Synthetic studies on d-biotin. Part 7: A practical asymmetric total synthesis of d-biotin via enantioselective reduction of meso-cyclic imide catalyzed by oxazborolidine

Article abstract of DOI:10.1016/j.tetasy.2003.08.034

A novel and convenient method for the stereoselective synthesis of d-biotin 1 starting from the commercially available cis-1,3-dibenzyl-2- imidazolidone-4,5-dicarboxylic acid 2 has been developed. The key features of this synthesis include the enantioselective reduction of a meso-cyclic imide, mediated by a chiral oxazborolidine catalyst, derived from (1S,2S)-(+)-threo-1- (4-nitrophenyl)-2-amino-1,3-propanediol and the direct introduction of a C ₅ side chain to the (3aS,6aR)-thiolactone through a modified di-Grignard reaction. Enantioselectivities of 98% in the oxazborolidine- catalyzed asymmetric reduction process have been achieved.

Full text of DOI:10.1016/j.tetasy.2003.08.034

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3667–3672
Synthetic studies on d-biotin. Part 7:† A practical asymmetric
total synthesis of d-biotin via enantioselective reduction of
meso-cyclic imide catalyzed by oxazborolidine
Fen-Er Chen,* Hui-Fang Dai, Yun-Yan Kuang and Hui-Qing Jia
Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China
Received 7 July 2003; accepted 25 August 2003
Abstract—A novel and convenient method for the stereoselective synthesis of d-biotin 1 starting from the commercially available
cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 has been developed. The key features of this synthesis include the
enantioselective reduction of a meso-cyclic imide, mediated by a chiral oxazborolidine catalyst, derived from (1S,2S)-(+)-threo-1-
(4-nitrophenyl)-2-amino-1,3-propanediol and the direct introduction of a C5 side chain to the (3aS,6aR)-thiolactone through a
modified di-Grignard reaction. Enantioselectivities of 98% in the oxazborolidine-catalyzed asymmetric reduction process have
been achieved.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
approaches based on this promising Sternbach strategy
that overcome drawbacks such as the need for an
intermediate resolution with possible recycling in the
preparation of a key chiral building block, (3aS,6aR)-
lactone 5,5 and the six-step conversion to 1 from
(3aS,6aR)-thiolactone 6. Therefore, the development of
an efficient desymmetrization of dicarboxylic acid 2 to
form 5 and one-step introduction of the carboxybutyl
side chain to 6 is far from over. Herein we report a new
and efficient method for the asymmetric synthesis of 1
based on the enantioselective oxazaborolidine-catalyzed
reduction of meso-cyclic imide 3.
There has been considerable interest in the development
of efficient routes for the synthesis of d-biotin 1, a
member of the Vitamin B complex group, because of its
importance in human nutrition and animal health.2
Although a large number of approaches involving dif-
ferent ingenious strategies for the control of the three
adjacent stereogenic centers have been documented,3
the Sternbach process, utilizing (3aS,6aR)-thiolactone
6, developed by the Goldberg and Sternbach at Hoff-
mann–La Roche in 1949, is still the most reliable source
of this essential vitamin with the overall synthesis
scheme having hardly changed over the past 53 years.
The unsurpassed efficiency and practicality of this
Sternbach strategy results from its ability to make good
use of a readily available fumaric acid with a symmetri-
cally bifunctional structure as the starting material for
the efficient construction of (3aS,6aR)-lactone 5, and
subsequently, to capitalize on the sterically well-differ-
entiated two faces of the cis-fused bicycle ring in the
(3aS,6aR)-thiolactone 6 to realize the controlled reac-
tion of the third stereogenic center during the introduc-
tion of the side chain to give 1.4 However, there are few
2. Results and discussion
The total synthesis of 1 is presented in Scheme 1, using
commercially available cis-1,3-dibenzyl-2-imidazolid-
ione-4,5-dicarboxylic acid 2 as the starting material.
