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Article

Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis

by
Anna Ananeva
1,
Olga Bakulina
1,*,
Dmitry Dar’in
1,
Grigory Kantin
1 and
Mikhail Krasavin
1,2,*
1
Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, 198504 Peterhof, Russia
2
Institute of Living Systems, Immanuel Kant Baltic Federal University, 236041 Kaliningrad, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(8), 2469; https://doi.org/10.3390/molecules27082469
Submission received: 16 March 2022 / Revised: 3 April 2022 / Accepted: 8 April 2022 / Published: 11 April 2022
(This article belongs to the Section Organic Chemistry)
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Versions Notes

Abstract

A N-(2-methoxy-2-oxoethyl)-N-(phenylsulfonyl)glycine monomethyl ester of the respective dicarboxylic acid was involved in a reaction with imines promoted by acetic anhydride at an elevated temperature. Instead of the initially expected δ-lactam products of the Castagnoli–Cushman-type reaction, medicinally important 3-amino-2-azetidinones were obtained as the result of cyclization, involving a methylene group adjacent to an acid moiety. In contrast, replacing alcohol residue with hexafluoroisopropyl in the same substrate made another methylene group (adjacent to the ester moiety) more reactive to furnishing the desired δ-lactam in the Castagnoli–Cushman fashion.

1. Introduction

Lactams of various ring sizes (β [1], γ [2], δ [3], ε [4], denoting 4-7-membered rings, respectively, and larger [5]) represent one of the most important heterocyclic moieties employed in medicinal chemistry and drug design [6]. While the size of the lactam ring has a strong bearing on the chemical and physicochemical properties [7] of the lactam-containing compounds as well as their specific biological activity profile [8], the broadly defined lactam chemical class can be confidently defined as privileged [9], i.e., capable of delivering compounds endowed with diverse biological activities (Figure 1). This mandates the development and constant broadening of the current arsenal of synthetic methods to access lactam scaffolds, all with feasible substitution patterns for de novo biological target interrogation and the subsequent medicinal chemistry optimization of the hits emerging from biological screening campaigns.
Aside from conventional methods of building the lactam core, such as intramolecular amine N-acylation (lactamization) [10], intramolecular amide N-alkylation [11], carbon–carbon-bond-forming reactions [12], various annulation approaches [13,14], the oxidation of cyclic amines [15] and reduction of cyclic imides [16], the reaction of cyclic C-H anhydrides 1 with imines, dubbed the Castagnoli–Cushman reaction [17], represents an efficient way to access 5- to 7-membered [4,18] polysubstituted lactams, often in a diastereoselective fashion [19].
Recently, we demonstrated that, in the well-known synthesis of tetrahydroisoquinolonic acids from imines and homophthalic anhydride (HPA), the latter can be efficiently replaced with 2-(2-methoxy-2-oxoethyl)benzoic acid (2) (HPA monoester) activated by CDI (1,1′-carbonyldiimidazole). This allowed tetrahydroisoquinolonic esters 3 to be obtained and the Castagnoli–Cushman chemistry reaction to be planted onto a new reagent space that did not require the use of cyclic anhydrides [20]. Encouraged by this finding, we proceeded to investigate if the same approach could be extended to dicarboxylic acid monoesters, such as 4, X = NSO2Ph (Scheme 1). Herein, we report our findings obtained during the course of this investigation.

