J. Am. Chem. Soc. 1996, 118, 1569-1570
1569
Scheme 1
Antimony-Templated Macrolactamization of
Tetraamino Esters. Facile Synthesis of Macrocyclic
Spermine Alkaloids, (()-Buchnerine, (()-Verbacine,
(()-Verbaskine, and (()-Verbascenine
Kazuaki Ishihara, Yoshichika Kuroki, Naoyuki Hanaki,
Suguru Ohara, and Hisashi Yamamoto*
School of Engineering, Nagoya UniVersity
Furo-cho, Chikusa, Nagoya 464-01, Japan
Selected results in macrocyclization of tetraamino esters are
listed in Table 1. Although tris(dimethylamino)borane was
previously found to be effective for the cyclization of triamino
esters giving 13-membered lactams (e.g., entry 6),2 no lactams
were obtained in the cyclization of 2c (entry 2).5 Among several
other organometallic reagents for the cyclization of tetraamino
esters 2a-c to 17-membered lactams 1a-c screened, we found
antimony(III) ethoxide to be quite effective (entries 3-5). A
solution of the ester 2a in dry, freshly distilled benzene was
treated with antimony(III) ethoxide (1.2 equiv) in benzene at
reflux for 14 h. Upon solvent removal in Vacuo the crude
product was directly chromatographed on silica gel to give the
pure lactam 1a in 76% yield (entry 5); this was homogeneous
ReceiVed October 23, 1995
The macrocyclic lactams containing the biogenetic base
spermine are of particular interest as synthetic targets for the
organic chemist in view of the broad activity which has been
established for spermine-containing compounds in biological
systems and because of the structural complexity of the
molecules themselves.1 We have been interested in the pos-
sibility of metal-templated cyclization of spermine derivatives
which would result in the direct formation of large-ring alkaloids
with amino groups at the positions where they are normally
formed in natural products.2 It was previously reported by
Kimura et al. that the one-pot macrocyclization of tetramines
with R,â-unsaturated esters slowly proceeds under reflux
conditions in methanol, usually, for 2 or 3 weeks to afford the
corresponding macrolactam in a moderate yield.3 Unfortunately,
they failed in an attempt to synthesize macrocyclic spermine
alkaloids using a similar manner and almost no cyclization
reaction occurred.3g Reported herein is a new synthetic strategy
in which the key reaction of synthetic planning is a macrocy-
clization of long open chains with R- and ω-functional groups,
taking advantage of an antimony-template effect.
(()-Buchnerine (1a) is an attractive target for our present
synthesis. This was isolated in 1993 by Lumbu and Hootele´
from Clerodendrum buchneri (Verbenaceae)4 and is character-
ized by the presence of a 17-membered ring reflecting spermine
and 4-methoxycinnamoyl precursory units. The synthetic design
was based on a strategy which can be summarized as follows
(Scheme 1): (1) A linear tetraamino ester such as 2a was
envisaged as an ideal progenitor of macrocyclic spermine
skeleton 1a. (2) Spermine (3), which is commercially available,
could be provided as a basic unit in 1a. (3) A 17-membered
ring of 1a could be elaborated Via the metal-templated cycliza-
tion of 2a.
1
by TLC, with IR, H NMR, and mass spectra in accord with
the assigned structure.4 Since none of the polymerization or
regioisomeric product was formed, the isolation of the lactam
was simple. Although titanium(IV) ethoxide and zirconium-
(IV) isopropoxide were somewhat effective reagents (19% and
23% from 2c, respectively), most of the tetraamino esters were
decomposed to spermine and R,â-unsaturated ester by â-elim-
ination.
The novel regioselective macrolactamization of tetraamino
esters 2a-c derived from spermine 3 with antimony(III)
ethoxide can be ascribed to the metal template effect. Interest-
ingly, antimony(III) ethoxide did not provide satisfactory results
in the cyclization of triamino ester 5 derived from spermidine
(entries 7 and 8). These results suggest that antimony(III) ion
is a rather suitable size as a metal template of a 17-membered
spermine macrolactam. Thus, the possible intermediates
4a-c generated by transamination of antimony(III) ethoxide
could reasonably be expected to undergo a facile, sterically
driven cyclization to 1a-c.6,7 Nevertheless, we cannot ex-
clude the possibility of a simple intramolecular hydrophilic
interaction of tetraamino esters in a nonpolar solvent such as
benzene.
