Synthetic Studies on d-Biotin, Part 6:1 An Expeditious and Enantiocontrolled Approach to the Total Synthesis of d-Biotin via a Polymer-Supported Chiral Oxazaborolidine-Catalyzed Reduction of meso-Cyclic Imide Strategy

Article abstract of DOI:10.1055/s-2003-41051

An efficient and highly enantioselective synthesis of d-biotin from the known cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid (5) was accomplished in 48% overall yield. The key reactions in the sequence involve the catalytic enantioselective reduction of meso-cyclic imide 6 using polymer-supported chiral oxazoborolidine, derived from (S)-α,α -diphenylprolinol and polymer-bound sulfonyl chloride, and the installation of the C₅ side chain at C4 in the thiolactone 9 via a Ni/C-catalyzed Fukuyama coupling reaction.

Full text of DOI:10.1055/s-2003-41051

PAPER
2155
Synthetic Studies on d-Biotin, Part 6:1 An Expeditious and Enantiocontrolled
Approach to the Total Synthesis of d-Biotin via a Polymer-Supported Chiral
Oxazaborolidine-Catalyzed Reduction of meso-Cyclic Imide Strategy
Total
S
ynthesi
e
s
of
d
-
Bi oti
n
n
-Er Chen,* Jian-Li Yuan, Hui-Fang Dai, Yun-Yan Kuang, Yong Chu
Department of Chemistry, Fudan University, Shanghai, 200433, P. R. China
Fax +86(21)65642021; E-mail: rfchen@fudan.edu.cn
Received 19 May 2003; revised 26 June 2003
Dedicated with best wishes to Professor Zong-Ru Guo on the occasion of his 65th birthday.
from (S)- , -diphenylprolinol and polymer-bound sulfo-
Abstract: An efficient and highly enantioselective synthesis of d-
biotin from the known cis-1,3-dibenzyl-2-imidazolidone-4,5-dicar-
boxylic acid (5) was accomplished in 48% overall yield. The key re-
actions in the sequence involve the catalytic enantioselective
reduction of meso-cyclic imide 6 using polymer-supported chiral
oxazoborolidine, derived from (S)- , -diphenylprolinol and poly-
mer-bound sulfonyl chloride, and the installation of the C5 side
chain at C4 in the thiolactone 9 via a Ni/C-catalyzed Fukuyama cou-
pling reaction.
nyl chloride, and the introduction of the C5 side chain at
C4 in the thiolactone 9 via a 5% Ni/C-catalyzed Fukuya-
ma coupling reaction.7
The required zinc reagent 4 was prepared starting from
1,4-dibromobutane. The monobromo nitrile 2 was ob-
tained in 80% yield upon treatment of 1,4-dibromobutane
with NaCN in DMF using a modification of the procedure
described by Voss et al.8 Iodination of 2 in acetone gave
the monoiodo nitrile 3 in 90% yield. The formation of zinc
reagent with monoiodo nitrile, 3 was performed under
modified Knochel’s conditions9 consisting of treatment of
activated zinc powder in a mixture of TMSCl and THF.
The reaction required 30 minutes at 30 °C for completion
and afforded the zinc reagent 4.
Key words: d-biotin, vitamin H, oxazaborolidine, polymer-sup-
ported chiral sulfonamide, enantioselective reduction, Fukuyama
coupling reaction
Over the past five decades, interest in the total synthesis
of d-biotin (1), a water-soluble vitamin, has increased as a
result of its significant biological properties for human nu-
trition and animal health.2 Though a number of synthetic
strategies have been developed that make use of the reso-
lution at an appropriate stage,3 enantioselective syntheses4
or starting from the chiral pool,5 the first industrial method
for the synthesis of 1 utilizing the (3aS,6aR)-thiolactone 9
as a key intermediate described by Goldberg and Stern-
bach at Hoffmann-La Roche in 1949, after subsequent
modifications, still remains nowadays the most attractive
and reliable approaches so far developed.6 However, the
potential of this Sternbach approach has not yet been fully
realized due to the lack of an efficient and simple method
for the desymmetrization of meso compounds such as di-
carboxylic acid 5 and its imides 6 to prepare (3aS,6aR)-
lactone 8. As a result, the economy of this Sternbach pro-
cess in today’s market place leaves much to be desired,
Herein we report an more economically efficient method
for the synthesis of 1, starting from the commercially
available cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarbox-
ylic acid (5), along the Sternbach’s route by employing
polymer- supported chiral oxazaborolidine-catalyzed
asymmetric reduction of 6.
The meso-cyclic imide 6 was prepared in 95% yield by
heating cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxyl-
ic acid (5) with benzylamine in the presence of 4 Å MS
(molecular sieves) with azeotropic removal of water using
a Dean–Stark apparatus, which provided better yields be-
cause the continuous removal of water forced the equilib-
rium toward the meso-cyclic imide 6. It is noteworthy that
xylene seems to be a better azeotropic agent than some
others, such as toluene and benzene, etc., hence the re-
moval of water was speedy.
With the meso-cyclic imide 6 in hand, our attention was
turned to the development of an efficient asymmetric re-
duction of 6 to the (3aS,6R,6aR)-hydroxylactam 7 as pre-
cursor for the formation of (3aS,6aR)-lactone 8 to
complete a formal catalytic asymmetric synthesis of 1.
