A Vicinal Diol Approach for the Total Synthesis of Molestin E, ent‐Sinulacembranolide A and ent‐Sinumaximol A

• Published in: Chemistry : a European journal 2022-11, Vol.28 (63), p.e202202464-n/a
• Main Authors: Hoff, Oskar, Kratena, Nicolas, Aynetdinova, Daniya, Christensen, Kirsten E., Donohoe, Timothy J.
• Format: Article
• Language: English
• Subjects: Biological Products - chemistry; cembranoids; Crystallography, X-Ray; Diols; Epoxides; Epoxy Compounds; macrolactones; Metathesis; Natural products; Single crystals; Stereochemistry; Stereoisomerism; Stereoselectivity; Synthesis; total synthesis
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202202464

In this work an approach for the synthesis of furanocembranoid natural products containing the C‐7,8‐diol moiety is disclosed. This culminated in the first total synthesis of the natural product molestin E, together with ent‐sinulacembranolide A and ent‐sinumaximol A as well as a thorough exploration of their chemistry. Late‐stage ring‐closure of the C‐7,8‐diols to the corresponding epoxides was also demonstrated. Key features of this synthetic strategy include a stereoselective Baylis‐Hillman reaction, ring‐closing metathesis and Shiina macrolactonisation. Chiral‐pool materials were deployed to ensure the desired absolute stereochemistry which was confirmed by late‐stage single crystal X‐ray diffraction. The convergent total synthesis of furanocembranoids (FC) molestin E, ent‐sinulacembranolide A and ent‐sinumaximol A was achieved in 20–21 steps in the longest linear sequence (LLS). Building blocks were coupled through a furan metalation sequence and macrocycle formation was effected by Shiina lactonisation. The primary target molestin E was elaborated late‐stage to 12 novel FC compounds.