Ricciocarpin, cascade synthesis

SCHEME 11.29. Michrowska and List s cascade synthesis of ricciocarpin. 

Scheme 7.44 Cascade conjugate hydrogen transfer/intramolecular Michael reaction and application to the total synthesis of (+ )-ricciocarpin A.

The synthesis is initiated by the organocatalyzed cascade that activates a,p-unsaturated aldehyde 8 with the formation of an iminium ion (Scheme 14.2). In this way, the imidazolidinone catalyst allows hydride transfer from the Hantzsch dihydropyridine 9 onto the highly activated conjugated alkene 11, which creates the nucleophilic enamine intermediate 12. Because of the chirality of the organocatalyst, stereoselective Michael addition (97% ee) to the adjacent enone occurs, with minor preference for the cis diastereomer (2 1 dr). Fortunately, this undesired diastereomer slowly epimerizes to the required trans isomer, which produces (-l-)-ricciocarpin A when treated with samarium triisopropoxide. Besides the Cannizzaro-like redox disproportionation, which allows the lactone producing Evans-Tihchenko reaction to occur, samarium(III) also enhances the epimerization to the trans isomer and therefore produces the desired isomer in high selectivity. 

Scheme 14.2 Imidazolinone-catalyzed hydride transfer/Michael addition cascade for the synthesis of (+)-ricciocarpin A.

In this very active field, Michrowska and List applied the combination of iminium-catalyzed 1,4 hydride addition and subsequent intramolecular 1,4 Michael addition for the one-pot synthesis of ricciocarpin, a molluscicidal natural product isolated from the liverwort Ricciocarpos natans (Scheme 11.29). This cascade reaction could be initiated by the single imidazolidinone (I )-3 that catalyzed both imi-nium hydride addition and Michael addition. Treatment of the Michael adduct with Sm(0/-Pr)3 induced the epimeriza-tion of the aldehyde carbon center to the more thermodynamically stable trans ring junction and subsequent Tishchenko reaction (redox process between the aldehyde... 

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