Treatment of dicarboxylic acid 2 with benzylamine in
xylene with a catalytic amount of pyridine and subse-
quent azeotropic removal of water, under reflux for 8 h
afforded the meso-cyclic imide 3 in a 90% yield. It is
worth mentioning that the reaction time was longer (15
h) and the yield of 3 decreased to 65% when no
pyridine was used. Enantioselective differentiation of
the prochiral functional groups in symmetrical bifunc-
tional compounds such as meso compounds is an
* Corresponding author. Tel.: +86 (21) 65642021; fax: 86-21-
65641740; e-mail: rfchen@fudan.edu.cn
† See Ref. 1.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.034

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F.-E. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 3667–3672
Scheme 1. Reagents and conditions: (a) BnNH2, pyridine, xylene, reflux, 8 h 90%; (b) LiH, BF3·Et2O, 12, THF, reflux, 8 h; (c)
KBH4, CaCl2, EtOH, rt 4 h, then 1 M aq HCl, rt, 92%; (d) CH3SC(S)SK, DMA, 120°C 6 h, 88%; (e) (i) BrMg(CH2)4MgBr, THF,
−30 to −25°C, 3 h; (ii) CO2, −30 to −25°C, 3 h; (iii) 1 M aq NH4Cl; (f) H2, 5% Pd/C, ZnCl2, toluene, 40 atm, 110°C, 6 h, 75%
(from 6 to 8); (g) H2SO4–HOAc–H2O (1.5:1.5:1), reflux, 12 h, 75%.
(−) - threo - 1 - (4 - nitrophenyl) - 2 - amino - 3 - triphenyl-
methoxypropanol as its crystalline hydrochloride salt.
The assignment of the stereochemistry of 4 was based
important strategy for creating new stereogenic centers.
A single, stereoselective transformation, namely the
reduction of one of the carbonyls leads to a product
with three contiguous stereocentres. Among various
asymmetric reductions, the oxazaborolidine–mediated
borane reduction is one of the most useful tools for the
reduction of meso-cyclic imides into chiral hydroxylac-
tams, which were eventually converted to the corre-
sponding chiral lactones via further reduction and acid
hydrolysis.6 Shimizu recently reported the enantioselec-
tive reduction of meso N-benzyl imide 3 into the corre-
sponding chiral hydroxylactam 4 with borane as the
reducing agent in the presence of an oxazaborolidine
1
on single crystal X-ray crystallography (Fig. 1) and H
NMR experiments. The coupling constant (J=5.5 Hz)
between C6ꢀHexo and C6aꢀH clearly indicates that
C6ꢀHexo and C6aꢀH are syn-disposed.
catalyst derived from L-threonine. In spite of its brevity
and high enantioselectivity (98%),7 the yield of 4 was
only moderate (65%). Due to borane and its complexes
such as BH3·THF or BH3·Me2S being expensive and
the reagents, which often did not store well, requiring a
lot of precautions because of their toxicity, this proce-
dure appeared less attractive for a large-scale produc-
tion of (3aS,6R,6aR)-hydroxylactam 4.
Our attention was drawn to the development of an
efficient, enantioselective reduction of meso-cyclic imide
3 into (3aS,6R,6aR)-hydroxylactam via the use of a
chiral oxazaborolidine catalyst, derived from (1S,2S)-
(+)-threo-1-(4-nitrophenyl)-2-amino-1,3-propanediol
with in situ generated borane from cheap, safe and
convenient lithium hydride and boron trifluoride ether-
ate. The meso-cyclic imide 3 was subjected to enantiose-
lective reduction upon treatment with LiH and
BF3·Et2O in the presence of (1S,2S)-(+)-threo-1-(4-
nitrophenyl)-2-amino-3-triphenylmethoxypropanol 12
under reflux in THF to give, after addition of satd.
