An improved asymmetric total synthesis of (+)-biotin via the enantioselective desymmetrization of a meso-cyclic anhydride mediated by cinchona alkaloid-based sulfonamide

Article abstract of DOI:10.1016/j.tetasy.2010.03.041

The highly enantioselective total synthesis of (+)-biotin 1 via the Hoffmann-Roche lactone-thiolactone strategy has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 with an overall yield of 35%. Two contiguous stereogenic centers at C-3a and C-6a were established through a rapid cinchona alkaloid-based sulfonamide-mediated enantioselective alcoholysis of meso-cyclic anhydride 3 to afford (4S,5R)-cinnamyl hemiester 4h, the direct precursor to (3aS,6aR)-lactone 5 with high enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuyama coupling reaction of (3aS,6aR)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-bromopentanoate.

Full text of DOI:10.1016/j.tetasy.2010.03.041

Tetrahedron: Asymmetry 21 (2010) 665–669
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Tetrahedron: Asymmetry
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An improved asymmetric total synthesis of (+)-biotin via the enantioselective
desymmetrization of a meso-cyclic anhydride mediated by cinchona
alkaloid-based sulfonamide
Fei Xiong a,b, Xu-Xiang Chen a, Fen-Er Chen a,b,
*
a Fudan-DSM Joint Laboratory for Synthetic Method and Chiral Technology, Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China
b Institutes of Biomedical Sciences, Fudan University, Shanghai 200031, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
The highly enantioselective total synthesis of (+)-biotin 1 via the Hoffmann–Roche lactone–thiolactone
strategy has been achieved starting from cis-1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid 2 with
an overall yield of 35%. Two contiguous stereogenic centers at C-3a and C-6a were established through
a rapid cinchona alkaloid-based sulfonamide-mediated enantioselective alcoholysis of meso-cyclic anhy-
dride 3 to afford (4S,5R)-cinnamyl hemiester 4h, the direct precursor to (3aS,6aR)-lactone 5 with high
enantioselectivity. A one-pot installation of the 4-carboxybutyl side chain was accomplished by a Fukuy-
ama coupling reaction of (3aS,6aR)-thiolactone 6 with the organozinc reagent prepared from ethyl 5-
bromopentanoate.
Received 2 February 2010
Accepted 26 March 2010
Available online 4 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
(O-propargylquinine)3c as catalysts have been realized in our labo-
ratory, but some limitations (low temperature, long reaction time)
It is well known that the preparation of (3aS,6aR)-lactone 5 from
meso-cyclic acid 2 or its anhydride 3 is the most important step in
the development of the commercial asymmetric total synthesis of
(+)-biotin 1 via the Roche lactone–thiolactone strategy developed
by Goldberg and Sternbach at the F. Hoffmann–La Roche company
in 1949.1 Not surprisingly, a considerable amount of effort devoted
to this transformation in this process has led to tremendous
achievements in the asymmetric desymmetrizations of 2 or 3 by uti-
lizing different chiral techniques.2 However, the chiral Lewis base-
catalyzed enantioselective alcoholysis of 3 has been proven to be
a robust and valid method for the preparation of the chiral
(4S,5R)-hemiester or (4R,5S)-hemiester, the direct precursor to 5
in recent years.3 The first organocatalytic approach toward this
key intermediate 5 described by Deng’s group3a in 2001 involved
the bis-cinchona alkaloid-catalyzed enantioselective methanolysis
of 3 and NaBH4-mediated chemoselective reduction of the carboxyl
group of (4R,5S)-hemiester after derivation with stoichiometric
cyanuric chloride and N-methylmorpholine. The difficulties of scal-
ing up 5 are well known in chemical process development due to the
use of the expensive DHQD-PHN catalyst with relatively high
molecular weight and the need for maintaining the cryogenic tem-
perature (ꢀ40 °C) for 28 h in terms of the high enantioselectivity
and yield. Two highly enantioselective conversions of 3 into the
desired 4 using commercially available quinine3b and its derivative
of Deng’s approach have not been overcome. Our continued syn-
thetic improvements for 4 have been carried out through desym-
metrization of 3 catalyzed by the bifunctional thiourea-based
catalysts derived from cinchona alkaloid and readily available
(1S,2S)-2-amino-1-(p-nitrophenyl)propane-1,3-diol.3d
Although
these two catalysts demonstrated excellent enantioselectivities
and yields at room temperature, they suffer from self-aggregation,
which results in low reactivity and strong dependence of the enanti-
oselectivity on the reaction concentration and temperature as Song
et al. have pointed out.4 Thus, the development of new versions of
catalytic alcoholysis of 3 for the preparation of 4 to complete com-
mercial asymmetric total synthesis of 1 is still in high demand.
