An improved large-scale preparation of Roche Lactone, an intermediate for the synthesis of (+)-biotin

Full text of DOI:10.1080/00304948.2015.1025640

This article was downloaded by: [New York University]
On: 16 May 2015, At: 01:08
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
An Improved Large-scale Preparation of
Roche Lactone, an Intermediate for the
Synthesis of (+)-Biotin
Fei Xiongabc, Zhong-Yuan Shenab, Xiao-Kang Liabd, Ya-Nan Penga, Hai-
Yan Zhua, Shu-Ping Zhangad, Yan-Yu Songa & Jia-Li Dua
a Department of Chemistry, University of Shanghai for Science and
Technology, Shanghai, 200093, P. R. China
b Hubei Key Laboratory of Drug Synthesis and Optimization, JingChu
University of Technology, P. R. China
c Department of Chemistry, Fudan University, Shanghai, 200043, P.
R. China
Click for updates
d School of Medical Instrument and Food Engineering, University of
Shanghai for Science and Technology, Shanghai, 200093, P. R. China
Published online: 13 May 2015.
To cite this article: Fei Xiong, Zhong-Yuan Shen, Xiao-Kang Li, Ya-Nan Peng, Hai-Yan Zhu, Shu-Ping
Zhang, Yan-Yu Song & Jia-Li Du (2015) An Improved Large-scale Preparation of Roche Lactone, an
Intermediate for the Synthesis of (+)-Biotin, Organic Preparations and Procedures International: The
New Journal for Organic Synthesis, 47:3, 242-248, DOI: 10.1080/00304948.2015.1025640
To link to this article: http://dx.doi.org/10.1080/00304948.2015.1025640
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Organic Preparations and Procedures International, 47:242–248, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1025640
OPPI BRIEFS
An Improved Large-scale Preparation of Roche
Lactone, an Intermediate for the Synthesis
of (C)-Biotin
Fei Xiong,1,2,3 Zhong-Yuan Shen,1,2 Xiao-Kang Li,1,2,4
Ya-Nan Peng,1 Hai-Yan Zhu,1 Shu-Ping Zhang,1,4
Yan-Yu Song,1 and Jia-Li Du1
1Department of Chemistry, University of Shanghai for Science and Technology,
Shanghai 200093, P. R. China
2Hubei Key Laboratory of Drug Synthesis and Optimization, JingChu University
of Technology, P. R. China
3Department of Chemistry, Fudan University, Shanghai 200043, P. R. China
4School of Medical Instrument and Food Engineering, University of Shanghai
for Science and Technology, Shanghai 200093, P. R. China
(C)-Biotin, an important water-soluble B series vitamin, is used as a food additive for ani-
mal and human health. The increasing academic and industrial interest in commercially
viable synthetic strategies for its preparation1–4 is justified by the continued growth of the
global market demand and its potential therapeutic applications as an anti-diabetic drug,5
Most of the literature on the synthesis of (C)-biotin emphasizes the importance of
(3aS,6aR)-lactone 4 as a chiral intermediate in the industrial preparation of (C)-biotin. Its
generation via the asymmetric de-symmetrization of meso-anhydrides such as 2 has been
reported.1–4 Deng’s group6 and ours7–13 reported the chiral Lewis base-catalyzed enantio-
selective methanolysis of 2 which utilized a catalytic asymmetric esterification approach
towards (3aS,6aR)-lactone 4. However, most of the reported routes could not be utilized
on manufacturing-scale because of the costly reagents required for the preparation of chi-
ral organo-catalyst and/or the complexity of the chemical process itself. Therefore, it was
deemed useful and desirable to develop a new practical and economical process.
As part of our long-standing interest in the development of an improved synthetic
route for (C)-biotin,7–14 a relatively large quantity (2~3 kg) of intermediate 4 was needed.
An alternative chiral technology for the de-symmetrization of 2 with the aid of chiral aux-
iliaries had been described15 and seemed potentially useful for scale-up and also for the
Submitted by August 10, 2014.
Address correspondence to Fei Xiong, Department of Chemistry, University of Shanghai for
Science and Technology, Shanghai 200093, P. R. China. E-mail: feixiong09@fudan.edu.cn or
fxiong@usst.edu.cn
242

