Iterative Assembly of Macrocyclic Lactones using Successive Ring Expansion Reactions

Abstract Macrocyclic lactones can be prepared from lactams and hydroxyacid derivatives via an efficient 3‐ or 4‐atom iterative ring expansion protocol. The products can also be expanded using amino acid‐based linear fragments, meaning that macrocycles with precise sequences of hydroxy‐ and amino acids can be assembled in high yields by “growing” them from smaller rings, using a simple procedure in which high dilution is not required. The method should significantly expedite the practical synthesis of diverse nitrogen containing macrolide frameworks.


1-Oxa-4-azacyclohexadecane (12a)
A mixture of laurolactam (155 mg, 0.786 mmol), DMAP (10 mg, 0.0786 mmol) and pyridine (380 μL, 4.72 mmol) in DCM (5.5 mL) under an argon atmosphere was stirred at RT for 5 mins. Next, a solution of acid chloride (1.18 mmol, 1.50 equiv. prepared using the general procedure) in DCM (3 mL) was added and the resulting mixture was heated, at reflux, at 50 °C for 16 h. The solvent was concentrated in vacuo, loaded onto a short silica plug and eluted with 2:1 hexane:ethyl acetate, to remove the majority of excess carboxylic acid and pyridine residues, and concentrated in vacuo. This material (4a) was re-dissolved in THF (7.8 mL) and placed under an argon atmosphere. Palladium on carbon (78 mg, Pd 10% on carbon) and water (1.42 mL, 78.6 mmol) was then added and the reaction vessel was backfilled with hydrogen (via balloon) several times, then stirred at RT under a slight positive pressure of hydrogen (balloon) for 1 h. The reaction was then purged with argon, filtered through Celite, washed with methanol where the solvent was removed in vacuo. The crude material was then redissolved in chloroform (7.8 mL) and triethylamine (165 µL, 1.18 mmol) added, and stirred at RT for 16 h, then reduced in vacuo. Purification by flash column chromatography (SiO2, 2:1 hexane:ethyl acetate → ethyl acetate) afforded the title compound as a white solid (177 mg, 88%). Data consistent with those previously reported in the literature. 1
The reaction was then purged with argon, filtered through Celite, washed with methanol where the solvent was removed in vacuo. The crude material was then re-dissolved in chloroform (6.7 mL) and triethylamine (140 µL, 1.01 mmol) added, and stirred at RT for 16 h, then reduced in vacuo. Purification by flash column chromatography (SiO2
The reaction was then purged with argon, filtered through Celite, washed with methanol where the solvent was removed in vacuo. The crude material was then re-dissolved in chloroform (

1-Oxa-4-azacyclotetradecane-3,14-dione (12i)
A mixture of azacycloundecan-2-one (133 mg, 0.786 mmol), DMAP (10 mg, 0.0786 mmol) and pyridine (380 μL, 4.72 mmol) in DCM (5.5 mL) under an argon atmosphere was stirred at RT for 5 mins. Next, a solution of acid chloride (1.18 mmol, 1.50 equiv. prepared using the general procedure) in DCM (3 mL) was added and the resulting mixture was heated, at reflux, at 50 °C for 16 h. The solvent was concentrated in vacuo, loaded onto a short silica plug and eluted with 2:1 hexane:ethyl acetate, to remove the majority of excess carboxylic acid and pyridine residues, and concentrated in vacuo. This material was re-dissolved in THF (7.8 mL) and placed under an argon atmosphere. Palladium on carbon (78 mg, Pd 10% on carbon) and water (1.42 mL, 78.6 mmol) was then added and the reaction vessel was backfilled with hydrogen (via balloon) several times, then stirred at RT under a slight positive pressure of hydrogen (balloon) for 1 h. The reaction was then purged with argon, filtered through Celite, washed with methanol where the solvent was removed in vacuo. The crude material was then re-dissolved in chloroform (7.8

