A Concise and Flexible Total Synthesis of (−)‐Diazonamide A

Diazonamide studies. A direct synthesis of the indole bis-oxazole fragment from tri- and tetra-peptides using biomimetic oxidative cyclizations

“…Of these, 3-indolyl oxazoles are known to result from the so-called Yonemitsu oxidation of tryptamine derivatives, 26,27 and the oxidation of the tyrosine ring followed by capture by the nucleophilic indole 3-position has precedent in the aforementioned Harran synthesis. 9 Our preliminary thoughts involved the construction of the indole bis-oxazole fragment of diazonamide A using a classical, stepwise approach that would provide an authentic sample from which to compare the outcome of any subsequent biomimetic transformations. Thus, it was envisaged that valinyloxazole-acid 5 would undergo amide coupling with aminoketone 6 followed by cyclodehydration providing the desired indole bis-oxazole 7, the identical target that would be obtained by oxidation then cyclodehydration of tripeptide 8 if the biomimetic hypothesis were successful (Scheme 2).…”

“…Final proof that the revised structure 2 was indeed that of diazonamide A came in 2002 when Nicolaou and co-workers published the first total synthesis of the natural product. 5,6 Subsequently, the Nicolaou group reported a second route to diazonamide A, 7,8 whilst Harran and co-workers accomplished their own total synthesis of the correct structure, 9 and Magnus and co-workers completed a formal synthesis. 10 Despite the fact that these efforts have now solved the structural problem of diazonamide A, it remains of considerable interest, not only because of its reported nanomolar in vitro cytotoxicity against human tumour cell lines, 1,2,11,12 but also as a challenging target for synthetic chemists.…”

“…13 As noted previously, the correct structure of diazonamide A 2 better fits a biosynthetic route in which the bicyclic core derives from modification of a TyrValTrpTrp tetrapeptide, 4 and Harran's own synthesis of the natural product involves the formation of the G-H-F-E aminal by an oxidative cyclization of a tyrosine derivative that likely mimics the biosynthesis. 9 In continuation of our own longstanding interest in diazonamide A 2, [14][15][16][17][18][19][20][21][22] which primarily involves the use of diazocarbonyl chemistry to construct strategic C-N bonds by rhodium carbene N-H insertion reactions, we were also intrigued by the possibility of a biomimetic route that involves the oxidative cyclization of the putative biosynthetic precursor, the TyrValTrpTrp tetrapeptide. We now report the full details of our endeavours in this area.…”

Funktionalisierung von C‐H‐Bindungen: neue Synthesemethoden für Naturstoffe und Pharmazeutika

“…[28] Die Umsetzung des Arylbromids 11 mit LiOH unter Lichteinstrahlung führte über das intermediäre Diradikal 12 mit 72 % Ausbeute zum Verknüpfungsprodukt 13.…”

From Amino Acids to Heteroaromatics—Thiopeptide Antibiotics, Nature's Heterocyclic Peptides

“…The amino acid origins of other heteroaromatic natural products are perhaps less clear. A more recent example is diazonamide A, [8][9][10][11] for which the putative biosynthetic precursor is the TyrValTrpTrp tetrapeptide, [12,13] which has to undergo a series of oxidation, cyclodehydration, and chlorination reactions to give the natural product. Although we have indicated the likely amino acid precursors to nostocyclamide, telomestatin, and diazonamide A as hexa-, octa-, and tetrapeptides, respectively, there is no implication that the biosynthetic pathway involves formation of all the peptide bonds before the various heterocyclization steps occur.…”