Very recently, Song et al.5 reported that various enantiopure
hemiesters could be efficiently prepared in excellent yields and
enantiomeric purities via the bifunctional cinchona alkaloid-based
sulfonamide-mediated alcoholysis of the corresponding meso-
cyclic anhydrides without requiring extended reaction time at
room temperature. This chiral technology offers a distinct advan-
tage over the two most useful catalytic protocols for meso-cyclic
anhydride desymmetrization with cinchona alkaloid derivatives
as the general base catalysts developed by the groups led by
Bolm6 and Deng3a as well as recently reported bifunctional thio-
urea-based catalytic systems of Song himself and Connon’s
group7 with respect to reaction rate, temperature, or/and concen-
tration. Therefore, the promising work of Song’s group came to
our specific attention due to the parallels with our ongoing
research concerning the asymmetric total synthesis of (+)-biotin
* Corresponding author. Tel./fax: +86 21 6564 3811.
E-mail address: rfchen@fudan.edu.cn (F.-E. Chen).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.041

666
F. Xiong et al. / Tetrahedron: Asymmetry 21 (2010) 665–669
5-dicarboxylic acid 2 (Scheme 1), which was subjected to dehydra-
O
O
O
tion in refluxing toluene with azeotropic removal of water to afford
meso-cyclic anhydride 3 in almost quantitative yield and with 99%
chemical purity.
BnN
H
HO2C
NBn
H
CO2H
BnN
H
NBn
H
BnN
H
ROOC
NBn
H
CO2H
a
b
c
O
O
O
With the prochiral cyclic anhydride 3 in hand, we were now in
a position to study its desymmetrization into (4S,5R)-hemiester 4
to accomplish the asymmetric total synthesis of 1. At the outset,
we selected Song’s protocol as being capable of facilitating the
asymmetric methanolysis of various meso-cyclic anhydrides med-
iated by cinchona alkaloid-based sulfonamide 10.5 However, under
these conditions, the asymmetric desymmetrization of 3 using
methanol as the test nucleophile in MTBE with 0.1 equiv of Song’s
catalyst 10 at ambient temperature affords the desired (4S,5R)-
hemiester 4a with very poor enantioselectivity (32% ee, Table 1,
entry 1). However, the enantioselectivity of 4a was improved up
to 82% ee when 1.1 equiv of catalyst 10 was used (Table 1, entry
3). No improvement in the enantioselectivity was noticed on fur-
ther increasing the catalyst loading from 1.1 to 1.2 equiv (Table 1,
entry 4). The optimization of other reaction conditions (solvent,
reaction temperature, and concentration) for this asymmetric
methanolysis was also undertaken. It was found that amongst five
different solvents examined (Table 1, entries 3, 11ꢀ14), the opti-
mum solvent in terms of enantioselectivity was MTBE. The enanti-
oselectivity of 4a was also found to be strongly dependant upon
the reaction temperature. As seen from entries 5–7 in Table 1, a
significant decrease in enantioselectivities and reaction rates
was observed when the reactions were conducted at 0 to ꢀ20 °C.
We subsequently observed that the change of the reaction
concentration of 3 in the solvent (from 0.15 to 0.025 M) led only
to subtle variation in the enantioselectivities (Table 1, entries 3,
8–10).
The enantiopure methyl monoester 4a (99% ee) could be easily
obtained after a single recrystallization from EtOAc and its abso-
lute configuration was established to be 4S and 5R by comparison
with our previous reported values of the specific rotation.9 Further-
more, the cinchona alkaloid-based sulfonamide catalyst 10 was
easily recovered quantitatively by the basification of its aqueous
hydrochloride salt solution and could be reused without compro-
mising either enantioselectivity or yield.
Having identified the optimized reaction conditions for the
asymmetric desymmetrization of 3, we next studied the effect
of variation of the nucleophile structure on this alcoholysis. To
this end, meso-cyclic anhydride 3 was treated with different alco-
hols in MTBE at room temperature in the presence of 1.1 equiv of
catalyst 10, and the results are summarized in Table 2. It is note-
worthy that the ease of this asymmetric alcoholysis is dependant
2
3
4
O
O
O
BnN
H
NBn
H
BnN
H
NBn
BnN
H
NBn
H
d
e
H
OH
O
O
CO2Et
S
S
O
5
6
7
O
BnN
H
NBn
H
H2N
H
NH2
H
2HBr
g
f
H
H
CO2Et
CO2H
S
S
9
8
O
HN
H
NH
OMe
N
h
H
N
H
N
O
CF3
CF3
H
CO2H
S
1
S
O
10
Scheme 1. The synthetic route to (+)-biotin 1. Reaction conditions: (a) toluene,
reflux, 10 h, 99%; (b) ROH, MTBE, 10, 25 °C; (c) KBH4, CaCl2, EtOH, 0–25 °C, then 5%
HCl, 60 °C, 30 min, 98%; (d) EtSC(S)SNa, DMA, 125 °C, 5 h, 70%; (e) Br(CH2)4CO2C2H5,
Zn, DMF, THF, toluene, 10% Pd/C, 80–30 °C, 30 h, 75%; (f) NaBH4, TFA, DCM, 0–25 °C,
12 h, 91%; (g) 47% HBr, reflux, 48 h; (h) diphosgene, anisole, 40% KOH, 12 h, 82%
(from 8 to 1).
