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Article

A Facile Synthesis of Fully Protected meso-Diaminopimelic Acid (DAP) and Its Application to the Preparation of Lipophilic N-Acyl iE-DAP

by
Yukako Saito
,
Yuichi Yoshimura
,
Hideaki Wakamatsu
and
Hiroki Takahata
*
Laboratory of Organic and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(1), 1162-1173; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules18011162
Submission received: 5 December 2012 / Revised: 8 January 2013 / Accepted: 9 January 2013 / Published: 16 January 2013
(This article belongs to the Special Issue Chemical Protein and Peptide Synthesis)
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Abstract

:
Synthesis of beneficial protected meso-DAP 9 by cross metathesis of the Garner aldehyde-derived vinyl glycine 1b with protected allyl glycine 2 in the presence of Grubbs second-generation catalyst was performed. Preparation of lipophilic N-acyl iE-DAP as potent agonists of NOD 1-mediated immune response from 9 is described.

1. Introduction

Peptidoglycan (PGN) is an essential component of the cell walls of virtually all bacteria. The function of the PGN is to preserve cell integrity by withstanding the internal osmotic pressure [1,2]. The biosynthesis of PGN is a well-recognized target for antibiotic development [3]. Bacterial cell wall PGN can function as a potent immunostimulator and an adjuvant for antibody production. PGN partial structures are recognized by the intracellular nucleotide-binding oligomerization domain proteins 1 and 2 (NOD1 and NOD2) that mediate host recognition of bacterial molecules [4,5,6]. The recognition core of Nod1 stimulatory molecules is γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP) which is a constituent of most Gram-negative and some Gram-positive bacteria. In addition, synthetic, lipophilic, N-acyl iE-DAP derivatives have been shown to be potent NOD 1 agonists [7]. Thus, DAP scaffold peptides would be expected to function as NOD 1 agonists. In connection with our interest in the synthesis of DAP [8], we report herein on a new synthesis of orthogonally protected meso-DAP and applications to preparing N-acyl iE-DAP from protected iE-DAP (Figure 1).

2. Results and Discussion

Because DAP-containing peptides such as iE-DAP and FK565 [9,10] have significant biological activities and functions, the synthesis of orthogonally protected meso-DAP as synthetic intermediates has been a subject of considerable interest by several groups [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. However, available methods suffer from several disadvantages, including the use of commercially inaccessible starting materials, harsh reaction conditions, multi steps, and lower product yields. We envisaged that orthogonally protected meso-DAP could be conveniently prepared by a cross metathesis (CM) between the readily available Garner aldehyde-derived vinyl glycine equivalent 1 and protected allyl glycine 2 (Scheme 1).
A variety of substituted olefins 1a–e as vinyl glycine equivalents were obtained from the Garner aldehyde in high yields according to the corresponding literature reports [27,28,29,30,31]. It is expected that a homocoupling of 1 would scarcely occur due to a bulkiness of N-Boc-oxazolidine. First, a coupling began with the CM of 1a with 2 [32,33]. Treatment of 1a (5 mmol) with 2 (1 mmol) using the Grubbs second-generation catalyst A (5 mol%, Figure 2) in CH2Cl2 under reflux gave a desired product 3 in 56% together with homo-coupling products traces of 4 and 5 (22%) (entry 1 in Table 1).
Next, the use of a combination of catalysts B [34] and C [34] gave lower yields (28% and 33%) of 3, respectively (entries 2 and 3). On the other hand, when toluene was used as the solvent in place of CH2Cl2, a higher yield (64%) of 3 was obtained (entry 4).
In addition, the use of CM using several substituted olefins 1b–e as vinyl glycine units in toluene was examined and the results are shown in Table 2. The use of 1b (E:Z = 1:10) gave the best yield (76%) of 3. Unfortunately, CM using other derivatives, such as 1c–e, resulted in lower yields (entries 4~6). Furthermore, the CM of 1b with the Hoveyda-Grubbs 2nd generation D [34] and the Blechert E [35] catalysts afforded lower yields (56% and 9%), respectively. Accordingly CM in conjunction with a combination of 1b and A as a catalyst resulted in better yields. Additionally, CM using the pure E isomer and the Z isomer of 1b resulted in nearly the same yields (75%) (entry 7). Furthermore, the CM in Table 2 produced no the homocoupling product 4 as expected.
With 3 in hand, our interest was focused on the synthesis of orthogonally protected meso-DAP. The hydrogenation of 3 in the presence of PtO2 as a catalyst gave 6, which was transformed by hydrolysis of the amino acetal with with p-TsOH in aqueous MeOH into the alcohol 7 in 81% yield in two steps. The primary alcohol of 7 was converted into the carboxylic acid 8 by oxidation with TEMPO, which was esterfied, without isolation, with benzyl alcohol using our developed 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI) [36] to yield the fully protected meso-DAP 9 in 94% yield in two-steps.
Having the desired 9 in hand, we embarked on the synthesis of N-acyl iE-DAP, which is known to function as a strong agonist for the stimulation of NOD 1 [6]. Deprotection of the tert-butoxycarbonyl group of 9 by treatment with trifluoroacetic acid followed by condensation of the resulting amine 10 [37] with Fmoc-d-Glu-OBn [38,39] using EDC in the presence of HOBT and triethylamine gave the protected iE-DAP 11 in 54% yield in two steps. Next, 11 was treated with diethylamine to afford the deprotected amine 12, which was subsequently acylated with capryloyl chloride and myristoyl chloride to produce the corresponding N-acyl derivatives 13 and 14 in 68% and 89% yields, respectively. Finally, the deprotection of 13 and 14 with Pd(OH)2 as the catalyst under hydrogen gave N-capryloyl iE-DAP 15 and N-myristoyl iE-DAP 16, respectively, in quantitative yields (Scheme 2).

