Cytotoxic alkaloids motuporamines A-C: synthesis and structural verification.

Article abstract of DOI:10.1021/ol991029e

[formula: see text] The unusual structure and biological properties of the marine alkaloids motuporamines A-C, as well as the uncertainty as to the position of the olefin within the ring of motuporamine C, led us to synthesize these compounds. The strategy utilized the ring-closing metathesis reaction to form the 14- and 15-membered rings and Michael addition and amidation chemistry to introduce the spermine-like unit. The syntheses, structure assignment verifications, and also the determination of the position of the olefin in motuporamine C are described.

Full text of DOI:10.1021/ol991029e

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1471-1473
Cytotoxic Alkaloids Motuporamines
A−C: Synthesis and Structural
Verification
William P. D. Goldring* and Larry Weiler
Department of Chemistry, UniVersity of British Columbia, 2036 Main Mall,
VancouVer, British Columbia V6T 1Z1, Canada
billg@chem.ubc.ca
Received September 8, 1999
ABSTRACT
The unusual structure and biological properties of the marine alkaloids motuporamines A−C, as well as the uncertainty as to the position of
the olefin within the ring of motuporamine C, led us to synthesize these compounds. The strategy utilized the ring-closing metathesis reaction
to form the 14- and 15-membered rings and Michael addition and amidation chemistry to introduce the spermine-like unit. The syntheses,
structure assignment verifications, and also the determination of the position of the olefin in motuporamine C are described.
The cytotoxic alkaloids motuporamines A (1), B (2), and C
(3) were recently isolated from the marine sponge Xexto-
spongia exigua (Kirkpatrick).1 Crude mixtures of motupor-
amines A-C were not readily separated. Preparation of the
diacetylated derivatives, which were easily separated by
reversed-phase HPLC, provided pure samples of diacetyl-
motuporamines A (4), B (5), and C (6). The structures of 4,
5, and 6 (Figure 1) were elucidated via analysis of spectral
it was determined to have the Z configuration. Analysis of
the NMR data obtained for 6 eliminated all of the positional
isomers except 6a and 6b.
The unusual structure and biological properties of the
motuporamines combined with the unresolved structure
ambiguity in motuporamine C led us to synthesize these
compounds. During the preparation of this manuscript the
synthesis of motuporamines A and B appeared.2 In an attempt
to resolve the structural ambiguity in motuporamine C,
compounds 6a and 6b were prepared. A general two-part
synthetic strategy involving the formation of the macrocyclic
amine in the first stage, and the formation of a spermine-
like unit from the nitrogen of this ring in the second stage
was employed in the synthesis of each compound. Recent
developments in our laboratory regarding the formation of
macrocyclic lactams via ring-closing metathesis (RCM)3 led
us to form the ring portions of 5, 6a, and 6b by this method.
The synthesis of motuporamine A (1) (Scheme 1) began
with the reduction of 2-azacyclotridecanone (7) with LAH.
The resulting macrocyclic amine was reacted with methyl
Figure 1. Motuporamines A (1), B (2), and C (3).
(1) Williams, D. E.; Lassota, P.; Andersen, R. J. J. Org. Chem. 1998,
63, 4838.
(2) Baldwin, J. E.; Vallmer, H. R.; Lee, V. Tetrahedron Lett. 1999, 40,
5401.
data. However, it was not possible to determine the position
(3) Goldring, W. P. D.; Hodder, A. S.; Weiler, L. Tetrahedron Lett. 1998,
39, 4955.
of the double bond within the macrocyclic ring of 6, although
10.1021/ol991029e CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/28/1999

Scheme 1
Scheme 3
acrylate. After removal of the solvent and excess reagent in
vacuo, the resulting â-amino ester was reacted with a 10-
fold excess of 1,3-diaminopropane.4 Evaporation of the
solvent and excess reagent in vacuo provided analytically
pure amide 8. Compound 8 was reduced with LAH to
provide motuporamine A (1) in an overall yield of 85%.
Finally, reaction of 1 with acetic anhydride in pyridine gave
diacetylmotuporamine A (4) in quantitative yield.5
chromatographic separation of the E and Z isomers,6 the Z
lactam 12a was converted into 3a, using the same sequence
of steps as in the synthesis of 1 from 7 (Scheme 1), in an
overall yield of 45%. Finally, reaction of 3a with acetic
anhydride in pyridine gave 6a in quantitative yield.
The synthesis of motuporamine B (2) (Scheme 2) began
with the hydrogenation of a mixture of 2-azacyclotetrade-
cenones (9a and 9b), independently formed by RCM,3 to
provide the saturated 14-membered lactam. The lactam was
converted into motuporamine B (2), using the same sequence
of steps as in the synthesis of 1 from 7 (Scheme 1), in an
overall yield of 75%. Finally, reaction of 2 with acetic
anhydride in pyridine gave diacetylmotuporamine B (5) in
quantitative yield.
Compound 3b was formed from 11b (Scheme 4), follow-
ing the same sequence of steps as in the synthesis of 3a from
11a (Scheme 3), in an overall yield of 44%. Finally, reaction
of 3b with acetic anhydride in pyridine gave 6b in 94% yield.
Scheme 4
Scheme 2
1
The H, 13C, COSY, HMQC, and HMBC NMR data, as
well as mass spectral data, for compounds 4 and 5 was
compared with the corresponding data reported for authentic
samples of diacetylmotuporamines A and B,1 respectively.
These comparisons allowed us to verify the structures as
assigned.
The NMR and mass spectral data for compounds 6a and
6b were compared with the corresponding data reported for
an authentic sample of diacetylmotuporamine C.1 This
comparison led us to conclude that compound 6a and the
The synthesis of 3a (Scheme 3) began with the formation
of the 15-membered lactam from diene-amide 11a via
RCM, using 5 mol % Cl2(PCy3)2RudCHPh. Following
(4) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin,
S.; Roeck, J.; Ryder, J.; Smith, P. Macromolecules 1986, 19, 2466.
(5) All new compounds were characterized by 1H and 13C NMR, IR,
and LRMS and HRMS.
(6) Morris, L. J. Chem. Ind. 1962, 1238.
Org. Lett., Vol. 1, No. 9, 1999
1472

authentic sample of diacetylmotuporamine C were identical.
Thus, the position of the double bond within the authentic
sample of motuporamine C is as it appears in 3a.
the assigned structure of each alkaloid. In addition, the
position of the double bond within motuporamine C was
determined to be in the same position as in 3a.
The synthesis of 1, 2, 3a, and 3b and their diacetylated
derivatives 4, 5, 6a, and 6b proceeded in excellent yields,
using a small number of steps, and without the use of
protective groups. The synthesis of 3a, 3b, 6a, and 6b
represents the first such synthesis of these compounds and
demonstrated the utility of ring-closing metathesis to form
15-membered lactams. The comparison of spectral data from
the synthetically prepared compounds to that of the authentic
samples of diacetylmotuporamines A-C allowed us to verify
Acknowledgment. We thank Professor R. J. Andersen
and Dr. Michael Pungente for assistance in the preparation
of this manuscript, and Dr. David E. Williams for providing
the NMR data of authentic diacetylmotuporamines A-C. We
are grateful for the financial support of the Natural Sciences
and Engineering Research Council of Canada.
OL991029E
Org. Lett., Vol. 1, No. 9, 1999
1473