Synthesis of epigoitrin from (R)-(+)-4-hydroxy-γ-butyrolactone

Article abstract of DOI:10.1002/jhet.1560

Epigoitrin is one of the major components of several natural species, including Isatis indigotica Fort, turnip, and cabbage. It presents antithyroid and antivirus activities. Here, we report an efficient and practical method for the chemical synthesis of epigoitrin from commercially available (R)-(+)-4-hydroxy-γ-butyrolactone.

Full text of DOI:10.1002/jhet.1560

1
290
Synthesis of Epigoitrin from (R)-(+)-4-Hydroxy-g-butyrolactone
Vol 50
Wei Yin and Chunhua Qiao*
College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
*
E-mail: qiaochunhua@suda.edu.cn
Received July 18, 2011
DOI 10.1002/jhet.1560
Published online 6 September 2013 in Wiley Online Library (wileyonlinelibrary.com).
HO
O
NH
O
S
O
Epigortrin
(
R)-(+)-4-Hydroxy- -butyrolactone
Epigoitrin is one of the major components of several natural species, including Isatis indigotica Fort, turnip,
and cabbage. It presents antithyroid and antivirus activities. Here, we report an efficient and practical method for
the chemical synthesis of epigoitrin from commercially available (R)-(+)-4-hydroxy-g-butyrolactone.
J. Heterocyclic Chem., 50, 1290 (2013).
INTRODUCTION
gave the trimethylsilyl-protected cyanohydrins adduct;
subsequent lithium aluminum hydride (LiAlH ) reduction
4
Epigoitrin (Fig. 1), which mainly exists in the radix of
Isatis indigotica Fort [1], was reported to exhibit a variety
of biological capabilities, including antithyroid and antivirus
activities [2,3]. Both epigoitrin and its enantiomer goitrin
display in vivo antithyroid activity [2]. However, only
epigoitrin presents strong antivirus activity [3]. Commer-
cially available goitrin was almost always a mixture of both
enantiomers, which makes confusions for evaluating the
compound’s pharmacodynamics, side effect, and the
accuracy of single dose content. On the other hand, further
biological exploration of epigoitrin was discouraged by the
limited natural source of I. indigotica Fort. Therefore, there
is a great need to develop a synthetic route for chemical
preparation of optically pure epigoitrin.
Up to date, chemical synthesis of epigoitrin was rarely
explored. In 1950, Martin G. E reported the first chemical
preparation of epigoitrin. This route employed 1-amino-3-
buten-2-ol as the key intermediate; after treating with aque-
ous alkali and carbon disulfide, epigoitrin was successfully
obtained [4]. The required 1-amino-3-buten-2-ol was
prepared from butadiene monoxide and aqueous ammonia;
this reaction leads to two regioisomers. To obtain each
isomer, fractional crystallization of their corresponding
oxalates was resorted. Overall, this synthetic method suffers
from the following drawbacks: the expensive starting
material butadiene monoxide and the difficulty to recover
the pure aminobutenol because of its high solubility in water.
Later on, preparation of 1-amino-3-buten-2-ol was further
optimized by Gardrat C. et al. According to the improved
procedure [5], addition of trimethylsiyl cyanide to acrolein
afforded 1-amino-3-buten-2-ol, and effective recovery of
this highly water soluble product was achieved by using
the triethanolamine/water hydrolytic system instead of
the classical water/sodium hydroxide/water system. Conse-
quently, the amino alcohol was converted into goitrin in
good yield when treated with carbon disulfide under aqueous
alkali condition. However, this synthetic route was not
applicable for the synthesis of epigoitrin because of the lack
of stereoselectivity. More recently, another research group
established the resolution of the racemic mixture of amino
alcohol by converting it to diastereomeric camphor sulfonic
acid ammonium salt [6].
