Synthesis of 4-methyldienoates using a vinylogous horner-wadsworth-emmons reagent. application to the synthesis of trichostatic acid

Article abstract of DOI:10.1021/jo902422y

Chemical Equation Presented The utility of the unsaturated phosphonate 1 as a vinylogous Horner-Wadsworth-Emmons reagent was explored in reactions with, aldehydes affording 4-methyldienoate esters. Factors that affect E/Z selectivity were studied. A simplified synthesis of trichostatic acid 3 was accomplished, to demonstrate utility of this reagent.

Full text of DOI:10.1021/jo902422y

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various substitution patterns have been studied which pro-
Synthesis of 4-Methyldienoates Using a Vinylogous
Horner-Wadsworth-Emmons Reagent. Application
to the Synthesis of Trichostatic Acid
duce substituted dienes.4 However, stereoselectivity and
reactivity issues may arise especially when reagents are
employed bearing a substituent adjacent to the phosphorus.5
For the present work, we chose to study the 4-methyl-
substituted phosphonate 1 for the rapid construction of the
4-methyldienoate system, which constitutes a structural
feature seen among several natural products arising from
propionate biosynthetic pathways.
Phosphonate 1 is prepared as an inconsequential mixture
of alkene positional isomers in one step through the Arbuzov
reaction6 of triethyl phosphite with (E)-methyl 3-bromo-
2-pentenoate (eq 1). Although the dimethyl phosphonate
analogue of 1 was prepared more than 20 years ago, the
original authors did not report on its reactivity and applica-
tions.7 Corresponding phosphonium ylides have seen syn-
thetic use. Problems encountered with their use include poor
or undetermined E/Z selectivity and mixtures of addition
products.8
€
John T. Markiewicz, Douglas J. Schauer, Joakim Lofstedt,
Steven J. Corden, Olaf Wiest, and Paul Helquist*
Department of Chemistry and Biochemistry, Walther Cancer
Research Center, University of Notre Dame, 251 Nieuwland
Science Hall, Notre Dame, Indiana 46556
phelquis@nd.edu
Received November 13, 2009
The utility of the unsaturated phosphonate 1as a vinylogous
Horner-Wadsworth-Emmons reagent was explored in
reactions with aldehydes affording 4-methyldienoate esters.
Factors that affect E/Z selectivity were studied. A simplified
synthesis of trichostatic acid 3 was accomplished to demon-
strate utility of this reagent.
Our study of 1 began by examining benzaldehyde as a
substrate under standard HWE conditions (Table 1). Using
lithium hexamethyldisilazide (LiHMDS) in THF at low
temperature, we obtained a 92:8 mixture of 2E,4E- and
2E,4Z-products with excellent purity (Table 1, entry 1). We
varied the solvent and counterion, which have previously
been demonstrated to affect the selectivity.1,9 The solvent
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C. W. Org. Lett. 2009, 11, 3950.
The Horner-Wadsworth-Emmons (HWE) condensa-
tion1 is a popular means of synthesizing functionalized
alkenes and is commonly employed to effect subunit coupl-
ing and ring closure in complex syntheses.2 Vinylogous
HWE reagents of the type (R1O)2P(O)CH2CHdCHCO2R2
have been employed to prepare dienes from the correspond-
ing carbonyl substrates.3 Several analogous reagents of
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Roush, W. R. J. Org. Chem. 2008, 73, 1031. (f) Andrus, M. B.; Wong, Y.; Liu,
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DOI: 10.1021/jo902422y
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Published on Web 02/16/2010
J. Org. Chem. 2010, 75, 2061–2064 2061
2010 American Chemical Society

Markiewicz et al.
JOCNote
TABLE 1. Optimization of Conditions with an Aromatic Aldehyde
TABLE 2. Optimization of Conditions with an Aliphatic Aldehyde
entry
solvent
THF
THF/HMPA LiHMDS
base
tempa (°C) E,E/E,Zb yieldc (%)
entry
solvent
THF
THF/HMPA LiHMDS
base
tempa (°C) E,E/E,Zb yieldc (%)
1
2
3
4
5
6
7
8
9
LiHMDS
-78
-78
-78
-78
-78
22
74:26
58:42
72:28
72:28
74:26
73:27
72:28
49:41
46:56
40:60
90
79
54
62
73
53
39
71
69
64
1
2
3
4
5
6
7
8
9
LiHMDS
-78
-78
-78
-78
-78
22
92:8
97
98
38
55
94
69
69
92
90
91
88:12
87:13
86:14
91:9
87:13
86:14
88:12
83:17
80:20
PhCH3
Et2O
LiHMDS
LiHMDS
PhCH3
Et2O
LiHMDS
LiHMDS
DME
DME
THF
THF
THF
LiHMDS
LiHMDS
DME
DME
THF
THF
THF
LiHMDS
LiHMDS
LiHMDS
NaHMDS
KHMDS
22
LiHMDS
NaHMDS
KHMDS
22
-78
-78
-78
-78
-78
-78
KHMDS/18-C-6d
10 THF
KHMDS/18-C-6d
10 THF
aTemperature at which the aldehyde is added. bRatios were measured
from the 1H NMR of the crude material. cYields measured by 1H NMR
using mesitylene as an internal standard. d18-C-6 = 18-crown-6.