HCl/Et2O and filtration, 4 in 85% yield and 98% enan-
tiomeric excess (determined by chiral HPLC analysis
using a chiral stationary phase), and recovered (1S,2S)-
Figure 1. X-Ray determined structure of 4.

F.-E. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 3667–3672
3669
Ligand 12 was readily prepared via a known procedure9
3. Conclusion
from commercially available (1S,2S)-(+)-thero-1-(4-
nitrophenyl)-2-amino-1,3-propanediol 9. The (1S,2S)-
In conclusion, we have completed an efficient synthesis
of d-biotin 1, proceeding in seven steps with 34.8%
overall yield from 2. The high overall yield, short route,
simple operation and use of readily accessible reagents
could allow a practical large-scale preparation of 1.
amine
9
was regioselectively protected using
di-tert-butyldicarbonate in methanol to give the deriva-
tive 10 (90%), which was O-alkylated with chlorotri-
phenylmethane in pyridine to afford compound 11 in
89% yield. Hydrolysis of 11 gave ligand 12 in 80% yield
(Scheme 2).
4. Experimental
4.1. General
The reduction of 4 with KBH4 in the presence of
anhydrous CaCl2 in EtOH at rt followed by treatment
with 1 M aq HCl gave the (3aS, 6aR)-lactone 5 in 92%
yield. The enantiomeric purity of 5 was determined to
be 96% by comparison of its specific rotation [h]2D0=+
56.8 (c 2, CHCl3) with that reported {lit.9 [h]D20=+59.2
(c 2, CHCl3)} which was then increased to 99% ee by
recrystallization from EtOH. The thiolactonization of 5
with potassium methylthioxanthogenate(MeSC (S)SK)
in DMA at 120°C for 6 h to afford the (3aS, 6aR)-thi-
olactone 6 in 88% yield.
Solvents were distilled from the appropriate drying
agents before use. Unless stated otherwise, all reactions
were monitored by TLC on silica gel 60 F254 (0.25 mm,
E. Merck). Spots were detected under UV light. Optical
rotations were measured at 20 3°C on a WZZ-2S digi-
tal automatic polarimeter. Melting points are deter-
mined on a WRS-1 digital melting point apparatus and
are uncorrected. The chiral HPLC analyses were per-
formed on a Shimadzu LC010AT instrument fitted with
a Chiralcel OD column (250×4.6 mm). IR spectra were
recorded on a Nicolet FI-IR 360 spectrometer. 1H
NMR spectra were obtained 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 measured with EI techniques. Elemental analysis
was carried on a Carlo Erba 1106 elemental analyzer.
Atomic coordinates can be obtained on request from
the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK. CCDC
number: 218562
The carboxylbutyl side chain of 1 was assembled by the
reaction of 6 with a di-Grignard reagent, derived from
1,4-dibromobutane with subsequent treatment of car-
bon dioxide to give the hydroxy acid 7, without purifi-
cation, which upon catalytic hydrogenesis under 40 atm
of hydrogen using 5% palladium–carbon in the pres-
ence of anhydrous ZnCl2 in toluene at 110°C provided
N,N-dibenzylbiotin 8 stereoselectively in 75% yield. It is
important to note that the reaction had to be main-
tained between −30 to −25°C during the addition of a
solution of 6 in THF to the di-Grignard reagent and
then afterwards during the carbon dioxide addition
forming the carboxylic acid group. A decrease in yield
(51%) was observed when the reaction was performed
between −10 to −5°C for 2 h in an attempt to make the
reaction go to completion.
4.2. N-Benzyl-cis-1,3-dibenzyl-2-imidazolidone-4,5-
dicarboximide, 3
A mixture of dicarboxylic acid 2 (35.4 g, 0.10 mol),
benzylamine (11.2 g, 0.105 mol), pyridine (12.5 mL,
0.16 mol) and xylene (200 mL) was stirred and refluxed
under a Dean–Stark trap for 8 h. The reaction mixture
was cooled to room temperature, whereupon H2O (100
Finally, the N,N-dibenzylbiotin 8 was efficiently con-
verted to d-biotin 1 in 75% yield through deprotection
with H2SO4–HOAc–H2O (1.5:1.5:1) under reflux for 12
h.
