A novel synthesis of (+)-biotin from L-cysteine

Article abstract of DOI:10.1021/jo025794+

(+)-Biotin (1) was synthesized in 25% overall yield over 11 steps from L-cysteine. The contiguous asymmetric centers at C-3a and C-6a were formed through a novel and highly stereoselective Lewis base-catalyzed cyanosilylation of α-amino aldehyde 3 to provide anti- O-TMS-cyanohydrin 4 with high stereoselectivity and in high yield (anti/syn = 92:8, 96%). Treatment of 4 with a di-Grignard reagent, 1,4-bis(bromomagnesio)butane, followed by carbon dioxide, efficiently installed the 4-carboxybutyl chain at C-4 to give keto acid 5. The final cyclization to bicyclic compound 7b, a precursor to 1, was realized by a palladium-catalyzed intramolecular allylic amination of cis-allylic carbonate 6b that was elaborated from 5.

Full text of DOI:10.1021/jo025794+

A Novel Syn th esis of (+)-Biotin fr om L-Cystein e†
Masahiko Seki,* Yoshikazu Mori, Masanori Hatsuda, and Shin-ichi Yamada
CMC Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku,
Osaka, 532-8505, J apan
m-seki@tanabe.co.jp
Received April 4, 2002
(+)-Biotin (1) was synthesized in 25% overall yield over 11 steps from L-cysteine. The contiguous
asymmetric centers at C-3a and C-6a were formed through a novel and highly stereoselective Lewis
base-catalyzed cyanosilylation of R-amino aldehyde 3 to provide anti-O-TMS-cyanohydrin 4 with
high stereoselectivity and in high yield (anti/syn ) 92:8, 96%). Treatment of 4 with a di-Grignard
reagent, 1,4-bis(bromomagnesio)butane, followed by carbon dioxide, efficiently installed the
4-carboxybutyl chain at C-4 to give keto acid 5. The final cyclization to bicyclic compound 7b, a
precursor to 1, was realized by a palladium-catalyzed intramolecular allylic amination of cis-allylic
carbonate 6b that was elaborated from 5.
In tr od u ction
few routes that involve (1) few steps, (2) inexpensive
reagents, and (3) mild reaction conditions. We have re-
cently disclosed a preliminary result concerning a ste-
reoselective synthesis of 1 from L-cysteine.11 Reported
herein are the full details of our exploratory efforts to
accomplish the novel and practical approach to 1.
(+)-Biotin (1) is a water-soluble vitamin isolated in
19411 that has aroused considerable attention as a
synthetic target because of the useful biological properties
for human nutrition and animal health.2 Since the first
total synthesis of 1 was accomplished about 50 years
ago,3,4 extensive research has been directed toward
finding ever more efficient synthetic methodology and
routes to 1.5 Although a great variety of synthetic
approaches have been reported, such as diastereomeric
or enzymatic resolutions,6 chiral pool methods with
L-cysteine,7 L-aspartic acid,8 or carbohydrates9 used as a
starting material, and asymmetric syntheses,10 there are
Our synthesis of 1 is based on a retrosynthetic analysis
depicted in Scheme 1. The crucial step to construct the
cis-fused bicyclic ring skeleton of 1 is an intramolecular
allylic amination of cis-allylic carbonate 6. Since the
palladium-catalyzed allylation takes place with retention
of the configuration,12 cis-isomer 6 is expected to be
required for the ring closure. Compound 6 may be derived
from keto acid 5 through esterification, O-methoxycar-
bonylation, removal of the Boc and the benzylidene
groups, dehydrative cyclization, reductive alkylation, and
ureido formation. The last five transformations are to be
conducted in a successive manner, i.e., without isolation
of the intermediates. The 4-carboxybutyl chain of 1 may
be installed by the reaction of O-TMS-cyanohydrin 4 with
a di-Grignard reagent prepared from 1,4-dibromobutane
and subsequent treatment with carbon dioxide. An anti-
selective cyanosilylation of R-amino aldehyde 3 is re-
quired to ensure the cis configuration of 6. Compound 3
may be readily prepared from L-cysteine via â-amino
alcohol 2.
* To whom correspondence should be addressed. E-mail: m-seki@
tanabe.co.jp
† This paper is dedicated to Professor Albert I. Meyers on the
occasion of his 70th birthday.
(1) du Vigneaud, V.; Hofmann, K.; Melvile, D. B.; Rachele, J . J . Biol.
Chem. 1941, 140, 763.
(2) (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.
(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.
(4) For recent improvements of the Goldberg-Sternbach synthesis,
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) For a review, see: De Clercq, P. J . Chem. Rev. 1997, 97, 1755.
(6) (a) Senuma, M.; Fujii, T.; Seto, M.; Okamura, K.; Date, T.;
Kinumaki, A. Chem. Pharm. Bull. 1990, 38, 882. (b) Iriuchijima, S.;
Hasegawa, K.; Tsuchihashi, G. Agric. Biol. Chem. 1982, 46, 1907.
(7) (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.
(8) Seki, M.; Shimizu, T.; Inubushi, K. Synthesis 2002, 361.
(9) Ravindranathan, T.; Hiremath, S. V.; Reddy, D. R.; Ramo Rao,
A. V. Carbohydr. Res. 1984, 134, 332.
(10) (a) Matsuki, K.; Inoue, H.; Takeda, M. Tetrahedron Lett. 1993,
34, 1167. (b) Choi, C.; Tian, S.-K.; Deng, L. Synthesis 2001, 1737.
(11) Seki, M.; Hatsuda, M.; Mori, Y.; Yamada, S. Tetrahedron Lett.
2002, 43, 3269.
(12) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173.
10.1021/jo025794+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/04/2002
J . Org. Chem. 2002, 67, 5527-5536
5527

Seki et al.
TABLE 1. Oxid a tion of â-Am in o Alcoh ol 2a
SCHEME 1
SO3-py Et3N
entry (equiv) (equiv)
T
(°C)
yield
(%)
deb
(%)
solvent
DMSO
DMSO
DMSO
1
2
3
4
2.0
2.0
2.0
2.5
2.0
2.0
2.0
2.5
20 82
30 58
40 24
97
97
96
DMSO-toluene 10 quant 96
(5:1)
(95)c (>99)d
a
The reactions were conducted on 10 mmol scale except entry
b
4 (0.2 mol scale). Determined by HPLC after reduction (NaBH4)
of the product 3 to 2. c Isolated yield after crystallization from
d
AcOEt-hexane. De after crystallization from AcOEt-hexane.
40 °C to give 3 in 58 and 24% yield, respectively (Table
1, entries 2, 3). The reaction was thus conducted at 10
°C in a nonfreezing mixture of DMSO and toluene (5:1)
to give the desired diastereomerically pure R-amino
aldehyde 3 in 95% yield after crystallization with AcOEt-
hexane (Table 1, entry 4).
The preparation of 3 was consequently carried out in
80% overall yield over four steps from L-cysteine without
need of expensive reagents, quite low temperature, or
silica gel column chromatography.
F or m a tion of th e Con tigu ou s Ster eogen ic Cen -
ter s. A highly anti-selective hydrocyanation of (R)-N-Boc-
2,2-dimethylthiazolidine-4-carbaldehyde (Garner’s alde-
hyde) with hydrogen cyanide in the presence of a Lewis
acid has been reported.15 We initially applied the proce-
dure to the synthesis of anti-O-TMS-cyanohydrin 4.
However, the cyanosilylation of 3 in the presence of Lewis
acid such as ZnI2, ZnBr2, or BF3-diethyl etherate was
problematic, leading to only traces of product 4. Mu-
kaiyama and co-workers have reported a high-yielding
Lewis base-catalyzed cyanosilylation of aldehydes.17 We
applied the procedure to the cyanosilylation of 3 (Table
2). Treatment of 3 with trimethylsilyl cyanide (TMSCN)
(1.1 equiv) in the presence of Et3N (10 mol %) at -10 °C
in CH2Cl2 afforded 4 in 96% yield albeit in a poor
selectivity (anti/syn ) 72:28) (Table 2, entry 1). We
speculated that use of a more sterically demanding Lewis
base should improve the diastereoselectivity, since a
hypervalent silicate formed from TMSCN and Et3N has
been assumed to be an active species in the cyanosily-
lation,17 and the stereochemical outcome may be ac-
counted for by a Felkin-Ahn model18 shown in Figure
1. In support of the hypothesis, more bulky secondary
and tertiary amines including Cy2NH, i-Pr2NH, 2,2,6,6-
tetramethylpiperidine, 1-ethylpiperidine, i-Pr2NEt, i-Pr3N,
and n-Bu3N in place of Et3N were employed as the
Lewis base to produce a higher degree of stereocontrol
ranging from anti/syn ) 77:13 to 90:10 (Table 2, entries
SCHEME 2a
a
Reagents and yields: (a) PhCHO, AcOK, EtOH, H2O, 96%;
(b) (i) SOCl2, EtOH (ii) Ca(BH4)2, EtOH, quant; (c) (Boc)2O,
Na2CO3, THF, H2O, 88%.