2. Results and Discussion

Our initial attempt to transfer the reaction conditions optimized for the reaction of HPA monoester 2 with imines (Scheme 1b) was not successful. Therefore, we screened for a suitable carboxylic acid activation regimen that would lead to an appreciable conversion and product yield (Table 1). Among the three other activators tried (oxalyl chloride, trifluoroacetic anhydride and acetic anhydride), only acetic anhydride gave the full conversion of 4 and the best isolated yield for the product (66%, entry 4), whose molecular weight and spectral characteristics appeared to correspond to the desired δ-lactam product 5a and demonstrated the predominant formation of one product diastereomer. Notably, the reaction turned out to be rather sensitive to thermal activation with a sharp decrease in the yield either when raising (entry 5) or reducing (entries 6–7) the temperature. Replacing chlorobenzene with other solvents (entries 8–9) did not improve the yields, while adding a base (entry 10) significantly diminished it.
However, a single-crystal X-ray analysis of the reaction product demonstrated, to our surprise, that it was not the expected δ-lactam 5a but rather the trans-diastereomer of β-lactam product 6a (Scheme 2). While the activation of α-C-H carboxylic acids toward such a reaction by acetic anhydride (in the presence of triethylamine) has been described in the literature [21,22], the formation of the β-lactam in the absence of any base (as in our case) is hitherto undescribed. Moreover, the fact that the use of the base is detrimental to the product yield (vide supra) makes this transformation rather unique.
Two possible reaction pathways can be suggested for this observed transformation (Scheme 3). They both begin with a carboxylic acid activation by acetic anhydride and the formation of mixed anhydride I. This intermediate can then either directly acylate imine to form intermediate II or be converted into a ketene III via AcOH elimination (the latter can be base-promoted by imine or traces of amine from imine decomposition). Ketene III also reacts with imine to provide the intermediate II. The last step is a Mannich-type cyclization involving the methylene group adjacent to carbonyl, resulting in formation of a C-C bond and beta-lactam cycle. The selective formation of β-lactams over δ- can be explained by the increased CH acidity of the methylene group closest to the positively charged iminium fragment of intermediate II compared to the second methylene group adjacent to an ester moiety.
In addition to the novelty of the discovered protocol for β-lactam synthesis, the medicinal importance of the 3-amino-2-azetidinone scaffold comprised by compound 6a is relatively clear. Indeed, it is the core of exemplary antibiotics, such as 7–10 [23] (Figure 2). This motivated us to explore the scope of the new protocol for β-lactams 6 preparation from monoester 4 and various imines using the optimized conditions (Ac2O, PhCl, 130 °C, 16 h).
Following from the results presented in Scheme 4, polysubstituted 3-amino-2-azetidinones 6a–o can be synthesized in a modest-to-high yield (up to 90%) and high trans-diastereoselectivity (see also Table S1) in case of aldimines (R3 = H), as confirmed by a single-crystal X-ray analysis of two reaction products (6a and 6m). The reaction appeared to work equally well for aldimines derived from both aliphatic and aromatic amines. Symmetrical hydrazones could also be productively involved in the reaction (cf., products 6k–m). In the case of (E)-chalcones, the diastereoselectivity of the reaction deteriorated; however, this was not a detriment to the product yield. The respective diastereomers were separated by HPLC and characterized (compound 6j). The notable products are 6n and 6o, which can be viewed as building blocks for further structural complexity buildup via alkyne-azide click chemistry.
Encouraged by the results obtained with dicarboxylic acid monoester 4, we proceeded to investigate the workability of the new base-free protocol for other carboxylic acids 11a–m in combination with aldimines, aiming to obtain β-lactams 12 (Scheme 5).
It turned out that the sulfonylamino-substituted acetic acids 11a–d were similarly effective in the β-lactam synthesis, furnishing the respective products 12a–d with good yields and a high diastereoselectivity. When replacing the nitrogen group (X = N) with sulfur, sulfone, oxygen, and carbon linkers had a strong effect on the reaction outcome. The thia-linked carboxylic acids (11e–11g) gave β-lactams in good to fair yields except for, surprisingly, the benzoyl-substituted substrate 11h. Sulfone-, oxygen- and carbon-linked substrates did not deliver the desired products, except for 1,3-dithiane substrate 11m, which furnished the diastereomerically pure product 12m in a modest yield.
Having explored the formation of β-lactams from dicarboxylic monoester 4 and carboxylic acids 11a–m, we continued pondering the possibility of forcing substrates such as 4 to react in the Castagnoli–Cushman fashion and furnish δ-lactam products. One possibility we considered would be to increase the C-H acidity of the ‘ester arm’ of the substrate, thereby making the closure of the six-membered ring more feasible. This could be achieved by placing electron-withdrawing substituents, such as perfluoroalkyl group, in the ester moiety. In our previous work on the surrogate Castagnoli–Cushman reaction of HPA monomethyl ester 2 and its analogs, we observed a notable increase in the reactivity of the 2,2,2-trifluoroethyl (TFE) ester compared to 2 [20]. Similarly, the TFE ester was found to be more reactive towards nucleophilic addition–elimination [24]. Moreover, TFE esters have been used as versatile acylation reagents in various reactions, including transesterification [25], amidation [26], and the kinetic resolution of aliphatic amines [27]. We reasoned that, aside from TFE analog of monoester 4, the hexafluoroisopropyl (HFIP) congener [28] would be even more predisposed to react with the Castagnoli–Cushman (rather than the previously observed) fashion and yield δ-lactams. Hence, we prepared monoesters 13 (TFE) and 14 (HFIP) (see Supplementary Information) and reacted them with N-butyl-1-(4-methoxyphenyl)methanimine (15) in chlorobenzene in the presence of acetic anhydride (Scheme 6). Expectedly, 14 proved more reactive towards imine 15 compared to its TFE counterpart (13) as it required a lower temperature for the reaction to be completed. Both ester products (16 and labile 17) were hydrolyzed to their respective carboxylic acids (18 and 19), and the spectral characteristics of the latter two compounds were compared to each other to reveal that compound 16 was the product of β-lactam synthesis, while compound 17 was the desired δ-lactam formed via the Castagnoli–Cushman reaction (Scheme 5). Indeed, the signals of the vicinal methine protons in 18 resonated differently (doublets at 4.81 and 4.40 ppm) compared to the same signals in 19 (doublets at 5.06 and 4.85 ppm). Small 3J coupling constants (2.0–2.2 Hz) were indicative of the trans-configuration of both carboxylic acids [29].
Considering the importance of the notable reactivity switch between monoesters 13 and 14 (β-lactam synthesis vs. Castagnoli–Cushman δ-lactam synthesis), we continued scrutinizing the differences in the structures of products 18 and 19 using NMR spectroscopy after our attempts to obtain crystals suitable for X-ray crystallography failed. The unequivocal difference between these compounds was identified in their correlational HMBC spectra. Specifically, compound 18 displayed two key correlations, 3J [CH-CON] and 3J [CH2-CO2H], in contrast to compound 19, where 3J [CH2-CON] and 3J [CH-CO2H] were observable (Figure 3).
Finally, we reasoned that β-lactam carboxylic acid 18 could be synthesized via the reaction of monomethyl ester 4 followed by the hydrolysis of ester 6p. Similarly, δ-lactam carboxylic acid 19 could be obtained via the Castagnoli–Cushman reaction of dicarboxylic acid 20 mediated by the in situ generation of the respective cyclic anhydride [18] (Scheme 7). To our delight, this synthetic strategy indeed led to the compounds whose spectral characteristics fully matched those of compounds 18 and 19 synthesized as described in Scheme 6.