Recently, Shimizu and co-workers have developed a high-
ly enantioselective reduction of meso-cyclic N-benzylim-
ides to chiral hydroxylactams with borane in the presence
of oxazaborolidine, derived from L- threonine.10 Howev-
er, the recovery and purification of the catalyst are also
problematic. Immobilization of chiral oxazaborolidine
catalysts would offer a solution to the problem. Polymer-
supported oxazaborolidine catalysts have wide uses in
asymmetric organic synthesis owing to the ease of isola-
tion of product from polymeric chiral catalyst, the conve-
nient work-up procedure,11 and the fact they can be
recovered by filtration at the end of the reaction without
loss of activity.12 Thus, efforts were made to utilize poly-
mer-supported chiral sulfonamide 13 (2.29 mmol/g, 200–
400 mesh) as a catalyst for enantioselective reduction of
Our synthetic route to 1 is outlined in Scheme 1. The es-
sential steps in the present synthesis involve the enantio-
selective reduction of meso-cyclic imide 6 catalyzed by a
polymer-supported chiral oxazaborolidine 13, derived
Synthesis 2003, No. 14, Print: 02 10 2003. Web: 22 08 2003.
Art Id.1437-210X,E;2003,0,14,2155,2160,ftx,en;F04403SS.pdf.
DOI: 10.1055/s-2003-41051
© Georg Thieme Verlag Stuttgart · New York

2156
F.-E. Chen et al.
PAPER
a
b
CN
CN
Br
Br
I
Br
2
3
c
CN
IZn
4
O
O
N
O
BnN
H
NBn
H
BnN
H
NBn
H
BnN
H
NBn
H
d
e
f
H
HO2C
CO2H
O
O
HO
O
N
Bn
Bn
5
6
7
O
O
O
BnN
H
NBn
g
h
BnN
H
NBn
BnN
NBn
H
H
H
H
CN
O
O
O
S
S
8
9
10
O
S
BnN
NBn
H
NH2
NH2
j
i
H
H
H
.
2HBr
H
H
CN
S
CO2H
11
12
O
Ph
Ph
O
O
HN
NH
k
S
OH
H
H
N
H
CO2H
S
13
1
Scheme 1 Reagents and conditions: a) NaCN, DMF, 35 °C, 2 h, 80%; b) NaI, acetone, reflux, 6 h, 90%; c) Zn, TMSCl, THF, reflux, then 3, 30
°C; d) PhCH2NH2, 4Å MS, xylene, reflux, 12 h 95%; e) 13, BH3·SMe2, THF, reflux, 6 h 91%; f) KBH4, LiCl, THF, r.t., 6 h, then 1 N aq HCl,
55 °C, 30 min, 90% (two steps); g) EtSC(S)SK, DMF, 125 °C, 3 h, 93%; h) 4, 5% Ni/C, toluene, THF, DMF, r.t., 30 h, 80% (two steps); i) H2,
Pd(OH)2/C, EtOAc, 30 °C, 6 h 92%; j) 48% HBr, toluene, reflux, 40 h; k) triphosgene, aq 4 N NaOH, anisole, 6 h, then 2 N aq HCl 90% (from
11 to 1)
6. The meso-cyclic imide 6 was reduced with BH3·SMe2 C6-Hexo and C6a-H. The 1H NMR data clearly indicated the
in the presence of polymer-supported sulfonamide cata- stereochemistry at C-6. The coupling constant of 5.5 Hz
lyst 13 under reflux for 6 hours. As expected, the reaction between C6-Hexo and C6a-H shows that C6-Hexo and C6a-H
proceeded enantiosecletively to provide the (3aS,6R,6aR)- are syn-disposed, and also the -orientation of the C-6 hy-
hydroxylactam 7 in 91% yield. The enantiomeric excess droxy group.
of 7 was determined to be >98.5% by chiral HPLC analy-
Further reduction of 7 with KBH4 in the presence of LiCl
sis. It is important to note that after the reduction was
in THF at room temperature for 2 hours, followed by acid
completed, the chiral polymer-supported sulfonamide
hydrolysis gave (3aS,6aR)-lactone 8 in 90% yield with
could be recovered by simple filtration by first washing
95% exantiomeric excess. It was enriched to 98.5% ee by
with refluxing methanol and then with hot water. Recy-
recrystallization from ethanol. The conversion of 8 into
the (3aS,6aR)-thiolactone 9 was carried out by a new
cling of the catalyst was tested by the reduction of 6. The
results are summarized in Table 1. The results show that
method
using
potassium
ethylthioxanthogenate
both enantiomeric excess and chemical yields gave repro-
ducible values when the chiral polymeric catalyst was re-
used five times. The absolute configuration of 7 was
confirmed both by its X-ray diffraction analysis (Figure 1)
and by the observation of the coupling constant between
EtSC(S)SK at 125 °C in DMF for 5 hours in 93% yield.
