An efficient synthesis of (±)-trichostatic acid and analogues: A new route to (±)-trichostatin A

Article abstract of DOI:10.1021/ol9029116

An efficient synthesis of rac-trichostatic acid (1) and Its analogues is reported starting from a commercially available aldehyde. Further manipulations of rac-1 led to rac-trichostatin A (TSA). Construction of the desired molecular architecture entails a two-component union, achieved through an in situ hydroboration followed by a Suzuki-Miyaura coupling with 2. The requisite homopropargyl alcohol was synthesized by exploiting allenylindium chemistry. This new protocol paved the way for the synthesis of analogues of trichostatic acid and hence TSA.

Full text of DOI:10.1021/ol9029116

ORGANIC
LETTERS
2010
Vol. 12, No. 4
832-834
An Efficient Synthesis of (()-Trichostatic
Acid and Analogues: A New Route to
(()-Trichostatin A
Anamitra Chatterjee, Joshua Richer, Tyler Hulett, Vijaya Bhaskara Reddy Iska,
Olaf Wiest, and Paul Helquist*
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, UniVersity of
Notre Dame, Indiana 46556
phelquis@nd.edu
Received December 17, 2009
ABSTRACT
An efficient synthesis of rac-trichostatic acid (1) and its analogues is reported starting from a commercially available aldehyde. Further
manipulations of rac-1 led to rac-trichostatin A (TSA). Construction of the desired molecular architecture entails a two-component union,
achieved through an in situ hydroboration followed by a Suzuki-Miyaura coupling with 2. The requisite homopropargyl alcohol was synthesized
by exploiting allenylindium chemistry. This new protocol paved the way for the synthesis of analogues of trichostatic acid and hence TSA.
(R)-(+)-Trichostatic acid (1) was first isolated from the culture
fluid of Streptomyces sioyaensis and showed differentiation
inducing activity in Friend leukemia cells.1 Apart from its
biological activity, the greater importance of trichostatic acid
is that it is both a hydrolysis product of (R)-(+)-trichostatin A
(TSA)2 and an advanced precursor for its synthesis.3 (R)-(+)-
TSA is one member of a potent class of histone deacetylase
inhibitors (HDACi’s). These compounds have recently emerged
as promising therapeutic agents for treating several diseases,
including many forms of cancer.4 (R)-(+)-TSA has shown
activity in studies of several cancer cell lines, rare genetic
diseases, and malaria.5 It also has promise for ex vivo expansion
of stem cells.6 The lack of efficient synthetic procedures for
the preparation of the trichostatic acid system prompted us to
develop a general route to prepare trichostatic acid and its
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Carew, J. S.; Giles, F. J.; Nawrocki, S. T. Cancer Lett. 2008, 269, 7. (c)
Wiech, N. L.; Fisher, J. F.; Helquist, P.; Wiest, O. Curr. Top. Med. Chem.
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769. (c) Garber, K. Nat. Biotechnol. 2007, 25, 17. (d) Paris, M.; Porcelloni,
M.; Binaschi, M.; Fattori, D. J. Med. Chem. 2008, 51, 1505. (e) Andrews,
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Pakchung, A. A. H. Int. J. Biochem. Cell Biol. 2009, 41, 736.
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E.; Komoda, Y.; Shibai, H. Agric. Biol. Chem. 1985, 49, 1365.
(2) Tsuji, N.; Kobayashi, M. J. Antibiot. 1978, 31, 939.
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(b) Mori, K.; Koseki, K. Tetrahedron 1988, 44, 6013. (c) Zhang, S.; Duan,
W.; Wang, W. AdV. Synth. Catal. 2006, 348, 1228. (d) HelquistP.; Lofstedt,
J. Process for Preparing Histone Deacetylase Inhibitors and Intermediates
thereof. U.S. Patent 7,235688, June 26, 2007.
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46, 5097. (b) Vanhaecke, T.; Papeleu, P.; Elaut, G.; Rogiers, V. Curr. Med.
Chem. 2004, 11, 1629. (c) Araki, H.; Yoshinaga, K.; Boccuni, P.; Zhao,
Y.; Hoffman, R.; Mahmud, N. Blood 2007, 109, 3570.
10.1021/ol9029116  2010 American Chemical Society
Published on Web 01/27/2010

