A breakthrough was reached upon recognition that the b-branched amino acid motifs for both 3 and 4 could, in principle, be derived from aziridine ring openings (Figure ). While addition to aziridines has previously been demonstrated as a useful strategy for the synthesis of b-branched amino acids, very few examples exist for comparable additions to a-carbonyl, b-aryl aziridines as was necessitated in the case of 2. In general, addition to aziridines requires the use of electron-withdrawing N-activators (such as tosyl or nosyl protecting groups), which could potentially introduce further synthetic issues. For instance, cleavage of N-tosyl is incompatible with use of an aryl bromide, preliminary experiments indicated difficulties in controlling the reactivity for Nnosyl, and rearrangement is a known issue for carbamate-based protecting groups. For these reasons, a more efficient approach was developed based on direct addition into free-NH aziridines. The b-branched motif of 4 could thus be traced back to addition of histidine into chiral aziridine 9 to forge the N-C39 bond of 2. To mitigate the risk of imidazole eliminating from tyrosine to form the corresponding para-quinone methide (QM) (Figure , highlighted in red), bromide was chosen as a stable surrogate for hydroxyl group of the natural tyrosine with the intention to introduce the requisite phenol moiety at a late stage. The synthesis of the western fragment 3 branched tryptophan-asparagine motif (Figure , highlighted in green) was envisioned in the same fashion by addition of 2-methyl furan into the corresponding aziridine 7. In this case, furan acts as an epimerization-proof synthetic precursor to the primary asparagine amide, to be unveiled towards the end of the synthesis. With a strategy in hand to address the challenge of synthesizing the b-branched amino acids 6 and 7, our attention next turned to construction of the two macrocycles and final assembly of 2.