A highly stereocontrolled total synthesis of (+)-biotin from L-cysteine

Article abstract of DOI:10.1016/S0040-4039(02)00537-3

(+)-Biotin was synthesized in 11 steps and in 25% overall yield from readily accessible L-cysteine through a Lewis base-catalyzed highly diastereoselective cyanosilylation of (2R,4R)-N-Boc-2-phenylthiazolidine-4-carbaldehyde 2 and a ring closure of a cis-allylic carbonate 5b utilizing a palladium-catalyzed intramolecular allylic amination.

Full text of DOI:10.1016/S0040-4039(02)00537-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3269–3272
A highly stereocontrolled total synthesis of (+)-biotin from
-cysteine
L
Masahiko Seki,* Masanori Hatsuda, Yoshikazu Mori and Shin-ichi Yamada
Product and Technology Development Laboratory, Tanabe Seiyaku Co., Ltd, 3-16-89 Kashima, Yodogawa-ku,
Osaka 532-8505, Japan
Received 20 February 2002; accepted 15 March 2002
Abstract—(+)-Biotin was synthesized in 11 steps and in 25% overall yield from readily accessible
L-cysteine through a Lewis
base-catalyzed highly diastereoselective cyanosilylation of (2R,4R)-N-Boc-2-phenylthiazolidine-4-carbaldehyde 2 and a ring
closure of a cis-allylic carbonate 5b utilizing a palladium-catalyzed intramolecular allylic amination. © 2002 Published by Elsevier
Science Ltd.
(+)-Biotin (1) has received considerable attention due to
the significant biological properties for human nutrition
and animal health.1 The industrial production of 1 (ca.
40 t/year) has been relying on a total synthetic method
due to the lack of an efficient fermentation method.2
Since the first total synthesis of (+)-biotin was accom-
plished about 50 years ago,3,4 a number of synthetic
routes have been devised.2 Among them, synthesis uti-
In retrosynthetic analysis (Scheme 1), an intramolecular
allylic amination of a carbonate 5 would set the stage
for the final cyclization required in the preparation of
the cis-fused bicyclic ring skeleton of 1. Since the
palladium-catalyzed allylation takes place with reten-
tion of the configuration,7 a cis isomer 5 is expected to
be required for the ring closure. Compound 5 may be
derived from a ketoacid 4 through esterification, O-
methoxycarbonylation, removal of the Boc and the
lizing
L
-cysteine as a starting material5 is one of the
steadiest approaches to 1 because of its inherent struc-
tural features having required heteroatoms (nitrogen
and sulfur atoms) and a stereogenic center correspond-
ing to the (+)-biotin ring skeleton. However, there are
few approaches based on this strategy that overcome
such drawbacks as need for multi-steps, expensive or
hazardous reagents and quite low temperature.6 A more
O
RN
NH
1
CO2Me
S
6
efficient synthetic method utilizing the
ton is thus still in much demand. We report herein a
practical synthesis of 1 from -cysteine based on a
L-cysteine skele-
L
O
novel strategy involving a highly diastereoselective
cyanosilylation and a palladium-catalyzed intramolecu-
lar allylic amination.
Ph
Boc
NH2
N
RN
OCO2Me
S
OH
CO2Me
O
S
O
CO2H
5
4
3
RN
NH
3a
4
Ph
Ph
S
Boc
CO2H
S
Boc
N
N
(+)-Biotin (1)
S
OTMS
CN
CHO
2
3
Keywords: vitamines; amino nitriles; Grignard reactions/reagents;
allylation; palladium and compounds.
Scheme 1.
* Corresponding author. E-mail: m-seki@tanabe.co.jp
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00537-3

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M. Seki et al. / Tetrahedron Letters 43 (2002) 3269–3272
The carboxybutyl chain of 1 was installed by the reac-
tion of the in situ generated O-TMS-cyanohydrin 3
with di-Grignard reagent5a,13 derived from 1,4-dibro-
mobutane and subsequent treatment with carbon diox-
ide (Scheme 2). While the yield was poor in THF
(20%), the use of ether considerably improved the reac-
tion to give a ketoacid 414 in 61% yield based on 2.
