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School of Pharmaceutical Sciences & Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou 450001, China
Department of Urology, University of California, Irvine, Orange, CA 92868, USA
Author to whom correspondence should be addressed.
Molbank 2018, 2018(3), M1016;
Received: 11 August 2018 / Revised: 25 August 2018 / Accepted: 28 August 2018 / Published: 30 August 2018
(This article belongs to the Collection Molecules from Catalytic Processes)


Efficient large-scale and feasible industrial synthesis of the 1-oxacephem core structure from 6-aminopenicillanic acid (6-APA) has been reported for several decades. Via the industrial synthesis route, a byproduct (compound 9) containing a butenolide unit was purified and characterized by NMR and HRMS in this work. It is worth noting that compound 9 is an entirely new compound. Additionally, a plausible mechanism and effects on the formation of 9 by different Lewis acids were proposed. The discovery of compound 9 could improve the purity of this feasible industrial synthesis and provide considerable cost savings.
Keywords: industrial feasible synthesis; 6-APA; butenolide; 1-oxacephem industrial feasible synthesis; 6-APA; butenolide; 1-oxacephem

1. Introduction

Antibacterial substances are of great importance and necessity in treating infectious diseases caused by pathogenic bacteria [1,2,3]. Due to its unique antimicrobial activity and novel structure among the synthetic antibiotics, the 1-oxacephem core structure as an important pharmaceutical scaffold has attracted immense interest from medicinal chemists [4,5,6]. A variety of synthetic compounds prepared from the 1-oxacephem intermediate, including prominent antibiotics such as Flomoxef, Moxalactam, and OCP-9-176 (Figure 1), have a broad spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria [7,8,9].
A feasible industrial route by which to synthesize 1-oxacephem 8 in good yield starting from commercially available 6-aminopenicillanic acid (6-APA) (Figure 2) was reported by Nagata of the Shionogi company [10,11]. In this sophisticated method designed to retain all the carbon atoms, preparing epioxazolinoazetidinones having an unconjugated ester moiety at the β-lactam nitrogen was a breakthrough. However, byproducts of and probable mechanisms in this industrial synthesis of 1-oxacephem 8 have not been systematically explored. In this work, we focused on the byproduct 9 ((1R,5S)-6-(4-methyl-2-oxo-2,5-dihydrofuran-3-yl)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one).

2. Results and Discussion

Intramolecular etherification proceeded from the less-hindered β side with stereoselectivity to furnish a versatile exomethylene intermediate 7 in 79% yield and accompanied by a byproduct 9 in 15% yield. The probable mechanism which afforded the butenolide 9 catalyzed by boron fluoride ethyl ether involved two reactions: (a) an intramolecular transesterification and (b) isomerization of the double bond promoted by a Lewis acid (Scheme 1).
Systematic studies of the reaction conditions to obtain byproduct 9 in highest yield revealed that Lewis acids played key roles (Table 1). When the reaction was catalyzed by BF3·Et2O and Yb(OTf)3, the major product was compound 7 (Table 1, entries 1 and 6) with yields of 90% and 56%, respectively. Our best result was achieved with BF3·Et2O at 25 °C, conditions in which 7 was formed in 90% yield, along with only a small amount of readily separable 9 (Table 1, entry 1). When the Lewis acid was changed to LiCl or ZnCl2, byproduct 9 was obtained as a dominant product (Table 1, entries 2, 3, 4).
To our surprise, when EtOH was used as the solvent instead of EtOAc (Table 1, entry 3), the yield of byproduct 9 increased to 92%. These results suggested that ethyl alcohol and Lewis acid LiCl were suitable for this transformation to generate the byproduct 9 in an excellent yield.

3. Materials and Methods

3.1. General Information

All the reactions were monitored by thin-layer chromatography. The byproducts were purified by column chromatography over silica gel (Qingdao Haiyang Chemical Co., 200–300 mesh, Qingdao, China). Melting points were determined on a Beijing Keyi XT4A apparatus (Beijing synthware glass, Beijing, China). All NMR spectra were recorded with a Bruker DPX 400 MHz spectrometer (Agilent, Santa Clara, CA, USA) with TMS as the internal standard. Chemical shifts are given as δ ppm values relative to TMS. Mass spectra (MS) were recorded on an Esquire 3000 mass spectrometer (Varian, Palo Alto, CA, USA) by electrospray ionization (ESI).

3.2. Synthesis of (1R,5S)-6-(4-Methyl-2-oxo-2,5-dihydrofuran-3-yl)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one (9)

A solution of LiCl (1 mol %) was added to intermediate 6 (1 eq, 1 g) in EtOH (10 mL) in a round-bottom flask and reacted at room temperature for 7 h. The reaction system was evaporated to give a residue, which was purified by silica gel flash column chromatography (EtOAc/n-hexane = 1:7) to afford the product 9, yield 92%. White solid; m.p. 199.2–200.3 °C; [α] D 25 + 18.9° (C 1.05, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 6.81 (d, J = 3.3 Hz, 1H), 5.45 (d, J = 3.3 Hz, 1H), 4.73 (s, 2H), 2.18 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 168.64, 167.16, 163.73, 148.48, 132.40, 128.59, 128.50, 126.73, 119.77, 84.70, 82.26, 71.77, 13.17; HRMS (ESI): m/z calcd for C15H12N2O4 (M + H)+, 285.0875; found, 285.0880.

4. Conclusions

In summary, byproduct 9 was obtained in the industrial synthesis of the 1-oxacephem core structure from 6-aminopenicillanic acid. To the best of our knowledge, this is the first report about the byproduct 9. We explored the effects on the formation of azetidinone-fused butenolide 9 caused by different Lewis acids and explored its probable mechanism of formation. The study of byproduct 9 is valuable for efficient large-scale and feasible industrial synthesis of the 1-oxacephem core structure.

Supplementary Materials

Supplementary materials are available online.

Author Contributions

D.-J.F. and E.Z. designed and synthesized the compounds. V.P., M.-A.T., L.S. and X.Z. revised the manuscript. D.-J.F. wrote the manuscript and H.-M.L. was responsible for the correspondence of the manuscript. All authors read and approved the final manuscript.


Thanks for the funding of Zhengzhou University.


This work was supported by MEDCHEMEXPRESS. Our thanks to the MCE Award for Scientists Promoting Biology and Medicine Research, and to the CSC scholarship.

Conflicts of Interest

The authors declare no conflict of interest.


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Figure 1. Synthetic 1-oxacephem antibiotics.
Figure 1. Synthetic 1-oxacephem antibiotics.
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Figure 2. Feasible industrial synthesis of 1-oxacephem 8.
Figure 2. Feasible industrial synthesis of 1-oxacephem 8.
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Scheme 1. The probable mechanism of formation of 9 catalyzed by a Lewis acid (BF3·Et2O).
Scheme 1. The probable mechanism of formation of 9 catalyzed by a Lewis acid (BF3·Et2O).
Molbank 2018 m1016 sch001
Table 1. Screening of the reaction conditions.
Table 1. Screening of the reaction conditions.
EntryLewis Acid aTemperatureSolventYields of 7 bYields of 9 b
1BF3·Et2O25 °CEtOAc90%1%
2LiCl25 °CEtOAc33%60%
3LiCl25 °CEtOH1%92%
4ZnCl225 °CEtOAc29%65%
5FeCl325 °CEtOAc46%42%
6Yb(OTf)325 °CEtOAc56%36%
a 1 mol % Lewis acid was used. b Isolated yields.
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