Efficient, enantioselective organocatalytic synthesis of trichostatin A

Article abstract of DOI:10.1002/adsc.200606106

An efficient, highly stereocontrolled total synthesis of trichostatin A (1) has been achieved in 9 steps with 17.4% overall yield and >99% optical purity from readily available achiral starting materials. The key features of this synthesis include the L-proline-promoted, highly enantioselective cross-aldol reaction as a crucial step for the construction of the C-6 chiral center and the minimization of racemization by final step oxidation of the OH group to a ketone at position 7.

Full text of DOI:10.1002/adsc.200606106

FULL PAPERS
DOI: 10.1002/adsc.200606106
Efficient, Enantioselective Organocatalytic Synthesis of
Trichostatin A
Shilei Zhang,a Wenhu Duan,a, b,* and Wei Wangb, c,*
a
Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Graduate
School of the Chinese Academy of Sciences, Shanghai 201203, Peopleꢀs Republic of China
Phone: (+86)-21-5080-6032; e-mail: whduan@mail.shcnc.ac.cn
Department of Medicinal Chemistry, School of Pharmacy, East China University of Science & Technology, Shanghai
b
200237, Peopleꢀs Republic of China
Department of Chemistry, University of New Mexico, Albuquerque, NM 87131-0001, USA
c
Phone: (+1)-505-277-0756; Fax: (+1)-505-277-2609; e-mail: wwang@unm.edu
Received: March 15, 2006; Accepted: May 9, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient, highly stereocontrolled total C-6 chiral center and the minimization of racemiza-
synthesis of trichostatin A (1) has been achieved in 9 tion by final step oxidation of the OH group to a
steps with 17.4% overall yield and >99% optical ketone at position 7.
purity from readily available achiral starting materi-
als. The key features of this synthesis include the l-
proline-promoted, highly enantioselective cross-aldol Keywords: aldol reaction; asymmetric organocataly-
reaction as a crucial step for the construction of the sis; HDAC inhibitors; proline; trichostatin A
Introduction
tively. In Moriꢀs asymmetric synthesis of trichostatin
A (1), the approach starting from chiral (R)-methyl 3-
The intriguing biological activity of trichostatin A (1) hydroxy-2-methylpropionate suffers from a long syn-
on histone deacetylases (HDACs) has elicited a con- thetic sequence (18 steps) and a low overall yield
siderable amount of attention from both the synthetic (6.1%).[5] In this paper, we disclose a practical, enan-
and the biological communities (Figure 1).[1] As a tioselective organocatalytic route to the preparation
potent and specific HDAC inhibitor,[2] trichostatin A of the title compound in 9 steps with a significantly
(1) has been extensively used as a valuable biological improved yield (17.4% overall) from readily avail-
tool for studying the functions of the enzyme and as a able, achiral starting materials.
lead compound for developing new anti-cancer
agents.[1–3] To date, surprisingly, only two methods for
its total synthesis have been described, reported by Results and Discussion
the research groups of Fleming[4] and Mori,[5] respec-
Our synthesis strategy is described in Scheme 1. To
develop an efficient, enantioselective approach to the
synthesis of (+)-trichostatin A (1), two critical issues
need to be addressed: building the chiral center at C-
6 and minimizing its racemization during the course
of the synthesis because of the adjacent carbonyl
chiral center C-6 easily undergoes racemization. We
postulate that one stone can kill two birds at the same
time by using a catalytic, enantioselective aldol reac-
tion as a key step to form a chiral b-hydroxy aldehyde
4, which can be accessed by an l-proline-catalyzed
cross-aldol reaction between aldehydes 5 and 6.[6–10]
The aldol adduct 4 serves as a precursor for the syn-
thesis of the key intermediate 3 via the Wittig reac-
Figure 1. (+)-Trichostatin A (1) and trichostatic acid (2).
