A novel synthetic strategy for the stereospecific total synthesis of (±)-biotin

Article abstract of DOI:10.1016/j.tetlet.2010.05.035

A concise and efficient TEA-mediated desymmetrization of meso-thioanhydride 6 with 5-ethoxy-5-oxopentylzinc bromine has been developed, which affords a convenient strategy for the stereospecific total synthesis of (±)-biotin 1.

Full text of DOI:10.1016/j.tetlet.2010.05.035

Tetrahedron Letters 51 (2010± 3670–3672
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A novel synthetic strategy for the stereospecific total synthesis of (± ±)-iotin
a,b
a
a
a,b,*
Fei Xiong , Xu-Xiang Chen , Zhi-Qian Liu , Fen-Er Chen
a
Fudan-DSM Joint Laboratory for Synthetic Method and Chiral Technology, Department of Chemistry, Fudan University, Shanghai 200433, People’s Republic of China
Institutes of Biomedical Sciences, Fudan University, Shanghai 200031, People’s Republic of China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and efficient TEA-mediated desymmetrization of meso-thioanhydride 6 with 5-ethoxy-5-
oxopentylzinc bromine has been developed, which affords a convenient strategy for the stereospecific
total synthesis of (± ±-biotin 1.
Received 23 March 2010
Revised 7 May 2010
Accepted 11 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Due to its unique molecular structure and significant biological
properties for human nutrition and animal health, the total chem-
ical synthesis of biotin 1, a member of important water-soluble
B-complex group of vitamins, has become indispensable to both
we describe a facile and convenient total synthesis of 1 which in-
volves a novel strategy via a desymmetrization of meso-thioanhy-
dride with carbon-based nucleophile.
In our retrosynthetic analysis, we reasoned that the selective
ionic hydrogenation of meso-thiolactol 3 would provide 2, the
direct precursor to biotin 1 (Scheme 1±. meso-Thiolactol 3 would
then in turn be accessed from 4 via a acid-catalyzed intramolecular
cyclization. Intermediate 4 could be available from the chemose-
lective reduction of the carboxyl group in compound 5 which in
1
industry and academia. Since the first successful example was re-
ported by Goldberg and Sternbach at F. Hoffmann-La Roche com-
pany in 1949, tremendous advances in the development of
various synthetic approaches toward this vitamin have been
achieved. As part of our ongoing research in this field,3 herein
2
O
O
O
HN
H
NH
H
BnN
H
NBn
H
BnN
H
NBn
H
H
H
OH
S
CO H
2
S
CO
2
Et
S
CO Et
2
Biotin 1
2
3
O
O
O
S
BnN
H
NBn
H
BnN
H
O
NBn
H
BnN
H
NBn
H
O
O
CO Et
CO Et
2
2
SH
O
SHO
4
5
6
O
BnN
H
NBn
H
O
O
O
7
Scheme 1. Retrosynthetic analysis of (± ±-biotin.
*
Corresponding author. Tel./fax: +86 21 65643811.
E-mail address: rfchen@fudan.edu.cn (F.-E. Chen±.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.035

