Synthetic studies toward the haouamines

Article abstract of DOI:10.1021/ol052262h

(Chemical Equation Presented) A concise synthetic approach toward the haouamines based on Stork-Danheiser alkylation and Friedel-Crafts chemistry is described. A novel electrophilic aromatic substitution with concomitant formation of an enol triflate is r

Full text of DOI:10.1021/ol052262h

ORGANIC
LETTERS
2006
Vol. 8, No. 1
23-25
Synthetic Studies toward the
Haouamines
Marc A. Grundl and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
trauner@cchem.berkeley.edu
Received September 18, 2005
ABSTRACT
A concise synthetic approach toward the haouamines based on Stork−Danheiser alkylation and Friedel−Crafts chemistry is described. A
novel electrophilic aromatic substitution with concomitant formation of an enol triflate is reported.
The haouamines are a pair of structurally intriguing alkaloids
recently isolated from the ascidian Aplidium haouarianum.1
In cytotoxicity tests against five cancer cell lines, haouamine
A was found to strongly inhibit growth of human colon
carcinoma cells HT-29 and haouamine B displayed moderate
activity against mice endothelial MS-1 cells.
ties. In particular, one of our approaches to haouamine B
also relies on an intramolecular Friedel-Crafts reaction to
establish the diaryl quaternary center of the alkaloid. The
tertiary allylic alcohol employed as a substrate, however, is
a regioisomer of Rawal’s type and is assembled using a
Stork-Danheiser alkylation sequence.
Structurally, both alkaloids feature an indeno tetrahydro-
pyridine moiety that contains a diaryl quaternary center and
an anti-Bredt double bond. The tetrahydropyridine ring is
fused to a highly strained 11-membered cyclophane ring
system. In addition, the molecules show interesting dynamic
behavior, existing as an equilibrating mixture of isomers that
could stem from atropisomerism of the cyclophane moiety
or from nitrogen inversion. These features, in combination
with the presence of a basic amine and multiple phenolic
hydroxy groups, make the haouamines a formidable synthetic
challenge.
Molecules as complex and unprecedented as the haou-
amines are sure to attract the attention of the synthetic
community. Indeed, very recently Rawal has reported an
approach to haouamine A that hinges on an intramolecular
Friedel-Crafts alkylation (Scheme 1).2
Figure 1. The haouamines.
Our general approach to the haouamines starts with readily
available 3,5-dimethoxypyridine (5),3 which was converted
into the vinylogous ester 6 in three straightforward steps
(Scheme 2).4 Deprotonation and alkylation of 6 with either
This report prompted us to give an account of our own
studies, which although distinct bear some strategic similari-
(1) Garrido, L.; Zubia, E.; Ortega, M. J.; Salva, J. J. Org. Chem. 2003,
68, 293.
(3) Testaferri, L.; Tiecco, M.; Tingoli, M.; Bartoli, D.; Massoli, A.
Tetrahedron 1985, 41, 1373.
(2) Smith, N. D.; Hayashida, J.; Rawal, V. J. Org. Lett. 2005, 7,
4309.
(4) Phillips, S. T.; Rezac, M.; Abel, U.; Kossenjans, M.; Bartlett, P. A.
J. Am. Chem. Soc. 2002, 124, 58.
10.1021/ol052262h CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/13/2005