1 via a catalytic enantioselective alcoholysis strategy. Herein, we
report an improved asymmetric total synthesis of 1 based upon
the cinchona alkaloid-based sulfonamide-mediated enantioselec-
tive alcoholysis of meso-cyclic anhydride 3 into (4S,5R)-hemiester
4 and a one-pot introduction of a 4-carboxybutyl chain at C-4 in
the (3aS,6aR)-thiolactone 6 by Fukuyama coupling reaction8 as
key steps.
2. Results and discussion
Our asymmetric total synthesis of (+)-biotin 1 commenced with
the commercially available cis-1,3-dibenzyl-2-imidazolidone-4,
Table 1
Optimization of the reaction conditions in the methanolytic desymmetrization of meso-cyclic anhydride 3a
Entry
Cat. (equiv)
Solvent
T (°C)
Concnb (M)
T (min)
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0.1
0.8
1.1
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Et2O
25
25
25
25
0
ꢀ10
ꢀ20
25
25
25
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.15
0.05
0.025
0.1
0.1
0.1
60
25
5
99
98
99
98
99
97
98
98
99
97
97
99
98
99
32
72
82
82
72
64
54
78
82
82
46
80
78
70
5
30
60
120
5
5
5
5
5
5
5
25
25
25
25
Dioxane
THF
Toluene
0.1
a
b
c
Unless otherwise noted, all reactions were performed with 0.5 mmol of 3 and 2.5 mmol of methanol.
Refers to the concentration of 3 in the solvent.
Yield of isolated product 4a.
d
Determined by chiral HPLC analysis.

F. Xiong et al. / Tetrahedron: Asymmetry 21 (2010) 665–669
667
Table 2
Asymmetric alcoholysis of meso-cyclic anhydride 3 with different alcoholsa
3. Conclusions
Entry
ROH
Product
Yieldb (%)
eec (%)
In conclusion, we have successfully developed an improved
synthetic process for the enantioselective total synthesis of (+)-bio-
tin. The application of the cinchona alkaloid-based sulfonamide-
mediated alcoholysis strategy for the construction of the two con-
tiguous stereogenic centers of the biotin skeleton allows rapid ac-
cess to (4S,5R)-cinnamyl hemiester 4h in an enantiomerically
enriched form under extremely mild conditions, which appears
to be more compatible with industrial scale and has some advan-
tages over the existing synthesis. The reactions described here
could be an attractive alternative for the industrially viable synthe-
sis of (+)-biotin.
1
2
3
4
5
6
7
1-Propanol
2-Propanol
Allyl alcohol
Propargyl alcohol
Benzyl alcohol
Cyclohexanol
4b
4c
4d
4e
4f
98
98
95
97
97
96
98
24
80
26
24
64
ꢀ6
92
4g
4h
trans-Cinnamyl alcohol
a
Unless otherwise noted, all reactions were performed with 0.5 mmol of 3 and
2.5 mmol of ROH in 5 mL of MTBE at room temperature.
b
Yield of isolated product.
Determined by chiral HPLC analysis of the corresponding lactones, which were
c
obtained by selective reduction of the ester group with LiBEt3H followed by acid-
catalyzed lactonization.10
4. Experimental
4.1. General
upon the steric properties of a nucleophile. The best result was
achieved for the reaction of 3 with trans-cinnamyl alcohol yield-
ing the corresponding chiral cinnamyl hemiester 4h in excellent
yield with enantioselectivities of 92% ee (Table 2, entry 7),
whereas poor enantioselectivities (24% ee) were achieved when
1-propanol, allyl alcohol, and propargyl alcohol were employed
as the nucleophiles (Table 2, entries 1, 3, and 4). In comparison
with methanol, the ee of 4f stemming from the ring-opening
reaction of 3 with benzyl alcohol as the nucleophile was only
moderate ee (64% ee) (Table 2, entry 5) and almost the racemic
product 4g was obtained when using cyclohexanol as the nucleo-
phile (Table 2, entry 6).
The chemoselective reduction of ester function in 4h was
accomplished at room temperature using KBH4 in the presence
of anhydrous CaCl2 in EtOH, followed by a lactonization on heat-
ing the resulting calcium salts of (4S,5R)-hydroxy acid with 5% aq
HCl for 30 min to provide the desired key intermediate chiral
lactone 5 in 98% overall yield with 99% enantiomeric excesses.
