Synthesis of polyamine alkaloids by the condensation of a chiral β-lactam with a cyclic imino ether. (S)-dihydroperiphylline and its derivatives

Article abstract of DOI:10.1246/cl.2000.1104

The synthesis of 13-membered polyamine alkaloid, (S)-dihydroperiphylline, was achieved by the condensation of a chiral β-lactam, (S)-4-phenyl-2-azetidinone, with a cyclic imino ether of a 9-membered lactam, followed by reductive ring expansion. Both of th

Full text of DOI:10.1246/cl.2000.1104

1104
Chemistry Letters 2000
Synthesis of Polyamine Alkaloids by the Condensation of a Chiral β-Lactam with
a Cyclic Imino Ether. (S)-Dihydroperiphylline and Its Derivatives
Haruo Matsuyama,* Ayako Kurosawa, Toshio Takei, Nahoko Ohira, Masato Yoshida, and Masahiko Iyoda*
Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397
(Received July 6, 2000; CL-000644)
The synthesis of 13-membered polyamine alkaloid, (S)-
dihydroperiphylline, was achieved by the condensation of a chi-
ral β-lactam, (S)-4-phenyl-2-azetidinone, with a cyclic imino
ether of a 9-membered lactam, followed by reductive ring
expansion. Both of these reactions proceeded with retention of
configuration around the chiral center to give the optical pure
13-membered alkaloids.
Macrocyclic lactams containing a biogenetic base such as
spermine and spermidine represent a new class of polyamine
alkaloids which have a framework of β-amino acid and are of
particular interest as synthetic targets in view of the broad bio-
logical activity, for instance as antibiotics and antihyperten-
sives.1
(S)-Dihydroperiphylline (1) is one of six alkaloids isolated
from the leaves of Peripterygia marginata by Husson et al.2
All these alkaloids contain a 13-membered ring system derived
from dicinnamoylspermidine. The total synthesis of (+)-1 was
first accomplished by Wasserman and Matsuyama in 1981.3
More recently, the enantioselective route to 1 from N-Boc-(S)-
β-phenyl-β-alanine, prepared from diethyl L-tartrate in 15 steps,
was reported by Kaseda et al.4 Yamamoto et al. reported the
synthesis of (S)-1 by the lactam cyclization reaction of a tri-
amine derivative of (S)-(–)-β-amino acid using an aminoborane
reagent.5
Asymmetric synthesis of β-amino acid derivatives using
chiral vinyl sulfoxides has proven to be useful methodology for
the synthesis of chiral compounds.6 Davis et al. reported the
enantioselective synthesis of β-amino acids by addition of an
enolate to chiral sulfinimines.7 We recently reported the conju-
gate addition reaction of 6- and 5-membered cyclic hydrazines
such as piperidazine (2) and pyrazolidine to chiral vinyl sulfox-
ides and synthesized the chiral 9- and 8-membered lactams with
high optical purity (up to 95% ee). The asymmetric syntheses
of a 13-membered lactam alkaloid, celacinnine, and an 8-mem-
bered lactam alkaloid, homaline, were accomplished by this
method.8,9
The present study provides a facile route to the synthesis of
13-membered alkaloid, (S)-dihydroperiphylline (1), starting
from (S)-4-phenyl-2-azetidinone (8). A total synthesis of 1
involves a six-step sequence by successive ring expansions of
smaller heterocyclic units. Our procedure (Schemes 1 and 2)
permits clear-cut differentiation of the two secondary amino
groups in the 13-membered lactam system by selective acyla-
tion in an early step. This method utilizes, as key steps, the
condensation of a chiral β-lactam with a cyclic imino ether of a
9-membered lactam and following reductive ring-expansion.
Both of these reaction processes proceeded with retention of
configuration around the chiral center to give an optical pure
lactam.
