Total synthesis of (+)-biotin via a quinine-mediated asymmetric alcoholysis of meso-cyclic anhydride strategy

Article abstract of DOI:10.1016/j.tetasy.2008.05.020

A concise asymmetric total synthesis of (+)-biotin 1 has been accomplished in which the absolute stereochemistry of C_3a, C_6a of 1 was established by utilizing an efficient and practical quinine-mediated asymmetric alcoholysis of meso-cyclic anhydride 2 in a single step, the C₄ stereochemistry was installed by a direct stereoselective ionic hydrogenation of the thiolactol 7.

Full text of DOI:10.1016/j.tetasy.2008.05.020

Tetrahedron: Asymmetry 19 (2008) 1436–1443
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of (+)-biotin via a quinine-mediated asymmetric alcoholysis of
meso-cyclic anhydride strategy
Jian Huang a, Fei Xiong a,b, Fen-Er Chen a,b,
*
a Fudan-DSM Joint Laboratory for Synthetic Method and Chiral Technology, Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, PR China
b Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise asymmetric total synthesis of (+)-biotin 1 has been accomplished in which the absolute stereo-
chemistry of C3a, C6a of 1 was established by utilizing an efficient and practical quinine-mediated asym-
metric alcoholysis of meso-cyclic anhydride 2 in a single step, the C4 stereochemistry was installed by a
direct stereoselective ionic hydrogenation of the thiolactol 7.
Received 3 April 2008
Accepted 12 May 2008
Available online 28 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
The recently emerged catalytic asymmetric alcoholysis7 of
meso-cyclic anhydrides has provided a powerful protocol for the
(+)-Biotin 1 is one of the water-soluble B-complex vitamins
bearing a cis-fused bi-heterocyclic core and three adjacent stereo-
genic centers in the all-cis configuration (Fig. 1). Due to its unique
structure and biological importance for human nutrition and ani-
mal health,1 this vitamin has attracted considerable attention from
both industry and academia for more than 50 years.2 In the previ-
synthesis of a broad range of important chiral building blocks, such
as hemiesters, -amino acids, and -hydroxy acids. The cinchona
a
a
alkaloids were found to be excellent directing additives, which
could promote the ring opening of a wide variety of meso-cyclic
anhydrides to afford the corresponding hemiester with high
enantioselectivity in excellent yield.8 Herein, we report an inex-
pensive and easily available cinchona alkaloid-quinine-mediated
desymmetrization of meso-cyclic anhydride 2 to prepare (4S,5R)-
hemiester 3, a direct precursor to (3aS,6aR)-lactone 4, to complete
an efficient total synthesis of 1.
ously reported approaches toward 1, the stereochemistry of C3a
,
C6a of 1 was established by different strategies, such as diastereo-
meric or enzymatic resolution,3 chiral pool methods,4 and asym-
metric syntheses,5 while the C4 stereocenter was installed in
most cases via a catalytic hydrogenation under high temperature
and high hydrogen pressure.2 In continuation of our work on the
total synthesis of (+)-biotin,6 we herein report a concise total syn-
thesis of 1, featuring a highly efficient asymmetric alcoholysis and
a mild ionic hydrogenation as the key steps to incorporate the
three contiguous stereogenic centers.
2. Results and discussion
Our project started with the screening of the optimal reaction
conditions by using methanol as the test nucleophile in the qui-
nine-mediated asymmetric alcoholysis of commercially available
cyclic anhydride 2 to prepare the key chiral building block-
(3aS,6aR)-lactone 4 (Scheme 1). The results are illustrated in Table
1. As shown in Table 1, the desired hemiester 3a was obtained in
nearly quantitative yield and good enantioselectivity (78.1% ee)
when the asymmetric alcoholysis of 2 was run at ꢀ50 °C in a mixed
solvent of toluene/carbon tetrachloride (1:1) (entry 1). Increasing
the reaction temperature dramatically decreased the enantiomeric
excess of 3a and reached a minimum at around 25 °C (entries 2–5).
A major effect was noted upon varying the concentration of the
substrate 2. An increase in ee occurred upon lowering the substrate
concentration (entries 1, 6, and 7), allowing the formation of hemi-
ester 3a in 82% ee (entry 7) at a lower reaction concentration
(0.02 M). Also, a number of solvents were screened in the asym-
metric alcoholysis including toluene, toluene/carbon tetrachloride
(1:1), diethyl ether, tetrahydrofuran, ethyl acetate, and acetone
O
HN
NH
3a H
H
6a
H
4
CO2H
S
(+)-Biotin 1
Figure 1. The structure of (+)-biotin.
* Corresponding author. Tel./fax: +86 21 65643811.
E-mail address: rfchen@fudan.edu.cn (F.-E. Chen).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.020

J. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 1436–1443
1437
O
O
O
1) NaBH4, 2) H+
BnN
H
NBn
H
MeOH, quinine
BnN
H
NBn
BnN
H
NBn
H
H
CO2H
MeO2C
O
O
O
O
O
4
2
3a
Scheme 1. The preparation of (3aS,6aR)-lactone 4.
