Direct Access to Substituted 4-CF3 β-Lactams at the C-3 Position

Mono- and disubstituted 4-CF3 β-lactams at the C-3 position have been obtained stereoselectively under basic conditions. A wide range of function such as alcohols, alkyls, aryls, esters, and double and triple bonds have been introduced.

INTRODUCTION β-Lactams (2-azetidinones) are of major interest not only for their biological properties, such as antibiotics (Georg, 1993) and enzyme inhibitors (Alcaide et al., 2007), but also for their usefulness as intermediates in organic chemistry, for example, in the synthesis of peptidomimetics and alkaloids (Ojima, 1995). 2-Azetidinones motivated the scientific community to study and exploit them. Thus, several methods of β-lactam synthesis have been developed (Pitts and Letcka, 2014;Hosseyni and Jarrahpour, 2018).

RESULTS AND DISCUSSION
Herein, we disclose the straightforward synthesis of mono-and difunctionalized 4-CF 3 β-lactams at the C-3 position. First, 4-CF 3 β-lactams 1 and 2 were synthesized according to the literature (Trulli et al., 2018), and the same method was applied to the synthesis of the N-PMBn protected GRAPHICAL ABSTRACT | Stereoselective access to C-3 mono-and disubstituted 4-CF 3 β-lactams under basic conditions. SCHEME 1 | Approaches of C-3 monosubstituted 4-CF 3 β-lactams. 4-CF 3 β-lactam 3. Then, we attempted the C-3 monodeprotonation of the 4-CF 3 β-lactams 1-3 (Trulli et al., 2018) with diverse bases such as LDA, LiHMDS, and LTMP. Thus, the addition of benzaldehyde at different conditions (temperature, time, concentration of base) was conducted. The best conditions were achieved when 1.5 eq of LiHMDS in THF at −25 • C was applied for 30 min, followed by the addition of 2 eq of aldehyde. The reaction mixture was kept for an additional 2 h at the same temperature and then it was let warm at room temperature overnight. The reaction is stereoselective and the best yields in corresponding 3-functionalized β-lactams 4 were obtained from 1 possessing the para-methoxyphenyl group. From β-lactams 2 and 3, moderate yields were obtained. Our significant results are summarized in the following Table 1. The relative configuration was determined by 1 H-NMR according to the coupling constant of cis (3R * , 4S * ) (6 Hz) and trans (3S * , 4S * ) (3 Hz) between H-3 and H-4. The addition occurred exclusively from the opposite side of the bulky trifluoromethyl substituent. This result has already been observed during our reactions of Li/Br exchange from 3-Br 4-CF 3 lactams and aldehydes (Decamps et al., 2014).
With these efficient conditions in hand, other electrophilic reagents have been investigated with the 4-CF 3 β-lactam 1 ( Table 2). Aldehydes were trapped by the enolate to afford the corresponding 3-functionalized 4-CF 3 β-lactams 7 and 8 as a mixture of diastereoisomers. Products were isolated and separated in good yields and with excellent stereoselectivity. The relative configuration of compounds 7 and 8 is trans (3S * , 4S * ). Compounds 7 and 8 prepared from Li/Br exchange at −100 • C were obtained with an inverse stereoselectivity (Decamps et al., 2014). Next, the reactivity of alkyl halides has been undertaken. When reaction was performed with 1.2 eq of MeI, a mixture of C-3 mono-and disubstituted lactams 9 and 14 was obtained ( Table 2, entry 3). Thus, with 2 eq of MeI, the product 14 was exclusively obtained in good yield (68%) ( Table 2, entry  4). Similarly, with 1.2 eq of EtI, the same dependence was observed (Table 2, entry 5), but with 2 eq of EtI, C-3 disubstituted product 15 was obtained in much lower yield compared to 14 ( Table 2, entry 6), due to the formation of a large number of unexpected products. From 1.2 eq of allyl bromide, C-3 mono-and disubstituted lactams were isolated ( Table 2, entry  7). Surprisingly, with the propargyl bromide, only the C-3 monosubstituted azetidinone 12 was obtained (Table 2, entry 8).