F. Xiong et al. / Tetrahedron Letters 51 (2010) 3670–3672
3671
O
O
O
BnN
H
NBn
H
BnN
H
NBn
H
BnN
H
NBn
H
a
b
c
HO C
CO
2
H
O
2
O
O
O
S
O
8
7
6
O
O
O
S
BnN
H
O
NBn
H
BnN
H
NBn
H
BnN
H
NBn
H
d
e
OH
2
CO Et
CO Et
CO Et
2
2
SHO
SHO
5
4
3
O
O
S
BnN
H
NBn
H
HN
H
NH
H
g
f
H
H
CO
2
Et
CO H
2
S
2
(±)-Biotin, 1
Scheme 2. Reagents and conditions: (a± SOCl
4 3
NMM, THF, NaBH , 25 °C to 0 °C; (e± 2 N aq HCl, 25 °C, 82% (from 6 to 3±; (f± Et SiH, TFA, DCM, 25 °C, 91%; (g± 47% HBr, xylene, reflux, then triphosgene, activated charcoal, 80%.
2
, reflux, 4 h, 98%; (b± Na
2
SÁ9H
2
O, THF, H
2 2 4 2
O, rt, 49%; (c± Br(CH ± CO Et, Zn, DMF, THF, toluene, TEA, 25 °C; (d± cyanuric chloride,
turn would be produced in a straightforward one-pot sequence from
desymmetrization of the meso-thioanhydride 6 with C-5 functional-
ized carbon-based nucleophile (5-ethoxy-5-oxopentylzinc bro-
mine±. Compound 6 could be directly elaborated from meso-cyclic
anhydride 7 following a protocol reported previously.3
Our synthesis commenced with the preparation of meso-cyclic
anhydride 7 from the commercially available cis-1,3-dibenzyl-2-
imidazolidone-4, 5-dicarboxylic acid (8± as outlined in Scheme 2.
tion of the pentanoic acid side chain of biotin skeleton. Investiga-
tion of the structurally diverse set of chiral ligands to fulfill the
enantioselective desymmetrization of meso-thioanhydride 6 in
optically pure form to accomplish the asymmetric total synthesis
of (+±-biotin is currently under way and the results will be reported
in due course.
c,4
Acknowledgment
2
Treatment of meso-dicarboxylic acid 8 with SOCl at refluxing tem-
perature under solvent-free conditions afforded the meso-cyclic
anhydride 7 in nearly quantitative yield, which was quantitatively
This work was supported by the DSM Nutritional Products Ltd
in Switzerland.
5
converted into meso-thioanhydride 6 with a 99% purity upon treat-
ment with Na
2 2
SÁ9H O in THF at room temperature.
References and notes
With the meso-thioanhydride 6 in hand, our attention was
turned to explore an efficient and straightforward process for the
installation of the pentanoic acid side chain on biotin skeleton
through a desymmetrization of 6 with carbon-based nucleophile.
Thus, the TEA-mediated ring opening of 6 with organozinc reagent,
in situ prepared from ethyl 5-bromopentanoate and zinc powder,
was conducted in a mixed solvents of DMF/THF/toluene at 35 °C.
As expected, this reaction proceeded smoothly to afford the ring-
opening product 5. The carbonyl group of 5 was then chemoselec-
4
tively reduced with NaBH in THF at 0 °C after derivation of the thi-
ohydroxy group with cyanuric chloride in the presence of N-
methylmorpholine to afford thiol 4, subsequent treatment with
1
.
(a± Mistry, P. S.; Dakshinamurti, K. Vitam. Horm. 1964, 22, 1–55; (b± Whitehead,
C. C. Ann. N.Y. Acad. Sci. 1985, 447, 86–95; (c± Maebashi, M.; Makino, Y.;
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3
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(
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6
Chem. Abstr. 1999, 133, 43370.; (c± Chen, F. E.; Huang, Y. D.; Fu, H.; Chen, Y.;
Zhang, D. M.; Li, Y. Y.; Peng, Z. Z. Synthesis 2000, 14, 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. F.; Yang, M. G.
Chem. J. Chin. Univ. 2002, 23, 1060–1064. Chem. Abstr. 2002, 137, 279008.; (f±
Chen, F. E.; Yuan, J. L.; Dai, H. F.; Kuang, Y. Y.; Zhang, D. M.; Li, Y. Y.; Peng, Z. Z.
Synthesis 2003, 14, 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, H. Q.; Chen, X. X.; Dai, H. F.; Xie, B.; Kuang, Y. Y.; Zhao, J. F. Chem. Pharm.
Bull. 2005, 53, 743–746; (j± Chen, F. E.; Zhao, J. F.; Xiong, F. J.; Xie, B.; Zhang, P.
Carbohydr. Res. 2007, 342, 2461–2464; (k± Huang, J.; Xiong, F.; Chen, F. E.
Tetrahedron: Asymmetry 2008, 19, 1436–1443; (l± Dai, H. F.; Chen, W. X.; Zhao, L.;
Xiong, F.; Sheng, H.; Chen, F. E. Adv. Synth. Catal. 2008, 350, 1635–1641; (m±
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2
N aq HCl via acid-catalyzed intramolecular cyclization afforded
7
the key intermediate meso-thiolactol 3 in 82% overall yield and
its H NMR and mass spectra were in agreement with those we
1
3
l
previously reported. The ionic hydrogenation of 3 was realized
at room temperature by reacting with Et SiH in the presence of
the TFA to afford the desired pentanoate 2 in 91% yield. Finally,
± ±-biotin 1 was achieved by subjecting 2 to simultaneous deben-
3
3
k
(
zylation and ester hydrolysis with 47% aq HBr followed by in situ
4
.
Kates, M. J.; Schauble, J. H. J. Heterocycl. Chem. 1995, 32, 971–978.
treatment of the resulting diamineÁ2HBr with triphosgene in 80%
3k
1
13
5. Synthesis of 7: A mixture of 8 (3.54 g, 10 mmol± and thionyl dichloride (7.3 mL,
00 mmol± was stirred under reflux for 4 h. The mixture was cooled down to
2
yield after recrystallization from H O. The NMR ( H and C±
1
and mass spectra data for 1 matched well with those of authentic
25 °C and the precipitated crystals formed were filtered and dried at 80 °C in
vacuo for 3 h to give colorless product 7 (3.3 g, 98%± as a white powder. Mp
(
+±-biotin.
3c
2
37.1–237.8 °C (Lit.: 236–238 °C±.
In summary, we have uncovered a novel desymmetrization
strategy for the stereospecific total synthesis of (± ±-biotin 1. This
method should be of great value in terms of simplicity in elabora-
6.
Synthesis of 5: To a suspension of zinc powder (1.62 g, 24.8 mmol± in anhydrous
DMF (8 mL± was added iodine (0.2 g, 0.8 mmol± under nitrogen atmosphere and
the mixture was heated to 80 °C. Ethyl 5-bromopentanoate (3.45 g, 16.5 mmol±

