A Facile Synthesis of a Key Intermediate for (+)-Biotin via Strecker Reaction

Article abstract of DOI:10.1055/s-2003-42399

The Strecker reaction of (2R,4R)-2-phenyl-3-phenoxycarbonylthiazolidine-4- carbaldehyde (4b), which was readily prepared from L-cysteine, with benzylamine and trimethylsilyl cyanide provided α-amino nitrile 5b stereoselectively (syn-anti, 2:1), Amidation of 5b and subsequent cyclization gave bicyclic compound 6, which, upon reduction with zinc dust, hydrolysis and subsequent cyclization, furnished thiolactone 2, a key intermediate for (+)-biotin (1).

Full text of DOI:10.1055/s-2003-42399

PAPER
2311
A Facile Synthesis of a Key Intermediate for (+)-Biotin via Strecker Reaction
Synthesis of
a
K
ey
o
Intermediat
s
for
(
+)-B
h
iotin via
S
tr
i
e
cke
r
R
k
eaction azu Mori, Mayumi Kimura, Masahiko Seki*
Process Chemistry Research Laboratories, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan
E-mail: m-seki@tanabe.co.jp
Received 9 June 2003; revised 15 July 2003
Abstract: The Strecker reaction of (2R,4R)-2-phenyl-3-phenoxy-
carbonylthiazolidine-4-carbaldehyde (4b), which was readily pre-
pared from L-cysteine, with benzylamine and trimethylsilyl cyanide
provided -amino nitrile 5b stereoselectively (syn–anti, 2:1). Ami-
dation of 5b and subsequent cyclization gave bicyclic compound 6,
which, upon reduction with zinc dust, hydrolysis and subsequent
cyclization, furnished thiolactone 2, a key intermediate for (+)-bi-
otin (1).
Keywords: amino acids, amino aldehydes, ring closure, stereo-
selectivity, vitamins, biotin, Strecker reaction
Much attention has recently been paid to (+)-biotin (1) be-
cause of the useful biological properties for human nutri-
tion and animal health.1 Industrial production of 1 has,
however, been carried out by the total synthetic method
Scheme 1
due to lack of efficient alternatives such as those based on
fermentation. Among a number of synthetic approaches to
stereoselectively by Strecker reaction of -amino alde-
hyde 4 that can be readily prepared from L-cysteine (3).
1,2 a method utilizing thiolactone 2 as a key intermediate
is considered to be most attractive.3 Although extensive
research has been directed toward an efficient synthetic Protection of the amino and thiol groups of 3 as an N,S-
method for 2,4,5 there’s still much room for developing a benzylidene acetal followed by reduction to -amino alco-
more practical one. We report herein a facile synthesis of hol 8 was conducted according to our reported procedure
2 through the Strecker reaction of (2R,4R)-2-phenyl-3- (Scheme 2).6 Although compound 8 consists of a mixture
phenoxycarbonylthiazolidine-4-carbaldehyde (4b) that of diastereomers, N-methoxy- (or N-phenoxy-) carbonyl-
can be readily prepared from L-cysteine (3) (Figure 1).
ation of 8 proceeded with isomerization to give carbam-
ates 9a,b both as a single diastereomer in high yields. The
oxidation of 9a,b was best conducted by the treatment
with sulfur trioxide–pyridine complex (SO3–py) in
DMSO7 to afford 4a,b in high yields. It should be noted
that N-phenoxycarbonyl derivative 4b is easy to crystal-
lize and so can be isolated as stable solids without purifi-
cation by silica gel column chromatography.
O
O
O
H2N
BnN
NBn
HN
NH
OH
SH
O
S
S
CO2H
3
2
1
With the -amino aldehydes 4a,b in hand, the Strecker re-
action of 4a,b was investigated. Treatment of 4a with ben-
zylamine in the presence of molecular sieves (MS, 4 Å) in
dichloromethane effected imine formation and, upon ad-
Figure 1
We envisioned a synthetic scheme as outlined in
Scheme 1. The target compound 2 was planned to be syn-
thesized from a known carboxylic acid 7.5 Compound 7
can be obtained via reductive cleavage of the carbon–sul-
fur bond of bicyclic amide 6 whose carboxylic acid con-
gener is an intermediate of the Merck’s approach.5
Compound 6 would be expected to be derived from syn-
-amino nitrile syn-5 through amidation and subsequent
cyclization. The compound syn-5 should be prepared
dition of trimethylsilyl cyanide (TMSCN), furnished
-
amino nitrile 5a in 84% yield with moderate selectivity
(syn–anti, 2:1). The same level of stereocontrol was ob-
served when N-phenoxycarbonyl derivative 4b was em-
ployed as the substrate. The structure of the major isomer
syn-5a was fully substantiated by a single crystal X-ray
analysis of the corresponding hydrochloride salt
(Figure 2).8 The stereochemical outcome for the Strecker
reaction may be rationalized by the reaction pathway de-
picted in Scheme 3. A preferred conformation of in situ
generated imine 10 may be the one in which the bulky car-
bamate group directs toward cis to the hydrogen atom on
SYNTHESIS 2003, No. 15, pp 2311–2316
Advanced online publication: 29.09.2003
DOI: 10.1055/s-2003-42399; Art ID: F05203SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
3