Large-scale Preparation of Roche Lactone
243
recovery and recycling of the reagents for use in subsequent batches. The process
involves the diastereoselective esterification of 2 with a chiral alcohol in the presence of
tri(n-butyl)amine to generate the diastereomeric half ester, the direct precursor of
(3aS,6aR)-lactone 4. Furthermore, the chiral auxiliary (S)-(-)-1,1-diphenyl-1,2-propane-
diol could be recovered from the subsequent chemo-selective reduction step by simple
extraction of the reaction mixture. The present article describes an improved scalable pro-
cess for the synthesis of (3aS,6aR)-lactone 4 wherein its optical purity and that of the final
product. (C)-biotin, can be controlled.
Our asymmetric synthesis of 4 began by conversion of commercially available cis-
1,3-dibenzyl-2-imidazolidone-4,5-dicarboxylic acid (1) to moisture-sensitive meso-anhy-
dride 2 in quantitatively yield and nearly 100% purity using our previous patent proce-
dure.16 A particularly attractive feature is that the resulting reaction mixture may be used
for the next step directly without isolation and purification.
We next explored the scalability and reproducibility of de-symmetrization of meso-
anhydride 2 into half-ester 3 to accomplish the stereoselective production of (3aS,6aR)-lac-
tone 4. The process reported in a patent,15 utilizing 1 equiv. of tri(n-butyl)amine for the dia-
stereoselective esterification of 2 with 1.01 equiv. of (S)-(-)-1,1-diphenyl-1,2-propanediol
was followed. After compound 2 had been completely converted to 3 (HPLC), it was sepa-
rated from tri-(n-butyl)amine by washing the reaction mixture with 2 M HCl. The monoester
3 was readily obtained in 93% yield after a single recrystallization from isopropanol. Its
purity was determined by comparison with our reported values of the specific rotation of the
corresponding derivative (3aS,6aR)-lactone 4,17 obtained by selective reduction of the ester
group of 3 followed by acid-catalyzed lactonization.15 Unfortunately, under these conditions,
the diastereomeric purity of 3 was poor (78~87% de) thus putting in doubt the reproducibility
of this method and making its utility in the scale-up to a multi-kilogram scale problematic.
Our recent studies toward the synthesis of (C)-biotin,7–14 demonstrated that the mois-
ture-sensitivity of meso-anhydride 2 is deleterious to the chiral amine-mediated enantiose-
lective alcoholysis of 2 for the preparation of (3aS,6aR)-lactone 4. Thus one of the critical
points of this process would be to control the purity of meso-anhydride 2 under these
Scheme 1

