Studies towards the synthesis of diazonamide A. Synthesis of the indole bis-oxazole fragment

Article abstract of DOI:10.1016/S0040-4039(00)01120-5

The indole bis-oxazole 2, a potential intermediate for the synthesis of the marine natural product diazonamide A 1, has been synthesised, and attempts to construct the model macrocycle (ring B) 3 are also described; in both approaches rhodium carbenoid N-H insertion reactions are used in key steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01120-5

Tetrahedron Letters 41 (2000) 6897±6900
Studies towards the synthesis of diazonamide A.
Synthesis of the indole bis-oxazole fragment
Mark C. Bagley, S. Lucy Hind and Christopher J. Moody*
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Received 24 May 2000; accepted 29 June 2000
Abstract
The indole bis-oxazole 2, a potential intermediate for the synthesis of the marine natural product
diazonamide A 1, has been synthesised, and attempts to construct the model macrocycle (ring B) 3 are also
described; in both approaches rhodium carbenoid N±H insertion reactions are used in key steps. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: rhodium carbenoid insertion; indoles; oxazoles.
In the preceding letter we described the synthesis of a tyrosine-derived benzofuranone,1 a key
intermediate (rings G±H±I) in our projected synthesis of diazonamide A 1, a structurally unique
marine metabolite with potent antitumour properties.2,3 We now report our approach to the
tryptophan-derived indole fragment of diazonamide A 1, and describe the synthesis of the model
indole bis-oxazole 2,4 together with our attempts to construct the right hand macrocycle (ring B)
3 of the natural product by intramolecular biaryl bond formation.
With the relatively strained nature of the ring B macrocycle in mind, our synthesis was planned
so that one of the oxazole rings (ring E) was formed at a late stage by cyclodehydration of an
* Corresponding author. E-mail: c.j.moody@ex.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01120-5

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appropriate 1,4-dicarbonyl compound. Therefore, our initial model studies sought to demonstrate
the viability of this approach. The starting material was the valine-derived oxazole-4-carboxylic
acid 5, prepared by our previously developed route based on rhodium carbenoid N±H insertion
reactions.5 Thus, dirhodium(II) acetate-catalysed reaction of methyl 2-diazo-3-oxobutanoate with
(S)-N-benzyloxycarbonylvalinamide 4 resulted in carbenoid insertion into the primary amide
N±H bond; cyclodehydration of the intermediate 1,4-dicarbonyl compound using Wipf's protocol6
gave the corresponding oxazole-4-ester, alkaline hydrolysis of which gave the required oxazole
carboxylic acid 5 (Scheme 1). Activation of the acid by mixed anhydride formation followed by
coupling with tryptamine (76%) or tryptophan methyl ester (82%) gave the indoles 6 and 7.
Oxidation of 6 and 7 with DDQ7 gave the keto amides 8 and 9, the required 1,4-dicarbonyl
precursors of the second oxazole ring (Scheme 1). The closely related ketoamide 13 was also
prepared by an alternative method. Addition of ethyl diazoacetate (EDA) to the indole-3-carb-
oxaldehyde 10 in the presence of diethylzinc8 gave the corresponding a-diazo-b-hydroxyester,
oxidation of which with o-iodoxybenzoic acid (IBX)9 gave the a-diazo-b-ketoester 11. Dirhodium-
(II)-catalysed reaction in the presence of the oxazole-4-carboxamide 12, prepared from the carb-
oxylic acid 5, resulted in carbenoid N±H insertion and formation of the desired ketoamide 13.
The sequence was repeated with the 4-bromoindole 14 to give the corresponding ketoamide 16,
the 4-bromo substituent being incorporated to allow subsequent sp2±sp2 coupling at this position.
Scheme 1.

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With two routes to the indole±oxazole 1,4-dicarbonyl compounds available, the subsequent
cyclodehydration to form the second oxazole ring was readily demonstrated. Thus, treatment of 9
with triphenylphosphine/iodine/triethylamine gave the model indole bis-oxazole 2, comprising the
C±D±E±F rings of diazonamide A, in excellent yield (Scheme 2).
Scheme 2.
In order to adapt the above methodology to the synthesis of the indole bis-oxazole containing
ring B macrocycle of the natural product we required a route to the model macrocycle 3, and our
initial attempts focused on an intramolecular biaryl coupling. In order to construct the dibromo-
precursor 20 by amide bond formation, the relevant acid (5-(3-bromobenzyl)oxazole-4-carboxylic
acid 17) and amine (4-bromotryptophan methyl ester 19) components were required. The oxazole
17 was obtained from the valinamide 4 by another carbenoid N±H insertion, followed by cyclo-
dehydration and ester hydrolysis as shown in Scheme 1. 4-Bromotryptophan methyl ester 19 was
prepared as shown in Scheme 3. Thus, Wadsworth Emmons reaction of N-Boc-4-bromoindole-3-
carboxaldehyde 14 with trimethyl 2-[N-(tert-butoxycarbonyl)amino]phosphonoacetate (itself
prepared in 93% yield by a rhodium carbenoid N±H insertion reaction of trimethyl diazophos-
phonoacetate with tert-butyl carbamate10) gave the dehydrotryptophan derivative 18 in good
yield. Hydrogenation followed by removal of the two Boc groups then gave the required 4-bromo
tryptophan derivative 19 (Scheme 3).
Scheme 3.
The oxazole acid 17 was activated using mixed anhydride methodology, and coupled with the
tryptophan 19 to give the required dibromo compound 20, the precursor for the intramolecular
biaryl coupling reaction. However, all attempts to e€ect the intramolecular biaryl coupling of
dibromide 20 using various conditions [e.g. NiCl2, PPh3, Nal, Zn11 or Pd(PPh3)4, Me6Sn12] failed
to give any of the desired macrocycle 3 (Scheme 4).13

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Scheme 4.
With the failure to e€ect the desired intra-molecular biaryl coupling, e€orts were concentrated
on carrying out an inter-molecular coupling at an earlier stage in the synthesis; the results of this
approach are described in the following letter.14
Acknowledgements
We thank the Association for International Cancer Research for a studentship (to S.L.H.), the
Leverhulme Trust for ®nancial support, and the EPSRC Mass Spectrometry Service at Swansea
for mass spectra.
References
1. Lach, F.; Moody, C. J. Tetrahedron Lett. 2000, 41, 6893±6896.
2. Lindquist, N.; Fenical, W.; Duyne, G. D. V.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303±2304.
3. For a compilation of references to other approaches to the synthesis of diazonamide A, see Ref. 1.
4. For other syntheses of indole bis-oxazoles related to diazonamide A, see: (a) Boto, A.; Ling, M.; Meek, G.;
Pattenden, G. Tetrahedron Lett. 1998, 39, 8167±8170; (b) Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41,
831±834.
5. Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1998, 591±600.
6. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604±3606.
7. Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213±1216; Oikawa, Y.; Yoshioka, T.; Mohri, K.; Yonemitsu,
O. Heterocycles 1979, 12, 1457±1462.
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10. Ferris, L.; Haigh, D.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1996, 2885±2888.
11. Kageyama, H.; Miyazaki, T.; Kimura, Y. Synlett 1994, 371±372.
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13. Others have also reported a failure to construct the 4-arylindole by intramolecular biaryl bond formation; see Ref.
4a.
14. Bagley, M. C.; Moody, C. J.; Pepper, A. G. Tetrahedron Lett. 2000, 41, 6901±6904.