2312
Y. Mori et al.
PAPER
-
OR
SiMe3
H
O
O
NC
H
Ph
S
N
S
+
Ph
N
OR
BnNH2
N
H
TMSCN
CHO
Ph
Si Face Attack
10
4
O
Ph
OR
N
H
N
S
Ph
CN
syn-5
Scheme 3
Scheme 2 Reagents and methods: (a) PhCHO, H2O, EtOH, 96%;
(b) (i) SOCl2, EtOH (ii) Ca(BH4)2, EtOH, quant.; (c) ClCO2R,
Na2CO3, THF, H2O, 9a 88%, 9b 86%; (d) SO3–py, Et3N, DMSO, 4a
91%, 4b 92%; (e) (i) BnNH2, CH2Cl2, MS (4 Å) (ii) TMSCN, 5a 84%,
5b quant.
amide 12a because of the poor solubility of the hydrochlo-
ride or sulfate salt of 5a. Katritzky’s protocol11 using hy-
drogen peroxide and a catalytic amount of potassium
carbonate in DMSO was eventually found to effect the
amidation of 5a and 5b to give 12a and 12b in 65% and
60% yield, respectively. In the case of N-phenoxycarbon-
yl derivative 12b, the product was obtained almost exclu-
sively as the syn-isomer. No bicyclic compound 11 or 6
was found in the reaction mixture, which may be the result
of selective decomposition of anti-5b through a retro-
Strecker reaction. The anti-isomer anti-5b might more
readily adopt the sterically least cumbered antiperiplanar
conformation than the syn-isomer syn-5b due to much less
steric hindrance between the cyano group and the thiazo-
lidine moiety (Figure 3). This may permit much easier
deprotonation of the amino hydrogen of anti-5b than that
of syn-5b resulting in the preferential retro Strecker reac-
tion of anti-5b. Cyclization of 12a to bicyclic compound
6 was then examined. Only a trace of 6 was, however,
found in the reaction mixture even after prolonged heating
of 12a in DMF (150 °C for 8 h). Compound 12b carrying
a more reactive phenoxycarbonyl group was then tested
and, upon heating at 100 °C for 2 hours in DMF, facile cy-
clization was found to take place to give 6 in 60% yield.
In considering the structure of the Merck’s intermedi-
ate,5,13 the structure of 6 was assigned as the one whose C-
2 position carrying a phenyl group had been epimerized
during the cyclization to direct toward the convex face.
Compound 6 was treated with zinc dust in acetic acid to
effect the reductive cleavage5 of the carbon–sulfur bond.
After filtration of the reaction mixture to remove excess
zinc dust, the filtrate containing thiol amide was directly
treated with hydrochloric acid (110 °C, 2 h) to give car-
boxylic acid 7 in high yield (87%, two steps). Conversion
the -methine carbon of the imino group.9 Trimethylsilyl
cyanide should then attack intramolecularly the si face of
10 by means of activation through coordination of the imi-
no group to the hypervalent silicon atom.10 This may re-
sult in the preferential formation of the syn-isomer over
the anti counterpart.
Figure 2 ORTEP II diagram of syn-5a hydrochloride.