Scheme 2. Reagents and conditions: (a) (Boc)2O, MeOH, reflux, 20 min, 90%; (b) TrCl, pyridine, CH2Cl2, 90°C, 30 min, 89%; (c)
5.4 M aq HCl, CH2Cl2, 50°C, 2 h, 80%.

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F.-E. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 3667–3672
mL) was added. The organic phase was separated, the
aqueous phase extracted with xylene (3×35 mL) and the
combined organic phases washed successively with 1 M
aq HCl (3×25 mL), satd. aq NaCl (3×35 mL) and H2O
(3×40 mL), dried over Na2SO4 and evaporated under
reduced pressure to give the crude product, which was
then recrystallized from toluene to form the pure 3 (38.3
g, 90%) as a white solid. Mp 115–117°C; IR (KBr,
cm−1): 3432, 1709, 1979, 1643; 1H NMR (CDCl3): l 4.25
(s, 2H, C3aꢀH and C6aꢀH), 4.26, 4.29, 4.72, 4.78 (4×d,
4H, J=15.38, 15.42, 2×ArCH2), 4.55 (s, 2H, ArCH2N),
7.19–7.37 (m, 15H, 3×ArH); MS m/z (% ret. Int.): 425
(M+, 28), 334 (5), 237 (6), 132 (12), 91 (100). Anal. calcd
for C26H23N3O3 requires: C, 73.39; H, 5.45; N, 9.88.
Found: C, 73.20; H, 5.38; N, 9.61.
drous EtOH (550 mL) at 0–5°C, followed by a solution
of anhydrous CaCl2 (27.75 g, 0.25 mol) at the same tem-
perature. The reaction mixture was warmed gradually to
room temperature and stirred for 4 h. Then 1 M aq HCl
(145 mL) was added dropwise to the reaction mixture.
The reaction mixture was stirred at 55–60°C for 45 min.
After cooling to room temperature, the reaction mixture
was extracted with EtOAc (4×75 mL). The combined
organic phases were washed successively with satd. aq
NaCl (3×45 mL) and H2O (3×45 mL), dried over
Na2SO4, and evaporated under reduced pressure to give
the crude product, which was recrystallized from EtOH
to afford the pure 5 (88.87 g, 92%) as a white solid. Mp
119–120°C [h]2D0=+58.6 (c 2, CHCl3) {lit.8 mp115–
116°C, [h]2D0=+59.2 (c 2, CHCl3)}; 96% ee. [HPLC con-
ditions: u=254 nm; eluent: n-hexane:2-propanol (9:1);
flow rate, 0.8 mL/min]. Recrystallization from EtOH
gave 82.11 g (85%, 99% ee) of 5, mp 120–121°C, [h]2D0=
+61.5 (c 2, CHCl3). IR (KBr, cm−1): 1776, 1705, 1210,
4.3. (3aS,6R,6aR)-1,3,5-Tribenzyl-6-hydroxy-tetra-
hedro-4H-pyrolo [3,4-d] imidazole-2,4(1H)-dione, 4
1
1185, 1028, 970; H NMR (CDCl3): l 3.25 (dd, 1H, J=
To a stirred suspension of LiH (1.0 g, 125 mmol) in dry
THF (25 mL) was added BF3·Et2O (23.8 mL, 187
mmol). Once the vigorous reaction had subsided, the
reaction mixture was stirred at room temperature for 30
min. The chiral ligand 12 (5.7 g, 12.5 mmol) was then
added and the reaction mixture heated at reflux for a
further 30 min. Then a solution of meso-cyclic imide 3
(21.3 g, 50 mmol) in dry THF (150 mL) was added
dropwise over a period of 4 h. The reaction mixture was
stirred under reflux for an additional 30 min. After cool-
ing to room temperature, the reaction mixture was