Regrettably, when 2 eq or more of allyl or propargyl bromide was used, many side products were present in the crude mixture. With another type of electrophile, the ethyl chloroformate, the C-3 monosubstituted lactam was obtained with 1.2 eq, and a mixture of C-3 mono-and disubstituted was observed with 2 eq (Table 2, entries 9 and 10, respectively). No improvement was observed when temperature and solvent, base, and its concentration were modified. Moreover, in almost each case, yields of the products were poor to moderate.
To synthesize C-3 disubstituted 4-CF 3 β-lactams, we started our studies with the previous conditions involving LiHMDS in THF at −25 • C and MeI as electrophile with the 3-Me 4-CF 3 β-lactams 9. Fortunately, the corresponding C-3 disubstituted compound 14 was obtained in excellent yield (86%). Due to this new result, we investigated first the synthesis of non-symmetrical C-3 disubstituted 4-CF 3 β-lactams from 9 (Scheme 4). From alkyl halides such as EtI, allyl, and propargyl bromides corresponding to 4-CF 3 β-lactams 19-21 were obtained in reasonable to good yields and in excellent stereochemical purity (Scheme 4). From the ethyl chloroformate, the lactam 22 was obtained in 45% yield. Interestingly, 4-CF 3 β-lactams 20-22 are very attractive because of the presence of various functions for functionalizing them or incorporating into bioactive molecules for example. Likewise, the reaction gave very SCHEME 2 | Approaches of C-3 disubstituted 4-CF 3 β-lactams. good results with the aldehydes, which led to alcohols 23-25 with an excellent stereoselectivity. Then, we investigated reactions of 3-Ph 4-CF 3 β-lactams 18 with the same electrophiles using the previous conditions (Scheme 5). Unfortunately, with aldehydes, only traces of products were detected. This surprising result could be explained by the steric hindrance of the 3-Ph group in 18 relative to the 3-Me group in 9. Nevertheless, we investigated the reactions with the other electrophiles. In the case of the methyl and ethyl iodides, the reactions occurred to incorporate the methyl and the ethyl group in α position of the phenyl group. Compounds 26 and 27 were isolated in good yield, 73 and 69%, respectively. Reasonable yields were obtained with the allyl and the propargyl bromides, 53% (28) and 47% (29), respectively. The chloroformate reacted with the enolate intermediate, leading to the desired 4-CF 3 β-lactam 30 in 50% yield.
All products 14 and 19-30 were isolated pure and with an excellent stereoselectivity. Furthermore, if reactions were performed with lactams 9 or 18 as a cis or trans or in mixture, the results were the same, which means that the enolate intermediate is identical regardless of the ratio cis/trans. Then, the addition of the electrophile occurred at the opposite of the CF 3 group. Thus, we can suppose the following mechanism reported in Scheme 6.
The configuration of the addition products of different electrophiles to enolate was studied and determined by NMR analysis of compounds 19-30. For each product, 2D 1 H-19 F HOESY NMR spectra were performed. We observed correlation between the CF 3 group and the 3-Me or 3-Ph group and correlation between CF 3 and geminal proton due to the bulkiness of this substituent. As an example, for the product 23a, the 1 H-19 F HOESY spectrum (see Supplementary Figure 1) showed correlations for the both mentioned interactions of the CH 3 with CF 3 as well as CHCF 3 with CF 3 on the same intensity level.

