, all amino and carboxylate groups with different protections enabled the selective manipulation of the individual functionalities.

With the optimized reaction conditions, we next examined an extensive range of aryl iodides to produce a 3-aryloxyphenylalanine derivative bearing a diaryl ether moiety. A variety of functional groups of aryl iodides are known to tolerate this reaction condition, including alkoxyl, formyl, acetyl, nitro, carbonyl, iodo, and cyano groups. Both electron-rich and electron-deficient aryl iodides underwent this reaction to produce the corresponding diaryl ethers in good yields. A high yield was provided by 4-iodobenzaldehyde (6e, 88%), whereas 3-iodobenzaldehyde provided a 52% yield under standard conditions. Furthermore, aromatics with aldehyde and methoxyl groups were also compatible, with reduced yields (6g, 30%). Notably, the reaction of 1,4-diiodobenzene with phenol 1 produced the coupling product 6j in 64% yield, which was a 3-(4-iodoaryloxy)-phenylalanine derivative and provided a handle for potential further functionalization.

In conclusion, we have developed a convenient and highly convergent synthesis of the isodityrosine unit of seongsanamide A–D and its derivatives bearing a diaryl ether moiety. The synthetic sequence is based on a palladium-catalyzed C(sp³)–H functionalization and a Cu/ligand-catalyzed coupling reaction. Initially, we developed a Pd-catalyzed mono-arylation of β-methyl C(sp³)–H of an alanine derivative using the 2-thiomethylaniline directing group. A wide range of aryl iodides could be applied in this protocol to provide various aromatic α-amino acid compounds; these compounds could be used for the synthesis of various tyrosine and DOPA derivatives. Subsequently, the CuI/N,N-dimethylglycine-catalyzed coupling of DOPA derivatives with aryl iodides was accomplished to prepare diaryl ethers and the synthesis of isodityrosine derivatives. Our convergent synthetic method facilitates a concise way for the efficient preparation of various DE-based analogs for drug development efforts. The specific introduction of DE-based units into biologically active small molecules and a study of the impact on the physicochemical properties and potential biological activities are currently being performed.

3. Materials and Methods

3.1. General Experimental Methods

Chemicals were acquired from commercial sources and used as received. Nuclear magnetic resonance (NMR) spectra were recorded on Bruker Ascend-400 and Bruker Ascend-500 spectrometers at the following spectrometer frequencies. Multiplicities are assigned as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and app (apparent).The exact mass was obtained using a time-of-flight (TOF) detector on Agilent 6530-Q-TOF. Thin layer chromatography (TLC) was carried out with 0.2 mm thick silica gel plates. Visualization was accomplished by using UV light. Column chromatography was performed on silica gel (200–300 mesh).

3.2. Synthesis of the Phenylalanine Derivatives3a–v

A Schlenk tube was charged with 1 (1.5 mmol), ), aryl iodide (1.5 equiv., or 2.0 equiv. used for synthesis of 3o), Pd(OAc)₂ (0.2 equiv.), AgOAc (2.0 equiv.), and DMPU (5.0 equiv.), evacuated, and backfilled with N₂. The reaction mixture was stirred at 80 °C for 48 h. The suspension was filtered, and the filtrate was concentrated, followed by column chromatography on silica gel (eluting with 1:5 to 1:2 ethyl acetate/petroleum ether) to provide the desired product.

(S)-N-(3-(4-Methoxy-3-formylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3a). 3a was obtained as a solid. ¹H NMR (400 MHz, CDCl₃) δ 10.30 (s, 1H), 8.94 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 7.82 (dt, J = 7.1, 3.5 Hz, 2H), 7.79–7.67 (m, 2H), 7.64 (d, J = 2.2 Hz, 1H), 7.52–7.38 (m, 2H), 7.29 (dd, J = 13.5, 6.0 Hz, 1H), 7.06 (td, J = 7.6, 1.0 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.24 (dd, J = 10.6, 5.9 Hz, 1H), 3.84 (s, 3H), 3.68 (qd, J = 14.3, 8.3 Hz, 2H), 2.20 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 189.45, 167.81, 166.20, 160.89, 137.97, 136.49, 134.63, 133.53, 131.43, 129.33, 129.13, 129.08, 125.64, 124.97, 124.82, 123.82, 120.70, 112.27, 56.30, 55.79, 33.40, 19.22; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₃N₂O₅S⁺: 475.1322, found: 475.1448.

(S)-N-(3-(3-Formylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3b). 3b was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 9.88 (s, 1H), 8.95 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.81 (dt, J = 7.4, 3.7 Hz, 2H), 7.76–7.71 (m, 3H), 7.68 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.5 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 5.33 (dd, J = 10.9, 5.7 Hz, 1H), 3.80 (ddd, J = 25.2, 14.3, 8.4 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 192.11, 167.76, 166.03, 138.13, 137.90, 136.85, 135.14, 134.73, 133.56, 131.33, 130.59, 129.57, 129.39, 128.34, 125.59, 125.04, 123.83, 120.66, 56.01, 34.14, 19.22; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₅H₂₁N₂O₄S⁺: 445.1217, found: 445.1223.