Table 1
Table 2
Optimization of the reaction conditions in the asymmetric alcoholysis of cyclic
Asymmetric alcoholysis of cyclic anhydride 2 with different alcoholsa
anhydride 2a
O
O
O
O
BnN
H
NBn
H
BnN
H
RO2C
NBn
H
CO2H
ROH, quinine
toluene
BnN
H
NBn
H
BnN
H
MeO2C
NBn
H
CO2H
MeOH, quinine
solvent
O
O
O
O
O
O
3
2
3a
2
Entry
ROH
Yieldb (%)
eec (%)
Entry Temperature
Solvent
Concentration Yieldb
eec
(%)
1
2
3
4
5
6
7
8
9
Methanol (a)
Ethanol (b)
1-Propanol (c)
Trifluoroethanol (d)
2-Propanol (e)
Allyl alcohol (f)
Propargyl alcohol (g)
Benzyl alcohol (h)
Cyclohexanol (i)
99
98
90
90
82
84
80
41
—
80
86
78
—
(°C)
of 2 (M)
(%)
1
2
3
4
5
6
7
ꢀ50
ꢀ40
ꢀ20
0
CCl4/toluene
(1:1)
CCl4/toluene
(1:1)
CCl4/toluene
(1:1)
CCl4/toluene
(1:1)
CCl4/toluene
(1:1)
CCl4/toluene
(1:1)
CCl4/toluene
(1:1)
Et2O
0.05
99
78.1
76
d
ꢀ
0.05
0.05
0.05
0.05
0.1
97
95
92
90
98
99
94
95
93
73
d
ꢀ
64
10
trans-Cinnamyl alcohol (j)
91
77
a
25
58
Reaction conditions:
2 (3.36 g, 10 mmol), ROH (30 mmol), quinine (3.57 g,
11 mmol), in toluene (500 mL), at ꢀ50 °C, 72 h.
b
ꢀ50
ꢀ50
72
Isolated yields.
c
Determined by chiral HPLC analysis of the corresponding lactones, which were
0.02
82
obtained by selective reduction of the ester group with LiBEt3H followed by acid-
catalyzed lactonization.9
d
d
8
9
10
11
12
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
0.05
0.05
0.05
0.05
0.05
ꢀ
ꢀ
Conversion <10% after 96 h.
Toluene
THF
AcOEt
99
90
93
80
77
62
53
40
the absolute configuration of 3g was determined as (4S) and (5R)
by comparison of the specific rotation of the lactone 4, transformed
from 3g, with the reported values.6h
Acetone
a
Reaction conditions: 2 (3.36 g, 10 mmol), MeOH (1.22 mL, 30 mmol), quinine
(3.57 g, 11 mmol), 72 h.
It is worth noting that the alkaloid used in the asymmetric alco-
holysis can be recovered quantitatively by a simple acidic extrac-
tion followed by basification of the aqueous phase, extraction of
the alkaline aqueous solution with CH2Cl2, and evaporation of
the solvent. To demonstrate the reusability of quinine, we per-
formed a preparative scale reaction by using the recovered quinine
as a directing additive and methanol as a nucleophile. The desired
hemiester 3a was obtained with 82% ee in 99% yield.
With this efficient method in hand for the preparation of the
(4S,5R)-hemiester, the next task was to convert the chiral hemiest-
er into (3aS,6aR)-lactone 4 via a one-pot reduction and lactoniza-
tion (Scheme 2). Thus, chemoselective reduction of the ester
group of 3g with NaBH4 in the presence of CaCl2 in anhydrous eth-
anol, followed by acid-catalyzed lactonization afforded the impor-
tant intermediate (3aS,6aR)-lactone 4 in 90% yield with 97% ee.
Treatment of 4 with sodium thioacetate in DMF at 150 °C provided
the key building block-(3aS,6aR)-thiolactone 5 in 72% isolated
yield.
b
Isolated yields.
c
Determined by chiral HPLC analysis of the corresponding lactones, which were
obtained by selective reduction of the ester group with LiBEt3H followed by acid-
catalyzed lactonization.9
d
Conversion <10% after 96 h.
and it was found that non-polar toluene was most suitable for this
reaction in which 77% ee of 3a was obtained (entry 9). Further-
more, no reaction was observed when the asymmetric alcoholysis
was performed in diethyl ether (entry 8).
Next, we examined the asymmetric alcoholysis of 2 with differ-
ent alcohols as nucleophile under the above-optimized reaction
conditions. As Table 2 shows, in terms of enantioselectivity, prop-
argyl alcohol turned out to be the best (86% ee, entry 7) and trifluo-
roethanol proved to be the worst (41% ee, entry 4), while 2-
propanol and cyclohexanol were inert to the reaction (entries 5
and 9). No significant difference was observed among the remain-
ing alcohols. The enantiomeric excess of the crude hemiesters (3a–
c, 3f–h) could be increased to 90–97% by a single recrystallization
from ethyl acetate/cyclohexane (1:1). In the event, 3g crystallized
nicely from ethyl acetate/cyclohexane (1:1), allowing the ee to be
enriched to 97% in 83% yield. The relative configuration of the
hemiesters was confirmed by an X-ray crystallographic analysis
of the representative compound 3g, as depicted in Figure 2 while
We then proceeded to install the carboxybutyl side chain at the
C4 of thiolactone 5 using a modified Fukuyama coupling proce-
dure.10 Treatment of 5 with the in situ generated zinc reagent 6
in the presence of the nanopalladium (LDH–Pd0) catalyst11 allowed
a convenient installation of the carboxybutyl side chain to afford
thiolactol 7 as an inseparable mixture of diastereoisomers (ratio
3:1, as determined by 1H NMR spectroscopy) (Scheme 3). The next

1438
J. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 1436–1443
Figure 2. ORTEP drawing of the X-ray structure of hemiester 3g.
O
O
i) NaBH4, CaCl2, EtOH
0oC to rt, 18h
BnN
H
NBn
H
BnN
H
NBn
H
ii) 1M HCl, 60oC, 0.5h
90%
CCH2O2C
CO2H
HC
O
O
4
3g
O
BnN
NBn
AcSNa, DMF
H
H
150oC, 45min
72%
O
S
5
Scheme 2. Synthesis of (3aS,6aR)-thiolactone 5.
step was to eliminate the hydroxyl group of thiolactol 7 to incorpo-
rate the required C4S stereocenter. In previously reported
approaches toward 1, the thiolactol intermediate was usually
subjected directly to an acid treatment without purification to
afford an olefin derivative, catalytic hydrogenation under high
temperature and pressure created the third stereogenic center.
