A versatile approach to β-amyloid fibril-binding compounds exploiting the shirakawa/hayashi protocol for trans-alkene synthesis

Article abstract of DOI:10.1021/ol8029593

Application of the Sonogashira coupling reaction followed by a trans-selective alkyne reduction proved highly adaptable for the efficient synthesis of a class of β-amyloid fibril binding compounds possessing a styrylbenzene motif such as FSB, an FSB dimer

Full text of DOI:10.1021/ol8029593

ORGANIC
LETTERS
2009
Vol. 11, No. 4
999-1002
A Versatile Approach to ꢀ-Amyloid
Fibril-Binding Compounds Exploiting the
Shirakawa/Hayashi Protocol for
trans-Alkene Synthesis
Tri H. V. Huynh, Mette Louise H. Mantel, Katrine Mikkelsen, Anders T. Lindhardt,
Niels Chr. Nielsen, Daniel Otzen, and Troels Skrydstrup*
Center for Insoluble Protein Structures, Interdisciplinary Nanoscience Center, Aarhus
UniVersity, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
Received December 23, 2008
ABSTRACT
Application of the Sonogashira coupling reaction followed by a trans-selective alkyne reduction proved highly adaptable for the efficient
synthesis of a class of ꢀ-amyloid fibril binding compounds possessing a styrylbenzene motif such as FSB, an FSB dimer, and 19F-BAY94-9172.
In recent years, there has been high interest for the develop-
ment of imaging agents for ꢀ-amyloid plaque detection as a
diagnostic tool for Alzheimer’s disease (AD).1 The ability
to visually detect Alzheimer’s plaques is vital for preclinical
and clinical drug development programs focused on the
treatment of this dementia disease.2,3 Positron emission
tomography (PET) and magnetic resonance imaging (MRI)
represent viable detection techniques for plaque identification
via the exploitation of specifically isotope-labeled fibril-
binding compounds. A promising class of such binders are
the styrylbenzene derivatives as illustrated in Scheme 1, such
as (E,E)-1-fluoro-2,5-bis(3-carboxy-4-hydroxystyryl)benzene
(FSB)3b-d and (E)-4-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-
styryl)-N-methylaniline (BAY94-9172), the latter of which
has entered phase II clinical studies as an AD detection agent
for PET studies.4
We have recently reported on a short synthesis of FSB
exploiting the Mizoroki-Heck reaction as a key assembly
step for the bis-styrylbenzene construction.5 Although FSB
was produced in an overall yield of 34%, we felt the synthesis
(1) For some recent reviews, see: (a) Selkoe, D. J. Nat. Biotechnol. 2000,
18, 823. (b) Hardy, J. J. Alzheimers Dis. 2006, 9, 151. (c) Goedert, M.;
Spillantini, M. G. Science 2006, 314, 777.
(4) (a) Halford, B. Chem. Eng. News 2008, 86, 13. (b) Rowe, C. C.;
Ackerman, U.; Browne, W.; Mulligan, R.; Pike, K. L.; O’Keefe, G.; Tochon-
Danguy, H.; Chan, G.; Berlangieri, S. U.; Jones, G.; Dickinson-Rowe, K. L.;
Kung, H. P.; Zhang, W.; Kung, M. P.; Skovronsky, D.; Dyrks, T.; Holl,
G.; Krause, S.; Friebe, M.; Lehman, L.; Lindemann, S.; Dinkelborg, L. M.;
Masters, C. L.; Villemange, V. L. Lancet. Neurol. 2008, 7, 129. (c) Chandra,
R.; Oya, S.; Kung, M.-P.; Hou, C.; Jin, L.-W.; Kung, H. F. J. Med. Chem.
2007, 50, 2415. (d) Zhanga, W.; Oyaa, S.; Kunga, M.-P.; Houa, C.; Maierc,
D. L.; Kunga, H. F. Nucl. Med. Biol. 2005, 32, 799.
(2) Qu, W.; Kung, M.-P.; Hou, C.; Oya, S.; Kung, H. F. J. Med. Chem.
2007, 50, 3380, and references cited therein
.
(3) (a) Skovronsky, D. M.; Zhang, B.; Kung, M.-P.; Kung, H. F.;
Trojanowski, J. Q.; Lee, V. M.-Y. Proc. Natl. Acad. Sci. U.S.A. 2000, 97,
7609. (b) Sato, K.; Higuchi, M.; Iwata, N.; Saito, T. C.; Sasamoto, K. Eur.
J. Med. Chem. 2004, 39, 573. (c) Higuchi, M.; Iwata, N.; Matsuba, Y.;
Sato, K.; Sasamoto, K.; Saido, T. C. Nat. Neurosci. 2005, 8, 527. (d)
Masuda, M.; Suzuki, N.; Taniguchi, S.; Oikawa, T.; Nonaka, T.; Iwatsubo,
(5) Mantel, M. L. H.; Søbjerg, L. S.; Huynh, T. H. V.; Ebran, J.-P.;
Lindhardt, A. T.; Nielsen, N. C.; Skrydstrup, T. J. Org. Chem. 2008, 73,
3570.
T.; Hisanaga, S.-i.; Goedert, M.; Hasewaga, M. Biochemistry 2006, 45, 6085
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10.1021/ol8029593 CCC: $40.75
Published on Web 01/22/2009
2009 American Chemical Society

