Synthetic studies of norzoanthamine. Preparation of the diene-yne-diene precursor of an ABC-ring fragment

Article abstract of DOI:10.1246/cl.2005.1058

The diene-yne-diene precursor of the ABC-ring fragment of norzoanthamine, a bioactive alkaloid from the colonial zoanthid Zoanthus sp., was prepared. Copyright

Full text of DOI:10.1246/cl.2005.1058

1058
Chemistry Letters Vol.34, No.7 (2005)
Synthetic Studies of Norzoanthamine.
Preparation of the Diene-yne-diene Precursor of an ABC-ring Fragment
Taiji Irifune,ꢀy Tomohiro Ohashi,y Takao Ichino,y Emi Sakai,y Kiyotake Suenaga,y;# and Daisuke Uemuray;yy
yDepartment of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602
yyInstitute for Advanced Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602
(Received April 20, 2005; CL-050541)
The diene-yne-diene precursor of the ABC-ring fragment of
norzoanthamine, a bioactive alkaloid from the colonial zoanthid
Zoanthus sp., was prepared.
Norzoanthamine (1)1 is a zoanthamine-type alkaloid2 that
was identified in the colonial zoanthid Zoanthus sp. in 1995.
Zoanthamines have interesting biological activities.1–3 In partic-
ular norzoanthamine hydrochloride suppresses the decreases in
bone weight and strength in ovariectomized mice without seri-
ous side effects.1c,4 Thus, norzoanthamine (1) is a good candi-
date for a potential anti-osteoporotic drug. Most zoanthamines
have a complicated heptacyclic ring system with three contigu-
ous quaternary centers in the C ring and an amino acetal. More-
over, since they are regarded as terpenoids based on their molec-
ular formulas, zoanthamines are thought to have a polyketide-
type biogenetic pathway (3 ! 2).1b,1c The biological activities,
structural features and biogenesis of norzoanthamine have at-
tracted the attention of synthetic chemists.5 However, only one
total synthesis of norzoanthamine (1) has been reported by
Miyashita and co-workers in 2004.5n We report here the prepa-
ration of the diene-yne-diene precursor of the ABC-ring frag-
ment of norzoanthamine (1).
Scheme 1. Retrosynthesis of norzoanthamine (1).
Scheme 2. Reagents and conditions: (a) 9, n-BuLi, ether, ꢁ78 ꢂC,
75%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, ꢁ78 ꢂC, quant.; (c)
Al2O3, hexane, rt, 97%; (d) PDC, MS4A, CH2Cl2, rt, 82%; (e)
1-propynylmagnesium bromide, ether, ꢁ78 ꢂC, 94%; (f) Red-
AlÒ, ether, rt, then I2, ether/THF = 2/1, 0 ꢂC, 73%.
hol, selective desilylation and oxidation gave aldehyde 10. Final-
ly, addition of 1-propynylmagnesium bromide to 10, (Z)-selec-
tive hydroalumination, and iodation produced vinyl iodide 6.
The synthesis of diene-yne 7 began with methyl enol ether
11.9 Reduction with DIBAL-H, followed by the Wittig reaction
and protection of the resultant hydroxyl group, produced the
ethyl ester (Scheme 3), which was reduced and oxidized to give
aldehyde 13. Finally, 13 was converted to diene-yne 7 in 69%
yield by the Ohira–Bestmann procedure.
The synthesis of the diene-yne-diene fragment 15 began
with the Sonogashira coupling reaction between vinyl iodide
6 and diene-yne 7. This reaction produced the diene-yne-ene
quantitatively, which was smoothly oxidized to the enone with
Dess–Martin periodinane (DMP), although other oxidants gave
complex mixtures (Scheme 4). Finally, (Z)-selective conversion
of enone to the methyl enol ether with KHMDS and methyl flu-
orosulfonate in THF/HMPA produced the diene-yne-diene 1510
in good yield. Diene-yne-diene 15 was very weak against acids,
Figure 1.
Our strategy is shown in Scheme 1. Although some
groups used the Diels–Alder reaction to produce an ABC-ring
fragment,5a,5e,5m,5n there is no strategy that involves a linear-car-
bon-chain intermediate. Therefore, we expected that the polyene
fragment 5 or its derivatives might undergo sequential cycliza-
tions6 to produce the ABC-ring fragment 4. The polyene precur-
sor would be prepared by the Pd-catalyzed coupling reaction be-
tween vinyl iodide 6 (C15–C24 fragment) and diene-yne 7 (C7–
C14 fragment).