Resu lts a n d Discu ssion
P r ep a r a tion of r-Am in o Ald eh yd e 3 fr om L-Cys-
tein e. Compound 3 was prepared by oxidation of â-amino
alcohol 2 which was derived from L-cysteine according
to a reported procedure7c,13 (Scheme 2). Although the
oxidation of 2 by Swern oxidation has been reported to
proceed in 81% yield, it requires a reaction temperature
as low as -60 °C.7c To eliminate the unpractical low
reaction temperature, an oxidation employing sulfur
trioxide pyridine complex (SO3-py)14 was examined (Table
1). Treatment of 2 with SO3-py (2.0 equiv) in the presence
of Et3N (2.0 equiv) in DMSO at 20 °C afforded 3 with
97% de in 82% yield (Table 1, entry 1). The yield was,
however, poorer at higher temperature such as 30 and
(15) Marcus, J .; Vandermeulen, G. W. M.; Brussee, J .; van der Gen,
A. Tetrahedron: Asymmetry 1999, 10, 1617.
(16) O-TMS cyanohydrin 3 was desilylated quantitatively by the
treatment with aqueous citric acid, and the yield and the diastereo-
meric ratio were determined by HPLC. The structure of the cyanohy-
drin was confirmed by single-crystal X-ray analysis.
(17) Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem. Lett. 1991,
537.
(13) Gonzalez, A.; Lavilla, R.; Piniella, J . F.; Alvarez-Larena, A.
Tetrahedron 1995, 51, 3015.
(14) (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.
(18) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
18, 2199. (b) Anh, N. T. Top. Curr. Chem. 1980, 88, 114.
5528 J . Org. Chem., Vol. 67, No. 16, 2002

A Novel Synthesis of (+)-Biotin
TABLE 2. Cya n osilyla tion of 3 in th e P r esen ce of Lew is
Ba sea
TABLE 3. F or m a tion of th e 4-Ca r boxybu tyl Ch a in w ith
a Di-Gr ign a r d Rea gen ta
entry
solvent
t (h)
yieldc (%)
1
2
3
4
5
THF
Et2O
Et2O/toluene (1:3)
n-Bu2O
1
1
1
0.5
0.5
20
61
74
76
79d
n-Bu2O/toluene (1:2)
a
The reactions were conducted on 10 mmol scale except entry
5 (0.15 mol scale). The ratio obtained for all conditions. c Deter-
mined by HPLC. Isolated yield.
b
d
[(n-BuO)3P and (i-PrO)3P] led to product 4 only at higher
reaction temperature (25 °C) with poorer diastereose-
lectivities (Table 2, entries 11 to 14). An electron-defi-
cient Ph3P did not exert any catalytic activity (Table 2,
entry 15).
In sta lla tion of th e 4-Ca r boxybu tyl Ch a in . The
4-carboxybutyl chain was formed by the reaction of in
situ generated O-TMS-cyanohydrin 4 with di-Grignard
reagent7a,19 derived from 1, 4-dibromobutane and subse-
quent treatment with carbon dioxide (Table 3). Selection
of the solvent significantly affected the efficiency of the
coupling reaction. While the yield was poor in THF (20%),
use of ether led to product 5 in 61% yield based on 3
(Table 3, entries 1 and 2). The structure of anti-5 was
unequivocally confirmed by single-crystal X-ray analysis.
Choice of a mixed solvent of ether and toluene (1:3)
further improved the yield to give 5 in 74% yield (Table
3, entry 3). Use of the much safer solvent system of
n-butyl ether and toluene (1:2) was found to give 5 in
79% yield (Table 3, entry 5).
a
b
The reactions were conducted on 1 mmol scale. Determined
by HPLC analysis of the crude mixture after desilylation with
aqueous citric acid.16
Keto acid 5 was then esterified and purified by crystal-
lization to give enantiomerically and diastereomerically
pure keto ester 10 in 73% yield (Scheme 3).
Rem ova l of th e P r otective Gr ou p s a n d th e Rin g
Closu r e. Removal of the protective groups and cycliza-
tion to the tetrahydrothiophene ring were initially in-
vestigated on hydroxy ketone 10 (Scheme 4). Treatment
of 10 with HCl in AcOEt smoothly effected cleavage of
the Boc and the benzylidene moieties. Ketone 13 along
with cyclized product 14 (13/14 ) 3:1, 75%) were isolated
after treatment with benzyl isocyanate. Compound 13
should be formed by an endo-selective dehydration of diol
12 in accordance with the Zaitsev’s rule.20 Conversion of
F IGURE 1. A proposed mechanism for the Lewis base-
catalyzed cyanosilylation of 3.
2-4 and 6-9). Further screening of the Lewis bases
resulted in a finding that trialkylphosphines efficiently
catalyzed the cyanosilylation. Among the trialkylphos-
phines tested, tri-n-butylphosphine effected the cyanosi-
lylation with an excellent diastereoselectivity in high
yield (anti/syn ) 92:8, 96%) (Table 2, entry 10). Use of
more sterically hindered trialkylphosphines (i-Pr3P and
t-Bu3P) or more electron deficient trialkyl phosphites
(19) Silverman, G. S.; Rakita, P. E. In Handbook of Grignard
Reagent; Marcel Dekker: New York, Basel, Hong Kong, 1996; pp 497-
526.
(20) Smith, M. B.; March, J . In March’s Advanced Organic Chem-
istry; A Wiley-Interscience Publication: J ohn Wiley & Sons: New York,
2001; p 1314.
J . Org. Chem, Vol. 67, No. 16, 2002 5529

Seki et al.
SCHEME 3a
a
Reagents and yields: (a) (i) Me2SO4, K2CO3, DMF, (ii) crystal-
lization from AcOEt-hexane, 73%; (b) ClCO2Me, Et3N, DMAP,
THF, quant.
SCHEME 4a
F IGURE 2. The ORTEP II diagram of compound 14.
SCHEME 5a
a
Reagents and yields: (a) (i) HCl-AcOEt, (ii) BnNCO, Et3N,
THF, 75%, 13/14 ) 3:1; (b) DBU (0.1 equiv), THF, 73%.
13 to 14 was alternatively conducted in good yield by the
treatment with DBU (0.1 equiv) in THF. Compound 14
was, however, found to have a configurationally incorrect
C-4 side chain and to be completely racemic when derived
from 13 using DBU.21
a
Reagents and yields: (a) (i) HCl-AcOEt, (ii) KOCN, 74%.
1). However, in this case, a considerable amount of
epimerization at the C-3 position of 6a was observed (cis/
trans ) 62:38) (Table 4, entry 1). Use of toluene as the
solvent and addition of MeOH not only improved the yield
but also reduced the amount of epimerization to give 6a
in a ratio of cis/trans ) 94:6 and in 74% yield (Table 4,
entry 3). Use of acetyl chloride (20 equiv) in the presence
of methanol (30 equiv) as a convenient source for hydro-
gen chloride considerably improved the reaction to give
6a in higher yield with the original asymmetric center
virtually retained as such (86%, cis/trans ) 98:2) (Table
4, entry 4).
With compound 6a in hand, we attempted the pal-
ladium-catalyzed ring closure of 6a (Table 5). Treatment
of 6a with Pd(OAc)2 (30 mol %) in the presence of P(OEt)3
and NaHCO3 in aqueous THF24afforded the desired
cyclized product 7a albeit in a poor yield (30%) (Table 5,
entry 1). Either lack of base or use of a strong base (NaH)
Because the N-benzyl group in the cyclized product 14
occupies the concave side of the bicyclic ring skeleton as
shown by the X-ray structure (Figure 2), the 4-meth-
oxycarbonylbutyl chain is formed cis to the hydroxyl
group to avoid the steric repulsion between the N-benzyl
group and the 4-methoxycarbonylbutyl chain. In an
attempt to obtain the correct stereocenter at the C-4
position, a substrate 15 carrying an unsubstituted ureido
group was then tried in the cyclization. While treatment
of 11 with HCl in AcOEt followed by KOCN simulta-
neously effected the ureido formation and the cyclization,
no stereocontrol was found at the C-4 position resulting
22
in a 1:1 mixture of epimers 16 (Scheme 5).
To obtain desirable exo-olefin circumventing the forma-
tion of the configurationally labile ketones 13 and 15,
compound 10 was converted to carbonate 11 (Scheme 3).
This may permit the preferential formation of an exo-
olefin over an endo-olefin by taking advantage of an
inductive and/or a steric effect of the carbonate.23
As expected, treatment of 11 with HCl in AcOEt in the
presence of MS 4 Å gave exo-olefin 6a in good yield (83%)
after treatment with potassium cyanate (Table 4, entry
(21) While compound 14 obtained from 13 using DBU showed no
optical rotation, that derived from 10 under less basic conditions had
an optical rotation of [R]24 +2 (c, 1.01, CHCl3).
