Synthesis of (-)-(3S)-1-(3-aminopropyl)-3-methylazacyclodecane, the structure proposed for the marine alkaloid haliclorensin

Article abstract of DOI:10.1016/S0040-4039(01)00435-X

The total synthesis of both enantiomers of the title compound has been achieved in seven steps with 19% overall yield. The synthetic diamine differs in its NMR data and optical rotation from haliclorensin, a marine alkaloid for which the same structure ha

Full text of DOI:10.1016/S0040-4039(01)00435-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3287–3289
Synthesis of (−)-(3S)-1-(3-aminopropyl)-3-methylazacyclodecane,
the structure proposed for the marine alkaloid haliclorensin
Markus R. Heinrich and Wolfgang Steglich*
Chemie Department, Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenandtstraße 5-13 (F), D-81377 Munich, Germany
Received 27 February 2001; accepted 9 March 2001
Abstract—The total synthesis of both enantiomers of the title compound has been achieved in seven steps with 19% overall yield.
The synthetic diamine differs in its NMR data and optical rotation from haliclorensin, a marine alkaloid for which the same
structure had been proposed. © 2001 Published by Elsevier Science Ltd.
Haliclorensin (1), a diamino alkaloid with an azacy-
clodecane ring, was isolated from the South African
marine sponge Haliclona tulearensis by Kashman et al.1
in 1998. The structure of the alkaloid was determined
from its spectroscopic data and the synthesis of various
model compounds. Haliclorensin forms part of the
The synthetic steps leading to 1 are depicted in Scheme
1. Condensation of 4-pentenylamine (3)4 with o-
nitrobenzenesulfonyl chloride furnished sulfonamide
4,5,6 which was converted to the protected secondary
amine 6 by reaction with the optically pure alcohol 5
under Mitsunobu conditions.7 (2S)-2-Methyl-5-hexen-
1-ol (5) was obtained in optically pure form in five steps
from commercially available methyl (2R)-3-hydroxy-2-
methylpropanoate with 73% overall yield.8
structure of halitulin (2),
a
more complex
bisquinolylpyrrole alkaloid from the same organism
that exhibits strong cytotoxic activity against mouse
leukemia cells.2
The ring-closing metathesis of diene 6 to the azacy-
cloalkene 79 was carried out under standard conditions
using the Grubbs catalyst in dry dichloromethane.10 We
observed that the formation of dimers and oligomers is
the predominant reaction, which can, however, be min-
imized by using concentrations lower than 0.5 mmol/L.
The removal of the protecting group from 7 with PhSH
and K2CO3 according to Fukuyama6 furnished the free
amine 8 that was converted to the b-aminonitrile 911 by
treatment with acrylonitrile. Hydrogenation of 9 over
Raney-Ni in MeOH saturated with NH3 yielded the
primary amine, and catalytic hydrogenation over Pd/C
in dry MeOH removed the double bond and yielded
(−)-(3S)-1-(3-aminopropyl)-3-methylazacyclodecane
(1).12 (−)-1 was obtained from the known compounds 3
and 5 in seven steps with 19% overall yield. In the same
manner (+)-1, was prepared from (2R)-2-methyl-5-
hexen-1-ol (5). Compound 1 was completely character-
ized by its spectroscopic data and the structure was
confirmed by NMR experiments (Table 1).
In order to apply our biomimetic strategy3 for the
synthesis of 3,4-diarylpyrrole alkaloids to halitulin (2)
we have prepared both enantiomers of haliclorensin (1)
and determined the stereochemistry of the (−)-form as
3S.
Unfortunately, the 13C NMR shifts of the synthetic
compound (Table 1) differ considerably from the values
given for haliclorensin1 which makes the proof of iden-
tity ambiguous.13 Furthermore, the optical rotation
Keywords: haliclorensin; alkaloids; marine metabolites; sponges; syn-
thesis; metathesis.
* Corresponding
author.
Fax:
+49-89-21807756;
e-mail:
wos@cup.uni-muenchen.de
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00435-X