3. Experimental

3.1. General

Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 series FT-IR spectrometer. Mass spectra (MS) were recorded on a JEOL JMN-DX 303/JMA-DA 5000 spectrometer (Tokyo, Japan). Microanalyses were performed on a Perkin-Elmer CHN 2400 Elemental Analyzer (Tokyo, Japan). Optical rotations were measured with a JASCO DIP-360 or JASCO P-1020 digital polarimeter. Proton nuclear magnetic resonance (1H-NMR) spectra were recorded on JEOL JNM-EX 270 (270 MHz) or JEOL JNM-AL 400 (400 MHz) or JNM-LA (600 Mhz) spectrometer (Tokyo, Japan), using tetramethylsilane as an internal standard. The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Column chromatography was carried out on Merck Silica gel 60 (230–400 mesh) or KANTO Silica Gel 60N (40–50 μm) for flash chromatography.

3.2. Synthesis

(S)-tert-butyl 2,2-dimethyl-4-vinyloxazolidine-3-carboxylate (1a) [27], (S)-tert-butyl 2,2-dimethyl-4-(prop-1-en-1-yl)oxazolidine-3-carboxylate (1b) [28], (S)-tert-butyl 4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (1c) [29], (S)-tert-butyl 4-(3-hydroxyprop-1-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (1d) [30], (S)-tert-butyl 2,2-dimethyl-4-styryloxazolidine-3-carboxylate (1e) [31] and (S)-benzyl 2-(((benzyloxy)carbonyl)amino)pent-4-enoate (2) [32,33] were prepared by the reported procedures.
(S)-tert-Butyl 4-((R)-5-(benzyloxy)-4-(benzyloxycarbonylamino)-5-oxopent-1-enyl)-2,2-dimethyl-oxazolidine-3-carboxylate (3), (4S,4′S)-di-tert-butyl 4,4′-((E)-ethene-1,2-diyl)bis(2,2-dimethyloxazolidine-3-carboxylate) (4), and (2R,7R,E)-dibenzyl 2,7-bis(((benzyloxy)carbonyl)amino)oct-4-enedioate (5)
To a solution of N-Cbz-(R)-allylglycine benzyl ester (124 mg, 0.36 mmol) and (Z)-(S)-N-Boc-2,2-dimethyl-4-(1-propenyl)oxazolidine (408 mg, 1.8 mmol) in dry CH2Cl2 (1.8 mL) was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl-idene][benzylidine]-ruthenium (IV) dichloride (2nd Grubbs catalyst) (15 mg, 0.018 mmol). After the mixture was refluxed for 7 h, the solvent was evaporated. The residue was chromatographed using (n-hexane/AcOEt = 2:1) as eluent to yield 4 (17 mg), 3 (109 mg, 56%), and 5 (26 mg, 22%).
3: [α]25D +9.73° (c 1.49, CHCl3). IR (neat) cm−1: 3329, 2937, 1726, 1697, 1389, 1366, 1255, 1176. 1H-NMR (400 MHz, CDCl3) δ 1.31–1.56 (15H, m), 2.53–2.60 (2H, m), 3.62 (1H, dd, J = 2.17, 8.93 Hz), 3.97 (1H, dd, J = 6.04, 8.94 Hz), 4.17 (0.5H, br s), 4.30 (0.5H, br s), 4.44–4.49 (1H, m), 5.06–5.24 (4H, m), 5.35–5.56 (3H, m), 7.34 (10H, s). 13C-NMR (100 MHz, CDCl3) δ 23.4, 24.8, 26.5, 27.2, 28.1, 28.3, 34.6, 58.6, 66.7, 66.8, 67.0, 67.8, 67.9, 68.1, 79.5, 80.1, 93.4, 93.8, 125.1, 125.6, 128.0, 128.1, 128.1, 128.4, 128.5, 134.1, 135.1, 136.0, 151.7, 155.6, 171.3. EI-MS m/z 538 (M+). Anal. Calcd for C30H38N2O7: C, 66.90; H, 7.11; N, 5.20. Found: C, 66.80; H, 7.31; N, 5.38.
4: [α]23D +31.5° (c 0.9, CHCl3). 1H-NMR (400 MHz, CDCl3) 1.43–1.83 (30H, m), 3.37 (2H, d, J = 8.7 Hz), 4.03–4.05 (2H, m), 4.29–4.44 (2H, m), 5.59 (1H, br s). EI-MS m/z 426 (M+). HRMS Calcd for C22H38N2O6: 426.2730. Found 426.2728.
5: m.p. 73–74 °C. [α]24D −4.31° (c 1.05, CHCl3). IR (KBr) cm−1:3320, 3064, 3035, 2956, 1741, 1692, 1536, 1346, 1262, 1221, 1052. 1H-NMR (400 MHz, CDCl3) δ 2.35–2.46 (4H, m), 4.40–4.45 (2H, m), 5.08–5.18 (8H, m), 5.24–5.26 (2H, m), 5.40 (2H, br d, J = 7.73 Hz), 7.32 (20H, s). 13C-NMR (100 MHz, CDCl3) 35.3, 53.4, 66.9, 67.2, 128.1, 128.1, 128.4, 128.5, 128.5 128.6, 135.2, 136.2, 155.7, 171.4. EI-MS m/z 650 (M+). HRMS Calcd for C38H38N2O8: 650.2628. Found 650.2624.
To a solution of N-Cbz-(R)-allylglycine benzyl ester (139 mg, 0.41 mmol) and (Z)-(S)-N-Boc-2,2-dimethyl-4-(1-propenyl)oxazolidine (497 mg, 2.06 mmol) in dry toluene(3 mL) was added 2nd Grubbs catalyst (18 mg, 0.021 mmol). After the mixture was refluxed for 4 h, the solvent was evaporated. The residue was chromatographed using (n-hexane/AcOEt = 3:1) as eluent to yield 3 (168 mg, 76%).