Piperidazine (2) was condensed with ethyl acrylate to form
7-oxo-1,6-diazabicyclo[4.3.0]nonane (3), and the N–N bond of
3 could be readily cleaved with sodium (3 equiv) in liquid
ammonia to form the amino lactam 4 (Scheme 1).3 Treatment
of 4 with trans-cinnamoyl chloride in dichloromethane in the
presence of 4-(dimethylamino)pyridine yielded 5.3 Conversion
of 5 to imino ether 6 was achieved by using Meerwein’s
–
reagent (Me3O+ BF4 ).3,10 A convenient preparation of the
desired (–)-methyl β-phenyl-β-alanate (7) was carried out
according to the reported procedure.11,12 The enantiomerically
24
24
pure β-lactam 8 ([α]D –132° (c 1.00, MeOH); lit. [α]D
–132° (c 1.0, MeOH))12 was synthesized in 50% yield by
cyclization of (–)-methyl β-phenyl-β-alanate (7) using LDA (2
equiv) in THF at –78 °C for 4 h by a modification of the reported
procedure,13 and subsequently was recrystallized from chloro-
form–hexane (Scheme 1). In the formation of the bicyclic 4-
oxotetrahydropyrimidine derivative 10 from 6, we adapted the
addition–ring expansion process in which a β-lactam reacts
with a cyclic imino ether to produce the corresponding 4-oxote-
trahydropyrimidine derivative 10.14 Thus, heating 6 with (S)-4-
phenyl-2-azetidinone (8) in chlorobenzene for 21 h yielded the
ring-enlarged product 10 (67%, [α]D25 +35.1° (c 1.70, CHCl3)),
most probably through the intermediate 9. The conversion of
10 to dihydroperiphylline (1) was accomplished in one step
(81%) by treatment with sodium cyanoborohydride (3 equiv) in
acetic acid (2 h at 25 °C, 1 h at 50 °C, 12 h at 25 °C) (Scheme
2).14 This reduction was carried out under conditions mild
enough to leave the exocyclic double bond in 10 unaffected.
The physical (mp 82–83 °C as colorless crystals), optical
([α]D25 +3.6° (c 1.00, CHCl3)), and NMR spectral data of 1 thus
25
prepared are consistent with those (mp 82.5–83.5 °C; [α]D
+3.6° (c 1.0, CHCl3)) of the reported (+)-(S)-dihydroperi-
phylline.4,5
Similarly, heating 8 with the imino ether 11 in chloroben-
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
1105
References and Notes
1
Reviews: a) U. Bachrach, “Function of Naturally Occuring
Polyamines,” Academic Press, New York (1973). b) M.
Hesse and H. Schmid, “Macrocyclic Spermidine and
Spermine Alkaloids,” from Int. Rev. Sci., ed. by H. D. Hey
and K. Wiesner, Butterworth, London (1976), Series II,
Vol. 9, p. 265. c) M. M. Badawi, K. Bernauer, P. Van den
Broek, D. Groger, A. Gueggisberg, S. Johne, I. Kompis, F.
Schneider, H.-J. Veith, M. Hesse, and H. Schmid, Pure
Appl. Chem., 33, 81 (1973). d) H. H. Wasserman and J. S.
Wu, Heterocycles, 17, 581 (1982).
2
3
A. Hocquemiller, A. Cave, and H.-P. Husson, Tetrahedron,
33, 645 (1977).
zene gave the ring-enlarged product 12 (48%, [α]D25 +10.8° (c
1.10, CHCl3)). The optical purity (100% ee) of 12 was deter-
mined by HPLC measurement using an optically active column
(Daicel Chiralpak AD). This result shows that the condensation
reaction of 8 with 11 proceeded with retention of configuration
around the chiral center. The reduction of 12 was achieved
under similar conditions to those for 10 and gave the optically
active 13-membered lactam 13 (80%, [α]D25 +11.4° (c 2.00,
CHCl3)) (Scheme 3).
