Highly enantioselective methanolysis of meso-cyclic anhydride mediated by bifunctional thiourea cinchona alkaloid derivatives: Access to asymmetric total synthesis of (+)-biotin

Article abstract of DOI:10.1002/jhet.1512

An enantioselective asymmetric total synthesis of (+)-biotin (1) via the Hoffmann-Roche lactone-thiolactone strategy has been accomplished from commercially available cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid (2). Strategic transformations include a cinchona alkaloid-based bifunctional thiourea mediated methanolytic desymmetrization of prochiral cyclic anhydride 3 to produce the enantiomerically enriched precursor of Roche lactone 5 and an improved introduction of the 4-carboxybutyl side chain at C-4 position of Roche thiolactone 6 via Grignard reaction.

Full text of DOI:10.1002/jhet.1512

Month 2013 Highly Enantioselective Methanolysis of Meso-Cyclic Anhydride Mediated
by Bifunctional Thiourea Cinchona Alkaloid Derivatives: Access to
Asymmetric Total Synthesis of (+)-Biotin
a,b,c
a
a
a
a,b
Fei Xiong,
Fang-Jun Xiong, Wen-Xue Chen, Hui-Qing Jia, and Fen-Er Chen *
a
Fudan-DSM Joint Lab for Synthetic Method and Chiral Technology, Department of Chemistry, Fudan University,
Shanghai 200433, China
b
Institutes of Biomedical Sciences, Fudan Univesity, Shanghai 200031, China
c
College of Science, Univesity of Shanghai for Science and Technology, Shanghai 200093, China
*
E-mail: rfchen@fudan.edu.cn
Received June 8, 2011
DOI 10.1002/jhet.1512
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
An enantioselective asymmetric total synthesis of (+)Àbiotin (1) via the Hoffmann–Roche lactone–
thiolactone strategy has been accomplished from commercially available cis-1,3-dibenzyl-2-imidazolidone-
4,5-dicarboxylic acid (2). Strategic transformations include a cinchona alkaloid-based bifunctional thiourea
mediated methanolytic desymmetrization of prochiral cyclic anhydride 3 to produce the enantiomerically
enriched precursor of Roche lactone 5 and an improved introduction of the 4-carboxybutyl side chain at C-4
position of Roche thiolactone 6 via Grignard reaction.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
alkaloid-based bifunctional thiourea and a novel C0 + C5
strategy for the installation of the 4-carboxybutyl side
chain at C-4 position of (3aS,6aR)-thiolactone 6 to
complete an efficient stereocontrolled total synthesis
of (+)-biotin 1.
Among numerous approaches reported to date [1,2], the
total synthesis of (+)-biotin 1 via the chiral amines catalyzed
asymmetric alcoholysis of readily accessible prochiral
meso-cyclic anhydride 3 into Roche’s lactone 5 is valued
for its ability to establish two contiguous stereogenic cen-
ters at C-3a and C-6a of the biotin skeleton with high level
of enantiocontrol. Recent progress in the enantioselective
conversion of 3 into 5 has resulted in the advent and devel-
opment of various thiourea bifunctional organocatalysts,
which do not require the strictly controlled cryogenic reac-
tion condition compared with other established methodolo-
gies [3–5]. Our group recently reported the first thiourea
bifunctional organocatalyst for the desymmetrization of 3
that involved a chiral base derived from (1S,2S)-2-amino-1-
RESULTS AND DISCUSSION
Our synthetic route to the target compound 1 is depicted
in Scheme 1. The commercially available cis-1,3-dibenzyl-
2-imidazolidone-4,5-dicarboxylic acid 2 was treated with
thionyl dichloride in anhydrous toluene at refluxing tem-
perature for 2 h to form the corresponding meso-cyclic
anhydride 3 in 98% yield and with 99% chemical purity.
In combination with the experiences in the facile nucle-
ophilic opening of meso-cyclic anhydride 3, we first
investigated the nucleophilic opening of 3 in the presence
of cinchona alkaloid-based bifunctional thiourea 10a
(Fig. 1, 10 mol%) under our previous reaction conditions
[6]. Gratifyingly, the methanolytic desymmetrization reac-
tion proceeded readily at room temperature, and the desired
(4S,5R)-hemiester 4 was obtained in almost quantitative yield
(
p-nitrophenyl)propane-1,3-diol, and the corresponding ester
enantiomer are available in 96% yield with 82% ee [6].
