M. Seki et al. / Tetrahedron Letters 44 (2003) 8905–8907
8907
2,489,232, Nov. 22, 1949, Chem. Abstr. 1951, 45, 184b; (b)
Goldberg, M. W.; Sternbach, L. H. US Patent 2,489,235,
Nov. 22, 1949; Chem. Abstr. 1951, 45, 186a; (c) Gerecke,
M.; Zimmermann, J.-P.; Ashwanden, W. Helv. Chem. Acta
1970, 53, 991.
7. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama,
T. Tetrahedron Lett. 1998, 39, 3189.
8. Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989,
949.
Scheme 7. Reagents and conditions: (i) (i) IZn(CH2)4CO2Et,
Pd(OH)2/C (0.65 mol%), THF, toluene, DMF, 30°C, (ii) HCl,
92%; (j) (i) H2, Pd(OH)2/C; MeOH, H2O, (ii) NaOH, 90%; (k)
MeSO3H, mesitylene, 74%.
9. Compound 14 was isolated as stable solids in high yield by
simple addition of water to the reaction mixture.
10. Synthesis of 8: A solution of 7 (100 g, 0.28 mol) in DMF
(200 mL) was stirred at 90°C for 3 h under N2 atmosphere.
To the mixture was added dropwise conc. HCl (200 mL,
1.9 mol) at 90°C over 1.75 h. After stirring the mixture at
the same temperature for 1.25 h, water (100 mL) was added
dropwise at 85°C over 30 min. The mixture was cooled
down to 0°C and the solids formed were collected to afford
8 (95.1 g, 95%) as colorless crystals. mp 159–160°C;
[h]2D0=+48.8 (c 0.62, DMF); optical purity: >99% ee
[HPLC: Chiralcel AD (Daicel), EtOH/hexane/THF=
10:90:0.1, 0.8 mL/min, 40°C, 225 nm]; IR (KBr) w=1735,
1625 cm−1; 1H NMR (DMSO-d6) l 7.58 (1H, s), 7.37–7.22
(10H, m), 4.83 (1H, d, J=16.0 Hz), 4.54 (1H, d, J=16.0
Hz), 4.13 (1H, d, J=16.0 Hz), 4.06 (1H, d, J=16.0 Hz),
3.82 (1H, d, J=4.0 Hz), 3.61–3.58 (1H, m), 2.75–2.65 (2H,
m), 2.13–2.11 (1H, m); 13C NMR (DMSO-d6) l 170.6,
160.7, 136.9, 136.4 (4s), 128.8–127.5, 58.3, 58.0 (8d), 46.5,
46.3, 23.4 (3t); SIMS m/z 357 (M++1). Anal. calcd for
C19H20N2O2S; C, 64.02; H, 5.66; N, 7.86; Found: C, 63.83;
H, 5.38; N, 7.96.
The resulting vinyl sulfide 10 was subjected to low
pressure hydrogenation (0.9 MPa) by the use of
Pd(OH)2/C and subsequent removal of the protective
groups by MeSO3H15 to furnish (+)-biotin (1) in 67%
yield (two steps involving recrystallization of 1). The
product 1 obtained by the present synthesis showed
complete identity with an authentic sample with respect
to IR, NMR, MS, and optical rotation.16
In conclusion, a novel and practical synthesis of (+)-
biotin (1) was accomplished. The use of the minimally
protected intermediates, i.e. 2-thiazolidinone deriva-
tives, considerably reduced the number of steps and
(+)-biotin is now accessible in 10 steps and in 31%
overall yield from readily available L-cysteine. The syn-
thesis of 1 using thiolactone 9 as a key intermediate was
accomplished by Goldberg and Sternbach 50 years
ago,6a,b which was thoroughly revised by the present
work. Short steps, high yield, and ease of operation of
the present approach would permit the hitherto most
efficient access to 1. Since the thermal migration of the
carbonyl group to oxygen atom other than sulfur atom
is possible (as for 12 to 13a), the use of 2-thiazolidinone
derivatives for protecting a thiol group would allow not
only the facile synthesis of 4-mercaptomethyl-2-imida-
zolidinone derivatives (e.g. 13b and 14) but also 4-mer-
captomethyl-2-oxazolidinone counterparts (e.g. 13a).
11. Poetsch, E.; Casutt, M. Chimia 1987, 41, 148.
12. The compound trans-9 was isolated as stable solids and
independently subjected to the isomerization with pyridine
to give 9. The structure of trans-9 was confirmed by
converting to thiol carboxylic acid 8 by hydrolysis (KOH,
MeOH, H2O). The structure of 8 was substantiated by
X-ray crystallographic analysis whose X-ray data has been
deposited to Cambridge Data Centre.
13. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.
14. Synthesis of 9: To a solution of 8 (100 g, 0.28 mol) in CHCl3
(400 mL) were added pyridine (32 mL, 0.39 mol) and TFA
(8.7 mL, 0.11 mol) at 0°C followed by a solution of DCC
(86.8 g, 0.42 mol) in CHCl3 (136 mL) at 25°C and the
mixture was stirred at 0°C for 1 h and refluxed for 6 h. The
mixture was cooled down to 25°C and the solids formed
were collected. The filtrate was evaporated and the residue
was purified by silica gel column chromatography (hexane/
AcOEt=2:1) to afford 9 (88.1 g, 93%) as colorless crystals.
Mp 122–123°C (lit.:6c 125.5–127°C); [h]2D5=+90.5 (c, 1.0,
CHCl3) {lit.:6c [h]D20=+91.3 0.9 (c, 1.0, 0.1N NaOH)}; IR
(KBr) w=1697, 1686 cm−1; 1H NMR (CDCl3) l 7.39–7.25
(10H, m), 5.04 (1H, d, J=15.0 Hz), 4.69 (1H, d, J=15.0
Hz), 4.37 (1H, d, J=15.0 Hz), 4.36 (1H, d, J=15.0 Hz),
4.16–4.09 (1H, m), 3.81 (1H, d, J=7.8 Hz), 3.38 (1H, dd,
J=13.0, 5.6 Hz), 3.29 (1H, dd, J=13.0, 2.2 Hz); 13C NMR
(DMSO-d6) l 205.6, 158.1, 137.1, 136.7 (4s), 128.5–127.3,
62.4, 56.0 (12d), 45.2, 44.6, 32.5 (3t); SIMS m/z 339
(M++1).
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