Much safer solvent system of n-butyl ether and toluene
(1:2) was found to give 4 in 79% yield.
benzylidene groups, dehydrative cyclization and a ure-
ido formation. The carboxybutyl chain of 1 was envis-
aged to arise from the reaction of an O-TMS-cyano-
hydrin 3 with a di-Grignard reagent prepared from
1,4-dibromobutane followed by reacting with carbon
dioxide. An anti-selective cyanosilylation of an a-amino
aldehyde 2 is required to ensure the cis configuration of
5.
Compound 2 was prepared from
L-cysteine in four
The ketoacid 4 was esterified and purified by crystal-
lization to give enantiomerically and diastereomerically
pure ketoester 715 in 73% yield. The hydroxyl group of
7 was then protected as a methyl carbonate, which, in a
later step, functioned as an activating group for the ring
closure. Treatment of 8 with acetyl chloride in the
presence of methanol effected the successive transfor-
steps and in 80% yield by modification of the reported
procedure,5c,8 employing sulfur trioxide pyridine as an
alternative oxidant.9
The synthesis of the anti-O-TMS-cyanohydrin 3 was
initially tested in the presence of a Lewis acid. How-
ever, all attempts using popular Lewis acids such as
zinc iodide failed accompanied by a considerable
decomposition of the reactant 2 and/or the product 3.
Mukaiyama and co-workers have reported a high-yield-
ing Lewis base-catalyzed cyanosilylation of aldehydes.10
We applied the procedure to the cyanosilylation of 2
(Table 1).11 Upon treatment of 2 with trimethylsilyl
cyanide (TMSCN) (1.1 equiv.) in the presence of Et3N
(10 mol%) at −10°C in CH2Cl2, the reaction rapidly
took place to afford the desired O-TMS-cyanohydrin 3
in 96% yield albeit in a poor selectivity (anti/syn=
72:28) (Table 1, entry 1). Since a hypervalent silicate
formed from TMSCN and Et3N has been assumed to
be an active species in the cyanosilylation and the
stereochemical outcome might be accounted for by the
Felkin–Ahn model, a more sterically demanding Lewis
base should improve the diastereoselectivity. As
expected, when i-Pr2NEt in place of Et3N was
employed as the Lewis base, the diastereoselectivity was
remarkably elevated (anti/syn=89:11, 97%) (Table 1,
entry 2). Further screening of the bulky Lewis bases
resulted in a finding that tri-n-butylphosphine can effect
the cyanosilylation with an excellent diastereoselectivity
and in high yield (anti/syn=92:8, 96%) (Table 1, entry
5). To the best of our knowledge, this represents the
Ph
Boc
N
a
d
OR1
S
2
O
CO2R2
4: R1 = H, R2 = H
7: R1 = H, R2 = Me
8: R1 = CO2Me, R2 = Me
b
c
O
O
NH2
RN
NH
RN
OCO2Me
f, g
e
1
CO2Me
CO2Me
S
S
5a: R= H
6a: R = H
5b: R= Bn
6b: R = Bn
Scheme 2. (a) (i) TMSCN, n-Bu3P, −10°C, CH2Cl2, (ii)
BrMg(CH2)4MgBr, n-Bu2O, toluene, −3 to −25°C, (iii) CO2,
(iv) aq. citric acid, 79%; (b) Me2SO4, K2CO3, 25°C, DMF,
73%; (c) ClCO2Me, Et3N, DMAP, 0°C, THF, quant.; (d) for
5a: (i) AcCl, MeOH, toluene, 0°C, (ii) KOCN, H2O, 25°C,
86%; for 5b: (i) AcCl, MeOH, toluene 0°C, (ii) PhCHO,
NaBH3CN, THF, H2O, 5°C, (iii) KOCN, H2O, 25°C, 82%;
(e) for 6a: Pd(OAc)2, NaHCO3, P(OEt)3, THF, H2O, 38°C,
30%; for 6b: Pd(OAc)2, NaHCO3, P(OEt)3, DMF, n-Bu4NCl,
100°C, 77%; (f) H2, Pd(OH)2/C, 25°C, AcOEt; (g) aq. HBr,
reflux, 85% (two steps).
first example of
a
Lewis base-catalyzed highly
diastereoselective cyanosilylation.12
Table 1. A Lewis base-catalyzed cyanosilylation of 2a
Ph
Boc
Ph
TMSCN
(1.1 equiv)
Boc
N
N
S
S
OTMS
CN
Additive
(10 mol%)
CHO
CH2Cl2
2
3
Entry
Additive
T (°C)
t (h)
anti/synb
Yield (%)b
1
2
3
4
5
Et3N
−10
−10
−10
25
0.5
0.5
0.5
19
72:28
89:11
77:23
88:12
92:8
96
97
92
84
96
i-Pr2NEt
n-Bu3N
t-Bu3P
n-Bu3P
−10
0.5
a The reactions were conducted on 1 mmol scale.
b Determined by HPLC analysis of the crude reaction mixture after desilylation with aqueous citric acid.

