Biomimetic approaches to diazonamide A. Direct synthesis of the indole bis-oxazole fragment by oxidation of a TyrValTrpTrp tetrapeptide

Article abstract of DOI:10.1039/b604294e

Oxidation of a protected TyrValTrpTrp tetrapeptide results in direct formation of the indole bis-oxazole core of diazonamide A. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604294e

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Biomimetic approaches to diazonamide A. Direct synthesis of the indole
bis-oxazole fragment by oxidation of a TyrValTrpTrp tetrapeptide
Jonathan Sperrya and Christopher J. Moody*ab
Received (in Cambridge, UK) 23rd March 2006, Accepted 26th April 2006
First published as an Advance Article on the web 9th May 2006
DOI: 10.1039/b604294e
Our retrosynthetic analysis of diazonamide A 1 (Scheme 1)
involves an initial simplification and disconnection of the
a-hydroxy isovaleric acid side chain and the two chlorine atoms.
Oxidation of a protected TyrValTrpTrp tetrapeptide results
in direct formation of the indole bis-oxazole core of diazon-
amide A.
The marine secondary metabolite diazonamide A, isolated from
the colonial ascidian Diazona chinensis, was reported to have
potent in vitro cytoxicity against human tumor cell lines.1 This
biological activity,2 together with its unique and complex structure,
assigned on the basis of an X-ray crystallographic study of a
derivative,1 ensured that diazonamide A immediately captured the
imagination of synthetic organic chemists. Therefore in the 15 years
since the structure of diazonamide A was reported in 1991, some
10 research groups have published approaches to this fascinating
natural product.3–12 The story acquired a new dimension in 2001
when Harran and co-workers completed a total synthesis of the
reported structure only to discover that not only was it rather
unstable, but it was also different from the natural product.13,14 On
the basis of his own studies and a re-examination of the original
X-ray data, Harran proposed an alternative structure 1 for
diazonamide A. Unequivocal proof that the revised structure 1
was indeed that of diazonamide A came when Nicolaou and co-
workers published the first total synthesis of the natural product.15
Subsequently, the Nicolaou group reported a second route to
diazonamide A,16 whilst Harran and co-workers completed their
own total synthesis of the correct structure.17 Despite the fact that
Nicolaou’s and Harran’s efforts in total synthesis have laid to rest
the structural problem of diazonamide A, such is its attraction as a
target molecule that it continues to hold the attention of a number
of research groups.
Importantly, the revised structure of diazonamide A 1 better fits
a biosynthetic route in which the bicyclic core derives from
modification of a TyrValTrpTrp tetrapeptide,14 and Harran’s own
synthesis of the natural product involves the formation of the
G-H-F-E aminal by an oxidative cyclisation of a tyrosine
derivative that likely mimics the biosynthesis.17 In continuation
of our own longstanding interest in diazonamide A 1,18–24 which
primarily involves the use of diazocarbonyl chemistry to construct
strategic C–N bonds by rhodium carbene N–H insertion reactions,
we were intrigued by the possibility of a biomimetic route that
started from the putative biosynthetic precursor, the
TyrValTrpTrp tetrapeptide itself. We now report the first results
from this study.
aDepartment of Chemistry, University of Exeter, Stocker Road, Exeter,
UK EX4 4QD
bSchool of Chemistry, University of Nottingham, University Park,
Nottingham, UK NG7 2RD. E-mail: c.j.moody@nottingham.ac.uk
Scheme 1
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It was established early on that both these chlorines could be
introduced by a late stage electrophilic chlorination reaction.25,26
However, as did Magnus and co-workers,26 we recognised an