analogues.7 These compounds could then serve as direct
precursors of new HDACi’s.The synthesis of the (()-trichostatic
acid system presented here provides a shorter, more efficient
route to this series of compounds than the previous reports.
In our retrosynthetic analysis, the formation of the trichostatic
acid (1) backbone was envisaged to arise from the correspond-
ing ester, which can be assembled via Suzuki-Miyaura cross-
coupling between a vinyl bromide 2 and a vinylborane, derived
from a homopropargyl alcohol (Scheme 1). Further analysis of
Gratifyingly, a stoichiometric amount of InI and catalytic
PdCl2(dppf) furnished the desired compound 5 in excellent yield
(94%, entry 3). The poor anti/syn selectivity observed was of
no consequence in our synthesis as we planned to remove the
newly generated benzylic stereocenter in due course. Most
importantly from a general perspective, the success of this
reaction demonstrates the usefulness of this propargylation
procedure even with an electron-rich aromatic aldehyde.
Interestingly, exposure of other homologues of the mesylate,
containing an ethyl or a hydrogen moiety at the terminal
acetylene, yielded the corresponding homopropargyl alcohols
(6 and 7) as precursors of trichostatic acid analogues in comparable
yields and diastereoselectivities (Table 1, entries 4 and 5).
Scheme 1. Retrosynthetic Analysis of (()-TSA
Having prepared the rac-homopropargylic alcohol 5 in
good yield, the free alcohol was protected as a methyl ether
under solvolytic condition to provide 8 in excellent yield
(90%) (Scheme 2). Following a similar protocol as described
Scheme 2. Synthesis of rac-Trichostatic Acid and TSA
this advanced intermediate revealed a convergent approach,
whereby the corresponding aldehyde can be coupled with a
propargyl mesylate, using allenylmetal chemistry as described
by Marshall et al.8
Aromatic aldehydes have rarely been documented as sub-
strates in the Marshall allenylmetal chemistry.8b We expected
electron-rich aromatic aldehydes, as would be implemented in
a trichostatic acid system, to be especially challenging substrates.
In initial model studies (Table 1), using an allenylzinc reagent,
Table 1. Preparation of Homopropargylic Alcoholsa
by Roush et al.,9 in a one-pot procedure, hydroboration was
performed using diisopinocampheylborane. After completion,
the reaction was quenched with MeOH followed by a
sequential addition of the coupling partner 2, Pd catalyst,
and TlOEt at room temperature to furnish the desired coupled
product 9 (81%) as a single isomer (E,E). Hydrolysis of the
ester was effected using a 0.5 M aqueous solution of LiOH
to provide the free acid 10 in quantitative yield. The crude
acid 10 was subjected to oxidation without further purifica-
tion using DDQ to provide rac-trichostatic acid (1) (94%).
Next, we turned our attention toward the preparation of a
variety of analogues7 of trichostatic acid (1) using the modified
propargylation product 6 and 7. The choice of analogues was
based upon the consideration of the multiple hydrophobic
regions present in the 11 Å channel of histone deacetylase-like
protein (HDLP) complex of TSA as revealed by X-ray
crystallographic analysis (Figure 1).10 Among several amino
isolated
entry product
R
R′
method yield (%) anti/synb
1
2
3
4
5
3
4
5
6
7
H
Me
Me
A
A
B
B
B
40
48
94
86
80
56/44
54/46
48/52
44/56
52/48
NO2
Me2N Me
Me2N Et
Me2N
H
a Method A: Pd(OAc)2, PPh3, Et2Zn, THF, -78 °C to rt, 1 h. Method
B: PdCl2(dppf) (5 mol %), InI, THF-HMPA, rt, 10 min. b Determined by
1H NMR.
benzaldehyde and p-nitrobenzaldehyde functioned well as
substrates (entries 1 and 2), whereas 4-(dimethylamino)benzal-
dehyde failed to provide any product. Undeterred, we adopted
a modified protocol employing an allenylindium reagent.8a
(8) (a) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 696. For
a review, see: (b) Marshall, J. A. Chem. ReV. 2000, 100, 3163.
(9) Handa, M.; Scheidt, K. A.; Bossart, M.; Zheng, N.; Roush, W. R. J.
Org. Chem. 2008, 73, 1031.
(7) Charrier, C.; Roche, J.; Gesson, J.-P.; Bertrand, P. J. Chem Sci. 2009,
121, 471.
Org. Lett., Vol. 12, No. 4, 2010
833