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Synthesis of Trichostatin A
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ed the desired aldol adduct 4 with the best results (>
99% ee, 16/1 anti/syn ratio) (Scheme 2). It should be
noted that we found that, in this case, it was not nec-
essary to add 6 dropwise to a solution of 5 for the
cross-aldol reaction, as was required in MacMillanꢀs
procedure since the more reactive p-nitrobenzalde-
hyde (5) was used.[7d] Because of its quick decomposi-
tion on silica gel,[11] compound 4 was directly convert-
ed into acetal 7. The more stable 7 enabled us to de-
termine the stereoselectivities by its conversion into
the respective Mosher esters (see Supporting Infor-
mation).[12] Without purification, crude 4 was trans-
formed into a, b-unsaturated ester 8 by a Wittig reac-
tion with Ph3P=CHACHTER(UNG CH3)CO2Me in 93% yield in two
steps. The DIBAL-H mediated reduction was fol-
lowed by MnO2 oxidation[13] to give aldehyde 10a as
a major product in 80% yield in a two-step conver-
sion and the overoxidized dicarbonyl species 10b was
identified as a minor product (9% yield).
Alternatively, compound 10a could been obtained
by reaction of 4 with 2-(triphenylphosphoranylidene)-
propionaldehyde (11) in one step,[14] however, the
low yield and poor Z/E selectivity were observed
(Scheme 3).
Scheme 1. Retrosynthetic analysis of trichostatin A (1).
The resulting aldehyde 10a underwent a Horner–
tion. Oxidation of the hydroxy group in 3 in the last Emmons reaction with triethyl phosphonoacetate (13)
step can lead to the target molecule 1 so that racemi- to produce conjugated ester 14 in an excellent yield
zation can be significantly minimized during the syn- (Scheme 4).[15] It is realized that the C-6 chiral center
thesis. As demonstrated, the synthetic route we ex- in trichostatin A (1) is prone to racemization under
plore here can allow us to obtain 1 with an ee value both acid and basic conditions, and in Moriꢀs ap-
of >99%.
proach, it took four more steps to prepare 1 from tri-
After surveying several sets of reaction conditions, chostatic acid (2) (Figure 1) in only 27% yield.[5]
we found that by using MacMillanꢀs protocol,[7d] the Therefore, as discussed earlier, our strategy was to
l-proline-catalyzed cross-aldol reaction between p-ni- perform the oxidation of the alcohol in the last step
trobenzaldehyde (5) and propionaldehyde (6) afford- in order to avoid this problem. The nitro group in 14
Scheme 2. Synthesis of intermediate 10a.
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Conclusions
In conclusion, we have achieved a short, enantioselec-
tive synthesis of trichostatin A (1) in 9 steps with
17.4% overall yield. The key step in the synthesis is
the utilization of l-proline-promoted aldol reactions
to establish the chiral center in a completely stereo-
controlled manner. Optically pure target molecule (>
99% ee) has been obtained by the developed synthet-
ic route. To our knowledge, this synthesis is the short-
est reported so far using readily available, cheap achi-
ral materials. Our current efforts are directed toward
applying this strategy for the large-scale synthesis of
trichostatin A (1) and the preparation of its analogues
to explore their biological activities.
Scheme 3. An alternative approach to synthesis of 10a.
was selectively reduced to the amine in 15 by Lind-
larꢀs catalyst-promoted hydrogenation without touch-
ing the unsaturated conjugated system.[16] Pure prod-
uct 15 was obtained by recrystallization from a mix-
ture of ethyl acetate and petroleum ether in 62%
yield. Reductive amination[17] by the treatment with
Experimental Section
General Remarks
All non-aqueous reactions were performed in flame-dried
glassware under an atmosphere of dry Ar, unless otherwise
specified. THF was freshly distilled from sodium/benzophe-
none under Ar; CH2Cl2 was freshly distilled from CaH2
under Ar. All other solvents were reagent grade. Petroleum
ether refers to a mixture of alkanes with the boiling range
HCHO and NaBHCAHTREU(GN OAc)3 in THF furnished the di-
methylamine 16, which was subsequently exposed to
NH2OH/MeOH solution to provide the hydroxamic
acid 3. Finally, benefiting from the strong electron-do-
nating effect of the p-dimethylamine group, the ben-
zylic hydroxy group of 3 was selectively oxidized by
DDQ in dioxane without affecting the hydroxamic
acid group to give the target trichostatin A (1).[5] The
spectral data for the synthesized trichostatin A (1)
matched those of the naturally occurring com-
pound[18] and its optical purity was determined by
chiral HPLC analysis with>99% ee.[19]
1
60–908C. H and 13C NMR spectra were recorded on Varian
Mercury-300 and Varian Mercury-400 spectrometers. Chem-
ical shifts are reported in ppm from tetramethylsilane with
the solvent resonance as the internal standard. The follow-
ing abbreviations were used to explain the multiplicities: s=
singlet, d=doublet, t=triplet, q=quartet, dd=doublet of
doublets, m=multiplet, br=broad. Infrared spectra were re-
corded on a Nicolet 750FT-IR. Optical rotations were mea-
sured on a Perkin–Elmer model 341 polarimeter. Mass spec-
trometry was performed on Finnigan MAT 95 and Finnigan
LCQ Deca spectrometers. High resolution mass spectra
were measured on Finnigan MAT 95 and MicroMass Q-Tof
ultimaTM mass spectrometers.