Having achieved construction of (3aS,6aR)-lactone 9
from 8 in excellent yield, we then proceeded to install the
C5 side chain to 9 using a modification of the Fukuyama
Synthesis 2003, No. 14, 2155–2160 © Thieme Stuttgart · New York

PAPER
Total Synthesis of d-Biotin
2157
O
S
BnN
H
NBn
H
10.5%
CN
H
Figure 2 Significant NOE enhancement observed for 10
Figure 1 X-ray crystal structure of 7
Table 1 The Recycling of the Chiral Polymer-Supported Sulfona-
mide in the Reduction of 6 in THF at Refluxing Temperature
Entry
Yield (%)a
95.0
Ee (%)
98.6
Figure 3 X-ray crystal structure of 11
1
2
3
4
5
Finally, on refluxing 11 with 47% aq HBr, diamine·2HBr
salt 12 was obtained in a one-pot debenzylation and hy-
drolysis and ring opening reaction which, without purifi-
cation, was allowed to react with triphosgene in the
presence of 4 N aq NaOH in anisole at 30 °C for 6 hours
to afforded d-biotin (1) in 90% yield.
94.5
98.5
95.0
98.5
94.7
98.4
94.7
98.4
In conclusion, we have developed an efficient, asymmet-
ric total synthesis of d-biotin in 48% overall yield, starting
from commercially available 1,3-dibenzyl-2-imidazoli-
done-4,5-dicarboxylic acid (5) by employing a polymer-
supported chiral oxazaborolidine-catalyzed reduction of
meso-cyclic imide 6 and a Ni/C-catalyzed Fukuyama cou-
pling reaction to carry out the introduction of the C5 side
chain to the thiolactone 9.
a Yields of isolated pure products.
b Determined by chiral HPLC analysis.
coupling procedure.13 Treatment of 9 with 4 (1.5 equiv) in
the presence of Ni/C in a mixed solvent of toluene, THF
and DMF at room temperature for 30 hours provided the
1
(Z)-vinyl nitrile 10 in 80% yield. The H NOE experi-
ments were carried out to assign the configuration of the
double bond in 10 (Figure 2). An enhancement of 10.5%
to the signal of the C3a-H was observed when the olefinic
hydrogen was irradiated, indicating the geometry of 10 is
(Z)-configured.
Melting points were determined on a WRS-1 digital melting point
apparatus and are uncorrected. Elemental analyses were performed
on a Carlo-Erba 1106 elemental analyzer. IR spectra were recorded
1
on a Nicolet FI-IR 360 spectrometer. H NMR spectra were ob-
Catalytic hydrogenation of 10 with a catalytic amount of
Pd(OH)2 on charcoal in EtOAc led stereospecifically to
the saturated nitrile 11 in 92% yield. The absolute config-
uration of 11 was unambiguously confirmed by X-ray
crystallographic analysis (Figure 3).
tained on a Bruker AMX × 300 spectrometer. Chemical shifts are
reported relative to internal TMS. Mass spectra were measured on a
HP-5988A spectrometer by direct inlet at 70 eV. HRMS were mea-
sured with EI techniques. Optical rotations were measured at r.t. (20
°C) on a Perkin-Elmer 241 MC polarimeter. Chiral HPLC analyses
for the determination of enantiomeric purity of 9 were performed on
a Shimadzu LC010AT provided with variable detector, working
at = 254 nm and fitted with a Chiralcel OD column (25 × 0.46
cm). Conditions: hexane–propan-2-ol (6:4) as eluent, flow rate 0.6
mL/min. Unless otherwise stated, all chemicals were obtained from
commercial suppliers and used without further purification. THF
were freshly distilled from sodium benzophenone ketyl prior to use.
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F.-E. Chen et al.
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Polymer-supported chiral catalyst 13 was prepared according to the
(3 × 10 mL). The aqueous layer was extracted with EtOAc (3 × 40
mL) and then the combined organic layers were successively
washed with H2O (3 × 40 mL), sat. aq NaHCO3 and sat. aq NaCl
(3 × 40 mL), and dried (Na2SO4). Evaporation of the solvent gave
the crude product, which was purified by column chromatography
on silica gel (hexane–EtOAc, 2:1) to give pure 7 (38.9 g, 91%) as a
white solid; mp 128–131 °C; [ ]D20 +69.1 (c = 0.1, CH2Cl2).
reported procedure.14
4-Bromovaleronitrile (2)
To a stirred solution of 1.4-dibromobutane (21.6 g, 0.1 mol) in DMF
(100 mL) was added NaCN (4.9 g, 0.1 mol) and the reaction mixture
was stirred for 2 h at 35 °C. After cooling to.r.t., the mixture was
poured into H2O (200 mL), and the aqueous layer was extracted
with Et2O (3 × 30 mL). The combined organic layers were washed
with sat. aq NaCl (3 × 50 mL) and H2O (3 × 40 mL) and dried
(Na2SO4). Evaporation of the solvent and fractional distillation of
the residue under reduced pressure afforded 2 (13.0 g, 80%) as a
colorless oil; bp 118–121 °C/13 Torr (Lit.8 bp 114–115 °C/12 Torr).
IR (KBr): 3313, 2933, 1700, 1452, 1236, 1080, 740, 701 cm–1.