quenched with CH3OH (75 mL). To the resulting solu-
tion was added sat. HCl/Et2O (80 mL) with stirring and
ice bath cooling over 10 min. After 30 min, the solvent
was removed under reduced pressure. To the residue
was added AcOEt (250 mL) and the mixture cooled to
0–5°C. Colorless crystals of (1S,2S)-(+)-threo-1-(4-
nitrophenyl)-2-amino-3-triphenylmethoxypropanol 12
hydrochloride were collected by filtration and converted
to the amino alcohol 12 (recovery 5.46 g, 95.8%). The
filtrate was washed successively with H2O (3×45 mL),
satd. aq NaHCO3 (3×30 mL) and sat. aq NaCl (3×25
mL), dried over Na2SO4, and evaporated under reduced
pressure. Purification of the resulting residue by flash
chromatography on silica gel (2:1, hexane /EtOAc)
afforded pure 4 (18.2 g, 85%) as a white solid. Mp 128–
131°C; [h]2D0=+68.9 (c 0.1, CH2Cl2). 98% ee [HPLC con-
ditions: u=254 nm; eluent: n-hexane: 2-propanol (6:4);
flow rate, 0.6 mL/min]. IR (KBr, cm−1): 3313, 2933,
2.3, 12.8 Hz, CHendo S), 3.35 (dd, 1H, J=5.6, 12.8 Hz,
CHexo S), 3.96 (m, 1H, J=8.8 Hz, C3a-H), 4.20 (3×d,
1H, J=2.3, 5.4, 8.0 Hz, C6a-H), 4.24, 4.32, 4.46, 4.95 (4×
d, 4H, J=14 Hz, 2×ArCH2), 7.27–7.38 (m, 10H, ArH);
MS m/z (% ret. Int.): 322 (M+, 25), 265 (58), 245 (78),
187 (62), 91 (100); HRMS (EI) calcd for C19H18N2O3
322.3466, found: 322.3487. Anal. calcd for C19H18N2O6
required: C, 70.81; H, 5.59; N, 8.70. Found: C, 70.58; H,
5.42; N, 8.53.
4.5. (3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-thieno[3.4-
d]imidazole-2.4( 1H)-dione, 6
To a stirred solution of 5 (32.2 g, 0.10 mol) in DMA
(150 mL) was added potassium methylthioxanthogenate
(16.2 g, 0.1 mol). The reaction mixture was stirred at
120°C under N2 atm for 6 h. After cooling to room tem-
perature, H2O (145 mL) was added to the reaction mix-
ture. The reaction mixture was then extracted with
toluene (4×40 mL). The combined organic phases were
washed with satd. aq NaCl (3×35 mL) and H2O (3×35
mL), dried over Na2SO4, and evaporated under reduced
pressure to give the crude product, which was then
purified by recrystallization with EtOAc to afford pure 6
(29.74 g, 88%) as a crystalline powder. Mp 124–125°C
[h]2D0=+90.4 (c 1, CHCl3) {lit.10 mp 125–127°C, [h]2D0=
+90.8 (c 1, CHCl3)}; 99.1% ee [HPLC conditions: u=
254 nm; eluent: n-hexane:AcOEt (2:1); flow rate, 0.4
1
mL/min]. IR (KBr, cm−1): 1705, 1695, 1424, 1225; H
1
1700, 1452, 1236, 1080, 740, 701; H NMR (DMSO-
NMR (CDCl3): l 3.24 (dd, 1H, J=2.2, 12.8 Hz,
CHendoS), 3.35 (dd, 1H, J=5.5, 12.8 Hz, CHexoS), 3.82
(d, 1H, J=8.0 Hz, C3a-H), 4.14 (3×d, 1H, J=2.2, 5.5,
8.0 Hz, C6a-H), 4.35, 4.38, 4.67, 5.00 (4×d, 4H, J=15.2
Hz, 2×ArCH2), 7.27–7.35 (m, 10H, ArH); MS m/z (%
ret. Int.): 338 (M+, 5), 310 (25), 277 (8), 264 (66), 91
(100). Anal. calcd for C19H18N2OS required: 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.
