Total synthesis of apratoxin A

Article abstract of DOI:10.1021/ja036050w

Apratoxin A, a cyclodepsipeptide isolated from cyanobacterial Lyngbya spp, has been synthesized. The total synthesis features stereocontrolled access to the novel polyketide and the late-stage installation of the sensitive 2,4-disubstituted thiazoline moi

Full text of DOI:10.1021/ja036050w

Published on Web 06/26/2003
Total Synthesis of Apratoxin A
Jiehao Chen and Craig J. Forsyth*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
Received May 9, 2003; E-mail: forsyth@chem.umn.edu
Scheme 1. Retrosynthetic Disconnections of Apratoxin A
Apratoxins A-C (1-3, respectively, Figure 1) are intriguing
marine natural products of mixed biogenetic origin. Isolated from
cyanobacterial Lyngbya spp. collected in Guam1 and Palau2 by
Moore, Paul, and co-workers, 1-3 are cyclodepsipeptides that
embody both polypeptide and polyketide domains. These include
highly methylated amino acids joined via proline ester and thiazoline
moieties to a novel 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid.
The R,â-unsaturated thiazoline of 1-3 derives from a modified
cysteine moiety and is sensitive toward acid-induced dehydration
leading to (E)-34,35-dehydroapratoxin A (4).2
Scheme 2. Synthesis of the Prolyl Ester-Polyketide Domain 7
Figure 1. Structures of the apratoxins.
The unique structural features of 1 are accompanied by high
levels of cytotoxicity against KB and LoVo cancer cells, with in
vitro IC50 values of 0.52 and 0.36 nM, respectively.1 However, 1
was poorly tolerated in vivo in mice. Although the mode of action
of 1 remains unknown, it appears to effect neither microtubule
polymerization dynamics nor topoisomerase I. Apratoxin C dis-
played an in vitro cytotoxicity profile similar to that of 1, but 2
and 4 were from 1 to 2 orders of magnitude less potent. These
results suggest that in vitro cytotoxicity of the apratoxins is closely
related to subtle primary structural variations that are manifested
in larger tertiary changes in molecular conformation. The small
amounts of the apratoxins available via isolation from natural
sources presently limit more in-depth biological studies.
For the total synthesis of 1, the robust proline ester was installed
early, while assembly of the sensitive thiazoline moiety was deferred
until a late stage. Methods to form the â-oxy thiazoline directly
from carboxylate and vicinal amino thiol partners are limited.
However, we found that the â-oxy thiazoline moiety could be
constructed without complication under neutral conditions using a
one-pot Staudinger reduction-intramolecular aza-Wittig (S-aW)
process that utilizes an R-azido thiolester.3 Hence, disconnection
of 1 at the isoleucine-proline amide and thiazoline moiety was
chosen to access the cyclic depsipeptide via R-azido thiolester 5
(Scheme 1). Thiolester 5 could be elaborated from triamide 6 and
polyketide-prolyl ester 7.
an R,â-unsaturated δ-valeryl lactone. Conjugate addition of a higher
order methyl cuprate7 installed the C37 methyl group in 10.
Reductive opening of the lactone and silylation of the resultant
primary alcohol gave secondary alcohol 11. The hydroxyl moiety
of 11 could be esterified efficiently with N-Boc-L-proline under
Yamaguchi conditions8 to obtain 12. The derived aldehyde 14 was
subjected to an anti-selective aldol reaction with (R)-2-benzoyloxy-
3-pentanone9 (15) to yield â-hydroxyketone 16. The tert-butyldi-
methylsilyl group was chosen for protection of the C35 hydroxyl
group of 16 to provide 17. Excision of the benzoyloxy-containing
chiral directing functionality led to the target carboxylic acid 7.
The synthesis of 7 began with acylation4 of 85 with acrylic acid
to provide diene 9 (Scheme 2). Ring-closing metathesis6 of 9 gave
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10.1021/ja036050w CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Convergent Synthesis of Apratoxin A
Triamide 6 was assembled in a C f N fashion beginning with
isoleucine derivative 18 (Scheme 3). Coupling of N-deblocked 18
with N-Boc,N-methyl-L-alanine yielded 19. Carbamate cleavage
followed by a second PyAOP-mediated condensation10 with N-
Boc,O-methyl-tyrosine gave diamide 20. To implement the key
S-aW strategy, an R-azido thiolester would be incorporated from
the latent vincinal diol in modified cysteine surrogate 21.11 Hence,
21 was joined with 20 to yield triamide 22. Thiol 6 was derived
from 22 in a stepwise fashion.12 Thiolester formation13 between 6
and 7 followed by cleavage of the C30 PMB ether and treatment
with diphenylphosphoryl azide under Mitsunobu conditions pro-
vided R-azido thiolester 27.14 Attempts to cleave the C35 TBS ether
at the ultimate step of our initial total synthesis effort were
unsuccessful,15 so the TBS group was exchanged for TES at the
stage of 27 to give 5. Thiazoline formation was then accomplished
by treating the R-azido thiolester 5 with Ph3P in THF under
anhydrous conditions to generate 28.3,16 No elimination across
C34,35 occurred, as had been observed with 4.2 The one-pot,
intramolecular S-aW conditions were uniquely successful among
alternatives explored for thiazoline formation.
Acknowledgment. This work was supported by a Bristol-Myers
Squibb Unrestricted Grant in Synthetic Organic Chemistry (C.J.F.).
We thank Drs. H. Luesch, R. E. Moore, and V. J. Paul for an
authentic sample of 1.
Supporting Information Available: Experimental procedures and
characterization data for compounds 1, 5-13, 17, and 19-32 (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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to afford the cyclic depsipeptide 32. Finally, the TES group of 32
was removed uneventfully to deliver 1, which matched an authentic
sample.11
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(11) See Supporting Information.
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The total synthesis of 1 features stereocontrolled access to the
novel polyketide domain and the late-stage installation of the
sensitive 2,4-disubstituted thiazoline moiety using an intramolecular
S-aW process. In addition to corroborating the structure of 1, this
work will enable further studies of the apratoxins and their
analogues.
(17) Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
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