1H NMR (DMSO-d6): = 3.77–3.8 (m, 2 H, C3a-H and C6a-H), 4.90
(2 d, 1 H, J = 5.5 Hz, CHOH), 4.20, 4.40, 4.90, 4.93, 5.03, 5.12 (6 d,
6 H, 3 × ArCH2), 7.21–7.40 (m, 15 H, 3 × ArH).
MS (EI): m/z (%) = 427 (M+, 11), 264 (20), 106 (4), 91 (100).
IR (film): 2213 cm–1 (C N).
1H NMR (CDCl3): = 3.37 (br t, 2 H, J = 7.1 Hz, CH2Br), 2.66 (br
t, 2 H, J = 7.0 Hz, CH2CN), 1.79–2.29 (br m, 4 H, 2 × CH2).
Anal. Calcd for C26H25N3O3: C, 73.05; H, 5.89; N, 983. Found: C,
72.89, H, 5.65; N, 9.69.
MS (EI): m/z calcd for C26H25N3O3: 427.5018; found 427.4990.
MS (EI): m/z (%) = 162 (M+, 15.5), 82 (100), 55 (90), 54 (40).
(3aS,6aR)-1.3-Dibenzyltetrahydro-4H-furo[3,4-d]imidazole-
2,4(1H)-dione (8)
4-Iodovaleronitrile (3)
To a stirred mixture of KBH4 (26.9 g, 0.5 mol) and LiCl (2.12 g, 50
mmol) in THF (100 mL) was added dropwise a solution 6 (106.75
g, 0.25 mol) in THF (400 mL) at 10 °C. The reaction mixture was
stirred at r.t. for 2 h, then 1 N aq HCl (150 mL) was added dropwise.
The mixture was stirred at 55 °C for 30 min. After cooling to r.t., the
mixture was extracted with EtOAc (4 × 80 mL) and the combined
organic layers were washed with sat. aq NaCl (3 × 40 mL) and H2O
(3 × 40 mL), and dried (Na2SO4). Evaporation of the solvent under
reduced pressure gave the crude product, which was purified by re-
crystallization from EtOH to afford pure 8 (72.5 g, 90%) as white
needles; mp 117–119 °C [ ]D25 +59.3 (c = 1.0, CHCl3){Lit.3f
mp117–119 °C, [ ]D25 +59.2 (c = 1.0, CHCl3)}.
To a stirred solution of 2 (16.2 g, 0.1 mol) in acetone (150 mL) was
added NaI (19.5 g, 0.13 mol). The reaction mixture was stirred un-
der reflux for 6 h. After cooling to r.t., the mixture was filtered
through Celite and the filtrate was evaporated to remove the solvent.
The residue was distilled under reduced pressure to afford 3 (18.8 g,
90%) as a pale yellow oil; bp 97–99 °C/1 Torr (Lit.15 bp 98 °C/1
Torr).
IR (film): 2213 cm–1 (C N).
1H NMR (CDCl3): = 3.50 (br t, 2 H, J = 7.0 Hz, CH2I), 2.64 (br t,
2 H, J = 7.0 Hz, CH2CN), 1.78–2.28 (br m, 4 H, 2 × CH2)
MS (EI): m/z (%) = 209 (M+, 16.2), 127 (11.6), 82 (100), 55 (89),
54 (38).
IR (KBr): 1778, 1702, 1208, 1183, 1030, 968 cm–1.
1H NMR (CDCl3): = 3.24 (dd, 1 H, J = 2.3, 12.8 Hz, CHexoO),
3.36 (dd, 1 H, J = 5.6, 12.8 Hz, CHendoO), 3.95 (m, 1 H, J = 8.8 Hz,
C3a-H), 4.19 (3 d, 1 H, J = 2.3, 5.4, 8.0 Hz, C6a-H), 4.25, 4.31, 4.47,
4.94 (4 d, 1 H, J = 14 Hz, 2 × ArCH2), 7.28–7.37(m, 10 H, ArH).
MS (EI): m/z (%) = 322 (M+, 24), 265 (55), 245 (78), 187 (60), 91
(100).
cis-1,3-Dibenzyl-N-benzyl-2-imidazolidone-4,5-dicarboximide
(6)
A mixture of cis-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid
(5; 10 g, 28 mmol), benzylamine (3.3 g, 30.8 mmol), 4 Å MS (0.5
g), and xylene (75 mL) was refluxed using a Dean–Stark apparatus
for 12 h. After cooling to r.t., the mixture was filtered to remove the
molecular sieves and the filtrate was washed successively with 1 N
aq HCl (3 × 25 mL), sat. aq NaCl (3 × 40 mL) and H2O (3 × 35 mL),
dried (Na2SO4) and evaporated under reduced pressure to give the
crude product, which was recrystallized from toluene to afford pure
6 (11.3 g, 95% ) as a white solid; mp 114–116 °C.
HRMS (EI): m/z calcd for C19H18N2O3: 322.3466; found: 322.3487.
Anal. Calcd for C19H18N2O6: C, 70.81; H, 5.59; N, 8.70. Found: C
70.58, H 5.42, N 8.53.
(3aS,6aR)-1,3-Dibenzyltetrahydro-4H-thieno[3,4-d]imidazole-
2,4(1H)-dione (9)
IR (KBr): 3437, 1711, 1686, 1648 cm–1.
