Formal Synthesis of -Leucascandrolide

Ozonolysis of the double bond in 1,4-cyclohexadiene 943 followed by reductive work-up and dehydration provides the dihydropyran-4-one 944, an intermediate during a formal synthesis of leucascandrolide (Equation 369) <2002CC2066>. 

A diastereoselective ewrfo-cyclization into an oxidatively generated oxocarbenium ion was a key step in a formal synthesis of leucascandrolide A. Exposing 56 to CAN provided cw-tetrahydropyran 57 in high yield and with excellent stereocontrol (Scheme 3.20). This transformation provides further evidence that oxidative electrophile formation is tolerant of several functional groups and can be applied to complex molecule synthesis. The synthetic sequence also utilized a Lewis acid mediated ionization reaction to form an oxocarbenium ion in the presence of the homobenzylic ether (58, 59), illustrating that two carbocation precursors that ionize through chemically orthogonal conditions can be incorporated into the same structure. 

Lee, Kiyoun Kim, Hyoungsu Hong, Jiyong. A Stereoselective Formal Synthesis of Leucascandrolide A Org. Lett. 2011, 13, 2722-2725. 

The tandem Mukaiyama aidoi reaction-Prins cyciization was utilized during the formal total synthesis of leucascandrolide A by S.D Rychnovsky. The addition of the activated aldehyde to the enol ether resulted in the formation of an oxocarbenium ion, which was captured intramolecularly by the allylsilane moiety to form a new tetrahydropyran ring. The reduction of the crude reaction mixture with NaBH4 was performed to remove the unreacted aldehyde starting material, thereby facilitating the chromatographic purification of the product. The product was isolated as a 5.5 1 mixture of epimers at C9. 

Wipf, P. and Reeves, J.T. (2002) A formal total synthesis of leucascandrolide A. Chem. Commun., 2066-2067. 

Since Leighton s first total synthesis, total syntheses of leucascandrolide A have been achieved by Rychnovsky (formal), Carreira, Wipf (formal), Kozmin (racemic), Paterson, Williams (formal), Crimmins (formal), and Panek. In this section, these syntheses are briefly introduced. 

Cossy and coworkers also employed a Class 2 RCM to form the B ring in their formal total synthesis of the anticancer macrolide leucascandrolide A (Scheme 60) [108]. Using catalyst G-II followed by in situ reduction afforded the lactone 221... 

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