To avoid the violent reaction conditions and catalytic poison
encountered in the catalytic hydrogenation, we attempted to
reduce the tertiary hydroxyl group of 7 directly, via an ionic hydro-
genation.12 Fortunately, treatment of 7 with Et3SiH in the presence
of TFA at ambient temperature led to the pentanoate 8 as a single
diastereoisomer13 with the required C4S configuration. The stereo-
chemistry of C4 was confirmed by 1H–1H NOESY NMR spectral
analysis (Fig. 3).14 Alternatively, the pentanoate 8 could also be
obtained by the same hydride reduction of compound 9, the dehy-
dration product of 7.
from the re-face to yield the kinetic-favored 8 as the major
product, while the formation of 10 by si-face attack is nearly
neglectable.
Finally, on refluxing 8 with 47% aq HBr, a one-pot debenzyla-
tion, hydrolysis, and ring opening reaction furnished the diami-
neꢁ2HBr salt which, without purification, was allowed to react
with triphosgene at ambient temperature in the presence of acti-
vated charcoal as catalyst15 to afford (+)-biotin in 82% yield
(Scheme 4), which was identical in all respects to that previously
described in the literature.6h
3. Conclusions
In conclusion, a facile, concise, and efficient catalytic asymmetric
total synthesis of (+)-biotin has been accomplished from the easily
accessible cyclic anhydride 2 in 28% overall yield. The pivotal reac-
tion sequence includes a quinine-mediated asymmetric desymmet-
rization and a mild ionic hydrogenation for the installation of the
A plausible mechanism of this hydride reduction is proposed
as shown in Figure 4. The ionic hydrogenation proceeds through
the formation of a carbenium intermediate, then hydride attack

J. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 1436–1443
1439
, LDH-Pd0
CO2Bn
O
i)
O
IZn
THF, toluene, DMF, 30oC, 24h
6
BnN
H
NBn
H
BnN
H
NBn
H
OH
ii) Sat. aq. NH4Cl
75%
CO2Bn
S
O
S
7
5
18% HCl, 60oC, 5h
95%
Et3SiH,TFA, CH2Cl2
0oC to rt, 12h, 92%
O
O
BnN
NBn
H
Et3SiH, TFA,
BnN
H
NBn
H
H
H
CH2Cl2, 0oC to rt, 12h,
92%
CO2Bn
S
CO2Bn
S
8
9
Scheme 3. Introduction of carboxybutyl side chain.
Figure 3. 2D NOESY spectrum of 8. Note: peak 1 in the figure is the cross peak between H-3a (d 3.84 ppm) and H-4 (d 3.03–3.06 ppm).
three contiguous stereocenters. We believe the efficient synthetic
method should permit ready access to this important vitamin.
noted, all reactions were carried out under argon or nitrogen using
standard Schlenk and vacuum line techniques. All melting points
are uncorrected, and were measured on a WRS-1B digital melt-
ing-point apparatus. 1H (400 MHz) and 13C (100 MHz) NMR spectra
were recorded on a Bruker Avance 400 spectrometer in CDCl3 or
DMSO-d6 using tetramethylsilane (TMS) or DMSO (1H d 2.49) and
4. Experimental
4.1. General
CDCl3 ( (
13C d 77.0) or DMSO-d6 13C d 39.5) as internal standards.
J-values are given in Hertz. Mass spectra were recorded on a
Waters Quattro Micromass instrument using electrospray ioniza-
tion (ESI) techniques. IR spectra were recorded on a Jasco FT/IR-
4200 spectrometer. Optical rotations were obtained on a Jasco
P1020 digital polarimeter. HPLC analysis was performed using a
THF was distilled from sodium/benzophenone, dichlorometh-
ane and toluene from calcium hydride, and DMF from calcium hy-
dride under reduced pressure. The alcohols used were purified
according to standard methods.16 Other reagents were obtained
from commercial sources and used as received. Unless otherwise

1440
J. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 1436–1443
O
O
BnN
H
NBn
H
BnN
H
NBn
H
TFA
OH
OH2
CO2Bn
S
S
CO2Bn
7
- H2O
O
S
O
BnN
H
NBn
H
BnN
NBn
H
TFA
Si
H
CO2Bn
CO2Bn
S
H
9
Re
Re
Si
O
BnN
H
NBn
O
H
H
BnN
H
NBn
H
CO2Bn
S
8
H
CO2Bn
S
10
Figure 4. Proposed mechanism for the ionic hydrogenation.
O
H2N
H
NH2
H
BnN
NBn
H
2HBr
47%HBr, xylene,
ref lux 36h
H
H
H
CO2H
S
CO2Bn
S
8
i) 10% NaOH
ii) Cl3COCOOCCl3,
activated charcoal,
tol., rt, 12h
80% from 8
O
S
HN
H
NH
H
H
CO2H
(+)-Biotin 1
Scheme 4. Synthesis of (+)-biotin.
Chiralcel AD-H column, 4.6 ꢂ 250 mm, k = 210 nm. Elemental anal-
sults of elemental analyses for C, H, N, and S were within 0.4% of
the theoretical values.
yses were performed on a CARLOERBA 1106 instrument and the re-

J. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 1436–1443
1441
4.2. General procedure for the asymmetric alcoholysis of cyclic
anhydride 2
(d, J = 14.8 Hz, 1H), 5.00 (d, J = 14.8 Hz, 1H), 4.75 (br s, 1H), 4.46–
4.27 (m, 2H), 4.18–4.06 (m, 4H); 13C NMR (100 MHz, CDCl3) d
171.4, 166.7, 159.4, 135.3, 135.1, 128.9, 128.63, 128.59, 128.17,
128.09, 61.2, 60.8, 56.9, 56.4, 46.9, and 46.7; ESI-MS m/z 415.1
[M+H]+, 437.1 [M+Na]+.
