Densely functionalized natural products continue to capture the attention of synthetic chemists for their distinctive and complex molecular architectures. The aminocyclopentitol class of natural products, including pactamycin 1, jogyamycin 2 and related compounds (Figure ), are a unique subgroup of natural products that display a dense network of functional groups and a high degree of molecular complexity. This complexity prompted one paper to express the opinion these natural products were likely "inaccessible to synthesis," but their formidable structures and potent antimalarial activities have made them popular synthetic targets. Pactamycin 1, the most well-known member of this class, was isolated from Streptomyces pactum in 1961, 3 but its structure was not assigned until 1972. Cranomycin 3 was isolated in 1964 from a culture broth of Streptomyces SE-801 and later found to be present in two other species of Streptomyces. Jogyamycin 2 is a more recent addition to this family, having been isolated from a strain of Streptomyces in 2012 by Otogura, Omura and co-workers. In addition to the natural aminocyclitols 1-3, the Mahmud group has leveraged their discovery of the gene cluster responsible for the biosynthesis of pactamycin 1 to produce the genetically engineered analogs TM-025 4 and TM-026 5. Compounds 1-5 exhibit nM levels of potency against drugresistant malaria; 6,7,8 however, the activities of 1-3 are non-selective. Interestingly, genetically engineered analogs 4-5 showed reduced mammalian cell cytotoxicity, 7c although their structures differ slightly from 1-3. As genetic engineering cannot provide tailored analogs, a modular synthetic approach to these scaffolds would be valuable. Challenging structural features include stereodefined heteroatoms at each carbon of the cyclopentane core, three contiguous stereocenters at C1-C3 each possessing a different amine functionality and three fully substituted carbons at C1, C4 and C5. The syn-relationship between the C1 urea and the C2 amine and the transrelationship between the C4-C5 tertiary alcohols can also cause undesired cross-reactivity. The total synthesis of 1 has been achieved, but the alcohol of the C1 side chain plays a key role in the success of these approaches; the lack of this linchpin in jogyamycin 2 requires a reimagining of the strategy for accessing this natural product and its analogs. Figure . Representative aminocyclopentitol natural products and analogs.