A convergent three-component total synthesis of the powerful immunosuppressant (-)-sanglifehrin a.
The potent immunosuppressive agent (-)-sanglifehrin A (5), initially discovered in a soil sample from Malawi, has been synthesized in a highly convergent and stereocontrolled manner. The enantioselective approach relies on initial construction of the iodovinyl carboxylic acid 14, which is coupled to tripeptide 59 in advance of a key macrolactonization step that generates 61a. An alternative protocol that involves the linkage of 14 to 46 for possible construction of the large ring failed due to an inability to bring about a corresponding macrolactamization maneuver. An efficient means for elaborating the C26-N42 spirolactam western sector of 5 is also detailed. This requisite fragment was assembled through the proper adaptation of consecutive aldol tactics for construction of the nine stereogenic centers, six of which are contiguous. The first aldol process consisted of the tin triflate-mediated reaction of the aldehyde derived from 72 with enantiopure ketone 73 to generate the syn C36-C37 relationship resident in 75. Once the conversion of 75 to 78 had been completed, the attachment to ketone 66 was effected with (+)-DIPCl, thereby setting the C33-C34 relationship as anti. Once functional group modifications had given rise to 62, spirolactamization was achieved to deliver predominantly 94, thereby setting the stage for the acquisition of vinyl stannane 13 and its subsequent palladium-catalyzed Stille coupling to 61b. Controlled acidic hydrolysis completed the synthesis of 5. Other important features of the present route are addressed where relevant.
Paquette
Leo A
LA
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA. paquette.l@osu.edu
Duan
Maosheng
M
Konetzki
Ingo
I
Kempmann
Christoph
C
D007166:Immunosuppressive Agents / Q000138:chemical synthesis*; D007783:Lactones / Q000138:chemical synthesis*; D013141:Spiro Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism
D007166:Immunosuppressive Agents; D007783:Lactones; D013141:Spiro Compounds; C121329:sanglifehrin A