Concise, biomimetic total synthesis of d,l-marcfortine C

Abstract

A biomimetic total synthesis of the fungal metabolite marcfortine C utilizing an intramolecular Diels-Alder reaction is described. In addition, a key stereoselective oxaziridine-mediated oxidation/pinacol rearrangement of indole 24 was used to complete the total synthesis.

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.…”

“…90 Readily available β-hydroxypipecolic acid was coupled to reverse-prenylated tryptophan derivative 66 and carried through the analogous sequence deployed for the stephacidin A synthesis. The final spiro -oxindole oxidation required “protecting” the tertiary amine as the corresponding tosylate salt, which permitted smooth and diastereoselective oxidation and spiro -rearrangement to D,L -marcfortine C. This synthesis required a total of fifteen steps from commercially available 6-hydroxyindole with an overall yield of 3.7%.…”

“…The final spiro -oxindole oxidation required “protecting” the tertiary amine as the corresponding tosylate salt, which permitted smooth and diastereoselective oxidation and spiro -rearrangement to D,L -marcfortine C. This synthesis required a total of fifteen steps from commercially available 6-hydroxyindole with an overall yield of 3.7%. 90 …”

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.…”

“…Tryptophan derivative 142 used in the above synthesis of stephacidin A was also employed in the biomimetic total synthesis of marcfortine C (164) [33]. 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].…”