As a byproduct, epigoitrin could also be prepared by
enzymatic cleavage of thioglucoside, which was isolated
from Crambe abyssinica seeds [7–10]. In the absence of
ferrous salts, hydrolysis of thioglucoside by myrosinase
leads to an intermediate b-hydroxy isothiocyanate, which
spontaneously undergoes cyclization to give epigoitrin
(Scheme 1) [7,9]. Likewise, the source of the starting
material thioglucoside and utilization of enzyme myrosinase
limited the practical application of this method to prepare
large-scale epigoitrin. Herein, we report a new practical
method for the stereoselective synthesis of epigoitrin
(Scheme 2).
RESULTS AND DISCUSSION
To construct the chiral center of epigoitrin, we take
advantage of the intrinsic chiral center of the commercially
©
2013 HeteroCorporation

November 2013
Starting from (R)-(+)-4-Hydroxy-g-butyrolactone:
1291
A Concise Route for Stereoselective Synthesis of Epigoitrin is Developed
mixture successfully accomplished the oxazole ring in one
pot. Nevertheless, once the azido group was converted to
amino, the facile intramolecular cyclization would provide
5-membered ring amide. To avoid this byproduct formation,
a rigorous reaction condition should be employed at this
*
O
NH
S
R-
ꢀ
Figure 1. Structure of epigoitrin.
step. The optimized reaction condition is À10 C and less
than 2 h hydrogenation time. Our initial attempt employing
lithium aluminum hydride (LiAlH ) as reductant to achieve
4
available material (R)-(+)-4-hydroxy-g-butyrolactone (Alfa
Aesar, 5 g/RMB2034.90). Reaction of this lactone with
trimethylsilyl iodide provided the ring-open product 2 [12].
compound 5 is not promising; a messy TLC along the
reaction discouraged the utilization of this reactive reagent.
Finally, a milder reagent sodium boron hydride (NaBH4)
successfully completed the reduction. Apparently, the
terminal double bond in epigoitrin could be formed by an
E2 elimination. Therefore, we first converted the hydroxyl
to a better leaving group mesylate. Surprisingly, the
commonly used organic base 1,8-Diazabicycloundec-7-ene
Next the iodide is replaced by an azido group to give
,
compound 3; the yield in both steps is higher than 90%. To
construct the thio-1,3-oxazole ring, the azido was first
reduced to amino group through Pd/C-catalyzed hydrogena-
tion; addition of thiocarbonyldiimidazole to this reaction
Scheme 1. General pathway of myrosinase-catalyzed hydrolysis of epiprogoitrin [11].
OH
O
HO
HS
HO
Myrosinase
H2O
D-Glucose
HO
HO
S
OH
O3SO
-O3SO
N
-
N
Thiohydroximate-O-sulphonate
Thioglucoside
HSO4-
A
c
H
id
p
p
l
tr
a
H
,
u
F
e 2
e
N
+
OH
S
Lossen
rearrangement
OH
S
C
N
CN
N
OH
S-1-cyano-2-hydroxy-3-butene
2
unstable
isothiocyanate
NH
O
S
2(R)
Epigoitrin
Scheme 2. Synthesis of epigoitrin from (R)-(+)-4-hydroxy-g-butyrolactone.
O
O
HO
MeSiI, CH3CH2OH
91%
O
NaN3, DMF
O
1
. H2, Pd/C
2. TCDI
0%
O
HO
O
HO
9
4%
5
1
I
2
N3
3
O
NH
O
O
OH
OMs
1. NaI
NaBH4
71%
CH3SO2Cl
85%
O
O
O
NH
NH
S
4
6
S
5
S
I
2
. t-BuOK
O
90% in 2 steps
NH
Epigoitrin
NH
S
S
7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
292
W. Yin and C. Qiao
Vol 50
+
6
2
1.13, 40.84, 14.24, 12.20. HRMS Calcd for [M + Na ]:
80.9645; found [ESI ]: 280.9640; error 1.78ppm.
(
could not affect the elimination purpose. The monitoring
TLC plate indicated the starting material was disappeared
within 10 min; however, lost of UV positive product genera-
tion suggested that 1,8-diazabicycloundec-7-ene may execute
+
R)-Ethyl 4-azido-3-hydroxybutanoate (3). To a solution
of 2 (3.15 g, 12.2mmol, 1.0 equiv.) in 20mL, dry DMF was
added NaN (1.8 g, 27.7 mmol, 2.27 equiv) at room temperature.
