Synthesis of an L-proline modified mimetic of the A83586C antitumour cyclodepsipeptide

Article abstract of DOI:10.1039/b204018b

A mimetic of the A83586C cyclodepsipeptide has been synthesised via a three-segment coupling protocol involving dipeptides 9, 8 and 7; in contrast to our previous synthesis of A83586C, where the HATU-mediated macrolactamisation proceeded in 25% yield, the

Full text of DOI:10.1039/b204018b

Synthesis of an -proline modified mimetic of the A83586C antitumour
L
cyclodepsipeptide†
Karl J. Hale* and Linos Lazarides
The Christopher Ingold Laboratories, The Department of Chemistry, University College London, 20 Gordon
Street, London, UK WC1H 0AJ. E-mail: k.j.hale@ucl.ac.uk
Received (in Cambridge, UK) 26th April 2002, Accepted 1st July 2002
First published as an Advance Article on the web 19th July 2002
A mimetic of the A83586C cyclodepsipeptide has been
synthesised via a three-segment coupling protocol involving
dipeptides 9, 8 and 7; in contrast to our previous synthesis of
A83586C, where the HATU-mediated macrolactamisation
proceeded in 25% yield, the corresponding macro-lactamisa-
tion of seco-amino acid 18 occurred in ca. 78% yield.
unit was guided by two factors. First, cyclisation at an activated
proline residue is usually free of racemisation risk, and second,
(3S)-piperazic acid has previously functioned as a very effective
mimic of
-proline in ACE-inhibitory drugs such as cilazapril.6
L
It seemed logical, therefore, to reverse the roles for the situation
at hand.
We anticipated obtaining 4 from the chemoselective union of
53 with 6. A [2 + 2 + 2]-fragment condensation was envisaged
for constructing the linear hexadepsipeptide precursor of 6; the
A83586C1 and GE32 are exciting new anticancer agents with a
mechanism of action thought to involve the selective inhibition
of deregulated E2F transcription factors within cancer cells.2
Some time ago, we reported the first asymmetric total
synthesis of A83586C3 and its 4-epi-analogue.4 4-Epi-
A83586C has a (3R)-piperazic acid component replacing the
(3S)-Piz unit. While this modification does actually serve to
improve the yield of macrolactamisation from 25 to 70%,3,4 it
has a seriously detrimental effect on antitumour potency; the
4-epi-analogue being much less active as an antitumour drug.5
High-field NMR studies on 4-epi-A83586C4 suggest that its
C(8)-carbonyl assumes a cis-orientation relative to the C(7)-
piperazine-NH, which is opposite to A83586C, where a trans-
relationship is believed to exist between these two groupings.1
The combined experimental data suggests that significant
conformational perturbations to this region are not well
tolerated.
key ring-closure would be effected through the
termini (Scheme 1).
Dipeptide 14 (Scheme 2) was prepared from N(Z)-
L
-pro and
D
-Thr
L
-proline
(10) by amidation with tert-butyl carbazate,7 hydrogenolytic
removal of the Z-group from 11 with a Pd/C catalyst, and silver
cyanide mediated coupling8 of 12 with 13. Fmoc9 cleavage of
14 with Et2NH in acetonitrile subsequently procured amine 9.
The coupling of dipeptides 9 and 83 proceeded smoothly when
mediated by BOP-Cl10 and Et3N at low temperature for 1.5 h;
tetrapeptide 15 was isolated in 89% yield after chromatography.
Fmoc-deprotection and subsequent reaction of 16 with acid
chloride 73 under silver cyanide-assisted conditions8 furnished
the desired depsipeptide 17 in 73% yield. The Boc-protected
As part of an ongoing programme aimed at identifying a more
readily synthesised analogue of A83586C that has similar
conformational properties and improved potency, we selected
the
L
-proline-modified congener 4 as a candidate for study. Our
-proline replacement for the (3S)-piperazic acid
choice of an
L
† Electronic supplementary information (ESI) available: characterisation
data. See http://www.rsc.org/suppdata/cc/b2/b204018b/
Scheme 1 Retrosynthetic strategy for the
congener (4).
L-proline modified A83586C
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CHEM. COMMUN., 2002, 1832–1833
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Scheme 2 Synthetic route to the
L
-proline modified mimetic 6.
acyl-hydrazide of the
L
-proline residue in 17 was next converted
Notes and references
to the corresponding acid by successive treatment with TFA (to
remove the Boc groups) and N-bromosuccinimide in aqueous
THF. The latter reaction is thought to create a hydrolytically-
labile acyl diazene.11 The macrolactamisation of seco-aminoa-
cid 18 proceeded smoothly when HATU12 was used to activate
the proline residue under high-dilution conditions. The desired
macrolactam 19 was isolated in 48% overall yield for the three
steps from 17. The Troc group of 19 was now detached with Zn
in aqueous AcOH13 and compound 20 acylated with ZCl to
obtain 21. This protocol enabled 21 to be obtained highly pure
by flash chromatography prior to it being hydrogenated over Pd
on C in methanolic HCl. The latter process worked efficiently,
compound 6 being recovered in essentially quantitative yield.
Future work will attempt to chemoselectively couple 6 to the
pyran activated ester 53 to obtain 4. It is envisaged that the
solution conformation and antitumour activity of 4 will then be
determined to see how they compare with A83586C. Attempts
will also be made to exploit cyclodepsipeptide 6 for high-
throughput parallel synthesis work aimed to identifying simpli-
fied new anticancer drugs that act by an E2F inhibitory
mechanism.
1 A83586C: T. A. Smitka, J. B. Deeter, A. H. Hunt, F. P. Mertz, R. M.
Ellis, L. D. Boeck and R. C. Yao, J. Antibiot., 1988, 41, 726.
2 GE3: Y. Sakai, T. Yoshida, T. Tsujita, K. Ochiai, T. Agatsuma, Y.
Saitoh, F. Tanaka, T. Akiyama, S. Akinaga and T. Mizukami, J.
Antibiot., 1997, 50, 659.
3 For the first total synthesis of A83586C, see: K. J. Hale and J. Cai, J.
Chem. Soc. Chem. Comm, 1997, 2319.
4 Total synthesis of 4-epi-A83586C: K. J. Hale, J. Cai and G. Williams,
Synlett, 1998, 149.
5 Full details of the biological testing of 4-epi-A83586C will be reported
elsewhere along with other analogues.
6 M. R. Attwood, C. H. Hassall, A. Krohn, G. Lawton and S. Redshaw, J.
Chem. Soc., Perkin Trans. 1, 1986, 1011.
7 R. A. Boissonnas, St. Guttman and P. A. Jaquenoud, Helv. Chim. Acta,
1960, 43, 1349.
8 P. L. Durette, F. Baker, P. L. Barker, J. Boger, S. S. Bondy, M. L.
Hammond, T. J. Lanza, A. Pessolano and C. G. Caldwell, Tetrahedron
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9 L. A. Carpino and G. Y. Han, J. Org. Chem., 1972, 37, 3404.
10 R. D. Tung and D. H. Rich, J. Am. Chem. Soc., 1985, 107, 4342.
11 H. T. Cheung and E. R. Blout, J. Org. Chem., 1965, 30, 315.
12 L. A. Carpino, J. Am. Chem. Soc., 1993, 115, 4937.
13 (a) T. B. Windholz and D. B. R. Johnston, Tetrahedron Lett., 1967,
2555; (b) F. R. Pfeiffer, S. R. Cohen and J. A Weisbach, J. Org. Chem.,
1969, 34, 2795.
We would like to thank AVERT for a postgraduate
studentship and Novartis USA for additional financial sup-
port.
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