Lithium and proton templated ω-polyazamacrolactamization, new general routes to macrocyclic polyamines

Article abstract of DOI:10.1016/S0040-4039(02)01660-X

A general, lithium templated/catalyzed ω-polyazamacrolactamization method for the synthesis of macrocyclic polyamines including spermidine and spermine alkaloids is presented. The formation of 12-, 13-, 16-, 17-, and 19-membered N₃, N₄, N₅, and N₆ containing rings is described. A proton templated/catalyzed macrolactamization of some ω-polyazaaminoesters is also observed.

Full text of DOI:10.1016/S0040-4039(02)01660-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7213–7216
Lithium and proton templated v-polyazamacrolactamization,
new general routes to macrocyclic polyamines
Konstantin Drandarov and Manfred Hesse*
Organisch-chemisches Institut der Universit a¨ t Z u¨ rich, Winterthurerstrasse 190, CH-8057 Z u¨ rich, Switzerland
Received 5 July 2002; revised 6 August 2002; accepted 8 August 2002
Abstract—A general, lithium templated/catalyzed v-polyazamacrolactamization method for the synthesis of macrocyclic
polyamines including spermidine and spermine alkaloids is presented. The formation of 12-, 13-, 16-, 17-, and 19-membered N ,
3
N , N , and N containing rings is described. A proton templated/catalyzed macrolactamization of some v-polyazaaminoesters is
4
5
6
also observed. © 2002 Elsevier Science Ltd. All rights reserved.
The macrocyclic polyamines (azacrowns) are of great
importance for the supramolecular, bioorganic, and
medicinal chemistry. Depending on the ring size and
the number of N-atoms their polyaza cavities possess
remarkable receptor selectivity for protons, metal
mony templated for the spermine (N ) alkaloids
4
5c,d,6
protoverbine (18) and buchnerine (20).
In order to find a convenient procedure, suitable for the
preparation of differently sized polyazamacrolactams,
we recognized lithium halides as potential template
agents and catalysts for v-polyazamacrolactamization.
This expectation appeared from the facts that: (a) LiBr
1
a
cations, and anions. The spermidine and spermine
polyazamacrolactam alkaloids (13–16, 18–21, and their
derivatives) are naturally occurring azacrowns. The
receptor/ligand properties of these compounds signifi-
7
catalyzes the ester aminolysis and (b) in aprotic sol-
1b
vents lithium halides form stabile chelate complexes
cantly contribute to their diverse biological activity.
8
with polyamines. Thus, we could expect that in proper
dilution in aprotic solvents a,v-polyaminoesters of the
type 5–10 (Scheme 1) would form with lithium halides
transition chelates kept by a central polycoordinated
Several methods for synthesis of macrocyclic
polyamines have been described. The Richman–Atkins2
alkylative ring closure of linear N,N%-bistosylamides
and the ‘Zip-reaction’ (lactam N-aminoalkylation, fol-
lowed by acid- or base-catalyzed intramolecular
transamidative ring expansion) have been frequently
used for this purpose.
+
Li atom, which approximates the reacting a,v-func-
tionalities of the molecule and additionally coordinat-
ing/activating the ester CꢀO group could promote a
ring closure by intramolecular aminolysis to the corre-
3
sponding macrolactams (as shown for the N -a,v-
3
aminoester 9b, Scheme 1).
A number of polyazamacrolactams have been prepared
by statistical one-pot Michael addition–v-macrolac-
tamization by several weeks reflux of polyamines with
+
In accordance with the expected template role of Li for
4
the arrangement of the intermediate chelate, the pres-
ence of the interchain N-atoms, their number, and
presumably the distance between them should be cru-
cial for the formation of the macrocycles. In this order,
by aza-Michael addition of several polyamines (4a–g),
including spermidine (4c,d) and spermine (4e), to the
sterically hindered a,b-unsaturated acid esters 1–3, were
a,b-unsaturated Me-esters in MeOH. Usually this
method leads to low yields of the macrocycle and
1a,4
complex mixture of by-products.