3
672
F. Xiong et al. / Tetrahedron Letters 51 (2010) 3670–3672
was then added dropwise and the resulting mixture was kept stirring at 80 °C
for 4 h. After cooling the mixture to 25 °C, a solution of 6 (2.11 g, 6 mmol± in THF
10 mL± and toluene (10 mL± was added dropwise to a mixture of the 5-ethoxy-
-oxopentylzinc bromine in Et N (0.8 mL, 6 mmol±. The reaction mixture was
stirred for 24 h at 35 °C, and then the reaction was quenched with saturated aq
NH Cl (25 mL±. 2 N aq NaOH (30 mL± was added to the mixture, and the aqueous
layer was washed with Et O. The aqueous layer was acidified with 2 N aq HCl
and extracted with Et O. The combined organic layers were dried over MgSO
filtered, and concentrated in vacuo to give the crude product 5, which was
subjected to next step without further purification.
Synthesis of 3: To a solution of cyanuric chloride (1.66 g, 9 mmol± in THF (25 mL±
at 25 °C was added N-methylmorpholine (0.79 g, 7.8 mmol±, and then the
solution of 5 (2.89 g, 5 mmol± in THF (25 mL± was added in one portion into the
mixture. After stirring for 3 h, the reaction mixture was filtered and a solution of
NaBH (0.48 g, 12.6 mmol± in H O (11 mL± was added dropwise into the filtrate
4
2
(
5
at 0 °C. The resulting mixture was stirred for 10 min after which 2 N aq HCl
(55 mL± was added to the mixture. The resulting mixture was stirred at 25 °C for
3 h and then extracted with AcOEt (3 Â 30 mL±. The combined organic layers
3
4
2 4
were washed with brine, dried over Na SO , and concentrated in vacuo. The
2
residue was purified by chromatography on a silica gel column (AcOEt/PE = 2/1±
to afford 3 (2.30 g, 82%± as a colorless oil. IR (KBr±: = 2961, 2594, 1670, 1387,
±: d = 7.24–7.32 (m, 10H±, 5.10 (d, 1H,
2
4
,
m
À1
1
1259, 665 cm
;
H NMR (CDCl
3
J = 15.6 Hz±, 4.88 (d, 1H, J = 15.6 Hz±, 4.10–4.20 (m, 4H±, 4.02 (d, 1H,
J = 22.4 Hz±, 3.94 (d, 1H, J = 22.4 Hz±, 3.65 (m, 1H±, 2.72 (m, 2H±, 2.24–2.33 (m,
4H±, 1.60–1.62 (m, 2H±, 1.44–1.45 (m, 2H±, 1.23–1.27 (m, 3H±; ESI-MS m/z 469
7
.
+
[M+H] .