(2R,6S)-Benzyl 2-(benzyloxycarbonylamino)-6-(tert-butoxycarbonylamino)-7-hydroxyheptanoate (6)
A mixture of 3 (263 mg, 0.49 mmol) in the presence of PtO2 (1.8 mg, 0.02 mmol) under hydrogen atomosphere in AcOEt (3.5 mL) was stirred for 14 h at room temperature. After the mixture was filtered through Celite, the filtrate was evaporated to provide (S)-tert-Butyl 4-((R)-5-(benzyloxy)-4-(benzyloxycarbonylamino)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (6) (257 mg, 97%) as an oil. [α]25D +11.18° (c 1.2, CHCl3). IR (neat) cm−1: 3340, 2979, 2938, 1695, 1532, 1456, 1392, 1366, 1257, 1210, 1174. 1H-NMR (400 MHz, CDCl3) δ 1.26–1.84 (21H, m), 3.61–3.67 (1.5H, m), 3.82 (1H, br s), 4.41 (1H, br s), 5.09 (2H, s), 5.15 (2H, s), 5.42 (0.5H, br d, J = 7.25 Hz), 5.60 (0.5H, br d, J = 6.76 Hz), 7.33 (10H, s). 13C-NMR (100 MHz, CDCl3) δ 21.8, 23.1, 24.4, 26.7, 27.5, 28.3, 29.6, 32.0, 32.4, 32.5, 33.1, 53.8, 56.8, 57.0, 66.7, 66.8, 66.9, 67.1, 79.4, 80.1, 93.1, 93.6, 128.0, 128.2, 128.4, 128.5, 135.2, 139.2, 152.3, 155.9, 172.1. EI-MS m/z 540 (M+).
Seven drops of water were added to a mixture of carboxylic acid (299 mg, 0.55 mmol) and p-TsOH·H2O (0.07 mmol, 13 mg) in MeOH (5 mL) and then the mixture was stirred for 36 h at room temperature. The whole was evaporated. AcOEt (40 mL) was added to the residue. The mixture was successively washed with sat. NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, and evaporated. The residue was purified with chromatography using (n-hexane/AcOEt = 1:1) as eluent to yield 6 (225 mg, 81%) as solid. M.p. 66–67 °C. [α]25D −2.27° (c 1.0, CHCl3). IR (KBr) cm−1: 3353, 2939, 1742, 1694, 1537, 1289, 1247, 1171, 1048. 1H-NMR (400 MHz, CDCl3) δ 1.31–1.42 (13H, m), 1.54–1.70 (1H, m), 1.80–1.89 (1H, m), 3.45–3.55 (3H, m), 4.39–4.44 (1H, m), 4.83 (1H, br s), 5.09 (2H, s), 5.12–5.21 (2H, m), 5.57 (1H, br s), 7.30–7.36 (10H, m). 13C-NMR (100 MHz, CDCl3) δ 21.3, 28.3, 30.5, 32.5, 52.0, 53.3, 64.5, 67.0, 67.1, 79.4, 128.0, 128.1, 128.2, 128.4, 128.4, 128.6, 135.2, 136.1, 156.2, 156.2, 172.2. EI-MS m/z 500 (M+). HRMS Calcd for C27H36N2O7: 500.2523. Found 500.2503.
(2R,6S)-Dibenzyl 2-(benzyloxycarbonylamino)-6-(tert-butoxycarbonylamino)heptanedioate (9)
2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) (7 mg, 0.045 mmol) and 2 M NaClO2 (0.43 mL, 0.86 mmol) were added to a solution of 7 (225 mg, 0.45 mmol) in MeCN: sodium phosphate buffer consisted of a 1:1 mixture of 0.67 M NaH2PO4 and 0.67 M Na2HPO4 (pH = 6.5 ) (3:2, 6.5 mL) at 40 °C. A diluted solution of commercial bleach (25.5 μL) in H2O (485 μL) was then added to the gradually over 0.5 h, and the reaction was stirred at 40 °C for 18 h. The reaction was cooled to room temperature and quenched with sat. aq. Na2SO3 until the mixture became colorless. The solvent was evaporated, the aqueous mixture acidified to pH < 3 with 1 M HCl and extracted with ether (10 mL) five times. Organic layers were washed with brine, dried overNa2SO4 and evaporated to yield (2S,6R)-7-(benzyloxy)-6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-7-oxoheptanoic acid (8). Without further purification, a mixture of 8 and BBDI (164 mg, 0.54 mmol) and benzyl alcohol (48 mg, 0.45 mmol) in CH2Cl2 (2 mL) was stirred for 19 h at room temperature. AcOEt (40 mL) was added to the mixture and the whole was successively washed with 5% HCl (10 mL) and brine (10 mL). The solvent was dried over Na2SO4 and evaporated. The residue was purified with chromatography using n-hexane/AcOEt (3:1) to yield 7 (256 mg, 94%, 2 steps). M.p. 82–83 °C. [α]24D −0.28° (c 1.4, CHCl3). IR (neat) cm−1: 3345, 2955, 1741, 1716, 1525, 1367, 1215, 1167. 