3. Conclusions

With the aim of involving a dicarboxylic acid monomethyl ester in the recently described Ac2O-promoted Castagnoli–Cushman-type reaction, we identified a novel protocol for β-lactam synthesis instead. A series of 25 novel compounds were prepared in 35–90% yields, mostly as single trans-diastereomers as confirmed by X-ray analysis. The type of substituent in the β-position in the carboxylic acid group of the monoester was found to be crucial for the reaction outcome, while the variation in the imine component was well-tolerated. Additionally, it was discovered that replacing the monomethyl ester with its hexafluoroisopropyl congener not only led to a reduction in the reaction temperature, but also to a marked reactivity switch as the reaction proceeded along the Castagnoli–Cushman-type pathway and furnished the respective δ-lactam. An investigation of the scope of the latter reaction is currently underway in our laboratories and will be reported on in due course.

4. Materials and Methods

NMR spectra were acquired with 400 MHz Bruker Avance III spectrometer (400.13 MHz for 1H, 376.49 MHz for 19F and 100.61 MHz for 13C) or 500 MHz Bruker Avance III (500.03 MHz for 1H and 125.73 MHz for 13C) in CDCl3 or DMSO-d6 and were referenced to residual solvent proton signals (δH = 7.26 and 2.50, respectively) and solvent carbon signals (δC = 77.16 and 39.52, respectively). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, ddd = doublet/doublets of doublets; coupling constants, J, are reported in Hz. Mass spectra were acquired with an HRMS-ESI-qTOF spectrometer Nexera LCMS-9030 or MaXis II Bruker Daltonic GmbH (electrospray ionization mode, positive ions detection). IR spectrums were recorded with Fourier transform infrared Shimadzu spectrophotometer IRAffinity-1. Flash column chromatography on silica (Merck, 230–400 mesh) was performed with Biotage Isolera Prime instrument. TLC was performed on aluminium-backed pre-coated plates (0.25 mm) with silica gel 60 F254 with a suitable solvent system and was visualized using UV fluorescence. Preparative HPLC was carried out in a compact preparative system ECOM ECS28P00, equipped with spectrophotometric detector or Shimadzu LC-20AP. Column: YMC-Pack SIL-06, 5 µm, 250 × 20 mm or Agilent Zorbax prepHT XDB-C18, 5 μm, 21.2 × 150 mm. Chlorobenzene was distilled from P2O5 and stored in molecular sieves 4 Å (>24 h). 2-(Benzenesulfonyl-(cyanomethyl)amino)acetic acid (11a) was obtained from commercial sources. Synthesis of other starting materials is reported in ESI. CCDC 2,154,010 (6a) and 2,154,011 (6m) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk (accessed on 22 February 2022).

4.1. General Procedure for Preparation of Beta Lactams 6a–p, 12a–m, 16 and Their Analytical Data

In a screw-cap vial equipped with a magnetic stir bar, imine (1.1 eq) and the corresponding substituted monocarboxylic acid (0.05–1.3 mmol) were mixed in chlorobenzene (0.058 M, 1–6 mL). Then, acetic anhydride (1.1 eq) was added. The resulting mixture was placed in a pre-heated to 130 °C oil bath or metal heating block. After 16h, the mixture was cooled to room temperature, and the solvent was evaporated. The residue was purified by column chromatography in silica gel with a linear gradient (5–75%) of acetone in hexane (total volume of eluent, 400 mL) to provide pure compounds, 6a–p and 12a–m.