Enabled by this potential approach and our continued interest
in the development of a simple and highly enantioselective
stoichiometric process for the asymmetric total synthesis
of (+)-biotin 1, we reported herein a new enantioselective
methanolytic desymmetrization of 3 mediated by cinchona
©
2013 HeteroCorporation

F. Xiong, F.-J. Xiong, W.-X. Chen, H.-Q. Jia, and F.-E. Chen
Vol 000
Scheme 1. The synthetic route to (+)-biotin (1).
Eventually, almost the enantiopure product 4 was di-
rectly attained when the catalyst loading was improved
to 110 mol% (Table 2, entry 8). Among four different
solvents examined, the optimum solvent in terms of
enantioselectivity was aprotic, H-bond accepting sol-
vents such as MTBE (Table 2, entries 8 and 10–12).
The absolute configuration of methyl monoester 4 was
determined to be 4S and 5R by comparison with our
group’s previously reported value of the specific optical
rotation [7]. It is noteworthy that the cinchona alkaloid-
based bifunctional thiourea catalyst 10d was easily recov-
ered quantitatively after the resulting reaction mixture was
extracted with the 10% aq. Na CO and could be reused
Figure 1. The structures of bifunctional organocatalysts QN-TU 10.
after 24 h, whereas the ee was modest (Table 1, entry 1).
Encouraged by these promising results, a range of bifunc-
tional catalysts 10b–d with various groups was screened.
Interestingly, almost the racemic product 4 was obtained
with bifunctional catalysts 10b and 10c, which have a
significant less acidic thiourea moiety than 10a (Table 1,
entries 2 and 3). Finally, we delightly found that bifunc-
tional thiourea catalyst 10d with an aliphatic cyclohexyl
substitution is more effective than 10a for the desymmetri-
zation of anhydride 3 to afford 4 in 55% ee at room temper-
ature, probably owning to both steric and electronic
reasons (Table 1, entry 4). With the most efficient chiral
thiourea catalyst 10d in hand, we next further examined
the methanolytic desymmetrization of meso-cyclic anhy-
dride 3 in the presence of 10d under various reaction
conditions, and the results are illustrated in Table 2. The
ee was improved to 82% when the concentration of 3
was diluted to 0.0042 M (Table 2, entry 4). Further dilut-
ing the concentration to 0.0025 M resulted in a slight
decrease of enantioselectivity (Table 2, entry 5). In addi-
tion to the remarkable reaction concentration effect,
improving the catalyst loading also had a positive effect
on the enantioselectivity (Table 2, entries 1 and 6–9).
2
3
without compromising either enantioselectivity or yield
(Table 3).
The corresponding (3aS,6aR)-lactone 5 was, in turn,
obtained in almost quantitatively yield and 99% enantio-
meric excess by freshly prepared LiBH chemoselective
4
reduction of the ester group of (4S,5R)-halfester 4 and sub-
sequent lactonization under acidic conditions. Treatment of
5 with sodium butyl thioxanthogenate [n-BuSC(S)SNa] in
ꢀ
anhydrous N,N-dimethylacetamide at 125 C for 6 h
effected the thiolactonization to form the key intermediate
(3aS,6aR)-thiolactone 6 in 77% yield.
Synthesis of N,N-dibenzyl biotin 8 started with the
installation of the carboxybutyl side chain at C-4 posi-
tion of thiolactone 6 by Grignard reagent derived from 2-
(4-bromobutyl)-4,5-dihydrooxazole in anhydrous THF
and dehydration/deprotection with 5 % aq. HCl at refluxing
temperature in one pot to obtain the (Z)-configurated
unsaturated acid 7, followed by 10% Pd/C-catalyzed ste-
reospecific hydrogenation of 7, resulting construction of
the third stereocenter of biotin skeleton in highly
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Asymmetric Total Synthesis of (+)-Biotin
Table 1
Screening studies of the organocatalytic asymmetric alcoholysis of
a
meso-cyclic anhydride 3.