1H-NMR (400 MHz, CDCl3) δ 1.22–1.42 (11H, m), 1.53–1.67 (2H, m), 1.75–1.88 (2H, m), 4.26–4.31 (1H, m), 4.34–4.39 (1H, m), 5.02 (1H, br d, J = 7.25 Hz), 5.06–5.20 (6H, m), 5.33 (1H, br d, J = 7.25 Hz), 7.26–7.34 (15H, m). 13C-NMR (100 MHz, CDCl3) δ 20.8, 28.2, 31.8, 32.1, 53.0, 53.6, 67.0, 67.1, 79.9, 128.1, 128.1, 128.3, 128.4, 128.5, 128.6, 128.6, 135.2, 135.3, 136.1, 155.4, 155.9, 172.0, 172.3. EI-MS m/z 604 (M+). Anal. Calcd for C34H40N2O8: C, 67.53; H, 6.67; N, 4.63. Found: C, 67.29; H, 6.81; N, 4.43.
(2S,6R)-Dibenzyl 2-((R)-4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-(benzyloxy)-5-oxopentan-amido)-6-(benzyloxycarbonylamino)heptanedioate (11)
TFA (0.6 mL) was added to a mixture of 9 (78 mg, 0.13 mmol) in CH2Cl2 (0.7 mL) and then the mixture was stirred for 2 h at room temperature. CH2Cl2 (5 mL) was added to the reaction mixture and the whole neutralized with sat. NaHCO3. The mixture was extracted with CH2Cl2, dried over Na2SO4 and evaporated to yield an amine 10. Fmoc-d-Glu benzyl ester (59 mg, 0.129 mmol) was added to a solution of the prepared amine 10 in DMF (1.5 mL). Et3N (20 μL, 0.142 mmol), HOBt (21 mg, 0.155 mmol), and EDC·HCl (27 mg, 0.142 mmol) were successively added to the mixture at −20 °C. The reaction was stirred for 20 min at the same temperature and then was done at room temperature for 20 h. After addition of AcOEt (100 mL), the mixture was successively washed with 1 N HCl, brine (10 mL × 2), water (10 mL), and 5% NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified with chromatography using (n-hexane/AcOEt = 1:1) as eluent to yield 11 (70 mg, 57%, 2 steps) as an oil. [α]23D −2.0° (c 1.6, CHCl3). IR (neat) cm−1: 3367, 2920, 2851, 1734, 1722, 1662, 1534, 1250, 1211. 1H-NMR (400 MHz, CDCl3) δ 1.30–1.39 (1H, m), 1.56–1.67 (3H, m), 1.77–1.84 (2H, m), 1.91–2.00 (1H, m), 2.20 (3H, br s), 4.14–4.19 (1H, m), 4.32–4.48 (3H, m), 4.55 (1H, dd, J = 7.24, 13.04 Hz), 5.06–5.18 (9H, m), 5.34 (1H, br d, J = 7.24 Hz), 5.71(1H, br d, J = 7.73 Hz), 6.51 (1H, br d, J = 6.76 Hz), 7.29–7.40 (24H, m), 7.58 (2H, br d, J = 7.25 Hz), 7.75 (2H, br d, J = 7.73 Hz). 13C-NMR (100 MHz, CDCl3) δ 20.8, 28.6, 31.3, 31.9, 32.0, 47.1, 51.9, 53.3, 53.5, 66.9, 67.0, 67.1, 119.9, 119.9, 125.1, 127.0, 127.7, 128.0, 128.1, 128.2, 128.2, 128.4, 128.5, 128.6, 135.1, 135.2, 135.2, 136.1, 141.2, 141.2, 143.6, 143.8, 156.0, 156.3, 171.8, 171.8, 171.9, 171.9. FAB-MS m/z 946 (M++1). HRMS Calcd for C56H55N3O11: 946.3870. Found 946.3934.
(2S,6R)-Dibenzyl 2-((R)-4-heptanecarbonylamino-5-(benzyloxy)-5-oxopentanamido)-6-(benzyloxycarbonylamino)heptanedioate (13)
Et2NH (2.5 mL) was gradually added to a solution of 11 (62 mg, 0.066 mmol) in THF (1 mL) with ice cooling over 20 min. The reaction was stirred at room temperature for 3 h and then was evaporated. The residue was purified with chromatography using (CHCl3/MeOH = 100:1) as eluent to yield (2S,6R)-Dibenzyl 2-((R)-4-amino-5-(benzyloxy)-5-oxopentanamido)-6-(benzyloxycarbonylamino)heptanedioate (12). [α]24D −3.1° (c 1.0, CHCl3). IR (neat) cm−1: 3309, 2925, 1739, 1648, 1534, 1215. 1H-NMR (400 MHz, CDCl3) δ 1.21–1.41 (2H, m), 1.56–1.66 (3H, m), 1.74–1.83 (3H, m), 2.06–2.11 (1H, m), 2.21–2.28 (1H, m), 2.32–2.38 (1H, m), 3.45–3.49 (1H, m), 4.32–4.37 (1H, m), 4.55–4.60 (1H, m), 5.07–5.15 (8H, m), 5.38 (1H, br d, J = 7.73 Hz), 6.59 (1H, br d, J = 7.73 Hz), 7.30–7.33 (20H, m). 13C-NMR (100 MHz, CDCl3) δ 20.8, 29.7, 31.6, 31.9, 32.4, 51.7, 53.5, 53.5, 66.7, 67.0, 67.1, 67.1, 128.0, 128.1, 128.2, 128.3, 128.3, 128.4, 128.4, 128.5, 128.6, 128.6, 135.2, 135.5, 136.1, 156.0, 172.0, 172.0, 172.1, 175.4. FAB-MS m/z 724 (M++1). HRMS Calcd for C41H45N3O9: 724.3189. Found 724.3230.
