Scheme 16. Hydrolysis of model compound

The synthesis of macrocycle 17 was optimized to 46 % overall yield of both isomers and 22 % overall yield of the meso isomer in nine steps. During this synthesis a method was developed to separate the pro-meso isomer from the pro-d/1 isomer of the amides. This method was very reproducible and there was good recovery of compound from the column. A method was also developed to separate the meso isomer from the d/1 isomer that resulted from isomerization of the meso isomer to a 1 1 mixture of meso and d/1 during the reduction of pro-meso to the meso isomer. However, this method was tedious and not very reproducible therefore care must be taken to prevent isomerization during the reduction of the amide. With an optimized synthesis of the macrocycle 17 at hand, enough macrocycle was made available to explore synthesis of the attachment of the side arm. 

The side arms were introduced via a Buchwald-Hartwig reaction. While the yield of the reaction was low and the reaction was not reproducible, this was the first example of a Buchwald-Hartwig reaction on a macrocyclic system of this kind. In addition, this was the first example of a Buchwald-Hartwig reaction to di-arylate a diamine system. 

To a solution of 4-nitrophenylacetic acid (3.62 g, 20.0 mmol) in methanol (30.0 mL, 0.670 M) was added concentrated sulfuric acid (0.500 mL) and the reaction was refluxed at 70 °C overnight. The volatile components were removed under reduced pressure and the residue was taken up in EtOAc (100 mL), washed with sat d NaHC03 (3 x 50.0 mL), washed with brine, dried over MgSCL and filtered. The volatile components were removed under reduced pressure to give 3.78 g of crude 24 as a white solid in 97.0 % yield, which was carried on to the next step without further purification. 

To a solution of (4-nitro-phenyl)-acetic acid methyl ester 24 (8.11 g, 41.6 mmol) in ethanol (208 mL) was added 10% Pd/C (3.20 g) and NH4HCOO (14.0 g in 10 equal portions every 5 min) while stirring at room temperature. The reaction was stirred for 24 h, followed by 

To a solution of (8-m ethoxy carbonylmethyl-6//, 72/2-5, ll-methano-dibenzo[bf][ 1,5] diazocin-2-yl)-acetic acid methyl ester 26 (4.88 g, 133 mmol) in MeOH/H20 (3 1 v/v) (17 mL) 

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