Scheme 3. Synthesis of Various Analogues of Trichostatic Acid
16 and 17 with Ipc2BH was again regioselective, and Suzuki
coupling with 2 furnished the unsaturated esters 19 and 20 as
single E,E isomers in moderate yields. Hydrolysis of the esters
followed by DDQ oxidation of 22 and 23 provided the
corresponding rac-trichostatic acid derivatives 12 and 13 in 30%
and 26% overall yields, respectively. All the compounds in this
series can potentially be converted into hydroxamic acid
derivatives (which we have already confirmed in the conversion
of (()-trichostatic acid itself to provide rac-TSA; see the
Supporting Information) or to alternative Zn-binding analogues.
In conclusion, we have developed a cost-effective and
scalable route for the preparation of rac-trichostatic acid and
analogues starting from a commercially available aromatic
aldehyde by a shorter route and in higher yields (overall 61%
for 1) than the previous reports.3 Minor modifications of our
route led for the first time to the ethyl (11), benzyl (12) and
phenyl (13) analogues of rac-trichostatic acid. An enanti-
oselective version of this route is currently being studied in
our laboratory. The modified route and the HDACi activities
of the analogues will be reported in due course.
Figure 1. (Top) X-ray structure (yellow) and the best docked
structures (green) of the HDLP-TSA complex.11
acid residues, we were particularly interested in the two parallel
phenyl groups of residues Phe141 and Phe198 near the middle
of the channel that leads to the active site.11 In order to take
advantage of these aromatic groups to increase favorable
interactions with analogues, we planned to replace the C-4
methyl group present in trichostatic acid with an ethyl, benzyl,
or phenyl group. The stronger binding of these analogues to
the active site may be expected to reduce the need for
incorporating the hydroxamic acid group of TSA. Short
physiological lifetime and undesired side effects may be
attributed to this reactive functional group and therefore use of
alternative binding groups may be desirable.
The synthesis of the racemic C-4 ethyl analogue 11 com-
menced from compound 6 (Scheme 3). Following a protocol
similar to the previous scheme, 11 was obtained in excellent
yield (53% overall) and selectivity. For the preparation of the
racemic C-4 benzyl (12) and phenyl (13) analogues, installation
of the benzyl12 and phenyl13 groups at the terminal alkyne group
of 7 was achieved using literature procedures.Gratifyingly, the
in situ hydroboration of the protected homopropargyl alcohols
Acknowledgment. Financial support by Ara Parseghian
Medical Research Foundation, The Edison Foundation, and
Circagen are gratefully acknowledged. We would also like
to thank Dr. Norbert L. Wiech (Chromatin Therapeutics),
Dr. Jed Fisher (University of Notre Dame), Leslie Patterson
(University of Notre Dame), and John Markiewicz (Univer-
sity of Notre Dame) for assistance and valuable discussions.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) Finnin, M. S.; Donigian, J. R.; Cohen, A.; Richon, V. M.; Rifkind,
R. A.; Marks, P. A.; Breslow, R.; Pavletich, N. P. Nature 1999, 401, 188.
(11) Wang, D.-F.; Wiest, O.; Helquist, P.; Lan-Hargest, H.-Y.; Wiech,
N. L. J. Med. Chem. 2004, 47, 3409.
(12) Larsen, C. H.; Anderson, K. W.; Tundel, R. E.; Buchwald, S. L.
Synlett 2006, 2941.
(13) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905.
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