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. Author manuscript; available in PMC: 2017 Nov 1.
Published in final edited form as: Bioorg Med Chem Lett. 2016 Sep 16;26(21):5340–5345. doi: 10.1016/j.bmcl.2016.09.027

Scheme 2. Retrosynthetic analysis (a) and synthesis (b) of macrocyclic cyclo-lactyl-AMS analogue 5b.

Scheme 2

Reagents and conditions: a) ethynyltrimethylsilane (1.5 equiv), n-BuLi (1.7 M in hexanes, 1.5 equiv), toluene, 0 °C, 15 min, then Et2AlCl (1.5 equiv), 0 °C, 45 min, then 6, 0 → 23 °C, 90 min, 94%; b) TBAF (1.0 M in THF, 1.0 equiv), THF, 23 °C, 2 h, 92%; c) TBSCl (4.3 equiv), imidazole (3.5 equiv), CH2Cl2, 0 → 23 °C, 42 h, 86%; d) 11 (1.5 equiv), 12 (1.0 equiv), i-PrNEt2 (2.0 equiv), CuI (0.70 equiv), Pd(PPh3)4 (0.35 equiv), DMF, 23 °C, 23 h, 94%; e) sulfamoyl chloride (5.6 equiv), DMA, 0 °C, 1 h, 76%; f) 30% Pd/C (2.5 equiv), H2 (balloon), MeOH, 23 °C, 6 h, 100%; g) LiOH (0.4 M aq, 1.5 equiv), THF, MeOH, 0 → 23 °C, 15 h; h) PyBOP (1.8 equiv), HOBt (2.8 equiv), DBU (1.5 equiv), CH3CN, 23 °C, 4.5 h, 48% over 2 steps; i) 5:1 TFA/H2O, 0 → 23 °C, 3 h, then MeOH, 0 °C, 37%. DMA = N,N-dimethylacetamide; DMF = N,N-dimethylformamide; HOBt = hydroxybenzotriazole; Lac = lactyl; PyBOP = benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; TBAF = tetrabutylammonium fluoride.