The resulting reaction mixture was then heated at 100 C for 3 h
before being cooled to room temperature and filtered. The
remaining salt was washed with ether and filtered. The combined
organic fractions were concentrated under reduced pressure, and
the resulting yellow oil was subjected to column chromatography
3
as a too strong base. Subsequently, milder base Et N as well
ꢀ
3
as K CO was employed. In both cases, no product formation
2
3
announced that either base could accomplish the elimination
function. Hereby, the mesylate was further transformed to
iodo 7. Finally, a strong base, t-BuOK, fulfilled the elimina-
tion reaction to supply the target epigoitrin 8 at a satisfactory
yield. Essentially, our chemically prepared product was
nuclear magnetic resonance as well as optical rotation
identical with the natural product.
(
petroleum ether : ethyl acetate = 5:1) to give 3 as a light
1
yellow oil (2.0 g, 94%). H NMR (400 MHz, CDCl
4
1
3
) d
.15 (m, 3H), 3.42–3.20 (m, 3H), 2.58–2.44 (m, 2H),
.25 (t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl ) d
3
172.10, 77.48, 77.16, 76.84, 67.40, 61.10, 55.64, 38.55,
4.17. HRMS Calcd for [M + Na ]: 196.0693; found
ESI ]: 196.0695; error 1.02 ppm.
R)-Ethyl 2-(2-thioxooxazolidin-5-yl)acetate (4). (R)-Ethyl
-azido-3-hydroxybutanoate (1.84 g, 10.6 mmol, 1.0 equiv.) was
13
+
1
[
+
(
CONCLUSIONS
4
dissolved in 20-mL anhydrous EtOH, and 10% Pd/C (100mg)
In summary, the biologically important component
epigoitrin was successfully prepared from commercially
available (R)-(+)-4-hydroxy-g-butyrolactone. This developed
synthetic route is composed of seven reaction steps, with an
overall yield of 23%.
was added. The solution was stirred for 4 h under H atmosphere
2
at 1 atm. The solution was filtered through Celite to remove the
catalyst, and the resulting solution was concentrated in vacuo to
afford a crude oil, which was used without further purification. To
the aforementioned product in 10mL, CH Cl was added
2 2
thiocarbonyl diimidazole (TCDI) (2.84 g, 15.9mmol, 1.5 equiv.),
and the solution was stirred overnight and concentrated. The
residue was purified by flash chromatography (petroleum
EXPERIMENTAL
ether : ethyl acetate= 2:1) to give 4 as a yellow oil (1.0 g, 50%).
1
All solvents and reagents were obtained from commercially
available sources and were dried and distilled prior to use. The
starting material (R)-(+)-4-hydroxy-g-butyrolactone was purchased
H NMR (300 MHz, CDCl ) d 8.34 (s, 1H), 5.33–5.10 (m, 1H),
3
4.12 (q, J = 7.1 Hz, 2H), 3.97 (t, J = 9.6 Hz, 1H), 3.53
(t, J = 8.7 Hz, 1H), 2.94 (dd, J = 16.7, 5.7 Hz, 1H), 2.77 (dd,
13
from Alfa Aesar (5g/RMB2034.90). CH
Cl
2 2
was dried over CaH
2
J = 16.7, 7.5 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). C NMR (75MHz,
for 2 h, then distilled and collected. DMF was dried over MgSO4
overnight, then distilled under vacuum and collected. TLC analysis
was carried on Yellow Sea Sil G/UV 450 on polyester plates using
different solvents system. Flash chromatography was carried out
on silica gel using petroleum as the initial elution followed by differ-
ent elution mixtures (dichloromethane/methanol; ethyl acetate/
CDCl ) d 188.99, 169.06, 78.67, 61.35, 49.19, 38.77, 14.07.
HRMS Calcd for [M + H ]: 190.0532; found [ESI ]:190.0532;
error: 0 ppm.
3
+
+
(R)-5-(2-Hydroxyethyl) oxazolidine-2-thione (5). To a stirred
solution of 4 (400 mg, 2.11 mmol, 1.0 equiv) in a mixture of 10 mL
of anhydrous methanol and 10 mL of dry THF was added NaBH4
(160 mg, 4.22 mmol, 2 equiv). The reaction mixture was stirred for
1
13
ꢀ
petroleum ether). H and C NMR spectra were recorded at 25 C
1
ꢀ
on 300MHz or 400MHz. H NMR spectrum was recorded using
2h at 0 C, concentrated in vacuo; the residue was purified by flash
1
3
TMS as the internal reference; C NMR spectrum was recorded
using the residual solvent as the internal reference. Chemical
shifts (d) are given in parts per million (ppm). Coupling constants
chromatography (dichloromethane : methanol = 40:1) to give 5 as
1
a white solid (220 mg, 71%). H NMR (300MHz, CD OD) d
3
5.20–5.08 (m, 1H), 3.95 (t, J = 9.5 Hz, 1H), 3.84–3.75
(
J) are reported as Hertz. NMR abbreviations are used as follows:
(m, 2H), 3.55 (dd, J = 10.0, 7.8 Hz, 1H), 2.18–1.94 (m,
1
3
s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet.
The solutions are taken from a concentrated sample dissolved in
CDCl , CD OD, and DMSO-d .
2H).
3
C NMR (75 MHz, CD OD) d 190.60, 81.97,
+
58.53, 50.18, 8.20. HRMS Calcd for [M + H ]: 148.0427;
+
3
3
6
found[ ESI ]:148.0427.
(
R)-Ethyl 3-hydroxy-4-iodobutanoate (2). To a solution of
R)-(+)-4-hydroxy-g-butyrolactone (1.5 g, 14.8 mmol, 1.0 equiv.)
and absolute EtOH (2.6mL, 44.4 mmol, 3 equiv.) in dry CH Cl
60 mL), Me SiI (3mL, 22mmol, 1.5 equiv.) was slowly added
(R)-2-(2-Thioxooxazolidin-5-yl) ethyl methanesulfonate (6). To
a stirred solution of 5 (87 mg, 0.59mmol, 1.0 equiv) and
(
2
2
triethylamine (123mL, 0.89mmol, 1.5 equiv) in dry CH Cl2
2
(
3
(10 mL) was added methane sulfonylchloride (55mL, 0.71mmol,
ꢀ
within 45min. The reaction mixture was stirred overnight at room
temperature. The solvent was evaporated, and the oily brown
1.2 equiv) dropwise at 0 C. The whole mixture was stirred
ꢀ
for 0.5 h at 0 C and evaporated. The residue was purified
residue was dissolved in Et
washed with 5% aqueous Na
MgSO ), and evaporated; the residual oil was subjected to
2
O (150 mL). The organic layer was
by flash chromatography (dichloromethane : methanol = 60:1)
1
S O
2 2 3
solution (2Â 10 mL), dried
to give 6 (114 mg, 85%). H NMR (300 MHz, CDCl ) d
3
(
8.00 (s, 1H), 5.25–4.98 (m, 1H), 4.42 (t, J = 5.9 Hz, 2H),
4
column chromatography (petroleum ether : ethyl acetate= 5:1) to
afford 2 as a pale yellow oil (3.55 g, 91%). H NMR (400 MHz,
3.95 (t, J = 9.4 Hz, 1H), 3.50 (dd, J = 9.7, 7.8 Hz, 1H), 3.06
1
13
(s, 3H), 2.35–2.14 (m, 2H). C NMR (75 MHz, CDCl ) d
3
CDCl
3
) d 4.16 (q, J = 7.0 Hz, 2H), 4.03–3.93 (m, 1H), 3.30
189.17, 79.48, 65.66, 49.14, 37.57, 34.18. HRMS Calcd
for [M + H ]: 226.0202; found [ESI ]: 226.0197; error
2.21 ppm.
+
+
(
(
m, 2H), 3.14 (br.s, 1H), 2.61 (dd, J = 16.4, 7.8 Hz, 2H), 1.26
t, J = 7.1 Hz, 3H). C NMR (100 MHz, CDCl ) d 171.83, 67.57,
1
3
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2013
Starting from (R)-(+)-4-Hydroxy-g-butyrolactone:
1293
A Concise Route for Stereoselective Synthesis of Epigoitrin is Developed
(R)-5-(2-Iodoethyl) oxazolidine-2-thione (7). To a solution
Acknowledgment. The financial support from Chinese National
of 6 (114 mg, 0.51 mmol, 1.0 equiv) in 4-mL acetone was added
NaI (152 mg, 1.02 mmol, 2.0 equiv). The reaction mixture was
refluxed overnight and concentrated. The residue was purified by
flash chromatography (petroleum ether : ethyl acetate = 3:1) to give
Science Foundation (81072514) is gratefully acknowledged.
REFERENCES AND NOTES
7
as a white solid. This crude product is used in the next step to
[
[
1] Huang, Q.S.; Yoshihira, K.; Natori, S. Planta Med 1981, 42, 308.
2] Tookey, H. L.; Van Etten, C. H.; Daxenbichler, M. E. Toxic
1
prepare compound 8 without further purification. H NMR
300 MHz, CDCl ) d 5.14–5.01 (m, 1H), 3.94 (t, J= 9.2 Hz, 1H),
.51–3.39 (m, 1H), 3.25–3.37 (m, 2H), 2.33–2.49 (m, 1H), 2.28–2.10
(
3
3
Constituents of Plant Foodstuffs, 2nd Ed, I. E. Liener (Ed). Academic
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[3] Xu, L.-H.; Huang, F.; Cheng, T.; Wu, J Chin J Nat Med 2005,
, 359.
13
(m, 1H). C NMR (75 MHz, CDCl ) d 189.30, 82.87, 48.72,
3
3
3
8.22, À1.01.
[
[
[
4] Ettlinger, M. G. J Am Chem Soc 1950, 72, 4792.
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(R)-5-Vinyloxazolidine-2-thione (epigoitrin). To a solution
of 7 (100mg, 0.39 mmol, 1.0 equiv) in anhydrous THF (4 mL)
was added a solution of t-BuOK (112.3mg) in anhydrous THF
Guza, R.; Moser, A.; Thompson, C.; York, D. M.; Tretyakova, N. Chem
Res Toxicol 2010, 23, 118.
ꢀ
ꢀ
(
1.0mL) at 0 C. The reaction mixture was stirred for 4 h at 0 C,
concentrated in vacuo. The residue was purified by flash
[7] Leoni, O.; Bernardi, R.; Gueyrard, D.; Rollin, P.; Palmieri,
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1
[
8] Daxenbichler, M. E.; VanEtten, C. H.; Wolff, I. A. Bio Chem
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[9] Daubos, P.; Grumel, V.; Iori, R.; Leoni, O.; Palmieri, S.;
Rollin, P. Ind Crop Prod 1998, 7, 187.
8
as a white solid (45 mg, 90%). H NMR (300 MHz, CDCl ) d
3
1
8
.23 (s, 1H), 6.05-5.85 (m, 1H), 5.52–5.26 (m, 3H), 3.92 (t,
1
3
J = 9.4 Hz, 1H), 3.53 (t, J = 9.4 Hz, 1H). C NMR (75 MHz,
CDCl ) d 189.52, 133.02, 120.71, 83.50, 77.58, 77.16, 76.74,
4
3
[
[
10] Austin, F. L.; Gent, C. A.; Wolff, I. A. Can J Chem 1968, 46, 1507.
11] Galletti, S.; Bernardi, R.; Leoni, O.; Rollin, P.; Palmieri,
+
+
9.21. HRMS Calcd for [M + H ]: 130.0321; found [ESI ]:
ꢀ
ꢀ
1
30.0321. [a] = +73 (c = 1, CHCl ); reported [a] = +72
S. J Agric Food Chem 2001, 49, 471.
D
3
D
(
c = 1, CHCl
3
) [7].
[12] Larcheveque, M.; Henrot, S. Tetrahedron 1990, 46, 4277.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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