Scheme 1. ꢀ-Amyloid Fibril-Binding Compounds
could be improved as well as modified to be flexible enough
to allow for the introduction of alternative isotope labeling.
In this paper, we demonstrate a highly effective synthesis
of FSB, an FSB dimer, and BAY94-9172 through a common
assembly strategy (Scheme 1) exploiting a sequence of
Sonogashira coupling steps and an ensuing stereoselective
alkyne reduction to the corresponding trans-alkene with
water as the hydrogen source.
any of the potential cis isomers. Although the original
Shirakawa/Hayashi protocol called for 1.5 equiv of
Me3SiSiMe3 and 2.5 equiv of H2O, the simultaneous reduc-
tion of the two acetylenes required 5 equiv of the disilane
Scheme 2. Synthesis of FSB
To evaluate the efficiency of the Sonogashira/reduction
protocol for the installation of the trans-alkene functionalities
in the fibril-binding compounds, this approach was first tested
on the synthesis of FSB as shown in Scheme 2.
Coupling of 1,4-dibromo-2-fluorobenzene with TMS-
acetylene exploiting traditional Sonogashira coupling condi-
tions provided the bis-acetylene 1 in near-quantitative yield.6
Liberation of the acetylenes to 2 was accomplished with
potassium carbonate in methanol (94%),7 which was fol-
lowed by a second Sonogashira double coupling with the
acetal derivative of 4-iodosalicylic acid 3 providing com-
pound 4 in 84% yield.
For the stereoselective reduction of the disubstituted
alkynes to the trans-olefins, we examined a recently reported
method by Shirakawa and Hayashi.8 In this protocol, the
reduction is catalyzed by a Pd(II) source in the presence of
hexamethyldisilane and remarkably with H2O as the hydro-
gen source. This reduction step performed admirably with 4
providing the protected FSB 5 in 82% yield with no sign of
(6) For some references on the Sonogashira reaction, see: (a) Sono-
gashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467. (b)
Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107, 874. (c) Sasaki, T.; Morin,
J.-F.; Lu, M.; Tour, J. M. Tetrahedron Lett. 2007, 48, 5817. (d) Yi, C.;
Hua, R. J. Org. Chem. 2006, 71, 2535. (e) Ko¨llhofer, A.; Pullmann, T.;
Plenio, H. Angew. Chem., Int. Ed. 2003, 42, 1056, and references therein.
(7) Price, D. W.; Dirk, S. M.; Maya, F.; Tour, J. M. Tetrahedron 2003,
59, 2497.
(8) Shirakawa, E.; Otsuka, H.; Hayashi, T. Chem. Commun. 2005, 5885.
1000
Org. Lett., Vol. 11, No. 4, 2009

