Ingo Konetzki

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.

The first total synthesis of the fungal metabolite caloporoside 1, a strong and selective inhibitor of phospholipase C, is described. Both sugar units of its complex disaccharidic segment were obtained from 3,4,6-tri-O-benzyl-d-glucopyranose 14 as a common building block, with d-gluco → d-manno inversions as the key strategic elements. This particular substitution reaction occurred readily on the acyclic segment (27 → 28), whereas ultrasonication was required to override adverse stereoelectronic effects upon formation of β-d-mannopyranoside unit 34. The (16R)-hydroxyheptadecylsalicylic acid part of 1 was efficiently prepared by a palladium-catalyzed Suzuki cross coupling reaction of aryltriflate 7 with the 9-alkyl-9-BBN derivative formed from alkene 6 and 9-H-9-BBN.