To a solution of quinine (3.57 g, 11 mmol) in toluene (500 mL)
was added 2 (3.36 g, 10 mmol) at ꢀ50 °C under nitrogen. After
being stirred for 10 min, alcohol (30 mmol) was added dropwise
and then the resulting mixture was stirred at the same tempera-
ture for 72 h. During this period, the material gradually turned
clear. Subsequently, the resulting solution was concentrated in va-
cuo to dryness, the residue was dissolved in ethyl acetate. The
solution was washed with 2 M HCl and brine. After phase separa-
tion, the organic phase was dried over Na2SO4, and concentrated
to afford the desired product with (3h, 3j) or without (3a–c, 3f,
and 3g) further purification by flash chromatography.
4.2.5. (4S,5R)-1,3-Dibenzyl-5-(allyloxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 3f
Compound (4S,5R)-3f was prepared by the quinine-mediated
ring opening of 2 in the presence of allyl alcohol in 94% yield.
Mp: 107.7–109.8 °C; ½a D25
¼ þ7:81 (c 1.0, CHCl3); ee = 80%; IR
ꢃ
(KBr): 3061, 2929, 1755, 1657, 1450, 1356, 1235, 1200, 936, 754,
703 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.76 (br s, 1H), 7.30–7.18
;
(m, 10H), 5.84–5.74 (m, 1H), 5.26–5.18 (m, 2H), 5.06 (d,
J = 14.8 Hz, 1H), 4.98 (d, J = 14.8 Hz, 1H), 4.54–4.43 (m, 2H), 4.12–
4.03 (m, 4H); 13C NMR (100 MHz, CDCl3) d 170.7, 167.7, 159.7,
135.47, 135.43, 130.9, 128.73, 128.54, 128.50, 127.86, 119.4, 66.4,
57.2, 56.7, 46.7, and 46.6; ESI-MS m/z 395.3 [M+H]+, 417.3
[M+Na]+. Anal. Calcd for C22H22N2O5: C, 66.99; H, 5.62; N, 7.10.
Found: C, 66.87; H, 5.75; N, 7.22.
To recover quinine, the acidic aqueous phase was basified with
Na2CO3 and extracted with CH2Cl2. The combined organic phase
was dried over MgSO4 and concentrated under reduced pressure
to recover quinine (pure as determined by 1H NMR) quantitatively.
4.2.1. (4S,5R)-1,3-Dibenzyl-5-(methoxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 3a
Compound (4S,5R)-3a was prepared by the quinine-mediated
ring opening of 2 in the presence of methanol in 99% yield. Mp:
4.2.6. (4S,5R)-1,3-Dibenzyl-5-(propargyloxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 3g
144–146 °C; ½a 2D5
ꢃ
¼ þ2:2 (c 1.0, CHCl3); [Lit.6h Mp: 150–151 °C,
Compound (4S,5R)-3g was prepared by quinine-mediated ring
opening of 2 in the presence of propargyl alcohol in 95% yield.
½
a 2D5
ꢃ
¼ þ7:31 (c 1.0, DMF)]; ee = 82%; IR (KBr): 3258, 2943, 1756,
1713, 1449, 1411, 1252, 968, 799, 598, 458 cmꢀ1
;
1H NMR
Mp: 132.7–135.8 °C; ½a D25
¼ þ14:3 (c 1.0, CHCl3); ee = 86%; IR
ꢃ
(400 MHz, CDCl3) d 7.36–7.19 (m, 10H), 6.85 (br s, 1H), 5.09 (d,
J = 14.8 Hz, 1H), 4.98 (d, J =14.8 Hz, 1H), 4.13–4.04 (m, 4H), 3.63
(s, 3H); 13C NMR (100 MHz, CDCl3) d 171.7, 168.5, 159.5, 135.57,
135.52, 128.85, 128.79, 128.64, 128.56, 127.98, 127.93, 57.3, 56.7,
52.6, 46.89, and 46.80; ESI-MS m/z 391.1 [M+Na]+.
(KBr): 3299, 3026, 2919, 1751, 1652, 1464, 1440, 1203, 978,
704 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.33–7.20 (m, 10H), 6.62
;
(br s, 1H), 5.08 (d, J = 14.8 Hz, 1H), 5.00 (d, J = 14.8 Hz, 1H), 4.66–
4.56 (m, 2H), 4.12–4.06 (m, 4H), 2.50 (t, J = 2.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 171.5, 167.3, 159.5, 135.48, 135.36, 128.87,
128.84, 128.67, 128.60, 128.02, 128.00, 76.43, 75.97, 57.04, 56.51,
53.1, 46.85, 46.78; ESI-MS m/z 393.3 [M+H]+, 415.3 [M+Na]+. After
recrystallization from ethyl acetate/cyclohexane (1:1), the enantio-
merically pure (4S,5R)-3g was obtained in 83% yield, Mp: 135.8–
4.2.2. (4S,5R)-1,3-Dibenzyl-5-(ethoxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 3b17
Compound (4S,5R)-3b was prepared by the quinine-mediated
ring opening of 2 in the presence of ethanol in 98% yield. Mp:
137.8 °C; ½a 2D5
¼ þ15:6 (c 1.0, CHCl3); ee = 97%. Anal. Calcd for
ꢃ
130–132 °C; ½a 2D5
¼ þ3:7 (c 1.0, CHCl3); ee = 84%; IR (KBr): 3059,
ꢃ
C
22H20N2O5: C, 67.33; H, 5.13; N, 7.14. Found: C, 67.52; H, 5.10;
2982, 1746, 1657, 1469, 1363, 1209, 1026, 747, 701, 597 cmꢀ1
;
N, 7.25.