2-Methyl-1-oxa-4-azacyclohexadecane-3,16-dione (16d)
A mixture of laurolactam (155 mg, 0.786 mmol), DMAP (10 mg, 0.0786 mmol) and pyridine (380 μL, 4.72 mmol) in DCM (5.5 mL) under an argon atmosphere was stirred at RT for 5 mins. Next, a solution of acid chloride (1.18 mmol, 1.50 equiv. prepared using the general procedure) in DCM (3 mL) was added and the resulting mixture was heated, at reflux, at 50 °C for 16 h. The solvent was concentrated in vacuo, loaded onto a short silica plug and eluted with 2:1 hexane:ethyl acetate, to remove the majority of excess carboxylic acid and pyridine residues, and concentrated in vacuo. This material was re-dissolved in THF (7.8 mL) and placed under an argon atmosphere. Palladium on carbon (78 mg, Pd 10% on carbon) and water       -1-oxa-4,14-diazacycloheptadecane-3,13,17-trione (17h) A mixture of 5-benzyl-1,5-diazacyclotetradecane-2,6-dione (65 mg, 0.205 mmol), DMAP (3 mg, 0.0205 mmol) and pyridine (100 μL, 1.23 mmol) in DCM (1.5 mL) under an argon atmosphere was stirred at RT for 5 mins. Next, a solution of acid chloride (0.308 mmol, 1.50 equiv. prepared using the general procedure) in DCM (1 mL) was added and the resulting mixture was heated, at reflux, at 50 °C for 16 h. An additional solution of acid chloride (0.308 mmol, 1.50 equiv. prepared using the general procedure) in DCM (1 mL) was added and heated, to reflux, at 50 °C for a further 16 h in order to achieve reaction completion. The solvent was then concentrated in vacuo, loaded onto a short silica plug and eluted with 2:1 hexane:ethyl acetate, to remove the majority of excess carboxylic acid and pyridine residues, and concentrated in vacuo. This material was re-dissolved in THF (2. prepared using the general procedure) in DCM (2 mL) was added and heated, to reflux, at 50 °C for a further 24 h in order to achieve reaction completion. The solvent was then concentrated in vacuo, loaded onto a short silica plug and eluted with 2:1 hexane:ethyl acetate, to remove the majority of excess carboxylic acid and pyridine residues, and concentrated in vacuo. The crude material was then re-dissolved in DCM (4.1 mL) and DBU (0.620 mL, 4.083 mmol) was added, followed by stirring at RT for 16 h, before the solvent was removed in vacuo.

12-Benzyl-1,16-dioxa-4,12-diazacyclononadecane-3,11,15,19-tetraone (18c)
A mixture of 5-benzyl-1-oxa-5,13-diazacyclohexadecane-2,6,14-trione (90 mg, 0.250 mmol), DMAP (3 mg, 0.0250 mmol) and pyridine (121 μL, 1.50 mmol) in DCM (2.0 mL) under an argon atmosphere was stirred at RT for 5 mins. Next, a solution of acid chloride (0.375 mmol, 1.50 equiv. prepared using the general procedure) in DCM (1 mL) was added and the resulting mixture was heated, at reflux, at 50 °C for 16 h. The solvent was then concentrated in vacuo, loaded onto a short silica plug and eluted with 2:1 hexane:ethyl acetate, to remove the majority of excess carboxylic acid and pyridine residues, and concentrated in vacuo. This material was re-dissolved in THF (2.5 mL) and placed under an argon atmosphere. Palladium on carbon (25 mg, Pd 10% on carbon) and water (450 µL, 25 mmol) was then added and the reaction vessel  Compound 6c [5] m0034tcs_Proton                Computational studies of the selected systems The imides, cyclols and ring expanded products in the chosen systems were initially built using either Spartan student 6 or Spartan'14 7 and optimised using Density Functional Theory (DFT)/B3LYP/6-31G* 8 in vacuum. Conformational searches of the optimised structures were performed at Molecular Mechanics Force Field (MMFF) level. 9 All the generated structures were retained and their energies were calculated using DFT/B3LYP/6-31G*. The lowest energy geometry in each case was selected, fully optimised and determined to be minima by the absence of negative vibrational modes, in vacuum using DFT/B3LYP/6-31G*. The final optimisations and frequency calculations were also done in solvated model system (non-polar solvents) using DFT/B3LYP/6-31G* and the results were similar to those performed in vacuum.
All the steps described above were also repeated using Hartree-Fock (HF)/6-31G* 10 in vacuum, with conformational searches performed at MMFF level. The final frequency calculations were done using HF/6-31G* in vacuum. All the results were in close agreement with those performed at the DFT level of theory. 0.0 0.0 0.0 Table S18. Relative free energies (∆G°) of the lowest energy geometries of 9d/11d/13d at two levels of theory (DFT/B3LYP/6-31G* in a vacuum and in non-polar solvents) and HF/6-31G* in a vacuum) in kcal/mol.