Convergent synthesis of the ABC-ring moiety of zoanthenol: Intramolecular Mizoroki-Heck reaction

Article abstract of DOI:10.1016/S0040-4039(01)01110-8

The highly congested ABC-ring moiety of zoanthenol was stereoselectively synthesized via an alkoxylithium-mediated coupling between the A-ring and C-ring moieties followed by a Mizoroki-Heck-type ring closure.

Full text of DOI:10.1016/S0040-4039(01)01110-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5783–5787
Convergent synthesis of the ABC-ring moiety of zoanthenol:
intramolecular Mizoroki–Heck reaction
Go Hirai, Hiroki Oguri, Sameh M. Moharram, Koji Koyama and Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, and CREST,
Japan Science and Technology Corporation (JST), Sendai 980-8578, Japan
Received 9 May 2001; accepted 21 June 2001
Abstract—The highly congested ABC-ring moiety of zoanthenol was stereoselectively synthesized via an alkoxylithium-mediated
coupling between the A-ring and C-ring moieties followed by a Mizoroki–Heck-type ring closure. © 2001 Elsevier Science Ltd.
All rights reserved.
Zoanthamine alkaloids, which are isolated from the
marine zoanthid Zoanthus sp., have densely functional-
ized heptacyclic structures and interesting biological
activities. Zoanthamine (1) exhibits inhibitory activity
towards phorbol myristate-induced inflammation,1
while norzoanthamine (2) suppresses the decrease in
bone weight and strength in overiectomized mice with-
out serious side effects.2 Norte and co-workers recently
reported zoanthenol (3), which possesses an aromatized
A-ring, as a new member of this family.3 The unique
structural topologies and biological activities of these
alkaloids have attracted increasing attention among
synthetic chemists.4,5 Notably, the groups of Tanner5a
and Williams5d have reported synthetic approaches to
the AB(C)-ring skeleton of zoanthamines via
intramolecular Diels–Alder reactions.
A critical problem in the total synthesis of the zoan-
thamines is the stereo-controlled construction of the
three consecutive quaternary carbon centers (C9, C12
and C22) in the C-ring. A strategy to incorporate the
angular methyl groups at C9 and C22 has been devel-
oped.4a However, the quaternary ring junction at C12
remained to be constructed; our retrosynthetic analysis
is outlined in Scheme 1.6 We envisioned that an
intramolecular Mizoroki–Heck cyclization7 of 7 in a
PO
MOMO
PO
OP
OMOM
OP
21
22
9
12
12
OH
OH
O
OH
Mizoroki-Heck
Pd
10H
10
H
H
H
syn-elimination
PO
PO
ABC-ring Moiety: 4
5
6
PO
A
O
Pd(0)
TfO
21
20
OP
OP
OP
+
C
SnBu3
OP
21
H
PO
12
OH
8
9
10
H
PO
7
Scheme 1.
* Corresponding author. E-mail: hirama@ykbsc.chem.tohoku.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01110-8

5784
G. Hirai et al. / Tetrahedron Letters 42 (2001) 5783–5787
O
A
R
OH
17
moieties (9). In this paper, we describe a convergent
and stereoselective synthesis of the ABC-ring moiety (4)
of 3 based on a Mizoroki–Heck type ring closure.
H
H
17
O
H
20
20
O
H
B
B
A
12
1
12
1
C
The synthesis of the C-ring began with 10 which pos-
sesses the C22 angular methyl group, and which was
readily available from 2,6-dimethylphenol as reported
earlier (Scheme 2).4a The enone (10) was reduced with
DIBAL-H diastereoselectively to give diol (11). Selec-
tive protection of the C10 alcohol as its t-
butyldiphenylsilyl (TBPS) ether and subsequent
oxidation of the C21 alcohol yielded enone (12).