1H NMR (400 MHz, CDCl3) d 8.00 (br s, 1H), 7.32–7.20 (m, 10H),
5.09 (d, J = 14.8 Hz, 1H), 4.99 (d, J = 14.8 Hz, 1H), 4.12–4.04 (m,
6H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 171.8,
167.9, 159.6, 135.62, 135.57, 128.83, 128.77, 128.61, 128.56,
127.94, 127.90, 62.0, 57.2, 56.7, 46.8, 46.7, and 13.9; ESI-MS m/z
405.3 [M+Na]+.
4.2.7. (4S,5R)-1,3-Dibenzyl-5-(benzyloxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 3h19
Compound (4S,5R)-3h was prepared by the quinine-mediated
ring opening of 2 in the presence of benzyl alcohol, and purified
by flash chromatography (AcOEt/hexane 2:1) in 93% yield as a
viscous oil, which slowly crystallized upon standing. Mp: 57.7–
4.2.3. (4S,5R)-1,3-Dibenzyl-5-(n-propoxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 3c17
60.6 °C; ½a 2D5
ꢃ
¼ þ12:2 (c 1.0, CHCl3); ee = 78%; IR (KBr): 3031,
2945, 1752, 1664, 1454, 1236, 1201, 967, 741, 700 cmꢀ1
;
1H
Compound (4S,5R)-3c was prepared by the quinine-mediated
ring opening of 2 in the presence of n-propanol in 90% yield. Mp:
NMR (400 MHz, CDCl3) d 7.34–7.10 (m, 15H), 5.12–4.97 (m, 4H),
4.11–4.00 (m, 4H), 3.70 (br s, 1H); 13C NMR (100 MHz, CDCl3) d
170.8, 167.8, 159.5, 135.65, 135.53, 128.83, 128.76, 128.70,
128.63, 128.61, 128.58, 127.94, 127.89, 67.7, 57.2, 56.5, 46.80,
46.79; ESI-MS m/z 467.2 [M+Na]+.
78–82 °C;
3065, 2984, 1744, 1655, 1469, 1359, 1209, 1073, 952, 750,
700 cmꢀ1 1H NMR (CDCl3, 400 MHz) d 9.75 (br s, 1H), 7.31–7.20
½
a 2D5
ꢃ
¼ þ2:5 (c 1.0, CHCl3); ee = 80%; IR (KBr):
;
(m, 10H), 5.08 (d, J = 14.8 Hz, 1H), 5.01 (d, J = 14.8 Hz, 1H), 4.10–
3.92 (m, 6H), 1.58 (tq, J = 7.2, 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H);
13C NMR (CDCl3, 100 MHz) d 171.8, 168.1, 159.7, 135.61, 135.59,
128.84, 128.80, 128.63, 128.59, 127.95, 127.94, 67.6, 57.3, 56.8,
46.8, 46.7, 21.6, and 10.3; ESI-MS m/z 397.2 [M+H]+, 419.2
[M+Na]+.
4.2.8. (4S,5R)-1,3-Dibenzyl-5-[(2E)-3-phenyl-2-propenyl-
oxycarbonyl]-2-oxo-imidazolidine-4-carboxylic acid 3j
Compound (4S,5R)-3j was prepared by the quinine-mediated
ring opening of 2 in the presence of trans-cinnamyl alcohol, and
purified by flash chromatography (AcOEt/hexane 2:1) in 91% yield
as a viscous oil. ½a D25
¼ þ22:9 (c 1.0, CHCl3); ee = 77%; IR (KBr):
ꢃ
4.2.4. (4S,5R)-1,3-Dibenzyl-5-(trifluoroethoxycarbonyl)-2-oxo-
imidazolidine-4-carboxylic acid 3d18
3028, 2941, 1752, 1665, 1450, 1239, 1198, 966, 747, 700 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 10.39 (br s, 1H), 7.42–7.27 (m, 15H),
6.63 (d, J = 16.0 Hz, 1H), 6.24 (dt, J = 16.0, 6.4 Hz, 1H), 5.18 (d,
J = 15.2 Hz, 1H), 5.09 (d, J = 15.2 Hz, 1H), 4.81–4.67 (m, 2H), 4.27–
4.12 (m, 4H); 13C NMR (100 MHz, CDCl3) d 169.3, 167.4, 159.7,
135.56, 135.13, 135.05, 134.47, 128.38, 128.19, 127.78, 127.52,
Compound (4S,5R)-3d was prepared by the quinine-mediated
ring opening of 2 in the presence of trifluoroethanol in 90% yield.
Mp: 234.8–236.4 °C;
(KBr): 3443, 2984, 1756, 1664, 1468, 1284, 1206, 1187, 750,
701 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.35–7.19 (m, 10H), 5.10
½
a 2D5
ꢃ
¼ þ3:2 (c 1.0, CHCl3); ee = 41%; IR
;

1442
J. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 1436–1443
126.30, 121.59, 65.9, 60.2, 57.1, 56.6, 46.4, 46.3; ESI-MS m/z 493.4
[M+Na]+, 509.4 [M+K]+. Anal. Calcd for C28H26N2O5: C, 71.47; H,
5.57; N, 5.95. Found: C, 71.17; H, 5.33; N, 5.76.
