( 1 R , 5 S )-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

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.


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].

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.

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.

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 BF 3 •Et 2 O 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 BF 3 •Et 2 O 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 ZnCl 2 , 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.

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).

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).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.

Table 1 .
Screening of the reaction conditions.

Lewis Acid a Temperature Solvent Yields of 7 b Yields of 9 b
a 1 mol % Lewis acid was used.b Isolated yields.

Table 1 .
Screening of the reaction conditions.
a 1 mol % Lewis acid was used.b Isolated yields.