(S)-N-(3-(4-Formylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3c). 3c was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 9.91 (d, J = 11.3 Hz, 1H), 8.94 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.81 (dt, J = 7.5, 3.8 Hz, 2H), 7.78–7.70 (m, 4H), 7.44 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.31 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 5.34 (dd, J = 10.7, 6.0 Hz, 1H), 3.87–3.72 (m, 2H), 2.17 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 191.94, 167.71, 165.95, 144.18, 137.87, 135.37, 134.77, 133.57, 131.28, 130.25, 129.78, 129.41, 125.57, 125.07, 123.85, 120.63, 55.76, 34.56, 19.21; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₅H₂₁N₂O₄S⁺: 445.1217, found: 445.1221.

(S)-N-(3-(4-(Benzyloxy)-3-formylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline(3d). 3d was obtained as a solid. ¹H NMR (500 MHz, CDCl₃) δ 10.40 (s, 1H), 8.94 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.82 (dt, J = 7.3, 3.7 Hz, 2H), 7.76–7.70 (m, 2H), 7.67 (d, J = 2.1 Hz, 1H), 7.47–7.41 (m, 2H), 7.38 (d, J = 4.3 Hz, 4H), 7.36–7.32 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 5.24 (dd, J = 10.7, 5.7 Hz, 1H), 5.10 (s, 2H), 3.68 (ddd, J = 25.1, 14.4, 8.3 Hz, 2H), 2.20 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 189.36, 167.80, 166.18, 160.11, 137.96, 136.45, 136.03, 134.63, 133.55, 131.43, 129.52, 129.35, 128.91, 128.83, 128.41, 127.42, 125.61, 125.16, 124.97, 123.83, 120.69, 70.62, 56.27, 33.43, 19.23; HRMS(ESI): m/z [M + H]⁺calcd. for C₃₂H₂₇N₂O₅S⁺: 551.1635, found: 551.1674.

(S)-N-(3-((4-Acetylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3e). 3e was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 8.95 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.81 (dt, J = 9.7, 4.8 Hz, 3H), 7.79 (s, 1H), 7.73 (dd, J = 5.3, 3.1 Hz, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 8.4 Hz, 3H), 7.07 (t, J = 7.5 Hz, 1H), 5.70–4.91 (m, 1H), 4.21–3.39 (m, 2H), 2.52 (s, 3H), 2.18 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 197.86, 167.76, 166.08, 142.55, 137.93, 136.05, 134.73, 133.60, 131.34, 129.42, 129.31, 128.91, 125.56, 125.04, 123.85, 120.64, 55.88, 34.36, 26.70, 19.24; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₃N₂O₄S⁺: 459.1373, found: 459.1376.

(S)-N-(3-(3-Acetylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3f). 3f was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 8.96 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.84–7.79 (m, 2H), 7.78 (s, 1H), 7.76–7.70 (m, 3H), 7.44 (d, J = 7.7 Hz, 2H), 7.35–7.28 (m, 2H), 7.07 (td, J = 7.6, 1.0 Hz, 1H), 5.32 (dd, J = 10.9, 5.7 Hz, 1H), 3.78 (ddd, J = 25.2, 14.3, 8.4 Hz, 2H), 2.47 (s, 3H), 2.19 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 197.92, 167.78, 166.15, 137.92, 137.54, 137.43, 134.70, 133.79, 133.52, 131.37, 129.36, 129.16, 129.03, 127.08, 125.63, 125.02, 123.79, 120.70, 56.13, 34.25, 26.71, 19.21; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₃N₂O₄S⁺: 459.1373, found: 459.1378.

(S)-N-(3-(3-(Benzyloxy)phenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3g). 3g was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.86–7.79 (m, 2H), 7.75–7.68 (m, 2H), 7.47–7.40 (m, 1H), 7.37–7.33 (m, 4H), 7.33–7.27 (m, 2H), 7.13 (dd, J = 14.3, 6.4 Hz, 1H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 6.90–6.80 (m, 2H), 6.76 (dd, J = 8.2, 2.1 Hz, 1H), 5.33 (dd, J = 10.7, 5.9 Hz, 1H), 4.91 (q, J = 11.6 Hz, 2H), 3.70 (qd, J = 14.2, 8.3 Hz, 2H), 2.20 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.86, 166.46, 159.06, 138.31, 138.01, 136.92, 134.52, 133.51, 131.51, 129.87, 129.31, 128.63, 128.03, 127.54, 125.59, 124.91, 123.72, 121.59, 120.68, 115.25, 113.85, 69.93, 56.31, 34.49, 19.19; HRMS(ESI): m/z [M + H]⁺calcd. for C₃₁H₂₇N₂O₄S⁺: 523.1686, found: 523.1734.