1H NMR (CDCl3): = 4.25 (s, 2 H, C3a-H and C6a-H), 4.26, 4.29,
4.73, 4.76 (4 d, 4 H, J = 15.38, 15.42, 2 × ArCH2), 4.56 (s, 2 H,
ArCH2N), 7.18–7.36 (m, 15 H, 3 × C6H5).
MS (EI): m/z (%) = 425 (M+, 26), 334 (3), 237 (7), 132 (12), 91
(100).
To a stirred solution of 8 (32.2 g, 0.1 mol) in DMF (200 mL) was
added potassium ethylthioxanthogenate (17.6 g, 0.1 mol). The reac-
tion mixture was stirred at 125 °C under N2 for 3 h. After cooling to
r.t., H2O (150 mL) was added to the mixture before it was extracted
with toluene (4 × 40 mL). The combined organic lagers were
washed with sat. aq NaCl (3 × 40 mL) and H2O (3 × 3 mL), and
dried (Na2SO4). The solvent was evaporated under reduced pressure
and the crude product obtained was purified by recrystallization
from EtOAc to afford pure 9 (31.4 g, 93%); mp 125–126 °C
[ ]D +90.2 (c = 1.0, CHCl3) {Lit.16 mp 125–127 °C [ ]D20 +90.8
(c = 1.0, CHCl3)}.
HRMS (EI): m/z calcd for C26H23N3O3: 425.4860; found: 425.4874.
Anal. Calcd for C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C,
73.14; H, 5.40; N, 9.59.
(3aS,6R,6aR)-1,3,5-Tribenzyl-6-hydroxytetrahydro-4H-pyro-
lo[3,4-d]imidazole-2,4(1H)-dione (7)
IR (KBr): 1704, 1691, 1423, 1222 cm–1.
To a suspension of polymer-supported chiral catalyst 13 (6.1 g, 15
mmol) in THF (450 mL), was added dropwise a 2 M solution of
BH3·SMe2 in THF (55 mL, 110 mmol). The suspension was re-
fluxed with stirring under N2 for 1 h, and then a solution of 6 (42.5
g, 100 mmol) in THF (180 mL) was added dropwise. The reaction
mixture was refluxed with stirring for 6 h. After cooling to r.t., the
mixture was treated with 0.5 N aq HCl (15 mL) and filtered. The
polymeric catalyst was washed with EtOAc (3 × 25 mL) and H2O
1H NMR (CDCl3): = 3.25 (dd, 1 H, J = 2.2, 12.8 Hz, CHexoS), 3.36
(dd, 1 H, J = 5.5, 12.8 Hz, CHendoS), 3.81 (d, 1 H, J = 8.0 Hz, C3a-
H), 4.15 (3 d, 1 H, J = 2.2, 5.5, 8.0 Hz, C6a-H), 4.34, 4.37, 4.68, 5.01
(4 d, 4 H, J = 15.2 Hz, 2 ArCH2), 7.28–7.35 (m, 10 H, ArH).
MS (EI): m/z (%) = 338 (M+, 3), 310 (23), 277 (7), 264 (68), 91
(100).
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PAPER
Total Synthesis of d-Biotin
2159
Anal. Calcd for C19H18N2OS: C, 67.46; H, 5.33; N, 8.28; S, 9.47.
Found: C, 67.23; H, 5.23; N, 8.12; S, 9.31.
duced pressure. A solution of NaOH (40 g, 0.1 mol) in H2O (245
mL) was added to the residue and the stirring was continued for 25
min at r.t. A solution of triphosgene (59.4 g, 0.2 mol) in anisole (300
mL) was added, and the reaction mixture was stirred at 30 °C for 6
h. The mixture was controlled to keep pH of the solution within 8–
9 by addition of 4 N aq NaOH. The mixture was diluted with H2O
(150 mL) and extracted EtOAc (4 × 40 mL). The aqueous layer was
acidified to pH 2 with 2 N aq HCl with stirring to give a precipitate.
The precipitated product was collected by filtration, and recrystal-
lized from H2O to afford pure 1 (22 g, 90%) as a white crystalline
powder; mp 231–232 °C, [ ]D25 +91.2(c = 1.0, 0.1 N NaOH) {Lit.4g
mp 232–233 °C, [ ]D22 +91.2 (c = 1.0, 0.1 N NaOH)}.
(3aS,6aR)-1,3-Dibenzyltetrahydro-1H-thieno[3,4-d]imidazol-
2(3H)-one-4-ylidenepentane Nitrile (10)
To a stirred suspension of activated zinc powder (23 g, 0.35 mol) in
THF (55 mL) was added 1, 2-bromoethane (1.75 g, 9.3 mmol). The
reaction mixture was stirred under reflux for 15 min. After cooling
to r.t., TMSCl (0.69 g, 6.4 mmol), was added, and the slurry was
stirred at r.t. for 20 min. Compound 3 (37.6 g, 0.18 mol) was then
added, and the mixture was stirred at 30 °C to give a solution of the
zinc regent 4 in THF. To this stirred solution of 4 in THF was added
9 (20 g, 59.2 mmol), 5% Ni/C (1.8 g), toluene (60 mL) and DMF (5
mL) and stirring was continued for 30 h at r.t. The mixture was fil-
tered through Celite. The catalyst was washed with toluene (3 × 20
mL) and the combined organic layers were evaporated under re-
duced pressure. The residue was dissolved in Et2O (150 mL) and the
solution was washed successively 1 N aq HCl (3 × 30 mL) sat. aq
NaHCO3 (4 × 30 mL) and sat. aq NaCl (3 × 25 mL) and dried
(Na2SO4). Evaporation of the solvent gave the crude product, which
was purified by chromatography on a silica gel column (hexane–
EtOAc, 3:1) to afford pure 10 (19.1 g, 80%) as a colorless oil;
[ ]D20 +27.4 (c = 0.1, CH2Cl2).
