Novel and practical asymmetric synthesis of an azetidine alkaloid, penaresidin B

Article abstract of DOI:10.1016/S0040-4039(02)02743-0

A novel and efficient asymmetric synthesis of the potent actomyosin ATPase activator, penaresidin B, is described in a short and complete stereoselective manner by featuring the elaboration of the fully functionalized homochiral lactam, which can also be

Full text of DOI:10.1016/S0040-4039(02)02743-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 977–979
Novel and practical asymmetric synthesis of an azetidine
alkaloid, penaresidin B
Hidemi Yoda,* Takuya Uemura and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 5 November 2002; revised 21 November 2002; accepted 29 November 2002
Abstract—A novel and efficient asymmetric synthesis of the potent actomyosin ATPase activator, penaresidin B, is described in
a short and complete stereoselective manner by featuring the elaboration of the fully functionalized homochiral lactam, which can
also be regarded as an advanced intermediate for the synthesis of other azetidine alkaloids. © 2003 Elsevier Science Ltd. All rights
reserved.
Marine sponges have frequently afforded a wide variety
of sphingosine-related compounds,1 in which penare-
sidins A (1) and B (2) isolated in 1991 from an Oki-
nawan marine sponge Penares sp. by Kobayashi et al.
are the first sphingosine-derived alkaloids possessing an
interesting azetidine ring structure.2 Tested as an insep-
arable mixture, these two compounds exhibit potent
actomyosin ATPase-activating activity. As shown in
Figure 1, the exact absolute configurations of five
ers.7 The structure of the substituted azetidine closely
related to penaresidins was confirmed to be 3 by the
synthesis of Mori et al.8 except for the side-chain
stereochemistry. Due to their significant activities and
unique structural characteristics, they have been the
subject of extensive synthetic efforts which have culmi-
nated in several syntheses.8,9 Synthetic strategies
described to date including our recent method,12b how-
ever, in general require multistep reactions or crucial
techniques and were not necessarily satisfactory. The
purpose of the present communication is to report a
novel and convenient process for the asymmetric syn-
thesis of 2, which in turn would make it possible to
provide a new opportunity for the synthesis of other
azetidine alkaloids.
stereogenic centers in
1 were established to be
2S,3R,4S,15S and 16S, and the initially proposed struc-
ture of penaresidin B was revised to be 23 after struc-
tural characterization based on spectroscopic
methods2,4 supplemented by synthetic studies.3,5,6 On
the other hand, a new azetidine alkaloid, penazetidine
A (3), possessing potent protein kinase C inhibitory
activity was isolated in 1994 from the Indo-Pacific
marine sponge Penares sollasi by Crews and co-work-
As shown in Scheme 1, we investigated the utilization
of amino sugar for the synthesis of the functionalized
Figure 1. Penaresidin A (1), penaresidin B (2) and penazetidine A (3).
Keywords: penaresidin; azetidine alkaloid; lactam; nucleophilic addition; arabinofuranose.
* Corresponding author. Tel.: +81 53 478 1150; fax: +81 53 478 1150; e-mail: tchyoda@ipc.shizuoka.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02743-0

