The diazo route to diazonamide A: studies on the tyrosine-derived fragment

Abstract

Various approaches to the tyrosine-derived fragment of the marine secondary metabolite diazonamide A are described. Initial efforts were focused on the originally proposed structure of the natural product, and a feasibility study established that a model 4-aryltryptamine could be readily prepared. Protected 4-bromotryptamine underwent Pd0-catalyzed coupling with the boronic acid derived from 2-bromophenyl allyl ether by Claisen rearrangement, O-methylation and lithiation-boration. The resulting biaryl was elaborated into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Z-valinamide gave the desired tryptamine-oxazole following cyclodehydration of the intermediate ketoamide. A potential precursor to the benzofuran ring of the original structure of diazonamide A was prepared in eight steps from N-Z-tyrosine tert-butyl ester. Iodination, O-protection and Stille coupling gave the cinnamyl alcohol 25, converted via the bromide into the allyl aryl ether 27. Subsequent Claisen rearrangement and oxidative cleavage of the alkene gave the lactol 29, converted into the desired benzofuranone 31. The revision in the structure of diazonamide A to 2 resulted in the targeting of an alternative tyrosine-derived model benzofuranone 41 synthesized in four steps from N-Z-tyrosine methyl ester 36 by a route involving Claisen rearrangement of cinnamyl ether 37. Poor yields in this sequence prompted an investigation into the intramolecular Heck reaction as a route to benzofuranone 50. Coupling of 3-iodotyrosine 44 with 2-phenylbutenoic acid 48 gave ester 49 that readily underwent intramolecular Heck reaction to give benzofuranone 50, albeit with poor stereocontrol.

Transition metals in organic synthesis: Highlights for the year 2005

“…Synthetic targets included, prodigiosines [198], chartelline alkaloids [199], eupomatilone-3 [200], 9,10-deoxytridachione [201], hamigeran B [202], leprapinic acid and calycin [203], dehydrocoelenterazine analogs [204], gymnocin A (Eq. (11)) [205], murrastifoline A [206], styelsamine C and norsegoline [207], trispheridine [208], dragmacin F [209], ningalin D [210], eupomatilones [211], lucilactaene [47], epoxyquinols A-C and epoxytwinol A [212], mukonine [213], cepharanone [214], ␣ v ␤ 3 antagonist [215], alternariol [216], core of roseophilin [21], (−)-callystatin A [217], dibenzo[c,p]chrysene [218], GABA agonist [219,220], diazonamide A [221], dityrosine, trityrosine, pulcherosine [222], lamellarin D [223], integramycin [224], (+)-discodermolide and analogues [225,226], AB-ring system of hexacyclinic acid [227], ␦-trans-tocotrienoloic acid [135], spirofungins [228], kwakhurin [229], toward (+)-and (−)-deplanchein [230], combretastatin analogs [231], diazonamide A [75], cadiolide B [232], pukeleimide A [233], toward apoptolidin [234], polycitone A and B …”

“…Intermolecular amide nitrogen-hydrogen bond insertions were used in approaches to martefragine [731] and diazonamide A [75,221]. Intramolecular nitrogen-hydrogen bond insertions to give cis-2,4-disubstituted azetidin-3-ones [732] and (−)-ciscarboxyazetidine-3-acetic acid [733] were reported.…”

“…(31)) [436] and of alkenes with O-pentafluorobenzoylamidoximes [437] were reported. Intramolecular Heck reactions [394,[438][439][440][441][442] were used as the key step toward an array of synthetic targets for example, stephacidin A [443], 1-epi aglycon of cripowellins A and B [444], hamigeran B [202], mensacarcin [445], (−)-galanthamine and (−)-morphine [446], gelsemine [447], 5-substituted azepino [3,4-b]indoles [448], komaroviquinone and faveline methyl ether [449], pseudopteroxazole [450], diazonamide A [75], 4,7-azaindoles [451], substituted tryptophans (Eq. (32)) [452], 3,5,7-substituted indoles [453], morphine fragments [454], (+)-wortmannin [255], umbrosone [85] and the tricyclic core of cyathin diterpenoids [455].…”

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

“…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.…”

A direct route for the preparation of Fmoc/O Bu protected iodotyrosine

“…12,16 Carboxybenzyl (Cbz) protected iodotyrosines 3 have also been previously accessed. 17,18 While these can be used in solution phase synthesis the aforementioned combination of protecting groups are not compatible with fluorenylmethyloxycarbonyl (Fmoc) based solid phase peptide (SPPS) synthesis. For example, 1 and 2 could only be incorporated at the N-terminus of an Fmoc SPPS-synthesised peptide sequence and in the case of 2 additional steps would be required to remove the methyl ether after peptide cleavage from the solid support.…”