Scheme 4. Synthesis of trichostatin A (1).
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Synthesis of Trichostatin A
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127.4, 123.5, 77.2, 51.9, 41.3, 16.4, 12.6; MS (ESI): m/z=
302.08 (M+ +Na); HR-MS (ESI): m/z=302.0995, calcd. for
C14H17NO5Na (M+ +Na): 302.1004.
(2S,3R)-3-Hydroxy-2-methyl-3-(4-nitrophenyl)propa-
nal (4)
To a solution of p-nitrobenzaldehyde (5; 3.02 g, 20 mmol)
and l-proline (460mg, 4 mmol, 0.2 equivs.) in 70mL of
DMF was added propionaldehyde (6; 2.88 mL, 40mmol, 2.0
equivs.) in one portion at 08C. The resulting mixture was
then stirred at same temperature for 5 h to reach comple-
tion. The reaction was quenched by addition of water and
extracted with EtOAc. The organic layer was washed with
brine and dried over MgSO4, filtered, and the solvent was
removed under reduced pressure. The resulting oil was used
without further purification for next step; 1H NMR
(400 MHz, CDCl3): d=9.80(1H, d, J=1.2 Hz), 8.22 (2H, d,
J=8.8 Hz), 7.55 (2H, d, J=8.4 Hz), 4.97 (1H, d, J=8.0Hz),
3.41 (1H, br), 2.77 (1H, m), 1.00 (3H, d, J=7.6 Hz).
AHCTRE(UNG 4R,5R,E)-2, 4-Dimethyl-5-(4-nitrophenyl)pent-
2-ene-1,5-diol (9)
To a solution of compound 8 (0.927 g, 3.33 mmol) in THF
(10mL) was added dropwise DIBAL-H (11.5 mL, 1.0 m in
toluene, 11.5 mmol, 3.45 equivs.) at ꢀ708C under an argon
atmosphere over a period of 30min. After being stirred at
the same temperature for another 30min, the reaction mix-
ture was quenched with saturated Rochelle salt solution
(20mL) and the temperature of the mixture was raised to
room temperature. After being stirred at room temperature
for 1 h vigorously, the mixture was extracted with EtOAc.
The organic layer was washed with brine and dried over
MgSO4, filtered, and concentrated under reduced pressure.