d6):l 3.77–3.79 (m, 2H, C3aꢀH and C6aꢀH), 4.91 (2×d,
1H, J=5.5 Hz, CHOH), 4.21, 4.41, 4.90, 4.94, 5.04, 5.14
(6×d, 6H, 3×ArCH2), 7.20–7.41 (m, 15H, 3×ArH); MS
m/z (% ret. Int.): 427 (M+, 13), 264 (22), 106 (5), 91
(100). Anal. calcd for C26H25N3O3 required C, 73.05; H,
5.89; N, 9.83. Found: C, 72.89; H, 5.65; N, 9.69; HRMS
(EI) calcd for C26H25N3O3: 427.5018, found 427.4989.
4.4. (3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-furo[3,4-d]-
imidazole-2.4(1H)-dione, 5
4.6. (3aS,4S,6aR)-1,3-Dibenzyl-tetrahydro-1H-
thieno[3,4-d]imidazole-2(3H)-one-4-ylpentanoic acid, 8
To a stirred mixture of KBH4 (26.9 g, 0.50 mol) and
anhydrous EtOH (75 mL) was added dropwise a solu-
tion of hydroxylactam 4 (128.25 g, 0.30 mol) in anhy-
To a stirred suspension of Mg turnings (11 g, 0.45 mol)
in dry THF (150 mL) was added dropwise 1,4-dibromo-

F.-E. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 3667–3672
3671
butane (21.6 g, 0.10 mol) at 30–35°C under nitrogen.
When the reaction started, the remaining 1,4-dibromo-
butane (74.52 g, 345 mmol) in dry THF (320 mL) was
added dropwise at 30–35°C over a period of 1 h.
Stirring continued at the same temperature for 45 min,
followed by cooling to −30 to −25°C, and dropwise
addition of a solution of thiolactone 6 (50.7 g, 0.15
mol) in dry THF (250 mL) at this temperature. The
reaction mixture was stirred for an additional 3 h at
−30 to −25°C, and the carbon dioxide was led in at −30
to −25°C for 3 h. Then, the reaction mixture was
quenched with satd. aq NH4Cl (200 mL) and extracted
with toluene (4×150 mL). The combined organic phases
were washed successively with satd. aq NaCl (3×50 mL)
and H2O (3×40 mL) and dried over Na2SO4. The
solvent was concentrated under reduced pressure to
approximately a volume of 300 mL to give a solution of
hydroxy acid 7 in toluene. To this stirred solution of
hydroxy acid 7 was added ZnCl2 (5.0 g, 37 mmol) and
5% Pd/C (5.0 g). The reaction mixture was hydro-
genated under a hydrogen pressure of 40 atm at 110°C
for 6 h. After cooling to room temperature, H2O (40
mL) was added. Stirring continued at room tempera-
ture for a further 15 min. The catalyst was removed by
filtration and the filtrate evaporated under reduced
pressure to give the crude product 8 as a pale yellow
oil, which was left to stand overnight in an refrigerator
to be crystallized and recrystallized from iso-PrOH/hex-
ane (2:1) to afford pure 8 (47.8 g, 75%) as a white solid.
Mp 90–92°C; [h]D23=−26.7 (c 1, CH3OH) {lit.11 mp
91–92°C; [h]2D3=−26.8 (c 1, CH3OH)}; 98.9% ee [HPLC
conditions: u=254 nm; eluent: n-hexane:AcOEt (9:2);
3.14 (m, 1H, C4b-H), 4.17 (m, 1H, C3a-H), 4.36 (m, 1H,
C6aꢀH), 6.37 (s, 1H, NH), 6.47 (s, 1H, NH), 11.98 (br
s, 1H, CO2H). MS m/z (% rel. int.) 245 (M++1, 15), 227
(9), 184 (25), 112 (26), 97 (100), 85 (66). Anal. calcd for
C10H16N2O3S required: 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.
