Wang, G.; Krische, M.J.. “Total Synthesis of (+)-SCH 351448: Efficiency via Chemoselectivity and Redox-Economy Powered by Metal Catalysis” J. Am. Chem. Soc. 2016, 138, 8088-8091. DOI: 10.1021/jacs.6b04917
Ruthenium metathesis catalysts are versatile and Krische and co-workers have them working overtime on multiple transformations in their recent synthesis of the polyketide (+)-SCH 351448. In the past few years (+)-SCH 351448 has piqued interest as a potential starting point for developing therapeutic agents for hypercholesterolemia. A C2 symmetric, 28-membered macrocycle with 14 stereocenters, this polyketide is an excellent target for displaying the power of state of the art synthetic methods. The macrodiolide, (+)-SCH 351448, is synthesized in 14 linear steps utilizing 10 metal catalyzed reactions (Scheme 1), of which four are ruthenium catalyzed metathesis transformations!
Scheme 1. Retrosynthesis of (+)-SCH 351448
The ruthenium catalyzed metathesis transformations that Krische and co-workers utilize are varied and run the gamut from cross metathesis to macrocyclization.1 Of these four metathesis reactions, two of the transformations deserve a closer look. The first of these transformations is found in the route to synthesize Fragment B. In order to build up the needed tetrahydropyran motif, a tandem cross-metathesis / cyclization is performed (Scheme 2). Utilizing elegant methodology from Fuwa and co-workers to build tetrahydropyrans,2 terminal alkene 1 undergoes a cross metathesis with crotonaldehyde in the presence of (S)-camphorsulfonic acid (CSA) to yield tetrahydropyran 2. This transformation is particularly interesting because of the use of CSA to facilitate the intramolecular oxa-conjugate cyclization of the acyclic enone intermediate 3 formed via the cross metathesis.
Scheme 2. Tandem Cross Metathesis and Cyclization.
The second metathesis transformation that warrants a deeper dive is the cross coupling between Fragment A and Fragment B to yield one half of (+) – SCH 351448. In this reaction, benzoquinone is utilized to suppress the undesired alkene isomerization of Fragment B to an internal tri-substituted alkene. It has been seen that electron-deficient benzoquinones are effective for preventing olefin isomerization of aliphatic alkenes by potentially preventing the formation of ruthenium hydride species that may arise from stressful metathesis conditions (eg. high temperature).3
Scheme 3. Cross Metathesis of Fragment A and Fragment B.
This recent synthesis is a great example of the power of ruthenium metathesis catalysts and the variety of transformations they can provide. Finally, I would also be remiss not to mention how this synthesis provides beautiful examples of redox economical C-C bond formation displaying the methodology developed in the laboratory of Krische at UT, Austin!4 All combined, the use of metal catalyzed transformations delivers an efficient atom economical synthesis of (+)-SCH 351448.
1 Cossy, J.; Arseniyadis, S.; Meyer, C., Eds. Metathesis in Natural Product Synthesis: Strategies, Substrates and Catalysts. Wiley: Hoboken, 2010.
2 Fuwa, H.; Noto, K.; Sasaki, M. Org. Lett. 2010, 12, 1636.
3 Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160.
4 Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische, M. J. Angew. Chem., Int. Ed. 2014, 53, 9142.