This invention involves methods of apomorphine synthesis from different starting blocks to facilitate more robust drug development campaigns by enabling chemical substitutions at unexplored locations. It includes total synthesis of apomorphine from readily available fragments and whose synthetic design approach centers around being maximally amenable to diverted total syntheses (DTS) campaigns to enable access to aporphine analogs that were previously hard to access. The approach opens up significant opportunities for more targeted drug development to treat neurodegenerative diseases, such as Parkinson’s, with the potential to overcome long-standing limitations in apomorphine chemistry. Background: Apomorphine is a rare example of a first-generation drug that maintains status as the standard of care—it’s used as a rapid rescue treatment for Parkinson’s Disease “off” episodes. Eventual improvements in medicinal chemistry motivated by market competition generally to lead to new compounds with higher efficacy and reduced side effects. Apomorphine is an exception to the rule; however, it has three key deficiencies: it clears from the body quickly, administration requires injection, and it has emetic side effects (it's normally prescribed to induce vomiting in dogs by vets). Despite both the clear need for improvement and pharmaceutical campaigns to do so, the focus remained on natural product degradation approaches that greatly limit possible derivatives. Applications:
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