Et3N (9 μL, 0.063 mmol) and n-octanoyl chloride (9 μL, 0.053 mmol) were added to a solution of the amine 12 in CH2Cl2(1 mL) with ice cooling. The reaction was stirred at room temperature for 7 h and then evaporated. After addition of AcOEt (30 mL), the mixture was washed with 10% citric acid (10 mL) and brine (10 mL). The organic solvent was dried over Na2SO4 and evaporated. The residue was purified with chromatography using (n-hexane/AcOEt = 1:1)) as eluent to yield 13 (38 mg, 68%, 2 steps) as an oil. 1H-NMR (400 MHz, CDCl3) δ 0.87 (3H, t, J = 6.76 Hz), 1.19–1.41 (8H, m), 1.54–1.71 (6H, m), 1.75–1.93 (2H, m), 2.16–2.24 (6H, m), 4.33–4.38 (1H, m), 4.55 (1H, dd, J = 7.25, 12.57 Hz), 4.73–4.77 (1H, m), 5.09–5.15 (8H, m), 5.50 (1H, br d, J = 8.21 Hz), 6.46 (1H, br d, J = 7.25 Hz), 7.04 (1H, br d, J = 7.73 Hz), 7.29–7.33 (20H, m). FAB-MS m/z 850 (M++1). HRMS Calcd for C49H59N3O10: 850.4234. Found 850.4278.
(2S,6R)-Dibenzyl 2-((R)-4-tridecanecarbonylamino-5-(benzyloxy)-5-oxopentanamido)-6-(benzyloxycarbonylamino)heptanedioate (14)
According to the procedure described for a preparation of 13, a treatment of 11 (71 mg, 0.075 mmol) with Et2NH (2 mL) gave 12 (39 mg, 72%), which was converted with Et3N (8 μL, 0.058 mmol) and myristoyl chloride (16 μL, 0.058 mmol) into 14 (40 mg, 89%) as a solid. M.p. 90–92 °C. [α]27D −4.6° (c 1.3, CHCl3). 1H-NMR (400 MHz, CDCl3) δ 1H-NMR (400 MHz, CDCl3) δ 0.88 (3H, t, J = 6.76 Hz), 1.24–1.41 (22H, m), 1.56–1.92 (8H, m), 2.16–2.23 (4H, m), 4.33–4.36 (1H, m), 4.53–4.58 (1H, m), 4.71–4.77 (1H, m), 5.07–5.18 (8H, m), 5.55 (1H, br d, J = 8.21 Hz), 6.51 (1H, br d, J = 7.73 Hz), 7.06 (1H, br d, J = 7.73 Hz), 7.29–7.32 (20H, m). 13C-NMR (100 MHz, CDCl3) δ 14.1, 21.0, 22.6, 25.6, 29.0, 29.2, 29.3, 29.3, 29.5, 29.6, 29.6, 29.6, 31.1, 31.8, 31.9, 32.2, 36.5, 51.6, 52.0, 53.6, 67.0, 67.0, 67.1, 67.3, 128.0, 128.1, 128.2, 128.4, 128.4, 128.5, 128.6, 128.6, 135.1, 135.2, 135.3, 136.2, 156.0, 172.0, 172.1, 173.9. FAB-MS m/z 935 (M++2). Anal. Calcd for C55H71N3O10: C, 70.71; H, 7.66; N, 4.50. Found C, 70.73; H, 7.90; N, 4.48.
(2R,6S)-2-Amino-6-((R)-4-carboxy-4-octanamidobutanamido)heptanedioic acid (15)
A suspension of 13 (34 mg, 0.04 mmol) in the presence Pd(OH)2 (25 mg) under hydrogen atomosphere in MeOH (1.5 mL) was stirred for 3 h. The mixture was filtered through Celite. The filtrate was evaporate to yield 15 quantitatively as an oil. [α]23D −1.3° (c 1.0, MeOH:CHCl3 = 1:1). 1H-NMR (400 MHz, CDCl3) δ 0.90 (3H, t, J = 6.28 Hz), 1.31–1.32 (10H, m), 1.52–1.64 (4H, m), 1.73–1.76 (1H, m), 1.85–2.04 (4H, m), 2.14–2.19 (1H, m), 2.23–2.27 (2H, m), 2.35–2.38 (2H, m), 3.68 (br s, 1H), 4.37–4.40 (2H, m). 13C-NMR (100 MHz, CDCl3) δ 14.4, 22.6, 23.7, 26.9, 28.7, 30.2, 30.3, 31.6, 32.3, 32.9, 33.1, 36.9, 53.5, 53.6, 55.4, 173.8, 175.0, 175.4, 175.6, 176.4. FAB-MS m/z 446 (M++1).
(2R,6S)-2-Amino-6-((R)-4-carboxy-4-tetradecanamidobutanamido)heptanedioic acid (16)
A suspension of 14 (32 mg, 0.034 mmol) in the presence Pd(OH)2 (20 mg) under hydrogen atomosphere in MeOH (1.5 mL) was stirred for 3 h. The mixture was filtered through Celite. The filtrate was evaporate to yield 16 quantitatively as an oil. IR (neat) cm−1: 3425, 2919, 2850, 1710, 1637, 1538. 1H-NMR (400 MHz, CD3OD) δ 0.89 (3H, t, J = 6.76 Hz), 1.28–1.31 (20H, m), 1.52–1.63 (4H, m), 1.69–1.79 (1H, m), 1.83–2.02 (4H, m), 2.14–2.18 (1H, m), 2.24 (2H, t, J = 7.25 Hz), 2.36 (2H, t, J = 7.49 Hz), 3.78–3.81 (1H, m), 4.36–4.44 (2H, m). 13C-NMR (100 MHz, CD3OD) δ 14.4, 22.6, 23.7, 26.9, 28.6, 30.3, 30.5, 30.5, 30.7, 30.8, 30.8, 30.8, 31.3, 32.2, 33.1, 33.1, 36.8, 53.3, 53.4, 54.7, 172.9, 175.0, 175.1, 175.3, 176.5. FAB-MS m/z 530 (M++1). HRMS Calcd for C26H47N3O8: 530.3447. Found 530.3397.

4. Conclusions

In summary, a concise synthesis of N-acyl iE-DAP was accomplished starting from the protected meso-DAP 9 as a convenient synthon via the use of CM between the Garner aldehyde-derived vinyl glycine 1b and the protected allyl glycine 2 in nine steps in yields in the range of 22%~29%.

Acknowledgments

This work was supported in part by a grant of Strategic Research Foundation Grant-aided Project for Private Universities from Ministry of Education, Culture, Sport, Science, and Technology, Japan (MEXT).

References

  1. Rietschel, E.T.; Schletter, J.; Weidemann, B.; El-Samalouti, V.; Mattern, T.; Zahringer, U.; Seydel, U.; Brade, H.; Flad, H.D.; Kusumoto, S.; et al. Lipopolysaccharide and peptidoglycan: CD14-dependent bacterial inducers of inflammation. J. Microb. Drug Resist. 1998, 4, 37–44. [Google Scholar] [CrossRef] [PubMed]
  2. Van Heijenoort, J. Formation of the glycan chains in the synthesis of bacterial peptidoglycan. Glycobiology 2001, 11, 25R–36R. [Google Scholar] [CrossRef] [PubMed]
  3. Bugg, T.D.H.; Braddick, D.; Dowson, C.G.; Roper, D.I. Bacterial cell wall assembly: Still an attractive antibacterial target. Trends Biotechnol. 2011, 29, 167–173. [Google Scholar] [CrossRef] [PubMed]
  4. Chamaillard, M.; Hashimoto, M.; Horie, Y.; Masumoto, J.; Qiu, S.; Saab, L.; Ogura, Y.; Kawasaki, A.; Fukase, K.; Kusumoto, S. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat. Immunol. 2003, 4, 702–707. [Google Scholar] [CrossRef] [PubMed]
  5. Girardin, S.E.; Travassos, L.H.; Herve, M.; Blanot, D.; Boneca, I.G.; Philpott, D.J.; Sansonetti, P.J.; Mengin-Lecreulx, D. Peptidoglycan molecular requirements allowing detection by Nod1 and Nod 2. J. Biol. Chem. 2003, 278, 41702–41708. [Google Scholar] [CrossRef] [PubMed]
  6. Masumoto, J.; Yang, K.; Varambally, S.; Hasegawa, M.; Tomlins, S.A.; Qiu, S.; Fujimoto, Y.; Kawasaki, A.; Foster, S.J.; Horie, Y.; et al. Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo. J. Exp. Med. 2006, 203, 203–213. [Google Scholar] [CrossRef] [PubMed]
  7. Hasegawa, M.; Kawasaki, A.; Yang, K.; Fujimoto, Y.; Masumoto, J.; Breukink, E.; Nunez, G.; Fukase, K.; Inohara, N. A Role of Lipophilic Peptidoglycan-related Molecules in Induction of Nod1-mediated Immune Responses. J. Biol. Chem. 2007, 282, 11757–11764. [Google Scholar] [CrossRef] [PubMed]
  8. Saito, Y.; Shinkai, T.; Yoshimura, Y.; Takahata, H. A straightforward stereoselective synthesis of meso-, (S,S)- and (R,R)-2,6-diaminopimelic acids from cis-1,4-diacetoxycyclohept-2-ene. Bioorg. Med. Chem. Lett. 2007, 17, 5894–5896. [Google Scholar] [CrossRef] [PubMed]
  9. Gotoh, T.; Nakahara, K.; Iwami, M.; Aoki, H.; Imanaka, H. Studies on a new immunoactive peptide, FK-156. I. Taxonomy of the producing strains. J. Antibiot. 1982, 35, 1280–1285. [Google Scholar] [CrossRef] [PubMed]
  10. Gotoh, T.; Nakahara, K.; Nishiura, T.; Hashimoto, M.; Kino, T.; Kuroda, Y.; Okuhara, M.; Kohsaka, M.; Aoki, H.; Imanaka, H. Studies on a new immunoactive I peptide, FK-156 II. Fermentation, extraction and chemical and biological characterization. J. Antibiot. 1982, 35, 1286–1292. [Google Scholar] [CrossRef] [PubMed]
  11. Jurgens, A.R. Asymmetric synthesis of differentially protected meso-2,6-diaminopimelic acid. Tetrahedron Lett. 1992, 33, 4727–4730. [Google Scholar] [CrossRef]
  12. Williams, R.M.; Yuan, C. Asymmetric synthesis of 2,6-diaminopimelic acids. J. Org. Chem. 1992, 57, 6519–6527. [Google Scholar] [CrossRef]
  13. Holcomb, R.C.; Schow, S.; Ayral-Kaloustian, S.; Powell, D. An asymmetric synthesis of differentially protected meso-2,6-diaminopimelic acid. Tetrahedron Lett. 1994, 35, 7005–7008. [Google Scholar] [CrossRef]
  14. Gao, Y.; Lane-Bell, P.; Vederas, J.C. Stereoselective Synthesis of meso-2,6-Diaminopimelic Acid and Its Selectively Protected Derivatives. J. Org. Chem. 1998, 63, 2133–2143. [Google Scholar] [CrossRef]
  15. Davis, F.A.; Srirajan, V. Asymmetric Synthesis of (2S,6S)- and meso-(2S,6R)-Diaminopimelic Acids from Enantiopure Bis(sulfinimines). J. Org. Chem. 2000, 65, 3248–3251. [Google Scholar] [CrossRef] [PubMed]
