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Pseudodistomin B: Revised structure and first total synthesis
W40-4039/92 $5.00 + .OO Pcrgamm Plcss L4d
Tctmhcdnm Lemrs. Vol. 33, No. 48. pi. 1389-7390.1992 Priiwd in Great Britain
Pseudodistomin B: Revised Structure and First Total Synthesis Toshiko
Kiguchi, Yoko Yuumoto, Ichiya Ninomiya, and Takeaki Naito*
K&e Women’s College of Pharmacy, Motoymakdta, Higashinada, Kobe 658, Japan
Kanako Deki, Masami Ishibashi, and Jun’ichi Kobayashi* Faculty of Phamaceutical Sciences, Hokkaido University, Sappom 060, Japan
Keywords: total synthesis;pseuakxiistomin B; marine compound;ahodulin
anmgmist
Abstract: The structure of pseudodistomin B, novel antineoplastic piperidine alkaloid, has been revised to la on the bases of the degradation reaction and the first total synthesis of (-+)-pseudodistomin B acetate (lb).
In the course of our studies on bioactive substances from Okinawan marine organisms, we (J. K.) had isolated two piperidine alkaloids, pseudodistomins A and B, from the Okinawan ttmicate Pseudodistoma kanoko and their structures were deduced as 2 and 3 from their spectral data. 1 However, our recent work2 (T. N.) on the total synthesis of pseudodistomin tetrahydroacetate (4)3 has suggested that the deduced structures of the ahcenyl side chain in the patent alkaloids should he revised. Here we describe the structural revision of pseudodistomin B based on the degradation reaction of the acetate of natural specimen as well as the first total synthesis of the racemic acetate lb. Pseudodistomin B acetate (lb), which was prepared from natural specimen, was treated with ozone followed by reduction with sodium borohydride and acetylation with acetic anhydride and pyridme to afford the tetraacetate 5.4 The FABMS of 5 showed the (M+H)+ ion at m/z 385, clearly revealing that pseudodistomin B bears not a 3’5’~tridecadiene moiety but a 6’,8’-tridecadiene structure in the side chain. The structure of pseudodistomin B (la) was thus revised and further confirmed by the total synthesis of its acetate lb as follows. OR’
n-c*wAN
NHR2
/I,
lb
J
114 2)NaW 3) AczO/4r
R2 ls:R’=R’=H lb:R’=R’=Ac lc:R’=H,R’=Ac
7389
s
7390
Tosylation of the known2 alcohol 6, which was previously used as an intermediate for the synthesis of pseudodistomin tetrahydroacetate (4), gave the tosylate 7 in 70% yield. Coupling reaction5 of the tosylate 7 with (E, &+3,5decadienyhnagnesium bromide6 in the presence of dilithium tetrachlorocuprate proceeded smoothly at -20°C to give a 2:l mixture of the acetate lb and the corresponding alcohol lc in 61% yield. Acylation of the alcohol lc with acetic anhydride and pyridine gave the acetate lb which is found to be identical with natural pseudodistomin B acetate by comparisons of IR, 1H- and 13C-NMR spectra with those of the authentic specimen. As a result, the chemical degradation and the first total synthesis of (f)-pseudodistomin B acetate (lb) have proved that the structure of pseudodistomin B should be revised to la. Isolation of pseudodistomin A and reinvestigation of the deduced structure are now under progress.
OR
3
H
m-h,*-
4
AC
(CHzhCH3
5
AC
(cHz)aOAC
6
AC
(m&OH
7
AC
(CHd30Ts
NHR R’@
6
ru
N R
T&l, DMAP, Et3N
(adaa
7
ACKNOWLEDGEMENTS We are grateful to the Ministry of Education, Science, and Culture (Japan) for research grant. REFERENCES AND NOTES 1. Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata, Y.; Kobayashi, J. J. Org. Chem. 1987,52, 450-453.
2. Naito, T.; Yuumoto, Y.; Ninomiya, I.; Kiguchi, T. Tetrahedron Left. 1992,33,40334036.
3. Utsunomiya, I.; Ogawa, M.; Natsume, M. Heterocycles 1992,33,349-356. 4. 5 : 1H-NMR (CDC13,270 MHz) 6 5.61 (lH, br d, J=10.6 Hz, 5-NH), 5.18 (lH, m, 4-H), 4.93 (lH, m, 2-H), 4.31 (lH, br s, 5-H), 4.04 (2H, t, 5=6.6 Hz, 6’-Hz), 3.96 (lH, br d, J=15.0 Hz, 6-Heq), 3.27 (lH, br d, J=15.0 Hz, 6-Hax), and 2.08 - 2.02 (12H, m, AC x 4); EIMS m/z (S) 325 (M+-CH$ONH2,87), 282 (38), 181 (64), 139 (75), and 80 (100); FABMS (positive; matrix: m-nitrobenzyl alcohol) m/z 385 (M+H)+ ; HRFABMS m/z 385.2361, calcd for C1gH3306N2 (M+H): 385.2338. 5. Fouquet, G.; Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974,13,82-83. 6. Svirskaya, P. I.; Maiti, S. N.; Jones, A. J.; Khouw, B.; Leznoff, C. C. J. Chem. Ecol. 1984,10, 795-807. (Received in Japan 6 August 1992)
Tctmhcdnm Lemrs. Vol. 33, No. 48. pi. 1389-7390.1992 Priiwd in Great Britain
Pseudodistomin B: Revised Structure and First Total Synthesis Toshiko
Kiguchi, Yoko Yuumoto, Ichiya Ninomiya, and Takeaki Naito*
K&e Women’s College of Pharmacy, Motoymakdta, Higashinada, Kobe 658, Japan
Kanako Deki, Masami Ishibashi, and Jun’ichi Kobayashi* Faculty of Phamaceutical Sciences, Hokkaido University, Sappom 060, Japan
Keywords: total synthesis;pseuakxiistomin B; marine compound;ahodulin
anmgmist
Abstract: The structure of pseudodistomin B, novel antineoplastic piperidine alkaloid, has been revised to la on the bases of the degradation reaction and the first total synthesis of (-+)-pseudodistomin B acetate (lb).