ꢀ
b
c
Entry
Catalyst (mol%)
T ( C)
Time (h)
Yield (%)
ee (%)
1
2
3
4
10a (10)
10b (10)
10c (10)
10d (10)
25
25
25
25
24
24
24
24
98
99
97
98
47
4
6
55
a
All reactions were performed at RT by using 5 equiv. of methanol and 0.1 equiv. of catalyst QN-TU 10 in MTBE, 0.025 M solution related to anhydride.
Yield of isolated product.
b
c
Determined by chiral HPLC analysis.
Table 2
a
Optimization of the reaction conditions in the methanolytic desymmetrization of meso-cyclic anhydride 3.
ꢀ
b
c
Entry
Catalyst (mol%)
Solvent
Concentration of 3 (M)
T ( C)
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10d (10)
10d (10)
10d (10)
10d (10)
10d (10)
10d (20)
10d (70)
10d (110)
10d (120)
10d (110)
10d (110)
10d (110)
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Dioxane
Toluene
0.025
0.0125
0.00625
0.0042
0.0025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
25
25
25
25
25
25
25
25
25
25
25
25
24
24
24
24
24
20
15
10
10
10
10
10
98
98
99
98
98
98
98
99
98
98
99
98
55
62
80
82
81
63
70
97
97
95
64
72
1
1
1
0
1
2
2 2
CH Cl
a
All reactions were performed with 1 mmol of 3, 5 mmol of methanol, unless otherwise stated.
Yield of isolated product.
b
c
Determined by chiral HPLC analysis.
one-pot debenzylation and ring-opening furnish the
diamine 2HBr salt intermediate by refluxing 8 with 47%
aq. HBr, which, without purification, was allowed to
Table 3
.
Recycling of organocatalyst 10d in the methanolytic desymmetrization of
a
meso-cyclic anhydride 3.
react with diphosgene in the presence of activated char-
coal in anisole at 30 C for 20 h to afford the desired
b
c
Entry
Run
Yield (%)
ee (%)
ꢀ
(
+)-biotin (1) in 82% yield.
1
2
3
4
5
1
2
3
4
5
99
99
98
98
99
97
97
97
96
97
CONCLUSIONS
To summarize, a concise and improved asymmetric total
a
All reactions were performed with 1 mmol of 3, 5 mmol of methanol, and
10 mol% of 10d in 40 mL of MTBE at RT.
Yield of isolated product.
synthesis of (+)-biotin (1) has been accomplished from the
commercially available 1,3-dibenzyl-2-imidazolidone-4,5-
dicarboxylic acid (2) in 44% overall yield. We believe that
the highly efficient synthetic strategy described here would
enable fully stereocontrolled access to (+)-biotin via the
pivotal enantioselective methanolysis mediated by bifunc-
tional thiourea cinchona alkaloid derivatives.
1
b
c
Determined by chiral HPLC analysis.
stereoselective manner. The absolute stereochemistry at
C-4 position of 8 was confirmed by comparison with
the reported values of the specific rotation [8]. Finally,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

F. Xiong, F.-J. Xiong, W.-X. Chen, H.-Q. Jia, and F.-E. Chen
Vol 000
EXPERIMENTAL
anhydrous THF (15.0 mL) was added via syringe, and the
resulting suspension was allowed to stir at 40 C for 7 h. Then,
ꢀ
The bifunctional organocatalysts 10a–d were synthesized
according to published methods, and spectral data were found to
correspond with literature [9–11]. Reagents and chemicals were
obtained from commercial suppliers and used without further
purification. THF was distilled from Na/benzophenone and
5
% aq. HCl (37.0 mL) was added, and the resultant solution was
ꢀ
stirred at 60 C for 30 min. The mixture was poured into H
then cooled with an ice bath. The precipitated colorless crystals
were filtred and dried to afford 5 (3.18 g, 98.8%), which was pure
enough for use; mp 119.5–120.0 C, [a] = +60.3 (c = 2.0,
2
O and
ꢀ
2
5
D
ꢀ
2
5
CH Cl from CaH , and AcOEt and petroleum ether for column
2
2
2
CHCl ) ([7] mp 119–121 C, [a] = +61.3 (c = 2.0, CHCl )). IR
3 D 3
À1
chromatography were distilled before use. Melting points were
determined with a WRS-1B digital melting-point apparatus and
are uncorrected. Optical rotations were obtained on a Jasco
P1020 digital polarimeter. HPLC analysis of the enantiomeric
excesses of 4 and 5 was performed using Chiralcel OJ-H column
(
KBr) n (cm ): 3031, 2919, 1775, 1706, 1415, 1365, 1237,
1
1
7
209, 1146, 970, 754, 700, 639, 527; H NMR (CDCl ) d(ppm)
3
.24–7.36 (m, 10H), 5.05 (d, J = 15.2 Hz, 1H), 4.63 (d,
J = 15.2Hz, 1H), 4.37 (dd, J = 10.4, 15.2Hz, 2H), 4.09–4.16
13
(
3
m, 3H), 3.92 (d, J = 8.0 Hz, 1H). C NMR (CDCl ) d 172.7,
(
hexane/2-propanol/trifluoroacetic acid 92:8:0.2, l = 220 nm,
158.1, 136.0, 135.9, 129.0, 128.8, 128.7, 128.2, 128.0, 127.8,
70.1, 54.3, 52.4, 46.9, 45.2; ESI-MS: 345.2 ([M+ Na] ). Anal.