9 D 24
24
C
9 D
O
O
O
E
O
E
N
N
6
F
F
6
O
O
G
G
Zoanthamine: 1 (R = Me)
Norzoanthamine: 2 (R = H)
Zoanthenol: 3
We then synthesized the A-ring moiety as shown in
Scheme 3. Commercially available orcinol (14) was
converted to aldehyde (15) via protection, allylation8
and oxidation. Addition of tributylstannyllithium to 15
followed by protection gave a-alkoxystannane9 (16) in
good yield. The a-alkoxylithium species generated from
16 reacted with 12 from the b-face10,11 in a highly
stereo-controlled manner to give the adduct (17) as an
inseparable C20 diastereomeric mixture (2:1).12 How-
6-exo manner could afford the enol ether (5), which
would be transformed into the ABC-ring moiety (4). To
conduct this ring closure from the b-face of the tri-sub-
stituted olefin with syn palladium hydride elimination
from 6, the stereogenic centers at C21 and C10 of 7
must be controlled. The key precursor (7) would be
synthesized by combining the A-ring (8) and C-ring
H
HO
21
O
HO
21
9
21
O
b, c
a
22
H
9
10
10
H
H
H
OR
HO
RO
O
12: R=TBPS
13: R=MOM
10
11
d, e
Scheme 2. Reagents and conditions: (a) DIBAL-H, THF, −78°C, 84% (6:1); (b) TBPSCI, imidazole, DMF, rt; (c) Dess–Martin
periodinane, CH2Cl2, rt, 99% (2 steps); (d) TBAF, THF, reflux, 98%; (e) MOMCl, i-Pr2NEt, (CH2Cl)2, 50°C, 87%.
MOMO
OH
OMOM
OMOM
f, g
CHO
a-e
h
SnBu3
OPMBM
OPMBM
OH
14
16
15
PMBM = CH2OCH2C6H4p-OMe
MOMO
OMOM
R
OMOM
Pd(II)
OMOM
OMOM
cat. Pd
20
OMOM
21
12
OH
12
12
OH
OH
H
11
TBPSO
10
H
H
TBPSO
TBPSO
20
17: R = OPMBM
18: R = OTf
21: R = H
19
i, j
k
22: R = CH=CHCO2t-Bu
Scheme 3. Reagents and conditions: (a) MOMCl, i-Pr2NEt, CH2Cl2, 0°C, 61%; (b) PMBMCl, i-Pr2NEt, CH2Cl2, rt, 79%; (c)
n-BuLi, hexane, 0°C then allyl bromide, rt, 62%; (d) OsO4, NMO, t-BuOH–H2O (1:1), 89%; (e) NaIO4, THF–H2O (1:1), 80%; (f)
Bu3SnLi, THF, −78°C; (g) MOMCl, i-Pr2NEt, CH2Cl2, 0°C, 84% (2 steps); (h) n-BuLi, 12 (13 equiv.), THF, −78°C, 82% (2:1);
(i) DDQ, CH2Cl2–H2O (10:1), 62%; (j) Tf2O, Et3N, CH2Cl2, −78°C, 85%; (k) CH2ꢀCHCO2t-Bu, Pd2(dba)3 (10 mol%), dppb (40
mol%), KOAc, DMAc, 100°C, 56%.

G. Hirai et al. / Tetrahedron Letters 42 (2001) 5783–5787
5785
ever, Mizoroki–Heck reaction of triflate (18) did not
proceed and the major product was the reduced
product (21) under various internal cyclization condi-
tions. We reasoned that the cyclization of its Pd(II)
intermediate (19) was prevented sterically by the
neighboring TBPS ether group,13 as substantiated by
the formation of an intermolecular adduct (22) when
the reaction was conducted in the presence of t-butyl
acrylate.
appreciable yield, because a hydrolyzed product (27)
was otherwise produced (Entry 3). An optimal yield
of 28 (43%) was attained in the presence of 1,2,2,6,6-
pentamethyl piperidine (PMP),16 instead of KOAc,
which suppressed the formation of the reduction
product (26) (Entry 4).17,18 The stereochemistry of 28
was unambiguously determined by NOE experiments.
Finally, the enol ether (28)19 was hydrolyzed to afford
the targeted ABC-ring moiety (4).
Thus, the C10 alcohol was protected by the less-
demanding MOM group (13) (Scheme 2). The ketone
(13) was coupled with 16 to afford a separable 2:1
mixture of 23 and 24 (Scheme 4). The major
diastereomer (23) was subsequently converted into
triflate (25). An intramolecular Mizoroki–Heck reac-
tion of 25 proceeded using Pd2(dba)3–dppb as the cat-
alyst system.14,15 Optimized conditions are listed in
Table 1. More than 20 mol% of Pd2(dba)3–dppb
appeared necessary to realize this reaction in an
In conclusion, the key intermediate (25) was synthe-
sized via
a
stereo-controlled coupling reaction
between the A-ring (16) and C-ring (13) segments.
