Our retrosynthetic analysis is shown in Figure . Cycletryptomycin A and B (1-2) have complex three-dimensional structures on a highly tryptophan-linked macrocycle. Therefore, in order to conduct a scalable synthesis of these natural products, it is important to develop a mild and scalable synthetic method that is inexpensive and does not require harsh conditions. For this reason, we carried out a Zr-catalyzed dimerization of tryptophan derivatives followed by the rapid construction of two diketopiperazines by an amide formation reaction. The key reactions in this synthetic pathway are the linking of C22 and C18' by macrocyclization of tetratryptomycin A (3) and the linking of the nitrogen on the indole to C18' to form cyctryptomycin A and B (1-2). We first attempted to synthesize cyctryptomycin A and B (1-2) by oxidative cyclization of tetratryptomycin A (3) as an initial screening (Figure ). 11 More than 100 oxidation conditions were applied, including NCS, NBS, NIS, PhI(OAc)2, PhI(OCOCF3)2, FeCl3, V2O5, Mn(OAc)3, anodic oxidation, photo-oxidation, pig's liver and chicken's liver as oxidants. However, no cyctryptomycin A and B (1-2) could be obtained from tetratryptomycin A (3). The inaccessibility of oxidative cyclization is anticipated to be attributed to the distance between the two tryptophan moieties, resulting from the distal position of C22 and C18' of tetratryptomycin A (3), which unfavorably impedes cyclization. The computational chemistry analysis of the most stable conformation of tetratryptomycin A (3) in fact revealed that the C22-C18' distance is 18.4 Å and the N-C18' distance is 17.2 Å (Figure ). These calculations also indicate a mutual distal position of the two tryptophan moieties in tetratryptomycin A (3). This significant distance was suggested to impede the macrocyclization of tetratryptomycin A (3), and over 100 macrocyclization conditions were investigated. However, none of the conditions yielded the desired cyctetryptomycin A and B (1-2), and the two tryptophan moieties of 3 were either transformed into oxindoles or halogenated as the major by-products. In 2021, we identified the CttpC enzyme as a key component for the oxidative macrocyclization of tetratryptomycin A (3) to produce cyctetryptomycin A and B (1-2). However, the biosynthesis of cyctetryptomycin A and B (1-2) could not be achieved on a large scale, and only a few milligrams were obtained. 1 Consequently, we devised a plan to develop an inexpensive, non-toxic, mild, and scalable Zr-catalyzed dimerization of tryptophan derivatives, followed by their enzymatic oxidative macrocyclization, to synthesize cyctetryptomycin A and B (1-2) in large quantities. These compounds have the potential to serve as seed compounds for the treatment of neurodegenerative diseases such as ALS, Alzheimer's, and Parkinson's diseases.