Studies towards the synthesis of diazonamide A. Synthesis of the 4-(oxazol-5-ylmethyl) aryltryptamine fragment

Article abstract of DOI:10.1016/S0040-4039(00)01121-7

The oxazole substituted 4-aryltryptamine 5, a potential intermediate for the synthesis of the marine natural product diazonamide A 1, has been synthesised. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01121-7

Tetrahedron Letters 41 (2000) 6901±6904
Studies towards the synthesis of diazonamide A. Synthesis
of the 4-(oxazol-5-ylmethyl) aryltryptamine fragment
Mark C. Bagley, Christopher J. Moody* and Adrian G. Pepper
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Received 24 May 2000; accepted 29 June 2000
Abstract
The oxazole substituted 4-aryltryptamine 5, a potential intermediate for the synthesis of the marine
natural product diazonamide A 1, has been synthesised. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: indoles; Claisen rearrangement; Suzuki reaction; rhodium carbenoid insertion; oxazoles.
In the preceding two letters we described the synthesis of the tyrosine-derived benzofuranone
2,1 and the indole bis-oxazole 3,2 key intermediates (rings G±H±I and rings C±D±E±F) in our
projected synthesis of diazonamide A 1, a structurally unique marine metabolite with potent
antitumour properties.3,4 We also described our attempts to construct the right hand macrocycle
(ring B) of the natural product by intramolecular biaryl bond formation using the dibromide 4 as
substrate.2 With the failure to e€ect the key biaryl bond formation at the indole-4-position by an
intra-molecular coupling reaction, we turned our attention to an inter-molecular coupling at an
earlier stage in the synthesis, and the results of this approach are described herein.
The target of our studies was the highly substituted 4-aryltryptamine 5, which not only
contains the C±D±F±G ring system of the natural product, but also the functionality to form the
macrocyclic B-ring by a macrolactamisation reaction. In addition, oxidation of the CH2-group
a-to the indole ring with DDQ will provide the required 1,4-dicarbonyl compound for cyclode-
hydration to form the second oxazole (ring E).2 The indole component for the synthesis of the
4-aryltryptamine 5 was the di-Boc-protected 4-bromotryptamine 10, and this was prepared from
4-bromoindole 6 as shown in Scheme 1. Thus, Vilsmeier formylation of 4-bromoindole 6 gave the
known5 4-bromoindole-3-carboxaldehyde 7 in good yield. Henry reaction of the aldehyde with
nitromethane gave the nitroalkene 8, reduction of which with lithium aluminium hydride gave
4-bromotryptamine 9. Finally, protection of both the primary amine and the indole nitrogen as
their Boc derivatives gave the required 4-bromotryptamine derivative 10 (Scheme 1).
*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)01121-7

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Scheme 1.
The second component for the formation of the biaryl bond in 5 was the boronic acid 12,
readily prepared from 2-allyloxybromobenzene 11 by Lewis acid-catalysed Claisen rearrangement
(100%), O-methylation (85%) and treatment with t-butyllithium followed by trimethyl borate
(74%) (Scheme 2). The Suzuki coupling of 10 and 12 proceeded smoothly in the presence of
Pd(PPh3)4 and caesium carbonate to give the 4-aryltryptamine 13 in excellent yield (90%).6 The
oxazole ring was constructed using our rhodium carbenoid N±H insertion methodology,7 and
hence required the conversion of the allyl side chain into an a-diazo-b-ketoester. Oxidative
cleavage of the allyl group in a two-step process by dihydroxylation,8 followed by periodate gave

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Scheme 2.
the aldehyde 14 in good yield. Attempts to form the required a-diazo-b-ketoester 16 by addition
of ethyl diazoacetate in the presence of diethylzinc,9 followed by oxidation of the resulting
a-diazo-b-hydroxyester were unsatisfactory, and therefore an alternative procedure was adopted.
Addition of ethyl diazoacetate in the presence of tin(II) chloride10 gave the b-ketoester 15 in
excellent yield; the diazo group was reintroduced by standard diazo transfer methodology using
4-acetamidobenzenesulfonyl azide,11 and gave the required a-diazo-b-ketoester 16 setting the stage
for the key rhodium carbenoid N±H insertion reaction (Scheme 2). Dirhodium(II) acetate-
catalysed reaction of the a-diazo-b-ketoester 16 in the presence of (S)-N-benzyloxy-

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carbonylvalinamide resulted in selective carbenoid insertion into the primary amide N±H bond;
®nally, cyclodehydration of the intermediate 1,4-dicarbonyl compound 17 using Wipf's protocol12
gave the oxazole-4-ester 5, albeit in poor yield over the two steps, comprising the highly functio-
nalised 4-aryltryptamine fragment of diazonamide A 1.
Acknowledgements
We thank 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. Bagley, M. C.; Hind, S. L.; Moody, C. J. Tetrahedron Lett. 2000, 41, 6897±6900.
3. Lindquist, N.; Fenical, W.; Duyne, G. D. V.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303±2304.
4. For a compilation of references to other approaches to the synthesis of diazonamide A, see Ref. 1.
5. Somei, M.; Kizu, K.; Kunimoto, M.; Yamada, F. Chem. Pharm. Bull. 1985, 33, 3696±3708.
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Soc., Chem. Commun. 1999, 2211±2212.
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8. Eames, J.; Mitchell, H. J.; Nelson, A.; O'Brien, P.; Warren, S.; Wyatt, P. Tetrahedron Lett. 1995, 36, 1719±722.
9. Moody, C. J.; Mor®tt, C. N. Synthesis 1998,1039±1042.
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11. Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth. Commun. 1987, 17, 1709±1716.
12. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604±3606.