All attempts (heating with or without base such as NaH, of 7 to the target compound 2 was conducted by modifica-
K2CO3, DBU) to effect cyclization of -amino nitriles tion of the reported procedure5 (DCC, p-TsOH, pyridine,
5a,b to bicyclic compound 11 failed, possibly due to such r.t.). The use of toluene as a co-solvent and initial reaction
side reactions as those initiated by retro-Strecker reaction
(Scheme 4). The compounds 5a,b were thus converted to
at 25 °C followed by elevating the reaction temperature to
62 °C were found to considerably improve the yield (57%
amides 12a,b before the ring closure (Scheme 5). Treat- to 75%). Compound 2 obtained by the present synthesis
ment of 5a with concentrated HCl or H2SO4 did not give was fully characterized by comparison of the specific ro-
Synthesis 2003, No. 15, 2311–2316 © Thieme Stuttgart · New York

PAPER
Synthesis of a Key Intermediate for (+)-Biotin via Strecker Reaction
2313
tation, IR, MS and 1H NMR spectra with those of an au-
thentic sample.3c
TLC was carried out on E. Merck 0.25 mm precoated glass-backed
plates (60 F254). Development was accomplished using phosphomo-
lybdic acid (5%) in EtOH (heat) or visualized by UV light where
feasible. All solvents and reagents were used as received.
O
Ph
Bn
(2R,4R)-4-Hydroxymethyl-2-phenylthiazolidine-3-carboxylic
Acid Methyl Ester (9a)
N
N
5a, b
S
To a solution of 86 (19.5 g, 0.10 mol) in a mixed solvent of THF
(195 mL) and H2O (98 mL) were successively added methyl chlo-
roformate (10.4 g, 0.11 mol) and Na2CO3 (6.41 g, 0.060 mol) below
10 °C. The mixture was stirred at 10 °C for 30 min and extracted
with CH2Cl2. The extracts were washed with H2O and sat. aq NaCl,
dried (MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (hexane–EtOAc, 3:1) and the fractions
collected were evaporated and crystallized by adding hexane to give
9a.
CN
11
Scheme 4
O
O
Ph
Ph
OR
NHBn
OR
NHBn
CONH2
g
N
f
N
Yield: 22.3 g (88%); colorless crystals; mp 90–91 °C; [ ]D20 +146.4
(c 1.0, MeOH).
IR (KBr): 3414, 1682 cm–1.
1H NMR (CDCl3): = 7.40–7.22 (m, 5 H), 6.13 (s, 1 H), 4.60–4.51
(m, 1 H), 3.92–3.68 (m, 3 H), 3.65 (s, 3 H), 3.22 (dd, J = 12, 6.6 Hz,
1 H), 2.95 (br, 1 H).
S
S
CN
5a: R= Me
5b: R= Ph
12a: R= Me
12b: R= Ph
O
O
13C NMR (CDCl3): = 140.8 (s), 128.5, 127.7, 126.1, 66.2, 64.5 (5
d), 63.2 (t), 53.1 (q), 33.0 (t).
SIMS: m/z = 254 (M+ + 1).
Ph
Bn
Bn
Bn
N
N
h
i
N
N
2
S
CO2H
CONH2
Anal. Calcd for C12H15NO3S: C, 56.90; H, 5.97; N, 5.53; S, 12.66.
Found: C, 56.91; H, 6.03; N, 5.51; S, 12.83.
SH
6
7
(2R,4R)-4-Hydroxymethyl-2-phenylthiazolidine-3-carboxylic
Acid Phenyl Ester (9b)
Scheme 5 Reagents and conditions: (f) H2O2, K2CO3, DMSO, 12a
65%, 12b 60%; (g) DMF, 100 °C, 2 h, 60%; (h) (i) Zn, AcOH, 100 °C
(ii) HCl, H2O, AcOH, 110 °C, 87%; (i) DCC, p-TsOH, pyridine, to-
luene, 75%.
To a solution of 86 (1.95 g, 0.010 mol) in a mixed solvent of THF
(20 mL) and H2O (10 mL) were successively added phenyl chloro-
formate (1.72 g, 0.011 mol) and Na2CO3 (0.64 g, 0.006 mol) below
10 °C. The mixture was stirred at 10 °C for 30 min and extracted
with CH2Cl2. The extracts were washed with H2O and sat. aq NaCl,
dried (MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (hexane–EtOAc, 3:1) and the fractions
collected were evaporated and crystallized by adding hexane to give
9b.
S
S
Ph
Ph
H
NC
N
NHBn
N
NHBn
PhO
PhO
NC
H
O
O
syn-5b
anti-5b
Yield: 2.71
g (86%); colorless crystals; mp 130–131 °C;
[ ]D20 +116.7 (c 1.0, MeOH).
Figure 3
IR (KBr): 3448, 1703 cm–1.
1H NMR (CDCl3): = 7.51–7.42 (m, 2 H), 7.42–6.73 (m, 8 H), 6.28
(s, 1 H), 4.67 (br, 1 H), 4.08–3.88 (m, 2 H), 3.38–3.29 (m, 1 H), 3.06
(br, 1 H), 3.01 (br, 1 H).
13C NMR (CDCl3): = 150.6, 140.6 (2 s), 129.3, 128.6, 128.1,
126.3, 125.8, 121.4, 66.4, 65.0 (8 d), 64.3, 32.8 (2 t).
In conclusion, a facile synthesis of the (+)-biotin key in-
termediate 2 from L-cysteine 3 was accomplished. The
compound 2 was synthesized in 9 steps and 18% overall
yield from readily accessible 3. As the compound 2 can be
converted to (+)-biotin (1) in 3 steps using our reported
procedure,12 (+)-biotin (1) is now accessible in 12 steps SIMS: m/z = 316 (M+ + 1).
from 3. While the present synthesis utilizes the same or
similar intermediates (6 and 7) as those of the Merck’s ap-
proach,5 it is advantageous in terms of ease of operation
and use of readily accessible reagents.13 Further improve-
ments for a more practical synthesis of 2 are currently un-
der investigation and will be reported elsewhere in due
course.
Anal. Calcd for C17H17NO3S: C, 64.74; H, 5.43; N, 4.44; S, 10.22.
Found: C, 64.69; H, 5.39; N, 4.41; S, 10.22.
(2R,4R)-4-Formyl-2-phenylthiazolidine-3-carboxylic Acid Me-
thyl Ester (4a)
To a solution of 9a (2.53 g, 0.010 mol) in DMSO (30 mL) were add-
ed Et3N (3.04 g, 0.030 mol) at 25 °C, followed by SO3–pyridine
(4.77 g, 0.030 mol) at 5 °C, and the mixture was stirred at the same
temperature for 10 min and at 25 °C for 30 min. The mixture was
poured into ice–H2O, and extracted with EtOAc. The organic layer
was washed with aq citric acid (10%) and H2O, dried (MgSO4), and
concentrated at reduced pressure to give 4a. The crude product 4a
was used for the next step without further purification.
Mps are uncorrected. 1H and 13C NMR spectra (400 and 100 MHz,
respectively) were recorded with tetramethylsilane used as an inter-
nal standard. Optical rotations were measured at the indicated tem-
perature with a sodium lamp (D line, 589 nm). Silica gel column
chromatography was performed using Kieselgel 60 (E. Merck).
Yield: 2.29 g (91%); viscous oil.
Synthesis 2003, No. 15, 2311–2316 © Thieme Stuttgart · New York

2314
Y. Mori et al.
PAPER
(2R,4R)-4-Formyl-2-phenylthiazolidine-3-carboxylic Acid Phe-
nyl Ester (4b)
1H NMR (CDCl3): = 7.42–7.23 (m, 10 H), 6.14 (s, 1 H), 4.73 (br,
1 H), 4.08 (d, J = 13 Hz, 1 H), 3.94–3.85 (m, 1 H), 3.84 (dd, J = 13,
5.8 Hz, 1 H), 3.71 (br s, 3 H), 3.29 (d, J = 12 Hz, 1 H), 3.21 (dd,
J = 12, 5.9 Hz, 1 H), 1.76 (br, 1 H).
13C NMR (CDCl3): = 137.9 (s), 128.6, 128.4, 128.2, 127.8, 126.1
(5 d), 118.8 (s), 53.5 (q), 53.2 (d), 51.7, 33.3 (2 t).
SIMS: m/z = 368 (M+ + 1).
HRMS: m/z calcd for C20H22N3O2S (M + H)+: 368.1433; found:
To a solution of 9b (30.0 g, 0.095 mol) in DMSO (300 mL) were
added Et3N (28.9 g, 0.286 mol) at 25 °C, followed by SO3–pyridine
(45.3 g, 0.285 mol) at 5 °C, and the mixture was stirred at the same
temperature for 10 min and at 25 °C for 30 min. The mixture was
poured into ice–H2O and extracted with EtOAc. The organic layer
was washed with aq citric acid (10%) and H2O, dried (MgSO4), and
evaporated. To the residue was added hexane and the solids formed
were collected to give 4b.
368.1452.
Yield: 27.5
g (92%); colorless crystals; mp 101–102 °C;
[ ]D20 +148.8 (c 1.0, MeOH).
Strecker Reaction of 4b
To a solution of 4b (9.9 g, 0.032 mol) in CH2Cl2 (100 mL) were suc-
cessively added MS (4 Å; 10.0 g) and benzylamine (3.4 g, 0.032
mol), and the mixture was stirred at 25 °C for 4.5 h. To the mixture
was added TMSCN (6.3 g, 0.064 mol) at 5 °C and it was stirred at
25 °C for 20 h. The mixture was filtered and the filtrate was evapo-
rated. The residue was purified by silica gel column chromatogra-
phy (hexane–CHCl3–EtOAc, 10:10:1) to give syn-5b and anti-5b
(13.6 g, quant; syn–anti, 2:1), both as a viscous oil.
IR (KBr): 1741, 1715 cm–1.
1H NMR (CDCl3): = 9.85 (s, 1 H), 7.58–7.43 (m, 2 H), 7.43–6.80
(m, 8 H), 6.31 (s, 1 H), 4.98 (br, 1 H), 3.46–3.26 (m, 2 H).
13C NMR (CDCl3): = 197.8 (d), 150.6, 140.0 (2 s), 129.3, 128.7,
128.5, 126.8, 125.9, 121.3, 70.1, 66.3 (8 d), 30.2 (t).
SIMS: m/z = 314 (M+ + 1).
Anal. Calcd for C17H15NO3S: C, 65.16; H, 4.82; N, 4.47; S, 10.23.
Found: C, 64.89; H, 4.82; N, 4.45; S, 10.27.
(R)-Benzylamino-2-[(2R,4R)-3-phenoxycarbonyl-2-phenylthia-
zolidin-4-yl]acetonitrile (syn-5b)
Strecker Reaction of 4a
[ ]D23 +137.3 (c 0.1, MeOH).
To a solution of 4a (1.00 g, 4.0 mmol) in CH2Cl2 (10 mL) were suc-
cessively added MS (4 Å; 1.0 g) and benzylamine (0.43 g, 4.0
mmol), and the mixture was stirred at 25 °C for 4.5 h. To the mix-
ture was added TMSCN (0.47 g, 4.8 mmol) at 25 °C and it was
stirred at 25 °C for 20 h. The mixture was filtered and the filtrate
was evaporated. The residue was purified by silica gel column chro-
matography (hexane–EtOAc, 6:1) to give syn-5a and anti- 5a (1.23
g, 84%; syn–anti, 2:1) both as a viscous oil.
IR (KBr): 3325, 2227, 1715 cm–1.
1H NMR (CDCl3): = 7.47 (d, J = 6.3 Hz, 2 H), 7.43–7.06 (m, 11
H), 6.85 (d, J = 7.3 Hz, 2 H), 6.30 (s, 1 H), 5.04–4.93 (m, 1 H),
4.21–4.04 (m, 2 H), 3.89–3.76 (m, 1 H), 3.54–3.41 (m, 1 H), 3.25–
3.06 (m, 1 H), 2.23 (br, 1 H).
13C NMR (CDCl3): = 150.6, 138.0 (2 s), 129.3, 128.6, 128.5,
128.2, 127.7, 125.9, 121.3 (7 d), 118.4 (s), 66.6, 63.5, 54.1 (3 d),
51.8, 33.9 (2 t).
(R)-Benzylamino-2-[(2R,4R)-3-methoxycarbonyl-2-phenylthia-
zolidin-4-yl]acetonitrile (syn-5a)
SIMS: m/z = 430 (M+ + 1).
HRMS: m/z calcd for C25H24N3O2S (M + H)+: 430.1590; found:
IR (KBr): 3327, 2215, 1697 cm–1.
430.1598.
1H NMR (CDCl3): = 7.43–7.22 (m, 10 H), 6.17 (s, 1 H), 4.88 (br,
1 H), 4.13 (d, J = 13 Hz, 1 H), 4.02 (br, 1 H), 3.82 (d, J = 13 Hz, 1
H), 3.64 (s, 3 H), 3.36 (dd, J = 12, 6.3 Hz, 1 H), 3.12 (d, J = 12 Hz,
1 H), 2.04 (br, 1 H).
13C NMR (CDCl3): = 140.1, 138.0 (2 s), 128.5, 128.0, 127.6, 125.8
(4 d), 118.5 (s), 66.5, 63.3, 53.8 (3 d), 53.4 (q), 51.8, 34.1 (2 t).
(S)-Benzylamino-2-[(2R,4R)-4-phenoxycarbonyl-2-phenylthia-
zolidin-4-yl]acetonitrile (anti-5b)
[ ]D22 +33.0 (c 0.1, MeOH).
IR (KBr): 3319, 2230, 1718 cm–1.