The residue was used for the next reaction without further
purification; [a]2D4: +100.68 (c 0.638, CHCl3); IR (KBr): n=
3373, 2966, 2928, 2872, 1606, 1518, 1456, 1348, 1109, 1013,
ACHTREUNG(1R,2S)-3, 3-Dimethoxy-2-methyl-1-(4-nitrophenyl)-
propan-1-ol (7)
To a solution of 4 (2 mmol) in 4 mL of MeOH was added
trimethyl orthoformate (0.32 g, 3 mmol, 1.5 equivs.) and p-
toluenesulfonic acid monohydrate (38 mg, 0.2 mmol,
0.1 equiv.). The resulting pale yellow solution was stirred at
room temperature for 1 h, then quenched by addition of sa-
turated aqueous NaHCO3 and extracted with EtOAc. The
organic layer was washed with brine and dried over MgSO4,
filtered, and concentrated under reduced pressure. The resi-
due was purified on silica gel (petroleum ether/EtOAc, 6:1)
to afford a colorless oil; yield: 0.45 g (88%, two steps from
5); [a]2D3: ꢀ6.948 (c 3.10, CHCl3); IR (KBr): n=3444, 2939,
2834, 1666, 1606, 1520, 1456, 1348, 1196, 1107, 1068, 947,
851, 754, 704 cmꢀ1 1H NMR (300 MHz, CDCl3): d=8.18
;
(2H, d, J=8.7 Hz), 7.50(2H, d, J=8.7 Hz), 5.34 (1H, dd,
J=9.9, 1.5 Hz), 4.46 (1H, d, J=7.8 Hz), 4.01 (2H, s), 2.69
(1H, m), 2.6–1.8 (2H, br), 1.61 (3H, d, J=1.2 Hz), 0.84
(3H, d, J=6.9 Hz); 13C NMR (100 MHz, CDCl3): d=150.3,
147.2, 137.9, 127.6, 126.3, 123.3, 78.0, 68.0, 40.5, 17.2, 14.1;
MS (EI): m/z (%)=233 [M+-H2O], 216, 203, 185 (6.0), 153
(100), 142 (70), 136 (46), 106 (20), 100 (23), 82 (84), 77 (12),
67 (28), 60(8).
852, 756, 708 cmꢀ1 1H NMR (300 MHz, CDCl3): d=8.20
;
(4R,5R,E)-5-Hydroxy-2,4-dimethyl-5-(4-nitrophenyl)-
(2H, d, J=8.7 Hz), 7.51 (2H, d, J=8.7 Hz), 4.72 (1H, d, J=
8.4 Hz), 4.31 (1H, d, J=5.7 Hz), 3.50(3H, s), 3.42 (3H, s),
2.11 (1H, m), 0.69 (3H, d, J=7.2 Hz); 13C NMR (100 MHz,
CDCl3): d=150.7, 147.7, 128.2, 123.8, 108.9, 75.8, 56.5, 54.1,
42.8, 12.6; MS (EI): m/z (%)=256 [M+ +H], 223 (2.0), 152
(10), 75 (100), 72 (67); HR-MS (EI): m/z=256.1199, calcd.
for C12H18NO5 (M+ +H): 256.1185.
pent-2-enal (10a)
To a solution of compound 9 in CH2Cl2 (40mL) was added
g-MnO2 (3.2 g). The resulting mixture was then stirred at
room temperature for 1 h to reach completion. The mixture
was filtered and washed with a large amount of EtOAc. The
organic layer was concentrated under reduced pressure and
purified by silica gel column chromatography (petroleum
ether/AcOEt, 3/1) to give 10a as a crystalline product; yield:
663 mg (80% in two steps). Compound 10b was obtained as
a by-product; yield: 73 mg (8.9% in two steps).
ACHTREUNG(4R,5R,E)-Methyl 5-Hydroxy-2, 4-dimethyl-5-
(4-nitrophenyl)pent-2-enoate (8)
Compound 10a: mp 92–948C; [a]2D1: +76.58 (c 0.702,
CHCl3); IR (KBr): n=3518, 2968, 2928, 1670, 1641, 1606,
To a solution of 4 (20mmol) in 40mL of CH 2Cl2 was added
(1-methoxycarbonylethylidene)triphenylphosphorane
1518, 1350, 1184, 1086, 1013, 845, 746 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d=9.40(1H, s), 8.20(2H, d, J=8.7 Hz),
7.51 (2H, d, J=8.7 Hz), 6.46 (1H, d, J=9.6 Hz), 4.80(1H,
dd, J=5.7, 2.7 Hz), 3.05 (1H, m), 2.36 (1H, d, J=3.3 Hz),
1.60(3H, d, J=0.6 Hz), 1.08 (3H, d, J=7.2 Hz); 13C NMR
(100 MHz, CDCl3): d=195.2, 154.4, 149.9, 147.3, 140.2,
127.1, 123.5, 76.9, 41.3, 16.6, 9.3; MS (EI): m/z (%)=249
[M+], 233 (11), 218 (7), 205 (3), 152 (27), 122 (4), 106 (8), 98
(100), 83 (17), 77 (10), 69 (13), 55 (4); HR-MS (EI): m/z=
249.1005, calcd. for C13H15NO4 (M+): 249.1001.
