Evolution of concise and flexible synthetic strategies for trichostatic acid and the potent histone deacetylase inhibitor trichostatin A

Article abstract of DOI:10.1002/ejoc.201201233

(R)-(+)-Trichostatic acid and (R)-(+)-trichostatin A (TSA) are natural products that have attracted considerable attention in the field of epigenetic therapies. TSA in particular is a naturally occurring hydroxamic acid having potent activity as a histone deacetylase inhibitor (HDACi) and having significant potential for treatment of a myriad of genetically based diseases. Development of TSA and other trichostatic acid derivatives into useful small-molecule therapies has been hindered by the low natural abundance and high cost associated with these compounds. We report herein our collective efforts towards the development of concise and scalable routes for the synthesis of trichostatic acid and TSA in both racemic and enantioenriched forms. Three independent synthetic pathways were developed with varying degrees of efficiency and convergency. In the first synthesis, the key step was a vinylogous Horner-Wadsworth-Emmons condensation. A Marshall propargylation reaction was used as the key step in the second synthesis, and Pd-catalyzed α-alkenylation of a ketone zinc enolate by using various functionalized alkenyl or dienyl halides was developed for the third synthesis. The second pathway proved to be readily amenable to an enantioselective modification, and both the second and third pathways were straightforwardly adapted for the facile preparation of new analogues of trichostatic acid and TSA. Three synthetic strategies have been developed for trichostatic acid and trichostatin A. Each strategy has a different key bond-forming step; a vinylogous Horner-Wadsworth-Emmons condensation, a Marshall propargylation, and coupling of a ketone enolate with various alkenyl halides. Two of the syntheses were efficient and able to produce analogues. Two of the syntheses were enantioselective. Copyright

Full text of DOI:10.1002/ejoc.201201233

FULL PAPER
DOI: 10.1002/ejoc.201201233
Evolution of Concise and Flexible Synthetic Strategies for Trichostatic Acid
and the Potent Histone Deacetylase Inhibitor Trichostatin A
Casey C. Cosner,[a] Vijaya Bhaskara Reddy Iska,[a] Anamitra Chatterjee,[a]
John T. Markiewicz,[a] Steven J. Corden,[a] Joakim Löfstedt,[a] Tobias Ankner,[b]
Joshua Richer,[a] Tyler Hulett,[a] Douglas J. Schauer,[a] Olaf Wiest,[a,c] and Paul Helquist*[a]
Keywords: Medicinal chemistry / Natural products / Synthetic methods / Asymmetric synthesis / Enzyme inhibitors /
Histone deacetylase inhibitor
(R)-(+)-Trichostatic acid and (R)-(+)-trichostatin A (TSA) are
natural products that have attracted considerable attention
in the field of epigenetic therapies. TSA in particular is a
naturally occurring hydroxamic acid having potent activity
as a histone deacetylase inhibitor (HDACi) and having sig-
nificant potential for treatment of a myriad of genetically
based diseases. Development of TSA and other trichostatic
acid derivatives into useful small-molecule therapies has
been hindered by the low natural abundance and high cost
associated with these compounds. We report herein our col-
lective efforts towards the development of concise and scal-
able routes for the synthesis of trichostatic acid and TSA in
both racemic and enantioenriched forms. Three independent
synthetic pathways were developed with varying degrees of
efficiency and convergency. In the first synthesis, the key
step was a vinylogous Horner–Wadsworth–Emmons conden-
sation. A Marshall propargylation reaction was used as the
key step in the second synthesis, and Pd-catalyzed α-alkenyl-
ation of a ketone zinc enolate by using various functionalized
alkenyl or dienyl halides was developed for the third synthe-
sis. The second pathway proved to be readily amenable to
an enantioselective modification, and both the second and
third pathways were straightforwardly adapted for the facile
preparation of new analogues of trichostatic acid and TSA.
organelles within cells.[6] The potential for HDACi as drugs
has been substantiated by the Federal Drug Administration
approval of vorinostat (suberoylanilide hydroxamic acid,
SAHA, Zolinza™) and romidepsin (Istodax™) for the treat-
ment of cutaneous T-cell lymphoma.[7,8]
Besides vorinostat and romidepsin, a large number of ad-
ditional HDACi have been identified, one of the most po-
tent being trichostatin A (TSA, 1, Scheme 1). TSA is the
hydroxamic acid derivative of trichostatic acid (2).[9] The
latter acid is itself a naturally occurring compound, which
was first isolated from Streptomyces sioyaensis and which
was reported to induce differentiation of leukemia cells.[10]
TSA was originally isolated from Streptomyces hygro-
scopicus and was first reported to have antibacterial activity.
It was later found to have an inhibition constant, Ki, of
3.4 nM as an HDACi[11] and to be active in studies of can-
cer, lupus, malaria, and several other diseases.[2,12]
Most recently, we have found that treating human NPC
cells with TSA significantly lowered the levels of accumu-
lated cholesterol within storage organelles as a means of
correcting the phenotype of this disease.[13] As our labora-
tory has a vested interest in the development of therapeutic
agents for lysosomal storage disorders,[13,14] we became in-
terested in the synthesis of trichostatic acid, TSA, and ana-
logues for further study as potential treatments for NPC
and other members of this class of diseases.
Introduction
Within the last decade, members of several protein
classes known as histone deacetylases have become popular
cellular targets for epigenetic regulation of gene expression.
Arising from these studies have been a number of histone
deacetylase inhibitors (HDACi) that are small-molecule
drugs. These compounds have most commonly been recog-
nized for their anticancer activity.[1] HDACi also have po-
tential for the treatment of other ailments,[2] including in-
flammatory diseases,[3] malaria,[4] motor neuron dis-
eases,[5]and Niemann–Pick type-C disease (NPC). NPC is a
rare fatal lysosomal lipid storage disorder characterized by
abnormal accumulation of cholesterol and other lipids in
[a] Department of Chemistry and Biochemistry, University of
Notre Dame,
Notre Dame, Indiana 46556, U.S.A
Fax: +1-574-631-6652
E-mail: phelquis@nd.edu
Homepage: http://chemistry.nd.edu/faculty/detail/phelquis/
[b] Department of Organic Chemistry, Arrhenius Laboratory,
Stockholm University,
Stockholm, Sweden
[c] School of Chemical Biology and Biotechnology, Peking
University, Shenzhen Graduate School,
Shenzhen 518055, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201233.
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Synthetic Strategies for Trichostatic Acid and Trichostatin A
been able to obtain by using two of these routes. To set the
stage for presentation of these more recent results, we begin
with brief overviews and critical evaluations of our pre-
viously published syntheses.
Previously Published Syntheses
First-Generation Synthesis
Although each of the earlier reported syntheses of tricho-
static acid and TSA by other investigators relied on dif-
ferent strategies, many of them retained identical or at least
similar steps. The most noticeable of these steps are those
employed for the formation of the conjugated diene moiety.