4.8. X-Ray structure analysis of 4
Crystals of C26H25N3O3 (427.50) suitable for X-ray
analysis were obtained from EtOAc. A colorless mono-
clinic crystal of dimensions 0.40×0.30×0.30 mm was
mounted on a Rigaku AFC7R diffractometer. Determi-
nation of the cell parameters was performed by least
squares refinement of 25 reflections. The compound
crystallizes in the monoclinic system, space group
P21,21,21 with a=10.910 (6), b=9.189 (6), c=10.949 (4)
3
,
,
A; i=104.87 (4)°Z=2; V=1060.9 (10) A ; v(Mo-
Kh)=0.089 mm−1; Dcalcd=1.338 g cm−3; F(000)=452
reflections were collected in the range of 1.92°<q<
25.17° using Mo-Ka radiation (graphite monochroma-
,
tor, u=0.71073 A), ꢀ−2q scan mode. The structure was
solved by direct methods and expanded using difference
Fourier techniques and refined by full-matrix, least-
square to R=0.0811, R=0.1905 with ꢀ=1/[|2(Fo)+
(0.1035 P2+1.3711 P) R (where P=(Fo +2Fc )/3) by
using the 1232 observed reflections having I>2.00|(I)
for 284 parameters refined. All non-hydrogen atoms
were refined anisotropically.
2
2
Acknowledgements
1
flow rate, 0.8 mL/min]. H NMR (CDCl3): l 1.38–1.69
(m, 6H, 3×CH2), 2.19 (t, 2H, J=6.56 Hz, CH2COOH),
2.71 (4×d, 2H, J=2.34, 4.39 Hz, C6aꢀH and C6bꢀH),
3.06 (m, 1H, C4bꢀH), 3.89 (dd, 1H, J=5.56 Hz, C3aꢀH),
3.96 (m, 1H, C6aꢀH), 4.03, 4.15, 4.75, 5.00 (4×d, 4H,
J=15.1, 15 Hz, 2×CH2C6H5), 7.23–7.37 (m, 10H, 2×
ArH). HRMS (EI) calcd for C24H28N2O3S 424.5628,
found: 424.5639. Anal. calcd for C24H28N2O3S
required: C, 67.90; H, 6.65; N, 6.60; S, 7.55. Found: C,
67.69; H, 6.49; N, 6.48; S, 7.36.
This investigation was generously supported by partial
funds provided by the Ministry of Chemical Industry of
China (Grant No. 96107).
References
1. Part 6. Chen, F. E.; Yuan, J. L.; Dai, H. F.; Kuang, Y.
Y.; Chu, Y. Synthesis 2003, in press.
2. (a) Mistry, P. S.; Dakshinamurti, K. Vitam. Horm. 1964,
22, 1; (b) Maebashi, M.; Makino, Y.; Furukawa, Y.;
Ohinata, K.; Kimura, S.; Sato, T. J. Clin. Biochem. Nutr.
1993, 14, 211; (c) Coggeshall, C. J.; Heggers, P. J.;
Robson, C. M.; Baker, H. Ann. N.Y. Acad. Sci. 1985,
447, 389.
3. For a review, see: De Clercq, P. J. Chem. Rev. 1997, 97,
1755.
4. Uskokovic, M. R. In Encyclopedia of Chemical Technol-
ogy, 3rd ed.; Kirk, R. E.; Othemr, D. E., Eds.; Wiley:
New York, 1984; Vol. 24, p. 41.
5. (a) Matsuki, K.; Inoue, H.; Takeda, M. Tetrahedron Lett.