(8.35 g, 24 mmol, 1.2 equivs.). The resulting yellow mixture
was refluxed for 5 h. The reaction mixture was concentrated
under reduced pressure and purified by silica gel column
chromatography (petroleum ether/AcOEt, 5/1) to give a col-
orless oil; yield: 5.19 g (93% in two steps); [a]2D4: +102.28 (c
1.024, CHCl3); IR (KBr): n=3537, 2960, 1714, 1649, 1603,
1514, 1437, 1342, 1265, 1240, 1221, 1065, 856, 748, 704 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d=8.17 (2H, d, J=8.7 Hz),
7.49 (2H, d, J=8.7 Hz), 6.69 (1H, dd, J=9.9, 1.5 Hz), 4.66
(1H, d, J=6.6 Hz), 3.71 (3H, s), 2.82 (1H, m), 2.61 (1H, s),
1.73 (3H, d, J=1.5 Hz), 0.95 (3H, d, J=6.9 Hz); 13C NMR
(100 MHz, CDCl3): d=168.3, 149.8, 147.4, 142.3, 129.4,
Compound 10b: 1H NMR (300 MHz, CDCl3): d=9.45
(1H, s), 8.34 (2H, d, J=9.0Hz), 8.10 (2H, d, J=9.0Hz),
6.70(1H, dd, J=9.6, 1.5 Hz), 4.59 (1H, m), 1.89 (3H, d, J=
1.5 Hz), 1.45 (3H, d, J=6.9 Hz).
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give 244 mg of crude product and, after recrystallization
from petroleum ether and AcOEt, the crystalline material;
yield: 172 mg (62%); mp 126–1288C; [a]2D3: +1778 (c 0.850,
CHCl3); IR (KBr): n=3458, 3346, 2976, 1695, 1618, 1518,
ACHTREUNG
1392, 1311, 1292, 1246, 1186, 1028, 986, 829, 582 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d=7.36 (1H, dd, J=15.6,
0.6 Hz), 7.11 (2H, d, J=8.4 Hz), 6.66 (2H, d, J=8.4 Hz),
5.84 (1H, d, J=10.2 Hz), 5.81 (1H, d, J=15.6 Hz), 4.36
(1H, d, J=7.5 Hz), 4.21 (2H, q, J=7.2 Hz), 3.67 (2H, br),
2.84 (1H, m), 1.77 (3H, d, J=1.2 Hz), 1.30(3H, t, J=
7.2 Hz), 0.86 (3H, d, J=6.9 Hz); 13C NMR (100 MHz,
CDCl3): d=167.4, 149.4, 145.9, 144.1, 133.7, 132.5, 127.7,
116.0, 114.8, 78.3, 60.1, 41.2, 16.8, 14.2, 12.4; MS (EI): m/z=
289 [M+], 271 (2), 198 (5), 168 (14), 149 (5), 139 (5), 122
(100), 94 (16), 77 (11); HRMS (EI): m/z=289.1687, calcd.
for C17H23NO3 (M+): 289.1678.
To a solution of 4a (0.5 mmol) in 1 mL of CH2Cl2 and 5 mL
of toluene was added 2-(triphenylphosphoranylidene)-pro-
pionaldehyde (11; 318 mg, 1 mmol, 2 equivs.). The resulting
yellow mixture was refluxed for 3 h. The reaction was con-
centrated under reduced pressure and purified by silica gel
column chromatography (petroleum ether/AcOEt, 2/1) to
give the compound 10a and 12 (yield: 54 mg, 43% in two
1
steps). The ratio of 10a:12 was 5:3 determined by H NMR
analysis.