Calcd for C H N O : C, 70.79; H, 5.63; N, 8.69. Found: C,
70.70; H, 5.60; N, 8.57.
+
0
7
.5 mL/min) and Chiralcel OD-H column (hexane/2-propanol
0:30, l = 220 nm, 0.5 mL/min). H and C NMR spectra were
1
13
19 18 2 3
recorded on a Bruker Avance-400 spectrometer (400 and
1
00 MHz, respectively) in CDCl or DMSO-d6 by using
(3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-thieno[3,4-d]-imidazole-
2,4(1H)-dione (6). Under the atmosphere of argon, a mixture of
5 (3.22 g, 10.0 mmol) and sodium butylthioxanthogenate (2.26 g,
12.0mmol) in anhydrous N,N-dimethylacetamide (25.0 mL) was
3
1
13
tetramethylsilane or DMSO ( H d 2.49) and CDCl
or DMSO-d
were recorded on a Waters Quattro-Micromass instrument by
using electrospray ionization (ESI) techniques.
3
( C d 77.0)
13
6
( C d 39.5) as internal standards. Mass spectra
ꢀ
ꢀ
stirred at 125 C for 6 h and then cooled to rt (25 C). The
Cis-1,3-dibenzyltetrahydro-2H-furo[3,4-d]imidazole-2,4,6-
trione (3). A mixture of 2 (5.00 g, 14.0 mmol), trionyl dichloride
resulting mixture was poured into H O and extracted three times
2
with CH Cl (3 Â 30.0 mL). The combined organic phases were
2
2
(
5.00 mL, 70.0 mmol), and toluene (65.0 mL) was stirred under
then washed with H O (2Â 50.0 mL) and brine (2 Â 50.0mL)
2
ꢀ
reflux for 2 h. After cooled to rt (25 C), the precipitated crystals
were filtered and washed with anhydrous toluene. The solid
product was dried at 80 C in vacuo for 3 h to give the pure
and dried (Na SO ). The organic phase was concentrated to
2
4
give crude product, which was purified by recrystallization
from 2-propanol to afford 6 (2.60 g, 76.9%) as a white solid;
ꢀ
ꢀ
ꢀ
25.4
product 3 (4.60g, 97.9%) as a white powder; mp 237.7–238.3 C
mp 125.1–126.0 C, [a]
= +90.3 (c = 1.0, CHCl ) ([4] mp
D
3
ꢀ
À1
ꢀ
124–126 C, [a] = +90.5 (c = 1.0, CHCl )). IR (KBr) n
D 3
(cm ): 3030, 2934, 2889, 1703, 1697, 1453, 1412, 1361,
1218, 1148, 1051, 997, 903, 808, 647, 581, 485; H NMR
25
([8] mp 237–239 C). IR (KBr) n (cm ) 1805, 1732, 1675,
1
À1
1
1
220; H NMR (CDCl ) d(ppm) 7.15–7.35 (m, 10H), 5.15 (d,
3
1
H, J =14.8Hz), 4.22 (d, 1H, J = 14.8 Hz), 4.18 (s, 2H), 4.15
+
(
s, 2H); ESI-MS 337.4 ([M+ 1] ). Anal. Calcd for C H N O :
(CDCl ) d(ppm) 7.37–7.25 (m, 10H), 5.03 (d, J = 14.8 Hz, 1H),
1
9
16
2
4
3
C, 67.85; H, 4.79; N, 8.33. Found: C, 67.80; H, 4.68; N, 8.23.