The subsequent intramolecular Mizoroki–Heck reac-
tion of 25 constructed the B-ring and simultaneously
introduced the C12 quaternary center of 28. The con-
vergent synthetic route presented herein offers an
efficient strategy for the total synthesis of 3 and fur-
ther synthetic efforts in this direction will be reported
in due course.
R
OMOM
OMOM
R
OMOM
20
OMOM
a
20
+
+
13
16
(1.3 eq)
OH
OH
H
H
MOMO
MOMO
23 R=OPMBM
25 R=OTf
24 R=OPMBM
b, c
MOMO
R
OMOM
OMOM
MOMO
H
H
H
OMOM
OMOM
Table 1
d
DMAc
120 °C
4 days
12
12
OH
OH
OH
in a sealed tube
H
H
H
MOMO
MOMO
O
25 R=OTf
26 R=H
28
4
NOE
27 R=OH
Scheme 4. Reagents and conditions: (a) n-BuLi, THF, −78°C, 23 (58%), 24 (32%); (b) lithium(di-t-butylbiphenyl), THF, −78°C,
90%; (c) Tf2O, Et3N, CH2Cl2, −78°C, 85%; (d) 1 N HCl aq., THF, rt, 89%.
Table 1. Intramolecular Mizoroki–Heck reaction of 25a
Entry
Pd complex (equiv.)
Base (equiv.)
Yield of 28 (%)
Yields of products (%)
1
2
3
4
Pd(OAc)2 (0.5)–PPh3 (2)
Pd2(dba)3 (0.25)–dppb (1)
Pd2 (dba)3 (0.1)–dppb (0.4)
Pd2(dba)3 (0.25)–dppb (1)
KOAc (10)
KOAc (10)
KOAc (10)
PMP (5)
20
33
15
43
26 (7)
26 (33)
26 (15), 27 (30)
26 (trace)
a Carried out in N,N-dimethylacetamide (DMAc) at 120°C for 2 days in a sealed tube.

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G. Hirai et al. / Tetrahedron Letters 42 (2001) 5783–5787
MeO
OMe
MeO
OMe
OMOM
O
OMe
20
21
n-BuLi
Pd(OAc)2
DMSO
OMOM
OMOM
+
12
THF, -78 °C
21
SnBu3
OMe
24
7
12
OH
9
92 %
quant.
H
H
29
TBPSO
TBPSO
30
31
1
Scheme 5. Selected data for 31 (major diastereomer at C20): H-NMR (500 MHz, CDCl3) l 7.71 (4H, m, TBPS), 7.42 (6H, m,
TBPS), 7.09 (1H, t, J=8.5 Hz, Ar), 6.48 (2H, d, J=8.5 Hz, Ar), 6.08 (1H, br, 7-H), 5.93 (1H, dd, J=9.5, 1.5 Hz, 8-H), 5.39 (1H,
d, J=1.5 Hz, 11-H), 4.72 (1H, br, 10-H), 4.37 (1H, d, J=6.5 Hz, MOM), 4.25 (1H, d, J=6.5 Hz, MOM), 4.19–4.14 (2H, m, 20-H,
24-H), 3.75 (6H, s, OMe), 3.06 (1H, dd, J=14, 12 Hz, 19-H), 2.70 (3H, s, MOM), 2.36–2.28 (3H, m, 9-H, 19-H, 23-H), 1.96 (3H,
s, 12-CH3), 1.52 (1H, d, J=10 Hz, 23-H), 1.33 (3H, s, 22-CH3), 1.12 (9H, s, TBPS).; MALDI-TOF MS Calcd for C40H50NaO6Si
(M+Na) 677.3275, Found 677.3496.
Acknowledgements
Lett. 1998, 39, 6241; (g) Hikage, N.; Furukawa, H.; Takao,
K.; Kobayashi, S. Chem. Pharm. Bull. 2000, 48, 1370.
6. In this paper, carbon numbers correspond to zoanthenol
(3), see Ref. 3.