additional possibility that the 4-chlorooxazole might derive by a
decarboxylative chlorination of the corresponding oxazole-4-
carboxylic acid. This again relates to the putative biosynthetic
precursor to diazonamide A in that C-4 of the ring-B oxazole
derives from the a-carbon of tryptophan and therefore would
originally bear a carboxylic acid. Hence the initial target is the
macrocyclic core 2 that can be envisaged to result from a series of
oxidative cyclisations of the tetrapeptide 3 as depicted in Scheme 1.
Of these, the oxidation of the tyrosine ring followed by capture by
the nucleophilic indole 3-position has precedent in the aforemen-
tioned Harran synthesis,17 and 3-indolyl oxazoles are known to
result from the so-called Yonemitsu oxidation of tryptamine
derivatives.27,28
The synthesis of the substrate tetrapeptide started with the
formation of the known Boc-TrpTrp-OMe dipeptide 429 by
reaction of Boc-Trp-OH with H-Trp-OMe using HBTU in the
presence of 1-hydroxybenzotriazole (HOBt) and Hu¨nigs base as
the peptide coupling agent.30 Removal of the N-Boc protecting
group under acidic conditions was followed by a second HBTU-
mediated coupling with Z-Val-OH to give the tripeptide 5. Finally,
hydrogenolysis of the N-Z protecting group and a further HBTU-
coupling to Z-Tyr-OH gave the protected TyrValTrpTrp tetra-
peptide 6 in an overall yield of 27.2% from Boc-Trp-OH
(Scheme 2).
The stage was now set for oxidative cyclisation of the
tetrapeptide, and after initial experimentation with simpler model
systems (not shown) it was discovered that the Yonemitsu
oxidation conditions were the most appropriate. Therefore,
treatment of the tetrapeptide 6 with DDQ in anhydrous THF
gave the indole bis-oxazole 7 directly, albeit in poor yield (17%).{
This result establishes the possibility that such an (enzymatic)
oxidation of the indole-3-carbinyl position in tryptophan residues,
followed by cyclodehydration, could form the basis of the
biosynthesis of the heterocyclic core of diazonamide A 1.
Notwithstanding the poor yield in the final step, the advanced
intermediate 7 is available in just six steps from Boc-Trp-OH.
We thank the EPSRC for support of this work (Senior Research
Fellowship to CJM), and the EPSRC Mass Spectrometry Centre
at Swansea for mass spectra.
Notes and references
{ Compound 7, mp 146–148 uC (from ethyl acetate); [a]2D5 + 40.0 (c 0.1,
THF); (Found: MH+, 793.2980. C45H40N6O8 + H requires 793.2986); nmax
(KBr)/cm21 3411, 2960, 2915, 1704, 1668, 1617, 1589, 1516, 1457, 1375,
1337, 1244, 1218, 1130, 1086, 1052, 745; dH (400 MHz; d6-DMSO) 12.00
(2 H, br s, 2 NH), 9.21 (1 H, d, J 2.9, ArH), 9.11 (1 H, s, OH), 8.82 (1 H, d,
J 8.7, NH), 8.72 (1 H, d, J 2.9, ArH), 8.18 (1 H, d, J 7.8, ArH), 8.13 (1 H, d,
J 7.7, ArH), 7.40–7.38 (2 H, m, ArH), 7.73–7.05 (12 H, m, 11 ArH and
NH), 6.58–6.56 (2 H, m, ArH), 5.08–5.01 (1 H, m, CH), 4.93 (2 H, s, CH2),
4.39 (1 H, m, CH), 3.91 (3 H, s, OMe), 2.95 (1 H, m, CH of CH2), 2.70
(1 H, m, CH of CH2), 2.46 (1 H, m, CHMe2), 1.11 (3 H, d, J 6.6, CHMe2),
1.03 (3 H, d, J 6.6, CHMe2); dC (100 MHz; d6-DMSO) 172.6, 163.1, 160.9,
156.4, 156.2, 153.9, 152.7, 149.1, 137.5, 136.6, 136.5, 130.7 (CH), 129.2
(CH), 128.8 (CH), 128.7 (CH), 128.5, 128.14 (CH), 128.09 (CH), 128.0
(CH), 127.9 (CH), 125.2, 125.0, 123.4, 123.1 (CH), 121.6 (CH), 121.4 (CH),
119.8, 115.5 (CH), 115.2 (CH), 112.8 (CH), 112.7 (CH), 103.2, 102.7, 65.6
(CH2), 56.8 (Me), 53.0 (CH), 52.3 (CH), 31.7 (CH), 19.6 (Me), 19.1 (Me), 1
CH2 not observed; m/z (ES+) 793 (3%, MH+), 698 (3), 687 (12), 685 (39),
684 (95), 669 (11), 651 (10), 641 (10), 638 (17), 637 (31), 579 (9), 494 (9), 420
(11), 394 (10), 365 (9), 337 (9), 310 (9), 309 (10), 280 (19), 266 (23), 239 (21),
223 (29), 219 (52), 205 (50), 170 (53), 169 (80), 168 (100), 144 (20), 117 (15),
108 (58), 107 (63), 91 (30), 79 (99), 77 (98), 53 (28), 52 (81), 46 (70).
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