4S,5R)-1,3-Dibenzyl-5-(methoxycarbonyl)-2-oxo-imidazolidine-
-carboxylic acid (4). Methanol (0.160g, 5.00mmol) was added
dropwise into the suspension of 3 (0.336 g, 1.00mmol) and
bifunctional thiourea catalyst 10d (0.510 g, 1.10 mmol) in MTBE
4.68 (d, J = 15.6 Hz, 1H), 4.37 (d, J =15.6 Hz, 1H), 4.36
(
(d, J =14.8 Hz, 1H), 4.15–4.11 (m, 1H), 3.81 (d, J = 8.0 Hz, 1H),
3.37 (dd, J =12.4, 5.6 Hz, 1H), 3.28 (dd, J =12.4, 2.0 Hz, 1H);
4
13
3
C NMR (CDCl ) d 203.4, 158.2, 136.4, 136.2, 128.87, 128.78,
128.66, 128.0, 127.91, 127.73, 62.1, 55.8, 46.5, 45.2, 33.0;
+
(
40.0 mL) under argon atmosphere. The resulting mixture was
ESI-MS: 361.1 ([M + Na] ). Anal. Calcd for C H N O S: C,
1
9 18 2 2
ꢀ
stirred at rt (25 C) for 10h then extracted with 10% aq. Na
2
CO
3
67.43; H, 5.36; N, 8.28; S, 9.47. Found: C, 67.28; H, 5.23; N,
8.20; S, 9.31.
(
2 Â 30.0mL). The organic phase was dried (MgSO ) and
4
concentrated to recover the catalyst 10d. The combined aqueous
phases were adjusted to pH= 5 with 2 M HCl then extracted with
AcOEt (2 Â 30.0 mL). The combined organic layers were washed
(3aS,6aR)-1,3-Dibenzyl-tetrahydro-1H-thieno[3,4-d]-imidazole-
2(3H)-one-4-yl-pentanoic acid (7). A suspension of magnesium
(0.960 g, 40.0 mmol) in anhydrous THF (10.0 mL) was added
ꢀ
with brine (2 Â 30.0mL), dried (MgSO ), and concentrated under
1,2-dibromoethane (0.100g, 1.00mmol) at 45 C under nitrogen
4
reduced pressure to give the crude product, which was purified by
recrystallization from AcOEt to afford 4 (0.360g, 97.8%) as a
atmosphere. When the reaction was started, the solution of 2-(4-
bromobutyl)-4,5-dihydrooxazole (3.79 g, 20.0mmol) in anhydrous
THF (30.0 mL) was added dropwise into the resulting suspension
within 1 h and stirred at reflux for another 1 h. The solution of 6
(3.38 g, 10.0mmol) in anhydrous THF (70.0 mL) was then added
ꢀ
25.2
D
white solid; mp 149.6–150.7 C, [a]
= +7.30 (c = 1.0, DMF)
ꢀ
25
D
([7] mp 150–151 C, [a]
= +7.31 (c = 1.0, DMF)). IR (KBr) n
À1
(cm ) 3258, 2943, 1756, 1713, 1449, 1411, 1252, 968, 799, 598,
1
ꢀ
4
1
4
1
1
58; H NMR (CDCl
3
) d(ppm) 7.36–7.19 (m, 10H), 6.85 (br s,
dropwise into the freshly prepared Grignard reagent at À15 C
H), 5.09 (d, J = 14.8 Hz, 1H), 4.98 (d, J = 14.8Hz, 1H); 4.13–
within 2 h followed by stirring at reflux for 3 h. After cooling the
1
3
ꢀ
.04 (m, 4H), 3.63 (s, 3H); C NMR (CDCl ) d 171.7, 168.5,
mixture to rt (25 C), 5% aq. HCl (30.0mL) was added with
3
59.5, 135.57, 135.52, 128.85, 128.79, 128.64, 128.56, 127.98,
stirring at reflux for 2 h. The organic phase was separated, and the
aqueous phase was extracted with AcOEt (3 Â 20.0mL). The
+
27.93, 57.3, 56.7, 52.6, 46.89, 46.80; ESI-MS 391.1 ([M+ Na] ).