1H NMR (CDCl3): = 7.47 (br, 2 H), 7.38–6.81 (m, 13 H), 6.24 (br
s, 1H), 4.85–4.80 (m, 1 H), 4.11 (d, J = 13 Hz, 1 H), 4.06 (br, 1 H),
3.88 (d, J = 13 Hz, 1 H), 3.33 (br, 2 H), 1.84 (br, 1 H).
13C NMR (CDCl3): = 150.7, 137.8 (2 s), 129.3, 128.7, 128.4,
127.8, 126.3, 125.8 (6 d), 53.3 (d), 51.7 (t).
SIMS: m/z = 368 (M+ + 1).
(R)-Benzylamino-2-[(2R,4R)-3-methoxycarbonyl-2-phenylthia-
zolidin-4-yl]acetonitrile Hydrochloride (syn-5a·HCl)
Mp 167 °C; [ ]D20 +68.4 (c 0.5, MeOH).
IR (KBr): 1712, 1570 cm–1.
SIMS: m/z = 430 (M+ + 1).
1H NMR (DMSO-d6): = 7.60 (d, J = 7.1 Hz, 2 H), 7.49–7.22 (m,
8 H), 6.08 (s, 1 H), 4.92–4.84 (m, 1 H), 4.74 (br, 1 H), 4.31 (d,
J = 13 Hz, 1 H), 4.17 (d, J = 13 Hz, 1 H), 3.59–3.49 (m, 1 H), 3.53
(s, 3 H), 3.43–3.35 (m, 1 H).
HRMS: m/z calcd for C25H24N3O2S (M + H)+: 430.1590; found:
430.1575.
2-Benzylamino-2-[(2R,4R)-3-methoxycarbonyl-2-phenylthiazo-
lidin-4-yl]acetamide (12a)
13C NMR (DMSO-d6): = 139.7 (s), 129.6, 128.5, 128.0, 127.6,
To a solution of 5a (7.74 g, 0.021 mol) in DMSO (45 mL) were suc-
cessively added K2CO3 (1.2 g, 0.0085 mol) and aq H2O2 (30%; 3.6
mL, 0.032 mol) at 10 °C. After the mixture was stirred at 25 °C for
17 h, H2O (154 mL) was added, and the mixture was extracted with
CHCl3–MeOH (10:1). The extracts were washed with H2O, dried
(MgSO4), and evaporated. The residue was purified by silica gel
column chromatography (hexane–EtOAc, 2:1, to CHCl3–
MeOH, 20:1) to give 12a.
126.4, 66.3, 61.8 (7 d), 53.0 (q), 51.0 (d), 50.2, 32.2 (2 t).
SIMS: m/z = 368 (M+ + 1).
Anal. Calcd for C20H22N3O2SCl: C, 59.47; H, 5.49; N, 10.40.
Found: C, 59.43; H, 5.50; N, 10.29.
(S)-Benzylamino-2-[(2R,4R)-3-methoxycarbonyl-2-phenylthia-
zolidin-4-yl]acetonitrile (anti-5a)
[ ] D22 +5.0 (c 0.1, MeOH).
Yield: 5.26 g (65%); syn–anti, 2:1; viscous oil.
IR (KBr): 3322, 3188, 1668 cm–1.
IR (KBr): 3316, 2232, 1701 cm–1.
Synthesis 2003, No. 15, 2311–2316 © Thieme Stuttgart · New York

PAPER
Synthesis of a Key Intermediate for (+)-Biotin via Strecker Reaction
2315
1H NMR (CDCl3): = 7.43 (br, 1 H), 7.36–7.12 (m, 10 H), 6.24 (s,
1 H), 6.16 (br, 1 H), 4.75–4.68 (m, 1 H), 3.71–3.63 (m, 1 H), 3.67
(s, 3 H), 3.45–3.32 (m, 3 H), 3.15 (dd, J = 12, 6.3 Hz, 1 H).
SIMS: m/z = 386 (M+ + 1).
HRMS: m/z calcd for C20H23N3O3S (M+): 385.1461; found:
IR (KBr): 1735, 1625 cm–1.
1H NMR (DMSO-d6): = 13.19 (br, 1 H), 7.37–7.22 (m, 10 H), 4.82
(d, J = 15 Hz, 1 H), 4.64 (d, J = 15 Hz, 1 H), 4.13 (d, J = 15 Hz, 1
H), 4.05 (d, J = 15 Hz, 1 H), 3.81 (d, J = 5.3 Hz, 1 H), 3.63–3.55 (m,
1 H), 2.76–2.64 (m, 2 H), 2.15–2.11 (m, 1 H).
385.1451.