1H and 13C NMR spectra were recorded on a Bruker Avance 400
spectrometer (400, 100 MHz, respectively) in CDCl3 or DMSO-d6
using tetramethylsilane (TMS) or DMSO (1H d 2.49) and CDCl3
(
13C d 77.0) or DMSO-d6 (13C d 39.5) as internal standards. IR spec-
tra were recorded on a JASCO FT/IR-4200 spectrometer. Mass spec-
tra were recorded on a Waters Quattro Micromass instrument
using electrospray ionization (ESI) techniques. Optical rotations
were obtained on a JASCO P1020 digital polarimeter. Melting
points were measured with a WRS-1B digital melting point appara-
tus and are uncorrected. HPLC analysis of the enantiomeric ex-
cesses of 4a and 4b–4h was performed using chiralcel OJ–H
column (hexane/IPA/TFA = 92/8/0.2, k = 220 nm, 0.5 mL/min) and
OD–H column (hexane/IPA = 70/30, k = 220 nm, 0.5 mL/min) Un-
less otherwise noted all reactions were conducted in oven-dried
glassware under inert atmosphere of dried Ar or N2. THF was dis-
tilled from sodium/benzophenone, toluene, and CH2Cl2 from cal-
cium hydride and DMA from calcium hydride under reduced
pressure. The alcohols used were purified according to standard
methods,11 other reagents were obtained from commercial sources
and used as received.
Thiolactonization of
5 using sodium ethyl thioxanthogenate
[EtSC(S)SNa] in anhydrous N,N-dimethylacetamide (DMA) at
125 °C for 5 h worked perfectly well to furnish a 70% yield of
the chiral thiolactone 6. The 10% Pd/C-catalyzed Fukuyama cou-
pling of 6 with 5-ethoxy-5-oxopentylzinc bromine, in situ pre-
pared from ethyl 5-bromopentanoate and zinc powder,
smoothly proceeded in a mixed solvents of DMF, THF, and toluene
at 30 °C for 30 h to afford the desired coupling product 7 in 75%
yield.
4.2. cis-1,3-Dibenzyltetrahydro-2H-furo[3,4-d]imidazole-2,4,6-
trione 3
A mixture of 2 (10 g, 28 mmol) and toluene (190 mL) was stir-
red under reflux with azeotropic removal of water for 10 h. After
cooled to room temperature, the precipitated colorless crystals
were filtered and dried at 80 °C in vacuo for 3 h to give the pure
product 3 as a white powder; yield: 9.31 g (99%); mp 237.1–
In our earlier reported procedures,3b,c the tertiary hydroxyl
group of
7 was effectively reduced into the corresponding
pentanoate 8 in excellent chemical yields upon treatment with
triethylsilane and TFA or BF3ꢁOEt2 in CH2Cl2 under mild reac-
tion conditions. But these two methods required expensive
triethylsilane, making them unacceptable in industrial synthe-
sis. However, the ionic hydrogenation of 7 was realized at room
temperature by using NaBH4 as the reducing reagent in the
presence of TFA in dichloromethane to afford the desired 8 in
91% yield. Its absolute stereochemistry at C-4 was confirmed
by comparison with the reported values of the specific rota-
tion.3c The reduction did not go to completion when trichloro-
acetic acid or concd H2SO4 was utilized in the place of TFA as
acid media even prolonging the reaction time from 12 to 24 h
and enhancing the reaction temperature from room temperature
to 60 °C.
One-pot debenzylation and ring-opening which afford the dia-
mineꢁ2HBr salt 9 were carried out by heating the pentanoate 8
with 47% aq HBr at refluxing temperature for 48 h, which, without
further purification, was allowed to react with trichloromethyl
chloroformate in the presence of 40% KOH in anisole at 35 °C to
provide (+)-biotin 1 in 82% overall yield.
237.6 °C [lit.12 mp 237–239 °C]; IR (KBr):
m
= 1805, 1740, 1687,
1227 cmꢀ1
;
1H NMR (CDCl3): d: 4.15 (s, 2H), 4.18 (s, 2H), 4.22 (d,
1H, J = 14.8 Hz), 5.15 (d, 1H, J = 14.8 Hz), 7.15–7.35 (m, 10H); MS
(ESI): m/z = 337.4 (M+1)+.
4.3. General procedure for the asymmetric alcoholysis of 3 with
various alcohols
Alcohol (2.5 mmol) was added dropwise into a suspension of 3
(0.168 g, 0.5 mmol) and 10 (0.329 g, 0.55 mmol) in MTBE (5 mL)
under argon atmosphere. Upon completion of the addition the
reaction mixture was stirred for 5 min at room temperature and
then evaporated in vacuo. The residue was dissolved in AcOEt
(10 mL), the solution was washed with 2 M HCl (3 ꢂ 10 mL), and
dried over Na2SO4. Evaporation of the solvent yielded the corre-
sponding hemiester 4a–4h. To recover the cinchona alkaloid-based
sulfonamide 10, the combined acidic aqueous phases were basified
with NH4OH and extracted several times with CH2Cl2. After drying

668
F. Xiong et al. / Tetrahedron: Asymmetry 21 (2010) 665–669
over Na2SO4, the organic phase was concentrated in vacuo to give
catalyst 10 in almost quantitative yield.