IR (KBr): 3311, 2933, 1705, 1665 cm–1.
1H NMR (DMSO-d6): = 1.30–1.61 (m, 6 H, 3 × CH2), 2.17 (t, 2 H,
J = 7.3 Hz, CH2CO2H), 2.58 (dd, 1 H, J = 1.7, 12.5 Hz, CHendoS),
2.80 (dd, 1 H, J = 4.7, 12.5 Hz, CHexoS), 3.14 (m, 1 H, C4-H), 4.17
(m, 1 H, C3a-H), 4.36 (m, 1 H, C6a-H), 6.37 (s, 1 H, NH), 6.47 (s, 1
H, NH), 11.98 (br s, 1 H, CO2H).
EI-MS: m/z (%) = 245 (M+ + 1, 15), 227 (9), 184 (25), 112 (26), 97
(100), 85 (66).
Anal. Calcd for C10H16N2O3S: C, 49.16; H, 6.60; N, 11.47; S, 13.12.
Found: C, 49.01; H, 6.49; N, 11.50; S, 13.40.
IR (Film): 2224 (C N) cm–1.
1H NMR (CDCl3): = 1.39–1.86 (m, 4 H, 2 × CH2), 2.03 (t, 2 H,
CH2CN), 2.81 (2 × d, 1 H, J = 5.5, 12.2 Hz, CHexoS), 2.95 (d, 1 H,
J = 12.3 Hz, CHendoS), 4.13 (m, 1 H, C6a-H), 4.67 (d, 1 H, J = 7.9
Hz, C3a-H), 4.05, 4.34, 4.51, 4.96 (4 × d, 4 H, J = 15.5, 16.8, Hz,
2 × ArCH2).
X-Ray Structure Analysis of 7
Crystals of C26H25N3O3 (427.50) suitable for X-ray analysis were
obtained from EtOAc. A colorless monoclinic crystal of dimensions
0.40 × 0.30 × 0.30 mm was mounted on a Rigaku AFC7R diffracto-
meter. Determination of the cell parameters was performed by least
squares refinement of 25 reflections. The compound crystallized in
the monoclinic system, space group P21,21,21 with a = 10.910 (6),
b = 9.189 (6), c = 10.949 (4) Å; = 104.87 (4)º Z = 2; V = 1060.9
(10)Å3; (Mo-Ka) = 0.089 mm–1; Dc = 1.338 gcm–3; F(000) = 452
reflections were collected in the range of 1.92º < < 25.17 using Mo-
K radiation (graphite monochromator, = 0.71073 Å), -2 scan
mode. The structure was solved by direct methods and expanded us-
ing difference Fourier techniques and refined by full-matrix, least-
square to R = 0.0811, R = 0.1905 with = 1/[ 2(Fo) + (0.1035 P2
MS (EI): m/z (%) = 404 (M+, 7), 313 (62), 106 (10), 91 (100).
HRMS (EI): m/z calcd for C24H25N3OS: 403.7279; found:
403.7251.
Anal, Calcd for C24H25N3OS: C, 71.43; H, 6.24; N, 10.41. Found:
C, 71.54; H, 6.33; N, 10.28.
(3aS,4S,6aR)-1,3-Dibenzyltetrahydro-1H-thieno[3,4-d]imida-
zole-2(3H)-one-4-ylpentane Nitrile (11)
2
+ 1.3711 P) R (where P = (Fo + 2Fc2)/3) by using the 1232 observed
A suspension of Pd (OH)2/C (1.5 g) in EtOAc (100 mL) was preac-
tivated under a hydrogen pressure of 4 atm for 1.5 h. A solution of
10 (20.2 g, 50 mmol) in EtOAc (120 mL) was added. The reaction
mixture was shaken at 30 °C under 4 atm hydrogen pressure for 6 h,
and then filtered through Celite. The filtrate was evaporated under
reduced pressure to give the crude product, which was purified by
recrystallization from i-PrOH to afford pure 11 (18.7 g, 92%) as a
white solid; mp 93–94 °C, [ ]D25 –67.3 (c = 1.02, DMSO).
reflections having I > 2.00 (I) for 284 paremeters refined. All non-
hydrogen atoms were refined anisotropically.
X-Ray Structure Analysis of 11
Crystals of C24H26N3OS (404.54) suitable for X-ray analysis were
obtained from EtOAc. A colorless orthorhombic crystal of dimen-
sions 0.20 × 0.20 × 0.30 mm was mounted on a Rigaku AFC7R dif-
fractometer. Determination of the cell parameters was performed by
least squares refinement of 28 reflections. The compound crystal-
lized in the monoclinic system, space group P212121 with
a = 9.6929 (4), b = 11.059 (4), c = 42.0841(17) Å; Z = 8;
V = 4511.2 (3) Å3; (Mo-Ka) = 0.162 mm–1; Dc = 1.191 gcm–3; F
IR (KBr): 2270 cm–1.