M. Seki et al. / Tetrahedron Letters 43 (2002) 3269–3272
3271
mations involving removal of the Boc and benzylidene
groups, cyclization to the tetrahydrothiophene ring and
dehydration. The resulting crude amine hydrochloride
was treated with potassium cyanate to furnish a cis-
allylic carbonate 5a in 86% yield based on 8.
4. For recent improvements in the Goldberg–Sternbach syn-
thesis,2 see: (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.
5. (a) Poetsch, E.; Casutt, M. Chimia 1987, 41, 148; (b)
Fujisawa, T.; Nagai, M.; Koike, Y.; Shimizu, M. J. Org.
Chem. 1994, 59, 5865; (c) Deroose, F. D.; De Clercq, P.
J. J. Org. Chem. 1995, 60, 321; (d) Moolenaar, M. J.;
Speckamp, W. N.; Hiemstra, H.; Poetsch, E.; Casutt, M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2391; (e) Chaven,
S. P.; Tejwani, B.; Ravindranathan, T. J. Org. Chem.
2001, 66, 6197.
With the cis-allylic carbonate 5a in hand, we attempted
the palladium-catalyzed ring closure of 5a. Treatment
of 5a with Pd(OAc)2 in the presence of P(OEt)3 and
NaHCO3 in aqueous THF16 afforded the desired
cyclized product 6a albeit in a poor yield (30%). As De
Clercq and co-workers have pointed out an importance
of an N-benzyl group for the thermal cyclization of an
ene carbamoyl azide at C-3 and C-3a position of the
(+)-biotin ring skeleton,5c an N-benzyl derivative 5b
was tested in place of 5a. The compound 5b17 was
readily prepared from 8 in 82% yield by a slight modifi-
cation of the reaction sequence involving a reductive
alkylation with benzaldehyde. The compound 5b was
subjected to the same reaction conditions as those for
the cyclization of 5a, expectedly affording 6b in good
yield (60%). The structure of 6b was assigned by com-
6. The number of steps, expensive or hazardous reagents
and quite low temperature required for the known syn-
thesis of (+)-biotin starting from
L-cysteine: Poetsch
approach:5a 9 steps, BnNCO; Fujisawa approach:5b 12
steps, CH2N2, DIBALH, 1-pentyne, BnNCO, KH,
CsOH, −78°C; De Clercq approach:5c 12 steps, CH2N2,
NaBH3CN, NaN3, −60°C; Speckamp approach:5d 13
steps, BnNCO, DIBALH, MeO2C(CH2)3C(O)CH2Cl,
(TMS)CH2CO2Et, TBAF, TMSOTf, DBU, −78°C;
Ravindranathan approach:5e 12 steps, DIBALH, TBSCl,
DBU, TBSOTf, Ph3PꢀCHCHꢀCHCO2Me, −78°C.
7. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173.
8. Gonzalez, A.; Lavilla, R.; Piniella, J. F.; Alvarez-Larena,
A. Tetrahedron 1995, 51, 3015.
1
parison of the IR, H NMR and MS spectra with those
described in the literature.5c The reaction under solid–
liquid phase transfer conditions using a catalytic
amount of tetrabutylammonium chloride in DMF18
was found to be extremely effective to provide 6b in a
much improved yield (77%). Following the reported
procedure,5c the compound 6b was converted to (+)-
biotin (1) in 85% yield through hydrogenation and
subsequent deprotection with aqueous HBr.19
9. (a) Doering, W. V. E.; Parikh, J. R. J. Am. Chem. Soc.
1967, 89, 5505; (b) Hamada, Y.; Shioiri, T. Chem. Pharm.
Bull. 1982, 30, 1921.
10. Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem. Lett.
1991, 537.
