PAPER
An Efficient and Enantioselective Synthesis of d-Biotin
2007
EtOAc (3 ¥ 100 mL). The combined organic layers were washed
several times with sat. brine, and dried (Na2SO4). Removal of the
solvent under reduced pressure gave a yellow oil, which was puri-
fied by chromatography (EtOAc/hexane, 5:9) on a silica gel column
to afford pure 10 (13.8 g, 82%) as a white solid.
MS (EI): m/z (%) = 245 (M++1, 15), 227 (8), 199 (1), 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, 48.97; H, 6.45; N, 11.52; S, 13.39.
mp: 50-52 ∞C; [a]D = +208.7° (c 1.0, CHCl3).
IR (KBr): n = 1708, 1645, 1419, 1237 cm-1.
X-Ray Structure Analysis of 9
Crystals of C19H18N2O2S (338.42) suitable for X-ray analysis were
obtained from EtOH. A colorless prismatic crystal of dimensions
0.20 ¥ 0.20 ¥ 0.30 mm was mounted on a Rigaku AFC7R diffracto-
meter. Determination of the cell parameters was performed by least-
squares refinement of 19 reflections. The compound crystallizes in
the orthorhombic system, space group P212121(No.19) with
a = 12.010(3), b = 17.993(2), c = 7.895(2) Å; Z = 4; V = 1698.2 (6)
Å3 3; u(Mo-Ka) = 2.04 cm-1; Dc = 1.324 gcm-3; F(000) = 712.
2262 reflections were collected in the range 18.45<2q<24.18∞, us-
ing Mo-Ka radiation (graphite monochromator, l = 0.71069 Å), w-
2q scan mode. The structure was solved by direct method
(SHELXS86)19 and expanded using Fourier techniques20 and re-
fined by full-matrix least-square to R = 0.042 and Rw = 0.048 with
w = 1/s2(Fo) by using the 1657 observed reflections having
I>2.00s(I) for 218 parameters refined. All non-hydrogen atoms
were refined anisotropically.
1H NMR (CDCl3): d = 1.61-2.06 (m, 4H, 2 ¥ CH2), 2.13 (s, 3H,
CH3CO), 2.39 (t, 2H, J = 7.3 Hz, CH2CO), 2.72 (d, 1H, J = 12.6 Hz,
CHendoS), 2.93 (dd, 1H, J = 5.3, 12.6 Hz, CHexoS), 4.08 (m, 1H, C6a-
H), 4.28 (d, 1H, J = 7.7 Hz, C3a-H), 4.05, 4.22, 4.82, 4.95 (4 ¥ d, 4H,
J = 15.3, 15.7 Hz, 2 ¥ ArCH2), 5.42 (t, 1H, J = 7.2 Hz, CH), 7.27-
7.31 (m, 10H, 2 ¥ ArH).
MS (EI): m/z (%) = 420 (M+, 4), 363 (2), 329 (9), 238 (6), 187 (3),
91 (100).
Anal. Calcd for C25H28N2O2S: C, 71.43; H, 6.67; N, 6.67; S, 7.62.
Found: C, 71.21; H, 6.49; N, 6.43; S, 7.43.
HRMS: m/z Calcd for C25H28N2O2S: 420.5675. Found: 420.5659.
(3aS,6aR)-1,3-Dibenzyl-tetrahydro-1H-thieno[3,4-d]-imida-
zole-2(3H)-one-4-ylidenepentanoic Acid (11)
To a stirred solution of I2 (10 g, 39.4 mmol) and KI (7 g, 45 mmol)
in H2O (50 mL) was added dropwise 10% NaOH (100 mL). After
30 min, a solution of 10 (15 g, 35.7 mmol) in freshly distilled diox-
ane (260 mL) was slowly added, and the mixture was stirred at
60 ∞C for 2 h. After cooling to r.t., the mixture was filtered and the
solid material (iodoform) was washed with H2O (100 mL). The fil-
trate was treated with 5% Na2SO3 (30 mL) in order to destroy the
excess NaOI and then acidified to pH 2 with 15% HCl with stirring.
The precipitated product was collected by filtration, washed with
H2O, and recrystallized from i-PrOH/hexane to give pure 11
(11.3 g, 75%) as a white solid.
mp: 83-85 ∞C; [a]D20 = +236.2° (c 1.0, 0.1 N NaOH) {Lit.12 mp:
84-85 ∞C, [a]D = +236.2° (c 1.0, 0.1 N NaOH)}.
IR (KBr): n = 3432, 1725, 1662, 1485, 1452 cm-1.