978
H. Yoda et al. / Tetrahedron Letters 44 (2003) 977–979
,
Scheme 1. Reagents and conditions: (a) 1, (S)-HCꢀC(CH2)7CH(OMOM)CH2CH(CH3)2, BuLi, THF, −78–0°C; 82%; 2, PCC, 4 A
MS, CH2Cl2; 62%; (b) 1, CAN, CH3CN–H2O (9:1); 66%; 2, (Boc)2O, DMAP, Et3N, CH2Cl2; quant.; 3, Pd (black), 4.4%
HCOOH–MeOH; 95%; (c) 1, BnBr, Ag2O, CH3COOEt; 74%; 2, MOMCl, (i-Pr)2NEt, CH2Cl2; quant.; (d) 1, NaBH4, MeOH;
quant.; 2, MOMCl, (i-Pr)2NEt, CH2Cl2; quant.; 3, Pd (black), 4.4% HCOOH–MeOH; quant.; (e) 1, MsCl, Et3N, CH2Cl2; 2, NaH,
THF; 50% (two steps); (f) conc. HCl, MeOH; (g) Ac2O, pyridine, DMAP; quant.
after derivatization to the known tetraacetate 11, [h]D25
homochiral lactam intermediate with desired stereo-
+47.3° (c 0.75, CHCl3) {lit. [h]2D5 +47° (c 0.42, CHCl3)3}.
genic centers. When the acetylide elaborated from
leucine10 via the acetylene zipper reaction11 was treated
with the furanosylamine 5 prepared from -arabinose
D-
The spectral data of synthetic 11 were completely iden-
tical to those of the reported values in all respects.3
D
derivative 4 at low temperature followed by oxidative
degradation with PCC,12 it afforded the non-terminal
alkyne-lactam 6 with three substituents exclusively
(>99% d.e., determined by 13C NMR and HPLC) in
good yield. After exchange of the MPM(p-methoxyben-
zyl)-protecting group to the N-Boc function in 6 to
enhance the nucleophilicity, deprotection of the benzyl
groups accompanying simultaneous hydrogenation of
the triple bond was effected by using Pd (black) in 4.4%
HCOOH–MeOH to furnish the dihydroxylactam 7.
Then, 7 was regioselectively transformed through suc-
cessive Bn- and MOM-protections into the synthetically
useful homochiral lactam 8 in 74% and quantitative
yields, respectively. No base-induced racemization of
the g-position in 8 was observed in these reactions
(determined by 13C NMR). Reduction of 8 with NaBH4
cleanly opened the lactam ring and afforded the corre-
sponding acyclic alcohol quantitatively again, which
was in turn submitted to MOM-protection followed by
debenzylation with Pd (black) to afford the desired
N-Boc alcohol 9 in extremely high yield. In contrast to
Lin’s results9d construction of the azetidine ring was
accomplished under mild basic conditions after intro-
duction of the methanesulfonyl group to provide the
N-Boc and tri-O-methoxymethylated penaresidin B 10
in 50% yield (two steps).13 Finally, removal of the
protecting groups in 10 was conducted under acidic
conditions to complete the total synthesis of 1 in 12%
This process involves no separation of stereoisomers
through the entire sequence until penaresidin B was
synthesized from the starting
D
-arabinose derivative 4,
which constitutes a new synthetic strategy and repre-
sents a short and easily accessible pathway to penare-
sidins. We anticipate that the non-terminal alkyne
lactam such as 6 will serve as an advanced template for
the synthesis of other nitrogen-containing natural
alkaloids.
Acknowledgements
We thank Emeritus Professor Kenji Mori (The Univer-
sity of Tokyo) for valuable suggestions and discussions
1
in addition to his kind supply of the copies of the H
and 13C NMR spectra of penaresidin B tetraacetate.
This work was supported in part by a Grant-in-Aid
(No. 13640530) for Scientific Research from Japan
Society for the Promotion of Science.
References
1. (a) Kaufer, J. M.; Hakomori, S. Handbook of Lipids
Research, Sphingolipid Biochemistry Vol. 3; Plenum Press:
New York, 1983; (b) Sweeley, C. C. In Biochemistry of
Lipids and Membranes; Vance, D. E.; Vance, J. E., Eds.;
Benjamin/Commings: Menlo Park, CA, 1985; (c)
overall yield from the commercially available
D-ara-
binose derivative 4, whose structure was characterized

H. Yoda et al. / Tetrahedron Letters 44 (2003) 977–979
979
Kobayashi, J.; Ishibashi, M. Heterocycles 1996, 42, 943–
970.
2. Kobayashi, J.; Cheng, J.-f.; Ishibashi, M.; Wa¨lchli, M.
R.; Yamamura, S.; Ohizumi, Y. J. Chem. Soc., Perkin
Trans. 1 1991, 1135–1137.
3. Takikawa, H.; Maeda, T.; Seki, M.; Koshino, H.; Mori,
K. J. Chem. Soc., Perkin Trans. 1 1997, 97–111.
4. Kobayashi, J.; Tsuda, M.; Cheng, J.-f.; Ishibashi, M.;
Takikawa, H.; Mori, K. Tetrahedron Lett. 1996, 37,
6775–6776.
Y. Tetrahedron Lett. 1997, 38, 3813–3816; (d) Liu, D.-G.;
Lin, G.-Q. Tetrahedron Lett. 1999, 40, 337–340.
Penaresidin B: (a) Ref. 3; (b) Yoda, H.; Oguchi, T.;
Takabe, K. Tetrahedron Lett. 1997, 38, 3283–3284.
10. Mori, K. Tetrahedron 1976, 32, 1101–1106.
11. (a) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975,
97, 891–892; (b) Abrams, S. R. Can. J. Chem. 1984, 62,
1333–1334.
12. (a) Lay, L.; Nicotra, F.; Paganini, A.; Pangrazio, C.;
Panza, L. Tetrahedron Lett. 1993, 34, 4555–4558; (b)
Yoda, H.; Yamazaki, H.; Kawauchi, M.; Takabe, K.
Tetrahedron: Asymmetry 1995, 6, 2669–2672.
5. Hiraki, T.; Yamagiwa, Y.; Kamikawa, T. Tetrahedron
Lett. 1995, 36, 4841–4844.
13. Recently Lin et al. reported that the same type of nitro-
gen-directed cyclization to azetidine ring did not proceed
under any conditions,9d however, in our case the desired
cyclized product 10 was obtained in good yield (50%, two
steps) with no difficulty. These different results would be
ascribed to the steric bulkiness of both hydroxyl- and
amino-protecting groups.
6. Takikawa, H.; Maeda, T.; Mori, K. Tetrahedron Lett.
1995, 36, 7689–7692.
7. Alvi, K. A.; Jaspars, M.; Crews, P. Bioorg. Med. Chem.
Lett. 1994, 4, 2447–2450.
8. Yajima, A.; Takikawa, H.; Mori, K. Liebigs Ann. 1996,
1083–1089.
9. Penaresidin A: (a) Ref. 6; (b) Ref. 3; (c) Knapp, S.; Dong,