Remarkable results
have been reached using size adapted metal templated
v-macrolactamizaton methods, a boron templated for
the syntheses of the spermidine (N ) alkaloids celacin-
3
5
a,e
5b,d
nine (14)
and dihydroperiphylline (16),
and anti-
9
prepared the differently sized N , N , N , and N
3
4
5
6
aminoesters 5e, 6a–g, and 7e, which were transformed
10
by transesterification to their Me-homologues 8e, 9a–
g, and 10e. Compounds 8e, 9a–g, and 10e were used in
the next macrolactamization step. The results of this
reaction, summarized in Table 1, are in excellent agree-
ment with our preliminary expectations.
Keywords: spermidine; spermine; polyazamacrolactam alkaloids;
lithium template; proton template.
*
Corresponding author. Fax: +1-635-68-12; e-mail: mtbohley@
oci.unizh.ch
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01660-X

7
214
K. Drandaro6, M. Hesse / Tetrahedron Letters 43 (2002) 7213–7216
Scheme 1.
1
1a
11b
Thus, in the presence of LiI (10 equiv.) for 48 h at
procedure the larger N (8e, 9e, and 10e), N (9f), and
6
4
5
7
5°C, the N compound 9b (0.01 M solution in MeCN)
N (9g) Me-aminoesters were smoothly converted to the
3
was converted to the 12-membered N -macrolactam 12
corresponding N 17-membered (17, 18, and 20), N
3
4
5
1
1c
in 62% yield.
Similarly, the spermidine (N ) Me-
16-membered (22), and N 19-membered (23) polyaza-
3
6
11a
aminoesters 9c and 9d were macrolactamized to the
corresponding isomeric 13-membered N -macrocycles
3 and 15 in 55 and 50% yield. Using the same
macrolactams, respectively,
whereas the shortest
tested diethylenetriamine (N ) derived Me-aminoester
3
3
1
1
1
9a did not undergo macrolactamization to 24. Obvi-

K. Drandaro6, M. Hesse / Tetrahedron Letters 43 (2002) 7213–7216
7215
Table 1.
Michael-adduct
Yield (%)
“
Me-ester
“
Polyazamacrolactam
Yield (%)
Rf
Yield (%)
Rf
Rf
+
+
(
Li method)
(H method)
b
c
b
c
0.29b
5
6
6
6
6
6
6
6
7
e
a
b
45
67
65
0.35
0.72
0.29
0.31
0.25
0.55
0.67
0.49
0.58
8e
9a
9b
9c
9d
9e
9f
95
93
92
94
96
99
92
88
93
0.20
0.63
0.22
0.25
0.18
0.45
0.57
0.43
0.48
17
24
12
13
15
18
22
23
20
82
58
–
–
–
–
30
47
–
No reaction
6212c
55
50
83
74
76
85
–
0.53
0.65
0.88
0.71
0.80
0.67
c
c
b
a
a
c
c
b
c
d
e
f
24
22
a
a
c
c
b
b
b
b
b
b
b
b
b
b
56
61
53
63
b
b
g
e
9g
10e
b
–
0.70
a
Due to the unsymmetrical structure of spermidine, two isomeric Michael adducts (6c, 24%, and 6d, 22%) are formed, which corresponds to 46%
overall yield.
Silica gel, CHCl :MeOH:25% aq. NH 7:3:1.
Silica gel, CHCl :MeOH:25% aq. NH 8:2:0.2.
b
c
3
3
3
3
ously, the longer polyazahydrocarbon chains of 8e,
e–g, and 10e form less strained, i.e. more populated,
transition a,v-approximated chelates which results on
In conclusion, the here-described lithium templated v-
polyazamacrolactamization appears as a convenient,
simple, and versatile method for the synthesis of differ-
9
13
1
1f
ently functionalized polyazamacrolactams. Their fur-
higher yields of macrolactams (Table 1).
ther reduction (B H /THF as published in Ref. 4a)
2
6
allows the practical preparation of the corresponding
macrocyclic alkylpolyamines. The proton templated v-
polyazamacrolactamization should also be taken on
mind as an alternative choice for the preparation of
certain macrolactams.