  16. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. A simple asymmetric synthesis of (+)- and (−)-2,6-diaminopimelic acids. Tetrahedron: Asymmetry 2000, 11, 1259–1262. [Google Scholar] [CrossRef]
  17. Collier, P.N.; Patel, I.; Taylor, R.J.K. A concise, stereoselective synthesis of meso-2,6-diaminopimelic acid (DAP). Tetrahedron Lett. 2001, 42, 5953–5954. [Google Scholar] [CrossRef]
  18. Collier, P.N.; Campbell, A.D.; Patel, I.; Raynham, T.M.; Taylor, R.J.K. Enantiomerically Pure α-Amino Acid Synthesis via Hydroboration-Suzuki Cross-Coupling. J. Org. Chem. 2002, 67, 1802–1815. [Google Scholar] [CrossRef] [PubMed]
  19. Roberts, J.L.; Chan, C. Asymmetric synthesis of differentially protected meso-2,6-diaminopimelic acid. Tetrahedron Lett. 2002, 43, 7679–7682. [Google Scholar] [CrossRef]
  20. Sutherland, A.; Vederas, J.C. Conjugate addition of radicals generated from diacyloxyiodobenzenesto dehydroamino acid derivatives; a synthesis of diaminopimelic acid analogues. Chem. Commun. 2002, 224–225. [Google Scholar] [CrossRef]
  21. Galeazzi, R.; Garavelli, M.; Grandi, A.; Monari, M.; Porzi, G.; Sandri, S. Unusual peptides containing the 2,6-diaminopimelic acid framework: Stereocontrolled synthesis, X-ray analysis, and computational modelling. Part 2. Tetrahedron: Asymmetry 2003, 14, 2639–2649. [Google Scholar] [CrossRef]
  22. Spantulescu, M.D.; Jain, R.P.; Derksen, D.J.; Vederas, J.C. Photolysis of Diacyl Peroxides: A Radical-Based Approach for the Synthesis of Functionalized Amino Acids. Org. Lett. 2003, 5, 2963–2965. [Google Scholar] [CrossRef] [PubMed]
  23. Del, J.R.; Goodman, M. An Efficient RCM-Based Synthesis of Orthogonally Protected meso-DAP and FK565. J. Org. Chem. 2004, 69, 8946–8948. [Google Scholar]
  24. Chowdhury, A.R.; Boons, G. The synthesis of diaminopimelic acid containing peptidoglycan fragments using metathesis cross coupling. Tetrahedron Lett. 2005, 46, 1675–1678. [Google Scholar] [CrossRef]
  25. Kawasaki, A.; Karasudani, Y.; Otsuka, Y.; Hasegawa, M.; Inohara, N.; Fujimoto, Y.; Fukase, K. Synthesis of Diaminopimelic Acid Containing Peptidoglycan Fragments and Tracheal Cytotoxin (TCT) and Investigation of Their Biological Functions. Chem. Eur. J. 2008, 14, 10318–10330. [Google Scholar] [CrossRef] [PubMed]
  26. Wang, W.; Xiong, C.; Yang, J.; Hruby, V.J. An efficient synthesis of (2S,6S)- and meso-diaminopimelic acids via asymmetric hydrogenation. Synthesis 2002, 94–98. [Google Scholar]
  27. Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.; Adachi, I.; Takahata, H. Asymmetric synthesis of fagomine and its congeners. Tetrahedron: Asymmetry 2001, 12, 817–819. [Google Scholar] [CrossRef]
  28. Collado, I.; Pedregal, C.; Mazon, A.; Espinosa, J.F.; Blanco-Urgoiti, J.; Schoepp, D.D.; Wright, R.A.; Johnson, B.G.; Kingston, A.E. (2S,1′S,2′S,3′R)-2-(2′-Carboxy-3′-methylcyclopropyl) Glycine Is a Potent and Selective Metabotropic Group 2 Receptor Agonist with Anxiolytic Properties. J. Med. Chem. 2002, 45, 3619–3629. [Google Scholar] [CrossRef] [PubMed]
  29. Fa Liu, F.; Hu, T.-S.; Yao, Z.-J. Stereoselective synthesis of new modified conformationally constrained L-tyrosine analogue with potential applications to SH2 domain ligands. Tetrahedron 2005, 61, 4971–4981. [Google Scholar] [CrossRef]
  30. Devel, L.; Hamon, L.; Becker, H.; Thellend, A.; Vidal-Crosa, A. Synthesis of protected 2-amino-2-deoxy-D-xylothionolactam derivatives and some aspects of their reactivity. Carbohydr. Res. 2003, 338, 1591–1601. [Google Scholar] [CrossRef]
  31. Schmidtmann, F.W.; Benedum, T.E.; McGarvey, G.J. First Total Synthesis of 1-O-β-d-Glucopyranosyl-5-deoxyadenophorine and Its Aglycon Congener: Determination of the Absolute Configuration. J. Org. Chem. 2004, 69, 1497–1503. [Google Scholar]
  32. Robl, J.A. Heterocyclo-fused [1,3]oxazepines and –thiazepines and analogs as inhibitors of neutral endopeptiadase and angiotensin converting enzyme. U.S. Patent US 5508272 A, 16 April 1996. [Google Scholar]