(S)-N-(3-(4-(Benzyloxy)phenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3h). 3h was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 8.96 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.86–7.79 (m, 2H), 7.75–7.69 (m, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.39–7.32 (m, 4H), 7.30 (dd, J = 10.4, 4.8 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 5.27 (dd, J = 10.6, 6.1 Hz, 1H), 4.96 (s, 2H), 3.74–3.60 (m, 2H), 2.20 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.92, 166.58, 157.84, 138.08, 137.00, 134.50, 133.55, 131.53, 130.08, 129.33, 128.93, 128.66, 128.06, 127.58, 125.58, 124.89, 123.72, 120.71, 115.19, 70.04, 56.56, 33.67, 19.21; HRMS(ESI): m/z [M + H]⁺ calcd. for C₃₁H₂₇N₂O₄S⁺: 523.1686, found: 523.1700.

(S)-N-(3-(3,4-Dimethoxyphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3i). 3i was obtained as a solid. ¹H NMR (500 MHz, CDCl₃) δ 8.98 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.81 (dt, J = 7.5, 3.8 Hz, 2H), 7.76–7.69 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 7.9 Hz, 2H), 5.29 (dd, J = 10.9, 6.0 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.69–3.60 (m, 2H), 2.21 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.93, 166.59, 148.94, 147.94, 138.03, 134.57, 133.48, 131.51, 129.31, 129.03, 125.64, 124.93, 123.69, 121.20, 120.73, 111.84, 111.38, 56.53, 55.87, 55.80, 34.03, 19.16; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₅N₂O₅S⁺: 477.1479, found: 477.1492.

(S)-N-(3-(3-(Methoxycarbonyl)phenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3j). 3j was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 8.95 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.89 (s, 1H), 7.82 (dt, J = 9.7, 4.9 Hz, 3H), 7.77–7.70 (m, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.30 (dt, J = 15.8, 7.9 Hz, 2H), 7.06 (t, J = 7.6 Hz, 1H), 5.31 (dd, J = 10.8, 5.6 Hz, 1H), 3.83 (s, 3H), 3.76 (ddd, J = 25.1, 14.3, 8.4 Hz, 2H), 2.19 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.78, 166.83, 166.17, 137.97, 137.25, 134.60, 133.58, 131.42, 130.68, 130.18, 129.37, 128.93, 128.47, 125.58, 124.98, 123.79, 120.68, 56.19, 52.22, 34.19, 19.22; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₁N₂O₅S⁺: 475.1322, found: 475.1326.

(S)-N-(3-(4-(Benzyloxy)-3-(methoxycarbonyl)phenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3k). 3k was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 8.94 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.85–7.79 (m, 2H), 7.76–7.70 (m, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.47–7.40 (m, 3H), 7.35 (dd, J = 10.3, 4.8 Hz, 2H), 7.33–7.27 (m, 3H), 7.06 (td, J = 7.6, 1.3 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 5.26 (dd, J = 10.6, 6.0 Hz, 1H), 5.09 (s, 2H), 3.79 (s, 3H), 3.67 (qd, J = 14.4, 8.3 Hz, 2H), 2.20 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.85, 166.30, 166.24, 157.32, 138.01, 136.73, 134.58, 133.97, 133.56, 132.37, 131.49, 129.35, 128.84, 128.63, 127.88, 126.89, 125.61, 124.95, 123.80, 120.78, 120.71, 114.41, 70.71, 56.28, 52.06, 33.41, 19.21; HRMS(ESI): m/z [M + H]⁺calcd. for C₃₃H₂₉N₂O₆S⁺: 581.1741, found: 581.1753.

(S)-N-(3-(3-(Benzyloxy)-4-(methoxycarbonyl)phenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3l). 3l was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 8.95 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.87–7.80 (m, 2H), 7.73 (td, J = 5.2, 2.1 Hz, 2H), 7.70 (t, J = 5.5 Hz, 1H), 7.45 (d, J = 7.5 Hz, 3H), 7.37 (dd, J = 10.3, 4.7 Hz, 2H), 7.34–7.27 (m, 2H), 7.07 (td, J = 7.6, 1.3 Hz, 1H), 6.90 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H), 5.34 (dd, J = 9.5, 7.3 Hz, 1H), 5.02 (dd, J = 41.7, 11.9 Hz, 2H), 3.83 (s, 3H), 3.74 (dd, J = 12.0, 4.7 Hz, 2H), 2.19 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.80, 166.51, 166.13, 158.58, 143.11, 137.92, 136.65, 134.75, 133.55, 132.50, 131.39, 129.39, 128.64, 127.90, 126.92, 125.62, 125.05, 123.86, 121.26, 120.67, 119.34, 114.41, 70.69, 55.75, 52.05, 34.52, 19.20; HRMS(ESI): m/z [M + H]⁺calcd. for C₃₃H₂₉N₂O₆S⁺: 581.1741, found: 581.1752.

