Concise, convergent syntheses of (±)-trichostatin a utilizing a Pd-catalyzed ketone enolate α-alkenylation reaction

Article abstract of DOI:10.1021/ol200964m

Two concise, convergent syntheses of (±)-trichostatin A (1), a potent histone deacetylase inhibitor, have been accomplished. The key step in both is a Pd-catalyzed α-alkenylation reaction between ketone 2 and either dienyl bromide 3 or alkenyl bromide 9 u

Full text of DOI:10.1021/ol200964m

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3564–3567
Concise, Convergent Syntheses of (()-
Trichostatin A Utilizing a Pd-Catalyzed
Ketone Enolate r-Alkenylation Reaction
Casey C. Cosner and Paul Helquist*
251 Nieuwland Science Hall, Department of Chemistry and Biochemistry, University of
Notre Dame, Notre Dame, Indiana 46556, United States
phelquis@nd.edu
Received April 12, 2011
ABSTRACT
Two concise, convergent syntheses of (()-trichostatin A (1), a potent histone deacetylase inhibitor, have been accomplished. The key step in both
is a Pd-catalyzed R-alkenylation reaction between ketone 2 and either dienyl bromide 3 or alkenyl bromide 9 using a modification of cross-
coupling conditions described by Negishi and Hartwig. A brief investigation has shown the potential utility of a Ni-catalyzed version of this
reaction. The overall synthetic routes are short and amenable to scaleup, providing access to trichostatin A via trichostatic acid as a direct
precursor.
Within the past decade, members of several protein
classes known as histone deacetylases (HDAC) have be-
come popular cellular targets for epigenetic regulation of
gene expression. Arising from these studies have been a
number of histone deacetylase inhibitors (HDACi) as
small molecule drugs. Many of these compounds have
most commonly been recognized for their remarkable
anticancer activity.1 HDACi also have potential for the
treatment of other ailments,2 including inflammatory
diseases,3 malaria,4 motor neuron diseases,5 and Niemannꢀ
Pick type C disease (NPC), a rare lipid storage disorder.6
The potential for these compounds to be useful drugs was
recently substantiated by the FDA approval of Vorinostat
(suberoylanilide hydroxamic acid, SAHA) for the treat-
ment of cutaneous T-cell lymphoma.7
Besides SAHA, several additional HDACi have been
identified, one of the most potent being (R)-(þ)-trichosta-
tin A (TSA, 1).8 Originally isolated from Streptomyces
hygroscopicus, (R)-(þ)-TSA has been reported to have a Ki
of 3.4 nM as an HDACi9 and to be active in studies of
cancer, lupus, malaria, and several other diseases.2,10 Most
recently, we have found that treating NPC cells with TSA
significantly lowered the levels of accumulated cholesterol
within the cells as a means of correcting the phenotype of
this disease.11 As our laboratory has a vested interest in the
(7) Grant, S.; Easley, C.; Kirkpatrick, P. Nat. Rev. Drug Discovery
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(8) Tsuji, N.; Kobayashi, M.; Nagashima, K.; Wakisaka, Y.; Koizumi,
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G. M. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 2628. (b) Andrews, K. T.;
Walduck, A.; Kelso, M. J.; Fairlie, D. P.; Saul, A.; Parsons, P. G.
Int. J. Parasitol. 2000, 30, 761.
(11) Pipalia, N. H.; Cosner, C. C.; Huang, A.; Chatterjee, A.;
Bourbon, P.; Farley, N.; Helquist, P.; Wiest, O.; Maxfield, F. R. Proc.
Natl. Acad. Sci. U.S.A. 2011, 108, 5620.
(12) (a) Cosner, C. C.; Markiewicz, J. T.; Bourbon, P.; Mariani, C. J.;
Wiest, O.; Rujoi, M.; Rosenbaum, A. I.; Huang, A. Y.; Maxfield, F. R.;
Helquist, P. J. Med. Chem. 2009, 52, 6494. (b) Rosenbaum, A. I.; Cosner,
C. C.; Mariani, C. J.; Maxfield, F. R.; Wiest, O.; Helquist, P. J. Med.
Chem. 2010, 53, 5281.
(1) (a) Johnstone, R. W. Nat. Rev. Drug Discovery 2002, 1, 287. (b)
Marks, P. A.; Rifkind, R. A.; Richon, V. M.; Breslow, R.; Miller, T.;
Kelly, W. K. Nat. Rev. Cancer 2001, 1, 194.
(2) Wiech, N. L.; Fisher, J. F.; Helquist, P.; Wiest, O. Curr. Top. Med.
Chem. 2009, 9, 257.
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Targets 2010, 11, 1449. (b) Halili, M. A.; Andrews, M. R.; Sweet, M. J.;
Fairlie, D. P Curr. Top. Med. Chem. 2009, 9, 309.
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r
10.1021/ol200964m
Published on Web 06/21/2011
2011 American Chemical Society

development of NPC therapeutics,12 we became interested
in the synthesis of TSA for further study as a potential
NPC treatment.
high functional group tolerance of organozinc reagents, we
decided to utilize zinc enolates in our studies.
The synthesis of the coupling components 2 and 3 on
multigram scales commenced with the addition of EtMgBr
to commercially available 4-(dimethylamino)benzaldehyde
(4) to furnish alcohol 5 in 98% yield (Scheme 2). The
subsequent oxidation was conducted using a new
Mn(OAc)3/catalytic DDQ oxidation protocol to furnish
ketone 2 in 91% yield.18 Dienyl bromide 3a containing a
methyl ester was synthesized in a single operation from the
known alkenyl bromide 619 using a one-pot oxidation/
Wittig protocol in 98% yield.20 Hydrolysis of the methyl
ester (NaOH) and re-esterification (p-methoxybenzyl al-
cohol, EDC) also provided facile access to the PMB ester
3b to allow for greater flexibility in removal of the ester
group in later stages of the synthesis.
TSA has been prepared a number of times,13 but some of
the previous syntheses are long or low-yielding. In aneffort
to combat this issue, our group recently reported two
distinct routes,14 including the shortest synthesis of TSA
to date.14b This latter route provided access to substantial
quantities of material for biological evaluation; however,
the starting materials are costly, and many of the reagents
are difficult to handle, making scaleup difficult. To over-
come these problems, we sought to devise a more effective
route to (()-TSA. We now wish to report our third and
significantly improved strategy for the synthesis of this
compound.
We quickly found efficient cross-coupling conditions
employing LiTMP and ZnCl2 to generate the zinc enolate
of ketone 2 followed by reaction with bromide 3a or 3b,
Pd(dba)2, and 1,10-bis(di-tert-butylphosphino)ferrocene
Scheme 1. Retrosynthetic Analysis of (()-TSA (1)
Scheme 2. Synthesis of Ketone 2 and Alkenyl Bromides 3a and
3b
In designing our synthesis of trichostatin A, we envi-
saged a key bond connection between C(5) and C(6) and
sought to accomplish this bond formation via a transition-
metal-catalyzed R-alkenylation reaction between ketone 2
and dienylhalide 3 (Scheme 1). While many R-alkenylation
examples have been reported in the literature,15 few have
been conducted intermolecularly.16 Furthermore, because
isomerization of the resulting β,γ-unsaturated product is a
potential problem, the use of mild conditions to conduct
this reaction is necessary for this approach to be viable.
Recently, zinc enolates have been shown to be effective in
related R-arylation reactions.17 Given the mild nature and
(dtbpf) to give the desired 7a or 7b in 73% or 82% yield,
respectively, with complete retention of diene configura-
tion and regiochemistry (eqs 1 and 2). The coupling is
very ligand-dependent and gave the best results with
electron-rich, sterically demanding alkyl phosphines.
Q-phos (employed by Hartwig in related reactions17a) and
t-Bu3P also promote the coupling but in lower yield than
dtbpf, whereas several phenylphosphines give greatly in-
ferior results. As a control, the reaction fails in the absence
of Pd. Furthermore, isomerization of the resulting
(13) (a) Fleming, I.; Iqbal, J.; Krebs, E. -P. Tetrahedron 1983, 39, 841.
(b) Mori, K.; Koseki, K. Tetrahedron 1988, 44, 6013. (c) Zhang, S.;
Duan, W.; Wang, W. Adv. Synth. Catal. 2006, 348, 1228.
€
(14) (a) Markiewicz, J. T.; Schauer, D. J.; Lofstedt, J.; Corden, S. J.;
Wiest, O.; Helquist, P. J. Org. Chem. 2010, 75, 2061. (b) Chatterjee, A.;
Richer, J.; Hulett, T.; Iska, V. B. R.; Wiest, O.; Helquist, P. Org. Lett.
2010, 12, 832.
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(15) (a) Piers, E.; Marais, P. J. Org. Chem. 1990, 55, 3454. (b) Sole,
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(16) For examples of transition-metal-catalyzed intermolecular
R-alkenylations, see: (a) Fauvarque, J.; Jutand, A. J. Organomet. Chem.
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1981, 209, 109. (b) Chieffi, A.; Kamikawa, K.; Ahman, J.; Fox, J. M.;
Buchwald, S. L. Org. Lett. 2001, 3, 1897. (c) Huang, J.; Bunel, E.; Faul,
M. M. Org. Lett. 2007, 9, 4343. (d) Taylor, A. M.; Altman, R. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900.
(17) (a) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 4976. (b) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F.
J. Am. Chem. Soc. 2003, 125, 11176. (c) Hlavinka, M. L.; Hagadorn,
J. R. Organometallics 2007, 26, 4105. (d) Hlavinka, M. L.; Hagadorn,
J. R. Tetrahedron Lett. 2006, 47, 5049. (e) Duez, S.; Bernhardt, S.;
Heppekausen, J.; Fleming, F. F.; Knochel, P. Org. Lett. 2011, 13, 1690.
(18) Cosner, C. C.; Cabrera, P. J.; Byrd, K. M.; Thomas, A. M. A.;
Helquist, P. Org. Lett. 2011, 13, 2071.
(19) (a) Handa, M.; Scheidt, K. A.; Bossart, M.; Zheng, N.; Roush,
W. R. J. Org. Chem. 2008, 73, 1031. (b) Nicolaou, K. C.; Fylaktakidou,
K. C.; Monenschein, H.; Li, Y.; Weyershausen, B.; Mitchell, H. J.; Wei,
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Org. Lett., Vol. 13, No. 14, 2011
3565

cross-coupled products was never observed under these
conditions.
To our delight, subjection of this material to the condi-
tions of the R-alkenylation provided the desired cross-
coupled product 10 in 92% yield after purification with
complete retention of the double bond configurations
(Scheme 4). Inspired by a report from Paterson’s group,22
we sought to conduct a one-pot deprotectionꢀoxidation
sequence to convert 10 into the corresponding aldehyde
using DDQ as the oxidant. While the protocol did fur-
nish the desired aldehyde, it was contaminated with an
N-dealkylated byproduct that was difficult to remove from
the desired product. This problem was overcome by again
employing the new catalytic DDQ/Mn(OAc)3 protocol.18
Under these conditions, the desired aldehyde 11 was
isolated in 85% yield and was completely free of the
N-dealkylated byproduct. The oxidation to the carboxylic
acid was troublesome.23 Although Pinnick oxidations are
typically very clean with little to no byproducts, very
For the next step of the synthesis of TSA, conventional
hydrolysis of the methyl ester 7a with metal hydroxides to
form trichostatic acid (8) was not possible, due to the
sensitivity of this system to basic conditions. Alternative
methods (LiI, NaCN, KOTMS) led to the recovery of
starting material or degradation of material. On the other
hand, the TSA core is stable toward many acidic condi-
tions, which permitted us to cleave the PMB ester 7b with
TFA and Et3SiH, furnishing (()-8 in 96% yield (Scheme 3).
Conversion into (()-TSA (1) was accomplished in 72%
yield by treatment with ethyl chloroformate and O-TBS
hydroxylamine followed by immediate deprotection with
Scheme 4. Synthesis of (()-TSA Using Alkenyl Bromide 9
Scheme 3. Synthesis of (()-TSA from Ester 7b
electron-rich aromatic rings are often chlorinated, even
in the presence of a large excess of chlorine scavengers
such as 2-methyl-2-butene. Indeed, this side reaction
was a problem for us, as we routinely obtained 30%
ꢀ45% of chlorinated material. Even employing DMSO
as the solvent did not completely prevent chlorination
of the substrate.24 However, addition of 1,3,5-tri-
methoxybenzene as an additional scavenger prevented
chlorination of our substrate25 and allowed us to obtain
8 cleanly in 72% yield after purification. The final step
was the installation of the hydroxmate, which we
accomplished in the same manner as that shown in
Scheme 3.
CsF.14b We find H2NOTBS to be particularly useful as an
easily prepared and readily handled, storable solid reagent.21
Having accomplished a very efficient synthesis of TSA,
webrieflyexaminedtherangeofalkenylhalidesthatwould
be useful in this same manifold, including the possibility of
extending the R-alkenylation to alkenyl bromides related
to 3 that do not possess an activating carbonyl group. To
assess this idea and to apply it toward the synthesis of TSA,
we prepared alkenyl bromide 9 in 91% yield over two steps
by LiAlH4 reduction of ester 3aand protection ofthe crude
alcohol with TBSCl (eq 3).
(23) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
(24) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
(25) Lindren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
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(21) Apfel, C; Banner, D. W.; Bur, D.; Dietz, M.; Hirata, T.;
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Hubschwerlen, C.; Locher, H.; Page, M. G. P.; Pirson, W.; Rosse, G.;
Specklin, J.-L. J. Med. Chem. 2000, 43, 2324.
(22) Paterson, I.; Woodrow, M. D.; Cowden, C. J. Tetrahedron Lett.
1998, 39, 6041.
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4713.
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Org. Lett., Vol. 13, No. 14, 2011

We next examined the use of the known nonconjugated
alkenyl bromide 12a26 or iodide 12b.27 Applying our
standard conditions (LiTMP, ZnCl2, Pd(dba)2, and
dtbpf) to the cross-coupling with ketone 2, we found
that bromide 12a suffered from low conversion, even
with the extended reaction times. In contrast, iodide
12b underwent smooth reaction to give the desired
product 13 in 88% yield (eq 4).
the possibility of the reaction being promoted by trace
quantities of another metal as a contaminant in the Ni
catalyst. Further work in these regards is currently underway.
In conclusion, we have developed two new concise,
scaleable routes for the production of (()-trichostatin A.
The key step in each is a Pd-catalyzed cross-coupling
between a zinc enolate and an alkenyl or dienyl halide,
resulting in the desired β,γ-unsaturated ketone. Other notable
features of the synthesis include use of a new catalytic
oxidation procedure at two points in the route and the
preliminary indication of Ni as a potentially useful and far
less expensive catalyst for the critical coupling reaction. We
are currently applying these routes to the synthesis of a variety
of TSA analogues. Further exploration of the cross-coupling
reaction is underway, particularly with the use of chiral ligands
for enantioselective applications such as the natural (þ)-TSA
and improvements in the use of Ni catalysts. The results of
these additional studies will be reported in due course.
We have also attempted to conduct the R-alkenylation
reaction using Ni(cod)2 as a less expensive catalyst. For
both the R-alkenylation and R-arylation reactions,
there are significantly fewer precedents for employing
Ni rather than Pd.16a,28 Most of our attempts with
Ni(cod)2 were disappointing; conversions of starting
material and isolated yields were often extremely low.
The most promising result was obtained when we
employed Ni(cod)2 with ketone 2 and alkenyl bromide
12a whereby the desired product 13 was obtained in
34% yield (eq 5). In this case, Q-phos outperformed dtbpf.
This result indicates that if further optimization is possible,
Ni has the potential to be an effective catalyst for the R-
alkenylation reaction. At this point, we are unable to rule out
Acknowledgment. Acknowledgment is made to the Ara
Parseghian Medical Research Foundation (APMRF), the
National Science Foundation, and the donors of the
American Chemical Society Petroleum Research Fund
for support of this research. C.C.C. is the recipient of the
J. Peter Grace Fellowship from the University of Notre
Dame. We gratefully acknowledge Dr. Douglas Schauer
(Ivy Tech Community College) and Dr. Anamitra Chat-
terjee (Notre Dame) for valuable discussions.
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Supporting Information Available. Detailed experimen-
tal procedures, copies of 1Hand13C NMR spectra, and char-
acterization data for all compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
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