1H NMR (CDCl3): = 1.58–1.75 (m, 6 H, 3 × CH2), 2.34 (t, 2 H,
J = 6.56 Hz, CH2CN), 2.71 (4 d, 2 H, J = 2.34, 4.39 Hz, C6a-H and
C6-H), 3.06 (m, 1 H, C4-H), 3.89 (dd, 1 H, J = 5.56 Hz, C3a-H), 3.96
(m, 1 H, C6a-H), 4.03, 4.15, 4.75, 5.00 (4 d, 4 H, J = 15.07, 15.0 Hz,
2 × CH2C6H5), 7.22–7.38 (m, 10 H, 2 × C6H5).
(000) = 1720 reflections were collected in the range of 1.90 <
28.30° using Mo-K radiation (graphite monochromator,
<
= 0.71073 Å), -2 scan mode. The structure was solved by direct
methods and expanded using difference Fourier techniques and re-
fined by full-matrix least-square to R = 0.0675, R = 0.1766 with
EI-MS: m/z (%) = 405 (M+, 18), 91 (100), 277 (48), 187 (21), 314
(20), 278 (17), 265 (16), 264 (14).
2
= 1/[ 2 (Fo) + (0.1035 P2 + 1.3711 P) R (where P = (Fo + 2Fc2)/3)
HRMS (EI): m/z calcd for C24H26N3OS: 404.5549; found:
404.5561.
by using the 10576 observed reflections having I > 2.00 (I) for 533
parameters refined. All non-hydrogen atoms were refined anisotro-
pically.
Anal. Calcd for C24H26N3OS: C, 71.11; H, 64.20; N, 9.38. Found:
7.90 C, 71.27; H, 61.83; N, 9.26; S, 7.79.
d-Biotin (1)
Acknowledgment
A mixture of 11 (40.4 g, 0.1 mol), 47% aq HBr (200 mL) and tolu-
ene (20 mL) was refluxed with vigorous stirring for 40 h. After
cooling to r.t., the organic layer was separated. The aqueous layer
was extracted with toluene (3 × 40 mL) and evaporated under re-
This work was supported by a Grant-in-Aid (96107) for Scientific
Research from the Minitry of Chemical Industry of China.
Synthesis 2003, No. 14, 2155–2160 © Thieme Stuttgart · New York

2160
F.-E. Chen et al.
PAPER
Uskokovic, M. R. Tetrahedron 1987, 43, 4887.
References
(f) Moolenaar, M. J.; Speckamp, W. N. Angew. Chem., Int.
Ed. Engl. 1995, 34, 21. (g) Chen, F. E.; Feng, X. M.; Zhang,
H.; Wan, J. L.; Bie, L. L.; Guan, C. S.; Yang, J. S.; Ling, X.
H. Acta Pharm. Sinica 1995, 30, 824; Chem. Abstr. 1996,
124, 232120. (h) Deroose, F. D.; De Clercq, P. J. J. Org
Chem. 1995, 60, 321. (i) Fujisawa, T.; Nagai, M.; Koike, Y.;
Shimizu, M. J. Org. Chem. 1994, 59, 5865. (j) Seki, M.;
Hatsuda, M.; Mori, Y.; Yamada, S. Tetrahedron Lett. 2002,
43, 3269. (k) Chavan, S. P.; Tejwani, R. B.; Ravindranathan,
T. J. Org. Chem. 2001, 66, 6197. (l) Seki, M.; Shimizu, T.;
Inubushi, K. Synthesis 2002, 3, 361. (m) Ogawa, T.;
Kawano, T.; Matsui, M. Carbohydr. Res. 1977, 57, C31.
(n) Ohrui, H.; Sueda, N.; Emoto, S. Agric. Biol. Chem. 1978,
42, 865. (o) Ravindranathan, T.; Hiremath, S. V.; Reddy, D.
R.; Ramo Rao, A. V. Carbohydr. Res. 1984, 134, 332.
(6) Uskokovic, M. R. Encyclopedia of Chemical Technology,
3rd ed., Vol. 24; Kirk, R. E.; Othmer, D. E., Eds.; Wiley:
New York, 1984, 41.
(7) Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc. 1999,
121, 5819.
(8) Voss, G.; Gerlach, H. Helv. Chim. Acta. 1983, 7, 227.
(9) Knochel, P.; Yeh, M. C. P.; Berk, S. C. J. Org. Chem. 1988,
53, 2390.
(10) Shimizu, M.; Nishigaki, Y.; Wakabayashi, A. Tetrahedron
Lett. 1999, 40, 8873.
(11) (a) Itsuno, S.; Nakano, M.; Ito, K. J. Chem. Soc., Perkin
Trans. 1 1985, 2615. (b) Itsuno, S.; Ito, K. J. Chem. Soc.,
Perkin Trans. 1 1984, 2887. (c) Itsuno, S.; Matsumoto, T. J.