D
(22) Product 16 was assigned to be a mixture of epimers at C-4
position, the ee of which was not determined while it showed some
optical rotation {[R]24 +25.1 (c, 1.01, CHCl3)].
D
5530 J . Org. Chem., Vol. 67, No. 16, 2002

A Novel Synthesis of (+)-Biotin
TABLE 4. Syn th esis of 6a fr om 11a
MeOH
(equiv)
mol sieves,
4 Å (wt %)
T
(°C)
t
yieldb
(%)
entry
reagent (equiv)
solvent
(h)
cis/transb
1
2
3
4
HCl-AcOEt (20)
HCl-AcOEt (20)
HCl-AcOEt (20)
AcCl (20)
0
0
10
30
1
1
1
0
AcOEt
25
0
0
7
5.5
5
83
74
74
86c
62:38
85:15
94:6
toluene
toluene
toluene
0
1
98:2
a
b
The reactions were conducted on 0.2 mmol scale. Determined by HPLC. c Isolated yield.
TABLE 5. P a lla d iu m -Ca ta lyzed Rin g Closu r e
entry
compd
R
Pd(OAc)2 (mol %)
base
n-Bu4NCl (mol %)
solvent
T (°C)
t (h)
product
7a
17
18
7b
yielda (%)
1
2
3
4
5
6
6a
6a
6a
6b
6b
6b
H
H
H
Bn
Bn
Bn
30
30
30
10
10
10
NaHCO3
none
NaH
NaHCO3
NaHCO3
NaHCO3
0
0
0
0
10
10
THF-H2O
THF-H2O
THF-H2O
THF-H2O
DMF
38
38
38
38
80
24
24
24
24
5
30b
78
66
60
7b
7b
63
DMF
100
2
77b
a
b
Determined by HPLC. Isolated yield.
SCHEME 6a
in place of NaHCO3 was detrimental, yielding a thiophene
17 or a 2-oxazolidinone derivative 18, respectively (Table
5, entries 2 and 3). De Clercq and co-workers have
pointed out the importance of an N-benzyl group in their
elegant thermal ring-closure of an ene carbamoyl azide
(23) After E1-elimination of the tertiary hydroxyl group in 12,
generated carbocation may be trapped by the vicinal hydroxyl group
to give oxiranium cation 22, which may be responsible for the selective
formation of endo-olefin 23. In the case of the carbonate derivative,
this neighboring group effect should be negligible due to the less basic
nature of the oxygen atom attached to the electron-deficient methoxy-
carbonyl group (inductive effect), and a steric factor of the carbonate
group may induce the exclusive formation of the exo-olefin.
a
Reagents and yields: (a) (i) AcCl, MeOH, toluene, (ii) PhCHO,
NaBH3CN, THF, H2O, (iii) KOCN, H2O, 82%.
at the C-3 and C-3a positions of the (+)-biotin ring
skeleton.7c Accordingly, an N-benzyl derivative 6b was
tested in place of 6a . Compound 6b was readily prepared
from 11 in 82% yield by a slight modification of the
reaction sequence involving a reductive alkylation with
benzaldehyde (Scheme 6). The Z-configuration and enan-
tiomeric purity (>99% ee) of 6b were unequivocally
confirmed by single-crystal X-ray analysis and HPLC,
respectively. Compound 6b was subjected to the same
reaction conditions as those for the cyclization of 6a ,
expectedly affording 7b in better yield (60%, Table 5,
entry 4). The reaction under solid-liquid-phase transfer
conditions at 100 °C using a catalytic amount of tetrabu-
tylammonium chloride in DMF25 was found to be ex-
(24) Seki, M.; Kondo, K.; Kuroda, T.; Yamanaka, T.; Iwasaki, T.
Synlett 1995, 609.
J . Org. Chem, Vol. 67, No. 16, 2002 5531

Seki et al.
SCHEME 7a
accomplished. A highly diastereoselective cyanosilylation
of an R-amino aldehyde derived from L-cysteine, a di-
Grignard reaction of the resultant O-TMS-cyanohydrin,
and a palladium-catalyzed intramolecular allylic amina-
tion efficiently established the contiguous stereogenic
centers and the bicyclic ring skeleton of (+)-biotin. The
high overall yield, lower number of steps, simple opera-
tional procedures, and use of the mild reaction conditions
permit ready access to (+)-biotin, a compound of growing
significance.
Exp er im en ta l Section
1
Gen er a l Meth od . Melting points are uncorrected. H and
a
Reagents and yields: (a) BnBr, NaH, DMF, 92%; (b) NaOH,
13C NMR spectra were recorded with tetramethylsilane used
as an internal standard. Optical rotations were measured at
the indicated temperature with a sodium lamp (D line, 589
nm). Silica gel column chromatography was performed using
Kieselgel 60 (E. Merck). Thin-layer chromatography (TLC)
was carried out on E. Merck 0.25 mm precoated glass-backed
plates (60 F254). Development was accomplished using 5%
phosphomolybdic acid in ethanol-heat or visualized by UV
light where feasible. All solvents and reagents were used as
received.
MeOH, H2O, 72%.
SCHEME 8a
(2RS,4R)-2-P h en ylth ia zolid in e-4-ca r boxylic Acid (8).13
To a solution of L-cysteine (121 g, 1 mol) in a mixed solvent of
water (0.65 L) and EtOH (0.2 L) were successively added
benzaldehyde (106 g, 1 mol) and ethanol (0.5 L). After the
mixture was stirred at 25 °C for 3 h, the crystals formed were
collected, washed with water, and dried to afford 8 (200 g,
a
Reagents and yields: (a) H2, Pd(OH)2/C, AcOEt, quant; (b) (i)
NaOH, MeOH, H2O (ii) MeSO3H, xylene, 84%.
tremely effective in providing 7b in much improved yield
(Table 5, entry 6, 77%).26 Olefin 7b had been tentatively
assigned11 to have E-configuration by comparison of the
1H and 13C NMR spectra with those described in a liter-
ature.7c However, the assignment in the literature7c was
found to be incorrect: Z-configuration of 7b was un-
equivocally confirmed by single-crystal X-ray analysis of
carboxylic acid 20 derived from 7b through N-benzylation
followed by hydrolysis (Scheme 7). The enantiomeric
purity of 7b was determined to be >99% ee by HPLC.
Con ver sion to (+)-Biotin (1). Compound 7b was
hydrogenated according to the reported procedure to give
21 in quantitative yield.7c Deblocking of 21 was sequen-
tially conducted through hydrolysis of the ester group
followed by cleavage of the benzyl group with methane-
sulfonic acid.27 Isolation of (+)-biotin (1) was best per-
formed by converting to the water soluble sodium salt,
treating the aqueous solution with activated charcoal and
subsequent crystallization with HCl (Scheme 8). Al-
though we have previously used a reported procedure7c
employing HBr for the conversion of 21 to 1, the present
protocol is practical since it avoids a tedious purification
by an ion exchange chromatography. The target com-
pound 1 obtained by the present method showed mp,
optical rotation, IR, NMR, and MS spectra in complete
accordance with those of the authentic sample.
1
95.6%) as colorless crystals. H NMR (DMSO-d6) δ 7.26-7.54
(m, 5H), 5.67 (s, 0.6H), 5.51 (s, 0.4H), 4.24 (dd, J ) 7.0, 4.6
Hz, 0.6H), 3.90 (dd, J ) 8.8, 7.0 Hz, 0.4H), 3.26-3.42 (m, 1H),
3.03-3.18 (m, 1H).
(2RS,4R)-4-(Hydr oxym eth yl)-2-ph en ylth iazolidin e (9).13
To ethanol (579 mL) was added SOCl2 (87 mL, 1.19 mol) below
0 °C and subsequently was added 8 (121 g, 0.578 mol). After
the mixture was stirred at 25 °C for 17 h, it was concen-
trated at reduced pressure. To the residue was added AcOEt,
and the mixture was evaporated. To the residue were added
CH2Cl2 and saturated aqueous NaHCO3. The organic layer was
separated and washed with water, dried over anhydrous
MgSO4, and concentrated at reduced pressure to give (2RS,4R)-
2-phenylthiazolidine-4-carboxylic acid ethyl ester (137 g, quant).
To a solution of CaCl2 (42 g, 0.38 mol) in EtOH (500 mL) was
added a solution of NaBH4 (19.6 g, 0.52 mol) in EtOH (660
mL) below -10 °C. To the suspension was added a solution of
(2RS,4R)-2-phenylthiazolidine-4-carboxylic acid ethyl ester
(137 g, 0.578 mol) in EtOH (270 mL) below -10 °C, and the
mixture was warmed to 10 °C for 2 h. To the mixture was
added HCl-MeOH (19.5 wt %, 390 mL). The mixture was
evaporated and 25% aq NH3 was added to adjust the pH value
to 9. The mixture was extracted with CH2Cl2, and the extract
was dried over anhydrous MgSO4 and concentrated at reduced
pressure to give 9 (115 g, quant). IR (KBr) ν ) 3239, 1464 cm-1
;
1H NMR (DMSO-d6) δ 7.19-7.54 (m, 5H), 5.61 (d, J ) 8.8 Hz,
0.4H), 5.51 (d, J ) 12 Hz, 0.6H), 4.85-4.91 (m, 0.6H), 4.75-
4.81 (m, 0.4H), 3.68-3.73 (m, 1.2H), 3.44-3.61 (m, 0.8H),
3.15-3.40 (m, 1H), 3.06 (dd, J ) 9.5, 6.1 Hz, 0.6H), 3.00-3.15
(m, 0.4H), 2.86 (dd, J ) 9.5, 9.5 Hz, 0.6H), 2.65-2.95 (m, 1.4H);
SIMS m/z 196 (M+ + 1).