967, 741, 700 cmꢀ1 1H NMR (CDCl3): d: 3.70 (br s, 1H), 4.11–
;
4.00 (m, 4H), 5.12–4.97 (m, 4H), 7.34–7.10 (m, 15H); 13C NMR
(CDCl3) d: 46.79, 46.80, 56.5, 57.2, 67.7, 127.89, 127.94, 128.58,
128.61, 128.63, 128.70, 128.76, 128.83, 135.53, 135.65 159.5,
167.8, 170.8; MS (ESI): m/z = 467.2 (M+Na)+.
4.3.1. (4S,5R)-1,3-Dibenzyl-5-(methoxycarbonyl)-2-oxo-imidazo
lidine-4-carboxylic acid 4a
White solid; yield: 0.182 g (99%); mp 145–147 °C; ½a D25:2
¼ þ6:0
ꢃ
(c 1.0, DMF) [lit.9 mp 150–151 °C; ½a 2D5
ꢃ
¼ þ7:3 (c 1.0, DMF)];
4.3.7. (4S,5R)-1,3-Dibenzyl-5-(cyclohexyloxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 4g
ee = 82%; IR (KBr):
m
= 3258, 2943, 1756, 1713, 1449, 1411, 1252,
968, 799, 598, 458 cmꢀ1
;
1H NMR (CDCl3): d: 3.63 (s, 3H), 4.13–
Yellow oil; yield: 0.209 g (96%); ee = ꢀ6%; IR (KBr):
m
= 3462,
4.04 (m, 4H), 4.98 (d, 1H, J = 14.8 Hz), 5.09 (d, 1H, J = 14.8 Hz), 6.85
(br s, 1H), 7.36–7.19 (m, 10H); 13C NMR (CDCl3) d: 46.80, 46.89,
52.6, 56.7, 57.3, 127.93, 127.98, 128.56, 128.64, 128.79, 128.85,
135.52, 135.57, 159.5, 168.5, 171.7; MS (ESI): m/z = 391.1 (M+Na)+.
2933, 2518, 1649, 1453, 1228, 765, 741, 700 cmꢀ1
;
1H NMR
(CDCl3): d: 1.13–1.32 (m, 5H), 1.52–1.55 (m, 1H), 1.70–1.72 (m,
2H), 1.87–1.90 (m, 2H), 3.61–3.66 (m, 1H), 3.99–4.08 (m, 4H),
5.04 (d, 2H, J = 15.2 Hz), 7.20–7.32 (m, 10H); 13C NMR (CDCl3) d:
8.8, 21.7, 25.9, 39.4, 46.3, 52.1, 58.2, 62.5, 68.7, 127.6, 137.2,
160.2, 168.8; MS (ESI): m/z = 459 (M+Na)+.
4.3.2. (4S,5R)-1,3-Dibenzyl-5-(n-propoxycarbonyl)-2-oxo-imida-
zolidine-4-carboxylic acid 4b
White solid; yield: 0.194 g (98%); mp 77–82 °C; ½a D25:2
ꢃ
¼ þ1:0 (c
4.3.8. (4S,5R)-1,3-Dibenzyl-2-oxo-5-[(3-phenylallyloxy)-carbonyl]
1.0, CHCl3) [lit.3b mp 78–82 °C;
½
a 2D5
ꢃ
¼ þ2:5 (c 1.0, CHCl3)];
imidazolidine-4-carboxylic acid 4h
ee = 24%; IR (KBr):
m
= 3065, 2984, 1744, 1655, 1469, 1359, 1209,
White solid; yield: 0.23 g (98%); mp 120.6–122.8; ½a D22:1
¼ þ7:0
ꢃ
1073, 952, 750, 700 cmꢀ1
;
1H NMR (CDCl3): d: 0.87 (t, 3H,
(c 1.0, CH3OH) [lit.3c mp 122.0–122.8 °C; ½a 2D1:9
¼ þ7:6 (c 1.0,
ꢃ
J = 7.2 Hz), 1.58 (tq, 2H, J = 7.2, 7.2 Hz), 4.10–3.92 (m, 6H), 5.01
(d, 1H, J = 14.8 Hz), 5.08 (d, 1H, J = 14.8 Hz), 7.31–7.20 (m, 10H),
9.75 (br s, 1H); 13C NMR (CDCl3) d: 10.3, 21.6, 46.7, 46.8, 56.8,
57.3, 67.6, 127.94, 127.95, 128.59, 128.63, 128.80, 128.84, 135.59,
135.61, 159.7, 168.1, 171.8; MS (ESI): m/z = 419.1 (M+Na)+.
CH3OH)]; ee = 92%; after recrystallization from AcOEt, 4h was ob-
tained in 92% yield with 98% ee, IR (KBr):
m
= 3449, 3028, 2930,
1751, 1711, 1664, 1450, 1357, 1238, 1196, 748, 701 cmꢀ1
;
1H
NMR (CDCl3): d: 4.02–4.13 (m, 4H), 4.62–4.72 (m, 2H), 5.01 (d,
J = 14.8 Hz, 1H), 5.09 (d, J = 14.8 Hz, 1H), 6.13–6.21 (dt, J = 16.0,
6.4 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 7.18–7.39 (m, 15H), 10.53
(br s, 1H); MS (ESI): m/z = 470.3 (M+1)+.
