Biomimetic Total Synthesis of Malbrancheamide and Malbrancheamide B

Abstract

The biomimetic total syntheses of both malbrancheamide and malbrancheamide B are reported. The synthesis of the two mono-chloro species enabled the structure of malbrancheamide B to be unambiguously assigned. The syntheses each feature an intramolecular Diels-Alder reaction of a 5-hydroxypyrazin-2(1H)-one to construct the bicyclo[2.2.2]diazaoctane core, which has also been proposed as the biosynthetic route to these compounds.

Structural and stereochemical diversity in prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring system from marine and terrestrial fungi

“…The Williams lab has been able to successfully devise a biomimetic total synthesis of stephacidin A and its C-6-epimer, and more recently demonstrated C6- epi -stephacidin A to be a natural metabolite and, as noted above, these stephacidin A congeners are the direct biosynthetic precursors to notoamide B and versicolamide B, respectively. Subsequent to the biomimetic stephacidin A synthesis, these workers have been able to readily adopt this approach for successful biomimetic total syntheses of premalbrancheamide, 87 malbrancheamide, 88 spiromalbramide, 89 marcfortine C, 90 notoamide T and its C-6-epimer, 63 also now known to be a natural metabolite as described above.…”

“…In contrast to the stephacidin substrate, the Mitsunobu dehydration stops at the stage of dehydroproline derivative 81 that has to be treated with aqueous KOH in methanol at room temperature or below to effect tautomerization to the requisite azadiene that then suffers IMDA cycloaddition to give the cycloadducts 83 and 84 in a ~1 : 2 anti : syn diastereomeric ratio in good overall yields. 88 Reduction of the tertiary amide in the presence of the secondary amide was readily achieved using di-isobutyl aluminum hydride. 88 …”

“…88 Reduction of the tertiary amide in the presence of the secondary amide was readily achieved using di-isobutyl aluminum hydride. 88 …”

Biomimetic Synthesis of Alkaloids Derived from Tryptophan: Dioxopiperazine Alkaloids

“…Danishefsky and coworkers also completed the total synthesis of the spirooxindole spirotryprostatin B [8]. l-Tryptophan methyl ester was converted into the oxindole derivative 32, followed by addition of prenyl aldehyde under basic conditions to afford an inseparable four-component mixture of spirooxindoles (33)(34)(35)(36)Scheme 4.7). Peptide coupling and subsequent treatment of the mixture with lithium bis(trimethylsilyl)amide (LHMDS) followed by selenylation presumably gave phenyl selenide mixture 38.…”

“…Pipecolic acid derivative 156 was coupled to acid 142 to form amide 157, which underwent cyclization to the dioxopiperazine following Fmoc-deprotection to give 158 as and 169, as well as the anti-epimers 168 and 170 (Scheme 4.29) [34]. Treatment of the syn-cycloadducts with excess DIBAL-H gave either malbrancheamide or malbrancheamide B.…”