(S)-N-(3-(3-Cyano-4-methoxyphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3m). 3m was obtained as a solid. ¹H NMR (500 MHz, CDCl₃) δ 8.91 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.84 (dt, J = 7.4, 3.7 Hz, 2H), 7.79–7.73 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 1.8 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 5.22 (dd, J = 10.8, 5.7 Hz, 1H), 3.84 (s, 3H), 3.66 (ddd, J = 25.3, 14.4, 8.3 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.76, 165.92, 160.36, 137.79, 135.05, 134.83, 134.06, 133.47, 131.26, 129.48, 129.33, 125.63, 125.07, 123.91, 120.65, 116.21, 111.81, 101.95, 56.13, 55.96, 33.15, 19.17; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₂N₃O₄S⁺: 472.1326, found: 472.1341.

(S)-N-(3-(4-Bromophenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3n). 3n was obtained as an oil. ¹H NMR (500 MHz, CDCl₃) δ 8.93 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.83 (dt, J = 7.2, 3.6 Hz, 2H), 7.78–7.70 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 5.27 (dd, J = 10.3, 6.4 Hz, 1H), 3.73–3.64 (m, 2H), 2.19 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.82, 166.19, 137.95, 135.82, 134.70, 133.59, 131.95, 131.39, 130.77, 129.40, 125.55, 125.01, 123.85, 121.09, 120.65, 56.03, 33.86, 19.24; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₄H₂₀BrN₂O₃S⁺: 495.0373, found: 495.0375.

(S)-N-(3-(4-Iodophenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3o). 3o was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 7.82 (dt, J = 7.1, 3.6 Hz, 2H), 7.77–7.71 (m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.2 Hz, 2H), 5.32–5.23 (m, 1H), 3.75–3.59 (m, 2H), 2.18 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.82, 166.18, 137.88, 136.47, 134.68, 133.54, 131.37, 131.03, 129.37, 125.53, 124.99, 123.84, 120.64, 92.62, 55.97, 33.95, 19.22; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₄H₂₀IN₂O₃S⁺: 543.0234, found: 543.0233.

(S)-N-(3-(3-Nitrophenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3p). 3p was obtained as a solid. ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.08 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.83 (dt, J = 7.0, 3.5 Hz, 2H), 7.79–7.71 (m, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.42 (dd, J = 16.3, 8.1 Hz, 2H), 7.31 (t, J = 7.8 Hz, 1H), 7.08 (td, J = 7.6, 1.1 Hz, 1H), 5.32 (dd, J = 10.8, 5.6 Hz, 1H), 3.83 (ddd, J = 25.2, 14.4, 8.2 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.70, 165.71, 148.45, 139.13, 137.79, 135.30, 134.88, 133.57, 131.24, 129.82, 129.43, 125.59, 125.13, 124.07, 123.95, 122.36, 120.64, 55.74, 34.07, 19.23; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₄H₂₀N₃O₅S⁺: 462.1118, found: 462.1161.

(S)-N-(3-(4-tert-Butoxycarbonylaminophenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3q). 3q was obtained as a solid. ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.81 (dt, J = 7.1, 3.6 Hz, 2H), 7.75–7.68 (m, 2H), 7.44 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.16 (dd, J = 25.0, 8.4 Hz, 4H), 7.06 (td, J = 7.7, 1.2 Hz, 1H), 6.37 (s, 1H), 5.27 (t, J = 8.4 Hz, 1H), 3.65 (t, J = 11.5 Hz, 2H), 2.20 (s, 3H), 1.47 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 167.90, 166.53, 152.72, 138.07, 137.33, 134.53, 133.57, 131.50, 131.11, 129.58, 129.35, 125.58, 124.90, 123.76, 120.70, 118.69, 80.55, 56.45, 33.76, 28.43, 19.22; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₉H₃₀N₃O₅S⁺: 532.1901, found: 532.1905.

(S)-N-(3-(4-Bromo-3-formylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3r). 3r was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 8.91 (s, 1H), 8.31 (t, J = 8.1 Hz, 1H), 7.87–7.81 (m, 2H), 7.78–7.72 (m, 3H), 7.50 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.35 (dd, J = 8.2, 2.3 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 5.27 (dd, J = 10.6, 5.8 Hz, 1H), 3.73 (qd, J = 14.1, 8.3 Hz, 2H), 2.18 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 191.51, 167.71, 165.80, 137.79, 137.40, 136.01, 134.80, 134.37, 133.58, 133.54, 131.28, 130.39, 129.38, 125.68, 125.59, 125.08, 123.94, 120.65, 55.69, 33.66, 19.23; HRMS(ESI): m/z [M + Na]⁺calcd. for C₂₅H₁₉BrN₂O₄SNa⁺: 545.0141, found: 545.0183.

(S)-N-(3-(3-Bromo-4-formylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3s). 3s was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H), 8.91 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.84 (dt, J = 7.0, 3.5 Hz, 2H), 7.76 (dt, J = 7.8, 3.9 Hz, 3H), 7.53 (d, J = 5.9 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.35–7.27 (m, 2H), 7.07 (td, J = 7.6, 1.2 Hz, 1H), 5.31 (dd, J = 10.8, 5.6 Hz, 1H), 3.95–3.56 (m, 2H), 2.17 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 191.50, 167.68, 165.64, 145.60, 137.74, 134.89, 134.47, 133.53, 132.42, 131.22, 130.21, 129.41, 128.65, 127.41, 125.61, 125.14, 123.97, 120.63, 55.39, 34.15, 19.21; HRMS(ESI): m/z [M + H]⁺calcd for C₂₅H₂₂BrN₂O₄S⁺: 525.0478, found: 525.0377.

