Studies toward the total synthesis of nakiterpiosin: construction of the CDE ring system by a transannular Diels-Alder strategy

Article abstract of DOI:10.1016/j.tetlet.2007.05.174

The transannular Diels-Alder (TADA) reaction was applied to the synthesis of the CDE ring system of nakiterpiosin (1). Tetracyclic compound 25 may be a key intermediate in the total synthesis of 1.

Full text of DOI:10.1016/j.tetlet.2007.05.174

Tetrahedron Letters 48 (2007) 5465–5469
Studies toward the total synthesis of nakiterpiosin: construction
of the CDE ring system by a transannular Diels–Alder strategy
Tomonori Ito,a Masahiro Ito,a Hirokazu Arimoto,b,*
Hiroyoshi Takamuraa,* and Daisuke Uemuraa,c
aGraduate School of Science, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan
bGraduate School of Life Sciences, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba, Sendai 981-8555, Japan
cInstitute for Advanced Research, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan
Received 26 April 2007; revised 29 May 2007; accepted 31 May 2007
Available online 6 June 2007
Abstract—The transannular Diels–Alder (TADA) reaction was applied to the synthesis of the CDE ring system of nakiterpiosin (1).
Tetracyclic compound 25 may be a key intermediate in the total synthesis of 1.
Ó 2007 Elsevier Ltd. All rights reserved.
Coral communities are good sources of medicines such
as antimicrobial and anticancer agents.1,2 However,
many reefs around the world are now increasingly threa-
tened due to overfishing, pollution, typhoons, global
warming and coral predators such as the crown-of-
thorns starfish Acanthaster planci.3 In addition, the
overgrowth of other organisms in coral communities
has been recognized as another factor that contributes
to their destruction.4 It has been reported that these
organisms produce toxic compounds; for example, the
steroidal alkaloids plakinamines A and B were isolated
from the marine sponge Plakina sp., which overgrows
coral heads.5 We previously reported the isolation and
structural determination of nakiterpiosin (1), a novel
cytotoxic C-nor-D-homosteroid6 from the marine
sponge Terpios hosinota, which overgrew coral commu-
nities in waters off the Ryukyu Islands (Scheme 1).7 The
limited availability of 1 from natural sources (0.4 mg
isolated from 30 kg of Terpios hosinota) has hampered
biological studies. Therefore, a method for the chemical
synthesis of this compound is needed. We report here
the results of our study toward the synthesis of 1 by a
transannular Diels–Alder (TADA) strategy.8,9
A retrosynthetic analysis of 1 is described in Scheme 1.
The carbon framework of 1 could be broken into penta-
cyclic core 2 and the C20–C26 unit 3. Compound 2 can
be prepared from 4 through oxidative functionalization.
Rings C and D of 4 can be constructed via a TADA
reaction. Lactone 5 could be synthesized via a Stille
coupling reaction of vinyl stannane 6 and benzyl bro-
mide 7.
Vinyl stannane 6 was synthesized as shown in Scheme 2.
Treatment of (R)-(+)-glycidol (8) with tert-butyldiphen-
ylsilyl (TBDPS) chloride and imidazole gave TBDPS
ether 9. After two-carbon elongation with trimethylsilyl-
acetylene, the silyl protecting groups were removed with
TBAF to afford diol 10 in 72% yield from 9. Diol 10 was
transformed into vinyl iodide 11 using Negishi’s carbo-
metalation.10 The reaction was unsuccessful when the
hydroxy groups of 10 were protected with acetonide.
The 1,2-diol moiety of 11 was protected with 2,2-
dimethoxypropane, and the resulting acetal was con-
verted to vinyl stannane 6, which is the coupling precur-
sor of the Stille reaction.
Next, we investigated the construction of the aromatic
part (Scheme 3). Treatment of 2-methyl-3-nitrobenzoic
acid (12) with sulfuric acid under reflux conditions in
methanol provided ester 13. Hydrogenation of the nitro
group in 13 followed by a Sandmeyer reaction gave phe-
nol 14 in 78% yield from 13. Bromination of phenol 14
proceeded smoothly in the presence of Br2 to exclusively
Keywords: Nakiterpiosin; Synthetic study; Transannular Diels–Alder
reaction.
*
Corresponding authors. Tel./fax: +81 52 789 4525 (H.T.); e-mail:
hiroyoshi@org.chem.nagoya-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.174