4.3.3. (4S,5R)-1,3-Dibenzyl-5-(isopropoxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 4c
Yellow oil; yield: 0.194 g (98%); ½a D20:8
ꢃ
¼ ꢀ8:2 (c 1.0, DMF) [lit.13
4.4. (3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-furo[3,4-d]imidazole-
2,4(1H)-dione 5
½
a 2D0
ꢃ
¼ ꢀ10:1 (c 1.0, DMF)]; ee = 80%; IR (KBr):
m = 3438, 3028,
2979, 2494, 1956, 1697, 1446, 1235, 1108, 957, 836, 753, 702,
458 cmꢀ1 1H NMR (CDCl3): d: 1.04 (d, 6H, J = 6.0 Hz), 3.50 (m,
;
To a stirred solution of 4h (4.70 g, 10 mmol) and anhydrous
CaCl2 (1.11 g, 10 mmol) in anhydrous ethanol (52 mL) was added
KBH4 (1.62 g, 30 mmol) in three portions at 0–5 °C. Stirring was
continued at the same temperature for 1 h, the reaction mixture
was allowed to warm up to room temperature and stirred for an-
other 18 h at 25 °C. The resulting mixture was then concentrated
and the residue was dissolved in ethyl acetate (30 mL). The solu-
tion was extracted with 10% aqueous Na2CO3 (3 ꢂ 30 mL) and
the combined aqueous phases were neutralized with concentrated
aqueous HCl and then treated with 5% aqueous HCl (37 mL) at
60 °C. After 30 min at this temperature, the solution was extracted
with CH2Cl2 (3 ꢂ 30 mL). The combined organic phases were dried
over Na2SO4 and concentrated in vacuo to afford 5 as a white solid;
1H), 3.69–4.07 (m, 4H), 4.77 (d, 1H, J = 14.4 Hz), 4.79 (d, 1H,
J = 14.4 Hz), 7.18–7.32 (m, 10H); 13C NMR (CDCl3) d: 8.8, 21.7,
25.9, 39.4, 46.3, 52.1, 58.2, 62.5, 68.7, 127.6, 137.2, 160.2, 168.8;
MS (ESI): m/z = 419 (M+Na)+.
4.3.4. (4S,5R)-1,3-Dibenzyl-5-(allyloxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 4d
White solid; yield: 0.187 g (95%); mp 106–109 °C; ½a D25:5
¼ þ2:6
ꢃ
(c 1.0, CHCl3) [lit.3b mp 107.7–109.8 °C; ½a 2D5
¼ þ7:8 (c 1.0, CHCl3)];
ꢃ
ee = 26%; IR (KBr):
m = 3061, 2929, 1755, 1657, 1449, 1356, 1235,
1200, 936, 754, 703 cmꢀ1 1H NMR (CDCl3): d: 4.12–4.03 (m, 4H),
;
4.54–4.43 (m, 2H), 4.98 (d, 1H, J = 14.8 Hz), 5.06 (d, 1H,
J = 14.8 Hz), 5.26–5.18 (m, 2H), 5.84–5.74 (m, 1H), 7.30–7.18 (m,
10H), 7.76 (br s, 1H); 13C NMR (CDCl3) d: 46.6, 46.7, 56.7, 57.2,
66.4, 119.4, 127.86, 128.50, 128.54, 128.73, 130.9, 135.43, 135.47,
159.7, 167.7, 170.7; MS (ESI): m/z = 417.3 (M+Na)+.
yield: 3.16 g (98%); mp 119.4–120.1 °C; ½a D25:3
¼ þ61:2 (c 2.0,
ꢃ
CHCl3) [lit.14 mp 120–121 °C; ½a 2D5
¼ þ61:5 (c 2.0, CHCl3)]; IR
ꢃ
(KBr):
m = 3031, 2919, 1775, 1706, 1415, 1365, 1237, 1209, 1146,
970, 754, 700, 639, 527 cmꢀ1 1H NMR (CDCl3): d: 3.92 (d, 1H,
;
J = 8.0 Hz), 4.09–4.16 (m, 3H), 4.37 (dd, 2H, J = 10.4 Hz, 15.2 Hz),
4.63 (d, 1H, J = 15.2 Hz), 5.05 (d, 1H, J = 15.2 Hz), 7.24–7.36 (m,
10H); 13C NMR (CDCl3) d: 45.2, 46.9, 52.4, 54.3, 70.1, 127.8,
128.0, 128.2, 128.7, 128.8, 129.0, 135.9, 136.0, 158.1, 172.7; MS
(ESI): m/z = 345.2 (M+Na)+.