(S)-N-(3-(4-Bromo-2-methoxypheny)-2-phthalimidopropionyl)-2-methylthioaniline (3t). 3t was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 7.85–7.79 (m, 2H), 7.78–7.70 (m, 2H), 7.45 (d, J = 7.7 Hz, 1H), 7.34–7.27 (m, 1H), 7.06 (td, J = 7.6, 1.2 Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.85 (dd, J = 7.9, 1.7 Hz, 1H), 5.44 (dd, J = 10.8, 5.0 Hz, 1H), 3.80 (s, 3H), 3.64 (ddd, J = 24.6, 13.8, 7.9 Hz, 2H), 2.22 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 167.88, 166.72, 158.38, 138.18, 134.47, 133.60, 132.17, 131.59, 129.42, 125.30, 124.78, 124.32, 123.66, 121.75, 120.55, 114.13, 55.76, 54.05, 29.94, 19.24; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₅H₂₂BrN₂O₄S⁺: 525.0478, found: 525.0515.

(S)-N-(3-(5-Formyl-2-methoxyphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3u). 3u was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 9.68 (s, 1H), 8.95 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 7.82–7.77 (m, 2H), 7.74–7.68 (m, 3H), 7.58 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.06 (td, J = 7.6, 1.1 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 5.48 (dd, J = 10.9, 4.8 Hz, 1H), 3.90 (s, 3H), 3.87–3.76 (m, 1H), 3.66 (dd, J = 13.8, 11.0 Hz, 1H), 2.21 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 190.72, 167.80, 166.55, 162.79, 138.08, 134.55, 133.55, 132.86, 131.44, 129.70, 129.39, 129.29, 126.26, 125.36, 124.83, 123.65, 120.56, 110.60, 56.02, 53.90, 30.21, 19.21; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₃N₂O₅S⁺: 475.1322, found: 475.1361.

(S)-N-(3-(2-(Benzyloxy)-5-formylphenyl)-2-phthalimidopropionyl)-2-methylthioaniline (3v). 3v was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 9.68 (s, 1H), 8.86 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.76 (dt, J = 7.0, 3.6 Hz, 2H), 7.69 (tt, J = 5.6, 3.0 Hz, 3H), 7.60 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 7.3 Hz, 2H), 7.46–7.36 (m, 3H), 7.31 (dd, J = 16.6, 7.7 Hz, 2H), 7.05 (td, J = 7.6, 1.3 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 5.55 (dd, J = 10.9, 4.8 Hz, 1H), 5.30–5.14 (m, 2H), 3.88 (dd, J = 13.8, 4.8 Hz, 1H), 3.71 (dd, J = 13.8, 11.0 Hz, 1H), 2.15 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 190.65, 167.80, 166.40, 161.94, 138.02, 135.87, 134.49, 133.50, 133.02, 131.42, 131.26, 129.85, 129.32, 128.92, 128.42, 127.47, 126.47, 125.47, 124.82, 123.64, 120.62, 111.94, 70.85, 53.75, 30.38, 19.11;HRMS(ESI): m/z [M + H]⁺calcd. for C₃₂H₂₇N₂O₅S⁺: 551.1635, found: 551.1676.

3.3. Synthesis of the Compounds 3a and 1

Methyl (S)-3-(4-methoxy-3-formylphenyl)-2-phthalimidopropionate (2a). 3a (3.0 g, 6.3 mmol), dry methanol (600 mL), conc. H₂SO₄ (5.0 mL) were added to a 500-mL round bottom flask. The mixture was stirred at 100 °C for 24 h under N₂. After cooling to room temperature, the resulting solution was evaporated, and the residue was diluted with ethyl acetate (200 mL) and brine (100 mL).The organic layer was separated and washed successively with water, saturated aqueous NaHCO₃ and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The organic layer was purified via column chromatography in a petroleum ether/ethyl acetate mixture of2:1 to produce corresponding product2a (1.8 g, 77%) as a solid.¹H NMR (500 MHz, CDCl₃) δ 10.31 (s, 1H), 7.84–7.75 (m, 2H), 7.74–7.65 (m, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.6, 2.4 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.08 (dd, J = 11.1, 5.1 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.60–3.42 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 189.55, 169.24, 167.54, 160.85, 136.37, 134.35, 131.65, 129.23, 129.09, 124.79, 123.72, 112.12, 55.76, 53.32, 53.08, 33.81; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₀H₁₈NO₆⁺: 368.1129, found: 368.1221.

