Syntheses of YCT-529: Net [3 + 2] Cycloaddition and One-Pot Bromination-Suzuki-Miyaura Coupling Strategies

We developed two synthetic pathways for the preparation of YCT-529 (1), a promising male contraceptive. The key reaction for the first strategy is a base-mediated [3 + 2] cycloaddition between alkyne 2 and 4-(diethoxymethyl)benzonitrile (4) to form the central pyrrole ring and the 4-formylbenzene moiety in intermediate 5, which was oxidized to the corresponding acid and converted to its sodium salt YCT-529 in 48% overall yield on a 2 g scale. The second strategy involved two key transformations, specifically, Suzuki-Miyaura reactions. The first step was the reaction between bromochromene 3 and pyrrole boronic acid 9, followed by NBS-mediated bromination of intermediate 8 and a second Suzuki-Miyaura coupling to append the benzoic acid methyl ester. A stepwise deprotection and hydrolysis strategy ensured the high purity of the final product, YCT-529, with an overall yield of 64% on a 10 g scale. The high-yielding transformations and operational simplicity underscore the robustness and versatility of the developed methods. The availability of alternative routes provides valuable options for scale-up and analog generation in future medicinal chemistry studies. Both methods are chromatography-free, avoid costly catalysts, and use N-acetyl-l-cysteine to efficiently remove the palladium.