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301
connects to the asparagine moiety. Alkylation of the
left-half segment 16, obtained from coupling of the
mono-Ns-putrescine 76 with N-tBoc-l-asparagine p-
nitrophenyl ester in 95% yield, with the right-half seg-
ment 17, produced from the mono-Ns-1,3-diaminopro-
pane 156 by the Cbz protection and subsequent
alkylation with 1,3-dibromopropane in high yield, gave
the desired polyamine backbone 18 in 94% yield. The
Boc deprotection of 18, followed by condensation with
indoleacetic acid N-hydroxysuccinimide ester10 gave the
fully protected toxin 19 in 84% yield. Deprotection of
19 in the usual manner finally afforded NPTX-473 (2)11
in a 45% overall yield from 7 via six steps.
mono-Ns-1,3-diaminopropane 15 and using the same
method as that for the Type D would give the Type E
toxin. Scheme 5 shows the synthesis of joramine (5). As
anticipated, the polyamine backbone 24 was smoothly
obtained from 15 through the acid 23, and subsequent
treatment in the usual manner gave the Type E toxin
joramine (5)11 in a 36% overall yield from 15 via nine
steps.
Thus, we have developed an efficient and versatile
synthesis of acylpolyamine spider toxins based on the
structural classification of the Nephila and Nephilengys
spider toxins using the 2-nitrobenzenesulfonamide
group(the Ns-strategy). The naturally occurring toxins
1–5 representing each structural type have been effi-
ciently synthesized by this method in a high overall yield
with few steps. This method is so versatile that it would
allow us to synthesize a variety of analogues as well as
naturally occurring toxins. Therefore, it would be highly
useful for SAR and mode of action studies of the acyl-
polyamine toxins in more detail. Studies along this line
are currently underway in this laboratory.
The b-alanine unit in Type D is replaced by the glycine
unit in Type C.4c Therefore, starting with methyl bro-
moacetate and basically the same method as that for
Type D would afford Type C toxins. Thus, as shown in
Scheme 4, the requisite right-hand segment 20 was
obtained from 7 by a series of the reactions of Cbz
protection, alkylation with methyl bromoacetate and
hydrolysis in a high overall yield. The treatment of 20
with a similar process as that used for 18 led the Type C
toxin NPTX-501 (3)11 in a 33% overall yield from 7 via
nine steps.
Acknowledgements
Similar to Type C, the Type E polyamine backbone is
only slightly different from Type D, that is, the 1,3-dia-
minopropane (C3) unit is on the right end instead of the
putrescine (C4) unit.4d Accordingly, starting with the
We are grateful to Drs. Toshiyuki Kan (The University
of Tokyo) and Shojiro Maki (The University of Electro-
Communications) for their helpful discussions and
technical assistance. Thanks are also due to Dr. H.
Naoki (Suntory Institute for Bioorganic Research) for
the measurement of the MS spectra. This work was
supported by the grant from the State of Sao Paulo
Research Foundation (FAPESP). K.K. is a fellow from
FAPESP (proc. 1998/11693-5). M.S.P. is a researcher
for the Brazilian Council for Scientific and Technologi-
cal Development (CNPq, 500079/90-0).
References and Notes
Scheme 4. Synthesis of NPTX-501 (3). Reagents and conditions: (a)
CbzCl, Et3N/CH2Cl2, 0 ꢀC to rt, 1 h, 95%; (b) methyl bromoacetate,
Cs2CO3/DMF, 50 ꢀC, 0.5 h, 86%; (c) NaOH/H2O–MeOH, 0 ꢀC to rt,
2 h, 86%; (d) HOSu, DCC/CH2Cl2, 0 ꢀC, 4 h; (e) 8, DMF, rt, 0.5 h,
83% (two steps); (f) TFA/CHCl3, 0 ꢀC to rt, 1 h; (g) indoleacetic acid–
OSu, Et3N/DMF, rt, 2 h, 88% (two steps); (h) 2-mercaptoethanol,
DBU/DMF, rt, 0.5 h; (i) H2–Pd(OH)2/AcOH, rt, 2 h, 65% (two steps).
1. (a) For reviews, see: McCormick, K. D.; Meinwald, J. J.
Chem. Ecol. 1993, 19, 2411. (b) Schafer, A.; Benz, H.; Fiedler,
W.; Guggisberg, A.; Bienz, S.; Hesse, M. In The Alkaloids:
Chemistry and Pharmacology, Cordell, G. A., Brossi, A., Eds.;
Academic: San Diego, 1994; Vol. 45, p1. (c) Mueller, A. L.;
Roeloffs, R.; Jackson, H. In The Alkaloids: Chemistry and
Pharmacology, Cordell, G. A., Brossi, A., Eds.; Academic: San
Diego, 1995; Vol. 46, p65.
2. For leading references on the synthesis, see: (a) Saito, H.;
Yuri, E.; Miyazawa, M.; Itagaki, Y.; Nakajima, T.; Miyashita,
M. Tetrahedron Lett. 1998, 39, 6479. (b) Wang, F.; Manku, S.;
Hall, D. G. Org. Lett. 2000, 2, 1581.
3. For leading references on the SAR studies, see (a) Moe,
S. T.; Smith, D. L.; Chien, Y.; Raszkiewicz, J. L.; Artman, L.;
Mueller, A. L. Pharm. Res. 1998, 15, 31. (b) Strømgaard, K.;
Brierly, M. J.; Andersen, K.; Sløk, F. A.; Mellor, I. R.;
Usherwood, P. N. R.; Krogsgaard-Larsen, P.; Jaroszewski,
J. W. J. Med. Chem. 1999, 42, 5224. (c) Bixel, M. G.; Krauss,
M.; Liu, Y.; Bolognesi, M. L.; Rosini, M.; Mellor, I. S.;
Usherwood, P. N. R.; Melchiorre, C.; Nakanishi, K.; Hucho,
F. Eur. J. Biochem. 2000, 267, 110.
Scheme 5. Synthesis of joramine (5). Reagents and conditions: (a)
methyl acrylate/EtOH, rt, 5 h; (b) CbzCl, Et3N/CH2Cl2, 0 ꢀC to rt, 2 h,
86% (two steps); (c) NaOH/H2O–MeOH, 0 ꢀC to rt, 1 h, 85%; (d)
HOSu, DCC/CH2Cl2, 0 ꢀC, 5 h; (e) 8, DMF, rt, 0.5 h, 82% (two
steps); (f) TFA/CHCl3, 0 ꢀC to rt, 1 h; (g) O-benzyl-p-hydroxybenzoic
acid–OSu, Et3N/DMF, rt, 2 h, 88% (two steps); (h) 2-mercaptoetha-
nol, DBU/DMF, rt, 0.5 h; (i) H2–Pd(OH)2/AcOH, rt, 3 h, 69% (two
steps).
4. (a) Itagaki, Y.; Fujita, T.; Naoki, H.; Yasuhara, T.;
Andriantsiferana, M.; Nakajima, T. Nat. Toxins 1997, 5, 1. (b)