In conclusion, (+)-biotin was synthesized in 11 steps
11. The O-TMS cyanohydrin 3 was desilylated quantitatively
by the treatment with aqueous citric acid and was
allowed to measure the yield and the diastereomeric ratio
by HPLC (Nucleosil 5C18, CH3CN/H2O=50:50, 40°C,
0.8 mL/min, 254 nm, anti: 8.1 min, syn: 9.4 min). The
structure of the cyanohydrin was confirmed by X-ray
crystallographic analysis.
and in 25% overall yield from readily accessible L-cys-
teine. The high overall yield, short steps, simple opera-
tion and use of readily accessible reagents would permit
not only the practical large-scale preparation of (+)-
biotin but also the synthesis of (+)-biotin derivatives
having promising biological properties.
12. A highly diastereoselective cyanosilylation of an (S)-N-
protected phenylalaninal using chiral Lewis-acid-base cat-
alyst, see: Manickam, G.; Nogami, H.; Kanai, M.;
Groger, H.; Shibasaki, M. Synlett 2001, 617.
Acknowledgements
13. Silverman, G. S.; Rakita, P. E. Handbook of Grignard
Reagent; Marcel Dekker: New York, Basel, Hong Kong,
1996; pp. 497–526.
The authors are indebted to Mr. Koichi Inubushi,
Tanabe Seiyaku Co., Ltd, for the X-ray crystallo-
graphic analysis.
14. Compound 4: mp 101–103°C; IR (Nujol) w=3470, 2976,
1
1702 cm−1; H NMR (CDCl3) l 7.58 (2H, d, J=6.6 Hz),
References
7.30–7.40 (3H, m), 6.07 (1H, s), 4.73 (1H, d), 4.42–4.51
(1H, m), 3.23 (1H, dd, J=12, 5.1 Hz), 3.02 (1H, dd,
J=12, 6.6 Hz), 2.57 (2H, br), 2.34 (2H, brt, J=7.0 Hz),
1.51–1.80 (4H, m), 1.33 (9H, s); SIMS m/z 424 (M++1).
The structure of 4 was confirmed by X-ray crystallo-
graphic analysis.
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. 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.
2. De Clercq, P. J. Chem. Rev. 1997, 97, 1755.
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.; Ashwanden, W. Helv.
Chim. Acta 1970, 53, 991.
15. The optical purity (>99% ee) of 7 was determined by
HPLC (CHIRALPAK AD, EtOH/n-hexane=5:95, 40°C,
0.5 mL/min, 254 nm, 7: 35.9 min, the antipode of 7: 25.2
min).
16. Seki, M.; Kondo, K.; Kuroda, T.; Yamanaka, T.;
Iwasaki, T. Synlett 1995, 609.
17. Compound 5b: mp 105–108°C; IR (KBr) 3432, 1754, 1728,
1
1656, 1612 cm−1; H NMR (CDCl3) l 7.44–7.21 (m, 5H),
5.90 (t, J=7.2 Hz, 1H), 5.63 (d, J=3.9 Hz, 1H), 5.16–

3272
M. Seki et al. / Tetrahedron Letters 43 (2002) 3269–3272
5.10 (m, 1H), 4.71 (d, J=18 Hz, 1H), 4.63 (brs, 1H), 4.61
30.5 (t), 30.0 (t), 24.1 (t); SIMS m/z 423 (M++1). The
structure of 5b was confirmed by X-ray crystallographic
analysis.
(d, J=18 Hz, 1H), 3.66 (s, 3H), 3.65 (s, 3H), 3.33 (dd,
J=10, 11 Hz, 1H), 3.01 (dd, J=6.9, 10 Hz, 1H), 2.30 (t,
J=7.5 Hz, 2H), 2.04–1.99 (m, 2H), 1.78–1.70 (m, 2H);
13C NMR (CDCl3) l 174.2 (s), 159.6 (s), 155.1 (s), 137.5
(s), 135.6 (s), 129.5 (d), 128.0 (d), 126.0 (d), 125.9 (d),
81.2 (d), 58.0 (d), 55.1 (q), 51.9 (q), 48.9 (t), 33.8 (t),
18. Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
19. Starting from 121 g of
L-cysteine, every step was con-
ducted at several gram quantities and 3.1 g of the final
product (1) was obtained.