A 15-step synthesis of (+)-ryanodol

• Published in: Science (American Association for the Advancement of Science) Vol. 353; no. 6302; pp. 912 - 915
• Main Authors: Chuang, Kangway V., Xu, Chen, Reisman, Sarah E.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 26-08-2016; The American Association for the Advancement of Science
• Subjects: Biochemistry; Biological Products - chemical synthesis; Calcium; Carbon; Chemical bonds; Chemical synthesis; Chemistry; Construction; Monoterpenes - chemistry; Oxidation; Oxidation-Reduction; Oxygen; Oxygen - chemistry; Receptors; Ryanodine - analogs & derivatives; Ryanodine - chemical synthesis; Ryanodine Receptor Calcium Release Channel - metabolism; Selenium Oxides - chemistry; Synthesis; Synthesis (chemistry); Terpenes
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aag1028

(+)-Ryanodine and (+)-ryanodol are complex diterpenoids that modulate intracellular calcium-ion release at ryanodine receptors, ion channels critical for skeletal and cardiac muscle excitation-contraction coupling and synaptic transmission. Chemical derivatization of these diterpenoids has demonstrated that certain peripheral structural modifications can alter binding affinity and selectivity among ryanodine receptor isoforms. Here, we report a short chemical synthesis of (+)-ryanodol that proceeds in only 15 steps from the commercially available terpene (S)-pulegone.The efficiency of the synthesis derives from the use of a Pauson-Khand reaction to rapidly build the carbon framework and a SeO₂-mediated oxidation to install three oxygen atoms in a single step. This work highlights how strategic C-0 bond constructions can streamline the synthesis of polyhydroxylated terpenes by minimizing protecting group and redox adjustments.