Total Synthesis of Arylomycin A₂, a Signal Peptidase I (SPase I) Inhibitor

Abstract

A concise total synthesis of arylomycin A₂ has been accomplished featuring a key intramolecular Suzuki-Miyaura reaction for the formation of the 14-membered meta,meta-cyclophane and direct coupling of a fully elaborated peptide side chain with the macrocyclic core.

Key words

total synthesis - cross-coupling - palladium - macrocycles - antibiotics

References and Notes

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11

Selected Physical and Spectroscopic Data
Compound 10: [α]_D ^²5 +86 (c 0.9, MeOH). ^¹H NMR (300 MHz, MeOD): δ = 7.61 (d, J = 2.0 Hz, 1 H), 7.12 (dd, J = 8.3, 2.0 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 5.47 (s, 1 H), 2.66 (s, 3 H), 1.48 (s, 9 H) ppm. HRMS (ES⁺): m/z calcd for C₁₄H₁₈NO₅NaI [M + Na]⁺: 430.0127; found: 430.0128.
Compound 5: [α]_D ^²5 +16 (c 1.0, CHCl₃). ^¹H NMR (300 MHz, CDCl₃, 1:1 mixture of rotamers): δ = 7.72 and 7.71 (d, J = 2.2 Hz, 1 H), 7.42 and 7.30 (d, J = 2.3 Hz, 1 H), 7.29-7.24 (m, 0.5 H, overlapped with solvent), 7.22 (dd, J = 8.5, 2.2 Hz, 0.5 H), 7.22 (dd, J = 8.5, 2.2 Hz, 0.5 H), 7.10 (dd, J = 8.5, 2.2 Hz, 0.5 H), 6.78 (d, J = 8.5 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 1 H), 6.58-6.32 (m, 1 H), 6.54 and 6.37 (d, J = 7.3 Hz, 1 H), 5.67-6.57 (m, 1 H), 4.81-4.70 (m, 1 H), 4.59-4.46 (m, 1 H), 3.88 and 3.87 (s, 3 H), 3.79 and 3.77 (s, 3 H,), 3.72 and 3.71 (s, 3 H), 3.11-2.96 (m, 2 H), 2.71 and 2.69 (s, 3 H), 1.48 and 1.47 (s, 9 H), 1.41-1.24 (m, 15 H) ppm. MS (ES⁺): m/z = 832 [M + Na]⁺. Anal. Calcd for C₃₅H₄₉N₃O₁₀IB: C, 51.93; H, 6.10; N, 5.19. Found: C, 51.83; H, 6.30; N, 5.10.
Compound 15: [α]_D ^²6 +44 (c 1.1, CHCl₃). ^¹H NMR (500 MHz, CDCl₃, 1:1.9 mixture of rotamers): δ = 7.20-7.25 (m, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.94 and 6.93 (d, J = 8.5 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.78 and 6.73 (s, 1 H), 6.75 and 6.68 (s, 1 H), 6.34-6.27 (m, 1 H), 6.26 and 6.21 (d, J = 8.5 Hz, 1 H), 5.93 and 5.61 (s, 1 H), 4.95-4.87 (m, 1 H), 4.77-4.67 (m, 1 H), 3.83 (s, 3 H), 3.82 and 3.81 (s, 6 H), 3.58-3.47 (m, 1 H), 3.05 and 3.04 (dd, J = 15.9, 6.9 Hz, 1 H), 2.71 and 2.70 (s, 3 H), 1.51 and 1.49 (br s, 9 H), 1.42-1.37 (m, 3 H) ppm. ^¹H NMR (500 MHz, DMSO-d ₆, 1:1 mixture of rotamers): δ = 9.06-9.01 (m, 1 H), 8.37 and 8.31 (d, J = 8.3 Hz, 1 H), 7.24-7.11 (m, 2 H), 7.10-7.05 (m, 1 H), 7.00 (d, J = 8.5 Hz, 1 H), 6.70-6.60 (m, 2 H), 5.92 and 5.74 (s, 1 H), 4.91-4.79 (m, 1 H,), 4.78-4.65 (m, 1 H), 3.78 (s, 3 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 3.33-3.27 (m, 1 H, overlapped with solvent), 3.07-2.96 (m, 1 H), 2.53 (s, 3 H, overlapped with solvent), 1.44 and 1.41 (s, 9 H), 1.18 (d, J = 6.8 Hz, 3 H) ppm. HRMS (ES⁺): m/z calcd for C₂₉H₃₇N₃O₈Na [M + Na]⁺: 578.2478; found: 578.2490.
