.
Angewandte
Communications
DOI: 10.1002/anie.201200205
Synthetic Methods
Synthetic (Æ)-Axinellamines Deficient in Halogen**
Hui Ding, Andrew G. Roberts, and Patrick G. Harran*
Pyrrole/imidazole alkaloids isolated from marine organisms
have drawn attention from laboratories worldwide. Their
structures, biosynthetic origins, preliminary biochemical
activities, and chemical syntheses form an extensive litera-
[1]
ture. This family of compounds contains hundreds of
[2]
members, often grouped based upon their oroidin content.
So-called monomers, dimers, and dimers of dimers are known.
Further diversity derives from oxidative transformations of
the monomeric and/or dimeric units. The most intricate
polycyclic “dimers” are uniquely challenging synthetic targets
and, despite numerous efforts, have been prepared by one
group. In a tactical tour-de-force, Baran and co-workers
[3]
synthesized axinellamines (1, Scheme 1), massadines, and
[
4]
Scheme 1. Axinellamines A (1a) and B (1b) and hypothetical dispac-
amide dimer 2.
palau’amine from a common intermediate. This work
evolved in stages, and beautifully leveraged collaborative
re-interpretation of data on natural samples to confirm
[5]
a uniform stereochemistry for the set. A refined synthesis
structural isomers. The full ensemble spirocycloisomerizes
with ease under non-oxidative conditions. This has allowed us
to synthesize axinellamines in partially halogenated forms,
thus providing new synthetic variants of the natural products
that may prove useful in medicinal and biochemical research.
Methyl-5-bromo-2-oxopentanoate (3, Scheme 2) is avail-
able on a mole scale by degrading carboethoxylated g-
butyrolactone with HBr/AcOH and esterifying the resultant
of (Æ)-axinellamines A and B has also been reported by the
[
6]
Baran research group.
Among the creative ways envisioned to prepare structures
a strategy reminiscent of early biosynthetic proposals
[
7]
[8]
1,
was attractive to us. The core of the molecules would derive
from a homodimeric precursor, and oxidative desymmetriza-
tion of which with hypochorite would install the halogenated
[
9]
[10]
spirocycle. Notwithstanding the tenuous and challenging
prospect of carrying two basic guanidine units intact through
the synthesis, this approach was intuitive and direct. For
a-ketoacid by the Fisher protocol. When 3 is condensed
with pyrrole-2-carboxylic acid hydrazide (4) and the product
saponified in situ, we obtain tetrahydropyridazinecarboxylic
acid 5 in high yield. The acid chloride derived from 5 is then
[9]
reasons discussed previously, we chose to work with an
oroidin synthon at a higher oxidation state, and targeted
a dispacamide dimer, for example 2, as our key intermediate.
The intention was to initiate oxidative spirocyclization at this
stage and subsequently diverge to 1 and related structures.
Herein, we report a unique system wherein alkylidenes of
type 2 actually exist as an alternate set of equilibrating
[
11]
used to N-acylate thiouron-derived methylisothiourea 6. In
[
*] Dr. H. Ding, A. G. Roberts, Prof. Dr. P. G. Harran
Department of Chemistry and Biochemistry
University of California Los Angeles
5
6
505A Molecular Sciences Building
07 Charles E. Young Drive East
Los Angeles, CA 90095-1569 (USA)
E-mail: harran@chem.ucla.edu
Homepage: http://www.chem.ucla.edu/harran/
[
**] Funding provided by the NIH (RO1-GM60591), the Donald J. &
Jane M. Cram Endowment, the Foote Family Endowment (fellow-
ship to A.G.R.), and a major instrumentation grant from the
National Science Foundation (CHE-1048804). We are grateful to Dr.
Saeed Khan (UCLA) for X-ray crystallographic analyses. We thank
members of the Garcia-Garibay laboratory for access to instru-
mentation. We are grateful to Dr. Paul B. Hurley and Robert S.
Jordan for experimental assistance.
Scheme 2. Reagents and conditions: a) 4, HOAc/MeOH, 08C; 3, 08C
to RT, 1 h; adjust to pH 6 (aq K CO (3m)) 658C, 1 h; LiOH
2
3
(
2.0 equiv), THF/H O, À108C, 45 min, 89%. b) 5, (COCl) (1.0 equiv),
2
2
DMF (1 mol%), CH Cl , RT, 3 h; 6 (1.8 equiv), Et N (1.8 equiv),
2
2
3
CH CN, RT, 5 h; (COCl) (1.0 equiv), 45 min, RT, 55%. c) 8, [18]crown-
3
2
6, KOtBu, THF, À108C, 3 min; ClCH OCH CH Si(CH ) (1.1 equiv),
2
2
2
3 3
À108C, 5 min, 60%.
4
340
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 4340 –4343