Fellowships to G.H. and S.M.M. from the Japanese
Society for the Promotion of Science are gratefully
acknowledged. This study was supported financially in
part by Suntory Institute for Bioorganic Research.
7. (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn.
1971, 44, 581; (b) Heck, R. F.; Nolley, J. P. J. Org. Chem.
1972, 37, 2320; (c) Excellent reviews, see: Tsuji, J. Palla-
dium Reagents and Catalysts. Innovations in Organic Syn-
thesis; Wiley: New York, 1995; (d) Link, J. T.; Overman,
L. E. In Metal-catalyzed Cross Coupling Reactions;
Diederich, F.; Stang, P. J., Eds.; Wiley–VCH: Weinheim,
1998 Chapter 6; (e) de Meijere, A.; Meyer, F. E. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379; (f) Shibasaki, M;
Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371.
8. The use of hexane as solvent is important to attain the
allylated product in good yield, see: Hosoya, T.; Takashiro,
E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994,
116, 1004.
9. Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
10. Attack of alkoxylithium species from the b-face was
supported by a model reaction as shown in Scheme 5. The
ketone (12) was reacted with 29, and the alcohol so formed
cyclized quantitatively to form the ether (31) when treated
with Pd(OAc)2. For a similar cyclization of cis-decalin
derivatives, see: Pratt, D. V.; Hopkins, P. B. J. Org. Chem.
1988, 53, 5885.
11. For a stereo-controlled addition to a related enedione
system, see: (a) Liotta, D.; Saindane, M.; Jamison, U. S.
W. C. L.; Grossman, J.; Phillips, P. J. Org. Chem. 1985,
50, 3241;
(b) Liu, C.; Burnell, D. J. J. Org. Chem. 1997, 62, 3683.
12. Arseniyadis, S.; Hernando, J. I. M.; del Moral, J. Q.;
Yashunsky, D. V.; Potier, P. Synlett 1998, 1010.
13. Rigby, J. H.; Deur, C.; Heeg, M. J. Tetrahedron Lett. 1999,
40, 6887.
References
1. (a) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.;
Venkateswarlu, Y.; Rosser, R. M.; Faulkner, D. J.; Chen,
M. H. M.; Clardy, J. J. Am. Chem. Soc. 1984, 106, 7983;
(b) Rao, C. B.; Anjaneyula, A. S. R.; Sarma, N. S.;
Venkateswarlu, Y.; Rosser, R. M.; Faulkner, D. J. J. Org.
Chem. 1985, 50, 3757; (c) Rao, C. B.; Rao, D. V.; Raju,
V. S. N.; Raju, B. W.; Sullivan, B. W.; Faulkner, D. J.
Heterocycles 1989, 28, 103; (d) Rahman, A.-U.; Alvi, K.
A.; Abbas, S. A.; Choudhary, M. I.; Clardy, J. Tetrahedron
Lett. 1989, 30, 6825; (e) Nakamura, H.; Kawase, Y.;
Maruyama, K.; Murai, A. Bull. Chem. Soc. Jpn. 1998, 71,
781; (f) Deranas, A. H.; Ferna´ndez, J. J.; Gav´ın, J. A.;
Norte, M. Tetrahedron 1998, 54, 7891.
2. (a) Fukuzawa, S.; Hayashi, Y.; Uemura, D.; Nagatsu, A.;
Yamada, K.; Ijuin, Y. Heterocycl. Commun. 1995, 1, 207;
(b) Kuramoto, M.; Hayashi, K.; Fujitani, Y.; Yamaguchi,
K.; Tsuji, T.; Yamada, K.; Ijuin, Y.; Uemera, D. Tetra-
hedron Lett. 1997, 38, 5683; (c) Kuramoto, M.; Hayashi,
K.; Yamaguchi, K.; Yada, M.; Tsuji, T.; Uemera, D. Bull.
Chem. Soc. Jpn. 1998, 71, 771.
3. Deranas, A. H.; Ferna´ndez, J. J.; Gav´ın, J. A.; Norte, M.
Tetrahedron 1999, 55, 5539.
4. (a) Hirai, G.; Oguri, H.; Hirama, M. Chem. Lett. 1999, 141;
(b) Moharram, S. M.; Hirai, G.; Koyama, K.; Oguri, H.;
Hirama, M. Tetrahedron Lett. 2000, 41, 6669.