4.3.5. (4S,5R)-1,3-Dibenzyl-5-(propargyloxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 4e
White solid; yield: 0.190 g (97%); mp 131–135 °C; ½a D25:7
¼ þ4:5
ꢃ
(c 1.0, CHCl3) [lit.3b mp 132.7–135.8 °C; ½a 2D5
¼ þ14:3 (c 1.0,
ꢃ
CHCl3)]; ee = 24%; IR (KBr):
m = 3299, 3026, 2919, 1751, 1652,
1464, 1440, 1203, 978, 704 cmꢀ1
;
1H NMR (CDCl3): d: 2.50 (t, 1H,
4.5. (3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-thieno[3,4-
d]imidazole-2,4(1H)-dione 6
J = 2.8 Hz), 4.12–4.06 (m, 4H), 4.66–4.56 (m, 2H), 5.00 (d, 1H,
J = 14.8 Hz), 5.08 (d, 1H, J = 14.8 Hz), 6.62 (br s, 1H), 7.33–7.20
(m, 10H); 13C NMR (CDCl3) d: 46.78, 46.85, 53.1, 56.51, 57.04,
75.97, 76.43, 128.00, 128.02, 128.60, 128.67, 128.84, 128.87,
135.36, 135.48, 159.5, 167.3, 171.5; MS (ESI): m/z = 393.3 (M+H)+.
A mixture of 5 (3.22 g, 10 mmol), sodium ethylthioxanthogen-
ate (1.92 g, 12 mmol), and anhydrous DMA (25 mL) was stirred at
125 °C under argon atmosphere for 5 h. After cooling, the mixture
was poured into H2O (30 mL) and extracted three times with
CH2Cl2 (3 ꢂ 30 mL). The combined organic phases were washed
successively with brine (30 mL) and H2O (30 mL), dried over
Na2SO4, and evaporated the solvent to give the crude product
which was then purified by recrystallization from iso-propanol to
afford the pure 6 as a white solid, yield: 2.37 g (70%); mp 125.5–
4.3.6. (4S,5R)-1,3-Dibenzyl-5-(benzyloxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 4f
White solid; yield: 0.215 g (97%); mp 57–59 °C; ½a D25:3
¼ þ11:5
ꢃ
(c 1.0, CHCl3) [lit.3b mp 57.7–60.6 °C; ½a 2D5
¼ þ12:2 (c 1.0, CHCl3)];
ꢃ
ee = 64%; IR (KBr):
m = 3031, 2945, 1752, 1664, 1454, 1236, 1201,

F. Xiong et al. / Tetrahedron: Asymmetry 21 (2010) 665–669
669
126.2 °C; ½a 2D5:3
ꢃ
¼ þ90:1 (c 1.0, CHCl3) [lit.15 mp 125–126 °C;
was added dropwise over 2 h and the resulting mixture was al-
lowed to stir at 35 °C overnight. The pH value of the reaction mix-
ture was maintained at 10 by addition of 40% aqueous KOH. The
separated aqueous phase was acidified to pH 1 with concentrated
aqueous HCl and cooled with ice water. The crystals that formed
were collected by filtration and recrystallized from H2O to give
pure 1 as a white crystalline powder, yield: 2.01 g (82%); mp
½
a 2D5
ꢃ
¼ þ90:2 (c 1.0, CHCl3)]; IR (KBr):
m = 3030, 2934, 2889, 1703,
1697, 1453, 1412, 1361, 1218, 1148, 1051, 997, 903, 808, 66698,
647, 581, 485 cmꢀ1 1H NMR (CDCl3): d: 3.28 (dd, 1H, J = 12.4,
;
2.0 Hz), 3.37 (dd, 1H, J = 12.4, 5.6 Hz), 3.81 (d, 1H, J = 8.0 Hz),
4.15–4.11 (m, 1H), 4.36 (d, 1H, J = 14.8 Hz), 4.37 (d, 1H, J =
15.6 Hz), 4.68 (d, 1H, J = 15.6 Hz), 5.03 (d, 1H, J = 14.8 Hz), 7.37–
7.26 (m, 10H); 13C NMR (CDCl3) d: 33.0, 45.2, 46.5, 55.8, 62.1,
127.73, 127.91, 128.0, 128.66, 128.78, 128.87, 136.2, 136.4, 158.2,
203.4; MS (ESI): m/z = 361.1 (M+Na)+.
232.1–233.0 °C; ½a D22:3
ꢃ
¼ þ91:3 (c 1.0, 0.1 N NaOH) [lit.16 mp
232–233 °C;
m
½
a 2D1:9
ꢃ
¼ þ91:2 (c 1.0, 0.1 N NaOH)]; IR (KBr):
= 3359, 3308, 2961, 2469, 1941, 1707, 1480, 1318, 1270, 1154,
1015, 842, 753, 651 cmꢀ1 1H NMR (DMSO): d: 1.37–1.30 (m,
;
4.6. Ethyl(3aS,4RS,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-
2-oxo-1H-thieno[3,4-d]imidazol-5-hydroxyl)pentanoate 7
2H), 1.62–1.41 (m, 4H), 2.20 (t, 2H, J = 7.6 Hz), 2.57 (d, 1H,
J = 12.4 Hz), 2.82 (dd, 1H, J = 12.4, 5.2 Hz), 3.12–3.07 (m, 1H),
4.15–4.11 (m, 1H), 4.30 (dd, 1H, J = 7.6, 5.2 Hz), 6.33 (s, 1H), 6.40
(s, 1H), 11.9 (s, 1H); 13C NMR (CDCl3) d: 25.0, 28.52, 28.57, 33.9,
40.0, 55.8, 59.6, 61.5, 163.1, 174.8; MS (ESI): m/z = 267 (M+Na)+.