4.1.1. Methyl N-((3RS,4RS)-1-Ethyl-2-oxo-4-(p-tolyl)azetidin-3-yl)-N-(phenylsulfonyl)glycinate (6a)

Yield 96 mg, 66%; dr 95:5, yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.65–7.62 (m, 2H), 7.57–7.51 (m, 1H), 7.41 (dd, J = 8.3, 7.4 Hz, 2H), 7.41 (dd, J = 8.3, 7.4 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 4.85 (d, J = 1.8 Hz, 1H), 4.41 (d, J = 1.0 Hz, 1H), 4.26 (d, J = 18.3 Hz, 1H), 4.15 (d, J = 18.3 Hz, 1H), 3.69 (s, 3H), 3.54–3.44 (m, 1H), 2.83 (dqd, J = 14.3, 7.2, 0.9 Hz, 1H), 2.38 (s, 3H), 1.07 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.7, 163.7, 138.7, 138.3, 133.2, 132.7, 129.6, 129.1, 127.5, 126.9, 71.6, 62.5, 52.4, 48.0, 35.4, 21.3, 12.6. HRMS (ESI) m/z: [M + Na]+ Calcd for C21H23N2O5NaS+ 439.1298; found 439.1307.

4.1.2. Methyl N-((3RS,4SR)-2-Oxo-4-(thiophen-2-yl)-1-(p-tolyl)azetidin-3-yl)-N-(phenylsulfonyl)glycinate (6b)

Yield 107 mg, 65%; dr > 95:5, dark orange solid. 1H NMR (500 MHz, CDCl3) δ 7.70 (dd, J = 8.4, 1.3 Hz, 2H), 7.62–7.55 (m, 1H), 7.46 (dd, J = 8.3, 7.4 Hz, 2H), 7.34 (dd, J = 5.0, 3.0 Hz, 1H), 7.29 (dd, J = 3.0, 1.3 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.09–7.03 (m, 3H), 5.43 (d, J = 2.1 Hz, 1H), 4.63 (d, J = 2.1 Hz, 1H), 4.31 (d, J = 18.4 Hz, 1H), 4.16 (d, J = 18.4 Hz, 1H), 3.67 (s, 3H), 2.27 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.7, 160.8, 138.3, 137.4, 134.7, 134.4, 133.5, 129.8, 129.3, 127.7, 127.2, 125.7, 123.7, 117.8, 71.5, 59.5, 52.6, 48.2, 21.1. HRMS (ESI) m/z: [M + H]+ Calcd for C23H23N2O5S2+ 471.1043; found 471.1050.

4.1.3. Methyl N-((2RS,3RS)-1-(Adamantan-1-yl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6c)

Yield 80 mg, 42%; dr > 95:5, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.64–7.55 (m, 2H), 7.53–7.47 (m, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.10 (d, J = 4.9 Hz, 1H), 4.88 (d, J = 4.9 Hz, 1H), 3.96 (d, J = 18.5 Hz, 1H), 3.88 (d, J = 18.5 Hz, 1H), 3.82 (s, 3H), 3.48 (s, 3H), 1.98 (br.s, 3H), 1.92 (br.s, 6H), 1.62–1.51 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 168.9, 163.4, 159.8, 139.2, 132.9, 129.5, 128.8, 128.4, 127.9, 113.8, 65.7, 60.6, 56.0, 55.3, 52.2, 49.3, 40.9, 36.1, 29.2. HRMS (ESI) m/z: [M + H]+ Calcd for C29H35N2O6S+ 539.2210; found 539.2219.

4.1.4. Methyl N-((2RS,3RS)-2-(4-Fluorophenyl)-1-(4-methoxybenzyl)-4-oxoazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6d)

Yield 105 mg, 59%; dr 89:11, yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.64–7.58 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 2H), 7.17 (dd, J = 8.7, 5.3 Hz, 2H), 7.06 (t, J = 8.6 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.72 (d, J = 14.8 Hz, 1H), 4.62 (d, J = 1.9 Hz, 1H), 4.46 (d, J = 1.5 Hz, 1H), 4.22 (d, J = 18.4 Hz, 1H), 4.05 (d, J = 18.4 Hz, 1H), 3.78 (s, 3H), 3.68 (d, J = 14.8 Hz, 1H), 3.60 (s, 3H).13C NMR (126 MHz, CDCl3) δ 169.6, 163.8, 163.0 (d, J = 247.7 Hz), 159.4, 138.4, 133.4, 131.4 (d, J = 3.2 Hz), 130.0, 129.2, 128.9 (d, J = 8.2 Hz), 127.7, 126.8, 116.1 (d, J = 21.6 Hz), 114.3, 72.0, 61.6, 55.4, 52.5, 47.9, 44.3. 19F NMR (376 MHz, CDCl3) δ-112.7. HRMS (ESI) m/z: [M + H]+ Calcd for C26H26FN2O6S+ 513.1490; found 513.1494.