flash chromatography (AcOEt/hexane 1:2) to give 7 as an insepara-
ble diastereoisomeric mixture (1.17 g, 75%; 3:1 by 1H NMR). Vis-
cous oil. IR (neat): 3340, 2938, 1730, 1684, 1451, 1240, 1158,
963, 738, 701 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.34–7.13 (m,
;
15H), 5.13 (d, J = 15.2 Hz, 0.6H), 5.10 (s, 0.5H), 5.07 (s, 1.5H), 5.07
(d, J = 15.6 Hz, 0.3H), 4.86 (d, J = 15.2 Hz, 0.6H), 4.81 (d,
J = 15.2 Hz, 0.2H), 4.36 (s, 0.6H), 4.12–3.89 (m, 3.0H), 3.68 (d,
J = 8.4 Hz, 0.2H), 3.60 (d, J = 10.0 Hz, 0.6H), 3.33 (s, 0.2H), 2.99–
2.95 (m, 0.8H), 2.81–2.77 (m, 0.8H), 2.33–2.25 (m, 2.5H), 2.01 (s,
0.7H), 1.90–1.85 (m, 0.7H), 1.67–1.36 (m, 4.5H), 1.25–1.21 (t,
J = 6.8 Hz, 0.5H); 13C NMR (100 MHz, CDCl3) d 173.11, 173.05,
161.16, 160.22, 136.85, 136.55, 136.36, 135.88, 128.66, 128.60,
128.55, 128.48, 128.45, 128.39, 128.35, 128.07, 128.03, 127.99,
127.90, 127.86, 127.73, 127.57, 127.52, 127.38, 127.35, 98.9, 95.5,
68.8, 66.0, 65.9, 61.3, 60.5, 60.1, 48.6, 47.1, 46.0, 45.8, 41.2, 36.8,
34.1, 33.89, 33.85, 33.71, 33.65, 25.36, 25.14, 24.96, 24.80, 23.95,
20.83, and 14.0; ESI-MS m/z 553.4 [M+Na]+. Anal. Calcd for
4.3. (3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-furo[3,4-d]-
imidazole-2,4(1H)-dione 4
To a solution of 3g (3.92 g, 10 mmol) and granulated CaCl2
(1.11 g, 10 mmol) in anhydrous ethanol (40 mL) was added NaBH4
(1.14 g, 30 mmol) in three parts at 0 °C. The resulting mixture was
allowed to stir for 1 h at 0 °C followed by another 18 h at 25 °C.
Then 5% aq HCl (30 mL) was added and the resultant solution
was stirred for 0.5 h at 55–60 °C. To the solution, H2O (50 mL)
was added and then cooled with an ice bath. Colorless crystals pre-
cipitated and were filtered, and dried to afford 4, which was pure
enough for use (2.9 g, 90%). Mp:119.2–120.5 °C; ½a D25
¼ þ60:5 (c
ꢃ
2.0, CHCl3) [Lit.6h Mp: 119–121 °C; ½a 2D5
¼ þ61:3 (c 2.0, CHCl3)];
ꢃ
C31H34N2O4S: C, 70.16; H, 6.46; N, 5.28; S, 6.04. Found: C, 70.33;
ee = 97%; IR (KBr): 3031, 2919, 1775, 1706, 1415, 1365, 1237,
1209, 1146, 970, 754, 700, 639, 527 cmꢀ1 1H NMR (400 MHz,
;
H, 6.32; N, 5.36; S, 6.25.
CDCl3) d 7.24–7.36 (m, 10H), 5.05 (d, J = 15.2 Hz, 1H), 4.63 (d,
J = 15.2 Hz, 1H), 4.37 (dd, J = 10.4 Hz, 15.2 Hz, 2H), 4.09–4.16 (m,
3H), 3.92 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 172.7,
158.1, 136.0, 135.9, 129.0, 128.8, 128.7, 128.2, 128.0, 127.8, 70.1,
54.3, 52.4, 46.9, and 45.2; ESI-MS m/z 345.2 [M+Na]+.
4.6. Benzyl(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
To
a solution of 7 (5 g, 9.4 mmol), triethylsilane (3.29 g,
28.3 mmol) in CH2Cl2 (50 mL) was added trifluoroacetic acid
(6.45 g, 56.6 mmol) dropwise at 0 °C. After the completion of addi-
tion, the mixture was allowed to rise to rt and stirred for 12 h. The
reaction was quenched with saturated aq NaHCO3 and then
extracted with AcOEt, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by flash chromatography (AcOEt/
4.4. (3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-thieno[3,4-d]-
imidazole-2,4(1H)-dione 5
To a solution of 4 (5 g, 15.5 mmol) in DMF (5 mL) was added
AcSNa (1.8 g, 18.3 mmol) at 140 °C under the protection of argon.
The mixture was stirred at 150 °C for 45 min, then cooled to rt.
Thirty millilitres of CH2Cl2 and 30 mL of water was added, after
which the aq phase was extracted with CH2Cl2. The combined
organic phase was washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was recrystallized from iso-
propanol to afford 5 as a white solid, 3.75 g, 72%. Mp: 124–
hexane 1:2) to give 8 as a viscous oil (4.45 g, 92%). ½a D25
¼ ꢀ20:7
ꢃ
(c 1.0, MeOH); IR (neat): 3030, 2930, 1731, 1698, 1449, 1237,
1160, 968, 745, 700 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.36–7.22
;
(m, 15H), 5.12 (s, 2H), 5.05 (d, J = 15.2 Hz, 1H), 4.73 (d,
J = 15.2 Hz, 1H), 4.14 (d, J = 15.2 Hz, 1H), 3.98–3.93 (m, 2H), 3.84
(dd, J = 9.6, 5.6 Hz, 1H), 3.08–3.03 (m, 1H), 2.72 (dd, J = 12.4,
4.0 Hz, 1H), 2.66 (dd, J = 12.4, 6.0 Hz, 1H), 2.35 (t, J = 6.8 Hz, 2H),
1.69–1.30 (m, 6H); 13C NMR (100 MHz, CDCl3) d 173.1, 160.9,
136.94, 136.83, 136.00, 128.65, 128.59, 128.49, 128.19, 128.12,
127.57, 127.55, 66.09, 62.6, 61.1, 54.1, 47.9, 46.5, 34.6, 34.0, 28.5,
28.3, and 24.6; ESI-MS m/z 515.2 [M+H]+. Anal. Calcd for
126 °C;
½
a 2D5
ꢃ
¼ þ90:5 (c 1.0, CHCl3) [Lit.6h Mp: 125–126 °C;
½
a 2D5
ꢃ
¼ þ90:2 (c 1.0, CHCl3)]; IR (KBr): 3030, 2934, 2889, 1703,
1697, 1453, 1412, 1361, 1218, 1148, 1051, 997, 903, 808, 66698,
647, 581, 485 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.37–7.25 (m,
;
10H), 5.03 (d, J = 14.8 Hz, 1H), 4.68 (d, J = 15.6 Hz, 1H), 4.37 (d,
J = 15.6 Hz, 1H), 4.36 (d, J = 14.8 Hz, 1H), 4.15–4.11 (m, 1H), 3.81
(d, J = 8.0 Hz, 1H), 3.37 (dd, J = 12.4, 5.6 Hz, 1H), 3.28 (dd, J = 12.4,
2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 203.4, 158.2, 136.4,
136.2, 128.87, 128.78, 128.66, 128.0, 127.91, 127.73, 62.1, 55.8,
46.5, 45.2, and 33.0; ESI-MS m/z 361.1 [M+Na]+.