  33. Robl, J.A.; Kronenthal, D.R.; Goderey, J.D., Jr. Bicyclic carboxylic acids as inhibitors of neutral endopeptidase and angiotensin-converting enzyme. Eur. Patent EP 629627A2, 21 December 1994. [Google Scholar]
  34. Schrodi, Y.; Pederson, R.L. Evolution and Applications of Second-Generation Ruthenium Olefin Metathesis Catalysts. Aldrichimica Acta 2007, 40, 45–52. [Google Scholar]
  35. Wakamatsu, H.; Blechert, S. A Highly Active and Air-Stable Ruthenium Complex for Olefin Metathesis. Angew. Chem. Int. Ed. 2002, 41, 794–796. [Google Scholar] [CrossRef]
  36. Saito, Y.; Watanabe, T.; Takahata, H. A novel 1-tert-butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI)-catalyzed esterification of N-protected amino acids with nearly equimolar amounts of alcohols in the presence of Boc2O. Tetrahedron Lett. 2006, 47, 3099–3102. [Google Scholar] [CrossRef]
  37. Conversion of 10 to meso-DAP has been accomplished by hydrogenlysis and the spectral data of hydrochloride salt of prepared meso-DAP was accordance with those of our reported values (ref. [8]).
  38. Demaria, S.; Metafora, V.; Metafora, S.; Ravagnan, G.; Carteni, M.; Pontoni, G.; Facchiano, A.; Lepretti, M.; Severino, B.; Caliendo, G.; et al. Effect of positive charge in VIP 16γ-glutamyl diamino derivatives on hVPAC1 and hVPAC2 receptor function. J. Pept. Sci. 2008, 14, 102–109. [Google Scholar] [CrossRef] [PubMed]
  39. Hard, I.; Torres, J.L.; Valencia, G.; Garcia-Anton, J.M.; Reig, F. Synthesis and biological activity of substance P analogues. Int. J. Peptide Protein Res. 1989, 33, 335–339. [Google Scholar]
Sample Availability: Contact the authors.
Molecules 18 01162 g001 550
Figure 1. Structures of meso-DAP and iE-DAP.
Figure 1. Structures of meso-DAP and iE-DAP.
Molecules 18 01162 g001
Molecules 18 01162 sch001 550
Scheme 1. Cross metathesis of Garner aldehyde-derived vinyl glycine equivalents 1 and protected allyl glycine 2.
Scheme 1. Cross metathesis of Garner aldehyde-derived vinyl glycine equivalents 1 and protected allyl glycine 2.
Molecules 18 01162 sch001
Molecules 18 01162 g002 550
Figure 2. Catalysts for cross metathesis.
Figure 2. Catalysts for cross metathesis.
Molecules 18 01162 g002
Molecules 18 01162 sch002 550
Scheme 2. Synthesis of N-acyl iE-DAP.
Scheme 2. Synthesis of N-acyl iE-DAP.
Molecules 18 01162 sch002
Table
Table 1. CM of 1a with 2.
Table 1. CM of 1a with 2.
Entry1CatalystSolventTime (h)Yield (%)
11aACH2Cl2756
21aBCH2Cl24.528
31aCCH2Cl23633
41aAToluene364
All reactions were carried out with a ratio (1a:2 = 5:1) under reflux.
Table
Table 2. CM of Garner aldehyde-derived vinyl glycine equivalents 1b–e with 2.
Table 2. CM of Garner aldehyde-derived vinyl glycine equivalents 1b–e with 2.
Entry1CatalystTime (h)Yield (%)
11bA476
21bD356
31bE49
41cA4trace
51dA39
61eA310
71b (E:Z = 10:1)A475
All reactions were carried out with a ratio (1:2 = 5:1) under reflux in toluene.

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Saito, Y.; Yoshimura, Y.; Wakamatsu, H.; Takahata, H. A Facile Synthesis of Fully Protected meso-Diaminopimelic Acid (DAP) and Its Application to the Preparation of Lipophilic N-Acyl iE-DAP. Molecules 2013, 18, 1162-1173. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules18011162

AMA Style

Saito Y, Yoshimura Y, Wakamatsu H, Takahata H. A Facile Synthesis of Fully Protected meso-Diaminopimelic Acid (DAP) and Its Application to the Preparation of Lipophilic N-Acyl iE-DAP. Molecules. 2013; 18(1):1162-1173. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules18011162

Chicago/Turabian Style

Saito, Yukako, Yuichi Yoshimura, Hideaki Wakamatsu, and Hiroki Takahata. 2013. "A Facile Synthesis of Fully Protected meso-Diaminopimelic Acid (DAP) and Its Application to the Preparation of Lipophilic N-Acyl iE-DAP" Molecules 18, no. 1: 1162-1173. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules18011162

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