To a suspension of zinc powder (1.62 g, 24.8 mmol) in anhy-
drous DMF (8 mL) was added iodine (0.2 g, 0.8 mmol) under nitro-
gen atmosphere and the reaction mixture was heated to 80 °C. Ethyl
5-bromopentanoate (3.45 g, 16.5 mmol) was then added dropwise
over 30 min and the resulting mixture was kept stirring at the same
temperature for 4 h. Compound 6 (2 g, 5.92 mmol), 10% Pd/C
(0.07 g), THF (30 mL), and toluene (40 mL) were added in one por-
tion into the resulting mixture and the mixture was stirred at
30 °C for 30 h. The reaction was quenched by saturated aq NH4Cl
(30 mL), and the mixture was filtered after being stirred for
10 min. The filtrate was extracted by AcOEt (3 ꢂ 30 mL). The com-
bined organic phases were washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was further purified by
chromatography on a silica gel column (AcOEt/PE = 1/1.5) to give
Acknowledgment
This work was supported by the DSM Nutritional Products Ltd
in Switzerland.
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7 as a yellow oil, yield: 2.08 g (75%); ½a D20:9
ꢃ
¼ þ20:2 (c 1.0, CHCl3)
[lit.3c
½
a 2D0
ꢃ
¼ þ20:9 (c 1.0, CHCl3)]; IR (KBr):
m
= 2961, 2594, 1670,
1387, 1259, 665 cmꢀ1 1H NMR (CDCl3): d: 1.23–1.27 (m, 3H),
;
1.44–1.45 (m, 2H), 1.60–1.62 (m, 2H), 2.24–2.33 (m, 4H), 2.72 (m,
2H), 3.65 (m, 1H), 3.94 (d, 1H, J = 22.4 Hz), 4.02 (d, 1H,
J = 22.4 Hz), 4.10–4.20 (m, 4H), 4.88 (d, 1H, J = 15.6 Hz), 5.10 (d,
1H, J = 15.6 Hz), 7.24–7.32 (m, 10H); MS (ESI): m/z = 469 (M+1)+.
4.7. Ethyl(3aS,4S,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-hexahydro-
2-oxo-1H-thieno[3,4-d]imidazol-5-yl)pentanoate 8
An ice cold solution of 7 (2.06 g, 4.4 mmol) and NaBH4 (0.5 g,
13.2 mmol) in dry CH2Cl2 (25 mL) was treated dropwise with tri-
fluoroacetic acid (3 g, 26.4 mmol) over 30 min. The reaction mix-
ture was then allowed to stir at 25 °C for 12 h under argon
atmosphere. After adding the saturated aq NaHCO3, the mixture
was extracted with CH2Cl2 (3 ꢂ 30 mL). The combined organic
phases were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. The residue was further purified by chromatogra-
phy on a silica gel column (AcOEt/PE = 1/1.5) to give 8 as a colorless
oil, yield: 1.81 g (91%);
½
a 2D2:1
ꢃ
¼ ꢀ24:1 (c 1.0, CH3OH) [lit.3c
½
a 2D1:9
ꢃ
¼ ꢀ24:9 (c 1.0, CH3OH)]; IR (KBr):
m = 1728, 1678, 1453,
1243, 700 cmꢀ1 1H NMR (CDCl3): d: 1.25–1.28 (t, 3H, J = 8 Hz),
;
1.57–1.65 (m, 6H), 2.27–2.31 (t, 2H, J = 7.2 Hz), 2.68, 2.72 (dddd,
2H, J = 5.6 Hz, J = 5.6 Hz), 3.05 (m, 1H), 3.86–4.12 (m, 6H), 4.72
(d, 1H, J = 15.2 Hz), 5.05 (d, 1H, J = 15.2 Hz), 7.23–7.34 (m, 10H);
13C NMR (CDCl3) d: 14.3, 24.7, 28.5, 28.7, 34.2, 34.8, 46.6, 48.0,
54.3, 60.3, 61.2, 62.6, 127.3, 128.3, 128.7, 136.9, 137.0, 161.1,
173.6; MS (ESI): m/z = 453.3 (M+1)+.
4.8. (+)-Biotin 1
A mixture of 8 (4.52 g, 10 mmol) and 47% aq HBr (40 mL) was
heated to reflux with vigorous stirring. After 48 h the reaction mix-
ture was extracted with toluene (3 ꢂ 30 mL) and the aqueous
phase was separated and concentrated in vacuo. The residue was
dissolved in H2O (18 mL). With vigorous stirring, the solution of tri-
chloromethyl chloroformate (8.91 g, 45 mmol) in anisole (40 mL)