Stereoselective synthesis of zoanthenol ABC-ring by radical strategy

Article abstract of DOI:10.1016/j.tetlet.2012.12.104

Zoanthenol, isolated from Zoanthus sp., possesses an extremely complex architecture including congested quaternary carbons. We describe a concise synthesis of the fully functionalized ABC-ring of zoanthenol based on sequential radical reactions. Copyright

Full text of DOI:10.1016/j.tetlet.2012.12.104

Tetrahedron Letters 54 (2013) 1389–1391
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of zoanthenol ABC-ring by radical strategy
Shuji Yamashita a, , Naoki Suda a, Yujiro Hayashi a, Masahiro Hirama a,b
⇑
a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Zoanthenol, isolated from Zoanthus sp., possesses an extremely complex architecture including congested
quaternary carbons. We describe a concise synthesis of the fully functionalized ABC-ring of zoanthenol
based on sequential radical reactions.
Received 27 November 2012
Revised 20 December 2012
Accepted 26 December 2012
Available online 3 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Marine natural product
Zoanthenol
Tandem radical cyclization
Atom transfer
Zoanthamine alkaloids, which are isolated from marine zoant-
hid Zoanthus sp., exhibit important biological and pharmacological
properties.1 Potent congeners, norzoanthamine,1e zoanthamine,1a
and zoanthenol (1, Fig. 1),1h consist of heptacyclic rings including
a polyfunctionalized phenanthrene carbocycle (ABC) and amino
acetal moieties (DEFG). Because of their unique biological activities
and complex architectures, the zoanthamine alkaloids have at-
tracted keen interest from the synthetic community. Although
many synthetic efforts have been devoted to their total synthe-
sis,2,3 only two groups have succeeded.4,5 Most challenging is an
efficient and stereocontrolled construction of the congested qua-
ternary carbons at the C9, C12, and C22 positions in the ABC-ring.
We describe herein a concise synthesis of the fully functionalized
ABC-ring of zoanthenol.
afforded epoxy alcohol 6 (70%) along with a small amount of the
diastereomeric epoxide (12%). One carbon homologation of the
primary alcohol 6 was achieved in three steps: TEMPO-catalyzed
oxidation of 6,9 carbonyl olefination of the resulting aldehyde,10
and a hydroboration/oxidation sequence to give the elongated pri-
mary alcohol 7. Finally, installation of the ethyl acrylate group by
treatment with ethyl propiolate and N-methylmorpholine (NMM)
afforded b-alkoxy acrylate 8.
With 8 in hand, we next focused on the construction of the qua-
ternary carbon at C9. After considerable experimentation, we
found that the titanium-mediated radical reaction produced the
desired compound 9 (Scheme 2). Treatment of 8 with titanocene
chloride, which was generated from titanocene dichloride and zinc
26
We envisioned the ABC-ring 2 to be accessible from b-ketoester
4 through sequential radical reactions (Fig. 1). The BC-ring would
be constructed utilizing an oxidative tandem radical cyclization
with concomitant formation of the C12 and C22 quaternary centers
(4?3). Another reductive radical reaction was designed to install
the three-carbon unit (C6–C8) at the C9 position (3?2).
The requisite b-ketoester 4 was synthesized from 7-methyl-
coumarin by conventional procedures.6 The key tricyclic system
3 was stereoselectively provided from 4 by a manganese-mediated
radical cyclization according to Snider’s procedure (Scheme 1).7
Despite the existence of an electron-rich aromatic ring, the ABC-
ring 3 was obtained in good yield (71%).8 The resulting ketone 3
was converted to olefin 5 by addition of MeLi, dehydration, and
subsequent isomerization. LAH reduction followed by epoxidation
HO
Me
MeO Me
17
O
H
OH
B
Me Me
25
A
B
Me
Me
A
Me
22
12
OTBS
27
Me
C
Me
D
24
H
C
9
9
6
8
O
O
CO2Et
N
E
1
Me
F
TBSO
radical-induced
atom transfer
O
2
G
30
Me
zoanthenol (1)
MeO
MeO
tandem radical
cyclization
A
A
B
Me Me
CO2Et
CO2Et
O
Me
Me
H22
12
C
O
4
3
⇑
Corresponding author. Tel.: +81 22 795 6564; fax: +81 22 795 6566.
E-mail address: s-yamashita@m.tohoku.ac.jp (S. Yamashita).
Figure 1. Structure and synthesis plan of zoanthenol.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.104

