Intramolecular cyclization strategies toward the synthesis of zoanthamine alkaloids

Article abstract of DOI:10.1016/j.tetlet.2011.07.054

Stabilized 2-amino-1,3-dienes can participate in intramolecular Diels-Alder (IMDA) reactions with pendant dienophiles. We found that these dienes can be readily prepared via standard palladium-mediated coupling reactions and have comparable reactivity to

Full text of DOI:10.1016/j.tetlet.2011.07.054

Tetrahedron Letters 52 (2011) 4920–4923
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular cyclization strategies toward the synthesis
of zoanthamine alkaloids
⇑
Derek Fischer, Thong X. Nguyen, Lynnie Trzoss, Marianna Dakanali, Emmanuel A. Theodorakis
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Stabilized 2-amino-1,3-dienes can participate in intramolecular Diels–Alder (IMDA) reactions with pen-
dant dienophiles. We found that these dienes can be readily prepared via standard palladium-mediated
coupling reactions and have comparable reactivity to 2-oxodienes. Application of these substrates to the
synthesis of tetracyclic model systems representing the ABCE motif of the zoanthamines is presented.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 2 June 2011
Revised 6 July 2011
Accepted 12 July 2011
Available online 22 July 2011
Keywords:
Zoanthamine
Cycloaddition
Aminodiene
Stille coupling
Diels–Alder reaction
Isolated from colonial zoanthids of the genus Zoanthus sp.,1
zoanthamine (1) has defined a new family of marine alkaloids that
have impressive chemical structures, significant pharmacological
potential and unknown biosynthesis.2,3 Common to all these
metabolites is a fused polycyclic framework, exemplified by the
structures norzoanthamine (2),4 zoanthenol (3)5 and zoanthamide
(4),6 that is presumably accountable for a wide range of bioactivi-
ties (Fig. 1). For example, compounds 1 and 4 were shown to inhi-
bit phorbol myristate acetate (PMA)-induced inflammation in
mouse ear,6,7 while 2 reportedly inhibits the growth of P-388
murine leukemia cells with an IC50 value of 24 l
g/ml.4b More
importantly, norzoanthamine (2) has been reported to suppress
the loss of bone weight in ovariectomized mice and thus it repre-
sents a promising candidate for an antiosteoporotic drug.1,8
The combination of challenging chemical structure and unex-
plored biology invited the development of chemical strategies to-
ward the synthesis of these metabolites, culminating in the
synthesis of norzoanthamine by the Miyashita9 and the Kobayashi
groups.10 More recently, Miyashita and co-workers also reported
the total synthesis of zoanthenol via oxidation of norzoanthamine
H
Figure 1. Structures of selected zoanthamine natural products.
⇑
Corresponding author. Tel.: +1 858 822 0456; fax: +1 858 822 0386.
E-mail address: etheodor@ucsd.edu (E.A. Theodorakis).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.054