This construction typically focused on a stepwise sequence
involving (1) olefination of an aldehyde by using an ester-
containing organophosphorus reagent, (2) reduction and
Scheme 1. Structures of target compounds.
Results and Discussion
Evaluation of the chemical literature reveals that several oxidation to generate an α,β-unsaturated aldehyde, and
syntheses of trichostatic acid and TSA have been re- (3) a second olefination. Although this sequence is com-
ported,[15] but some of these syntheses have been long and monly employed for diene synthesis in general, its repetitive
low yielding. To improve upon these earlier efforts, we kept nature adds a significant number of steps to a synthesis. We
the following criteria in mind to guide our planning: (1) mi- therefore initially sought to design a synthesis of trichos-
nimization of length and maximization of efficiency of any tatic acid in which this sequential construction is replaced
new routes, (2) flexibility for preparation of new analogues with a more direct approach. Our first synthesis of trichos-
for subsequent drug development efforts, and (3) amenabil- tatic acid achieved this goal by employing a condensation
ity to enantioselective synthesis. In working towards achiev- between aldehyde 3 and vinylogous HWE reagent 4 [see
ing these goals, we have developed and published initial ac- C(4)–C(5) in Scheme 2].[16]
counts of three quite diverse approaches to trichostatic acid
Aldehyde 3 was prepared by a sequence beginning with
and TSA, each with various advantages (Scheme 2). The an Evans aldol condensation[19] of commercially available
first approach utilized a vinylogous Horner–Wadsworth– 4-(dimethylamino)benzaldehyde (5) followed by straightfor-
Emmons (HWE) reaction to install the diene moiety as the ward functional group manipulations[20,21] of aldol product
key C(4)–C(5) bond-forming step.[16] The second relied on 10 (Scheme 3). The syn/anti conversion that occurred was
a Marshall propargylation reaction to form the C(6)–C(7) of no consequence because the configuration of the C(7)
bond,[17] and the third strategy was based on a Pd-catalyzed ether (trichostatic acid numbering scheme) was lost owing
α-alkenylation of an enolate to form C(5)–C(6) of the β,γ- to a later oxidation. Reaction with phosphonate 4[22] as a
unsaturated ketone moiety.[18] We now wish to report our mixture of alkene positional isomers furnished an 80%
collective findings on all three of our approaches to trichos- yield of 13 as a 2:1 mixture of E,E/E,Z dienes (Scheme 4).
tatic acid and TSA, including the evolution of our synthetic Preparative-scale separation of the isomers was unsuccess-
strategies, a newly developed enantioselective adaptation of ful, and attempts to affect double-bond isomerization by
one of the routes, and a summary of analogues that we have using standard methods failed to alter the ratio. Only after
Scheme 2. Key bond-forming strategies for three syntheses of TSA.
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Scheme 3. Synthesis of aldehyde 3.
further conversion to trichostatic acid could the diene iso- an enantioselective implementation, the low E,E/E:Z ratio
mers be separated chromatographically. This difficult sepa- of the HWE product and the difficulty in separating the
ration on a small scale resulted in a low yield of 30% of the diene isomers detracted from its efficiency and practicality.
isolated (+)-trichostatic acid (R)-2 as the correct E,E isomer
Second-Generation Synthesis
and with an ee of 87%. Although this route demonstrated
a concise approach for installation of the diene moiety of
TSA, and even though this route was directly amenable to
A quite different strategy was based upon a key bond
formation using a propargylation reaction described by
Marshall[23] [see C(6)–C(7) in Scheme 2] followed by a Su-
zuki–Miyaura coupling to construct the desired diene.[17]
Beginning again with aldehyde 5, reaction with an allenylin-
dium intermediate generated from racemic propargyl mesyl-
ate 6 provided racemic homopropargylic alcohol 15 in 94%
yield as an approximately 1:1 mixture of syn/anti dia-
stereomers (Scheme 5),[23] which again was inconsequential.
In a one-pot procedure, hydroboration of the alkyne in
homopropargyl ether 16 and Pd-catalyzed coupling of the
resulting alkenylborane with methyl (E)-3-bromometh-
acrylate provided exclusively E,E-13 in 81% isolated yield,
which marks a significant improvement over the first-gener-
ation synthesis. Subsequent steps provided racemic trichos-
tatic acid (Ϯ)-2 in 94% yield. Installation of the hydroxamic
acid group was accomplished by reaction of a mixed anhy-
Scheme 4. Completion of the first-generation of (R)-trichostatic
acid.
Scheme 5. Second-generation synthesis of (Ϯ)-TSA.
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Synthetic Strategies for Trichostatic Acid and Trichostatin A
dride with O-tert-butyldimethylsilyl (TBS) hydroxylamine for ethyl-TSA analogue 18, and 23 served as the precursor
followed by deprotection to furnish (Ϯ)-TSA (1) in 75% of hydrogen, benzyl, and phenyl analogues, 17, 19, and 20,
yield.
respectively.
The second synthesis proved to be amenable to the pro-
Third-Generation Synthesis
duction of trichostatic acid analogues whereby a range of
C(4) substituents could be introduced in place of the dienyl
methyl group in TSA (Scheme 6). The choice of analogues
was based upon analysis of the X-ray crystal structure of
the histone deacetylase-like protein complex of TSA.[24] We
chose to replace the C(4) methyl group with hydrogen (17)
as a point of comparison and most importantly with ethyl
(18), benzyl (19), and phenyl (20) groups to take advantage
of their interactions within the 11 Å binding channel. As
starting points for the synthesis of the desired analogues,
alcohols 21 and 22, were obtained by Marshall propargyl-
ation reactions by using the corresponding propargylic mes-
ylates (Scheme 7). Upon conversion of the desired homo-
propargyl alcohols into ethers, 24 served as the precursor
Although our second-generation synthesis proved to be
efficient, the sequence is entirely linear similar to many pre-
viously published syntheses of TSA.[15] Bearing in mind
that a more convergent route may have greater overall effi-
ciency, we devised a third-generation synthesis.[18] We saw
an opportunity to employ a transition metal-catalyzed
cross-coupling reaction between an alkenyl halide and an
enolate to form the C(5)–C(6) bond in a convergent manner
(see Scheme 2). α-Alkenylation of enolates has not been em-
ployed as commonly in an intermolecular sense[25] relative
to intramolecular applications of this coupling reaction.[26]
The synthesis started with aldehyde 5, which was sub-
jected to a Grignard reaction to provide alcohol 36 in 98%
yield (Scheme 8). The subsequent oxidation with some com-
mon protocols (Swern, Moffatt, IBX, etc.) either failed
completely or gave low yields of ketone 7, but a recently
reported catalytic 2,3-dichloro-5,6-dicyano-1,4-benzoquin-
one (DDQ)/Mn(OAc)3 oxidation method[27] provided 7 in
91% yield. The preparation of dienyl bromides 8a and 8b
employed readily available (E)-3-bromo-2-methyl-2-prop-
enol (37) in a one-pot oxidation/Wittig protocol to furnish
8a in 98% yield as a single E,E-isomer.[28] The methyl ester
was converted into p-methoxybenzyl ether (PMB) ester 8b
to permit a choice of ester deprotection strategies during
the later stages of the synthesis. Corresponding iodide 8c
was also prepared in parallel with the bromide.