Con clu sion
In summary, a novel and efficient synthesis of (+)-
biotin starting from readily accessible L-cysteine was
(2R,4R)-4-(Hydr oxym eth yl)-2-ph en ylth iazolidin e-3-car -
boxylic Acid ter t-Bu tyl Ester (2).7c To a solution of 9 (19.5
g, 0.10 mol) in a mixed solvent of THF (195 mL) and water
(98 mL) were successively added (Boc)2O (23.8 g, 0.11 mol) and
Na2CO3 (6.41 g, 0.06 mol) below 10 °C. The mixture was stirred
at 10 °C for 30 min and extracted with CH2Cl2. The extract
was washed with water and saturated aqueous NaCl, dried
(25) J effery, T. J . Chem. Soc. Chem. Commun. 1984, 1287.
(26) Since the ring closure of 6 to 2-imidazolidinone derivative 7
occurred at the position originally substituted with a carbonate, the
cyclization should proceed through a η3-allyl species in contrast to the
recently suggested pathway involving the aminopalladation. See:
Overman, L. E.; Remarchuk, T. P. J . Am. Chem. Soc. 2002, 124, 12.
For another example of the cyclization through a η3-allyl species, see:
Trost, B. M.; Genet, J . P. J . Am. Chem. Soc. 1976, 98, 8516.
(27) Takahashi, T.; Shimaji, K.; Maejima, K. J pn Tokkyo Koho J P
63-8954, Feb 2, 1979.
5532 J . Org. Chem., Vol. 67, No. 16, 2002

A Novel Synthesis of (+)-Biotin
over anhydrous MgSO4, and concentrated at reduced pressure.
The residue was purified by silica gel column chromatography
(hexane/AcOEt ) 3:1 to 2:1) to give 2 (26.1 g, 88%) as colorless
added n-Bu3P (3 g, 0.015 mol) and TMSCN (16.4 g, 0.165 mol)
at -10 °C, and the solution was stirred at the same temper-
ature for 30 min. The solution was concentrated at reduced
pressure. To the residue was added CH2Cl2 (150 mL), and the
solution was concentrated at reduced pressure to give the
O-TMS cyanohydrin 4 (58.9 g, quant). To a suspension of Mg
(23.0 g, 0.95 mol) in n-Bu2O (300 mL) was added a solution of
1,4-dibromobutane (97.2 g, 0.45 mol) in toluene (300 mL) at
40-70 °C for 30 min. After the mixture was stirred at 40-50
°C for 1 h, a solution of 4 (58.9 g, 0.15 mol) in toluene (300
mL) was added at -25 to -30 °C for 15 min, and the mixture
was stirred at the same temperature for 30 min. Carbon
dioxide was bubbled into the mixture at -30 °C for 1 h. The
reaction mixture was poured into 10% aq citric acid [citric acid
(101 g), water (909 g)] and extracted with AcOEt. The extract
was filtered, washed with water, dried over anhydrous MgSO4,
and concentrated at reduced pressure. To the residue was
added a mixture of citric acid, acetone, and water [citric acid
(45 g), acetone (360 g), water (90 g)], and the mixture was
stirred at 25 °C for 7.3 h. The mixture was concentrated at
reduced pressure, and to the residue were added water and
AcOEt. The organic layer was separated, washed with water,
dried over anhydrous MgSO4, and concentrated at reduced
pressure. The residue was purified by silica gel column
chromatography (AcOEt/hexane ) 1:2 to 2:1) to give 5 (50.0
g, 79%; anti/syn ) 13:1) (HPLC: Inertsil ODS-2, CH3CN/10
mM aq KH2PO4 (pH 3) ) 40:60, 40 °C, 1 mL/min, 230 nm,
crystals. mp 67-69 °C; [R]24 +102.6 (c, 1.0, CHCl3) [lit.:7c mp
D
46-48 °C; [R]20 +65.2 (c, 1.0, CHCl3)]; IR (Nujol) ν ) 3458,
D
1
1698, 1665 cm-1; H NMR (CDCl3) δ 7.23-7.39 (m, 5H), 6.03
(s, 1H), 4.49-4.63 (m, 1H), 3.83-4.01 (m, 2H), 3.26 (dd, J )
12, 6.7 Hz, 1H), 2.87 (dd, J ) 12, 4.0 Hz, 1H), 2.56 (brs, 1H),
1.26 (s, 9H); 13C NMR (CDCl3) δ 154.7, 141.1 (2s), 128.2, 127.6,
125.9 (3d), 81.3 (s), 66.1 (d), 64.6 (t), 63.9 (d), 32.7 (t), 27.9 (q);
SIMS m/z 296 (M+ + 1). Anal. Calcd for C15H21NO3S: C, 60.99;
H, 7.17; N,4.74. Found: C, 60.85; H, 7.03; N, 4.75; Diastereo-
meric purity: >99% de (HPLC: Inertsil ODS-2, CH3CN/10
mM aq KH2PO4 (pH 3) ) 40:60, 40 °C, 1 mL/min, 254 nm, cis
(2): 15.1 min, trans: 13.8 min).
(2R,4R)-4-F or m yl-2-p h en ylt h ia zolid in e-3-ca r b oxylic
Acid ter t-Bu tyl Ester (3).7c To a solution of 2 (59.1 g, 0.20
mol) in DMSO (296 mL) and toluene (59 mL) was added Et3N
(50.6 g, 0.50 mol) at 25 °C. To the solution was added SO3-
pyridine (79.6 g, 0.50 mol) at 10 °C, and the mixture was
stirred for 2 h. The mixture was poured into ice and water
(1.25 L) and extracted with AcOEt. The organic layer was
washed with 10% aqueous citric acid and water, dried over
anhydrous MgSO4, and concentrated at reduced pressure. The
crude crystals formed were suspended in hexane and collected
to give 3 (55.8 g, 95%) as colorless crystals. mp 84-85 °C (lit.:
7c oil); IR (Nujol) ν ) 1730, 1697 cm-1; 1H NMR (CDCl3) δ 9.79
(brs, 1H), 7.28-7.43 (m, 5H), 6.01 (brs, 1H), 4.82 (br, 1H),
3.15-3.40 (m, 2H), 1.28 (brs, 9H).
anti: 17.2 min, syn: 24.3 min). mp 101-103 °C; [R]23 +91.6
D
(c, 1.0, acetone); IR (Nujol) ν ) 3470, 2976, 1702 cm-1 1H
;
NMR (CDCl3) δ 7.58 (d, J ) 6.6 Hz, 2H), 7.30-7.40 (m, 3H),
6.07 (s, 1H), 4.73 (d, 1H), 4.42-4.51 (m, 1H), 3.23 (dd, J
) 12, 5.1 Hz, 1H), 3.02 (dd, J ) 12, 6.6 Hz, 1H), 2.57 (br, 2H),
A Typ ica l P r oced u r e for th e Cya n osilyla tion of 3
(Ta ble 2, en tr y 10). To a solution of 3 (0.293 g, 1 mmol) in
CH2Cl2 (9 mL) were successively added n-Bu3P (0.0249 mL,
0.1 mmol) and TMSCN (0.147 mL, 1.1 mmol) below -10 °C,
and the mixture was stirred at -10 °C for 0.5 h. The solution
was concentrated at reduced pressure to give the O-TMS
cyanohydrin 4 (0.393 g, quant). To the residue was added 10%
citric acid in MeOH (10 g), and the mixture was stirred at 25
°C for 4 h. The yield and diastereomeric ratio of the cyanohy-
drin (306 mg, 96%, anti/syn ) 92:8) were determined by HPLC
(Nucleosil 5C18, CH3CN/H2O ) 50:50, 40 °C, 0.8 mL/min, 254
nm, anti: 8.1 min, syn: 9.4 min) after the volume of the
mixture was adjusted to 100 mL by adding methanol. The
MeOH solution was evaporated, and AcOEt and water were
added to the residue. The organic layer was washed with water
and dried over anhydrous MgSO4 and concentrated at reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/CHCl3/AcOEt ) 5:5:1) to give the
anti-cyanohydrin (272 mg, 85%) and the syn-cyanohydrin (14
mg, 4%) both as colorless crystals.
2.34 (brt, J ) 7.0 Hz, 2H), 1.51-1.80 (m, 4H), 1.33 (s, 9Η); 13
C
NMR (CDCl3) δ 210.7, 179.1, 154.3, 140.6 (4s), 128.1, 127.9,
127.0 (3d), 81.7 (s), 76.2, 66.6, 65.0 (3d), 33.6, 28.9 (2t), 28.0
(q), 24.5, 23.9, 22.7 (3t); SIMS m/z 424 (M+ + 1). Anal. Calcd
for C21H29NO6S: C, 59.55; H, 6.90; N, 3.31. Found: C, 59.60;
H, 6.90; N, 3.13.
(S)-7-[(2R,4R)-3-(ter t-Bu toxyca r bon yl)-2-p h en ylth ia zo-
lid in -4-yl]-7-h yd r oxy-6-oxoh ep ta n oic Acid Meth yl Ester
(10). To a solution of 5 (50.0 g, 0.12 mol; anti/syn ) 13:1) in
DMF (200 mL) were successively added K2CO3 (17.1 g, 0.12
mol) and Me2SO4 (15.6 g, 0.12 mol) at 10 °C for 10 min. The
mixture was warmed to 25 °C for 2 h and stirred overnight at
25 °C. The mixture was diluted with AcOEt (300 mL), washed
with water and saturated aqueous NaCl, dried over anhydrous
MgSO4, and concentrated at reduced pressure. The residue was
dissolved in hot AcOEt (40 mL) and diluted with hexane (280
mL), and the mixture was cooled to 25 °C. The crystals formed
were collected to give 10 (37.9 g, 73%) as colorless crystals.
mp 110-113 °C; [R]20D +95 (c, 1.0, CHCl3); IR (Nujol) ν ) 3431,
(S)-2-[(2R,4R)-3-(ter t-Bu toxyca r bon yl)-2-p h en ylth ia zo-
lid in -4-yl]-2-h yd r oxya ceton itr ile (a n ti-Cya n oh yd r in ). mp
139-140 °C; [R]25 +118 (c, 1.0, CHCl3); IR (KBr) ν ) 3406,
1722, 1708, 1669 cm-1 1H NMR (CDCl3) δ 7.58 (d, J ) 6.6
;
D
1677 cm-1; 1H NMR (CDCl3) δ 7.24-7.46 (m, 5H), 6.04 (s, 1H),
4.84 (d, J ) 5.3 Hz, 1H), 4.66-4.72 (m, 1H), 3.31 (dd, J ) 12,
6.1 Hz, 1H), 3.16 (dd, J ) 12, 3.9 Hz, 1H), 1.30 (s, 9H); 13C
NMR (CDCl3) δ 140.5 (s), 129.0, 128.5, 126.4 (3d), 119.2, 83.3
(2s), 67.2, 65.7, 64.4 (3d), 32.9 (t), 28.4 (q); SIMS m/z 321 (M+
+ 1). Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29; N,8.74.
Found: C, 59.91; H, 6.19; N, 8.72.
Hz, 2H), 7.24-7.39 (m, 3H), 6.07 (s, 1H), 4.72 (br, 1H), 4.42-
4.50 (m, 1H), 3.66 (s, 3H), 3.22 (dd, J ) 12, 5.1 Hz, 1H), 3.02
(dd, J ) 12, 6.6 Hz, 1H), 2.56 (br, 2H), 2.29 (brt, J ) 7.0 Hz,
2H), 1.50-1.70 (m, 4H), 1.33 (s, 9H); 13C NMR (CDCl3) δ 173.7,
154.3, 140.8, 128.4 (4s), 128.2, 127.9, 127.1 (3d), 81.7 (s), 76.3,
66.6, 65.1 (3d), 51.5 (q), 39.6, 33.7, 31.3 (3t), 28.1 (q), 24.3, 22.9
(2t); SIMS m/z 438 (M+ + 1). Anal. Calcd for C22H31NO6S: C,
60.39; H, 7.14; N, 3.20. Found: C, 60.49; H, 7.21; N, 3.05;
Optical purity: >99% ee (HPLC: CHIRALPAK AD, EtOH/
n-hexane ) 5:95, 40 °C, 0.5 mL/min, 254 nm, 10: 35.9 min,
the antipode of 10: 25.2 min).
(R)-2-[(2R,4R)-3-(ter t-Bu toxyca r bon yl)-2-p h en ylth ia zo-
lid in -4-yl]-2-h yd r oxya ceton itr ile (syn -Cya n oh yd r in ). mp
117-118 °C; [R]25 +89.4 (c, 1.0, CHCl3); IR (KBr) ν ) 3305,
D
1657 cm-1; 1H NMR (CDCl3) δ 7.28-7.40 (m, 5H), 5.97 (s, 1H),
4.77-4.84 (m, 2H), 3.45 (dd, J ) 13, 6.9 Hz, 1H), 3.00 (dd, J
) 13, 0.9 Hz, 1H), 1.17 (s, 9Η); 13C NMR δ 139.9 (s), 129.1,
128.8, 126.5 (3d), 119.0, 83.7 (2s), 67.4, 66.2, 65.2 (3d), 32.9
(t), 28.2 (q); SIMS m/z 321 (M+ + 1). Anal. Calcd for
(S)-7-[(2R,4R)-3-(ter t-Bu toxyca r bon yl)-2-p h en ylth ia zo-
lid in -4-yl]-7-m eth oxyca r bon yloxy-6-oxoh ep ta n oic Acid
Meth yl Ester (11). To a solution of 10 (1.0 g, 2.29 mmol) and
Et3N (0.48 mL, 3.43 mmol) in THF (10 mL) were successively
added DMAP (cat.) and methyl chloroformate (0.21 mL, 2.74
mmol) at 0 °C. After the mixture was stirred for 1 h,
triethylamine (0.72 mL, 5.15 mmol) and methyl chloroformate
(0.32 mL, 4.11 mmol) were added to the mixture at 0 °C. After
the mixture was stirred for 1.5 h, it was diluted with AcOEt.
C
16H20N2O3S: C, 59.98; H, 6.29; N, 8.74. Found: C, 59.75; H,
6.19; N, 8.52.
(S)-7-[(2R,4R)-3-ter t-Bu t oxyca r b on yl-2-p h en ylt h ia zo-
lid in -4-yl]-7-h yd r oxy-6-oxoh ep ta n oic Acid (5). To a solu-
tion of 3 (44 g, 0.15 mol) in CH2Cl2 (225 mL) were successively
J . Org. Chem, Vol. 67, No. 16, 2002 5533

Seki et al.
The organic layer was washed with water and brine and dried
over anhydrous MgSO4. After evaporation of the solvent, the
residue was purified by silica gel column chromatography
(hexane/AcOEt ) 5:1) to give 11 (1.195 g, quant) as colorless
0.45 mL/min, 254 nm, 6b: 16.7 min, the antipode of 6b: 26.2
min).
(3a S,4Z,6a R)-5-{Hexa h yd r o-2-oxo-4H-th ien o[3,4-d ]im i-
d a zol-4-ylid en e}p en ta n oic Acid Meth yl Ester (7a ). To a
stirred solution of 6a (10 mg, 0.03 mmol) and NaHCO3 (5 mg,
0.06 mmol) in THF (0.6 mL) and water (0.1 mL) were added
triethyl phosphite (6.9 mg, 0.0416 mmol) and Pd(OAc)2 (2.0
mg, 0.009 mmol) at 25 °C, and the mixture was stirred at 37-
40 °C for 24 h. After evaporation of the solvent, the residue
was purified by silica gel preparative TLC (CHCl3/MeOH )
10:1) to give 7a (2.3 mg, 30% yield) as a colorless oil. IR (KBr)
crystals. mp 88-90 °C; [R]20 +51.8 (c, 1.0, MeOH); IR (KBr)
D
1750, 1730, 1699 cm-1; 1H NMR (CDCl3) δ 7.57-7.56 (m, 2H),
7.36-7.25 (m, 3H), 5.97 (br s, 1H), 5.42-5.29 (m, 1H), 4.72-
4.68 (m, 1H), 3.76 (br s, 3H), 3.66 (s, 3H), 3.21-3.08 (m, 2H),
2.88-2.60 (m, 1H), 2.50-2.40 (m, 1H), 2.40-2.33 (m, 2H),
1.70-1.68 (m, 4H), 1.25 (br s, 9H); 13C NMR (CDCl3) δ 205.6,
174.2, 171.7, 155.2, 154.4, 140.6, 135.2 (7s), 128.6, 128.2, 127.3,
77.4, 67.2, 62.6 (6d), 55.8, 51.9 (2q), 34.3, 32.2 (2t), 28.4 (q),
3238, 1731, 1690 cm-1; [R]22 +290 (c, 0.10, MeOH); 1H NMR
D
24.6, 22.8 (2t); SIMS m/z 496 (M+ + 1). Anal. Calcd for C24H33
-
(CDCl3) δ 5.55 (t, J ) 7.1 Hz, 1H), 4.83 (br s, 1H), 4.76 (br s,
1H), 4.68 (d, J ) 7.6 Hz, 1H), 4.51-4.49 (m, 1H), 3.68 (s, 3H),
3.24 (dd, J ) 5.7, 12 Hz, 1H), 3.02 (dd, J ) 3.1, 12 Hz, 1H),
2.34 (t, J ) 7.4 Hz, 2H), 2.18-2.11 (m, 2H), 1.79-1.76 (m, 2H);
13C NMR (CDCl3) δ 173.9, 161.9, 141.6 (3s), 122.9, 63.9, 58.3
NO8S; C, 58.17; H, 6.71; N, 2.83. Found: C, 58.12; H, 6.64; N,
2.82.