aTemperature at which the aldehyde is added. bRatios were measured
from the 1H NMR of the crude material. cYields measured by 1H NMR
using mesitylene as an internal standard. d18-C-6 = 18-crown-6.
had minimal affect on selectivity, giving approximately the
same ratio of E,E- and E,Z-products. We noted decreased
yields with less polar solvents (Table 1, entries 3 and 4). We
investigated performing the reaction in THF and DME at
elevated temperatures (Table 1, entries 6 and 7) based on
Heathcock’s observation that these conditions, which en-
courage equilibrium between the betaine and oxaphosphe-
tane before the irreversible elimination of phosphate, lead to
increased E-selectivity.9 However, we noticed slightly lower
selectivity and decreased yields with these conditions.
The effect of the metal ion was also investigated. It has
previously been established that the use of more strongly
dissociating metal ions increases the amount of the Z-con-
figuration due to a lack of reversibility of reactive inter-
mediates before the rate-limiting elimination of phosphate.10
Thus, the highest proportion of the E,Z-product was ob-
tained when KHMDS and 18-crown-6 were used (Table 1,
entry 10).
FIGURE 1. Key ROESY NMR cross-peaks for diene configura-
tion assignments.
We next performed the same study on the aliphatic
aldehyde hexanal (Table 2). In general, the stereoselectivities
for aliphatic aldehydes are poorer than aromatic substrates.
As before, the solvent and aldehyde addition temperature
had minimal effect on the diene selectivity. The same metal
ion effect that was seen with benzaldehyde was again noticed.
Upon use of KHMDS/18-crown-6, the amount of the E,Z-
product again increased, which led in this case to a reversal of
the selectivity in favor of the E,Z-product (Table 2, entry 10).
The diene configurations of 2a and 2b were assigned by
ROESY NMR (Figure 1). More specifically, we found a
NOE between the C(4) methyl group protons and the C(5)
proton for the minor isomer E,Z-2a. This correlation was
absent from the major isomer E,E-2a. For 2b, a correlation
was observed between the C(6) protons and the C(4) methyl
group for the major isomer E,E-2b. This correlation was
absent for the minor isomer E,Z-2b, which instead had a
cross-peak between the C(3) and C(6) protons.
examined a variety of aldehydes to probe the scope of the
reaction (Table 3). Again we established that aromatic
aldehydes perform with good stereoselectivity while alipha-
tic derivatives give lower E,E-selectivity. In many cases, the
minor E,Z-product could be separated by flash column
chromatography.
As expected, electron-rich aldehydes react at a much
slower rate than electron-poor aldehydes. Increasing the
number of alkyl branches on the R carbon of the aldehyde
negatively affects the E-selectivity (Table 3, entries 11). Not
included in Table 3 are cases of aldehydes for which poor
yields and products of poor purity are obtained, including a
very electron-rich aromatic aldehyde (p-dimethylamino-
benzaldehyde) and R,β-unsaturated aldehydes (acrolein,
cinnamaldehyde). Additionally, a complex mixture of iso-
meric β-hydroxyphosphonates as addition products was
isolated from the reaction with cinnamaldehyde. A ketone
(cyclohexanone) gave a very low yield.
From the survey of conditions above, we judged LiHMDS
in THF to be suitable for achieving modest to high E,E-
selectivity and good yields. Employing these conditions, we
As a specific application of this reaction, we chose to
develop a short synthesis of trichostatic acid 3. This com-
pound has been isolated from Streptomyces sioyaensis and
induces differentiation of leukemia cells.11 More impor-
tantly, 3 serves as a direct precursor to trichostatin A, one
(10) Brandt, P.; Norrby, P.-O.; Martin, I.; Rein, T. J. Org. Chem. 1998,
63, 1280.