(2E,4E,6R,7R)-Ethyl 7-Hydroxy-4, 6-dimethyl-7-
(4-nitrophenyl)hepta-2, 4-dienoate (14)
(2E,4E,6R,7R)-Ethyl 7-[4-(Dimethylamino)phenyl]-
7-hydroxy-4,6-dimethylhepta-2,4-dienoate (16)
To a suspension of sodium hydride (120mg, 60% in oil,
3.0mmol, 3.0equivs.) in THF (5.0mL) was added dropwise
To a solution of compound 15 (600 mg, 2.08 mmol) in THF
(35 mL) was added formaldehyde (505 mg, 37% aqueous,
6.23 mmol, 3.0equivs.). The mixture was stirred at room
temperature for 10min. Then sodium triacetoxyborohydride
(1.32 g, 6.23 mmol, 3.0equivs.) was added and the resulting
mixture was stirred at room temperature for 10h. The reac-
tion mixture was filtered and washed with EtOAc. The or-
ganic layer was concentrated under reduced pressure and
purified by silica gel column chromatography (petroleum
ether/AcOEt, 5/1 ! 3/1) to give the compound 16; yield:
527 mg (80%); [a]2D3: +1808 (c 0.441, CHCl3); IR (KBr): n=
3466, 2978, 1705, 1616, 1522, 1446, 1348, 1308, 1165, 1026,
a
solution of triethyl phosphonoacetate (13; 720 mL,
4.0mmol, 4.0equivs.) in THF (5.0mL) at room temperature
under argon over a period of 10min. After being stirred at
room temperature for another 20min, a solution of 10a
(249 mg, 1.0mmol) in THF (5.0mL) was added dropwise.
The resulting mixture was then stirred for 30min to reach
completion. The reaction was quenched by addition of satu-
rated aqueous NaHCO3 and the mixture extracted with
EtOAc. The organic layer was washed with brine, dried over
MgSO4, filtered, and the solvent was removed under re-
duced pressure. The residue was purified by silica gel
column chromatography (petroleum ether/AcOEt, 5/1) to
give a colorless oil; yield: 306 mg (96%); [a]2D3: +1288 (c
0.140, CHCl3); IR (KBr): n=3466, 3078, 2978, 1693, 1622,
984, 945, 820cm ꢀ1 1H NMR (300 MHz, CDCl3): d=7.36
;
(1H, dd, J=15.9, 0.6 Hz), 7.18 (2H, d, J=8.7 Hz), 6.70(2H,
d, J=8.7 Hz), 5.86 (1H, d, J=9.9 Hz), 5.81 (1H, d, J=
15.9 Hz), 4.37 (1H, d, J=7.5 Hz), 4.20(2H, q, J=7.2 Hz),
2.94 (6H, s), 2.87 (1H, m), 1.97 (1H, br), 1.79 (3H, d, J=
1.2 Hz), 1.30(3H, t, J=7.2 Hz), 0.85 (3H, d, J=6.9 Hz);
13C NMR (100 MHz, CDCl3): d=167.5, 150.3, 149.4, 144.2,
133.7, 130.3, 127.5, 116.1, 112.3, 78.4, 60.1, 41.2, 40.6, 16.9,
14.3, 12.5; MS (EI): m/z (%)=317 [M+], 299 (55), 226
(100), 211 (38), 150 (73); HR-MS (EI): m/z=317.1973,
calcd. for C19H27NO3 (M+): 317.1991.
1516, 1456, 1348, 1180, 1026, 847, 750, 704 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d=8.19 (2H, d, J=8.7 Hz), 7.50(2H, d,
J=8.4 Hz), 7.30(1H, dd, J=0.6, 15.9 Hz), 5.80 (1H, d, J=
15.3 Hz), 5.80(1H, d, J=10.5 Hz), 4.65 (1H, d, J=6.6 Hz),
4.20(2H, q, J=7.2 Hz), 2.87 (1H, m), 2.27 (1H, d, J=
3.0Hz), 1.67 (3H, d, J=0.9 Hz), 1.29 (3H, t, J=7.2 Hz),
0.97 (3H, d, J=6.6 Hz); 13C NMR (100 MHz, CDCl3): d=
167.5, 150.3, 148.9, 147.1, 141.7, 134.3, 127.3, 123.3, 116.6,
77.2, 60.3, 41.1, 16.9, 14.2, 12.3; MS (EI): m/z (%)=320
[M+ +H], 274 (7), 168 (100), 152 (23), 139 (34), 122 (24),
111 (13), 95 (81), 79 (18), 67 (6), 55 (5); HR-MS (EI): m/z=
320.1481, calcd. for C17H22NO5 (M+ +H): 320.1498.