Scheme 6. (Ϯ)-Hydrogen (17), (Ϯ)-ethyl (18), (Ϯ)-benzyl (19), and
(Ϯ)-phenyl (20) analogues of trichostatic acid.
Scheme 7. Synthesis of (Ϯ)-trichostatic analogues 17–20.
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Scheme 8. Synthesis of ketone 7 and alkenyl bromides 8a and 8b.
We chose to employ a Zn enolate in the key coupling deprotection under commonly used conditions (LiOH,
step owing to decreased basicity and precedents provided NaOH, LiI, KOTMS, NaCN), but PMB ester 39 was
in related α-arylation reactions.[29] Treatment of ketone 7 cleanly converted with TFA and Et3SiH into trichostatic
with lithium tetramethylpiperidide (LiTMP) and ZnCl2 fol- acid 2 in 96% yield. (Ϯ)-TSA [(Ϯ)-1] was obtained through
lowed by reaction with 8a or 8b, Pd(dba)2, and 1,1Ј-bis(di- use of the same procedure as in the preceding synthesis.[17]
tert-butylphosphanyl)ferrocene (dtbpf) furnished cross-cou-
In a slight modification of this synthesis, the coupling
pling products 38 and 39 in 73% and 82% isolated yields, reaction was performed with dienyl bromide 40 (prepared
respectively, with retention of diene configuration in two steps from 8a by using iBu2AlH and TBSOTf) con-
(Scheme 9). Other electron-rich sterically-demanding phos- taining a protected allylic alcohol rather than an ester to
phanes such as Q-Phos (used by Hartwig for similar reac- give cross-coupled product 41 in 92% yield (Scheme 10).
tions),[29a] tBu3P, and 1-(di-tert-butylphosphanyl)biphenyl This result demonstrates that activation of the dienyl brom-
also promoted the reaction but in lower yields than dtbpf, ide moiety by a conjugated electron-withdrawing group is
whereas the use of several arylphosphanes [Ph3P, not necessary for successful implementation of this cou-
(o-tolyl)3P, dppe, and dppf] failed completely. Dienyl iodide pling reaction. Oxidation of silyl ether 41 by using the cata-
8c was also a useful substrate as demonstrated below in lytic DDQ/Mn(OAc)3 system provided aldehyde 42 in a sin-
later analogue syntheses. Methyl ester 38 failed to undergo gle step,[27,30] whereas the use of stoichiometric quantities of
Scheme 9. Pd-catalyzed enolate coupling with dienyl bromides and subsequent formation of racemic TSA [(Ϯ)-1].
Scheme 10. Alternative synthesis of (Ϯ)-TSA by using a Pd-catalyzed α-alkenylation.
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Synthetic Strategies for Trichostatic Acid and Trichostatin A
DDQ furnished an N-demethylated side-product that was tophenone 43c derivatives as precursors of the trichostatic
inseparable from the desired product. Subsequent Pinnick acid analogues 45a–c (Scheme 11).
oxidation[31] by using DMSO[32] as the solvent and 1,3,5-
For these syntheses, dienyl iodide 8c was interchanged
trimethoxybenzene[33] as a chlorine scavenger followed by with previously employed bromide 8b to demonstrate its
further conversion as above again provided (Ϯ)-TSA.[17]
utility. We found that the coupling reaction works equally
well by using this alternative substrate and our usual cou-
pling conditions. The PMB-protected analogues thus ob-
tained were submitted to the same deprotection conditions
used above to yield corresponding carboxylic acids 45 in
good yields. The first of the analogues, 45a, has a gem-di-
methyl substitution pattern and has been reported pre-
viously,[34] but the second and third analogues appear to be
new. Clearly, the second- and third-generation syntheses are
conveniently complementary for analogue studies. On the
other hand, both of these routes would allow for facile vari-
ation of substitution patterns on the aromatic ring as an-
other element of structural diversity.
Assessment of the Three Pathways and Use in New Studies
The first synthesis was too inefficient and troublesome to
employ in further investigations owing to the poor stereo-
selectivity of the key phosphonate condensation reaction
and the difficulty separating the resulting diene isomers.
The second and third syntheses are far superior and permit
good throughput of material. They are also flexible in terms
of permitting facile synthesis of a number of types of ana-
logues of the trichostatic acid core. For example, the modi-
fied third synthesis (Scheme 10) provides ready access to
aldehyde 42, a potentially versatile intermediate for the pro-
duction of TSA analogues. The aldehyde functionality
serves as a direct precursor of several Zn-binding groups
other than the hydroxamic acid that are found in other
HDACi, including methyl ketones, epoxy ketones, o-amino-
benzamides, and thiols among others.[1–5] Introduction of
these Zn-binding elements into the TSA core could serve to
produce analogues that retain HDACi activity while minim-
izing possible deleterious properties associated with hy-
droxamic acids.
Enantioselective Synthesis of TSA and Analogues
Although we have successfully prepared (Ϯ)-TSA and
analogues by using our second- and third-generation syn-
theses, it is important to note that whereas (R)-1 is biolo-
gically active, its enantiomer, (S)-1, is inactive.[35] For this
reason, enantioselective syntheses of 1 are of great impor-
tance.[15b,15c] Although our first route clearly provided an
enantioselective entry to TSA, we ruled out its further use
owing to the other problems already discussed. Upon fur-
ther evaluation of our other routes, we judged our second-
Synthesis of Additional Analogues
Another aspect of analogue development is the afore- generation synthesis to be more readily amenable to the
mentioned variation of the substitution pattern of the production of single enantiomers at this time owing to pre-
diene-containing chain lying between the hydroxamic acid viously well-developed enantioselective versions of the Mar-
and aromatic group. Whereas the second-generation synthe- shall propargylation reaction used in a key step of this
sis proved to be readily amenable to variation of the substit- route.[23] Our third-generation synthesis, although attract-
uent at C(4), the third-generation synthesis is especially ively short and efficient, is based upon a metal-catalyzed
conducive to modifications at C(6) α to the ketone carbonyl enolate alkenylation reaction for which the development of
group based on the selection of other ketone substrates in appropriate enantioselective versions[25f,25g,25i,25k] is less ma-
place of 4-(dimethylamino)propiophenone (7) for use in the ture than for the Marshall reaction. We therefore decided
enolate alkenylation reaction. As a demonstration of this to make appropriate adaptations in our second-generation
variation, we have employed the readily prepared isobutyro- synthesis as a means for enantioselective production of the
phenone 43a, α-phenylacetophenone 43b, and α-benzylace- desired final products.