(2Z,3R,4R)-2-{4-(Meth oxycar bon yl)bu tyliden e}-3-(m eth -
oxyca r bon yloxy)-4-u r eid otetr a h yd r oth iop h en e (6a ). To
a stirred solution of MeOH (0.25 mL, 6.1 mmol) in toluene (1.0
mL) was added AcCl (0.29 mL, 4.0 mmol) at 0 °C. After the
mixture was stirred for 15 min, 11 (0.1 g, 0.2 mmol) was added
to the mixture at 0 °C. After the mixture was stirred for 1 h,
the solvent was evaporated and coevaporated with AcOEt (4
× 2.0 mL). To the residue were added THF (2.0 mL), water
(2.0 mL), and KOCN (32.8 mg, 0.4 mmol), and the mixture
was stirred at 25 °C for 12 h. After evaporation of the solvent,
the residue was extracted with CHCl3. The extract was dried
over anhydrous MgSO4 and evaporated. The residue was
purified by silica gel column chromatography (CHCl3/MeOH
) 50:1) to give 6a (57.8 mg, 86% yield) as colorless crystals.
(3d), 51.6 (q), 39.6, 33.4, 31.1, 24.1 (4t); SIMS m/z 257 (M+
1). Anal. Calcd for C11H16N2O3S; C, 51.54; H, 6.29; N, 10.93.
Found: C, 51.42; H, 6.05; N, 10.66.
+
(3a S,4Z,6a R)-5-{Hexa h yd r o-1-ben zyl-2-oxo-4H-th ien o-
[3,4-d ]im id a zol-4-ylid en e}p en ta n oic Acid Meth yl Ester
(7b).7c To a stirred mixture of 6b (1.7 g, 3.9 mmol), NaHCO3
(990 mg, 15 mmol), and tetrabutylammonium chloride (110
mg, 0.39 mmol) in DMF (78 mL) and H2O (13 mL) were added
P(OEt)3 (440 mg, 2.6 mmol) and Pd(OAc)2 (90 mg, 0.39 mmol)
at 25 °C, and the mixture was stirred at 100 °C for 2 h. After
evaporation of the solvent, the residue was dissolved in AcOEt
and washed with water, dried over anhydrous MgSO4, and
evaporated. The residue was purified by silica gel column
chromatography (hexane/AcOEt ) 2:1) to give 7b (1.1 g, 77%
mp 101-104 °C; [R]20 -98.6 (c, 1.0, MeOH); IR (Nujol) 3358,
D
1750, 1650, 1600 cm-1; 1H NMR (CDCl3) δ 5.77 (t, J ) 7.0 Hz,
1 H), 5.54 (br d, J ) 8.2 Hz, 1H), 5.39 (d, J ) 4.1 Hz, 1H), 4.78
(br s, 1H), 4.63-4.55 (m, 1H), 3.81 (s, 3H), 3.69 (s, 3H), 3.22
(dd, J ) 5.9, 11 Hz, 1H), 3.00 (dd, J ) 7.8, 11 Hz, 1H), 2.34-
2.28 (m, 2H), 2.09-2.05 (m, 2H), 1.82-1.77 (m, 2H); 13C NMR
(CDCl3) δ 174.8, 158.4, 155.2, 135.5 (4s), 124.4, 80.6 (2d), 55.5
(q), 53.7 (d), 52.1, 34.0, 33.7, 30.3, 24.0 (5t); SIMS m/z 333 (M+
+ 1). Anal. Calcd for C13H20N2O6S; C, 46.98; H, 6.07; N, 8.43.
Found: C, 46.96; H, 6.11; N, 8.32.
yield) as a colorless oil. IR (Nujol) 3218, 2948, 1726, 1698 cm-1
;
1H NMR (CDCl3) δ 7.36-7.27 (m, 5H), 5.55 (t, J ) 7.0 Hz,
1H), 5.10 (br s, 1H), 4.72 (d, J ) 15 Hz, 1H), 4.52 (d, J ) 7.6
Hz, 1H), 4.23-4.19 (m, 1H), 4.15 (d, J ) 15 Hz, 1H), 3.67 (s,
3H), 3.06-2.97 (m, 2H), 2.32 (t, J ) 7.4 Hz, 2H), 2.15-2.09
(m, 2H), 1.78-1.72 (m, 2H); 13C NMR (CDCl3) δ 174.3, 160.7,
142.3, 137.1 (4s), 129.1, 128.8, 128.1, 123.0, 62.0 (5d), 61.4 (s),
52.0 (q), 46.1, 36.4, 33.8, 31.5, 24.5 (5t); SIMS m/z 347 (M+
+
1); Optical purity: >99% ee (HPLC: CHIRALPAK AD, EtOH/
n-hexane ) 50:50, 30 °C, 0.45 mL/min, 254 nm, 7b: 32.3 min,
the antipode of 7b: 126.1 min).
(2Z,3R,4R)-2-{4-(Meth oxycar bon yl)bu tyliden e}-3-(m eth -
oxycar bon yloxy)-4-(3-ben zylu r eido)tetr ah ydr oth ioph en e
(6b). To a stirred solution of MeOH (5 mL, 120 mmol) in
toluene (20 mL) was added AcCl (5.4 mL, 80 mmol) at 0 °C.
After the mixture was stirred for 15 min, 11 (2.0 g, 4.0
mmol) was added to the mixture at 0 °C. The mixture was
stirred for 1 h, and the solvent was evaporated and co-
evaporated with AcOEt (4 × 40 mL). To the residue dissolved
in a mixed solvent of THF (20 mL) and a buffered aqueous
solution (20 mL, pH ) 4, citric acid-NaHCO3) were suc-
cessively added benzaldehyde (0.42 mL, 4.0 mmol) and
NaBH3CN (1 M in THF, 2.0 mL, 2.0 mmol) at 5 °C over 1 h.
After the mixture was stirred for 1.5 h, 1 M aq HCl (8.0 mL,
8.0 mmol) and KOCN (0.66 g, 8.0 mmol) were added at 5 °C.
The mixture was stirred at 25 °C for 21 h and diluted with
AcOEt. The organic layer was washed with water and brine
and dried over anhydrous MgSO4. After evaporation of the
solvent, the residue was purified by silica gel column chroma-
tography (hexane/AcOEt ) 2:1 to 1:2) to give 6b (1.4 g, 82%
2-{4-(Met h oxyca r b on yl)b u t yl}-4-(3-b en zylu r eid o)-3-
oxotetr a h yd r oth iop h en e (13). To a stirred suspension of
10 (880 mg, 2.01 mmol) in AcOEt (10 mL) was added 4 N HCl
in AcOEt (8.8 mL, 35.2 mmol) at 0 °C. After the mixture was
stirred at 25 °C for 2 h, the solvent was evaporated and
coevaporated with AcOEt (3 × 10 mL). The resulting residue
was dissolved in water (10 mL) and washed with AcOEt (10
mL). The organic phase was extracted with water (10 mL),
and combined aqueous solution was washed with AcOEt (10
mL), evaporated and coevaporated with toluene (3 × 10 mL).
To the residue dissolved in THF (8.8 mL) were successively
added benzylisocyanate (0.25 mL, 2.01 mmol) and Et3N (0.28
mL, 2.01 mmol) at 0 °C. After the mixture was stirred at 25
°C for 2.5 h, the mixture was diluted with AcOEt (20 mL).
The organic phase was washed with water and brine and dried
over anhydrous MgSO4. After evaporation of the solvent, the
residue was purified by silica gel column chromatography
(CHCl3/acetone ) 20:1 to CHCl3/MeOH ) 20:1) to give 13 (417
mg, 57%) as a yellow powder and 14 (128 mg, 18%) as colorless
yield) as colorless crystals. mp 105-108 °C; [R]20 -86.7 (c,
D
1.0, MeOH); IR (KBr) 3432, 1754, 1728, 1656, 1612 cm-1; H
1
1
crystals. 13: IR (KBr) 3289, 1737, 1626, 1569 cm-1; H NMR
NMR (CDCl3) δ 7.44-7.21 (m, 5H), 5.90 (t, J ) 7.2 Hz, 1H),
5.63 (d, J ) 3.9 Hz, 1H), 5.16-5.10 (m, 1H), 4.71 (d, J ) 18
Hz, 1H), 4.63 (brs, 1H), 4.61 (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) δ 174.2, 159.6, 155.1, 137.5,
135.6 (5s), 129.5, 128.0, 126.0, 125.9, 81.2, 58.0 (6d), 55.1, 51.9
(2q), 48.9, 33.8, 30.5, 30.0, 24.1 (5t); SIMS m/z 423 (M+ + 1).