The synthesis of vinyl iodide 6 began with aldehyde 87
(Scheme 2). Vinyl iodide 98 was treated with n-BuLi, and the re-
sulting lithiated 9 was added to 8 to give the allyl alcohol in 75%
yield. Subsequent protection of the hydroxyl group of allyl alco-
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
1059
3
4
5
a) R. M. Villar, J. Gil-Longo, A. H. Daranas, M. L. Souto, J. J.
´
Fernandez, S. Peixinho, M. A. Barral, G. Santafe, J. Rodrıguez,
and C. Jimenez, Bioorg. Med. Chem., 11, 2301 (2003). b) G.
´
´
´
Hirai, H. Oguri, M. Hayashi, K. Koyama, Y. Koizumi, S. M.
Moharram, and M. Hirama, Bioorg. Med. Chem. Lett., 14,
2647 (2004).
a) K. Yamaguchi, M. Yada, T. Tsuji, M. Kuramoto, and D.
Uemura, Biol. Pharm. Bull., 22, 920 (1999). b) K. Yamada,
M. Kuramoto, and D. Uemura, Recent Res. Dev. Pure Appl.
Chem., 3, 245 (1999). c) M. Kuramoto, K. Yamaguchi, T.
Tsuji, and D. Uemura, in ‘‘Drugs from the Sea,’’ ed. by N.
Fusetani, Karger, Basel (2000), p 98.
a) D. Tanner, P. G. Anderson, L. Tedenborg, and P. Somfai,
Tetrahedron, 50, 9135 (1994). b) D. Tanner, L. Tedenborg,
and P. Somfai, Acta Chem. Scand., 51, 1217 (1997). c) T. E.
Nielsen and D. Tanner, J. Org. Chem., 67, 6366 (2002). d)
D. R. Williams and G. S. Cortez, Tetrahedron Lett., 39, 2675
(1998). e) D. R. Williams and T. A. Brugel, Org. Lett., 2,
1023 (2000). f) N. Higasa, H. Furukawa, K. Takao, and S.
Kobayashi, Tetrahedron Lett., 39, 6237 (1998) g) N. Higasa,
H. Furukawa, K. Takao, and S. Kobayashi, Tetrahedron Lett.,
39, 6241 (1998). h) N. Higasa, H. Furukawa, K. Takao, and S.
Kobayashi, Chem. Pharm. Bull., 48, 1370 (2000). i) G. Hirai,
H. Oguri, and M. Hirama, Chem. Lett., 1999, 141. j) S. M.
Moharram, G. Hirai, K. Koyama, H. Oguri, and M. Hirama,
Tetrahedron Lett., 41, 6669 (2000). k) G. Hirai, H. Oguri,
S. M. Moharram, K. Koyama, and M. Hirama, Tetrahedron
Lett., 42, 5783 (2001). l) G. Hirai, Y. Koizumi, S. M.
Moharram, H. Oguri, and M. Hirama, Org. Lett., 4, 1627
(2002). m) M. Sakai, M. Sasaki, K. Tanino, and M. Miyashita,
Tetrahedron Lett., 43, 1705 (2002). n) M. Miyashita, M.
Sasaki, I. Hattori, M. Sakai, and K. Tanino, Science, 305,
495 (2004). o) S. Ghosh, F. Rivas, D. Fischer, M. A. Gonzalez,
and E. A. Theodorakis, Org. Lett., 6, 941 (2004).
Scheme 3. Reagents and conditions: (a) DIBAL-H, CH2Cl2,
ꢁ78 ꢂC; (b) 12, MeCN, reflux; (c) TBSCl, imidazole, DMF, rt,
49% (3 steps); (d) DIBAL-H, CH2Cl2, ꢁ78 ꢂC, 82%; (e) MnO2,
CH2Cl2, rt, 91%; (f) 14, K2CO3, MeOH, rt, 69%.
Scheme 4. Reagents and conditions: (a) 7, Pd(PPh3)4, CuI,
Et2NH, rt, quant.; (b) DMP, CH2Cl2, rt, 78%; (c) KHMDS,
FSO3Me, THF/HMPA = 10/1, ꢁ78 ꢂC, 96%.
but could be isolated.