D. Fischer et al. / Tetrahedron Letters 52 (2011) 4920–4923
4921
hydrochloride.11 In continuation of our synthetic efforts,12 we
sought to explore intramolecular cyclization strategies toward
the zoanthamine motif. Inspiration for these studies rose from a
biosynthetic scenario toward 1, proposed by Uemura, in which
an acyclic polyketide precursor 7 could undergo a polycyclization
cascade to form 1 (Fig. 2).4a,8b Although there were no details pro-
vided for such a proposal, one could envision two cyclization
scenarios. In the first case, condensation of the 1,2-aminoalcohol
at the C6 and C10 carbonyl groups of 7 could form a 2-aminodiene
intermediate 5 that upon cycloaddition with the pendant C21–C22
dienophile would produce the C ring of 1. Alternatively, a C9–C12
oxodiene could undergo cycloaddition with the C21–C22 dieno-
phile (intermediate 8) to form the C-ring of 6 and ultimately
zoanthamine (1). With these considerations in mind, we sought
to explore the intramolecular Diels–Alder (IMDA) reactions of 2-
amino- and 2-oxo-dienes for the formation of the C ring in zoan-
thenol model systems. It should be noted that Miyashita et al. have
successfully employed a similar oxodiene-based IMDA disconnec-
tion in their synthesis of norzoanthamine.9
Presumably due to their sensitivity toward hydrolysis,13
2-aminodienes have not been evaluated as substrates in intramo-
lecular cycloaddition reactions.14 The more stable 2-amido-1,3-
dienes behave predictably as substrates both in intermolecular15
and IMDA cycloadditions.16 Along these lines, we chose to evaluate
compound 15, containing a 2-amido-1,3-diene motif, as the cycli-
zation precursor (Scheme 1). The synthesis of 15 features a Stille
coupling between aryl iodide 11 and vinyl stannane 13. Fragment
11 was prepared in a two-step sequence from alcohol 9,17 namely
IBX oxidation followed by addition of vinyl Grignard 10 to the cor-
responding aldehyde (57% yield, 2 steps). On the other hand,
N-methylglutarimide 1218 was treated with LiHMDS and chloro-
diethylphosphonate to form an intermediate vinyl phosphonate,
which was then coupled with trans-1,2-bis(tri-n-butylstannyl)eth-
ylene to give vinyl stannane 13 in 35% overall yield. Stille coupling
of fragments 11 and 13 led to the formation of allylic alcohol 14
Scheme 1. Reagents and conditions: (a) 2.5 equiv IBX, MeCN, reflux, 1 h; (b)
1.5 equiv Me2C = CHMgBr (10), THF, 0 °C to rt, 12 h, 57% (over 2 steps); (c) 1 equiv
LiHMDS, 0 °C, then 1 equiv diethylchlorophosphate, THF, À78 °C; (d) 1.2 equiv
trans-1,2-bis(tri-n-butylstannyl)ethylene, 3 mol % Pd(PPh3)4, 10 equiv LiCl, THF, 0–
60 °C, 5 h, 35% (over 2 steps); (e) 1.2 equiv 13, 3 mol % of Pd(PPh3)4, 10 equiv LiCl,
THF, 25–95 °C, 2.5 h, 55%; (f) 4 equiv IBX, EtOAc, reflux, 2.5 h, 89%; (g) 200 °C, 11 h,
72%.
O
Me
Me
O
Me
Me
H
H
O
O
H
that after oxidation produced 2-amido-1,3-diene 15 (49% yield, 2
steps/one pot).
CO2H
21
Me
22
Me
O
Me
The cyclization of 15 was initially evaluated by NMR in deuter-
ated solvents, including 1,2-dichlorobenzene, bromobenzene and
m-xylene. Best results were obtained upon heating the reaction
at 200 °C (1,2-dichlorobenzene) where compound 16 was pro-
duced after 11 h in 72% yield. It is worth noting that 16 was iso-
lated as a single stereoisomer and its structure is reminiscent of
zoanthamide (4). The observed coupling constant of 11.8 Hz be-
tween the protons at C12 and C21 indicated a trans junction be-
tween the BC rings, suggesting an exo-selective Diels–Alder
cycloaddition. Furthermore, during this cycloaddition, the C10-
C11 enamine was isomerized at the thermodynamically more sta-
ble C9–C10 position. The chemical structure of compound 16 was
ultimately confirmed via a single crystal X-ray analysis.19
The exo-selectivity of this intramolecular Diels–Alder reaction
deserves some additional comments. Figure 3 depicts the two tran-
sition structures (TS) of compound 15. It is likely that the trans-TS
12
Me
C
CO2H
Me
Me
9
E
N
HO
OH
F
1
GO
H2N
Me
Me
5 (aminodiene
intermediate)
6
O
Me
O
Me
O
O
CO2H
CO2H
Me
Me
Me
Me
Me
Me
Me
O
Me
O
10
10
is favored due to the
nyl ring (A ring) and the diene which, in turn, bring carbons C9–
C18 to an almost plannar arrangement. The role of these -conju-
p-conjugative interactions between the phe-
O
OH
HO
HO
H2N
H2N
6
6
p
1
2
1
2
gative interactions has been investigated in similar substrates and
is reflected in the dihedral angle h formed between the diene and
the A ring.20 The cis-TS shows a nearly perpendicular diene-arene
dihedral angle whereas in the trans-TS the dihedral angle is smal-
ler, allowing a significantly increased conjugation between the two
groups.20 It should be noted that the exo (trans) product was found
Me
Me
7 (acyclic
8 (oxodiene
precursor)
intermediate)
Figure 2. Proposed biosynthesis pathways of zoanthamines.