Significantly different reactivity was observed for differ-
ently hindered aminoesters. Et-esters (not shown) react
much slower than the Me-esters, whereas t-Bu- and
11e
i-Pr-esters 5e, 6a–g, and 7e are nearly inert.
MeCN seems to be the best solvent for this reaction. In
4
protic solvents (MeOH) without catalyst (as published )
Acknowledgements
and with LiI the reaction leads to low yields of macro-
cycle and a number of by-products. LiBr catalyzes this
reaction similarly as LiI, whereas LiCl and NaI are
ineffective.
We thank the Swiss National Science Foundation for
the generous support. K.D. thanks the Dr. Helmut
Legerlotz-Stiftung for the financial assistance.
Surprisingly, with 1 equiv. acid (TsOH·H O) instead of
2
LiI in MeCN for 48 h at 75°C the N Me-aminoesters
References
4
8
e, 9e, and the N 9f (0.01 M solution) also undergo
5
11d
1
. (a) Kimura, E. Tetrahedron 1992, 48, 6175; (b) Bienz, S.;
Detterbeck, R.; Ensch, C.; Guggisberg, A.; H a¨ usermann,
U.; Meisterhans, C.; Wendt, B.; Werner, C.; Hesse, M. In
Putrescine, Spermidine, Spermine, and Related Polyamine
Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 2002; Vol. 58, in press.
macrolactamization.
Presumably, in this case the
intermediate a,v-approximated transition conformation
of the open chain aminoester is kept by a polycoordi-
nated central proton, shared between all N-atoms, sim-
ilarly to 11 (Scheme 1), which is an example of proton
template effect. Unfortunately, due to the specific
structures, containing b-aminoester fragment, the H -
1
2
+
2. (a) Richman, J. E.; Atkins, T. J. J. Am. Chem. Soc. 1974,
6, 2268; (b) Vriesema, B. K.; Buter, J.; Kellogg, R. M. J.
9
templated/catalyzed macrolactamization of the tested
aminoesters, is accompanied with significant rate of
retro-Michael reaction which results on lower yields of
the corresponding macrolactams (17, 18, 22) (Table 1).
This is more pronounced in the members with addi-
tional b-phenyl substitution (18 and 22). We could
expect that in case of a,v-polyaminoesters with a
polyamine chain attached at a- or g-position with
respect to the ester functionality the proton templated
v-polyazamacrolactamization would lead to better
Org. Chem. 1984, 49, 110; (c) Guggisberg, A.; Drandarov,
K.; Hesse, M. Helv. Chim. Acta 2000, 83, 3035; Dran-
darov, K.; Guggisberg, A.; Hesse, M. Helv. Chim. Acta
2002, 85, 979; (d) Sergeyev, S. A.; Hesse, M. Helv. Chim.
Acta 2002, 85, 161.
3
. (a) Hesse, M. Ring Enlargement in Organic Chemistry;
VCH: Weinheim; New York, 1991; (b) Matsuyama, H.;
Itoh, N.; Matsumoto, A.; Ohira, N.; Hara, K.; Yoshida,
M. J. Chem. Soc., Perkin Trans. 1 2001, 2924 and refer-
ences cited therein; (c) Begley, M. J.; Crombie, L.; Haigh,
D.; Jones, R. C. F.; Osborne, S.; Webster, R. A. B. J.
Chem. Soc., Perkin Trans. 1 1993, 2027.
+
results. Under the same (H -templated) reaction condi-
tions the N Me-aminoesters 9b–d react poorly.