Anal. Calcd for C20H26N2O6S; C, 56.86; H, 6.20; N, 6.63.
Found: C, 56.58; H, 6.04; N, 6.61; Optical purity: >99% ee
(HPLC: CHIRALPAK AD, EtOH/n-hexane ) 50:50, 40 °C,
(DMSO-d6) δ 7.35-7.22 (m, 10H), 6.81-6.69 (m, 2H), 6.50-
6.39 (m, 2H), 4.46-4.30 (m, 2H), 3.62-3.51 (m, 2H), 3.58 (s,
6H), 3.21-3.04 (m, 2H), 2.93-2.76 (m, 2H), 2.34-2.27 (m, 4H),
1.93-1.80 (m, 2H), 1.56-1.21 (m, 6H); 13C NMR (DMSO-d6) δ
200.5, 186.2, 170.3, 170.2, 153.5 (5s), 141.2, 140.0, 139.6, 71.2,
70.9 (5d), 64.2 (q), 61.8, 59.9 (2d), 55.9, 46.1, 46.0, 45.3, 43.8,
41.9, 41.3, 39.4, 39.1, 37.1, 37.0 (11t); SIMS m/z 365 (M+ + 1);
HRMS m/z (M + H)+: Calcd for C18H25N2O4S, 365.1535.
Found, 365.1501. 14: mp 173-174 °C; [R]20 +2 (c, 1.0,
D
MeOH); IR (neat) 3283, 1737, 1671 cm-1; 1H NMR (DMSO-d6)
5534 J . Org. Chem., Vol. 67, No. 16, 2002

A Novel Synthesis of (+)-Biotin
δ 7.34-7.20 (m, 5H), 7.10 (s, 1H), 6.39 (s, 1H), 4.78 (d, J ) 16
Hz, 1H), 4.17 (d, J ) 16 Hz, 1H), 3.81-3.80 (m, 1H), 3.56 (s,
3H), 3.14 (dd, J ) 6.3, 12 Hz, 1H), 2.70 (dd, J ) 3.0, 8.2 Hz,
1H), 2.42 (dd, J ) 4.7, 12 Hz, 1H), 2.15 (t, J ) 7.3 Hz, 2H),
1); HRMS m/z (M - H)-: Calcd for C11H14N2O3S, 256.0644.
Found, 256.0638.
(3a S ,4Z,6a R )-5-{H e xa h yd r o-1,3-d ib e n zyl-2-oxo-4H -
th ien o[3,4-d ]im id a zol-4-ylid en e}p en ta n oic Acid Meth yl
Ester (19). To a solution of 7b (50 mg, 0.14 mmol) in DMF (1
mL) were successively added NaH (12 mg, 0.29 mmol) and
benzyl bromide (49 mg, 0.29 mmol) at -40 °C, and the mixture
was warmed to 25 °C over 3 h. After the mixture was stirred
at 25 °C for 18 h, it was diluted with AcOEt. The organic phase
was washed twice with water, dried over anhydrous MgSO4
and evaporated. The residue was purified by preparative TLC
(hexane/AcOEt ) 2:1) to give 19 (58 mg, 92%) as a colorless
1.71-1.61 (m, 1H), 1.39-1.18 (m, 4H), 0.89-0.77 (m, 1H); 13
C
NMR (DMSO-d6) δ 173.5, 159.7, 140.3 (3s), 128.4, 127.3, 126.9
(3d), 99.5 (s), 65.7, 56.3 (2d), 51.5 (q), 41.8, 39.2, 28.8, 28.0,
24.3 (5t); SIMS m/z 365 (M+ + 1). Anal. Calcd for C18H24N2O4S;
C, 59.32; H, 6.64; N, 7.69; S, 8.80. Found: C, 59.30; H, 6.61;
N, 7.52; S, 8.68.
(3aR*,4R*,6aR*)-Hexah ydr o-3-ben zyl-3a-h ydr oxy-2-oxo-
1H-th ien o[3,4-d ]im id a zole-4-p en ta n oic Acid Meth yl Es-
ter (14). To a stirred solution of 13 (50 mg, 0.137 mmol) in
THF (0.5 mL) was added DBU (2 µL, 0.014 mmol) at 25 °C.
The mixture was stirred at 25 °C for 15 h and diluted with
AcOEt. The organic phase was washed with water and brine
and dried over anhydrous MgSO4. After evaporation of the
solvent, the crude crystals formed were suspended in MeOH
and collected to give 14 (36.7 mg, 73%) as colorless crystals.
The product 14 showed the same IR, NMR, and MS spectra
as those of the compound 14 prepared from 10 except the
1
oil. IR (neat) 1733, 1691 cm-1; H NMR (CDCl3) δ 7.37-7.24
(m, 10H), 5.42 (t, J ) 7.1 Hz, 1H), 4.96 (d, J ) 16 Hz, 1H),
4.81 (d, J ) 15 Hz, 1H), 4.28 (d, J ) 7.7 Hz, 1H), 4.22 (d, J )
15 Hz, 1H), 4.20-4.05 (m, 1H), 4.06 (d, J ) 16 Hz, 1H), 3.66
(s, 3H), 2.98 (dd, J ) 3.7, 12 Hz, 1H), 2.94 (dd, J ) 5.7, 12 Hz,
1H), 2.28 (t, J ) 7.4 Hz, 2H), 2.13-2.05 (m, 2H), 1.72-1.67
(m, 2H); 13C NMR (CDCl3) δ 173.7, 159.0, 138.0, 137.2, 137.1
(5s), 128.7 (2d), 127.9, 127.6, 127.5, 127.3, 125.6, 64.5, 59.0
(7d), 51.5, 46.5, 44.9, 37.1, 33.4, 31.1, 24.2 (6t); SIMS m/z 437
(M+ + 1); HRMS m/z (M + H)+: Calcd for C25H29N2O3S,
437.1899. Found, 437.1914.
optical rotation {[R]20 0 (c, 1.0, MeOH) }.
D
H exa h yd r o-3a -h yd r oxy-2-oxo-1H -t h ien o[3,4-d ]im id a -
zole-4-p en ta n oic Acid Meth yl Ester (16). To a stirred
suspension of 10 (880 mg, 2.01 mmol) in AcOEt (10 mL) was
added 4 N HCl in AcOEt (8.8 mL, 35.2 mmol) at 0 °C. After
the mixture was stirred at 25 °C for 2 h, the solvent was
evaporated and coevaporated with AcOEt (3 × 10 mL). The
resulting residue was dissolved in water (10 mL) and washed
with AcOEt (10 mL). The organic phase was extracted with
water (10 mL), and the combined aqueous solution was washed
with AcOEt (10 mL), evaporated, and coevaporated with
toluene (3 × 10 mL). To the residue dissolved in water (8.8
mL) was added KOCN (196 mg, 2.2 mmol) at 0 °C. After the
mixture was stirred at 25 °C for 15 h, it was diluted with
CHCl3 (20 mL). The organic layer was separated and dried
over anhydrous MgSO4. After evaporation of the solvent,
the residue was purified by silica gel column chromatogra-
phy (CHCl3/MeOH ) 10:1) to give 16 (407 mg, 74%) as a
(3a S ,4Z,6a R )-5-{H e xa h yd r o-1,3-d ib e n zyl-2-oxo-4H -
th ien o[3,4-d ]im id a zol-4-ylid en e}p en ta n oic Acid (20). To
a solution of 19 (118 mg, 0.26 mmol) in MeOH (1.2 mL) and
H2O (0.3 mL) was added NaOH (13 mg, 0.32 mmol) at 10 °C,
and the mixture was stirred at 25 °C for 17 h. After evapora-
tion of MeOH, the aqueous solution was washed with ether
and acidified by adding concd HCl. The mixture was extracted
with AcOEt, and the organic phase was washed with water,
dried over anhydrous MgSO4, and evaporated. The residue was
crystallized by adding hexane to afford 20 (82 mg, 72%) as
colorless crystals. mp 86-87 °C; [R]20 +234 (c, 1.0, MeOH);
D
IR (KBr) 1728, 1654 cm-1; 1H NMR (CDCl3) δ 11.15 (brs, 1H),
7.23-7.36 (m, 10H), 5.42 (t, J ) 7.1 Hz, 1H), 4.94 (d, J ) 16
Hz, 1H), 4.80 (d, J ) 15 Hz, 1H), 4.88 (d, J ) 7.7 Hz, 1H),
4.22 (d, J ) 15 Hz, 1H), 4.03-4.09 (m, 3H), 2.90-2.99 (m, 2H),
2.29 (t, J ) 7.3 Hz, 2H), 2.04-2.15 (m, 2H), 1.55-1.70 (m, 2H);
13C NMR (DMSO-d6) δ178.2, 159.0, 137.8, 136.9, 136.8 (5s),
128.6, 128.4, 128.0, 127.7, 127.6, 127.2, 125.6, 64.6, 58.9 (9d),
46.4, 44.8, 37.0, 33.3, 30.9, 23.9 (6t); SIMS m/z 423 (M+ + 1).
