Preparation of a psammaplysene-based library

Article abstract of DOI:10.1021/ol061599w

(Chemical Equation Presented) A 28-member focused library, based on the pseudosymmetric template of the marine alkaloids psammaplysenes, was prepared from combinations of components that were, in turn, derived from 4-iodophenol.

Full text of DOI:10.1021/ol061599w

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4251-4254
Preparation of a Psammaplysene-Based
Library
Savvas N. Georgiades and Jon Clardy*
Department of Biological Chemistry and Molecular Pharmacology, HarVard Medical
School, Boston, Massachusetts 02115
jon_clardy@hms.harVard.edu
Received June 29, 2006
ABSTRACT
A 28-member focused library, based on the pseudosymmetric template of the marine alkaloids psammaplysenes, was prepared from combinations
of components that were, in turn, derived from 4-iodophenol.
Synthetic libraries based on natural product templates have
emerged as important sources of structurally diverse small-
molecule probes of biological function.1 In this spirit, we
have extended our work on psammaplysenes A and B (Figure
1a), two closely related pseudosymmetric bromotyrosine-
derived alkaloids, originally isolated from the marine sponge
Psammaplysilla sp.2 They were initially identified in a high-
throughput screen as inhibitors of FOXO1a nuclear export
in cells with PTEN loss-of-function mutations.3 By interact-
ing with a still unknown target in the PI3K/PTEN/Akt
signaling pathway, they enhance the nuclear localization of
the FOXO1a transcriptional regulator and, in effect, coun-
teract inappropriate PI3K-generated stimulatory signals that
arise due to the deficiency of tumor suppressor phosphatase
PTEN. Because of the possible implications of modulating
this pathway and the limited supply of material from sponge
collections, we recently developed an efficient synthesis of
these two compounds4 in a way that could readily accom-
modate the synthesis of analogues and probes, especially a
focused library that would help define structure-activity
relationships.
As was the case for psammaplysenes A and B (Figure
1a), we set off to prepare a pool of acid and amine building
blocks that could be combined to provide a number of
analogues (Figure 1b). Variations of the original synthetic
pathway that led from a common starting material, 4-iodo-
phenol, to the two nonidentical halves of these pseudosym-
metric molecules were used to assemble a 28-member
collection of psammaplysene analogues, described herein.
The compounds we elected to prepare bear a single modi-
fication compared to the most potent of the original
structures, psammaplysene A (IC50 ) 5 µM).
(1) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem., Int. Ed.
2002, 41, 2879.
(2) Schroeder, F. C.; Kau, T. R.; Silver, P. A.; Clardy, J. J. Nat. Prod.
2005, 68, 574.
(3) Kau, T. R.; Schroeder, F.; Ramaswamy, S.; Wojciechowski, C. L.;
Zhao, J. J.; Roberts, T. M.; Clardy, J.; Sellers, W. R.; Silver, P. A. Cancer
Cell 2003, 4, 463.
The first set of building blocks comprises acids with
alternative halogen ring substituents. A variety of aromatic
(4) Georgiades, S. N.; Clardy, J. Org. Lett. 2005, 7, 4091.
10.1021/ol061599w CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/23/2006