In the course of our studies on bioactive substances from Okinawan marine organisms, we (J. K.) had isolated two piperidine alkaloids, pseudodistomins A and B, from the Okinawan ttmicate Pseudodistoma kanoko and their structures were deduced as 2 and 3 from their spectral data. 1 However, our recent work2 (T. N.) on the total synthesis of pseudodistomin tetrahydroacetate (4)3 has suggested that the deduced structures of the ahcenyl side chain in the patent alkaloids should he revised. Here we describe the structural revision of pseudodistomin B based on the degradation reaction of the acetate of natural specimen as well as the first total synthesis of the racemic acetate lb. Pseudodistomin B acetate (lb), which was prepared from natural specimen, was treated with ozone followed by reduction with sodium borohydride and acetylation with acetic anhydride and pyridme to afford the tetraacetate 5.4 The FABMS of 5 showed the (M+H)+ ion at m/z 385, clearly revealing that pseudodistomin B bears not a 3’5’~tridecadiene moiety but a 6’,8’-tridecadiene structure in the side chain. The structure of pseudodistomin B (la) was thus revised and further confirmed by the total synthesis of its acetate lb as follows. OR’
n-c*wAN
NHR2
/I,
lb
J
114 2)NaW 3) AczO/4r
R2 ls:R’=R’=H lb:R’=R’=Ac lc:R’=H,R’=Ac
7389
s
7390
Tosylation of the known2 alcohol 6, which was previously used as an intermediate for the synthesis of pseudodistomin tetrahydroacetate (4), gave the tosylate 7 in 70% yield. Coupling reaction5 of the tosylate 7 with (E, &+3,5decadienyhnagnesium bromide6 in the presence of dilithium tetrachlorocuprate proceeded smoothly at -20°C to give a 2:l mixture of the acetate lb and the corresponding alcohol lc in 61% yield. Acylation of the alcohol lc with acetic anhydride and pyridine gave the acetate lb which is found to be identical with natural pseudodistomin B acetate by comparisons of IR, 1H- and 13C-NMR spectra with those of the authentic specimen. As a result, the chemical degradation and the first total synthesis of (f)-pseudodistomin B acetate (lb) have proved that the structure of pseudodistomin B should be revised to la. Isolation of pseudodistomin A and reinvestigation of the deduced structure are now under progress.
OR
3
H
m-h,*-
4
AC
(CHzhCH3
5
AC
(cHz)aOAC
6
AC
(m&OH
7
AC
(CHd30Ts
NHR R’@
6
ru
N R
T&l, DMAP, Et3N
(adaa
7
ACKNOWLEDGEMENTS We are grateful to the Ministry of Education, Science, and Culture (Japan) for research grant. REFERENCES AND NOTES 1. Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata, Y.; Kobayashi, J. J. Org. Chem. 1987,52, 450-453.
2. Naito, T.; Yuumoto, Y.; Ninomiya, I.; Kiguchi, T. Tetrahedron Left. 1992,33,40334036.
3. Utsunomiya, I.; Ogawa, M.; Natsume, M. Heterocycles 1992,33,349-356. 4. 5 : 1H-NMR (CDC13,270 MHz) 6 5.61 (lH, br d, J=10.6 Hz, 5-NH), 5.18 (lH, m, 4-H), 4.93 (lH, m, 2-H), 4.31 (lH, br s, 5-H), 4.04 (2H, t, 5=6.6 Hz, 6’-Hz), 3.96 (lH, br d, J=15.0 Hz, 6-Heq), 3.27 (lH, br d, J=15.0 Hz, 6-Hax), and 2.08 - 2.02 (12H, m, AC x 4); EIMS m/z (S) 325 (M+-CH$ONH2,87), 282 (38), 181 (64), 139 (75), and 80 (100); FABMS (positive; matrix: m-nitrobenzyl alcohol) m/z 385 (M+H)+ ; HRFABMS m/z 385.2361, calcd for C1gH3306N2 (M+H): 385.2338. 5. Fouquet, G.; Schlosser, M. Angew. Chem., Int. Ed. Engl. 1974,13,82-83. 6. Svirskaya, P. I.; Maiti, S. N.; Jones, A. J.; Khouw, B.; Leznoff, C. C. J. Chem. Ecol. 1984,10, 795-807. (Received in Japan 6 August 1992)