4.1.5. Methyl N-((2RS,3RS)-1-Butyl-2-(4-nitrophenyl)-4-oxoazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6e)

Yield 98 mg, 59%; dr 42:58, dark orange oil. 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 2H), 8.25 (d, J = 8.7 Hz, 2H), 7.71–7.67 (m, 2H), 7.64 (dd, J = 8.5, 1.3 Hz, 2H), 7.62–7.54 (m, 4H), 7.53–7.50 (m, 2H), 7.49–7.47 (m, 2H), 7.46–7.42 (m, 2H), 5.26 (d, J = 4.7 Hz, 1H), 5.08 (d, J = 1.9 Hz, 1H), 4.97 (d, J = 4.8 Hz, 1H), 4.35 (d, J = 1.8 Hz, 1H), 4.26 (d, J = 18.4 Hz, 1H), 4.16 (d, J = 18.4 Hz, 1H), 3.99 (d, J = 18.3 Hz, 1H), 3.79 (d, J = 18.3 Hz, 1H), 3.72 (s, 3H), 3.61–3.49 (m, 2H), 3.48 (s, 3H), 2.94 (ddd, J = 13.8, 7.4, 6.2 Hz, 1H), 2.81–2.72 (m, 1H), 1.55–1.39 (m, 4H), 1.33–1.26 (m, 6H), 0.88 (q, J = 7.3 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 170.0, 168.4, 163.6, 163.3, 148.3, 148.3, 143.5, 141.8, 138.3, 138.2, 133.6, 133.5, 129.5, 129.4, 129.1, 128.0, 127.5, 127.4, 124.3, 123.8, 72.2, 68.1, 62.8, 62.1, 52.7, 52.3, 49.2, 48.2, 41.3, 40.9, 29.6, 29.3, 20.3, 20.2, 13.6, 13.6. HRMS (ESI) m/z: [M + H]+ Calcd for C22H26N3O7S+ 476.1486; found 476.1487.

4.1.6. Methyl N-((3RS,4RS)-1-Methyl-2-oxo-4-(3-(trifluoromethyl)phenyl)azetidin-3-yl)-N-(phenylsulfonyl)glycinate (6f)

Yield 101 mg, 63%; dr 92:8, light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.67–7.61 (m, 3H), 7.60–7.47 (m, 4H), 7.45–7.37 (m, 2H), 4.91 (d, J = 1.9 Hz, 1H), 4.43 (d, J = 0.9 Hz, 1H), 4.27 (d, J = 18.4 Hz, 1H), 4.14 (d, J = 18.3 Hz, 1H), 3.71 (s, 3H), 2.77 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.9, 164.0, 138.3, 136.8, 133.5, 131.5 (q, J = 32.5 Hz), 130.5, 129.7, 129.3, 127.6, 125.9 (q, J = 3.6 Hz), 125.0, 124.0 (q, J = 272.6 Hz), 123.7 (q, J = 3.8 Hz), 72.8, 64.5, 52.6, 48.2, 27.4. 19F NMR (376 MHz, CDCl3) δ-62.6. HRMS (ESI) m/z: [M + H]+ Calcd for C20H20F3N2O5S+ 457.1040; found 457.1041.

4.1.7. Methyl N-((2RS,3RS)-1-(4-(Adamantan-1-yl)phenyl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6g)

Yield 94 mg, 44%; dr > 95:5, yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.70–7.66 (m, 2H), 7.60–7.54 (m, 1H), 7.48–7.40 (m, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.23–7.17 (m, 4H), 6.90 (d, J = 8.7 Hz, 2H), 5.24 (d, J = 2.2 Hz, 1H), 4.65 (d, J = 2.2 Hz, 1H), 4.31 (d, J = 18.4 Hz, 1H), 4.11 (d, J = 18.4 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 2.08–2.03 (m, 3H), 1.81 (d, J = 2.9 Hz, 6H), 1.79–1.73 (m, 3H), 1.72–1.66 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 169.7, 161.4, 160.0, 148.1, 138.4, 134.3, 133.4, 129.2, 128.0, 127.7, 125.6, 119.9, 117.6, 114.5, 72.3, 62.9, 55.4, 52.6, 48.0, 43.2, 36.8, 36.0, 29.0. HRMS (ESI) m/z: [M + H]+ Calcd for C35H39N2O6S+ 615.2523; found 615.2520.

4.1.8. Methyl N-((2RS,3RS)-2-(3,4-Dimethoxyphenyl)-4-oxo-1-(4-(trifluoromethyl)phenyl)azetidin-3-yl)-N-(phenylsulfonyl)glycinate (6h)

Yield 181 mg, 90%; dr 93:7, yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.72–7.69 (m, 2H), 7.62–7.56 (m, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.48–7.44 (m, 2H), 7.37 (d, J = 8.5 Hz, 2H), 6.92–6.84 (m, 3H), 5.35 (d, J = 2.3 Hz, 1H), 4.62 (d, J = 2.3 Hz, 1H), 4.28 (d, J = 18.4 Hz, 1H), 4.12 (d, J = 18.4 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.67 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.7, 162.2, 149.7 (d, J = 3.9 Hz), 139.6, 138.2, 133.6, 129.3, 127.7, 127.4, 126.6 (d, J = 32.8 Hz), 126.5 (q, J = 3.6 Hz), 124.0 (d, J = 271.7 Hz), 119.5, 118.9, 117.8, 111.6, 109.6, 72.8, 64.0, 56.2, 56.1, 52.7, 48.4. 19F NMR (376 MHz, CDCl3) δ-62.3. HRMS (ESI) m/z: [M + H]+ Calcd for C27H26FN2O7S+ 579.1407; found 579.1411.