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Markiewicz et al.
JOCNote
TABLE 3. Exploration of a Variety of Substrates
the diene moiety. The pivotal compound required to reduce
this plan to practice was the chiral aldehyde 4 as a substrate
for reaction with 1 (eq 2).
Our synthesis of trichostatic acid14 3 commenced with the
Evans aldol reaction15 of p-dimethylaminobenzaldehyde 5
with chiral propionyloxazolidinone 6, giving rise to a single
detectable diastereomer 7 in high yield (Scheme 1). Because a
SCHEME 1. Synthesis of 4
base-induced retro-aldol reaction plagued subsequent steps
in the synthesis, the hydroxyl group was protected as the
methyl ether under solvolytic conditions. As expected, this
reaction produced an inconsequential mixture of diastereo-
mers. The major anti-diastereomer16 8 could readily be iso-
lated by crystallization, and the minor isomer could be
re-equilibrated under acidic conditions, although both dia-
stereomers have the correct configuration at the stereogenic
center that ispresentintrichostatic acid. Removal of the chiral
auxiliary under typical reductive conditions (LiBH4, Red-Al,
DIBAL, etc.) proved challenging due to competing reductive
ring-opening of the oxazolidinone. This problem was over-
come by first converting imide 8 to thiol ester 9. Instead of the
typically used low molecular weight thiols, the long-chain
dodecanethiol was employed as an essentially nonvolatile,
nonodoriferous scavenger reagent that endowed the lipophilic
product 9 with conveniently exploitable chromatographic
properties for ease of separation from more polar impurities.
The thiol ester 9 could then be reduced to the corresponding
aldehyde 4 in good yield using Pd/C and Et3SiH.17
aRatios were measured from the 1H NMR of the crude material.
bYield of the purified product.
of the best known and most potent histone deacetylase
inhibitors.12 Some of the previously reported syntheses of 3
or its derivatives have tended to be somewhat long, given the
only modest complexity of this system.13 Most commonly,
the diene portion has been built up linearly by sequential uses
of olefination reactions, whereas the advantage of using
reagent 1 would in principle be a one-step construction of
(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. (d) Duan, W.; Zhang, T. Method
for chiral synthesis of histone deacetylase inhibitor Trichostatin A. Chinese Patent
CN 2005-10030149, April 4, 2007. (e) Chatterjee, A.; Richer, J.; Hulett, T.; Iska,
V. B. R.; Wiest, O.; Helquist, P. Org. Lett. 2010, 12, 832.
€
(14) Helquist, P.; Lofstedt, J. Process for Preparing Histone Deacetylase
(11) Morioka, H.; Ishihara, M.; Takezawa, M.; Hirayama, K.; Suzuki,
E.; Komoda, Y.; Shibai, H. Agric. Biol. Chem. 1985, 49, 1365.
(12) (a) Dokmanovic, M.; Clarke, C.; Marks, P. A. Mol. Cancer Res.
2007, 5, 981. (b) Monneret, C. Eur. J. Med. Chem. 2005, 40, 1. (c) Wiech,
N. L.; Fisher, J. F.; Helquist, P.; Wiest, O. Curr. Top. Med. Chem. 2009, 9, 257.
Inhibitors and Intermediates Thereof. U.S. Patent 7,235,688, June 26, 2007.
(15) Gage, J. R.; Evans, D. A.; DeRussy, D. T.; Paquette, L. A. Org.
Synth. 1990, 68, 83.
(16) Assigned by X-ray diffraction (see the Supporting Information).
(17) Fukuyama, T.; Tokuyama, H. Aldrichim. Acta 2004, 37, 87.
J. Org. Chem. Vol. 75, No. 6, 2010 2063

Markiewicz et al.
JOCNote
SCHEME 2. Synthesis of Trichostatic Acid 3
examples of its condensation, and the synthesis of trichostatic
acid, see the Supporting Information.