H. H. Wasserman and H. Matsuyama, J. Am. Chem. Soc.,
103, 461 (1981). For other synthetic studies, see, a) R.
Hocquemiller, A. Cave, and H. -P. Husson, Tetrahedron,
33, 653 (1977). b) L. Crombie, R. C. F. Jones, and D.
Haigh, Tetrahedron Lett., 27, 5151 (1986).
T. Kaseda, T. Kikuchi, and C. Kibayashi, Tetrahedron
Lett., 30, 4539 (1989).
a) K. Ishihara, Y. Kuroki, and H. Yamamoto, Syntlett,
1995, 41. b) Y. Kuroki, K. Ishihara, N. Hanaki, S. Ohara,
and H. Yamamoto, Bull. Chem. Soc. Jpn., 71, 1221 (1998).
M. C. Carreno, Chem. Rev., 95, 1717 (1995).
4
5
6
7
F. A. Davis, R. T. Reddy, and R. E. Reddy, J. Org. Chem.,
57, 6387 (1992).
8
9
N. Itoh, H. Matsuyama, M. Yoshida, N. Kamigata, and M.
Iyoda, Heterocycles, 41, 415 (1995).
N. Itoh, H. Matsuyama, M. Yoshida, N. Kamigata, and M.
Iyoda, Bull. Chem. Soc. Jpn., 68, 3121 (1995).
10 L. A. Paquette, J. Am. Chem. Soc., 86, 4096 (1964). L. A.
Paquette and T. Kitahara, J. Am. Chem. Soc., 90, 3897
(1968).
11 The optically active amino ester 7 showed satisfactory chi-
roptical data, [α]D20 –22.5° (c 2.40, CHCl3), [α]D24 –12.9°
(neat). See, a) H. Pietsch, Tetrahedron Lett., 1972, 2789. b)
F. A. Davis, R. T. Reddy, and R. E. Reddy, J. Org. Chem.,
20
57, 6387 (1992); [α]D –20° (c 1.80, CHCl3) for (S)-7
(>95% ee). c) J. Jiang, K. K. Schumacher, M. M. Joullie,
F. A. Davis, and R. E. Reddy, Tetrahedron Lett., 35, 2121
(1994); [α]D20 +22.3° (c 1.99, CHCl3) for (R)-7 (>98% ee).
d) Y. Kuroki, K. Ishihara, N. Hanaki, S. Ohara, and H.
The condensation of 8 with the N-Cbz (Cbz =
CO2CH2C6H5) derivative 14 in chlorobenzene yielded 4-oxo-
tetrahydropyrimidine derivative 15 (84%, [α]D25 +62.9° (c 2.20,
CHCl3)). The 13-membered lactam 16 (78%, [α]D25 +5.8° (c
0.32, CHCl3); lit. [α]D25 +5.7° (c 1.0, CHCl3)) from 15 also dis-
played optical data agreement with the reported value (Scheme
3).4 In conclusion, this is the first example of 13-membered
lactam alkaloids using a chiral β-lactam as a chiral synthon,
and this method can be applicable to the synthesis of other
polyamine alkaloids containing a framework of β-amino acids.
25
Yamamoto, Bull. Chem. Soc. Jpn., 71, 1221 (1998); [α]D
–18.2° (c 1.46, CHCl3) for (S)-7 (>95% ee).
12 H. H. Wasserman and G. Berger, Tetrahedron, 39, 2459
(1983); [α]D24 –132° (c 1.0, MeOH) for (S)-8.
13 S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin
Trans. 1, 1994, 1129.
14 a) H. H. Wasserman and R. P. Robinson, Tetrahedron
Lett., 24, 3669 (1983). b) H. Matsuyama, M. Kobayashi,
and H. H. Wasserman, Heterocycles, 26, 85 (1987).
We thank the Ministry of Education, Science, Sports, and
Culture, Japan, for the Grant-in-Aid (11640542).