4.1.9. Methyl (E)-N-(4-Oxo-1,2-diphenyl-2-styrylazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6i)

Yield 29 mg, 76%; dr 66:34, dark orange oil. 1H NMR (500 MHz, CDCl3) δ 7.90–7.79 (m, 2H), 7.66 (d, J = 7.4 Hz, 2H), 7.60 (td, J = 7.6, 1.6 Hz, 2H), 7.54–7.46 (m, 3H), 7.46–7.27 (m, 26H), 7.20 (t, J = 8.0 Hz, 2H), 7.16–6.99 (m, 7H), 6.91 (d, J = 16.1 Hz, 1H), 6.70 (d, J = 16.2 Hz, 1H), 6.65 (d, J = 16.2 Hz, 1H), 5.28 (d, J = 1.0 Hz, 1H), 4.97 (s, 1H), 4.36 (d, J = 18.5 Hz, 1H), 4.04 (d, J = 18.5 Hz, 1H), 3.73 (d, J = 18.5 Hz, 1H), 3.50 (s, 3H), 3.47 (s, 3H), 3.28 (d, J = 18.5 Hz, 1H), 2.27 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 169.0, 161.2, 161.0, 139.5, 138.2, 137.8, 136.7, 136.7, 136.6, 135.9, 135.9, 135.1, 133.5, 133.3, 129.7, 129.2, 129.2, 129.1, 129.1, 129.0, 129.0, 128.9, 128.8, 128.7, 128.6, 128.6, 128.6, 128.3, 128.2, 128.1, 127.4, 127.1, 127.0, 126.3, 125.9, 124.8, 124.7, 124.0, 119.0, 118.6, 72.8, 70.9, 52.2, 52.2, 49.4, 48.1, 19.9. HRMS (ESI) m/z: [M + Na]+ Calcd for C32H28N2O5S+ 575.1611; found 575.1614.

4.1.10. Methyl (E)-N-(2-(4-Chlorostyryl)-1-(4-methoxyphenyl)-4-oxo-2-phenylazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6j)

Yield 39 mg, 89% (after flash chromatography); dr 66:34, yellow oil. This mixture was further separated by preparative HPLC on silica gel column YMC-Pack SIL-06, 5 µm, 250 × 20 mm (mobile phase hexane-acetone, 5–50% of acetone, total volume 600 mL; flow 20 mL/min, 25 °C) to afford pure diastereomers. Major isomer (16 mg): 1H NMR (500 MHz, CDCl3) δ 7.59–7.55 (m, 2H), 7.54–7.48 (m, 1H), 7.39–7.29 (m, 7H), 7.26 (d, J = 1.5 Hz, 4H), 7.21–7.17 (m, 2H), 7.00 (d, J = 16.3 Hz, 1H), 6.66 (d, J = 9.1 Hz, 2H), 6.52 (d, J = 16.2 Hz, 1H), 4.82 (s, 1H), 4.26 (d, J = 18.6 Hz, 1H), 3.92 (d, J = 18.5 Hz, 1H), 3.66 (s, 3H), 3.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.0, 160.2, 156.5, 138.0, 137.7, 134.5, 134.4, 133.5, 132.2, 130.1, 129.2, 129.1, 129.1, 128.7, 128.3, 128.2, 128.1, 126.4, 125.1, 119.9, 114.3, 70.9, 55.5, 52.3, 49.4. Minor isomer (7 mg): 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J = 8.4, 1.3 Hz, 2H), 7.64–7.57 (m, 1H), 7.53–7.46 (m, 4H), 7.46–7.39 (m, 5H), 7.30 (s, 4H), 6.87 (d, J = 16.2 Hz, 1H), 6.80 (d, J = 9.2 Hz, 2H), 6.62 (d, J = 16.2 Hz, 1H), 5.23 (d, J = 1.0 Hz, 1H), 3.76 (s, 3H), 3.68 (d, J = 18.5 Hz, 1H), 3.44 (s, 3H), 3.27 (d, J = 18.6 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 168.5, 160.4, 156.6, 139.5, 135.1, 134.4, 134.3, 133.4, 132.0, 130.1, 129.1, 129.1, 129.0, 128.8, 128.2, 128.2, 128.2, 128.1, 120.2, 114.4, 72.7, 55.6, 52.2, 48.1. HRMS (ESI) m/z: [M + H]+ Calcd for C33H30ClN2O6S+ 617.1508; found 617.1508.

4.1.11. Methyl N-((2RS,3RS)-1-(((E)-4-Methoxybenzylidene)amino)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6k)

Yield 25 mg, 65%; dr > 95:5, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 8.5, 1.3 Hz, 2H), 7.62 (s, 1H), 7.57 (tt, J = 6.9, 1.2 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.44 (t, J = 7.9 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H), 5.40 (d, J = 2.0 Hz, 1H), 4.44 (d, J = 2.1 Hz, 1H), 4.33 (d, J = 18.5 Hz, 1H), 4.19 (d, J = 18.5 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.70 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.9, 162.1, 160.2, 159.7, 147.7, 138.3, 133.5, 129.6, 129.3, 128.0, 127.7, 126.2, 125.9, 114.7, 114.3, 70.1, 66.6, 55.5, 55.5, 52.7, 48.1. HRMS (ESI) m/z: [M + H]+ Calcd for C27H28N3O7S+ 538.1642; found 538.1647.