Scheme 3. Synthesis of FSB Dimer
and 20 equiv of water for effective reduction. More
importantly, the method is sufficiently flexible to allow for
the preparation of the corresponding tetradeuterated deriva-
tive of 6 by simply replacing water with D2O. Undoubtedly,
this approach would also represent a viable method for the
facile introduction of tritium in such compounds.
The synthesis of the FSB-dimer began with 4-iodosalicylic
acid, which was easily converted to the mesylate 7 in two
steps. Pd-catalyzed coupling with TMS-acetylene provided
in nearly quantitative yield the terminal alkyne 8 after a
desilylation step. Subsequent Sonogashira coupling with
4-chloro-2-fluoro-1-iodobenzene provided the diaryl acety-
lene 9 in a 92% yield. This compound could in turn be
subjected to a third Sonogashira coupling with the acetylene
10 prepared from the salicylic acid derivative 3 in two steps.
More demanding coupling conditions were required in this
case due to the need of an aryl chloride, but the use of
Buchwald’s conditions performed well providing the di-
acetylene 11 in a 77% yield.9 Application of the alkyne
reduction step again proved effective (86% yield), leading
to the protected FSB derivative. Longer reaction time (24
h) and 30 equiv of H2O were nevertheless required for
obtaining a high yield of the bis-styrylbenzene.
Finally, a quantitative deprotection of 5 under basic
conditions provided FSB in an overall yield of 63% for the
five steps. This synthetic route to FSB is a substantial
improvement of other reported syntheses of FSB.3b,5
In work directed toward the investigation of FSB’s binding
selectivity with ꢀ-amyloid fibrils, we became interested in
developing an approach to access FSB dimers constructed
around a poly(ethylene glycol) spacer of varying lengths such
as the one depicted in Scheme 1. These compounds could
be exploited in binding studies with the fibril structure as a
means of determining distances between FSB binding sites.
Although a synthetic route based on the above FSB synthesis
could be applied, it nevertheless requires that the two aryl
hydroxyl groups are distinguished for selective functional-
ization. This in turn necessitates two sequential Sonogashira
couplings in order to introduce the two functionally different
salicylic acid derivatives to the central aromatic core. An
example of a synthesis of an FSB dimer with a diethylene
glycol linker is illustrated in Scheme 3.
The final steps in the synthesis of the FSB dimer initially
require a selective deprotection of one of the two phenolic
hydroxy groups. Gratifyingly, this could be accomplished
by means of short treatment with 1.5 equiv of LHMDS in
THF for 10 min at 0 °C, selectively removing the mesyl
group in a satisfactory 87% yield to give 12.10 To conclude,
2 equiv of the phenol 12 were reacted with the ditosylate 13
in the presence of potassium carbonate affording the protected
FSB dimer 14, which was quantitatively deprotected leading
Org. Lett., Vol. 11, No. 4, 2009
1001

to the isolation of the target compound as a yellow solid in a
good 37% overall yield from the mesylate 7.
was obtained from 4-iodophenol in three steps.4c The Pd-
catalyzed coupling step with commercially available 4-ethy-
nyl aniline proceeded as expected, leading to the diarylalkyne
16, which was reductively methylated and protected as its
Fmoc derivative 17 before the reduction step. Again, this
reduction performed efficiently leading to the stilbene
derivative, which was Fmoc-deprotected using DBU in
dichloromethane completing the short synthesis of 19F-
BAY94-9172.
To further evaluate the usefulness of the Sonogashira/
reduction protocol as a viable approach to accessing this class
of ꢀ-amyloid fibril-binding compounds, we turned our
attention toward the synthesis of 19F-BAY94-9172. As
illustrated in Scheme 4, this synthesis began with 15, which
Scheme 4.
Synthesis of 19F-BAY94-9172
In conclusion, we have successfully applied a Sonogashira
coupling reaction combined with a stereoselective alkyne
reduction as a viable approach to an important class of fibril-
binding compounds. Furthermore, as exemplified in the
synthesis of FSB, this synthetic route also allows for the
simple and multiple introduction of deuterium labeling.
Further work is now in progress through a combination of
isothermal calorimetry and solution- and solid-phase NMR
studies to understand the binding interactions of such
compounds with ꢀ-amyloid fibrils, the results of which can
lead to the development of even more potent and selective
fibril binders.
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foun-
dation, the Carlsberg Foundation, the OChem and iNANO
Graduate Schools, and the University of Aarhus.
Supporting Information Available: Experimental details
1
and copies of H NMR and 13C NMR spectra for new and
selected coupling products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL8029593
(9) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993.
(10) LHMDS proved superior compared to LDA where the latter also
removed the acetal protection group.
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Org. Lett., Vol. 11, No. 4, 2009