The synthesis of 2 is outlined in Scheme 1. To construct the eastern fragment 4, enantioenriched 9 (93:7 er) was prepared in good yield on multigram-scale in two steps, leveraging the multicomponent asymmetric aziridination developed by Wulff group (see SI for experimental detail). With ample quantities of free aziridine 9 in hand, a stereo-and regio-selective aziridine opening reaction was conducted using histidine derivative 11 as a nucleophile under acidic conditions. This reaction was subjected to extensive optimization (see Scheme 1 Table and SI for further detail) and showed a pronounced solvent dependence, wherein the use of trifluoroethanol (TFE) was found to be critical. The role of TFE in this reaction may be rationalized by a unique combination of high polarity, low nucleophilicity, and the ability to form H-bonding adducts with donor functionalities, aiding in the ring opening reaction of the aziridine. The major side reaction pathway under optimized conditions was identified as dimer formation by competing nucleophilic attack of the aziridine. The ratio between the desired product and dimer is critically influenced by the protonation equilibrium of the aziridine and nucleophile (see SI for a comparison of nucleophiles with varying pKa). The direct reaction between His 10 and aziridine 9 was hampered by extensive dimer formation due to an insufficient pKa difference. In comparison, utilization of less basic 5-Br-His 11 led to a subtle shift in protonation equilibrium resulting in reduced dimer formation to give the desired aziridine addition in 41-65% yield depending upon the equivalents of His 11 utilized. Subsequent reductive cleavage of the bromide under acidic conditions using Zn/AcOH proceeded with excellent selectivity for the bromo-imidazole in nearly quantitative yield and enabled access to the key b-branched amino acid coupled product 8. Subsequent steps included amide coupling with a protected serine residue to furnish cyclization precursor 12, which was subjected to TBAF, resulting in simultaneous Fmoc and (trimethylsilyl)ethyl (TSE) deprotection. After screening a variety of activation reagents, the combination of PyAOP with HOAt was found to be the most effective conditions under which to forge the macrocycle to yield 4 in 54% yield over two steps.