C31H34N2O3S: C, 72.34; H, 6.66; N, 5.44; S, 6.23. Found: C, 72.12;
H, 6.47; N, 5.69; S, 6.54.
4.7. Benzyl(3aS,4Z,6aR)-5-(1,3-dibenzyl-2,3,3a,4,6,6a-
hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-5-ylidene)
pentanoate 9
4.5. Benzyl(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
A mixture of 7 (5 g, 9.4 mmol), toluene (30 mL), and 18% HCl
(20 mL) was stirred at 60 °C for 5 h. After being cooled to rt, the
aq phase was extracted with toluene and the combined organic
phase was washed with satd aq NaHCO3 and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
flash chromatography (AcOEt/hexane 1:2) to give 9 as a viscous
To a suspension of zinc dust (0.528 g, 8.07 mmol) in THF
(2.0 mL) and toluene (1.5 mL) was added bromine (0.33 g,
2.06 mmol) dropwise at 10–20 °C, after which the mixture was
heated to 50 °C. Benzyl 5-iodopentanoate (1.31 g, 4.13 mmol)
was then added dropwise to the mixture at 50–60 °C. After being
stirred at the same temperature for 1 h, the zinc reagent 6 was
formed, then the mixture was cooled to 30 °C. A solution of com-
pound 5 (1.0 g, 2.95 mmol) in THF (2 mL), toluene (5 mL), DMF
(0.5 mL), and LDH–Pd0 (0.16 g, 0.15 mmol) were added in one part
and the resulting mixture was stirred at 30 °C for 24 h. Saturated
aq NH4Cl (15 mL) was added, the mixture was stirred at rt for
0.5 h, and then filtered. The filtrate was extracted with AcOEt.
The combined organic phase was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
oil (4.57 g, 95%). ½a D25
ꢃ
¼ þ154:4 (c 1.0, MeOH); IR (neat): 3029,
2930, 1732, 1696, 1449, 1236, 1158, 1027, 746, 700 cmꢀ1
;
1H
NMR (400 MHz, CDCl3) d 7.33–7.19 (m, 15H), 5.39 (t, J = 6.8 Hz,
1H), 5.07 (s, 2H), 4.83 (d, J = 16.0 Hz, 1H), 4.75 (d, J = 15.2 Hz,
1H), 4.23–4.17 (m, 2H), 4.05–3.99 (m, 2H), 3.59–3.46 (m, 1H),
2.92 (dd, J = 12.0, 3.2 Hz, 1H), 2.86 (dd, J = 12.0, 5.6 Hz, 1H), 2.29
(t, J = 7.2 Hz, 2H), 2.13–2.01 (m, 2H), 1.81–1.60 (m, 3H); 13C NMR
(100 MHz, CDCl3) d 172.3, 158.3, 137.4, 136.57, 136.49, 135.38,
128.06, 128.00, 127.87, 127.52, 127.40, 127.14, 126.97, 126.66,
124.88, 65.48, 64.04, 60.93, 58.41, 45.80, 44.36, 44.30, 36.47,
32.91, 30.37, 29.30, 28.52, and 23.50; ESI-MS m/z 513.4 [M+H]+.

J. Huang et al. / Tetrahedron: Asymmetry 19 (2008) 1436–1443
1443
Anal. Calcd for C31H32N2O3S: C, 72.62; H, 6.29; N, 5.46; S, 6.25.
References
Found: C, 72.45; H, 6.14; N, 5.31; S, 6.31.
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4.8. Benzyl(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
2. For reviews about the synthesis of (+)-biotin, see: (a) De Clercq, P. J. Chem. Rev.
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To
a solution of 9 (2 g, 3.9 mmol), triethylsilane (1.36 g,
11.7 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid
(2.67 g, 23.4 mmol) dropwise at 0 °C. After the completion of
addition, the mixture was allowed to rise to rt and stirred for
12 h. The reaction was quenched with saturated aq NaHCO3 and
then extracted with AcOEt, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by flash chromatography
(AcOEt/hexane 1:2) to give 8 as a viscous oil (1.84 g, 92%). The
spectral properties of the product were identical to those of 8
obtained from 7.
4. (a) Poetsch, E.; Casutt, M. Chimia 1987, 41, 148–150; (b) Fujisawa, T.; Nagai, M.;
Koike, Y.; Shimizu, M. J. Org. Chem. 1994, 59, 5865–5867; (c) Deroose, F. D.; De
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N.; Hiemstra, H.; Poetsch, E.; Casutt, M. Angew. Chem., Int. Ed. Engl. 1995, 34,
2391–2393; (e) Chavan, S. P.; Tejwani, R. B.; Ravindranathan, T. J. Org. Chem.
2001, 66, 6197–6201; (f) Seki, M.; Shimizu, T.; Inubushi, K. Synthesis 2002, 361–
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Puranik, V. G.; Rakeeb, A.; Deshmukh, A. S. Synthesis 2007, 1159–1164.