1390
S. Yamashita et al. / Tetrahedron Letters 54 (2013) 1389–1391
MeO
MeO
1. TBSOTf
2,6-lutidine
CH2Cl2, RT
2. H2, PtO2
AcOH, EtOH
MeO
MeO
Mn(OAc)3·2H2O
AcOH, RT
Me
Me
21
CO2Et
O
CO2Et
O
Me Me
H
Me Me
H
13
Me
71%
Me
22
12
H
Me
Me
OH
OTBS
CO2Et
3
4
85%
Me
HO
Me
1. MeLi, THF, 0 °C
2. SOCl2, DMAP
pyridine, 0 °C
TBSO
CO2Et
9
13
48%
3. TsOH·H2O
1. DDQ, AcOH
RT, sonication
2. silica gel
120 °C
1. LiAlH4, THF
reflux
2. m-CPBA
CH2Cl2,RT
toluene, 80 °C
64%
MeO
MeO
1. oxone, NaHCO3
acetone, CH2Cl2
H2O, RT
2. Me3Al, CH2Cl2
-50 °C
Me Me 23
H
Me Me
CO2Et
MeO Me
MeO
70%
19
Me
OH
20
Me
OH
H
Me Me
Me Me
6
O
5
Me
Me
H
H
OTBS
88%
OTBS
CO2Et
1. TEMPO, PhI(OAc)2, CH2Cl2,RT
2. Tebbe reagent, THF, 0 °C
Me
Me
30%
TBSO
TBSO
3. BH3·SMe2,THF; aq. H2O2, aq. NaOH, RT
CO2Et
zoanthenol ABC-ring (2)
Scheme 3. Synthesis of zoanthenol ABC-ring.
14
MeO
MeO
CO2Et
NMM, CH2Cl2
RT
Me Me
H
Me Me
H
Me
Me
24
86%
OH
O
to construct all quaternary carbons. The application of this strategy
to the total syntheses of zoanthenol and other zoanthamine alka-
loids is being actively investigated in our laboratory.
O
O
7
8
CO2Et
Scheme 1. Synthesis of b-alkoxy acrylate 8.
Acknowledgments
MeO
MeO
This work was supported financially by a Grant-in-Aid for Sci-
entific Research (B) and (C) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan, and the Suntory
Foundation for Life Sciences.
Cp2TiCl2, Zn
THF, RT
Me Me
Me Me
OH
24
24
Me
Me
59%
H
H
9
9
O
CO2Et
CO2Et
O
Me
HO
Supplementary data
8
9
Cp2TiCl
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.
104.
Me
Me
Me
Cp2TiCl
9
O
O
O
Ti
References and notes
Me
O
Me
O
Me
O
CO2Et
Ti
Ti
CO2Et
CO2Et
Ti
Ti
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11
Scheme 2. Radical-induced atom transfer.
12
in THF,11 afforded diol 9 in 59% yield with complete stereoselectiv-
ity. It is noteworthy that the acryl ester moiety of 8 was transferred
from the C24 oxygen to the C9 carbon, leading to the efficient
construction of the quaternary center and the configurational
inversion of C9. We speculated that this manipulation was acceler-
ated by the high oxophilicity of titanium via the successive reac-
tion intermediates 10, 11, and finally 12.
To complete the synthesis of the ABC-ring of zoanthenol, instal-
lations of methyl and hydroxy groups in the B-ring were performed
(Scheme 3). The diol 9 was protected as its TBS-ether and hydroge-
nated to give 13 in 85% overall yield. DDQ oxidation followed by
heating in the presence of silica gel afforded styrene derivative
14. Epoxidation of 14 and treatment with Me3Al realized the regio-
and stereoselective installation of the methyl and hydroxy groups
at C19 and C20, respectively, to give the fully functionalized ABC-
ring 2.
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In conclusion, we have developed a concise route to the zoan-
thenol ABC-ring. Key features of the synthesis are the oxidative
tandem radical cyclization and the radical-induced atom transfer

S. Yamashita et al. / Tetrahedron Letters 54 (2013) 1389–1391
1391
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6. The compound 4 was prepared from 7-methylcoumarin as follows (6 steps, 50%
overall yield).
1. H2, Pd/C
2. DIBAL
O
MeO
3. CH2=C(CH3)MgBr
4. MeI, K2CO3
5. CH3C(OEt)3, H+
O
CO2Et
O
Me
Me
6. CH3CH2CO2Et, LDA
4
50%