Scheme 11. Synthesis of C(6)-analogues of TSA by using Pd-catalyzed α-alkenylation.
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Scheme 12. Enantioselective synthesis of (R)-trichostatin A.
Our synthesis of (R)-(+)-1 is shown in Scheme 12. Rather
than by using a racemic propargyl mesylate as in Scheme 5,
we employed an enantiomerically enriched (S)-mesylate
(94% ee) in the Marshall reaction. The anticipated alcohol
(R)-21 was produced in 83% yield as a 1:1 mixture of syn-
and anti-diastereomers with the methyl-bearing C(6) having
the desired configuration in both isomers based upon sub-
sequent successful conversion of the mixture to (R)-(+)-
TSA. No assignment of ee values was made for this mix-
ture. After protection of the benzylic hydroxy group as
methyl ether (R)-23, the terminal alkyne was alkylated by
using LiTMP and MeI to furnish (R)-16 (92% over two
steps). The same cross-coupling conditions employed above
in our second-generation synthesis furnished intermediate
(R)-13. This material was subjected directly to hydrolysis to
produce free acid (R)-14, which was isolated in 81% over
four steps. Treatment of this material with DDQ furnished
(R)-trichostatic acid [(R)-2] in 87% yield after purification,
and subsequent conversion to (R)-trichostatin A [(R)-1;
81% ee] was accomplished as in the racemic synthesis.[17]
This route supplied enantioenriched (R)-TSA on a gram
scale.
Because of the literature report of the difference in ac-
tivity between the (R)- and (S)-enantiomers,[35] we used our
second-generation route to synthesize (+)-TSA (S-1, 91%
ee) (Scheme 13). The route and the reagents employed for
this compound were identical to those in Scheme 12, with
the exception of beginning with the (S)-enantiomer of the
starting propargyl mesylate. Likewise, we have synthesized
trichostatic acid analogues 19 and 20 in enantioenriched
form having the (R)-configuration at C(6) by replacing (Ϯ)-
23 with (R)-23 as a key intermediate in Scheme 7. However,
unlike the racemic analogues, we have further converted the
enantioenriched acids into corresponding hydroxamic acids
(R)-46 (80% ee) and (R)-47 (Ͼ95% ee). In all of these syn-
theses of enantioenriched TSA and analogues, the overall
enantioselectivities varied from 80 to Ͼ95% ee, which may
be attributed in part to the expected lability of the stereo-
genic center in these compounds being α to a ketone and
adjacent to a conjugated dienoic acid system.
Scheme 13. Enantioenriched TSA and analogues prepared by using
modifications of the second-generation synthesis.
Conclusions
We have described the evolution of our synthetic strate-
gies towards the production of trichostatic acid and TSA,
a potent histone deacetylase inhibitor. Each generation of
our syntheses permitted us either to design and implement
new chemistry or to modify existing methods to incorporate
a broader substrate scope into our pathways. Each synthesis
posed its own unique challenges that were addressed in sub-
sequent syntheses. The ultimate result is the availability of
two efficient and flexible syntheses of the desired com-
pounds from readily available materials. In new studies, the
two top performing syntheses exhibit complementary flexi-
bility for production of different series of TSA analogues.
One of the syntheses has been conducted enantioselectively
on a gram scale. The enantioselective route also proved
amenable for the synthesis of trichostatic acid analogues. In
addition to providing the compounds targeted in this work,
the chemistry presented here, especially the enolate alkenyl-
ation coupling reaction, is also expected to find use in a
variety of other synthetic applications. The biological ac-
tivity of the final products resulting from our routes is the
subject of ongoing studies.
Experimental Section
General Methods: All reactions were performed under an atmo-
sphere of argon unless otherwise stated. Tetrahydrofuran (THF)
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Synthetic Strategies for Trichostatic Acid and Trichostatin A
and diethyl ether were purified by using an Innovative Technol- (20 mL) was added LiTMP (1.55 g in 20 mL of THF, 10.6 mmol)
ogies™ solvent purification system. Anhydrous dichloromethane
and methanol were purchased from Aldrich in containers equipped
with Sure Seal septa. All reagents were used as received unless
otherwise noted. Flash chromatography was performed with 60 Å
silica gel (230–400 mesh). 1H NMR (300 and 500 MHz) and 13C
NMR (75 and 125 MHz) spectra were recorded with a Varian In-
at –78 °C through cannula. After the mixture was stirred for 30 min
at –78 °C, MeI (0.44 mL, 7.0 mmol) was added. The resulting mix-
ture was stirred for another 30 min at –78 °C before it was warmed
to 0 °C and stirred for 6 h. The reaction mixture was quenched
with saturated aqueous NH4Cl (20 mL). The organic layer was sep-
arated, and the aqueous layer was extracted with diethyl ether
(3ϫ20 mL). The combined organic layers were dried with MgSO4
ova-300
&
500 spectrometers, respectively, and 1H NMR
(400 MHz) and 13C NMR (100 MHz) were recorded with a Bruker and concentrated in vacuo. The crude mixture was purified by col-
DPX-400 spectrometer. All 1H NMR spectra were recorded in
CDCl3 or MeOD, and chemical shifts are given relative to CDCl3
umn chromatography (EtOAc/hexanes, 1:4) to obtain (R)-16
(1.33 g, 98%) as a 1:1 mixture of diastereomers. The 1H NMR
(δ =7.27 ppm) or CD3OD (3.34 and 4.87 ppm). 13C NMR spectra spectrum was identical with the previous report for the racemic
are referenced to CDCl3 (δ =77.23 ppm) or CD3OD (δ
=49.86 ppm). IR spectra were obtained with a Perkin–Elmer Para-
gon 1000 FT-IR spectrophotometer by using neat thin films or
CHCl3 solutions between NaCl plates. Mass spectra were recorded
with a JEOL JMS-AX505 HA double sector mass spectrometer.
Enantiomeric excess (ee) values were determined by using isocratic
1:99 2-propanol/hexanes with a CHIRALPAK OD column on a
Waters 600 HPLC.
