Application of inverse electron demand Diels-Alder reactions in total syntheses of nothapodytine B, (-)-mappicine, phomazarin, and ent-(-)-roseophilin

Concise total syntheses of naturally occurring nothapodytine B (mappicine ketone) and (−)-mappicine are detailed. The approach was based on the implementation of a room-temperature, inverse electron demand Diels-Alder reaction of an N-sulfonyl-1-aza-1,3-butadiene for assemblage of a pyridone D-ring precursor central to the structure. A Friedlander condensation was utilized for constructing the AB-ring system of nothapodytine B and (−)-mappicine. An acid-catalyzed reaction sequence was used to accomplish a deprotection with subsequent ring-closure for introduction of the C-ring in a single step; A concise total synthesis of phomazarin is detailed enlisting a heterocyclic azadiene inverse electron demand Diels-Alder reaction (1,2,4-triazine → pyridine) for preparation of the fully substituted and appropriately functionalized pyridine C-ring. Thus, [4+2] cycloaddition of triethyl 1,2,4-triazine-3,5,6-tricarboxylate with 1,1,2-trimethoxyethylene followed by conversion of the cycloadduct to the cyclic anhydride provided the phomazarin C-ring with the three carboxylates suitably differentiated. Linkage of the A- and C-rings through selective nucleophilic addition of an aryl lithium reagent to the least hindered carbonyl of the cyclic anhydride followed by Friedel-Crafts closure of the B-ring provided the fully functionalized phomazarin skeleton. The successful structural correlation of synthetic phomazarin with natural material and its derivatives confirmed the latest structural assignment for the natural product.; An asymmetric total synthesis of ent-(−)-roseophilin, the unnatural enantiomer of a novel antitumor antibiotic, was accomplished based on an approach enlisting a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate with an optically active enol ether bearing the C23 chiral center, followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine → 1,2-diazine → pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core. Condensation of the tricyclic core with the heterocyclic side chain followed by final deprotection provided (22S,23S)-roseophilin. Comparison of synthetic (22S,23S)-roseophilin ([α] 25_D, CD) with natural roseophilin established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(−)-roseophilin was found to be 2–10-fold more potent than natural (+)-roseophilin in cytotoxic activity.