In conclusion, the diene-yne-diene precursor of an ABC-
ring fragment of norzoanthamine (1) was prepared. Sequential
cyclizations to give the ABC-ring fragment based on the bioge-
netic hypothesis are currently in progress in our laboratory.
This work was supported in part by a Grant-in-Aid for Sci-
entific Research, and the 21st century COE program (Establish-
ment of COE on Materials Science) from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
6
The cyclization of 2-methoxy-1,3,5-hexatriene to enone was
reported. P. von Zezschwitz, F. Petry, and A. de Meijere,
Chem.—Eur. J., 7, 4035 (2001).
P. C. Bulman-Page and P. C. Paquette, Tetrahedron Lett., 24,
3555 (1982).
7
8
9 was prepared by benzyl protection of the corresponding
alcohol.
References and Notes
#
Present address: Department of Chemistry, University of
Tsukuba.
1
a) S. Fukuzawa, Y. Hayashi, D. Uemura, A. Nagatsu, K.
Yamada, and Y. Ijyuin, Heterocycl. Commun., 1, 207 (1995).
b) M. Kuramoto, K. Hayashi, Y. Fujitani, K. Yamaguchi, T.
Tsuji, K. Yamada, Y. Ijyuin, and D. Uemura, Tetrahedron
Lett., 38, 5683 (1997). c) M. Kuramoto, K. Hayashi, K.
Yamaguchi, M. Yada, T. Tsuji, and D. Uemura, Bull. Chem.
Soc. Jpn., 71, 771 (1998).
S. Ma and E. Negishi, J. Org. Chem., 62, 784 (1997).
`
M. Quimpere, L. Ruest, and P. Deslongchamps, Synthesis,
9
1992, 132.
10 1H NMR (400 MHz, C6D6) of 15: ꢀ 7.35–7.08 (m, 5H), 6.71
(br s, 1H), 5.89 (br s, 1H), 5.47 (t, J ¼ 8:1 Hz, 1H), 5.46 (t,
J ¼ 8:1 Hz, 1H), 4.64–4.62 (m, 1H), 4.36 (s, 2H), 3.62 (s,
3H), 3.56 (t, J ¼ 6:6 Hz, 2H), 3.45–3.35 (m, 2H), 3.24 (s,
3H), 2.77–2.72 (m, 1H), 2.65–2.60 (m, 1H), 2.54–2.47 (m,
1H), 2.35–2.28 (m, 1H), 2.22 (s, 3H), 2.24–2.21 (m, 2H),
1.87 (s, 3H), 1.79 (s, 3H), 1.63 (s, 3H), 1.04 (s, 9H), 0.97 (s,
9H), 0.16 (s, 3H), 0.14 (s, 3H), 0.05 (s, 6H). The stereochem-
istry of 15 was determined by an NOE experiment.
2
a) C. B. Rao, A. S. R. Anjaneyula, N. S. Sarma, Y.
Venkateswarlu, R. M. Posser, D. J. Faulkner, M. H. M. Chen,
and J. Clardy, J. Am. Chem. Soc., 106, 7983 (1984). b) C. B.
Rao, A. S. R. Anjaneyula, N. S. Sarma, Y. Venkateswarlu,
R. M. Posser, and D. J. Faulkner, J. Org. Chem., 50, 3757
(1985). c) C. B. Rao, D. V. Rao, V. S. N. Raju, B. W. Raju,
B. W. Sullivan, and D. J. Faulkner, Heterocycles, 28, 103
(1989). d) A.-U. Rahman, K. A. Alvi, S. A. Abbas, M. I.
Choudhary, and J. Clardy, Tetrahedron Lett., 30, 6825
(1989). e) H. Nakamura, Y. Kawase, K. Maruyama, and A.
Murai, Bull. Chem. Soc. Jpn., 71, 781 (1998). f) A. H. Daranas,
´
J. J. Fernandez, J. A. Gavın, and M. Norte, Tetrahedron, 54,
7891 (1998). g) A. H. Daranas, J. J. Fernandez, J. A. Gavın,
´
´
´
and M. Norte, Tetrahedron, 55, 5539 (1999).
Published on the web (Advance View) July 5, 2005; DOI 10.1246/cl.2005.1058