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.
(R)-2-Benzylamino-2-[(2R,4R)-3-phenoxycarbonyl-2-phenyl-
thiazolidin-4-yl]acetamide (12b)
To a solution of 5b (1.00 g, 2.3 mmol) in DMSO (5 mL) were suc-
cessively added K2CO3 (0.13 g, 0.94 mmol) and aq H2O2 (30%; 0.4
mL, 3.5 mmol) at 10 °C. After the mixture was stirred at 25 °C for
17 h, H2O (20 mL) was added, and the mixture was extracted with
a mixed solvent of CHCl3 and MeOH (CHCl3–MeOH, 10:1). The
extracts were washed with H2O, dried (MgSO4), and evaporated.
The residue was purified by silica gel column chromatography
(hexane–EtOAc, 2:1, to CHCl3–MeOH, 20:1) to give 12b.
(4S,5R)-1,3-Dibenzyl-2-oxoimidazo[4,5-c]tetrahydrothiophene-
2-one (2)
To a solution of 7 (0.10 g, 0.28 mmol) and pyridine (0.2 mL) in tol-
uene (0.1 mL) were added p-TsOH·H2O (3.2 mg, 0.017 mmol) and
DCC (0.070 g, 0.34 mmol), and the mixture was stirred at 25 °C for
1 h and at 62 °C for 19 h. The mixture was cooled to 25 °C, diluted
with EtOAc, and filtered. The filtrate was washed successively with
aq HCl (1 M) and H2O, dried (MgSO4) and concentrated at reduced
pressure. The residue was purified by silica gel chromatography
(hexane–EtOAc, 2:1) and the fractions collected were evaporated
and crystallized by adding hexane to give 2.
Yield: 0.63 g (60%); viscous oil.
IR (KBr): 3318, 3191, 1708, 1675 cm–1.
1H NMR (CDCl3): = 7.49 (br, 1 H), 7.37–6.95 (m, 13 H), 6.90 (d,
J = 7.8 Hz, 2 H), 6.35 (s, 1 H), 5.67 (br, 1 H), 4.82 (br, 1 H), 3.77
(d, J = 13 Hz, 1 H), 3.67–3.47 (m, 2 H), 3.42 (d, J = 12 Hz, 1 H),
3.30 (dd, J = 12, 6.2 Hz, 1 H).
Yield: 0.071 g (75%); colorless crystals; mp 122–123 °C (lit.3c 125–
127 °C); [ ]D20 +90.5 (c 1.0, CHCl3) {lit.3c +91.3 0.9 (c 1.0,
CHCl3)}.
IR (KBr): 1697, 1686 cm–1.
SIMS: m/z = 448 (M+ + 1).
HRMS: m/z calcd for C25H25N3O3S (M+): 447.1617; found:
1H NMR (CDCl3): = 7.39–7.25 (m, 10 H), 5.04 (d, J = 15 Hz, 1
H), 4.69 (d, J = 15 Hz, 1 H), 4.37 (d, J = 15 Hz, 1 H), 4.36 (d, J = 15
Hz, 1 H), 4.16–4.09 (m, 1 H), 3.81 (d, J = 7.8 Hz, 1 H), 3.38 (dd,
J = 13, 5.6 Hz, 1 H), 3.29 (dd, J = 13, 2.2 Hz, 1 H).
447.1632.
(1R,2S,4R)-3-Benzyl-4-carbamoyl-2-oxo-2-phenylimidazo[1,5-
c]thiazolidine (6)
SIMS: m/z = 339 (M+ + 1).
A solution of 12b (0.10g, 0.22 mmol) in DMF (1 mL) was stirred at
100 °C for 2 h. After cooling the mixture to 25 °C, H2O was added,
and the mixture was extracted with EtOAc, washed with H2O, dried
(MgSO4), and evaporated. To the residue was added EtOAc to give
6.
Acknowledgment
The authors are indebted to Mr. Hajime Hiramatsu, Tanabe Seiyaku
Co., Ltd., for the X-ray crystallographic analysis.
Yield: 0.047 g (60%); colorless crystals; mp 200 °C; [ ]D20 –101.2
(c 1.0, DMF).
IR (KBr): 3366, 3203, 1699, 1678 cm–1.