4.1.12. Methyl (E)-N-(1-((4-Methylbenzylidene)amino)-2-oxo-4-(p-tolyl)azetidin-3-yl)-N-(phenylsulfonyl)glycinate (6l)

Yield 14 mg, 40%; dr > 95:5, yellow oil. 1H NMR (500 MHz, DMSO-d6 +CDCl3) δ 7.62–7.59 (m, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.51 (s, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.13 (s, 4H), 7.06 (d, J = 8.1 Hz, 2H), 5.26 (d, J = 2.1 Hz, 1H), 4.47 (d, J = 2.0 Hz, 1H), 4.20 (d, J = 18.4 Hz, 1H), 4.05 (d, J = 18.4 Hz, 1H), 3.61 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H). 13C NMR (126 MHz, DMSO-d6 +CDCl3) δ 168.8, 159.3, 146.9, 140.7, 138.2, 137.7, 132.9, 130.5, 129.6, 129.3, 128.8, 128.7, 127.1, 126.8, 125.8, 69.6, 65.5, 51.9, 47.3, 20.9, 20.7. HRMS (ESI) m/z: [M + H]+ Calcd for C27H28N3O5S+ 506.1744; found 506.1750.

4.1.13. Methyl N-((3RS,4SR)-2-Oxo-4-(thiophen-2-yl)-1-(((E)-thiophen-2-ylmethylene)amino) azetidin-3-yl)-N-(phenylsulfonyl)glycinate (6m)

Yield 10 mg, 29%; dr > 95:5, brown oil. 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H), 7.72 (dd, J = 8.5, 1.2 Hz, 2H), 7.64–7.56 (m, 1H), 7.47 (t, J = 7.9 Hz, 2H), 7.39 (dt, J = 5.1, 1.0 Hz, 1H), 7.37 (dd, J = 5.1, 1.2 Hz, 1H), 7.20 (td, J = 3.7, 1.4 Hz, 2H), 7.06 (dd, J = 5.1, 3.6 Hz, 1H), 7.01 (dd, J = 5.0, 3.7 Hz, 1H), 5.74 (d, J = 2.1 Hz, 1H), 4.57 (d, J = 2.0 Hz, 1H), 4.32 (d, J = 18.4 Hz, 1H), 4.20 (d, J = 18.4 Hz, 1H), 3.70 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 183.1, 169.8, 159.4, 143.1, 138.2, 138.1, 137.6, 133.6, 131.8, 129.9, 129.4, 127.7, 127.7, 127.3, 126.7, 70.8, 63.3, 52.8, 48.3. HRMS (ESI) m/z: [M + H]+ Calcd for C21H20N3O5S3+ 490.0560; found 490.0571.

4.1.14. Methyl N-((3RS,4RS)-2-Oxo-1-(prop-2-yn-1-yl)-4-(p-tolyl)azetidin-3-yl)-N-(phenylsulfonyl)glycinate (6n)

Yield 61 mg, 41%; dr 89:11, dark brown oil. 1H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.5, 1.3 Hz, 2H), 7.58–7.52 (m, 1H), 7.43–7.36 (m, 2H), 7.19 (q, J = 8.1 Hz, 4H), 4.92 (d, J = 2.1 Hz, 1H), 4.58 (d, J = 2.1 Hz, 1H), 4.33–4.24 (m, 2H), 4.10 (d, J = 18.4 Hz, 1H), 3.70 (s, 3H), 3.53 (ddd, J = 17.8, 2.5, 0.9 Hz, 1H), 2.38 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.5, 163.9, 139.0, 138.4, 133.3, 132.0, 129.8, 129.2, 127.7, 127.0, 76.0, 73.0, 72.2, 62.6, 52.6, 48.0, 30.2, 21.4. HRMS (ESI) m/z: [M + H]+ Calcd for C22H23N2O5S+ 427.1322; found 427.1328.

4.1.15. Methyl N-((2RS,3RS)-1-(2-Azidoethyl)-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6o)

Yield 22 mg, 66%; dr > 95:5, orange oil. 1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 8.5, 1.3 Hz, 2H), 7.58–7.53 (m, 1H), 7.42 (td, J = 7.6, 1.7 Hz, 2H), 7.23–7.17 (m, 2H), 6.95–6.91 (m, 2H), 4.90 (d, J = 2.0 Hz, 1H), 4.52 (d, J = 1.9 Hz, 1H), 4.29 (d, J = 18.3 Hz, 1H), 4.14 (d, J = 18.3 Hz, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 3.60 (ddd, J = 14.5, 7.2, 5.4 Hz, 1H), 3.40 (ddd, J = 6.8, 6.0, 5.1 Hz, 2H), 2.92 (dddd, J = 14.6, 6.6, 5.0, 0.7 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 169.9, 164.6, 160.3, 138.5, 133.4, 129.2, 128.4, 127.7, 127.2, 114.6, 72.3, 63.4, 55.5, 52.6, 49.0, 48.1, 39.7. HRMS (ESI) m/z: [M + H]+ Calcd for C21H24N5O6S+ 474.1442; found 474.1442.