Methyl (S)-3-(4-methoxy-3-hydroxy-phenyl)-2-phthalimidopropionate (1). 2a (750 mg, 2.0 mmol), dichloromethane (50 mL), and meta-chloroperoxybenzoic acid(m-CPBA,85% purity, 770 mg, 3.8 mmol) were added to a 250-mL round bottom flask. The mixture was stirred at room temperature overnight. The resulting solution was diluted with dichloromethane(DCM, 300 mL), washed successively with saturated aqueous Na₂S₂O₃ and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude intermediate was used for the next step without further purification. A mixture of the concentrated residueandNaHCO₃ (3.4 g, 40 mmol) in tetrahydrofuran (THF,40 mL) and water (20 mL) was stirred at room temperature overnight. Then, the resulting solution was evaporated, and the residue was adjusted to pH<1 with 2 M HCl. The mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. This mixture was purified via column chromatography in a petroleum ether/ethyl acetate mixture of3:1 to produce corresponding product1 (540mg, 74% yield for two steps) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.85–7.73 (m, 2H), 7.74–7.60 (m, 2H), 6.72 (d, J = 1.5 Hz, 1H), 6.68–6.59 (m, 2H), 5.54 (s, 1H), 5.09 (dd, J = 11.2, 5.2 Hz, 1H), 3.76 (s, 6H), 3.46 (qd, J = 14.4, 8.2 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 169.51, 167.61, 145.51, 134.18, 131.73, 129.96, 123.61, 120.40, 115.19, 110.78, 55.90, 53.55, 52.97, 34.11; HRMS(ESI): m/z [M + H]⁺calcd. for C₁₉H₁₈NO₆⁺: 356.1129, found: 356.1138.

3.4. Synthesis of the 4-Aryloxyphenylalanine Derivatives 6a–l

A Schlenk tube was charged with 1 (0.56 mmol), aryl iodide (2.0 equiv., or 3.0 equiv. used for synthesis of 6j), CuI (1.0 equiv.), N,N-dimethylglycine hydrochloride salt (3.0 equiv.), Cs₂CO₃ (5.0 equiv.), and 5.6 mL of 1,4-dioxane, evacuated, and backfilled with N₂. The reaction mixture was stirred at 90 °C for 20 h. The suspension was filtered, and the filtrate was concentrated, followed by column chromatography on silica gel (eluting with 1:10 to 1:5 ethyl acetate/petroleum ether) to provide the desired product.

(S)-3-(3-{4-[(R)-2-Benzyloxycarbonyl-2-tert-butoxycarbonylamino]ethyl}phenoxy)-4-methoxyphenyl)-2-phthalimido-propionic acid methyl ester (6a). 6a was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (dt, J = 5.3, 2.7 Hz, 2H), 7.73–7.65 (m, 2H), 7.40–7.28 (m, 5H), 6.92 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 3H), 6.73 (s, 1H), 6.60 (d, J = 7.6 Hz, 2H), 5.14 (q, J = 12.3 Hz, 2H), 5.07–5.01 (m, 1H), 4.99 (d, J = 3.9 Hz, 1H), 4.64–4.51 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.53–3.35 (m, 2H), 3.01 (d, J = 5.7 Hz, 2H), 1.42 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 171.88, 169.30, 167.46, 156.96, 155.27, 150.35, 144.75, 135.34, 134.30, 131.66, 130.46, 129.74, 129.68, 128.75, 128.66, 125.28, 123.68, 121.83, 121.75, 117.06, 112.97, 80.11, 67.25, 56.01, 54.63, 53.49, 53.02, 37.56, 33.94, 28.45; HRMS(ESI): m/z [M + Na]⁺calcd. for C₄₀H₄₀N₂O₁₀Na⁺: 731.2575, found: 731.2584.

(S)-3-(3-{4-[(S)-2-Benzyloxycarbonyl-2-tert-butoxycarbonylamino]ethyl}phenoxy)-4-methoxyphenyl)-2-phthalimido-propionic acid methyl ester (6b). 6b was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (dt, J = 5.3, 2.7 Hz, 2H), 7.74–7.67 (m, 2H), 7.40–7.28 (m, 5H), 6.92 (d, J = 8.3 Hz, 1H), 6.88–6.78 (m, 3H), 6.72 (s, 1H), 6.59 (d, J = 7.5 Hz, 2H), 5.23–5.07 (m, 2H), 5.07–4.94 (m, 2H), 4.65–4.49 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.55–3.33 (m, 2H), 3.00 (d, J = 5.7 Hz, 2H), 1.42 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 171.86, 169.30, 167.46, 156.95, 155.27, 150.35, 144.69, 135.34, 134.30, 131.66, 130.46, 129.74, 129.69, 128.74, 128.66, 128.63, 125.27, 123.68, 121.82, 121.74, 117.02, 112.97, 80.07, 67.24, 56.01, 54.60, 53.46, 53.01, 37.54, 33.94, 28.44; HRMS(ESI): m/z [M + Na]⁺calcd. for C₄₀H₄₀N₂O₁₀Na⁺: 731.2575, found: 731.2577.

