Synthesis Of Alkoxy Heterocyclic And Fused Rings Derivatives Of S Nicotine From Natural Nicotine Progress Towards The Total Synthesis Of S Macrostomine

Author : Jiyong Hong
Publisher :
ISBN 13 : 9780493354873
Total Pages : 412 pages
Book Rating : 4.3/5 (548 download)

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Download or read book Application of Inverse Electron Demand Diels-Alder Reactions in Total Synthesis of Nothapodytine B, ( - )-mappicine, Phomazazarin, and Ent-( - )-roseophilin written by Jiyong Hong and published by . This book was released on 2001 with total page 412 pages. Available in PDF, EPUB and Kindle. Book excerpt: 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 [arrow right] 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 [arrow right] 1,2-diazine [arrow right] 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 ([[alpha]] [superscript]25 [subscript]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.