Facile synthesis of (+)-biotin via Fukuyama coupling reaction

Article abstract of DOI:10.1016/S0040-4039(00)00781-4

Treatment of a thiolactone 2 with a zinc reagent 3 in the presence of PdCl₂(PPh₃)₂ (10 mol%) allowed installation of a C-2 side chain of (+)- biotin in a highly efficient manner, which enabled synthesis of (+)biotin in three steps from 2. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00781-4

Tetrahedron Letters 41 (2000) 5099±5101
Facile synthesis of (+)-biotin via Fukuyama coupling reaction
Toshiaki Shimizu and Masahiko Seki*
Product & Technology Development Laboratory, Tanabe Seiyaku Co. Ltd., 3-16-89 Kashima, Yodogawa-ku,
Osaka 532-8505, Japan
Received 12 April 2000; accepted 26 April 2000
Abstract
Treatment of a thiolactone 2 with a zinc reagent 3 in the presence of PdCl2(PPh3)2 (10 mol%) allowed
installation of a C-2 side chain of (+)-biotin in a highly ecient manner, which enabled synthesis of (+)-
biotin in three steps from 2. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: palladium and compounds; sulfur compounds; vitamins; zinc and compounds.
(+)-Biotin 1 has received considerable attention as an important vitamin for human nutrition
and animal health.1 Since the ®rst total synthesis of (+)-biotin was accomplished about 50 years
ago, a number of synthetic methods have been developed.2 Among them, a method utilizing
thiolactone 2 as a key intermediate has been one of the most reliable approaches so far developed.3
The method is, however, not entirely satisfactory because a number of steps (six steps from 2 to
(+)-biotin) are needed for introducing the C-2 side chain to the thiolactone 2. Some improvements
for the installation of the C-2 side chain to the thiolactone 2 have been reported which involve: (1)
treatment with butylenedimagnesium chloride followed by in situ reaction with carbon dioxide;4
(2) reaction with 4-(2,4,10-trioxaadamantyl)butylmagnesium bromide;5 and (3) Wittig reaction
using 4-carboxybutyltriphenylphosphonium bromide.6 Although these methods can provide (+)-
biotin in two to three steps less than the original one, they need a much lower reaction tempera-
ture (ca. ^30ꢀC) and/or expensive reagents.
Fukuyama and co-workers have recently developed a novel ketone synthesis by a palladium-
catalyzed reaction of thiol esters with zinc reagents.7 We envisioned a possible use of the Fukuyama
* Corresponding author. E-mail: m-seki@tanabe.co.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00781-4

5100
coupling reaction for the installation of the C-2 side chain. Reported herein is a successful result
which realized the ecient synthesis of (+)-biotin from the thiolactone 2 via the Fukuyama coupling
reaction.
The zinc reagent 38 corresponding to the C-2 side chain was prepared from an iodide which can
be derived in a single step from d-valerolactone.9,10 Treatment of the thiolactone 2 with the zinc
reagent 3 (3 equiv.) in the presence of PdCl2(PPh3)2 (10 mol%) in a mixed solvent of THF, toluene
and DMF at 20ꢀC for 35 h gave an alcohol 4 which, without puri®cation, was allowed to react
ꢀ
.
with p-TsOH H2O (0.4 equiv.) in toluene at 20 C for 18 h to a€ord 4-ethoxycarbonylbutylidene
derivative 5 in 86% yield, exclusively, as a Z-isomer (Scheme 1).11,13 The compound 5 was con-
verted to (+)-biotin 1 according to the reported procedure3 through hydrogenation and sub-
sequent removal of the benzyl protective groups (73%, two steps). The product 1 obtained by the
1
present method revealed identity with an authentic sample with respect to mp, IR, H NMR,
25
mass spectra and speci®c rotation (mp 230±231ꢀC, ‰ꢀŠ +90.2 (c 1.01, 0.1 N NaOH) (lit.14 mp
D
25
229.5±230ꢀC, ‰ꢀŠ +91.3 (c 1.00, 0.1 N NaOH).
D
Scheme 1. a: (i) IZn(CH2)4CO2Et (3 equiv.) (3), PdCl2(PPh3)2 (10 mol%), THF, toluene, DMF, 20ꢀC, 35 h; (ii) p-
TsOH, toluene, 20ꢀC, 18 h; b: H2 (70 atm)/Pd-C, EtOH, 100ꢀC, 3 h; c: (i) 48% aq. HBr, re¯ux, 48 h; (ii) ClCO2ET,
NaOH; (iii) HCl.
In conclusion, a facile and ecient synthesis of (+)-biotin from the thiolactone 2 via the
Fukuyama coupling reaction was accomplished. The present method can provide (+)-biotin in
63% overall yield in three steps from the thiolactone 2, which is three steps shorter than the
conventional method based on the Grignard reaction.3 The short steps, high yield, simple
operations, ready availability of the reagents and mild reaction conditions would provide a
practical access to (+)-biotin. Further improvements of the present synthesis are under current
investigation and will be reported elsewhere in due course.
References
1. (a) Mistry, P. S.; Dakshinamurti, K. Vitam. Horm. 1964, 22, 1. (b) Coggeshall, C. J.; Heggers, P. J.; Robson,
C. M.; Baker, H. Ann. NY 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.
2. For a review, see: Clercq, P. J. D. Chem. Rev. 1997, 97, 1755.

