In the preceding paper, we described the synthesis of the vancomycin-related M(4-6)(5-7) bicyclic subunit 3 (Scheme 1), 1,2 a structural motif common to all members of this family of antibiotics exemplified by vancomycin aglycon (1). 3 Herein we describe the first synthesis of the vancomycin-related heptapeptide nucleus and the transformation of this intermediate to orienticin C (bis-dechlorovancomycin) aglycon (2). 4Our original strategy for the construction of the biaryl ethercontaining rings was based on a successful study that demonstrated that these macrocycles, in the absence of the biarylcontaining M(5-7) ring, could be constructed through a Tl(III)mediated oxidative cyclization. 5 In the current plan, the N-terminal tripeptide 4 incorporating the 4,4′-dimethoxydiphenylmethyl (Ddm)-protected asparagine was employed for the construction of the final M(2-4) macrocyclic subunit. The selection of this protecting group was predicated on its favorable impact on epimerization during the fragment coupling, 6 on suppression of the aspartate-iso-aspartate rearrangement, 6 and on protection of this residue during selective derivatization of the N-methyl amide at the end of the synthesis. Given the complexity of these natural products, orienticin C aglycon (2) 4 was chosen as our initial target.Deprotection of the Boc-protected bicyclic tetrapeptide 3 (30% TFA, DMS, CH 2 Cl 2 , 0°C) and fragment coupling with the N-terminal tripeptide 4 7 was carried out under standard conditions (1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), THF, 0°C) to afford heptapeptide 5 in excellent yield with no detectable epimerization (Scheme 1). Removal of the ring-2 allyl ether provided 6, which was cyclized under the optimized conditions developed for the M(2-4)(4-6) bicycle 5 (Tl(NO 3 ) 3 ‚3H 2 O, 30:1 CH 2 Cl 2 /MeOH, room temperature (rt); CrCl 2 , 0°C) to provide the desired tricycle 7 in approximately 20% yield as an inseparable mixture with two other unidentifiable byproducts. In spite of an extensive reevaluation of this methodology, no improvement in yield for this critical transformation could be achieved. We conclude that the enhanced rigidity of the biaryl-containing M(4-6)(5-7) bicycle, in comparison to that of the M(4-6) monocyclic counterpart employed in the model studies, 5,8 could be responsible for the failure of this transformation. A detailed investigation of this reaction will be published elsewhere. 9 Rather than proceeding with a substandard cyclization step, other diaryl ether-forming macrocyclization strategies were considered. On the basis of the existing precedent provided by Beugelmans, Rao, and Boger, 10 the nitroaromatic-based S N -Ar methodology was evaluated. Accordingly, the refunctionalization of bicyclic tetrapeptide 3 to phenol 8 was undertaken (Scheme 2). Protection of the ring-4 phenol as its derived allyl ether and subsequent deprotonation of the six amidic and alcoholic hydrogens with MeMgCl (18 equiv, THF/Et 2 O, 0°C, 2 h) was followed by lit...