5466
T. Ito et al. / Tetrahedron Letters 48 (2007) 5465–5469
Scheme 1. Retrosynthetic analysis of nakiterpiosin (1).
give 6-bromo isomer 15 in 83% yield.11 Protection of
phenol 15 with tert-butyldimethylsilyl (TBS) chloride
and subsequent reduction of the ester moiety with
diisobutylaluminum hydride (DIBALH) gave benzyl
alcohol 16. Treatment of benzyl alcohol 16 with
dihydropyran (DHP) followed by formylation of the
resulting tetrahydropyranyl (THP) ether gave aldehyde
17. The Horner–Wadsworth–Emmons reaction of 17
and triethyl 4-phosphonocrotonate 18 proceeded
smoothly to give the desired coupling product 19, which
possesses an E,E-diene moiety. THP ether 19 was di-
rectly converted to benzyl bromide 20, which is the cou-
pling partner of vinyl stannane 6, in the presence of
CBr4 and PPh3 in CH2Cl2 at 40 °C.12
Scheme 2. Synthesis of vinyl stannane 6. Reagents and conditions: (a)
TBDPSCl, imidazole, DMF, 0 °C, 94%; (b) trimethylsilylacetylene, n-
BuLi, BF3ÆOEt2, THF, À78 °C; (c) TBAF, THF, 0 °C, 72% (2 steps);
(d) AlMe3, Cp2ZrCl2, Cl(CH2)2Cl, 50 °C, then I2, THF, À30 °C, 55%;
(e) 2,2-dimethoxypropane, TsOH, DMF, rt, 96%; (f) t-BuLi, Et2O,
À78 °C, then Bu3SnCl, À78 °C, 88%.
Scheme 3. Synthesis of benzyl bromide 20. Reagents and conditions: (a) H2SO4, MeOH, reflux, 92%; (b) H2, Pd/C, EtOH, rt; (c) NaNO2, H2SO4,
reflux, 78% (2 steps); (d) Br2, CH2Cl2, À45 °C, 83%; (e) TBSCl, imidazole, DMF, rt, 92%; (f) DIBALH, CH2Cl2, À78 °C, 95%; (g) DHP, PPTS,
CH2Cl2, rt, 90%; (h) n-BuLi, THF, À78 °C, then DMF, À78 °C; (i) 18, NaH, THF, rt, 83% (2 steps); (j) CBr4, PPh3, CH2Cl2, 40 °C, 73%.

T. Ito et al. / Tetrahedron Letters 48 (2007) 5465–5469
5467
Scheme 4. Synthesis of lactone 24. Reagents and conditions: (a) 6 (1.2 equiv.), Pd2(dba)3, PPh3, DMF, 30 °C, 80%; (b) 1,3-propanedithiol, BF3ÆOEt2,
CH2Cl2, À78 °C, 85%; (c) TBSCl, imidazole, DMF, 0 °C; (d) DIBALH, CH2Cl2, À78 °C, 70% (2 steps); (e) MnO2, CH2Cl2, rt; (f) NaClO2,
NaH2PO4, 2-methyl-2-butene, THF/t-BuOH/H2O (3:3:1), rt; (g) MNBA, DMAP, CH2Cl2, rt, 56% (3 steps).
Scheme 4 shows the method for preparing the precursor
in the TADA reaction, lactone 24. Vinyl iodide 6 and
benzyl bromide 20 were coupled by a Stille reaction to
give the desired product 21 in 80% yield. After removal
of the acetonide moiety in the presence of 1,3-propane-
dithiol and BF3ÆOEt2, selective protection of the result-
ing primary alcohol with TBSCl and subsequent
reduction of the a,b-unsaturated ester moiety provided
diol 22. Chemoselective oxidation of the allylic alcohol
moiety of 22 with MnO2, followed by Pinnic oxidation,
gave seco-acid 23.13 After an extensive survey of known
macrolactonization methods, Shiina’s protocol14 was
found to be suitable for the synthesis of 24. Thus, treat-
ment of 23 with 2-methyl-6-nitrobenzoic anhydride
(MNBA) and 4-(dimethylamino)pyridine (DMAP) gave
the desired lactone 24, which is the precursor in the
TADA reaction, in 56% yield from 22.
refluxing toluene (entry 1) or under the conditions
reported by Grieco et al.15 (entry 2). Finally, heating
in 1,2,4-trichlorobenzene at 160 °C gave the TADA
products 25 and 26 in respective yields of 50% and
35% (entry 3). Unfortunately, the desired TADA prod-
uct 27 was not obtained.
The stereochemistries of 25 and 26 were determined
1
based on H–1H coupling constants and NOE experi-
ments (Fig. 1). With regard to TADA product 25, Ha
1
and Hb at C1 were assigned by H–1H coupling con-
stants (J1a,2 = 3.6 Hz and J1b,2 = 12.6 Hz). The observa-
tion of NOEs for 19-Me/Ha-1, 19-Me/H-2 and 19-Me/
H-5 indicated that 19-Me, Ha-1, H-2, and H-5 were in
syn relationships to each other. Based on the NOE
observations for Hb-1/H-8 and H-8/H-9, these three
protons were considered to be in syn relationships. Thus,
the structure of 25 was determined to be as depicted in
Figure 1. The stereochemistry of 26 was examined in a
similar manner. Based on the NOEs observed for
Our examination of the TADA reaction of 24 is summa-
rized in Table 1. Cyclization did not proceed, either in
Table 1. TADA reaction of 24
Entry
Conditions
Yield (%)
25
0a
0a
50
26
1
2
3
Toluene, reflux
5.0 M LiClO4/Et2O, reflux
1,2,4-Trichlorobenzene, 160 °C
0
0
35
a No reaction was observed.