5101
3. (a) Goldberg, M. W.; Sternbach, L. H. US Patent 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.; Aschwanden, W. Helv. Chim. Acta 1970, 53, 991.
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1986, 104, 168, 273f.
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Chem Abstr. 1984, 100, 34,338q.
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8. Lipshutz, B. H.; Wood, M. R.; Tirado, R. J. Am. Chem. Soc. 1995, 117, 6126.
9. Ethyl 5-iodopentanoate was prepared from d-valerolactone with some modi®cation of the reported methods:10
Into a solution of d-valerolactone (200 g, 2 mol) in CH3CN (1000 mL) was added NaI (330 g, 2.2 mol) followed by
TMS±Cl (239 g, 2.2 mol) at 25±30ꢀC and the mixture was stirred at the same temperature for 24 h. Ethanol (400
mL) was added and the mixture was stirred at 25±30ꢀC for 6 h. The mixture was evaporated in vacuo and the
residue was partitioned with AcOEt and water. The organic phase was separated and washed with 10% aq.
Na2S2O3 and water, dried over MgSO4 and evaporated. The residue was puri®ed by distillation (bp 85±87ꢀC/3
mmHg) to give the iodide (434 g, 85%).
10. (a) Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R. J. Org. Chem. 1979, 44, 1247. (b) Kolb, M.; Barth,
J. Syn. Commun. 1981, 11, 763.
11. Experimental procedure: Into a suspension of zinc powder (activated according to Ref. 12) (1.17 g, 17. 9 mmol) in
THF (2.7 mL) was added 1, 2-dibromoethane (40 mL, 0.46 mmol) and the mixture was heated to re¯ux for 3 min.
After cooling the mixture to 25ꢀC, TMS±Cl (40 mL, 0.32 mmol) was added, and the slurry was stirred for 15 min.
Ethyl 5-iodopentanoate (1.5 mL, 8.96 mmol) was then added and the mixture was heated to 35ꢀC and stirred for
30 min to a€ord the zinc reagent 3. Into the zinc reagent 3 were added thiolactone 2 (1.01 g, 2.98 mmol), toluene
(3.5 mL), DMF (0.27 mL) and PdCl2(PPh3)2 (209 mg, 0.3 mmol), and the mixture was stirred at 20ꢀC for 35 h.
The mixture was ®ltered through Celite and the ®ltrate was evaporated. Into the residue was added ether and the
mixture was washed successively with 1N HCl, sat. aq. NaHCO3 and brine, dried over ꢀMgSO4 and evaporated.
.
The residue was treated with p-TsOH H2O (226 mg, 1.19 mmol) in toluene (31 mL) at 20 C for 18 h. The mixture
was diluted with AcOEt and washed successively with sat. aq. NaHCO3, water and brine, dried over MgSO4 and
evaporated. The residue was puri®ed by silica gel column chromatography (hexane:AcOEt=5:2) to a€ord 5 (1.16
25
D
g, 86%) (‰ꢀŠ +190.9 (c, 0.95, MeOH)).
12. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis, Vol. 1; John Wiley and Sons: New York, London,
Sydney, 1967; p. 1276.
13. The double bond stereochemistry (Z-con®guration) of 5 was assigned by NOE experiments with 1H NMR
spectroscopy: enhancement (10%) of the signal of the C-3 hydrogen atom was observed in the compound 5
when the ole®nic hydrogen was irradiated.
14. Volkmann, R. A.; Davis, J. T.; Meltz, C. N. J. Am. Chem. Soc. 1983, 105, 5946.