3288
M. R. Heinrich, W. Steglich / Tetrahedron Letters 42 (2001) 3287–3289
Scheme 1. Reagents and conditions: (a) o-nitrobenzenesulfonyl chloride (1 equiv.), K2CO3 (1 equiv.), CH2Cl2, rt, 2.5 h. (b)
(2S)-2-Methyl-5-hexen-1-ol (1.2 equiv.), PPh3 (1 equiv.), DEAD (1 equiv.), dry THF, rt, 24 h. (c) Grubbs catalyst (0.1 equiv.),
CH2Cl2, reflux, 18 h. (d) PhSH (1.2 equiv.), K2CO3 (3 equiv.), dry DMF, rt, 1.5 h. (e) Acrylonitrile (1.1 equiv.), dry MeOH,
0°C“rt, 12 h. (f) Raney-Ni, 20 bar (290 psi) H2, NH3 satd MeOH, rt, 5 h. (g) Pd/C (10% Pd), 10 bar (145 psi) H2, dry MeOH,
rt, 12 h.
1
Table 1. 13C and H NMR data of synthetic 1 (600 MHz, DMSO-d6)
C
2
lc
H
lH (mult, J in Hz)
COSY
HMBC (H“C)
60.5
2a
2b
3
4a
4b
5a
5b
6
7a
7b
8a
8b
9a
9b
10a
10b
11
1%a
1%b
2%
2.31 (dd, J=12.5, 12.1)
2.06 (m)
1.87 (m)
1.53 (m)
1.30 (m)
1.81 (m)
1.35 (m)
1.36 (m)
1.74 (m)
1.36 (m)
1.53 (m)
1.44 (m)
1.63 (m)
2b, 3
2a, 3
2a, 2b, 4a, 11
3, 4b, 5b
4a
3, 4, 10, 11, 1%
3, 4, 10, 11, 1%
2, 4, 5, 11
2, 3, 5, 6, 11
5, 6
3
4
29.6
31.8
5
21.9
6
7
26.3
24.4
8
24.1
25.6
53.0
6
7
9
9b, 10a, 10b
9a, 10a, 10b
9a, 9b, 10b
9a, 9b, 10a
3
1%b, 2%
1%a, 2%
1%a, 1%b, 3%
2%
1.35 (m)
10
2.68 (ddd, J=13.2, 10.6, 4.0)
2.15 (ddd, J=13.2, 4.7, 4.4)
0.77 (d, J=6.8)
2.50 (m)
2.07 (m)
1.50 (quin, J=7.2)
2.54 (m)
2, 8, 9, 1%
2, 8, 9, 1%
2, 3, 4
2, 10, 2%, 3%
2, 10, 2%, 3%
1%, 3%
11
1%
19.5
52.6
2%
3%
31.0
40.5
3%
1%, 2%
given for the natural product {[h]2D0 −2.2 (c 1.3,
MeOH)} is much lower than that of synthetic (−)-1
{[h]D −70 (c 0.9, MeOH)}.
References
1. Koren-Goldshlager, G.; Kashman, Y.; Schleyer, M. J.
Nat. Prod. 1998, 61, 282–284.
2. Kashman, Y.; Koren-Goldshlager, G.; Gravalos, M. D.
G.; Schleyer, M. Tetrahedron Lett. 1999, 40, 997–1000.
3. Heim, A.; Terpin, A.; Steglich, W. Angew. Chem. 1997,
109, 158–159; Angew. Chem., Int. Ed. Engl. 1997, 36,
155–156.
Acknowledgements
We thank the Fonds der Chemischen Industrie for
financial support and Mrs. Sabine Voß for technical
assistance.
4. (a) Frank, K. E.; Aube, J. J. Org. Chem. 2000, 65,
655–666; (b) Toshimitsu, A.; Terao, K.; Uemura, S. J.

M. R. Heinrich, W. Steglich / Tetrahedron Letters 42 (2001) 3287–3289
3289
Org. Chem. 1986, 51, 1724–1729.
5. Beckwith, A. L. J.; Meijs, G. F. J. Org. Chem. 1987, 52,
1922–1930.
6. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373–6374.
123.8, 128.5, 129.9, 131.0, 131.1, 131.9, 133.5, 149.0.
HRMS calcd for C16H22N2O4S (M+) 338.1300. Found
338.1300. Anal. calcd C, 56.78; H, 6.55; N, 8.28; S, 9.48.
Found C, 56.73; H, 6.51; N, 8.01; S, 9.02. [h]D −88 (c 0.9,
MeOH).
7. Xiong, Y.; Moore, H. W. J. Org. Chem. 1996, 61, 9168–
9177.
10. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413–4450; (b) Fink, B. E.; Kym, P. R.; Katzenellenbo-
gen, J. A. J. Am. Chem. Soc. 1998, 120, 4334–4344.
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39, 1514–1520.
12. Compound 1: colorless oil. (−)-1, [h]D −70 (c 0.9,
MeOH); (+)-1, [h]2D0 +71 (c 0.6, MeOH). NMR data (see
Table 1). HRMS calcd for C13H28N2 (M+) 212.2253.
Found 212.2247. GC–MS m/z (rel. int.): 212 (7, M+), 182
(6, M+−CH2NH2), 168 (100, M+−C2H4NH2), 154 (28),
140 (8), 126 (38).
8. Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.; Nomura, K.;
Yoshii, E. J. Org. Chem. 1992, 57, 2888–2902.
9. Compound 7: pale yellow solid, mp 101–103°C. 1H NMR
(600 MHz, CDCl3): l 0.82 (d, 3H, J=6.7 Hz), 1.43–1.49
(m, 1H), 1.54–1.58 (m, 2H), 1.88–1.95 (m, 2H), 1.97–2.03
(m, 1H), 2.14–2.20 (m, 1H), 2.53 (dd, 1H, J=3.6 and 13.0
Hz), 2.73–2.80 (m, 1H), 2.95–2.99 (m, 2H), 3.02 (dd, 1H,
J=4.7 and 13.0 Hz), 3.11 (ddd, 1H, J=1.7, 5.0 and 14.4
Hz), 3.42 (dd, 1H, J=9.7 and 13.1 Hz), 5.44–5.46 (m,
2H), 7.54 (dd, 1H, J=1.9 and 7.2 Hz), 7.67–7.72 (m, 2H),
7.89 (dd, 1H, J=1.9 and 7.2 Hz). 13C NMR (75.5 MHz,
CDCl3): l 20.7, 23.2, 24.7, 26.7, 27.2, 35.0, 45.5, 57.9,
13. Professor Yoel Kashman, Tel Aviv, kindly informed us
about a current re-isolation of haliclorensin which will
allow a direct comparison.
.
.