244
Xiong et al.
ꢀ
cryogenic temperature conditions (¡10 C). Using the patent process made it impossible to
duplicate the diastereomeric purity of half-ester product 3 with any accuracy (78~87% de), a
problem that would evidently affect the optical purity of the final product, (C)-biotin. The
ꢀ
moisture sensitivity problem was blunted by the addition of 4A molecular sieves to the
reaction mixture. Our modified procedure led to the diastereomerically pure half-ester prod-
uct 3 (99%). In contrast to the patent method, we isolated 3 (and not its lithium salt) in 95%
yield (the patent reports only a theoretical yield) and it was purified by recrystallization
from isopropanol. Furthermore, the patent procedure does not describe the recovery of nei-
ther tri-(n-butyl)amine nor the chiral auxiliary (S)-(-)-1,1-diphenyl-1,2-propanediol in
detail. The recovery and recycling of these two compounds (in 94% and 97% yields respec-
tively) constitute an important factor in the utilization of our present method to the large
scale preparation of biotin.18 The ester group of chiral monoester 3 was efficiently reduced
into the corresponding lithium salt of the hydroxy acid upon treatment with lithium borohy-
dride at reflux followed by lactonization to the corresponding (3aS,6aR)-lactone 4 in 95%
yield and in 99% enantiomeric excess under acidic conditions.
In conclusion, an improved technology has been successfully developed for the manu-
facture of (3aS,6aR)-lactone 4, the key chiral intermediate of the industrial total synthesis of
(C)-biotin, using simple work-ups and without chromatographic separation. Chiral lactone 4
was finally obtained from the readily available cis-1,3-dibenzyl-2-imidazolidone-4,5-dicar-
boxylic acid (1) in 90% overall yield in 99% chemical and optical purity after three steps.
Experimental Section
Melting points were determined with a WRS-1B digital melting point apparatus and are
uncorrected. NMR spectra were recorded on a Bruker Avance 400 spectrometer using
TMS as an internal standard. Chemical shifts (d) are expressed in ppm. Optical rotations
were measured using a JASCO P1020 digital automatic polarimeter. Unless otherwise
noted, all the reagents were obtained from commercial sources and used as received.
cis-1,3-Dibenzyltetrahydro-2H-furo[3,4-d]imidazole-2,4,6-trione (2).-
A mixture of 1 (1.3 kg, 3.7 mol) and toluene (22.1 L) was refluxed under stirring with
azeotropic removal of water for 10 h. The reaction mixture was concentrated to a volume
of 18.5 L that was used directly in the next step. A sample of the product 2 indicated
~100% purity by HLPC analysis [mobile phase A: 85% H3PO4 (0.85 mL) and K2HPO4
(2.7 g) dissolved in 1000 mL H2O; mobile phase B: acetonitrile; gradient elution]. The
course of the reaction was monitored by HPLC and analysis with UV detection at 210 nm.
(4S,5R)-1,3-Dibenzyl-5-[(S)-1-hydroxy-1,1-diphenylpropan-2-yloxy)carbonyl]-2-
oxoimidazolidine-4-carboxylic Acid (3)
ꢀ
(S)-(-)-1,1-Diphenyl-1,2-propanediol (852.7 g, 3.74 mol) and 4A molecular sieves
(225 g) were added in one portion to a solution containing meso-cyclic anhydride 2
(1.24 kg, 3.7 mol) in toluene at ¡10ꢀC under nitrogen. After stirring for 10 min, tri(n-
butyl)amine (684.5 g, 3.7 mol) was added dropwise. After being stirred at ¡10ꢀC for
18 h, the mixture was filtered to remove the sieves and then the filtrate was concentrated
under vacuum and ethyl alcohol (1.85 L) was added. Upon addition of a solution of 2 M
HCl (11.1 L), the crude product precipitated gradually and the mixture was further stirred
for 0.5 h. The resulting solid was collected and washed with cooled isopropanol (4.6 L),