14. Reactions using other ligands [including PPh3, 1,3-bis-
(diphenylphosphino)propane (dppp), 1,2-bis(diphenyl-
phosphino)ethane (dppe), 1,5-bis(diphenyphosphino)-
pentane, 1,1%-bis(diphenylphosphino)ferrocene (dppf)]
provided only small amounts of product (28) and larger
amounts of the reduced product (26).
15. (a) Laschat, S.; Narjes, F.; Overman, L. E. Tetrahedron
1994, 50, 347; (b) Overman, L. E.; Rucker, P. V. Tetra-
hedron Lett. 1998, 39, 4643; (c) Hynes, J.; Overman, L. E.;
Nasser, T.; Rucker, P. V. Tetrahedron Lett. 1998, 39, 4647.
5. (a) Tanner, D.; Anderson, P. G.; Tedenborg, L.; Somfai,
P. Tetrahedron 1994, 50, 9135; (b) Tanner, D.; Tedenborg,
L.; Somfai, P. Acta Chem. Scand. 1997, 51, 1217; (c)
Williams, D. R.; Cortez, G. S. Tetrahedron Lett. 1998, 39,
2675; (d) Williams, D. R.; Cortez, G. S. Org. Lett. 2000,
2, 1023; (e) Hikage, N.; Furukawa, H.; Takao, K.;
Kobayashi, S. Tetrahedron Lett. 1998, 39, 6237; (f) Hikage,
N.; Furukawa, H.; Takao, K.; Kobayashi, S. Tetrahedron

G. Hirai et al. / Tetrahedron Letters 42 (2001) 5783–5787
5787
16. For the use of PMP in the Mizoroki–Heck reaction, see;
Overman, L. E. Pure Appl. Chem. 1994, 66, 1423 and
references cited therein.
(1H, dd, J=16, 8 Hz, 19-Ha), 2.65 (1H, m, 23-H), 2.50
(1H, m, 8-H), 2.39 (1H, m, 8-H), 2.29 (3H, s, 15-CH3),
2.04 (1H, dd, J=9.5, 6 Hz, 9-H), 1.77 (1H, m, 23-H),
1.37 (3H, s, 12-CH3), 0.60 (3H, s, 22-CH3); 13C-NMR
(125MHz, CDCl3) l 153.9 (C17), 152.3 (C10), 147.7
(C13), 136.9 (C15), 127.5 (C24), 125.5 (C7), 119.4 (C18),
118.9 (C16), 112.5 (C14), 104.9 (C11), 95.7 (MOM), 94.9
(MOM), 93.4 (MOM), 77.7 (C21), 74.9 (C20), 56.4
(MOM), 56.1 (MOM), 55.7 (MOM), 45.4 (C12), 43.7
(C9), 41.2 (C22), 33.5 (C23), 29.5 (C8), 27.9 (C22-CH3),
27.4 (C12-CH3), 26.5 (C19), 21.9 (C15-CH3); FT-IR
(film) w 3529, 2927, 1686, 1610, 1584, 1465, 1377, 1286,
1217, 1151, 1027, 922, 846, 772 cm−1; MALDI-TOF-MS
Calcd for C27H38NaO7 (M+Na) 497.252, Found 497.253.
17. Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci,
F.; Penco, S. J. Org. Chem. 1991, 56, 5796.
18. Addition of LiCl16 did not suppress the formation of 27.
1
19. Data for 28: H-NMR (500MHz, CDCl3) l 6.89 (1H, s,
14-H), 6.73 (1H, s, 16-H), 5.81 (1H, m, 7-H), 5.66 (1H,
m, 24-H), 5.16 (2H, s, MOM), 5.10 (1H, d, J=6.5 Hz,
MOM), 5.05 (1H, d, J=6.5 Hz, MOM), 5.03 (1H, s,
11-H), 4.94 (1H, d, J=7 Hz, MOM), 4.81 (1H, d, J=7
Hz, MOM), 3.94 (1H, dd, J=8, 6 Hz, 20-H), 3.62 (1H, s,
OH), 3.49 (3H, s, MOM), 3.47 (1H, dd, J=16, 6 Hz,
19-Hb), 3.47 (3H, s, MOM), 3.47 (3H, s, MOM), 2.76
.