Methyl (2E,4E)-5-(4-Chlorophenyl)-4-methylpenta-2,4-dieno-
ate (2g). A solution of phosphonate 1 (110 mg, 0.44 mmol, 1.5
equiv) in THF (2 mL) was cooled to -78 °C, and a commercial
solution of LiHMDS (0.4 mmol, 1.4 equiv)19 was added drop-
wise. The solution was warmed to 22 °C for 30 min and recooled
to -78 °C. A solution of the 4-chlorobenzaldehyde (42 mg, 0.30
mmol, 1.0 equiv) in THF (1 mL) was added dropwise. The
solution was stirred for 12 h, and the temperature was allowed
to rise to 22 °C. After the formation of product had ceased (GC
monitoring), the reaction was quenched by the addition of pH 7
phosphate buffer (1 M). The solution was combined with
CH2Cl2 and NaCl saturated aqueous solution, extracted with
CH2Cl2, and dried with MgSO4. The solvent was removed under
reduced pressure to afford the crude compound which was
purified using flash column chromatography (SiO2, 0-10%
EtOAc in hexanes) to yield 2g (65 mg, 93%) of the pure 2E,4E
isomer as a solid: mp = 76-77 °C; 1H NMR (600 MHz, CDCl3)
δ 7.49 (dd, J = 16.0, 0.8 Hz, 1H, HCdCCdO), 7.36 (dd J = 6.4,
2 Hz, 2H, ArH meta to Cl), 7.28 (dd, J = 6.8, 2.0 Hz, 2H, ArH
ortho to Cl), 6.80 (bs, 1H, Ar-CHdC), 6.00 (dd, J = 15.0, 0.8
Hz, 1H, CdCHCdO), 3.80 (s, 3H, OCH3) 2.03 (d, J = 1.2 Hz,
3H, CdCCH3); (lit.20 1H NMR) 13C NMR (150 MHz, CDCl3)
δ 167.9, 149.8, 137.7, 135.3, 134.8, 133.8, 130.9, 128.8, 117.7,
51.8, 13.9; HMRS (ESI) for C13H13O2ClNa [M þ Na]þ calcd
237.0677, found 237.0688.
In the key step of the synthesis, aldehyde 4 reacted with
phosphonate 1 using LiHMDS in THF to give dienoate 10
(Scheme 2) as the product in good yield as a 2:1 mixture of
E,E- and E,Z-isomers. Commonly used methods of Z/E-
alkene isomerization (treatment with thiols, photochemical
irradiation) were applied to no avail, which may reflect little
thermodynamic preference for the desired E,E-isomer.18
This mixture posed little difficulty in the synthesis in that it
could readily be carried through the pathway, and separation
of isomers could be effected at the end. Thus, the isomeric
mixture of 11 was subjected to simple ester hydrolysis and
benzylic ether oxidation to give trichostatic acid 3 as the
corresponding mixture of isomers. At this stage, the mixture
could be separated by employing flash or medium-pressure,
normal-phase chromatography to give the pure, desired E,E-
isomer with 87% ee suggesting partial loss of stereochemical
integrity during the sequence of steps (see the Supporting
Information regarding the sensitivity of 4).The1Hand13CNMR
spectra matched the published data for trichostatic acid.13b
Acknowledgment. This research was funded by the
Walther Cancer Institute, Circagen, and the Ara Parseghian
Medical Research Foundation. We wish to acknowledge Dr.
Norbert Weich, Jacob Plummer, and Jed Fisher for helpful
discussions. We thank the Podrasnik/McCanna Fellowships
for financial support of D.J.S. and the Grace Fellowship for
financial support of J.T.M. We thank Dr. Anamitra Chat-
terjee for providing a racemic sample of 3 for comparison.
We also thank Dr. William Boggess, Dr. Bruce Noll,
ꢁꢀ
Dr. Allen Oliver, Dr. Jaroslav Zajicek, Dr. Viktor Krchnak,
In conclusion, the reactions of vinylogous HWE reagent 1
with aldehydes provide 4-methyldienoate derivatives in one
simple step. This method permits rapid access to substituted
and functionalized diene subunits seen in a variety of natural
products and other compounds of interest.
Leslie Patterson, Tim Wencewicz, Lauren Fluery, and An-
drew Kosal for technical support.
Supporting Information Available: Further experimental
procedures, spectral data, and crystallographic data. This ma-
terial is available free of charge via the Internet at http://pubs.
acs.org.
Experimental Section
A representative procedure for the vinylogous HWE reaction
is provided here. For preparation of the reagent 1, the other
(19) The commercial solution was titrated prior to use following a
literature procedure: Ireland, R. E.; Meissner, R. S. J. Org. Chem. 1991,
56, 4566.
(18) At the B3LYP/6-211þG** þ CPCM (THF)//6-31G* level of theory,
(20) Rebuffat, S.; Davoust, D.; Giraud, M.; Molho, D. Bull. Soc. Chim.
Fr. Part 2. Chim. Mol. Org. Biol. 1974, 2892.
the two isomers are within 0.1 kcal/mol of each other.
2064 J. Org. Chem. Vol. 75, No. 6, 2010