Extensive route scouting was conducted to understand the basic reactivity and workable strategies for such systems (Figure ). Initially, the synthesis of the b-branched Asn fragment of the western fragment 3 was pursed by an epoxide opening reaction with enolate-type nucleophiles (Figure , strategy A). Although the primary alcohol obtained proved competent for construction of the western fragment, all attempts for its late-stage conversion to the corresponding primary amide were hampered by extensive epimerization of the benzylic a-carbonyl stereocenter (see SI). This issue necessitated the introduction of a non-epimerizable surrogate for the primary amide. For construction of the b-branched tyrosine moiety of the eastern fragment 4, a broad range of strategies were evaluated (Figure , strategies B-D). Linkages of this type are extremely rare and notoriously difficult to obtain synthetically. Indeed, no successful strategy has been uncovered to date. Attempted nucleophilic substitution reactions under either neutral, anionic or halogenide/Ag + -facilitated conditions led consistently to either formation of the corresponding unsaturated dehydro-amino acid or decomposition of the substrates (Figure , strategy B, see SI). Attempts to utilize addition of the histidine imidazole to an acyl aziridine moiety were hampered by the electronic nature of the acyclic twisted amide such obtained (Figure , strategy C). The lack of nN to π*C═O conjugation of this moiety lead to facile epimerization of the adjacent serine a-stereocenter even under mild conditions. Besides this, cleavage of the aziridine amide by nucleophiles was observed as a dominant side reaction (see SI). Further, a potentially biomimetic intramolecular cyclization by addition of the histidine imidazole to the corresponding tyrosinederived quinone methide was considered (Figure , strategy D). However, this approach led mostly to either decomposition or tautomerization to the corresponding dehydro-tyrosine (see SI). In addition to the approaches described, several other strategies were evaluated for b-amino acid synthesis; see SI for further detail.