Org. Chem. 2000, 65, 5879.
(1) Part 5: Chen, F. E.; Fu, H.; Meng, G.; Luo, Y. F.; Yan, M. G.
Chem. J. Chin. Univ 2002, 23, 1060; Chem. Abstr. 2002,
137, 279008.
(2) (a) Mistry, P. S.; Dakshinamurti, K. Vitam. Horm. 1964, 22,
1. (b) Coggeshall, C. J.; Heggers, P. J.; Robson, C. M.;
Baker, H. Ann. N. Y. Acad. Sci. 1985, 447, 389.
(c) Maebashi, M.; Makino, Y.; Furukawa, Y.; Ohinata, K.;
Kimura, S.; Sato, T. J. Clin. Biochem. Nutr. 1993, 14, 211.
(3) (a) Gerecke, M.; Zimmermann, J.-P.; Aschwanden, W. Helv.
Chim. Acta 1970, 53, 991. (b) Volkman, R. A.; Davis, J. T.;
Meltz, H. Chem. Lett. 1983, 1275. (c) Vasilevskis, J.;
Gualtieri, J. A.; Hutchings, S. D.; West, R. C.; Scott, J. W.;
Parrish, D. R.; Bizzarro, F. T.; Field, G. F. J. Am. Chem. Soc.
1978, 100, 7423. (d) Senuma, M.; Fujii, T.; Seto, M.;
Okamura, K.; Date, T.; Kinumake, A. Chem. Pharm. Bull.
1990, 38, 882. (e) Reiff, F.; Mueller, H. R.; Hedinger, A.;
Herold, T.; Casutt, M.; Schweickert, N.; Stoehr, J. S.; Kuhn,
W. Eur. Pat. Appl. E.P. 01731855, 1986; Chem. Abstr. 1986,
105, 153061. (f) Chen, F. E.; Ling, X. H.; Lu, Y. X.; Zhang,
X. Y.; Peng, X. H. Chem. J. Chin. Univ. 2001, 22, 1147;
Chem. Abstr. 2001, 135, 331286.
(4) (a) Iriuchijima, S.; Hasegawa, K.; Tsuchihashi, G. Agric.
Biol. Chem. 1982, 46, 1907. (b) Tokuyaroa, S.; Yamano, T.;
Aoki, I.; Takanohashi, K.; Nakahama, K. Chem. Lett. 1993,
741. (c) Yamano, T.; Tokuyama, S.; Aoki, I.; Nishiguschi,
Y.; Nakahama, K.; Takanohashi, K. Bull Chem. Soc. Jpn.
1993, 66, 1456. (d) Wang, Y. F.; Sih, C. J. Tetrahedron Lett.
1984, 25, 4999. (e) Matsuki, K.; Inoue, H.; Takeda, M.
Tetrahedron Lett. 1993, 34, 1167. (f) Aoki, Y.; Suzuki, H.;
Akiyama, H.; Akano, S. US Patent 3876656, 1975; Chem.
Abstr. 1974, 80, 95951. (g) Chen, F. E.; Huang, Y. D.; Fu,
H.; Cheng, Y.; Zhang, D. M.; Li, Y. Y.; Peng, Z. Z. Synthesis
2000, 2004. (h) Jaeschke, G.; Seebach, D. J. Org. Chem.
1998, 63, 1190. (i) Choi, C.; Tian, S. K.; Deng, L. Synthesis
2001, 1737.
(12) Shuttleworth, S. J.; Allin, S. M.; Sharma, P. K. Synthesis
1997, 1217.
(13) (a) Shimizu, T.; Seki, M. Tetrahedron Lett. 2000, 41, 5099.
(b) Shimizu, T.; Seki, M. Tetrahedron Lett. 2001, 42, 429.
(c) Shimizu, T.; Seki, M. Tetrahedron Lett. 2002, 43, 1039.
(d) Tokuyama, H.; Yokoshima, S.; Yamashita, T.;
Fukuyama, T. Tetrahedron Lett. 1998, 39, 3192.
(14) Hu, J. B.; Zhao, G.; Yang, G. S.; Ding, Z. D. J. Org. Chem.
2001, 66, 303.
(15) Booth, B.; Jibodu, X. O.; Prcenca, M. F. J. R. P. J. Chem.
Soc., Perkin Trans. 1 1983, 1067.
(16) Yamano, T.; Tokuyama, S.; Aoki, I.; Nishiguchi, Y.;
Nakahama, K.; Takanohshi, T. Bull. Chem. Soc. Jpn. 1993,
66, 1456.
(5) (a) Baggiolini, E. G.; Lee, H. L.; Pizzolato, G.; Uskokovic,
M. R. J. Am. Chem. Soc. 1982, 104, 6460. (b) Deroose, F.
D.; Declerca, P. J. Tetrahedron Lett. 1994, 35, 2615.
(c) Deroose, F. D.; De Clercq, P. J. Tetrahedron Lett. 1993,
34, 4365. (d) Corey, E. J.; Mehrotra, M. M. Tetrahedron
Lett. 1988, 29, 57. (e) Lee, H. L.; Baggiolini, E. G.;
Synthesis 2003, No. 14, 2155–2160 © Thieme Stuttgart · New York