Anal. Calcd for C H N O : C, 65.21; H, 5.47; N, 7.60. Found:
2
combined organic phases were washed with H O and brine
20 20 2 5
C, 65.10; H, 5.40; N, 7.57.
3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-furo[3,4-d]-imidazole-
,4(1H)-dione (5). Under the atmosphere of argon, a mixture of
KBH (1.10 g, 19.5 mmol) and LiBr (1.30 g, 15.0mmol) in
4
successively and dried (MgSO ). The organic phase was
(
concentrated to give crude product, which was purified by column
chromatography (benzene/AcOEt 4:1) to afford 7 (3.30 g, 78.2%)
2
ꢀ
D
as a white solid; mp 84.3–85.1 C, [a] = +236.1 (c=1.0, 0.1 N
20
20
4
ꢀ
D
NaOH) ([8] mp 84–85 C, [a] = +236.2 (c= 1.0, 0.1 N NaOH)).
1
anhydrous THF (15.0 mL) was stirred at reflux for 2 h. After
ꢀ
À1
cooling to rt (25 C), the solution of 4 (3.68 g, 10.0mmol) in
IR (KBr) n (cm ): 3432, 1725, 1662, 1485, 1452; H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Asymmetric Total Synthesis of (+)-Biotin
22
À1
(
CDCl ) d(ppm) 7.24–7.40 (m, 10H), 5.53 (t, J= 7.8 Hz, 1H), 4.97
= +90.7 (c= 1.0, 0.1 N NaOH)). IR (KBr) n (cm ) 3359, 3308,
D
3
(
4
4d, J= 15.5, 16.8 Hz, 4H), 4.62 (d, J= 7.9 Hz, 1H), 4.52, 4.34,
.16 (m, 1H), 4.05, 2.95 (d, J= 12.3 Hz, 1H), 2.81 (dd, J= 5.5, 12.1
2961, 2469, 1941, 1707, 1480, 1318, 1270, 1154, 1015, 842,
753, 651; H NMR (DMSO-d ) d(ppm) 11.9 (s, 1H); 6.40 (s,
6
1
Hz, 1H), 2.00 (t, J=7.4 Hz, 2H), 1.39–1.93 (m, 4H, 2 Â CH
2
);
1H); 6.33 (s, 1H); 4.30 (dd, J = 7.6, 5.2 Hz, 1H); 4.15–4.11
(m, 1H); 3.12–3.07 (m, 1H); 2.82 (dd, J = 12.4, 5.2 Hz, 1H);
2.57 (d, J = 12.4 Hz, 1H); 2.20 (t, J = 7.6 Hz, 2H); 1.62–1.41
+
ESI-MS 422 ([M + H] ). Anal. Calcd for C24
H N O
26 2 3
S: C, 68.22;
H, 6.20; N, 6.63; S, 7.59. Found: C, 68.31; H, 6.14; N, 6.55; S, 7.55.
3aS,4S,6aR)-1,3-Dibenzyl-tetrahydro-1H-thieno[3,4-d]-
imidazole-2(3H)-one-4-yl-pentanoic acid (8). A suspension
1
3
(
(m, 4H); 1.37–1.30 (m, 2H). C NMR (CDCl ) d 174.8,
3
163.1, 61.5, 59.6, 55.8, 40.0, 33.9, 28.57, 28.52, 25.0; ESI-
+
of 10% Pd/C (1.97g, 1.90 mmol), 7 (12.6 g, 30.0mmol), and H
2
O
MS 267.2 ([M + Na] ). Anal. Calcd for C10
H
16
N
2
O
3
S: C,
ꢀ
(
12.6 mL) in 2-propanol (71.0mL) was stirred at 120 C under
49.16; H, 6.60; N, 11.47; S, 13.12. Found: C, 49.97; H, 6.45;
N, 11.52; S, 13.39.