compound.[17] 1H NMR (300 MHz, CDCl3): δH = 7.23–7.15 (m, 4
H), 6.77–6.69 (m, 4 H), 3.94 (d, J = 2.4 Hz, 2 H), 3.92 (d, J =
2.4 Hz, 2 H), 3.23 (s, 6 H), 2.97 (s, 12 H), 2.83–2.63 (m, 2 H), 1.83
(d, J = 2.4 Hz, 3 H), 1.74 (d, J = 2.4 Hz, 3 H), 1.14 (d, J = 7.1 Hz,
3 H), 1.00 (d, J = 7.2 Hz, 3 H) ppm.
(2E,4E,6R)-7-[4-(Dimethylamino)phenyl]-7-methoxy-6-methylhepta-
2,4-dienoic Acid [(R)-14]: According to the previously published
procedure,[17] (–)-Ipc2BH (1.94 g, 6.77 mmol) was weighed in a
glove box into a round-bottom flask. The flask was placed in an
ice bath, and a solution of (R)-16 (1.30 g, 5.64 mmol) in THF
(20 mL) was added. The mixture was stirred for 2 h at 0 °C, and
then MeOH (0.53 mL, 13 mmol) was added. After 2 h, to the re-
The experimental procedures, characterization data, and Support-
ing Information for compounds described in Schemes 2, 3, 4, 5,
6, 7, and 8 have been published previously and are not repeated
here.[16b,17,18]
(R)-1-[4-(Dimethylamino)phenyl]-2-methylbut-3-yn-1-ol
[(R)-21]: sulting solution at 0 °C was added a solution of (E)-methyl 3-
Based on a previously published procedure,[17,23] to a solution of
(S)-but-3-yn-2-yl methanesulfonate (1.61 g, 10.9 mmol) and 4-(di-
methylamino)benzaldehyde (5, 1.25 g, 8.39 mmol) in dry THF
bromoacrylate (1.39 g, 8.46 mmol) in THF (20 mL), and the flask
was warmed to 25 °C. To the solution were added Pd(PPh3)4
(65 mg, 0.56 mmol, 10 mol-%) and TlOEt (1.2 mL, 17 mmol) in
(30 mL) and HMPA (6 mL) stirred at 0 °C, PdCl2(dppf) (31 mg, H2O (12 mL). The resulting off-white mixture was stirred for 1 h
0.42 mmol, 5 mol-%) and InI (4.06 g, 16.8 mmol) were added suc-
cessively. The resulting dark-green colored mixture was stirred for
1 h, during which time the color turned brick red. The reaction
mixture was quenched after 1 h by the addition of water (50 mL)
and was diluted with diethyl ether (50 mL). The organic layer was
separated, and the aqueous layer was further washed with diethyl
ether (3ϫ50 mL). The combined organic layers were washed with
brine, dried with anhydrous MgSO4 and concentrated under vac-
uum. The resulting crude mixture was purified by using flash
chromatography (hexane/EtOAc, 9:1) to give (R)-21 as a 1:1 mix-
ture of syn and anti diastereomers (1.41 g, 83%). The 1H NMR
spectrum was identical with the previous report for the racemic
compound.[17] 1H NMR (400 MHz, CDCl3): δH = 7.31–7.20 (m, 4
at 25 °C, and the mixture was diluted with 1 m aqueous NaHSO4
(20 mL). The mixture was filtered and extracted with Et2O
(3ϫ50 mL). The organic extracts were washed with brine, dried
with MgSO4, and concentrated. The crude product was purified by
flash chromatography (hexanes/EtOAc, 95:5 to 90:10) to give
methyl (2E,4E,6R)-7-[4-(dimethylamino)phenyl]-7-methoxy-6-
methylhepta-2,4-dienoate [(R)-13] with some inseparable impuri-
ties. This material was used directly without any further purifica-
tion. According to the published method,[17] this material (1.61 g,
5.08 mmol) was dissolved in MeOH (40 mL), and treated with
0.5 m aqueous LiOH (13 mL, 6.1 mmol). The resulting mixture was
stirred at 45 °C for 24 h and then neutralized with pH 7 buffer. The
volatile part was removed under vacuum, and the remaining yellow
H), 6.78–6.69 (m, 4 H), 4.62 (d, J = 2.5 Hz, 1 H), 4.43 (d, J = residue was washed with EtOAc (2ϫ20 mL). The aqueous layer
2.5 Hz, 1 H), 2.96 (s, 12 H), 2.90–2.82 (m, 1 H), 2.82–2.75 (m, 1 was acidified to approximately pH 4 by using 1 n HCl and was
H), 2.50–2.48 (b, 1 H), 2.22–2.20 (m, 1 H), 2.11–2.09 (m, 1 H), 1.17
(d, J = 2.54 Hz, 3 H), 1.11–1.06 (d, J = 2.54 Hz, 3 H) ppm.
extracted with CHCl3 (3ϫ50 mL). The combined organic extracts
were dried and concentrated under vacuum to give the crude prod-
uct as a yellowish syrup. The compound was purified by flash
chromatography (hexanes/EtOAc, 4:1 to 1:1) to obtain (R)-14
(1.38 g, 81%) as a 1:1 mixture of diastereomers. The 1H NMR
spectrum was identical with the previous report for the racemic
compound.[17] 1H NMR (300 MHz, CDCl3): δH = 7.45 (d, J =
15.6 Hz, 1 H), 7.31 (d, J = 15.6 Hz, 1 H), 7.19–7.08 (m, 4 H), 6.76–
6.65 (m, 4 H), 5.94 (d, J = 9.8 Hz, 1 H), 5.82–5.70 (m, 3 H), 3.95–
3.89 (m, 2 H), 3.20 (s, 3 H), 3.18 (s, 3 H), 2.98 (s, 6 H), 2.96 (s, 6
H), 2.94–2.83 (m, 2 H), 1.74 (s, 3 H), 1.63 (s, 3 H), 1.09 (d, J =
6.9 Hz, 3 H), 0.86 (d, J = 6.9 Hz, 3 H) ppm.
4-[(2R)-1-Methoxy-2-methylbut-3-yn-1-yl]-N,N-dimethylaniline
[(R)-23]: Based upon a published procedure,[17] to a solution of (R)-
21 (1.31 g, 6.45 mmol) in MeOH (45 mL) was added a solution of
0.1% TFA in MeOH (75 mL, v/v), and the mixture was stirred at
25 °C for 48 h. The resulting dark-brown solution was neutralized
by careful addition of Et3N, and all volatile materials were removed
under vacuum. The resulting crude mixture was purified by using
flash chromatography (hexane/EtOAc, 9:1) to give (R)-23 as a 1:1
mixture of syn and anti diastereomers (1.32 g, 94%). The 1H NMR
spectrum was identical to the previous report for the racemic com-
pound.[17] 1H NMR (400 MHz, CDCl3): δH = 7.26–7.14 (m, 4 H),
6.74 (d, J = 8.7 Hz, 4 H), 3.98 (d, J = 2.5 Hz, 2 H), 3.22 (s, 3 H),
3.21 (s, 3 H), 2.94 (s, 12 H), 2.90–2.83 (m, 1 H), 2.81–2.73 (m, 1
H), 2.16 (d, J = 2.4 Hz, 1 H), 2.03 (d, J = 2.4 Hz, 1 H), 1.21 (d, J
= 6.9 Hz, 3 H), 1.03 (d, J = 6.9 Hz, 3 H) ppm.
(R,2E,4E)-7-[4-(Dimethylamino)phenyl]-6-methyl-7-oxohepta-2,4-di-
enoic Acid [(R)-2]: According to a previously published method,[17]
(R)-14 (1.29 g, 4.27 mmol) was dissolved in CH2Cl2/H2O (50 mL,
2:1) and treated with DDQ (920 mg, 4.06 mmol) in 3 portions over
a period of 5 min at 0 °C. The resulting mixture was stirred vigor-
4-[(2R)-1-Methoxy-2-methylpent-3-yn-1-yl]-N,N-dimethylaniline ously for another 5 min at 0 °C and was diluted with CH2Cl2
[(R)-16]: To a solution of (R)-23 (1.27 g, 5.86 mmol) in dry THF (20 mL). The mixture was filtered through Celite, and the filter pad
Eur. J. Org. Chem. 2013, 162–172
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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169

P. Helquist et al.
FULL PAPER
was washed with CH2Cl2 (50 mL). The combined filtrates were
dried with MgSO4 and concentrated under vacuum to obtain red-
dish brown (R)-2 (1.07 g, 87%). The H NMR spectrum was iden-
(CH2Cl2). The NMR spectra were in agreement with literature
data. 1H NMR (400 MHz, CDCl3): δH = 7.93 (d, J = 9.1 Hz, 2 H),
7.30–7.15 (m, 5 H), 6.64 (d, J = 9.1 Hz, 2 H), 4.18 (s, 2 H), 3.05
(s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δc = 195.7, 153.5,
135.8, 130.9, 129.3, 128.5, 126.5, 124.6, 110.7, 44.9, 40.0 ppm.
1
tical with the previous report for the racemic compound.[17] [α]2D5
=
+138 (c = 0.095, Ethos); [ref.[15b] [α]2D2 = +138 (c = 0.35, MeOH)]
1H NMR (300 MHz, CDCl3): δH = 7.85 (d, J = 9.0 Hz, 2 H), 7.39 (ref.[37] 1H NMR. 13C NMR).
(d, J = 15.6 Hz, 1 H), 6.65 (d, J = 9.0 Hz, 2 H), 6.10 (d, J = 9.6 Hz,
1-[4-(Dimethylamino)phenyl]-3-phenyl-1-propanone (43c): To a solu-
1 H), 5.83 (d, J = 15.6 Hz, 1 H), 4.41 (dq, J = 9.6, 6.6 Hz, 1 H),
3.07 (s, 6 H), 1.95 (s, 3 H), 1.34 (d, J = 6.6 Hz, 3 H) ppm.
tion of tetramethylpiperidine (1 mmol, 168 μL) in THF (5 mL) at
–78 °C was added n-butyllithium (1 mmol, 400 μL, 2.5 m in hexane)
over a 5-min period. After the solution was stirred for 30 min at
–78 °C, 4-(dimethylamino)acetophenone was added in THF
(5 mL), and the reaction mixture was warmed to 0 °C. After
30 min, benzyl bromide (2 mmol, 240 μL) was added dropwise. The
mixture was stirred at 22 °C for 12 h. The reaction was quenched
with saturated aqueous NH4Cl. The aqueous phase was extracted
twice with Et2O. The combined organic extracts were dried with
MgSO4 and the solvents evaporated. Flash chromatography of the
crude material gave 43c as pale yellow crystals (90 mg, 35%) having
NMR spectra in agreement with literature data. 1H NMR
(400 MHz, CDCl3): δH = 7.90 (d, J = 9.1 Hz, 2 H), 7.34–7.15 (m,
5 H), 6.65 (d, J = 9.1 Hz, 2 H), 3.20–3.24 (m, 2 H), 3.01–3.09 [m,
overlapping with (δ = 3.05 ppm), 2 H], 3.05 (s, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δc = 195.4, 153.4, 141.8, 130.3, 128.46, 128.45,
126.0, 124.9, 110.7, 40.0, 39.7, 30.7 ppm. (ref.[38] 1H NMR. 13C
NMR).
(R)-(+)-Trichostatin A [(R)-1]: According to a previously published
method,[17] (R)-2 (1.02 g, 3.54 mmol) and Et3N (1.1 mL,
7.78 mmol) were dissolved in CH2Cl2 (20 mL) and cooled to 0 °C.
Chloroethyl formate (0.4 mL, 4 mmol) was added, and the solution
was stirred at 0 °C for 2 h followed by the addition of NH2OTBS
(780 mg, 5.3 mmol). After the mixture was stirred for 30 min, the
cooling bath was removed, and the mixture was warmed to 25 °C
and stirred for 2 h. The reaction mixture was diluted with CH2Cl2
(30 mL), and the organic layer was washed with water (20 mL).
The aqueous layer was extracted with CH2Cl2 (3ϫ30 mL). The
combined organic layers were washed with brine, dried with anhy-
drous MgSO4, and concentrated under vacuum to obtain crude O-
TBS protected hydroxamic acid which was used directly in the next
step without further purification. The crude compound was dis-
solved in anhydrous MeOH (30 mL), and dry CsF (645 mg,
4.24 mmol) was added. The mixture was stirred at 25 °C for 3 h
and diluted with EtOAc (50 mL). The organic layer was washed
with water (20 mL), and the aqueous layer was extracted with
EtOAc (3ϫ20 mL). The combined organic layers were combined,
dried with MgSO4, and concentrated under vacuum. The resulting
solid mass was triturated with hexanes/Et2O (4:1) to obtain pure
General Procedure for 44a–c: The previously published procedure
for the preparation of 39, was followed.[18] Tetramethylpiperidine
(0.38 mmol, 63 μL) was dissolved in THF (1 mL). The solution was
cooled to 0 °C, and nBuLi (0.38 mmol, 2.5 m in hexane, 150 μL)
was added dropwise. After 10 min, a solution of ketone 43
(0.34 mmol) in THF (1 mL) was added. After 20 min, the mixture
was warmed to 22 °C, and ZnCl2 (0.45 mmol, 62 mg) was added.
The resulting solution was stirred for 30 min during which all of
the solid ZnCl2 disappeared. The resulting zinc enolate solution
was added to a THF solution of alkenyl iodide 8c (0.29 mmol),
dtbpf (0.012 mmol), Pd(dba)2 (0.012 mmol). After TLC indicated
that the starting iodide was consumed (approximately 1 h), the re-
action mixture was poured into saturated aqueous sodium potas-
sium tartrate solution and extracted with two portions of Et2O.
The combined organic extracts were dried with MgSO4 and con-
centrated in vacuo. The residue was purified by using flash
chromatography (hexanes/EtOAc, 7:3) to give products 44.
44a: Obtained as an off white solid in 97% yield. 1H NMR
(400 MHz, CDCl3): δH = 7.86 (d, J = 8.8 Hz, 2 H), 7.32 (d, J =
9.0 Hz, 2 H), 7.31 (d, J = 43 Hz, 2 H), 6.89 (d, J = 8.4 Hz, 2 H),
6.65 (d, J = 8.8 Hz, 2 H), 6.36 (s, 2 H), 5.73 (d, J = 15.7 Hz, 1 H),
5.12 (s, 2 H), 3.81 (s, 3 H), 3.02 (s, 6 H), 1.45 (s, 3 H), 1.43 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δc = 201.3, 167.3, 161.2,
159.6, 152.8, 150.0, 148.3, 133.9, 131.8, 130.1, 128.3, 122.0, 116.2,
113.9, 110.2, 65.9, 55.3, 47.9, 39.9, 28.0, 12.6 ppm. HRMS (ESI):
calcd. for C26H32NO4 [M + H]+ 422.2331; found 422.2323.
1
(R)-1 (0.98 g, 92% overall). The H NMR spectrum was identical
with the previous report for the racemic compound.[17] [α]2D5 = +96
(c = 0.13, EtOH); [ref.[15b] [α]2D2 = +96 (c = 0.31 , MeOH)]; ee 81%.
1H NMR (300 MHz, CD3OD): δH = 7.83 (d, J = 9.0 Hz, 2 H), 7.15
(d, J = 15.6 Hz, 1 H), 6.70 (d, J = 9.0 Hz, 2 H), 5.89 (d, J = 9.6 Hz,
1 H), 5.83 (d, J = 15.6 Hz, 1 H), 4.54 (dq, J = 9.6, 6.6 Hz, 1 H),
3.03 (s, 6 H), 1.91 (d, J = 1.2 Hz, 3 H), 1.23 (d, J = 6.6 Hz, 3
H) ppm. IR (CHCl ): νν = 3427, 3236, 2928, 1659, 1599, 1551,
˜ ˜
3
1379, 1248, 1192, 1058, 972, 818 cm–1. HRMS (ESI): calcd for
C17H23N2O3 [M + H]+ 303.1703; found 303.1722.
(S)-(–)-Trichostatin A [(S)-1]: The preceding sequence of reactions
was followed except (S)-but-3-yn-2-yl methanesulfonate (807 mg,
5.5 mmol) was used in place of the (R)-enantiomer as the starting
material to provide (S)-21 (732 mg, 86%), (S)-23 (721 mg, 93%),
(S)-16 (728 mg, 95%), (S)-12 (872 mg as a crude product), (S)-13
(778 mg, 84%), (S)-14 (575 mg, 85%), and (S)-1 (498 mg, 89%):
[α]2D5 = –84 (c = 0.11, EtOH); [ref.[15b] [α]2D2 = –82 (c = 0.24,
MeOH)]; ee 91%. The 1H NMR spectra of all of these products
matched those of the (R)-enantiomers in the previous sequence of
reactions.
4-(Dimethylamino)isobutyrophenone (43a): Through use of the pre-
viously reported reaction sequence for the preparation of 7,[18] 4-
(dimethylamino)benzaldehyde and iPrMgBr provided 43a (64%) as
an off-white solid having an NMR spectra in agreement with litera-
1
44b: Obtained as a gray solid in 88% yield. H NMR (400 MHz,
CDCl3): δH = 7.82 (d, J = 9.2 Hz, 2 H), 7.33 (d, J = 15.6 Hz, 1 H),
7.27–7.13 (m, 5 H), 6.79 (d, J = 8.8 Hz, 2 H), 6.50 (d, J = 9.2 Hz,
2 H), 5.76 (d, J = 15.7 Hz, 1 H), 5.48 (d, J = 9.5 Hz, 1 H), 5.02 (s,
2 H), 3.70 (s, 3 H), 2.91 (s, 6 H), 1.78 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δc = 195.3, 167.0, 159.6, 153.4, 149.4, 140.0,
139.4, 133.1, 131.1, 130.0, 129.0, 128.3, 128.1, 127.0, 123.8, 116.8,
113.9, 110.7, 65.9, 55.3, 52.2, 39.9, 12.8 ppm. HRMS (ESI): calcd.
for C30H32NO4 [M + H]+ 470.2331; found 470.2316.
1
ture data. H NMR (400 MHz, CDCl3): δH = 7.90 (d, J = 9.1 Hz,
2 H), 6.66 (d, J = 9.1 Hz, 2 H), 3.50 (m, 1 H), 3.05 (s, 6 H), 1.19
(d, J = 6.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δc = 202.7,
153.2, 130.5, 124.0, 110.7, 40.0, 34.4, 19.5 ppm. (ref.[36] 1H NMR.
13C NMR).
1-[4-(Dimethylamino)phenyl]-2-phenylethanone (43b): The preceding
procedure was employed with benzylmagnesium chloride to give
43b (71%) as a slightly yellow solid after flash chromatography
1
44c: Obtained as a gray solid in 81% yield. H NMR (400 MHz,
CDCl3): δH = 7.71 (d, J = 8.8 Hz, 2 H), 7.24–7.00 (m, 8 H), 6.78
170
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 162–172

Synthetic Strategies for Trichostatic Acid and Trichostatin A
(d, J = 8.4 Hz, 2 H), 6.51 (d, J = 8.9 Hz, 2 H), 5.88 (d, J = 10.3 Hz,
1 H), 5.66 (d, J = 15.7 Hz 1 H), 5.01 (m, 2 H), 4.44 (m, 2 H), 3.70
(s, 3 H), 3.17 (m, 1 H), 2.75 (m, 1 H), 2.93 (s, 6 H), 1.41 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δc = 197.2, 167.0, 159.6,
153.5, 149.1, 139.6, 139.3, 134.3, 130.6, 130.1, 129.2, 128.3, 126.2,
124.2, 116.7, 113.9, 110.7, 65.9, 55.3, 49.1, 40.0, 38.7, 12.3 ppm.
HRMS (ESI): calcd. for C31H34NO4 [M + H]+ 484.2487; found
484.2487.
149.8, 144.6, 139.7, 137.0, 131.9, 129.4, 127.3, 124.6, 119.4, 111.9,
41.5, 40.1, 33.7, 19.0 ppm. IR (CHCl ): ν = 3415, 3228, 2920, 1651,
˜
3
1589, 1546, 1377, 1241, 1187, 964 cm–1. HRMS (ESI): calcd. for
C23H27N2O3 [M + H]+ 379.2012; found 379.2016.
(R,2E,4Z)-7-[4-(Dimethylamino)phenyl]-N-hydroxy-6-methyl-7-oxo-
4-phenylhepta-2,4-dienamide [(R)-47]: A previously published pro-
cedure[17] for the synthesis of (Ϯ)-20 was followed except (R)-23
(407 mg, 1.88 mmol) was used in place of the racemic material to
give (R)-27 (543 mg, 97%), (R)-31 (317 mg, 47%), (R)-35 (261 mg,
87%), and (R)-20 (191 mg, 81%). The spectroscopic data were
identical to the previous report for the racemic compound.[17]
Based on the procedure for synthesis of (R)-1, carboxylic acid (R)-
20 (173 mg, 0.49 mmol) was used in a reaction with ClCO2Et
(0.06 mL, 0.6 mmol), Et3N (0.15 mL, 1.1 mmol), NH2OTBS
(108 mg, 0.73 mmol) followed by treatment with CsF (89 mg,
0.59 mmol) to give (R)-47 (61 mg, 34%). [α]2D5 = +161 (c = 0.14,
General Procedure for 45a–c: The previously published procedure
for the conversion of 39 into 2 was followed.[18] PMB-protected
material 44 (0.5 mmol) was dissolved in CH2Cl2 (4 mL) at 22 °C.
Trifluoroacetic acid (0.75 mL) was added followed by triethylsilane
(0.75 mL, 10 equiv.). The reaction mixture was stirred until TLC
indicated complete consumption of starting material (approxi-
mately 10 min). Saturated aqueous NaHCO3 (10 mL) was added,
and the pH was adjusted to 3 by adding 2n HCl. The mixture was
extracted three times with CH2Cl2. The combined organic extracts
were dried with MgSO4 and concentrated in vacuo. Flash
chromatography (gradient elution with 0 to 7% MeOH in CH2Cl2)
of the residue yielded products 45 as white solids.
1
EtOH); ee Ͼ95%. H NMR (400 MHz, CD3OD): δH = 7.48–7.37
(m, 6 H), 7.20 (d, J = 9.0 Hz, 2 H), 6.57 (d, J = 8.9 Hz, 2 H), 6.27
(d, J = 10.2 Hz, 1 H), 5.33 (d, J = 15.6 Hz, 1 H), 4.08 (dq, J =
10.2, 6.6 Hz, 1 H), 2.99 (s, 6 H), 1.21 (d, J = 6.6 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δc = 201.8, 170.9, 155.4, 149.1,
143.3, 142.3, 137.4, 132.0, 130.1, 129.9, 128.7, 124.1, 121.3, 112.1,
1
45a: Obtained as a white solid in 71% yield. H NMR (400 MHz,
CDCl3): δH = 7.86 (d, J = 9.0 Hz, 2 H), 7.41 (d, J = 15.6 Hz, 1 H),
6.57 (d, J = 9.7 Hz, 2 H), 6.41 (s, 1 H), 5.70 (d, J = 15.6 Hz, 1 H),
3.03 (s, 6 H), 1.48 (s, 3 H), 1.44 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δc = 201.2, 172.4, 152.8, 151.9, 149.3, 133.9, 131.8, 121.9,
115.6, 110.2, 48.0, 39.9, 28.0, 12.6 ppm. HRMS (ESI): calcd. for
C18H24NO3 [M + H]+ 302.1756; found 302.1740.
103.8, 42.8, 39.7, 18.2 ppm. IR (CHCl ): ν = 3421, 3230, 2922,
˜
3
1653, 1591, 1545, 1379, 1241, 1188, 1051, 965 cm–1. HRMS (ESI):
calcd. for C22H24N2O3 [M + H]+ 365.1812; found 365.1860.
Supporting Information (see footnote on the first page of this arti-
cle): Supporting Information includes 1H NMR and 13C NMR
spectra and chiral HPLC traces of newly reported compounds.
1
45b: Obtained as a white solid in 75% yield. H NMR (400 MHz,
CDCl3): δH = 7.91 (d, J = 9.2 Hz, 2 H), 7.48 (d, J = 15.8 Hz, 1 H),
7.34–7.20 (m, 5 H), 6.61 (m, 3 H), 5.82 (d, J = 16.3 Hz, 1 H), 5.58
(d, J = 9.7 Hz, 1 H), 3.04 (s, 6 H), 1.93 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δc = 192.6, 169.2, 150.9, 148.8, 138.5, 136.7,
130.5, 128.5, 126.4, 125.5, 124.5, 121.2, 113.4, 108.1, 49.7, 37.4,
10.2 ppm. HRMS (ESI): calcd. for C22H24NO3 [M + H]+ 350.1756;
found 350.1742.
Acknowledgments
We thank the Ara Parseghian Medical Research Foundation, the
US National Science Foundation (NSF),, the Swedish National
Science Council, the Walther Cancer Institute, the Charles Edison
Fund, Circagen, and the donors of the American Chemical Society
Petroleum Research Fund for support of this research. The authors
acknowledge Prof. Per-Ola Norrby (Gothenburg University), Prof.
Jan-Erling Bäckvall (Stockholm University), Dr. Norbert Wiech
(Circagen LLC and Lysomics LLC), Dr. Jacob Plummer (Notre
Dame), and Dr. Jed Fisher (Notre Dame) for valuable discussions.
D. J. S. is a recipient of a Podrasnik/McCanna Fellowship, C. C. C.
and J. T. M. are recipients of J. Peter Grace Fellowships, and T. A.
is a recipient of an AstraZeneca postdoctoral fellowship. P. H. is
very grateful to the Swedish National Science Council for the award
of the Tage Erlander Guest Professorship during 2011–2012 at
Gothenburg University and Stockholm University.
1
45c: Obtained as a white solid in 71% yield. H NMR (400 MHz,
CDCl3): δH = 7.81 (d, J = 8.8 Hz, 2 H), 7.34 (d, J = 15.6 Hz, 1 H),
7.26–7.14 (m, 5 H), 6.62 (d, J = 8.8 Hz, 2 H), 6.02 (d, J = 10.0 Hz,
1 H), 5.72 (d, J = 15.7 Hz, 1 H), 4.54 (m, 1 H), 3.27 (dd, J = 5.6,
5.4 Hz, 1 H), 3.05 (s, 6 H), 2.85 (dd, J = 8.6, 8.3 Hz, 1 H), 1.53 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δc = 197.2, 172.1, 153.3,
150.9, 140.5, 139.2, 134.4, 130.6, 129.2, 128.3, 126.2, 124.2, 116.1,
110.7, 49.1, 40.0, 38.7, 12.3 ppm. HRMS (ESI): calcd. for
C23H26NO3 [M + H]+ 364.1913; found 364.1895.
(R,2E,4E)-4-Benzyl-7-[4-(dimethylamino)phenyl]-N-hydroxy-6-
methyl-7-oxohepta-2,4-dienamide [(R)-46]: A previously published
procedure[17] for the synthesis of (Ϯ)-19 was followed except (R)-
23 (455 mg, 2.10 mmol) was used in place of the racemic material
to give (R)-26 (606 mg, 92 %), (R)-30 (338 mg, 48 %), (R)-34
(241 mg, 74% yield), and (R)-19 (134 mg, 82%). The spectroscopic
data were identical to the previous report for the racemic com-
pound.[17] Based on the procedure for synthesis of (R)-1, carboxylic
acid (R)-19 (116 mg, 0.32 mmol) was used in a reaction with
ClCO2Et (0.04 mL, 0.4 mmol), Et3N (0.1 mL, 0.7 mmol), and
NH2 OTBS (71 mg, 0.48 mmol) followed by CsF (58 mg,
0.38 mmol) to give (R)-46 (37 mg, 31%). [α]2D5 = +129 (c = 0.16,
[1] a) R. W. Johnstone, Nat. Rev. Drug Discovery 2002, 1, 287–299;
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Received: September 17, 2012
Published Online: November 20, 2012
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