(S)-3-(3-{4-[(R)-2-(2-trimethylsilylethoxycarbonyl)-2-tert-butoxycarbonylamino]ethyl}phenoxy)-4-methoxyphenyl)-2-phthalimido-propionic Acid Methyl Ester (6c). 6c was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (dt, J = 7.6, 2.9 Hz, 2H), 7.75–7.69 (m, 2H), 6.91 (dd, J = 8.3, 1.8 Hz, 3H), 6.80 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 6.65 (d, J = 7.1 Hz, 2H), 5.04 (dd, J = 11.4, 5.1 Hz, 1H), 4.97 (d, J = 7.9 Hz, 1H), 4.49 (d, J = 5.4 Hz, 1H), 4.27–4.10 (m, 2H), 3.75 (s, 3H), 3.72 (d, J = 1.4 Hz, 3H), 3.45 (ddd, J = 25.8, 14.4, 8.3 Hz, 2H), 3.11–2.87 (m, 2H), 1.42 (s, 9H), 0.98 (dd, J = 9.7, 7.6 Hz, 2H), 0.04 (d, J = 0.7 Hz, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 172.15, 169.30, 167.46, 156.91, 155.28, 150.34, 144.78, 134.31, 131.69, 130.49, 130.08, 129.70, 125.23, 123.69, 121.76, 121.69, 117.04, 112.99, 79.97, 63.88, 56.03, 54.67, 53.49, 53.01, 37.64, 33.95, 28.46, 17.49, −1.38; HRMS(ESI): m/z [M + Na]⁺calcd. for C₃₈H₄₆N₂O₁₀SiNa⁺: 741.2814, found: 741.2805.

(S)-3-(3-{4-[(R)-2-Allyloxycarbonyl-2-tert-butoxycarbonylamino]ethyl}phenoxy)-4-methoxyphenyl)-2-phthalimido-propionic acid methyl ester (6d). 6d was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (dt, J = 7.5, 2.9 Hz, 2H), 7.75–7.70 (m, 2H), 6.91 (d, J = 8.3 Hz, 3H), 6.80 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 1.3 Hz, 1H), 6.65 (dd, J = 8.6, 2.4 Hz, 2H), 5.87 (ddt, J = 16.9, 11.3, 5.8 Hz, 1H), 5.28 (dd, J = 22.7, 13.8 Hz, 2H), 5.04 (dd, J = 11.4, 5.1 Hz, 1H), 4.99 (d, J = 5.0 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.56 (s, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.45 (dd, J = 16.9, 8.3 Hz, 2H), 3.02 (d, J = 5.3 Hz, 2H), 1.42 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 171.75, 169.30, 167.46, 156.96, 155.27, 150.34, 144.76, 134.31, 131.68, 130.48, 129.89, 129.70, 125.26, 123.69, 121.76, 121.69, 119.05, 117.09, 112.99, 80.08, 66.06, 56.03, 54.64, 53.47, 53.02, 37.65, 33.95, 28.45; HRMS(ESI): m/z [M + Na]⁺calcd. for C₃₆H₃₈N₂O₁₀Na⁺: 681.2419, found: 681.2408.

(S)-Methyl 2-phthalimido-3-(3-(4-formylphenoxy)-4-methoxyphenyl)-propanoate (6e). 6e was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 9.86 (s, 1H), 7.77 (dt, J = 6.9, 3.6 Hz, 2H), 7.74–7.68 (m, 2H), 7.68–7.62 (m, 2H), 7.04 (dd, J = 8.4, 2.1 Hz, 1H), 6.86 (dd, J = 5.3, 3.1 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2H), 5.07 (dd, J = 11.4, 5.2 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.50 (qd, J = 14.4, 8.3 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 190.90, 169.20, 167.51, 163.51, 150.60, 142.83, 134.41, 131.90, 131.59, 130.88, 130.05, 126.84, 123.69, 123.19, 116.20, 113.24, 55.98, 53.47, 53.09, 33.89; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₂NO₇⁺: 460.1391, found: 460.1394.

(S)-Methyl 2-phthalimido-3-(3-(3-formylphenoxy)-4-methoxyphenyl)-propanoate (6f). 6f was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 9.89 (s, 1H), 7.82–7.74 (m, 2H), 7.73–7.67 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.20 (dd, J = 2.3, 1.4 Hz, 1H), 7.08–7.02 (m, 1H), 7.00–6.94 (m, 1H), 6.83 (d, J = 8.6 Hz, 2H), 5.06 (dd, J = 11.3, 5.2 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.56–3.40 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 192.02, 169.25, 167.51, 158.89, 150.52, 143.76, 137.94, 134.34, 131.61, 130.21, 129.96, 126.24, 123.68, 122.87, 122.45, 117.03, 113.14, 55.99, 53.41, 53.06, 33.94; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₂NO₇⁺: 460.1391, found: 460.1394.