hydrogen pressure of 60atm for 20h. The mixture was cooled to
ꢀ
rt (25 C) and then filtered through Celite. The filtrate was
evaporated under reduced pressure to give the crude product,
Acknowledgment. We gratefully acknowledge the financial
support from the DSM Nutritional Products Ltd. in Switzerland.
which was purified by recrystallization from 2-propanol/hexane to
ꢀ
afford 8 (11.8 g, 92.9%) as a white solid; mp 91.2–92.3 C, [a]
23.6
ꢀ
23
=
À26.9 (c = 1.0, MeOH) ([12] mp 91–92 C, [a] = À26.7
D
D
À1
(
c = 1.0, MeOH)). IR (KBr) n (cm ) 2926, 1097, 1451, 1238,
REFERENCES AND NOTES
1
7
3
03; H NMR (CDCl ) d(ppm) 7.22–7.37 (m, 10H), 5.02 (4d,
J = 15.1, 15 Hz, 4H), 4.74, 4.16, 4.04, 3.97 (m, 1H), 3.90 (dd,
J = 5.56 Hz, 1H), 3.08 (m, 1H), 2.70 (4d, J = 2.35, 4.4 Hz, 2H),
[
1] De Clercq, P. J. Chem Rev 1997, 97, 1755.
[2] Seki, M. Med Res Rev 2006, 26, 434.
2
.20 (t, J = 6.6 Hz, 2H), 1.39–1.69 (m, 6H); ESI-MS 447.4
[3] Chio, C.; Tian, S. K.; Deng, L. Synthesis 2001, 1737.
[4] Huang, J.; Xiong, F.; Chen, F. E. Tetrahedron: Asymmetry
+
(
[M + Na] ). Anal. Calcd for C24
H N O
28 2 3
S: C, 67.90; H, 6.65; N,
.60; S, 7.55. Found: C, 67.80; H, 6.60; N, 6.50; S, 7.52.
+)-Biotin (1). A mixture of 8 (4.24 g, 10.0 mmol) and 47%
2
008, 19, 1436.
5] Dai, H. F.; Chen, W. X.; Zhao, L.; Xiong, F.; Sheng, H.; Chen,
F. E. Adv Synth Catal 2008, 350, 1635.
6
[
(
aq. HBr (40.0 mL) was heated to reflux for 48 h. The mixture was
[
[
6] Wang, S. X.; Chen, F. E. Adv Synth Catal 2009, 351, 547.
7] Chen, F. E.; Chen, X. X.; Dai, H. F.; Kuang, Y. Y.; Xie, B.;
ꢀ
cooled to rt (25 C) and then extracted with toluene (2 Â 50.0mL).
The aqueous phase was evaporated under reduced pressure, and
the solution of the residue in 40% aq. KOH (5.00 mL) was added
dropwise into a mixture of diphosgene (1.98 g, 10.0mmol) and
Zhao, J. F. Adv Synth Catal 2005, 347, 549.
[8] Chen, F. E.; Jia, H. Q.; Chen, X. X.; Dai, H. F.; Xie, B.;
Kuang, Y. Y.; Zhao, J. F. Chem Pharm Bull 2005, 53, 743.
[9] Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org Lett 2005,
7, 1967.
10] Li, X.; Deng, H.; Zhang, B.; Li, J. Y.; Zhang, L.; Luo, S. Z.;
Cheng, J. P. Chem Eur J 2010, 16, 450.
11] Kataja, A. O.; Koskinen, A. M. P. Arkivoc 2010, ii, 205.
[12] Takahash, T.; Minai, M.; Yamamoto, T.; Mizuno, T.;
Miyamoto, Y. European Patent 0,633,263, 1995; Chem Abstr 1995,
122, 187270r.
ꢀ
charcoal (50.0 mg) in anisole (10.0 mL) at 30 C. The resulting
mixture was stirred at 30 C for 20 h then filtered. The
separated aqueous phase was acidified to pH = 1 with 36% aq.
HCl and cooled with ice water. The crystals that formed were
ꢀ
[
[
collected by filtration and recrystallized from H O to afford 1
2
ꢀ
(2.00 g, 82.0%) as a white crystalline powder; mp 232.5–233.4 C,
2
3.6
ꢀ
[a] = +91.5 (c= 1.0, 0.1 N NaOH) ([4] mp 230–231 C, [a]
D
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet