An Efficient Method for the Resolution of Key Intermediate to D-Biotin via Chiral Amines

Article abstract of DOI:10.1081/SCC-120002519

An efficient method for the resolution of key intermediate to D-biotin in high chemical and optical yields is reported.

Full text of DOI:10.1081/SCC-120002519

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AN EFFICIENT METHOD FOR THE RESOLUTION OF KEY
INTERMEDIATE TO D-BIOTIN VIA CHIRAL AMINES
Yin-Xiang Lü a , Yong-Ming Huang a , Yue-Fang Huang b & Yang Lu a
a Department of Chemistry , Fudan University , Shanghai, 200433, P.R. China
b Research Centerfor Analysis and Measurement , Fudan University , Shanghai, 200433,
P.R. China
Published online: 16 Aug 2006.
To cite this article: Yin-Xiang Lü , Yong-Ming Huang , Yue-Fang Huang & Yang Lu (2002) AN EFFICIENT METHOD FOR THE
RESOLUTION OF KEY INTERMEDIATE TO D-BIOTIN VIA CHIRAL AMINES, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 32:5, 781-784, DOI: 10.1081/SCC-120002519
To link to this article: http://dx.doi.org/10.1081/SCC-120002519
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SYNTHETIC COMMUNICATIONS, 32(5), 781–784 (2002)
AN EFFICIENT METHOD FOR THE
RESOLUTION OF KEY INTERMEDIATE
TO D-BIOTIN VIA CHIRAL AMINES
Yin-Xiang Lu,1 Yong-Ming Huang,1,
*
Yue-Fang Huang,2 and Yang Lu1
2
1Department of Chemistry, Research Center for
Analysis and Measurement, Fudan University,
Shanghai, 200433, P.R. China
ABSTRACT
An efficient method for the resolution of key intermediate to
D-biotin in high chemical and optical yields is reported.
D-biotin, referred to as vitamin H or coenzyme R, was widely distrib-
uted in animals and plants. More of its functions had been recognized and
these findings had led to a timeless challenge for total synthesis of it.1
Enantiomerically pure alcohol 4-hydroxythieno[3,4-d]imidazole-2-one
(Q)-2 was an important intermediate in independent routes to D-biotin.2,3 In
the formal report,4,5 it was prepared by resolution via the corresponding
diastereomeric ethers, but the process was not very good for the material
4-chloroethieno[3,4-d]imidazole-2-one (6)-1 was not stable when exposed to
the air or light, the most efficient chiral auxiliary, (S)-(þ)-mandelic acid, was
more expensive and the final yield was not high when repeated.
*Corresponding author.
781
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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782LU
ET AL.
In this paper, for the preparation of enantiomerically pure alcohol
(Q)-2, required the following steps (see scheme): (a) reaction of anhydride
with racemic alcohol (6)-2 in pyridine leading to the corresponding racemic
ester (6)-3, (b) resolution of ester (6)-3 by salt formation with (þ)-amines in
methanol, ethanol or 2-propanol and recrystallization from the same solvent,
(c) recovery of the enantiomerically pure ester (Q)-3 as a dark red oil from the
salt by ethyl acetate–2 N H2SO4 extraction, and (d) hydrolysis of the ester
(Q)-3 in base solution to afford alcohol (Q)-2. Chiral GC analysis of ester
(Q)-3, previously methylated by diazomethane, indicated enantiomeric
excesses higher than 90%, the results were summarized in the table.
In conclusion, comparing to the literature method, the procedure
had following advantages: high chemical and optical yields, cheap chiral
Scheme.
Table. Results for the Preparation of Ester (Q)-3
Yielda (%)
e.e. (%)
3IIc
Entry
Amine
Solvent
3Ib
3IIc
3Ib
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
methanol
methanol
ethanol
2-propanol
ethanol
methanol
ethanol
2-propanol
2-propanol
38.2
41.6
40.3
44.2
43.5
45.041.4
42.8
33.035.2
34.2
36.7
38.6
40.9
42.3
39.7
94
98
96
99
98
96
91
93
98
93
99
95
38.3
30.1
97
91
91
94
90 92
aRefers to isolated yield according to alcohol (6)-2 as the starting material. bPhthalic
c
anhydride as the reacting material. Maleic anhydride as the reacting material.

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D-BIOTIN
783
auxiliaries, and convenient work-up, especially, the amines could be recov-
ered in good yields. Hence its commercial advantage was obvious.
EXPERIMENTAL
All melting points were uncorrected. IR spectra were recorded on a
Nexus FI-IR 470spectrophotometer. 1H NMR spectra were measured on
Bruker MSL-300 instrument using TMS as internal standard. Elemental
analyses were performed on a Carlo Erba 1106-type analyzer. Optical rota-
tions were taken on a WZZ-15 automatic polarimeter. GC analyses were
performed on b-DEXTM 120(GC-14BPTF). The amines were prepared
according to the known procedure,6–9 other reagents were purchased from
Aldrich Chemical Co. All reactions were carried out under nitrogen and
stirred magnetically.
General Procedure for the Preparation of Ester (Q)-3
A mixture of racemic alcohol (6)-2 (1.7 g, 5.0mmol), anhydride
(5.0mmol), pyridine (1 ml) and toluene (20ml) was stirred at 100 ꢀC for
2 h. After cooling, ethyl acetate (50ml) and 2 N H 2SO4 (2 ml) were added.
The organic phase was separated, washed with saturated brine, dried with
Na2SO4, and concentrated to give the racemic ester (6)-3 as dark red oil, the
oil was diluted in methanol, ethanol or 2-propanol (20ml) and treated at
65ꢀC with (þ)-amines (5 mmol). After slow cooling to about 5ꢀC, the pre-
cipitate was recovered by filtration and rinsed with the same cold alcohol.
The resulting solid was dried, refluxed with methanol, ethanol or 2-propanol
(20ml) for 1.5 h, cooled at 0 ꢀC, and filtered to give the pure salt between
ester (Q)-3 and (þ)-amines, the salt was suspended in ethyl acetate. After
removing (þ)-amines by acidic washing with H2SO4, the solvent was eva-
porated under vacuum to give the enantiomerically pure ester (Q)-3 as dark
red oil. To the water phase, 2 N NaOH was added, extracted with ethyl
acetate to afford (þ)-amines in good yields (>30% of the starting amines).
Select Analytical Data for Ester (Q)-3I (As Dark Red Oil)
IR (KBr): 3065, 2927, 1756, 1700, 1468, 1436 cmÀ1
;
1H NMR
(300 MHz, CDCl3), d, ppm: 2.74 (d, 1H, J ¼ 10.4 Hz), 3.06 (2d, 1H, J ¼ 4.1,
10.4 Hz), 3.68 (d, 1H, J ¼ 7.6 Hz), 4.20(2d, 1H, J ¼ 4.7, 7.9 Hz), 4.22, 4.36,
4.60, 4.78 (4d, 4H, J ¼ 14.3 Hz), 5.10(s, 1H), 7.01–7.68 (m, 14H); MS (EI),

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784
LU ET AL.
m/z: 488 (Mþ): Elem. anal., found% (calcd for C27H24N2O5S): C 66.2 (66.4),
30
H, 4.90(4.92), N 5.78 (5.74); ½aꢁD +130(c, 0.2, CHCl 3).
Select Analytical Data for Ester (Q)-3II (As Dark Red Oil)
IR (KBr): 3274, 2967, 2689, 2496, 1702, 1658, 1584, 1452 cmÀ1
;
1H NMR (300 Hz, CDCl3), d, ppm: 2.65 (d, 1H, J ¼ 10.8 Hz), 3.01 (2d, 1H,
J ¼ 4.1, 10.4 Hz), 3.48 (d, 1H, J ¼ 8.6 Hz), 3.86 (dd, 2H, J ¼ 7.8 Hz), 4.25
(2d, 1H, J ¼ 5.6, 7.4 Hz), 4.20, 4.44, 4.68, 4.82 (4d, 4H, J ¼ 13.3 Hz), 5.16 (s,
1H), 7.31–7.73 (m, 10H); MS (EI), m/z: 438 (Mþ); Elem. anal., found %
(calcd for C23H22N2O5S): C 62.64 (63.01), H 4.99 (5.02), N 6.38 (6.39);
30
½aꢁD +180(c, 0.5, CHCl 3).
General Procedure for the Preparation of Alcohol (Q)-2
The ester (Q)-3 (1.0mmol) was refluxed with 2 N NaOH (10ml) in
1,4-dioxane (20ml) for 4 h. The solvent was evaporated, water was added,
and the product was extracted into chloroform (5 ꢂ 10ml). The organic
extract was washed with saturated brine, dried over Na2SO4. The solvent
was evaporated, and the solid was recrystallized from dichloromethane and
hexane to give the enantiomerically pure alcohol (Q)-2 (0.30 g, 91%):
30
m.p. 164–166ꢀC, ½aꢁD +75:8 (c, 0.6, CHCl3). (literature4: m.p. 164–165ꢀC,
22
½aꢁD +76:0(c, 0.76, CHCl 3)).
REFERENCES
1. De Clercq, P.J. Chem. Rev. 1997, 97, 1755.
2. Holick, W.; Pauling, H. Eur. Patent Appl. 1985, 154, 225.
3. Gerecke, M.; Zimmermann, J.P.; Aschwanden, W. Helv. Chim. Acta
1970, 53, 991.
4. Bihovsky, R.; Bodepudi, V. Tetrahedron 1990, 46, 7667.
5. Bates, H.A.; Rosenbium, S.B. J. Org. Chem. 1986 51, 3447.
6. Gottarelli, G.; Samorl, B. J. Chem. Soc. (B) 1971, 2418.
7. Org. Synth., Coll. 1947, 2, 503.
8. Wu, M.J.; Pridgen, L.N. J. Org. Chem. 1991, 56, 1340.
9. Gu, M.M.; Jia, Y.Y.; Yao, Z.P. Experiment for Organic Chemistry.
Fudan University: Shanghai, 1991; 231 and 311.
Received in Japan October 30, 2000

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