3

7
216
K. Drandaro6, M. Hesse / Tetrahedron Letters 43 (2002) 7213–7216
4
. (a) Kimura, E.; Koike, T.; Takahashi, M. J. Chem. Soc.,
aminoesters perhydrochlorides 8e, 9a–e, and 10e, and
pertosylates of 9f and 9g were stirred for 0.5 h with an
amount of Amberlite IRA 400 in OH -form (strong
anionite, Fluka), corresponding to 10-fold excess of
exchange capacity, then filtered and evaporated.
Chem. Commun. 1985, 385; (b) Kimura, E.; Koike, T.;
Uenishi, K.; Hediger, M.; Kuramoto, M.; Joko, S.; Arai,
Y.; Kodama, M.; Iitaka, Y. Inorg. Chem. 1987, 26, 2975.
. (a) Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc.
®
−
5
1
981, 103, 6133; (b) Ischihara, K.; Kuroki, Y.;
11. (a) Lithium templated macrolactamization: To a 0.01 M
solution of the corresponding Me-aminoester in MeCN
Yamamoto, H. Synlett 1995, 41; (c) Ischihara, K.;
Kuroki, Y.; Hanaki, N.; Ohara, S.; Yamamoto, H. J.
Am. Chem. Soc. 1996, 118, 1569; (d) Ischihara, K.;
Kuroki, Y.; Hanaki, N.; Ohara, S.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 1998, 71, 1221; (e) For an alternative
synthetic approach to compound 13, see: McManis, J. S.;
Ganem, B. J. Org. Chem. 1980, 45, 2041.
. (−)-(S)-Protoverbine (18) and (−)-(S)-buchnerine (20)
were
procedure.
1
1b
were added 5 or 10 equiv.
of anhydrous LiI, then the
mixture was stirred at 75°C for 48 h. After evaporation of
the solvent, the residue was splashed with an aq. soln of
K CO , the mixture was heated at 70°C for 1 h, then
2
3
acidified, washed with CHCl , alkalinized with K CO ,
3
2
3
extracted five times with CHCl /i-PrOH 8:2 mixture. The
3
6
extract was evaporated and the residue purified by CC on
silica gel, eluted consecutively with MeOH to remove the
LiI and then CHCl /MeOH/25% aq. NH 8:2:0.2, 7:3:1;
prepared
recently
using
Richman–Atkins
2c
3
3
7
. Kunz, H.; Kullmann, R. Tetrahedron Lett. 1992, 33,
115.
(
b) 1 equiv. of LiI is not an effective catalyst, 5 equiv. are
6
optimal for the N , N , and N aminoesters, and 10
4
5
6
8
. (a) Raston, C. L.; Skelton, B. W.; Whitaker, C. R.;
White, A. H. J. Chem. Soc., Dalton Trans. 1988, 987; (b)
Raston, C. L.; Skelton, B. W.; Whitaker, C. R.; White,
A. H. Aust. J. Chem. 1988, 41, 1925.
. (a) Michael addition—a general procedure: The sterically
hindered i-Pr-(t-Bu)-esters were used in order to reduce
the aminolysis of the ester group. Thus, compounds 6a–g
and 7d were prepared by heating 3 equiv. of polyamine
equiv. for the N aminoesters; (c) the macrocyclization of
3
compound 9b gives together with the macrolactam 12
also about 15% of cyclodimer (R 0.85); (d) proton tem-
f
plated macrolactamization: A 0.01 M solution of the
corresponding Me-aminoester in MeCN, containing 1
9
equiv. of TsOH·H O was stirred at 75°C for 48 h. The
2
isolation of the macrocycles was carried out as mentioned
above; (e) without catalyst under the same reaction con-
ditions the Me-aminoesters are stable; (f) the spectral
9b
(
4a–g) and 1 equiv. of 2 (or 3) at 65°C for 48 h without
solvent. The reaction mixtures were diluted with CHCl3
3c
3b,5a
2d,3c,5b,5d
5c,5d
data of compounds 12, 13,
15,
17,
and separated directly by CC on silica gel by consecutive
elution with CHCl :MeOH:25% aq. NH3 8:2:0.2 then
7
were separated by CC on silica gel with
CHCl :MeOH:25% aq. NH 8:3:0.5. Compound 5e was
prepared from spermine (4e, 5 mmol) and commercially
available t-Bu acrylate (1, 5 mmol) in 20 ml MeCN for 15
h at rt. The crude material was purified by CC on silica
gel as above; (b) the commercially available (Fluka)
technical tetraethylenepentamine (4f) and pentaethylene-
hexamine (4g) were purified by recrystalization of their
perhydrochlorides from 60% aq. EtOH. TLC (silica gel,
2
c,5c,5d
2c,5c,5d,6
18,
and 20
have been described in the litera-
3
ture earlier.