5468
T. Ito et al. / Tetrahedron Letters 48 (2007) 5465–5469
Figure 1. Structural determination of 25 and 26.
Scheme 5. Reaction pathways to 25 and 26.
Ha-1/H-2, Ha-1/H-8, and H-8/H-9, these protons were
established to be in syn relationships. Furthermore,
NOEs for 19-Me/Hb-1 and 19-Me/H-5 suggested that
19-Me, Hb-1, and H-5 were oriented in a syn arrange-
ment. Therefore, the stereochemistry of 26 was eluci-
dated to be as shown in Figure 1.
istry of Education, Culture, Sports, Science and Tech-
nology, Japan.
References and notes
Compounds 25 and 26 could be formed by the prior
isomerization of the C7–C8 (E)-alkene of 24 to a (Z)-al-
kene. However, when the C7–C8 (Z)-alkene compound
was subjected to the conditions of entry 3 in Table 1,
the formation of TADA products was not observed.
Thus, reaction pathways to 25 and 26 are thought to
be as shown in Scheme 5. TADA reaction of 24 pro-
ceeded via the transition states TS1 or TS2 to give 27
or 28, and epimerization at the C8 center occurred to
form 25 or 26. We are planning to convert 25 to naki-
terpiosin (1) via epimerization at the C8 center.
1. Cragg, G. M.; Newman, D. J. Cancer Invest. 1999, 17,
153–163.
2. Long, B. H.; Carboni, J. M.; Wasserman, A. J.; Cornell,
L. A.; Casazza, A. M.; Jensen, P. R.; Lindel, T.; Fenical,
W.; Fairchild, C. R. Cancer Res. 1998, 58, 1111–
1115.
3. Teruya, T.; Suenaga, K.; Koyama, T.; Nakano, Y.;
Uemura, D. J. Exp. Mar. Biol. Ecol. 2001, 266, 123–
134.
4. Hughes, T. P. Science 1994, 265, 1547–1551.
5. Rosser, R. M.; Faulkner, D. J. J. Org. Chem. 1984, 84,
5157–5160.
6. For the review of synthetic studies on C-nor-D-homo-
steroids, see: Brown, E.; Ragault, M. Tetrahedron 1979,
35, 911–927.
7. (a) Teruya, T.; Nakagawa, S.; Koyama, T.; Suenaga, K.;
Kita, M.; Uemura, D. Tetrahedron Lett. 2003, 44, 5171–
5173; (b) Teruya, T.; Nakagawa, S.; Koyama, T.; Arim-
oto, H.; Kita, M.; Uemura, D. Tetrahedron 2004, 60,
6989–6993.
8. For our recent report on the synthesis of a marine natural
product by a TADA reaction, see: Araki, K.; Saito, K.;
Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed. 2004, 43,
81–84.
In conclusion, we synthesized 25, which possesses the
CDE ring framework of nakiterpiosin (1) by a TADA
reaction. Further studies toward the total synthesis of
nakiterpiosin are in progress.
Acknowledgement
This work was supported in part by a Grant-in-Aid for
Creative Scientific Research (16GS0206) from the Min-

T. Ito et al. / Tetrahedron Letters 48 (2007) 5465–5469
5469
9. For recent reviews of the TADA reaction, see: (a) Takao,
12. Wagner, A.; Heitz, M.-P.; Mioskowski, C. Tetrahedron
Lett. 1989, 30, 557–558.
K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105,
´
4779–4807; (b) Marsault, E.; Toro, A.; Nowak, P.;
13. Bal, B. S.; Childers, W. E., Jr.; Pinnic, H. W. Tetrahedron
1981, 37, 2091–2096.
14. Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J.
Org. Chem. 2004, 69, 1822–1830.
Deslongchamps, P. Tetrahedron 2001, 57, 4243–4260.
10. Negishi, E.-i.; Van Horn, D. E.; Yoshida, T. J. Am. Chem.
Soc. 1985, 107, 6639–6647.
11. Cresp, T. M.; Giles, R. G. F.; Sargent, M. V.; Brown, C.;
Smith, D. O. J. Chem. Soc., Perkin Trans. 1 1974, 2435–
2447.
15. Grieco, P. A.; Nunes, J. J.; Gaul, M. D. J. Am. Chem. Soc.
1990, 112, 4595–4596.