5. (a) Matsuki, K.; Inoue, H.; Takeda, M. Tetrahedron Lett. 1993, 34, 1167–1170; (b)
Choi, C.; Tian, S.-K.; Deng, L. Synthesis 2001, 1737–1741.
4.9. (+)-Biotin 1
6. (a) Chen, F. E.; Feng, X. M.; Zhang, H.; Wan, J. L.; Bie, L. L.; Guan, C. S.; Yang, C. S.;
Ling, X. H. Acta Pharm. Sinica 1995, 30, 824–830; . Chem. Abstr. 1996, 124,
232120; (b) Chen, F. E.; Peng, Z. Z.; Shao, L. Y.; Chen, Y. Acta Pharm. Sinica 1999,
34, 822–827; . Chem. Abstr. 1999, 133, 43370; (c) Chen, F. E.; Huang, Y. D.; Fu,
H.; Cheng, Y.; Zhang, D. M.; Li, Y. Y.; Peng, Z. Z. Synthesis 2000, 2004–2008; (d)
Chen, F. E.; Ling, X. H.; Lu, Y. X.; Peng, X. H. Chem. J. Chin. Univ. 2001, 22, 1141–
1146; . Chem. Abstr. 2001, 135, 331286; (e) Chen, F. E.; Fu, H.; Meng, G.; Luo, Y.
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2003, 2155–2160; (g) Chen, F.-E.; Dai, H.-F.; Kuang, Y.-Y.; Jia, H.-Q. Tetrahedron:
Asymmetry 2003, 14, 3667–3672; (h) Chen, F. E.; Chen, X. X.; Dai, H. F.; Kuang,
Y. Y.; Xie, B.; Zhao, J. F. Adv. Synth. Catal. 2005, 347, 549–554; (i) Chen, F. E.; Jia,
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A mixture of 8 (2.0 g, 3.89 mmol), 47% HBr (16 mL), and xylene
(12 mL) was stirred at reflux for 36 h. After being cooled to rt, the
aq phase was separated and concentrated under reduced pressure.
To the residue, 21 mL 10% aq NaOH was added. The resulting solu-
tion was added dropwise to a mixture of triphosgene (1.15 g,
3.89 mmol), activated charcoal (0.02 g), and toluene (21 mL) at
25 °C. The mixture was stirred at the same temperature for 12 h
and then filtered. The aq phase was acidified to pH 1 with concen-
trated aq HCl and cooled with ice water. The solid precipitated was
collected and washed with water to give 1 as colorless crystals
(0.76 g, 80%). Mp: 230–231 °C; ½a D22
¼ þ90:7 (c 1.0, 0.1 M NaOH)
ꢃ
(Lit.6h Mp: 231–233 °C; ½a 2D2
ꢃ
¼ þ91:2 (c 1.0, 0.1 M NaOH)); IR
7. For reviews about asymmetric alcoholysis, see: (a) Chen, Y.-G.; McDaid, P.;
Deng, L. Chem. Rev. 2003, 103, 2965–2983; (b) Spivey, A. C.; Andrews, B. I.
Angew. Chem., Int. Ed. 2001, 40, 3131–3134; (c) Atodiresei, I.; Schiffers, I.; Bolm,
C. Chem. Rev. 2007, 107, 5683–5712.
(KBr): 3359, 3308, 2961, 2469, 1941, 1707, 1480, 1318, 1270,
1154, 1015, 842, 753, 651 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d
;
11.9 (s, 1H), 6.40 (s, 1H), 6.33 (s, 1H), 4.30 (dd, J = 7.6, 5.2 Hz,
1H), 4.15–4.11 (m, 1H), 3.12–3.07 (m, 1H), 2.82 (dd, J = 12.4,
5.2 Hz, 1H), 2.57 (d, J = 12.4 Hz, 1H), 2.20 (t, J = 7.6 Hz, 2H), 1.62–
1.41 (m, 4H), 1.37–1.30 (m, 2H); 13C NMR (100 MHz, CDCl3) d
174.8, 163.1, 61.5, 59.6, 55.8, 40.0, 33.9, 28.57, 28.52, and 25.0;
ESI-MS m/z 267.2 [M+Na]+.
8. (a) Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195–196; (b) Bolm, C.;
Schiffers, I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984–6991; (c)
Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger, C. P. R. Tetrahedron:
Asymmetry 2003, 14, 3455–3467.
9. Jaeschke, G.; Seebach, D. J. Org. Chem. 1998, 63, 1190–1197.
10. (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett.
1998, 39, 3189–3192; (b) Shimizu, T.; Seki, M. Tetrahedron Lett. 2001, 42, 429–
432.
11. LDH–Pd0 was prepared according to the reference: Kantam, M. L.; Subhas, M.
S.; Roy, S.; Roy, M. Synlett 2006, 633–635. the content of palladium was
0.95 mmol/g.
4.10. X-ray crystallographic data of compound 3g
12. (a) Carey, F. A.; Tremper, H. S. J. Org. Chem. 1971, 36, 758–761; (b) Evans, D. A.;
Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033–10046; (c)
Kirsch, P.; Maillard, D. Eur. J. Org. Chem. 2006, 3326–3331; For a review about
ionic hydrogenation, see: (d) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M.
Synthesis 1974, 633–651.
Crystals of compound 3g suitable for X-ray analysis were ob-
tained by recrystallization from ethyl acetate/cyclohexane (1:1)
at room temperature. Crystallographic data (excluding structure
factors) for the structure of 3g in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 683359. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
13. Determined by 1H NMR spectra analysis (400 MHz) of 8.
14. The cross peak between H-3a (d 3.84 ppm) and H-4 (d 3.03–3.06 ppm) at
Figure 3 shows that strong NOE effects exists between the two protons and this
indicated that they had the same relative orientation (b).
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This work was supported by the DSM Nutritional Products Ltd
in Switzerland.