Anal. Calcd for C24H26N2O3S; C, 68.22; H, 6.20; N, 6.63.
Found: C, 68.14; H, 6.09; N, 6.49.
yellow powder. IR (KBr) 3276, 1710, 1685 cm-1; [R]24 +25.1
D
1
(c, 1.01, CHCl3); H NMR (DMSO-d6) δ 7.25 (br s, 1H), 7.03
(br s, 1H), 6.70 (br s, 1H), 6.57 (br s, 1H), 6.15 (s, 1H), 6.08
(s, 1H), 3.86-3.84 (m, 1H), 3.77-3.69 (m, 1H), 3.58 (s, 6H),
3.15-3.06 (m, 2H), 3.01-2.89 (m, 2H), 2.45-2.36 (m, 2H), 2.30
(m, 4H), 1.91-1.17 (m, 12H); SIMS m/z 275 (M+ + 1); HRMS
m/z (M - H)-: Calcd for C11H17N2O4S, 273.0909. Found,
273.0889.
(3a S,4S,6a R)-Hexa h yd r o-1-ben zyl-2-oxo-1H-th ien o[3,4-
d ]im id a zole-4-p en ta n oic Acid Meth yl Ester (21).7c
A
mixture of 10% Pd(OH)2 on carbon (50% wet) (1.6 g, 0.57 mmol)
in AcOEt (490 mL) was stirred at 25 °C for 1 h under H2 (4
atm). Then, a solution of 7b (1.9 g, 5.7 mmol) in AcOEt (200
mL) was added to the mixture. The mixture was stirred under
H2 (4 atm) at 25 °C for 2 h and filtered through activated
carbon under N2 atmosphere. The filtrate was evaporated to
give 21 (2.0 g, quant) as an amorphous solid. IR (KBr) 3216,
2928, 1727, 1694 cm-1; 1H NMR (CDCl3) δ 7.35-726 (m, 5H),
4.72 (d, J ) 15 Hz, 1H), 4.27-4.23 (m, 1H), 4.21-4.19 (m, 1H),
4.11 (d, J ) 15 Hz, 1H), 3.66 (s, 3H), 3.15 (m, 1H), 2.82 (d, J
) 13 Hz, 1H), 2.68 (dd, J ) 4.8, 13 Hz, 1H), 2.33 (t, J ) 7.3
Hz, 2H), 1.75-1.64 (m, 3H), 1.48-1.42 (m, 2H); 13C NMR
(CDCl3) δ 174.3, 161.8, 137.1 (3s), 129.1, 128.4, 128.1, 64.1,
59.7, 55.6 (6d), 51.9 (q), 36.6, 34.0, 28.7, 28.5, 25.1 (5t); SIMS
m/z 349 (M+ + 1).
(+)-Biotin (1). To a stirred solution of 21 (5.2 g, 0.015 mol)
in MeOH (10 mL) and water (31 mL) was added NaOH (2.4 g,
0.06 mol) at 25 °C. After the mixture was stirred at 40 °C for
3 h, the solvent was evaporated. The resulting mixture was
acidified with concd HCl, extracted with AcOEt (50 mL),
washed with water (50 mL), and dried over anhydrous MgSO4.
After evaporation of the solvent, the residue was coevaporated
with toluene (3 × 20 mL). To the mixture were added MeSO3H
(15.5 g, 0.16 mol) and xylene (16 mL) at 25 °C. After the
mixture was stirred at 135 °C for 3 h, it was cooled to 85 °C.
The lower phase was separated and poured into water (100
4-Ur eidoth ioph en e-2-pen tan oic Acid Meth yl Ester (17).
To a stirred solution of 6a (100 mg, 0.3 mmol) in THF (6.0
mL) were added P(OEt)3 (19.9 mg, 0.12 mmol) and Pd(OAc)2
(6.7 mg, 0.03 mmol) at 25 °C, and the mixture was stirred at
65-70 °C for 22 h. After evaporation of the solvent, the residue
was purified by silica gel preparative TLC (CHCl3/MeOH )
10:1) to give 17 (50.8 mg, 66%) as a colorless oil. IR (neat) 3445,
3355, 1710, 1683, 1540 cm-1 1H NMR (CDCl3) δ 7.04 (br s,
;
1H), 6.90 (d, J ) 1.5 Hz, 1H), 6.65 (d, J ) 1.5 Hz, 1H), 4.90
(br s, 2H), 3.67 (s, 3H), 2.80-2.72 (m, 2H), 2.38-2.31 (m, 2H),
1.73-1.64 (m, 4H); SIMS m/z 257 (M+ + 1); HRMS m/z (M -
H)-: Calcd for C11H15N2O3S, 255.0803. Found, 255.0816.
(3a S ,4Z,6a R )-5-{H e xa h yd r o-2-oxo-4H -t h ie n o[3,4-d ]-
oxa zol-4-ylid en e}p en ta n oic Acid Meth yl Ester (18). To
a solution of 6a (10 mg, 0.03 mmol) in THF (0.6 mL) were
successively added NaH (1 mg, 0.03 mmol), P(OEt)3 (6.9 mg,
0.0416 mmol), and Pd(OAc)2 (2.0 mg, 0.009 mmol) at 25 °C,
and the mixture was stirred at 37-40 °C for 40 min. After
evaporation of the solvent, the residue was purified by silica
gel preparative TLC (CHCl3/MeOH ) 10:1) to give 18 (6.0 mg,
78%) as a colorless oil. IR (neat) 1726 cm-1; 1H NMR (CDCl3)
δ 6.11 (br s, 1H), 5.89 (t, J ) 7.1 Hz, 1H), 5.38 (d, J ) 7.3 Hz,
1H), 4.61-4.54 (m, 1H), 3.68 (s, 3H), 3.22 (dd, J ) 5.5, 12 Hz,
1H), 3.02 (dd, J ) 2.2, 12 Hz, 1H), 2.34 (t, J ) 7.4 Hz, 2H),
2.26-2.10 (m, 2H), 1.85-1.68 (m, 2H); SIMS m/z 258 (M+
+
J . Org. Chem, Vol. 67, No. 16, 2002 5535

Seki et al.
mL). After the mixture was stirred at 10 °C for 1 h, the crystals
formed were collected and washed with water and acetone to
give the crude product. To a stirred suspension of the crude
crystals in water (45 mL) was added NaOH (0.54 g, 0.014 mol)
at 25 °C, and pH of the mixture was adjusted to 7.5-8.0 at 90
°C by adding concd HCl. Activated carbon (2.5 g) was added
to the mixture at same temperature and the mixture was
filtered. The filtrate was acidified to pH 1.6-1.8 with concd
HCl at 95 °C. After the mixture was stirred at 10 °C for 1 h,
the crystals formed were collected and washed with water to
give (+)-biotin (3.06 g, 84%) as colorless crystals. mp 231-
232 °C (lit.:28 229.5-230 °C), [R]24D +91.0 (c, 1.0, 0.1 N NaOH)
{lit.:28 [R]25D +91.3 (c, 1.0, 0.1 N NaOH)}; IR (neat) 3299, 2920,
4H), 1.36-1.32 (m, 2H); 13C NMR (DMSO-d6) δ 174.8, 163.1
(2s), 61.4, 59.5, 55.7 (3d), 40.0, 33.8, 28.44, 28.36, 24.9 (5t);
SIMS m/z 245 (M+ + 1). Anal. Calcd for C10H16N2O3S; C, 49.16;
H, 6.60; N, 11.47; S, 13.13. Found: C, 49.28; H, 6.63; N, 11.54;
S, 13.09.
Ack n ow led gm en t. The authors are indebted to Mr.
Koichi Inubushi and Mr. Hajime Hiramatsu, Tanabe
Seiyaku Co., Ltd., for the X-ray crystallographic analy-
sis.
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawings
of anti- and syn-cyanohydrin and compounds 5, 6b, and 20,
and copies of HPLC traces were used to determine diastereo-
selectivity and optical purity. This material is available free
of charge via the Internet at http//:pubs.acs.org.
1
1686 cm-1; H NMR (DMSO-d6) δ 12.02 (br s, 1H), 6.49 (br s,
1H), 6.40 (br s, 1H), 4.31 (dd, J ) 5.2, 7.6 Hz, 1H), 4.16-4.13
(m, 1H), 3.12-3.10 (m, 1H), 2.81 (dd, J ) 5.1, 12 Hz, 1H), 2.58
(d, J ) 12 Hz, 1H), 2.21 (t, J ) 7.3 Hz, 2H), 1.54-1.36 (m,
(28) Volkmann, R. A.; Davis, J . T.; Meltz, C. N. J . Am. Chem. Soc.
1983, 105, 5946.
J O025794+
5536 J . Org. Chem., Vol. 67, No. 16, 2002