Scalable Access to Arylomycins via C-H Functionalization Logic

Abstract

Arylomycins are a promising class of "latent" antibacterial natural products currently in preclinical development. Access to analogues within this family has previously required a lengthy route involving multiple functional group manipulations that is costly and time-intensive on scale. This study presents a simplified route predicated on simple C-H functionalization logic that is enabled by a Cu-mediated oxidative phenol coupling that mimics the putative biosynthesis. This operationally simple macrocyclization is the largest of its kind and can be easily performed on gram scale. The application of this new route to a formal synthesis of the natural product and a collection of new analogues along with their biological evaluation is also reported.

Figure 1

Contrasting retrosynthetic analyses of the arylomycin macrocycle (illustrated with natural variant arylomycin A₂).

Scheme 1. Synthesis of the Arylomycin Core via Oxidative Macrocyclization

Reagents and conditions: (a) 1 (1 equiv), HCl·NH₂-Ala-Tyr-OMe (1 equiv), HOBt (1 equiv), EDC (1.5 equiv), Et₃N (3.3 equiv), MeCN/DMF, 25 °C (72%); (b) [Cu(MeCN)₄][PF₆] (2 equiv), TMEDA (2 equiv), O₂, MeCN, then 2 (1 equiv), 25 °C (60%). Abbreviations: HOBt = 1-hydroxybenzotriazole, EDC = N-ethyl-N′-(3-(dimethylamino)propyl)carbodiimide hydrochloride, TMEDA = N,N,N′,N′-tetramethylethylenediamine.

Scheme 2. Development of Arylomycin Analogues: (A) Synthesis of Analogues via Decarboxylative Methodsa and (B) MIC Assay of Antibacterial Activity

Reagents and conditions: (a) 3 (1 equiv), AcCl (10 equiv), MeOH, 0 to 25 °C; (b) 5 (2 equiv), PyAOP (2 equiv), DIPEA (6 equiv), DMF, 50 °C (82%, 2 steps); (c) 6 (1 equiv), LiOH (10 equiv), THF/H₂O, 0 to 25 °C; (d) TFA/CH₂Cl₂ (1:6), 0 to 25 °C (41%, 2 steps); (e) N-Boc-2-bromoethan-1-amine (4 equiv), K₂CO₃ (5 equiv), DMF, 50 °C; (f) LiOH (10 equiv), THF/H₂O, 0 to 25 °C (69%, 2 steps); (g) TFA/CH₂Cl₂ (1:6), 0 to 25 °C (40%); (h) 8 (1 equiv), DIC (1.1 equiv), NHPI (1.1 equiv), CH₂Cl₂, 25 °C; (i) and (k) see Supporting Information for details. Abbreviations: DIPEA = N,N-diisopropylethylamine, DIC = N,N′-diisopropylcarbodiimide, NHPI = N-hydroxyphthalimide. 6 isolated as a 1:1 mixture of diastereomers at α-C of diaminobutyric acid; all assayed compounds diastereomerically pure in configuration shown (see Supporting Information for details). MRSA USA 300. MRSA COL. E. coli BAS901 (perm.).