Experimental Section
General Methods 1 H NMR, 13 C NMR, 19 F NMR, and 31 P NMR spectra were performed on Bruker ASCEND 600 (600 MHz) spectrometers. All 2D and 1D selective NMR spectra were recorded on a Bruker ASCEND 600 (600 MHz) spectrometer. Chemical shifts of 1 H NMR were expressed in parts per million downfield from tetramethylsilane (TMS) as an internal standard (δ = 0) in CDCl 3 . Chemical shifts of 13 C NMR were expressed in parts per million downfield and upfield from CDCl 3 as an internal standard (δ = 77.0). Chemical shifts of 19 F NMR were expressed in parts per million upfield from CFCl 3 as an internal standard (δ = 0) in CDCl 3 . All d.r. were evaluated on the basis of 19 F NMR reaction mixture. High-resolution mass spectra were recorded by electron spray (MS-ESI) techniques using a QToF Impact HD Bruker spectrometer. Reagent grade chemicals were used. THF was dried by refluxing with sodium metal-benzophenone TABLE 2 | Reactions of C-3 substituted 4-CF 3 β-lactam 1 with electrophiles.
(THF) and distilled under argon atmosphere. All moisturesensitive reactions were carried out under argon atmosphere using oven-dried glassware. Reaction temperatures below 0 • C were performed using a cooling bath (liquid N 2 /n-hexane or liquid N 2 /i-PrOH

General Procedure of the Synthesis Reformatsky Reaction of PMP-Aldimine With Methyl-and Phenyl-α-Bromo Esters
In a round-bottom flask, zinc (30 mmol) activated by acetic acid, dry THF (15 mL), trifluoromethyl aldimine (25 mmol), and 2bromo ester (30 mmol) were added under an argon atmosphere. The suspension was warmed to 50 or 60 • C and stirred at the same temperature (6 h). The mixture was quenched with saturated aqueous NH 4 Cl (5 ml) and then extracted with Et 2 O (7 × 10 ml).
The organic layers were washed with brine, dried over MgSO 4 , filtrated, and concentrated under reduced pressure to give the crude mixture that was purified using column chromatography (hexane/ethyl acetate or cyclohexane/ethyl acetate).

General Procedure of the Reactions of 4-CF 3 β-lactams With Electrophiles
In a round-bottom flask, dry THF (2 ml) was cooled to −25 • C and then LiHMDS (1.0 M in THF, 0.75 mmol) was added dropwise under an argon atmosphere. Then, the solution of βlactam (0.5 mmol) in dry THF (1 ml) was added. The suspension was stirred at the same temperature for 30 min and then the electrophile (1 or 0.6 mmol) was added dropwise (p-BrPhCHO was dissolved in 1 ml of dry THF). Then, the reaction mixture was stirred at the same temperature for 2 h and left overnight at room temperature. Then, the reaction mixture was cooled to 0 • C and carefully quenched by dropwise addition of saturated aqueous NH 4 Cl (1 ml), and then extracted with Et 2 O (2 × 5 ml). The organic layers were washed with brine, dried over MgSO 4 , filtrated, and concentrated under reduced pressure and purified using column chromatography (hexane/ethyl acetate or cyclohexane/ethyl acetate).

CONCLUSION
In conclusion, we developed a convenient and highly diastereoselective synthesis of C-3 mono-and disubstituted 4-CF 3 β-lactams. We showed that the enolate of 4-CF 3 β-lactams can be formed under basic conditions and then undergoes reaction with various electrophiles. These wide ranges of 4-CF 3 β-lactams variously functionalized are excellent synthons for constructing products of interest or for incorporating them into bioactive molecules.

DATA AVAILABILITY
All datasets generated for this study are included in the manuscript/Supplementary Files.

AUTHOR CONTRIBUTIONS
TC and BC carried out manuscript writing. MS carried out chemical synthesis, characterization, and manuscript writing. TM and MK contributed to manuscript writing and revision. BC, TC, and HK designed and managed the study. All authors listed have made substantial, direct, and intellectual contributions to the work, and approved it for publication.

FUNDING
This work was supported by grant no. POWR.03.02.00-00-I023/17 co-financed by the European Union through the European Social Fund under the Operational Program Knowledge Education Development.