(S)-Methyl2-phthalimido-3-(3-(3-formyl-4-methoxyphenoxy)-4-methoxyphenyl)-propanoate(6g). 6g was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 10.38 (s, 1H), 7.83–7.74 (m, 2H), 7.74–7.67 (m, 2H), 7.23 (d, J = 3.1 Hz, 1H), 7.08 (dd, J = 9.0, 3.2 Hz, 1H), 6.91–6.85 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 5.04 (dd, J = 11.3, 5.3 Hz, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.44 (qd, J = 14.4, 8.3 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 189.25, 169.32, 167.49, 157.75, 151.28, 149.93, 145.40, 134.27, 131.62, 129.69, 125.59, 125.41, 125.07, 123.67, 120.62, 116.84, 113.04, 112.90, 56.20, 56.00, 53.30, 53.00, 33.93; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₇H₂₄NO₈⁺: 490.1496, found: 490.1510.

(S)-Methyl 2-phthalimido-3-(4-methoxy-3-(4-nitrophenoxy)phenyl)-propanoate (6h). 6h was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 8.04–7.95 (m, 2H), 7.80–7.75 (m, 2H), 7.75–7.70 (m, 2H), 7.07 (dd, J = 8.4, 2.1 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.73–6.65 (m, 2H), 5.07 (dd, J = 11.4, 5.2 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.51 (qd, J = 14.4, 8.3 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 169.13, 167.49, 163.59, 150.51, 142.43, 142.26, 134.47, 131.54, 130.17, 127.29, 125.83, 123.70, 123.28, 115.76, 113.30, 55.94, 53.45, 53.12, 33.87; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₅H₂₁N₂O₈⁺: 477.1292, found: 477.1304.

(S)-Methyl 2-phthalimido-3-(3-(4-cyanophenoxy)-4-methoxyphenyl)-propanoate (6i). 6i was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.81–7.69 (m, 4H), 7.44–7.35 (m, 2H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 6.85 (t, J = 4.9 Hz, 2H), 6.75–6.64 (m, 2H), 5.06 (dd, J = 11.4, 5.2 Hz, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.49 (qd, J = 14.4, 8.3 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 169.14, 167.48, 161.89, 150.56, 142.51, 134.42, 133.97, 131.58, 130.12, 127.04, 123.68, 123.19, 119.12, 116.56, 113.25, 105.20, 55.95, 53.46, 53.10, 33.86; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₆H₂₁N₂O₆⁺: 457.1394, found: 457.1401.

(S)-Methyl 2-phthalimido-3-(3-(4-iodophenoxy)-4-methoxyphenyl)-propanoate (6j). 6j was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.83–7.68 (m, 4H), 7.40–7.32 (m, 2H), 6.96 (dd, J = 8.4, 2.1 Hz, 1H), 6.85–6.78 (m, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.49–6.41 (m, 2H), 5.04 (dd, J = 11.4, 5.2 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.55–3.36 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 169.23, 167.48, 158.04, 150.39, 144.11, 138.34, 134.37, 131.60, 129.87, 125.86, 123.68, 122.07, 119.04, 113.10, 84.92, 56.02, 53.55, 53.06, 33.89; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₅H₂₁INO₆⁺: 558.0408, found: 558.0411.

(S)-Methyl 2-phthalimido-3-(3-(4-acetylphenoxy)-4-methoxyphenyl)-propanoate (6k). 6k was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.81–7.75 (m, 3H), 7.71 (tt, J = 8.8, 2.5 Hz, 3H), 7.01 (dd, J = 8.4, 2.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 2H), 6.73–6.67 (m, 2H), 5.10–5.03 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 3.57–3.39 (m, 2H), 2.54 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 196.85, 169.22, 167.50, 162.31, 150.58, 143.11, 134.39, 131.57, 131.38, 130.54, 129.95, 126.55, 123.69, 123.00, 115.75, 113.18, 55.98, 53.47, 53.08, 33.90, 26.58; HRMS(ESI): m/z [M + H]⁺calcd. for C₂₇H₂₄NO₇⁺: 474.1547, found: 474.1573.

(S)-Methyl 2-phthalimido-3-(3-(4-methoxycarbonyl-3-benzyloxyphenoxy)-4-methoxyphenyl)-propanoate (6l). 6l was obtained as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 7.67 (dd, J = 5.4, 3.1 Hz, 2H), 7.62 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 (d, J = 7.3 Hz, 1H), 6.99 (dd, J = 8.4, 2.1 Hz, 1H), 6.82 (dd, J = 8.3, 5.3 Hz, 2H), 6.49 (d, J = 2.3 Hz, 1H), 6.15 (dd, J = 8.7, 2.3 Hz, 1H), 5.08 (s, 2H), 5.07–5.01 (m, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.64 (s, 3H), 3.55–3.39 (m, 2H); ¹³C NMR (126 MHz, CDCl₃) δ 169.21, 167.51, 166.29, 162.81, 160.25, 150.56, 143.14, 136.75, 134.38, 133.72, 131.56, 129.97, 128.64, 127.84, 126.95, 126.49, 123.67, 122.94, 113.97, 113.07, 107.60, 102.16, 70.47, 55.91, 53.54, 53.07, 51.89, 33.93; HRMS(ESI): m/z [M + H]⁺calcd. for C₃₄H₃₀NO₉⁺: 596.1915, found: 596.1930.