:3:1. The isomeric aminoesters 6c (less retained) and 6d
1
Compound 22: colorless solid; H NMR (CDCl ): 8.13
3
(
br. t, NHCꢀO); 7.4–7.2 (m, 5 arom. H); 4.04, 4.03 (2d,
3
3
J=9.6 Hz, PhCHN); 3.6–3.45 (m, 1H, NCH); 3.45–3.25
13
(
m, 1H, NCH); 2.95–2.25 (m, 20H, NCH+NH).
C
NMR (CDCl ): 171.62 (CꢀO); 142.59 (arom. quat. C);
3
1
4
28.53, 127.17, 126.40 (arom. CH); 59.58 (PhCHN);
8.59, 48.26, 48.16, 47.94, 47.19, 46.33, 44.28, 39.12
+
(
CH ). ESI-MS: 320 ([M+H] ).
2
1
Compound 23: colorless solid; H NMR (CDCl ): 8.22
3
(
br. t, NHCꢀO); 7.4–7.2 (m, 5 arom. H); 4.01, 4.00 (2d,
2
% NaCl in 25% aq. NH ): 4f R 0.5; 4g R 0.6, detection
3 f f
J=10 Hz, PhCHN); 3.5–3.3 (m, 2H, NCH); 2.9–2.4 (m,
2
1
by potassium iodoplatinate (Schlittler’s reagent, Schlit-
tler, E.; Hohl, J. Helv. Chim. Acta 1952, 35, 29). The free
bases 4f and 4g were obtained from 4f·5HCl and 4g·6HCl
13
5H, NCH+NH). C NMR (CDCl ): 171.88 (CꢀO);
3
42.78 (arom. quat. C); 128.50, 127.15, 126.48 (arom.
−
+
CH); 59.62 (PhCHN); 48.87, 48.70, 48.61, 48.42, 48.25,
and MeO Na in MeOH.
+
4
8.03, 46.26, 44.03, 39.09 (CH ). ESI-MS: 363 ([M+H] ).
1
0. Preparation of the Me-aminoesters 8e, 9a–g, and 10e: The
perhydrochlorides of the Me-esters 8e, 9a–e, and 10e were
prepared by 15 h reflux of the perhydrochlorides of 5e,
2
1
2. The proton templated synthesis of macrocyclic Schiff
bases was reported recently: Tian, Y.; Tong, J.; Frezen,
G.; Sun, J.-Y. J. Org. Chem. 1999, 64, 1442.
6
9
a–e and 7e in MeOH/HCl and the pertosylates of 9f and
g by 15 h reflux of the perhydrochlorides of 6f and 6g in
1
3. The present method was successfully used in our labora-
tory also for the preparation of a group of compounds
similar to the polyazamacrolactams shown here (Yur-
dakul, A. et al. in preparation).
mixtures of MeOH/5 equiv. TsOH·H O and MeOH/6
equiv. TsOH·H O, respectively. For liberation of the free
bases, the MeOH solutions of the corresponding Me-
2
2