isomers 12a and 12b under these conditions, thus offering
no advantage over the alkylation strategy.
Scheme 1. Rawal’s Approach toward Haouamine A
Scheme 3. Alternative Preparation of 8b
iodomethoxy benzyl bromide 7a or dimethoxy benzyl
bromide 7b gave 8a and 8b, respectively, as the only isolated
regioisomers. The regiochemical outcome of these reactions
Scheme 2. Preparation of Precursors 10a and 11
With 10a and 10b at hand, the stage was set to explore
various modes of cyclization that would yield the indeno
tetrahydropyridine moiety and set the biaryl quaternary
stereocenter of the haouamines. So far, attempts to achieve
this key bond formation with 10a using organometallic or
radical chemistry have been moderately successful. For
instance, radical cyclization of 10a afforded the desired
product 13, albeit in very low yield (Scheme 4).
Scheme 4. Radical Cyclization Approach
was confirmed by an X-ray structure of 8a (Figure 2). Cerium
chloride mediated addition of Grignard reagent 9 to 8a or
8b, followed by hydrolysis with concomitant elimination,
afforded aryl enones 10a and 10b, which correspond to
haouamines A and B, respectively.
By contrast, our approach to haouamine B based on
intramolecular Friedel-Crafts chemistry proved to be more
satisfying (Scheme 5). To this end, 10b was reacted with
aryl Grignard 9 to afford the tertiary allylic alcohol 14.
Dissolution of this compound in 4 M ethereal lithium
perchlorate followed by addition of catalytic amounts of
triflic acid resulted in the formation of indeno piperidine 16
in 66% yield. This reaction presumably proceeds through
the intermediacy of stabilized carbocation 15, which under-
goes the cyclization with a high degree of regio- and
stereoselectivity. Importantly, the choice of reaction condi-
tions proved to be crucial for the success of this reac-
tion. Under less polar and acidic conditions, simple elimina-
tion of the tertiary alcohol was observed to afford di-
hydropyridine 17. This N-acyl dienamine apparently fails
to undergo protonation (f 15) followed by cyclization
(f 16).
Figure 2. X-ray structure of 8a.
A more direct, alternative approach to piperidinone 8b was
briefly explored (Scheme 3). Addition of Grignard reagent
11 to the acyl pyridium salt formed from 5 and methyl
chloroformate was followed by hydrolysis of the resultant
crude product and formation of the vinylogous ester.
Unfortunately, 8b was formed as a mixture with its regio-
Alternative modes of Friedel-Crafts chemistry involving
the electrophilic activation of an enone were investigated as
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Org. Lett., Vol. 8, No. 1, 2006

Scheme 5. Friedel-Crafts Approach
Scheme 7. Friedel-Crafts Cyclization with Concomitant
Formation of an Enol Triflate
stannane 21 (prepared in one step from 9) afforded 16, which
proved to be identical in all respects to the material obtained
previously (see Scheme 5).
well. For instance, treatment of enone 10b with ethylene
glycol in the presence of trimethyl silyl triflate afforded
dioxolane 18 in good yield (Scheme 6).
In summary, we have achieved the synthesis of a sub-
stantial portion of the haouamines following concise synthetic
strategies that could be readily rendered asymmetric.6 Future
directions will be aimed at the completion of the synthesis
of haouamine B and the further exploration of transition
metal catalyzed cyclizations of substrates of type 10a. The
systematic exploration of Friedel-Crafts reactions involving
activated enones is also under investigation.
Scheme 6. Friedel-Crafts Cyclization with Concomitant
Formation of an Ethylene Ketal
Acknowledgment. M.A.G. thanks the Deutsche For-
schungsgemeinschaft for a postdoctoral fellowship. Financial
support by Eli Lilly, Glaxo Smith Kline, Amgen, Novartis,
and AstraZeneca is gratefully acknowledged. We also thank
Dr. Frederick J. Hollander and Dr. Allen G. Oliver for the
crystal structure determination of compound 8a.
Our most advanced compound, 16, was also prepared using
a novel electrophilic aromatic substitution that generates a
strategically positioned enol triflate directly (Scheme 7).
Treatment of 10b with triflic anhydride in the presence of
2,6-bis-tert-butyl pyridine (2,6-BTP) resulted in the formation
of compound 20.5 This reaction presumably involves trifloxy
allylic cation 19, which undergoes intramolecular nucleo-
philic attack by the electron-rich arene at a faster rate than
deprotonation.
Note Added after ASAP Publication. There was an MeO
substituent missing in the abstract graphic in the version
posted ASAP December 13, 2005; the corrected version
posted December 15, 2005.
Supporting Information Available: Spectroscopic and
analytical data for compounds 6, 8a, 8b, 10a,b 12a,b, 13,
14, 16, and 18-20, including a CIF file. This material is
available free of charge via the Internet at http://pubs.acs.org.
Enol triflate 20 is set up to undergo transition metal
catalyzed cross-coupling to install the trisubstituted double
bond of the haouamines. Indeed, Stille coupling of 20 with
OL052262H
(5) For related examples of electrophilic activation with triflic anhydride,
see: (a) Corey, E. J.; Tian, Y. Org. Lett 2005, 7, 5535. (b) Baraznenok, I.
L. Nenajdenko, V. G.; Balenkova, E. S. Synthesis 1997, 465.
(6) For an example of asymmetric Stork-Danheiser alkylations, see:
Dudley, G. B.; Takaki, K. S.; Cha, D. D.; Danheiser, R. L. Org. Lett. 2000,
21, 3407.
Org. Lett., Vol. 8, No. 1, 2006
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