Large-scale Preparation of Roche Lactone
245

246
Xiong et al.

Large-scale Preparation of Roche Lactone
247
then dried using a nitrogen press to provide the expected product 3 (1.986 kg, 95%) as an
off-white crystalline powder which was used directly in the next step without further
purification.
To recover the tri(n-butyl)amine, the acidic aqueous phase was basified carefully
with 40% NaOH until the pH was approximately pH 11 and the solution was then sub-
jected to steam distillation to give tri(n-butyl)amine in 94% yield.
(3aS,6aR)-1,3-Dibenzyl-tetrahydro-4H-furo[3,4-d]-imidazole-2,4(1H)-dione (4)
To a solution of 3 (1.941 kg, 3.44 mol) in THF (31.0 L) was added lithium hydroxide
ꢀ
monohydrate (141 g, 3.44 mol) at 25 C. After being stirred at the same temperature for
3 h, a freshly prepared solution of LiBH4 in THF (3.7 L, 30 g/L, 5.1 mol) was added in
portions (over 1.5 hrs) and the resulting mixture was stirred under reflux for 2 h. After
evaporation under reduced pressure, the residue was dissolved in toluene (14.0 L) and the
solution washed with water (13.0 L). Then aqueous washes were treated with 2 M HCl
ꢀ
ꢀ
(4.3 L) at 60 C over 0.5 h and this solution was gradually cooled to 0 C with stirring to
complete the crystallization of 4. The resulting solid was collected, washed with cooled
water, and dried to give 4 (1.052 kg, 95%) as a white solid in 99% purity [determined by
chiral HLPC analysis, chiralcel OD-H column, mobile phase: n-hexane-isopropanol
70:30, λ D 210 nm], mp. 119.8–120.5 C; lit. mp. 120–121 C; [a] D 61.0ꢁ (c 2.0,
17
25
ꢀ
ꢀ
CHCl3); [a] D25 61.5ꢀ (c 2.0, CHCl3).
To recover the chiral auxiliary, the toluene phase was dried over Na2SO4 and concen-
trated in vacuo to give (S)-(-)-1,1-diphenyl-1,2-propanediol (827.5 g, 97%) as a white
crystalline powder, which could be reused without purification.
1H NMR (CDCl3): d 7.24-7.36 (m, 10H), 5.05 (d, 1H, J D 15.2 Hz), 4.63 (d, 1H, J D
15.2 Hz), 4.37 (dd, 2H, J D 10.4 Hz, 15.2 Hz), 4.09–4.16 (m, 3H), 3.92 (d, 1H, J D
8.0 Hz); MS (ESI): m/z D 345.2 (MCNaC, Calcd.: 345.2).
Acknowledgements
The authors gratefully acknowledged the financial support from Shanghai Municipal Edu-
cation Commission and the open project program of Hubei Key Laboratory of Drug Syn-
thesis and Optimization, JingChu University of Technology (NO. OPP2014ZD01).
References
1. P. J. De Clercq, Chem. Rev., 97, 1755 (1997).
2. M. Seki, Med. Res. Rev., 26, 434 (2006).
3. B. Xie and F. E. Chen, Chin. J. Med. Chem., 18, 468 (2008); Chem. Abstr., 153, 313361 (2009).
4. Z. Zhong, X. F. Wu and F. E. Chen, Chin. J. Org. Chem., 32, 1792 (2012); Chem. Abstr., 158,
272707 (2012).
5. M. L. Lazo de la Vege-Monroy, E. Larrieta, M. S. Gerrnan, A. Baez-Saldana and C. Fernandez-
Mejia, J. Nutr. Biochem., 24, 169(2013).
6. C. Choi, S. K. Tian and L. Deng, Synthesis, 1737 (2001).
7. J. Huang, F. Xiong and F. E. Chen, Tetrahedron: Asymmetry, 19, 1436 (2008).

248
Xiong et al.
8. H. F. Dai, W. X. Chen, L. Zhao, F. Xiong, H. Sheng and F. E. Chen, Adv. Synth. Catal., 350,
1635 (2008).
9. S. X. Wang and F. E. Chen, Adv. Synth. Catal., 351, 547(2009).
10. F. Xiong, X. X. Chen and F. E. Chen, Tetrahedron: Asymmetry, 21, 665(2010).
11. X. X. Chen, F. Xiong, H. Fu, Z. Q. Liu and F. E. Chen, Chem. Pharm. Bull., 59, 488(2011).
12. F. Xiong, F. J. Xiong, W. X. Chen, H. Q. Jia and F. E. Chen, J. Heterocyclic Chem., 50, 1078
(2013).
13. F. Xiong, X. K. Li, M. Xu, S. P. Zhang, F. E. Chen, B. Liao, H. J. Hua and J. H. He, Asian J.
Chem., 26, 3659 (2014).
14. F. Xiong, X. X. Chen Z. Q. Liu and F. E. Chen, Tetrahedron Lett., 51, 3670 (2010).
15. C. Wehrli, PCT Int. Appl. WO 0094367, 2004; Chem. Abstr., 141, 395554 (2004).
16. F. Xiong and F. E. Chen, CN 101519407, 2009; Chem. Abstr., 151, 381352 (2009).
17. F. E. Chen, H. F. Dai, Y. Y. Kuang and H. Q. Jia, Tetrahedron: Asymmetry, 14, 3667 (2003).
18. The recovered ( S)-(-)-1,1-diphenyl-1,2-propanediol and tributylamine could be used at least
five times under the same conditions without compromising either the diastereomeric purity or
the yield.