1H NMR (CDCl3): d = 1.39-1.93 (m, 4H, 2 ¥ CH2), 2.00 (t, 2H,
J = 7.4 Hz, CH2CO), 2.81 (dd, 1H, J = 5.5, 12.1 Hz, CHexoS), 2.95
(d, 1H, J = 12.3 Hz, CHendoS), 4.16 (m, 1H,C6a-H), 4.62 (d, 1H,
J = 7.9 Hz, C3a-H), 4.05, 4.34, 4.52,4.97(4 ¥ d, 4H, J = 15.5, 16.8
Hz, 2 ¥ ArCH2), 5.56 (t, 1H, J = 7.8 Hz, CH), 7.24-7.40 (m, 10H,
2 ¥ ArH).
X-Ray Structure Analysis of 10
Crystals of C25H28N2O2S (420.57) suitable for X-ray analysis were
obtained from EtOAc. A colorless prismatic crystal of dimensions
0.20 ¥ 0.20 ¥ 0.30 mm was mounted on a Rigaku AFC7R diffracto-
meter. Determination of the cell parameters was performed by least-
squares refinement of 23 reflections. The compound crystallizes in
the orthorhombic system, space group P212121(No.19) with
a = 9.379(5), b = 41.524(5), c = 5.666(7) Å; Z = 4; V = 2206(2) Å 3;
u(Mo-Ka) = 1.71 cm-1; Dc = 1.266 gcm-3; F(000) = 896. 3006 re-
flections were collected in the range 14.39<2q<21.71∞, using Mo-
Ka radiation (graphite monochromator, l = 0.71069 Å), w-2q scan
mode. The structure was solved by direct method (SHELXS86)19
and expanded using Fourier techniques20 and refined by full-matrix
least-square to R = 0.055 and Rw = 0.058 with w = 1/s2(Fo) by using
the 1670 observed reflections having I>2.00s(I) for 272 parameters
refined. All non-hydrogen atoms were refined anisotropically.
Acknowledgement
This work was supported by a Grant-in-Aid (96107) for Scientific
Research from the Ministry of Chemical Industry of China. We also
gratefully acknowledge Prof. Xiang-Jun Li for helpful comments
and suggestions.
MS (EI): m/z (%) = 422 (M+, 6), 311 (6), 91 (100).
Anal. Cacld for C24H26N2O3S: C, 68.25; H, 6.16; N, 6.63; S, 7.58.
Found: C, 68.43; H, 5.91; N, 6.63; S, 7.36.
References
d-Biotin 1
(1) Du Vigneaud, V.; Hofmann, K.; Melville, D. B.; Gyorgy, P. J.
Biol. Chem. 1941, 140, 643.
(2) For a review on syntheses of d-biotin, see:
De Clercq, P. J. Chem. Rev. 1997, 97, 1755; and references
cited therein.
(3) For the applications of d-biotin, see:
Parry, R. J.; Naidu, M. V. Tetrahedron Lett. 1980, 21, 4783.
Trainor, D. A.; Parry, R. J.; Gitterman, A. J. Am. Chem. Soc.
1980, 102, 1467.
To a stirred suspension of 11 (42.2 g, 0.1 mol) and 10% Pd/C (15 g)
in formic acid (150 mL) was added methanesulfonic acid (150 mL)
in a single portion, and the mixture was stirred at reflux for 15 h. Af-
ter cooling to 50 °C, the catalyst was filtered off. The filtrate was
poured into H2O (350 mL) with stirring to give a precipitate, which
was recrystallized from H2O to yield pure 1 (20.8 g, 85%) as a white
crystalline powder.
mp: 232-233 °C; [a]D = +91.2° (c 1.0, 0.1 N NaOH) {Lit.18 mp:
229.5-230 °C, [a]D25 = +91.3° (c = 1.0, 0.1 N NaOH)}.
Ahler, M.; Müller, W.; Reichert, A.; Ringsdorf, H.; Venzmer,
J. Angew. Chem., Int. Ed. Engl. 1990, 29, 1269.
Baxter, R. L.; Camp, D. J.; Coutts, A.; Shaw, N. J. Chem. Soc.,
Perkin Trans. 1 1992, 255.
Marquet, A.; Frappier, F.; Guillerm, G.; Azoulav, M.;
Florentin, D. J. Am. Chem. Soc. 1993, 115, 2139.
Martini, H.; Retey, J. Angew. Chem., Int. Ed. Engl. 1993, 32,
278.
IR (KBr): n = 3305-3245, 2705-2500, 1705, 1665 cm-1.
1H NMR (DMSO-d6): d = 1.31-1.60 (m, 6H, 3 ¥ CH2), 2.18 (t, 2H,
J = 7.3 Hz, CH2COOH), 2.59 (dd, 1H, J = 1.7, 12.5 Hz, CHendoS),
2.81 (dd, 1H, J = 4.7, 12.5 Hz, CHexoS), 3.15 (m, 1H, C4b-H), 4.18
(m, 1H, C3a-H), 4.35 (m, 1H, C6a-H), 6.35 (s, 1H, NH), 6.48 (s, 1H,
NH), 11.99 (br s, 1H, COOH).
Synthesis 2000, No. 14, 2004–2008 ISSN 0039-7881 © Thieme Stuttgart · New York