toluene, respectively, in the presence of catalytic di-iso-
butylamine.7 The unsubstituted counterpart, 4-iodophenol,
was used directly in the next step. O-Alkylation of 1-5 with
1-chloro-3-(dimethylamino)-propane hydrochloride in CH3-
CN, in the presence of Cs2CO3 and catalytic NaI, led to
intermediate iodides 6a-10a, respectively. These were
subsequently converted to the corresponding methyl esters
6b-10b via a Heck reaction with methyl acrylate in DMF,
by means of a Pd(OAc)2/Bu4NBr/KOAc system.8 The esters
were hydrolyzed with KOH in MeOH/H2O to give zwitter-
ionic acids 6c-10c.9
Another set of acid building blocks was chosen to have
the same ring substitution as the natural product but variable
chain lengths and different tertiary amine heads (Scheme 2).
Scheme 2
Figure 1. Main retrosynthetic disconnection for the original
psammaplysenes and each library member.
electrophilic substitution conditions on 4-iodophenol (1) led
to compounds 2-5 (Scheme 1). Dibrominated phenol 2, a
Scheme 1
The 4-fold difference in IC50 values between psammaply-
senes A and B3 indicates some sensitivity at this site.
Precursor 2 was alkylated with chlorides of chain lengths k
) 2-3 and different alkyl substituents on the nitrogen,
including rings, to yield compounds 11a-18a. In most cases
where bulky substituents increased the steric requirement, a
shorter chain was used to offset this effect. A few large
substituents were used together with a longer chain to give
a sense of the steric limits. Heck reaction, followed by ester
hydrolysis, gave acids 11c-18c.
precursor to the natural products, was prepared using 2 equiv
of N-bromo-tert-butylamine in 1,2-dichlorobenzene.5,6 Mono-
brominated phenol 3 was obtained using 1 equiv of Br2 in
MeOH. The dichlorinated and monochlorinated compounds,
4 and 5, were formed using 1 and 2 equiv of SO2Cl2 in
The trans double bond in psammaplysenes constitutes a
distinguishing feature compared to other alkaloids of the
(7) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 1995, 36, 3893.
(8) Jeffery, T. Tetrahedron 1996, 52, 10113.
(9) Significant shifts downfield for the peaks corresponding to the methyl
and methylene protons on carbons directly attached to the nitrogens of the
acid building blocks suggest that the tertiary amines are protonated.
Therefore, the building blocks must be overall zwitterionic, given that they
are prepared and isolated in nonacidic conditions. Such pH-dependent shifts
are expected for strongly basic systems.
t
(5) For the preparation of BuNHBr, see: Boozer, C. E.; Moncrief, J.
W. J. Org. Chem. 1962, 27, 623.
(6) For ortho-directed bromination of unsubstituted phenol with tBuNHBr,
see: Jpn. Kokai Tokkyo Koho, 09291053, November 11, 1997, Heisei.
4252
Org. Lett., Vol. 8, No. 19, 2006

same family. Because its significance is unknown, building
blocks were prepared in which it was replaced by a triple or
a single bond (Scheme 3). By carrying out a zinc-mediated
Scheme 4
Scheme 3
Negishi cross-coupling10 with methyl propiolate and Pd-
(PPh3)4 in TEA on 7a instead of a Heck reaction with methyl
acrylate, we obtained triple-bond-containing ester 19b, which
by nature is more linear than its analogue, 7b. To obtain a
compound with higher flexibility, 7b was reduced under
microwave-assisted conditions with formic acid/TEA/
Wilkinson’s catalyst in DMSO.11 The fully saturated coun-
terpart, 20b, was obtained in good yield after 30 s at 150
°C. Both 19b and 20b gave the corresponding acids after
ester hydrolysis.
Primary amines 21e-26e were obtained as their dihydro-
chloride salts via Boc deprotection with HCl in dioxane.15
The net reductive amination of aryl bromoacetylides to
saturated phenethylamine systems provided the means for
preparing amine building blocks with various amine heads,
other than dimethyl (Scheme 5). Four examples were tried.
The pseudosymmetric psammaplysene skeleton allows the
use of the same key precursors, 1-5, as the starting point
for forming primary amine building blocks. Amines bearing
various halogen substitution patterns were first prepared
(Scheme 4). O-Alkylation of 1-5 with N-Boc-3-bromopro-
pylamine afforded intermediates 21a-25a. By treating only
2 with N-Boc-2-bromoethylamine, we prepared one single
building block with a shorter central linker (26a, m ) 2).
Iodides 21a-26a were submitted to standard Sonogashira12
cross-coupling with alkynyl-trimethylsilane to form TMS-
protected alkynes 21b-26b in excellent yields. A highly
efficient silver-catalyzed desilylative bromination with NBS
in acetone13 converted the latter to bromoacetylides 21c-
26c. Aminolysis with dimethylamine in THF/CH3CN, fol-
lowed by reduction with NaBH4 in MeOH, led to amines
21d-26d. In the aminolysis reaction, the dihalogenated
precursors appeared considerably more reactive than their
monohalogenated and nonhalogenated counterparts,14 sug-
gesting the reaction is sensitive to stereoelectronic factors.
Scheme 5
Key: aThis amine was used as the HCl salt, and an equimolar
amount of TEA was added to the reaction mixture. bA mixed THF/
CH3CN solvent was used in this case.
(10) Anastasia, L.; Negishi, E.-I. Org. Lett. 2001, 3, 3111.
(11) Our method was a modification of the one described in: Desai, B.;
Danks, T. N. Tetrahedron Lett. 2001, 42, 5963.
(12) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467.
(13) (a) Bowles, D. M.; Anthony, J. E. Org. Lett. 2000, 2, 85. (b) Tobe,
Y.; Nakagawa, N.; Kishi, J. Y.; Sonoda, M.; Naemura, K.; Wakabayashi,
T.; Shida, T.; Achiba, Y. Tetrahedron 2001, 57, 3629. (c) Tobe, Y.; Utsumi,
N.; Nagano, A.; Sonoda, M.; Naemura, K. Tetrahedron 2001, 57, 8075.
(14) Our stock of 21d was supplemented by an independent pathway,
alkylation of commercially available hordenine sulfate with N-Boc-3-
bromopropylamine (50% yield), to compensate for the low yield obtained
in the reductive aminolysis.
Interestingly, the reaction proceeds not only for acyclic
secondary amines but also for strained cyclic secondary
amines and for primary amines, even though in the last case,
(15) Han, G.; Tamaki, M.; Hruby, V. J. J. Pept. Res. 2001, 58, 338.
Org. Lett., Vol. 8, No. 19, 2006
4253