(2E,4E,6R,7R)-7-[4-(Dimethylamino)phenyl]-N,7-di-
hydroxy-4, 6-dimethylhepta-2, 4-dienamide (3)
To a solution of compound 16 (140mg, 0.44 mmol) in 4 mL
of MeOH was added NH2OH (10mL, 1.5 m in MeOH). The
resulting mixture was then stirred at room temperature for
2 h to reach completion. The reaction was quenched by ad-
dition of saturated aqueous NaHCO3 and the mixture ex-
tracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, filtered, and the solvent removed
under reduced pressure. The resulting oil was used without
further purification for the next step; 1H NMR (300 MHz,
CDCl3): d=7.24 (1H, d, J=15.6 Hz), 7.16 (2H, d, J=
8.4 Hz), 6.71 (2H, d, J=8.7 Hz), 5.80–5.73 (2H, m), 4.30
(2E,4E,6R,7R)-Ethyl 7-(4-Aminophenyl)-7-hydroxy-
4,6-dimethylhepta-2, 4-dienoate (15)
To a solution of compound 14 (306 mg, 0.96 mmol) in 10 mL
of MeOH was added 210mg of Lindlarꢀs catalyst and 90 mL
of quinoline. The resulting mixture was then stirred under
an H2 atmosphere for 10h. The reaction mixture was fil-
tered and washed with EtOAc. The organic layer was con-
centrated under reduced pressure and purified by silica gel
column chromatography (petroleum ether/AcOEt, 2/1) to
1232
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Adv. Synth. Catal. 2006, 348, 1228 – 1234

Synthesis of Trichostatin A
FULL PAPERS
(1H, d, J=7.5 Hz), 2.91 (6H, s), 2.81 (1H, m), 1.72 (3H, s),
0.76 (3H, d, J=6.3 Hz).
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Trichostatin A (1)
To a solution of compound 3 in dioxane (5 mL) was added
dropwise DDQ (0.10m in dioxane). The reaction process
was monitored by TLC to avoid addition of excess DDQ.
When compound 3 has disappeared, about 2.6 mL of DDQ
(0.26 mmol, 0.59 equivs.) had been consumed. The resulting
pale mixture was filtered and washed with dioxane. The or-
ganic layer was concentrated under reduced pressure and
purified by silica gel column chromatography (CH2Cl2/
MeOH, 20/1) to give a yellow solid; yield: 65 mg (49% in
two steps); mp 140–1438C; [a]2D1: +1068 (c 0.095, EtOH); IR
(KBr): n=3423, 3232, 2924, 1655, 1595, 1547, 1375, 1244,
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1188, 1171, 1059, 974, 824 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): d=7.85 (2H, d, J=9.0Hz), 7.20 (1H, d, J=
15.6 Hz), 6.66 (2H, d, J=9.0Hz), 5.96 (1H, d, J=9.9 Hz),
5.78 (1H, d, J=15.9 Hz), 4.41 (1H, m), 3.08 (6H, s), 1.90
(3H, s), 1.30(3H, d, J=6.6 Hz); 13C NMR (100 MHz,
CDCl3:CD3OD=7.5:1): d=199.5, 165.0, 153.5, 144.8, 139.9,
132.5, 130.5, 123.2, 115.2, 110.5, 40.4, 39.6, 17.5, 12.2; MS
(EI): m/z=302 [M+], 287 (0.6), 274 (3.5), 148 (100); HRMS
(EI): m/z=302.1621, calcd. for C17H22N2O3 (M+): 302.1630;
Daicel CHIRALPAK AS-H, hexane/EtOH, 50:50 with
0.1% TFA, flow rate 0.5 mLminꢀ1
, l=254 nm, tR =
14.78 min (major), minor one is not observed,>99% ee.
Acknowledgements
We are grateful for the financial support from the Depart-
ment of Medicinal Chemistry, School of Pharmacy, East
China University of Science & Technology. We also thank
Mr. Jian Wang for his help with the chiral HPLC analysis.
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1234
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Adv. Synth. Catal. 2006, 348, 1228 – 1234