References
1H NMR (DMSO-d6): = 7.72 (br, 1 H), 7.45–7.26 (m, 9 H), 7.16
(d, J = 7.1 Hz, 2 H), 5.74 (s, 1 H), 4.62 (d, J = 15 Hz, 1 H), 4.13–
4.05 (m, 1 H), 3.85 (d, J = 4.8 Hz, 1 H), 3.76 (d, J = 15 Hz, 1 H),
3.32–3.23 (m, 1 H), 2.92 (dd, J = 11, 9.1 Hz, 1 H).
13C NMR (CDCl3): = 170.5, 156.8, 137.9, 136.9 (4 s), 129.6,
128.8, 128.2, 128.0, 127.8, 126.1, 65.4, 65.1, 60.3, (9 d), 45.7, 35.0
(2 t).
(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) For a review, see: De Clercq, P. J. Chem. Rev. 1997, 97,
1755.
(3) (a) Goldberg, M. W.; Sternbach, L. H. US Patent 2489232,
1949; Chem. Abstr. 1951, 45, 184b. (b) Goldberg, M. W.;
Sternbach, L. H. US Patent 248923, 1949; Chem. Abstr.
1951, 45, 186a. (c) Gerecke, M.; Zimmermann, J.-P.;
Ashwanden, W. Helv. Chim. Acta 1970, 53, 991.
(4) For example, see: (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.
(c) Matsuki, K.; Inoue, H.; Takeda, M. Tetrahedron Lett.
1993, 34, 1167. (d) Chen, F. E.; Huang, Y.-D.; Fu, H.;
Cheng, Y.; Zhang, D.-M.; Li, Y.-Y.; Peng, Z.-Z. Synthesis
2000, 2004. (e) Choi, C.; Tian, S.-K.; Deng, L. Synthesis
2001, 1737. (f) Seki, M.; Shimizu, T.; Inubushi, K. Synthesis
2002, 361.
SIMS: m/z = 354 (M+ + 1).
Anal. Calcd for C19H19N3O2S: C, 64.57; H, 5.42; N, 11.89; S, 9.07.
Found: C, 64.48; H, 5.40; N, 11.88; S, 9.08.
(4R,5R)-1,3-Dibenzyl-5-(mercaptomethyl)imidazolidin-2-one-
4-carboxylic Acid (7)
A mixture of 6 (0.50 g, 1.4 mmol), zinc dust (0.93 g, 14 mmol) and
HOAc (5 mL) was stirred at 100 °C for 2 h. After cooling the mix-
ture to 25 °C, it was filtered and undissolved materials were washed
with EtOAc. The fitrate was evaporated, and to the residue were
added HOAc (1 mL), concd HCl (2.5 mL) and H2O (2.5 mL). The
mixture was stirred at 110 °C for 2 h, and it was cooled to 25 °C.
The crystals formed were collected, washed with hexane and dried
at reduced pressure to give 7.
(5) Poetsch, E.; Casutt, M. Chimia 1987, 41, 148.
(6) (a) Seki, M.; Hatsuda, M.; Mori, Y.; Yamada, S.
Tetrahedron Lett. 2002, 43, 3269. (b) Seki, M.; Mori, Y.;
Hatsuda, M.; Yamada, S. J. Org. Chem. 2002, 67, 5527.
Yield: 0.44
g (87%); colorless crystals; mp 159–160 °C;
[ ]D20 +48.8 (c 0.62, DMF).
Synthesis 2003, No. 15, 2311–2316 © Thieme Stuttgart · New York

2316
Y. Mori et al.
PAPER
(7) (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.
(8) The X-ray data of syn-5a have been deposited at the
Cambridge Crystallographic Data Centre.
(13) Poetsch and Casutt of the Merck Laboratories synthesized
the bicyclic intermediate 14 through reduction of a carbonyl
group of bicyclic hydantoin 13 derived from L-cysteine
followed by formation of the corresponding imidazolide,
cyanation and hydrolysis (Scheme 6).5
(9) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem. Int.
Ed. Engl. 1996, 35, 2708.
(10) Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem. Lett.
1991, 537.
(11) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989,
949.
(12) (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.
(d) Mori, Y.; Seki, M. Heterocycles 2002, 58, 125.
O
O
Ph
Ph
Bn
Bn
N
N
N
N
2
L-Cysteine
S
S
O
CO2H
13
14
Scheme 6
Although the approach can provide 2 in 9 steps, it requires
expensive or hazardous reagents such as BnNCO and CDI.
Synthesis 2003, No. 15, 2311–2316 © Thieme Stuttgart · New York