of iodide 22a to propargyl dimethylamine afforded 34d. This
was reduced under microwave-assisted conditions developed
above to give fully saturated 35d (n ) 3). Both compounds
were converted to the free amines after Boc removal.
Amide coupling, using diethyl phosphocyanidate with TEA
in THF, generated 28 new compounds, resulting from
combining all the different acid building blocks with the
primary amine eastern half of psammaplysene A, 22e, or
combining all the different amine building blocks with the
acid western half of psammaplysene A, 7c (Scheme 8).
Scheme 6
Scheme 8 a
not surprisingly, the yield is considerably lower. In all cases,
LC-MS analysis suggested that the intermediates were
ynamines or reversible bisamino adducts, in accord with our
previous observations.4
The scope of the amine addition reaction was further
studied to include examples where the amine was added in
mixtures with other nucleophiles (Scheme 6). If dimethyl-
amine was added to 22c as a 1:1 mixture with H2O, an adduct
was formed that tautomerized to amide 31d, in accord with
a previous report.16 This amide was successfully converted
to the corresponding thioamide (32d) with Lawesson’s
reagent in toluene.17 Upon addition of a 1:1 dimethylamine/
NH3 mixture to 22c, mixed aryl acetimidamide 33d was
obtained. Compounds 31d-33d were deprotected to the free
amines 31e-33e without any observed degradation.
a
Key: Yields for final products were determined by LC-MS prior
to purification. (Yields for all intermediates as shown in previous
schemes are isolated yields.)
In conclusion, a focused library of psammaplysene-like
molecules has been prepared in solution by combining
building blocks that derive via divergent pathways from a
common precursor, 4-iodophenol. This library will be
screened in diverse biological assays.
Scheme 7
Acknowledgment. We gratefully acknowledge the NIH
for funding of this project (CA24487 to J.C.). We thank Dr.
Masaki Fujita of HMS for assistance with purifications of
final products, Dr. Greg Heffron of the HMS NMR Facility
for assistance with 2D NMR, and Dr. Ralph Mazitschek of
the Broad Institute for inspiring discussions.
Finally, amine building blocks with a longer terminal
linker were prepared (Scheme 7). A Sonogashira coupling
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) Huh, D. H.; Jeong, J. S.; Lee, H. B.; Ryu, H.; Kim, Y. G.
Tetrahedron 2002, 58, 9925.
(17) Raucher, S.; Klein, P. Tetrahedron Lett. 1980, 21, 4061.
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