Angewandte
Chemie
DOI: 10.1002/anie.200906318
Natural Products
A Concise Formal Synthesis of Diazonamide A by the Stereoselective
Construction of the C10 Quaternary Center**
Cheng-Kang Mai, Matthew F. Sammons, and Tarek Sammakia*
Diazonamide A (1, Scheme 1) is a marine natural product
with potent antimitotic activity and an unusual architecture.[1]
Its mode of action has been studied, and although it displayed
The synthetic challenge posed by diazonamide A lies, in
great part, in the stereoselective construction of the highly
hindered quaternary C10, which has attracted the attention of
numerous synthetic groups.[5] These efforts have resulted in
three total syntheses by Nicolaou et al.[6a–d] and Harran et
al.,[6e] and a formal total synthesis by Magnus and co-
workers.[6f] We have studied a new approach wherein we
construct the C10 quaternary carbon using the arylation of a
3-aryloxindole.[7] We initially chose to study this construction
using a palladium-catalyzed arylation,[8] and performed a
model study to examine the order of bond formation in the
synthesis of this subunit. We studied these reactions using 3-
substituted oxindoles 3 and 4, which were arylated with
bromobenzene and bromooxazole 5,[9] respectively, using
modified Hartwig conditions[10] (Pd(OAc)2 or [Pd(dba)2],
tBu3PHBF4[11] in toluene at reflux; Scheme 2). We found that
Scheme 1. The structure and retrosynthesis of diazonamide A.
Cbz=phenylmethoxycarbonyl, MOM=methoxymethyl.
differential cytotoxicity in an NCI COMPARE[2] screen that is
consistent with a tubulin-active agent,[3] recent studies by
Harran, Wang, McKnight, and co-workers suggest a unique
mode of action involving the mitochondrial matrix enzyme,
ornithinine d-amino transferase (OAT).[4] Prior to these
studies, OAT had no known mitotic function, and diazona-
mide A does not inhibit the amino transferase activity of this
enzyme; however, it disrupts the interaction of OAT with
mitotic-spindle-promoting proteins. These same authors
showed that a close synthetic analogue of diazonamide A,
which lacks the two chlorine substituents, retained the
cytotoxicity of the natural product, but did not display overt
toxicity nor did it cause weight loss, a change in overall
physical appearance, or show any evidence of causing
neutropenia in mice.[4a] The limited supply, unique biological
activity, and structural complexity of diazonamide A renders
this molecule and analogues thereof important targets for
chemical synthesis.
Scheme 2. Arylation of 3-aryloxindoles 3 and 4. Boc=tert-butoxycar-
bonyl.
whilst the combination of substrate 3 and bromobenzene did
not provide the desired product, substrate 4 reacted cleanly
with bromooxazole 5 to produce compound 6 in 79% yield.
This method can be used to readily form a highly hindered
quaternary carbon atom. In an effort to optimize this reaction,
we incrementally reduced the catalyst loading from 5%;
surprisingly, the reaction proceeded even in the absence of
palladium with no decrease in yield. This indicated that the
reaction proceeded via an SNAr mechanism in the absence of
palladium (Scheme 2).[12] We are currently examining further
applications of this reaction for the formation of quaternary
carbon centers.
[*] C.-K. Mai, Dr. M. F. Sammons,[+] Prof. Dr. T. Sammakia
Department of Chemistry and Biochemistry
University of Colorado, Boulder, CO 80309-0215 (USA)
Fax: (+1)303-492-0439
E-mail: sammakia@colorado.edu
[+] Current Address: Pfizer Global Research and Development
Groton, CT 06340 (USA)
[**] This work was supported by a generous grant from the National
Institutes of Health (GM 48498). We wish to thank Dr. Joseph H.
Reibenspies (Texas A&M University) for acquiring the X-ray crystal
structure of 34, and Dr. Richard Shoemaker (University of Colorado)
for expert assistance with acquiring NMR spectroscopy data.
To apply this reaction to the synthesis of diazonamide A,
we prepared the bis(MOM)-protected cyclization precursor, 2
(Scheme 3). N-Cbz-l-tyrosine methyl ester (7)[13] was treated
with iPrMgCl, and the resulting phenoxide was coupled with
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 2397 –2400
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