The starting tetraamino ester 2a was prepared in 61% overall
yield by Michael addition of spermine 3 to ethyl 3-(4-
methoxyphenyl)propiolate8 and hydrogenation of the enamino
group over platinum oxide in the presence of CHCl3.9 2b was
also prepared in the same manner. On the other hand, 2c could
be directly prepared in 70% yield by Michael addition of
spermine 3 to ethyl acrylate.
The present cyclization process provided crucial information
leading to an unusually concise synthesis of other macrocyclic
spermine alkaloids, (()-verbacine (7),10 (()-verbaskine (8),10,11
and (()-verbascenine (9),10,12 from a common intermediate 1b
(Scheme 2).
(1) Reviews: (a) Bachrach, U. Function of Naturally Occurring
Polyamines; Academic Press: New York, 1973. (b) Hesse, M.; Schmid,
H. Macrocyclic Spermidine and Spermine Alkaloids. In International ReView
of Science, Series II, Vol. 9; Hey, H. D., Wiesner, K., Eds.; Butterworth:
London, 1976; p 265. (c) Badawi, M. M.; Bernauer, K.; Van den Broek,
P.; Groger, D.; Guggisberg, A.; Johne, S.; Kompis, I.; Schneider, F.; Veith,
H.-J.; Hesse, M.; Schmid, H. Pure Appl. Chem. 1973, 33, 81.
(2) We previously described that the use of boron-templated cyclization
of triamino esters with tris(dimethylamino)borane is highly efficient as a
key step in the total synthesis of macrocyclic spermidine alkaloids containing
13 members. (a) Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc. 1981,
103, 6133. (b) Ishihara, K.; Kuroki, Y.; Yamamoto, H. Synlett 1995, 41.
(3) (a) Machida, R.; Kimura, E.; Kodama, M. Inorg. Chem. 1983, 22,
2055. (b) Kimura, E.; Machida, R.; Kodama, M. J. Am. Chem. Soc. 1984,
106, 5497. (c) Kimura, E.; Koike, T.; Takahashi, M. J. Chem. Soc., Chem.
Commun. 1985, 385. (d) Kimura, E.; Koike, T.; Nada, H.; Iitaka, Y. J.
Chem. Soc., Chem. Commun. 1986, 1322. (e) Kimura, E.; Yamaoka, M.;
Morioka, M.; Koike, T. Inorg. Chem. 1986, 25, 3883. (f) Kimura, E.;
Shionoya, M.; Mita, T.; Iitaka, Y. J. Chem. Soc., Chem. Commun. 1987,
1712. (g) Kimura, E.; Koike, T.; Uenishi, K.; Hediger, M.; Kuramoto, M.;
Joko, S.; Arai, Y.; Kodama, M.; Iitaka, Y. Inorg. Chem. 1987, 26, 2975.
(h) Kimura, E.; Joko, S.; Koike, T.; Kodama, M. J. Am. Chem. Soc. 1987,
109, 5528. (i) Kodama, M.; Anan, H.; Koike, T.; Kimura, E. Bull. Chem.
Soc. Jpn. 1989, 62, 4044. (j) Kimura, E.; Kotake, T.; Koike, M.; Shionoya,
M.; Shiro, M. Inorg. Chem. 1990, 29, 4991. (k) Kimura, E.; Koike, T.;
Shiota, T.; Iitaka, Y. Inorg. Chem. 1990, 29, 4621. (l) Kimura, E.; Shionoya,
M.; Shiro, M. Inorg. Chem. 1991, 30, 4524.
(5) Tris(dimethylamino)borane, which has a tendency to form a tridentate
complex, was not appropriate for a macrolactamization of tetraamino esters.
(6) It has been known that triorganoantimony(III) compounds have a
strong tendency to form multidentate complexes. Thayer, J. S. Organome-
tallic Chemistry; VCH Publishers, Inc.: New York, 1988; p 56.
(7) It has been known that treatment of Sb(NMe2)3 with CH3CO2Et at
room temperature leads in a smooth reaction to Sb(OEt)3 and CH3CONMe2.
Krommes, P.; Lorberth, J. J. Organomet. Chem. 1975, 97, 59.
(8) Sakamoto, T.; Shiga, F.; Yasuhara, A.; Uchiyama, D.; Kondo, Y.;
Yamanaka, H. Synthesis 1992, 746.
(9) Secrist, J. A., III; Louge, M. W. J. Org. Chem. 1972, 37, 335.
Palladium on charcoal is not effective for hydrogenation of the enamino
group under comparable reaction conditions.2a
(4) Lumbu, S.; Hootele´, C. J. Nat. Prod. 1993, 56, 1418.
0002-7863/96/1518-1569$12.00/0 © 1996 American Chemical Society