1993, 34, 1167; (b) Matsuki, K.; Inoue, H.; Ishida, A.;
Takeda, M.; Nakagawa, M.; Hino, T. Chem. Pharm.
Bull. 1994, 42, 9; (c) Iruchijima, S.; Hasegawa, K.;
Tsuchihash, G. Agric. Biol. Chem. 1982, 46, 1907; (d)
Wang, Y. F.; Shi, C. J. Tetrahedron Lett. 1984, 25, 4999;
(e) Jaeschke, G.; Seebach, D. J. Org. Chem. 1998, 63,
1190; (f) Choi, C.; Tian, S. K.; Deng, L. Synthesis 2001,
1737; (g) Shimizu, M.; Matsukawa, K.; Fujisawa, T. Bull.
Chem. Soc. Jpn. 1993, 66, 2128.
4.7. d-Biotin, 1
To a stirred mixture of N,N-dibenzylbiotin (42.4 g, 0.10
mol), glacial acetic acid (150 mL) and H2O, (150 mL)
was added dropwise 98% H2SO4 (150 mL) at room
temperature, over a period of 25 min. The reaction
mixture was stirred under reflux for 12 h. After cooling
to room temperature, H2O (200 mL) was added. The
reaction mixture was extracted with toluene (4×65 mL).
The aqueous phase was concentrated under reduced
pressure to approximately a volume of 120 mL and
kept in a refrigerator overnight. The precipitated crys-
tals were collected by filtration and recrystallized from
H2O to give pure 1 (18.38 g, 75%) as a white crystalline
powder. Mp 230–232°C, [h]2D2=+91.1 (c 1, 0.1 M
NaOH) {lit.12 mp 232–233°C, [h]2D2=+91.2 (c 1, 0.1 M
1
NaOH)}; IR (KBr, cm−1): 3311, 2933, 1705, 1665; H
NMR (CDCl3): l 1.30–1.61 (m, 6H, 3×CH2), 2.17 (t,
2H, J=7.3 Hz, CH2CO2H), 2.58 (dd, 1H, J=1.7, 12.5
Hz, CHendoS), 2.80 (dd, 1H, J=4.7, 12.5 Hz, CHexoS),

3672
F.-E. Chen et al. / Tetrahedron: Asymmetry 14 (2003) 3667–3672
3876659, April 8, 1975; Chem. Abstr. 1974, 80,
6. (a) Romagnoli, R.; Roos, E. C.; Hiemsta, H.; Moolenaar,
M. J.; Speckamp, W. N. Tetrahedron Lett. 1994, 35, 1087;
(b) Ostendorf, M.; Romagnoli, R.; Pereiro, I. C.; Roos,
E. C.; Moolenaar, M. J.; Speckamp, W. N.; Hiemstra, H.
Tetrahedron: Asymmetry 1997, 8, 1773.
95951.
10. Yamano, T.; Tokuyama, S.; Aoki, I.; Nishiguchi, Y.;
Nakahama, K.; Takanohashi, T. Bull. Chem. Soc. Jpn.
1993, 66, 1456.
7. Shimizu, M.; Nishigaki, Y.; Wakabayash, A. Tetrahedron
11. Takahash, T.; Minai, M.; Yamamoto, T.; Mizuno, T.,
Miyamoto, Y. European Patent Appl, EP 0633263 A2,
Nov, 1, 1995; Chem. Abstr. 1995, 122, 187270.
12. Chen, F. E.; Huang, Y. D.; Fu, H.; Cheng, Y.; Zhang, D.
M.; Li, Y. Y.; Peng, Z. Z. Synthesis 2000, 2004.
Lett. 1999, 40, 8873.
8. Yuan, J. L.; Dai, H. F.; Chen, F. E. Org. Prep. Proced.
Int. 2003, in press.
9. Aoki, Y.; Suzuki, H.; Akiyama, H.; Akano, S. US Patent