Arylomycin A_{2 (} 1): [α]_D ^²4 +29 (c 0.3, MeOH). ^¹H NMR (500 MHz, MeOD, 1:6.4 mixture of isomers): δ = 8.91 (d, J = 8.0 Hz, 1 H), 8.61 (d, J = 8.1 Hz, 1 H), 8.17-8.05 (m, 2 H), 7.23 and 7.13 (d, J = 8.3 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 7.03 (br s, 1 H), 7.00 (br s, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 6.35 and 5.87 (s, 1 H), 4.99-4.94 (m, 1 H), 4.57-4.51 (m, 2 H, overlapped with solvent), 4.56-4.46 (m, 1 H), 4.25 (d, J = 17.1 Hz, 1 H), 4.08-4.00 (m, 2 H), 3.95-3.85 (m, 1 H), 3.46-3.36 (m, 1 H), 3.16-3.07 (m, 1 H), 3.11 and 2.89 (s, 3 H), 2.80 and 2.76 (s, 3 H), 2.57-2.42 (m, 2 H), 1.67-1.58 (m, 2 H), 1.52 (sept, J = 6.6 Hz, 1 H), 1.41 (d, J = 7.0 Hz, 3 H), 1.35 (d, J = 6.6 Hz, 3 H), 1.42-1.26 (m, 10 H), 1.21-1.15 (m, 2 H), 0.88 (d, J = 6.6 Hz, 6 H) ppm. ^¹H NMR (500 MHz, DMSO-d ₆, 1:3.1 mixture of isomers): δ = 12.81 (br s, 1 H), 9.69 (br s, 2 H), 9.07-8.95 and 8.35-8.27 (m, 1 H), 8.62-8.54 (m, 1 H), 8.03-7.87 (m, 2 H), 7.14 and 7.10 (d, J = 7.8 Hz, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 6.95 and 6.93 (br s, 1 H), 6.91-6.80 (m, 3 H), 6.29 and 5.85 (s, 1 H), 5.03-4.98 and 4.91-4.84 (m, 1 H), 4.97 and 3.44 (dd, J = 8.2, 5.8 Hz, 1 H), 4.83-4.73 (m, 1 H), 4.69-4.61 (m, 1 H), 4.41-4.30 (m, 1 H), 4.20 and 4.02 (d, J = 17.3 Hz, 1 H), 3.96 (dd, J = 17.3, 4.4 Hz, 1 H), 4.85-4.74 (m, 1 H), 3.71-3.62 (m, 1 H), 3.28-3.20 (m, 1 H), 3.16-3.07 (dd, J = 16.7, 12.1 Hz, 1 H), 2.93 and 2.76 (s, 3 H), 2.69 and 2.63 (s, 3 H), 2.39-2.27 (m, 2 H), 1.56-1.45 (m, 3 H), 1.25 (d, J = 7.3 Hz, 3 H), 1.32-1.20 (m, 10 H), 1.18 (d, J = 6.7 Hz, 3 H), 1.18-1.11 (m, 2 H), 0.85 (d, J = 6.6 Hz, 6 H). HRMS (ES^-): m/z calcd for C₄₂H₅₉N₆O₁₁ [M - H]^- 823.4242; found: 823.4269.

13

Abbreviations: DEPBT = 3-(diethyloxyphosphoryloxy)-1,2,3-benzotriazin-4 (3H)-one; EDC = 1-[3-(eimethyl-amino)propyl]-3-ethylcarbodiimide; HOBt = N-hydroxy-benzotriazole, SPhos = 2-dicyclohexylphosphino-2′,6′-di-methoxybiphenyl; MOP = (diphenylphosphino)-2′-meth-oxy-1,1′-binaphtyl; NMP = N-methylpyrolidinone.

17

Microwave experiments were conducted using a Discover microwave reactor from CEM. All experiments were performed in sealed tubes (capacity 10 mL) under argon atmosphere. Microwave irradiation of 300 W was used, the temperature being ramped from r.t. to 90 ˚C or 110 ˚C in 1 min. Once this temperature was reached, the reaction mixture was held at 90 ˚C or 110 ˚C for the indicated time.