4922
D. Fischer et al. / Tetrahedron Letters 52 (2011) 4920–4923
We then investigated the oxodiene cycloaddition pathway to
form the ABC core structure. Along these lines, silylated propargyl
alcohol 17 was converted to vinyl stannane 1822 and upon coupling
with iodide 9 produced compound 19 in 39% overall yield (Scheme
2). Oxidation of 19 followed by treatment of the resulting aldehyde
with vinyl Grignard 10 under CeCl323 led to the formation of allylic
alcohol 20 (72% yield over 2 steps). Oxidation at the C20 hydroxyl
group, gave rise to enone 21 in 91% yield. Methylation at C19,
deprotection of the C10 TBS ether followed by oxidation of the
resulting alcohol produced dienone 22 (70% over 3 steps). Selective
silylation of 22 formed the cyclization precursor 23 in 80% yield.
Upon heating in m-xylene, oxodiene 23 underwent the desired
cycloaddition, producing, after desilylation, tricycle 24 (60% yield
over two steps, 2:1 mixture of isomers at C19). The coupling con-
stant of the protons at C12 and C21 was found to be approximately
12.0 Hz indicating an exo-selective Diels–Alder reaction.24
In conclusion, inspired by biosynthetic hypotheses, we have
explored intramolecular cycloaddition approaches toward the con-
struction of the zoanthamine motif. We found that an amide-stabi-
lized 2-aminodiene can efficiently react with a dienophile, in an
exo-selective IMDA reaction, to produce model systems represent-
ing the ABCE ring scaffold of these natural products. Although 2-
amido-1,3-diene 15 is somewhat less reactive than the 2-oxo diene
23, it can yield the IMDA product at elevated temperatures. In turn,
this provides support for the use of stabilized 2-aminodienes in
cycloaddition reactions for the synthesis of polycyclic natural
products.
Figure 3. Transition structures (TS) of compound 15.
to be the major product in the synthesis of norzoanthamine by
Miyashita’s group. In their case the preference for the exo transi-
tion state has been proposed to result primarily from steric effects
due to the substitution at the C12 center.21
Overall, this strategy produced evidence that: (a) the ABCE ring
motif of zoanthenol could be produced with high stereocontrol via
an IMDA of an appropriately functionalized 2-aminodiene; and
(b) that a fully functionalized C22 quaternary center can be
incorporated prior to the cycloaddition. Thus, our studies further
show the ability of these motifs to participate in a predictable
manner in intramolecular cycloaddition reaction with pendant
dienophiles.16
Acknowledgments
We gratefully acknowledge the National Institutes of Health
(NIH) for financial support of this work through Grant Number
R01 GM081484. We thank the National Science Foundation for
instrumentation grants CHE9709183 and CHE0741968. We also
thank Dr. Anthony Mrse (UCSD NMR Facility); Dr. Yongxuan Su
(UCSD MS Facility) and Dr. Arnold L. Rheingold and Dr. Curtis E.
Moore (UCSD X-Ray facility).
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data and copies of the 1H and 13C NMR of new compounds,
as well as X-ray data of compound 16) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2011.07.054.
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