4.1.16. Methyl N-((2RS,3RS)-1-Butyl-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-N-(phenylsulfonyl)glycinate (6p)

Yield 58 mg, 36%, dr > 95:5, orange oil. 1H NMR (400 MHz, CDCl3) δ 7.64–7.59 (m, 2H), 7.53 (q, J = 7.1 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 4.80 (d, J = 2.0 Hz, 1H), 4.40 (d, J = 2.0 Hz, 1H), 4.28 (d, J = 18.3 Hz, 1H), 4.16 (d, J = 18.3 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.43 (dt, J = 14.6, 7.6 Hz, 1H), 2.72 (dt, J = 14.0, 6.7 Hz, 1H), 1.41 (p, J = 7.5 Hz, 2H), 1.26 (dddd, J = 9.9, 7.3, 5.8, 2.1 Hz, 2H), 0.85 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.8, 163.9, 160.1, 138.5, 133.3, 129.1, 128.4, 127.7, 127.6, 114.4, 71.8, 62.8, 55.5, 52.5, 48.1, 40.3, 29.6, 20.2, 13.6. HRMS (ESI) m/z: [M + H]+ Calcd for C23H29N2O6S+ 461.1741; found 461.1746.

4.1.17. N-(Cyanomethyl)-N-((3RS,4RS)-1-ethyl-2-oxo-4-(p-tolyl)azetidin-3-yl)benzenesulfonamide (12a)

Yield 85 mg, 57%; dr > 95:5, dark brown oil. 1H NMR (400 MHz, CDCl3) δ 7.64–7.54 (m, 3H), 7.46–7.39 (m, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 4.79 (d, J = 2.0 Hz, 1H), 4.66 (d, J = 18.3 Hz, 1H), 4.59 (d, J = 2.1 Hz, 1H), 4.29 (d, J = 18.5 Hz, 1H), 3.52 (dq, J = 14.8, 7.4 Hz, 1H), 2.92–2.80 (m, 1H), 2.41 (s, 3H), 1.10 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.8, 139.4, 137.1, 134.1, 132.1, 129.9, 129.6, 127.9, 127.1, 114.9, 71.2, 60.6, 35.8, 34.2, 21.4, 12.7. HRMS (ESI) m/z: [M + H]+ Calcd for C20H22N3O3S+ 384.1376; found 384.1374.

4.1.18. N-Benzyl-N-((2RS,3RS)-1-butyl-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-4-fluorobenzenesulfonamide (12b)

Yield 101 mg, 66%; dr > 95:5, yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.89 (ddd, J = 8.9, 5.0, 2.5 Hz, 2H), 7.36 (dd, J = 7.7, 1.9 Hz, 2H), 7.33–7.26 (m, 3H), 7.15 (t, J = 8.6 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.58 (d, J = 15.5 Hz, 1H), 4.53 (d, J = 1.7 Hz, 1H), 4.29 (d, J = 15.5 Hz, 1H), 4.16 (d, J = 2.1 Hz, 1H), 3.80 (s, 3H), 3.30 (dt, J = 14.5, 7.4 Hz, 1H), 2.61 (dt, J = 13.8, 6.7 Hz, 1H), 1.20 (q, J = 7.0 Hz, 2H), 1.13 (dt, J = 13.6, 6.9 Hz, 2H), 0.79 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.3 (d, J = 255.1 Hz), 165.0, 160.0, 136.4, 135.6 (d, J = 3.3 Hz), 130.4 (d, J = 9.4 Hz), 128.8, 128.4, 128.3, 127.8, 127.5, 116.4 (d, J = 22.5 Hz), 114.5, 72.6, 62.5, 55.4, 51.0, 40.2, 29.6, 20.2, 13.7. 19F NMR (376 MHz, CDCl3) δ-104.9. HRMS (ESI) m/z: [M + H]+ Calcd for C27H30FN2O4S+ 497.1905; found 497.1908.

4.1.19. Methyl N-((2RS,3RS)-1-Butyl-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-N-((2-nitrophenyl)sulfonyl)glycinate (12c)

Yield 214 mg, 67%; dr > 95:5, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.72–7.62 (m, 3H), 7.53 (ddd, J = 8.4, 6.9, 1.8 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 4.92 (d, J = 1.9 Hz, 1H), 4.57 (d, J = 1.8 Hz, 1H), 4.45 (d, J = 18.7 Hz, 1H), 4.38 (d, J = 18.8 Hz, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 3.47 (dt, J = 14.7, 7.6 Hz, 1H), 2.76 (dt, J = 13.6, 6.6 Hz, 1H), 1.51–1.38 (m, 2H), 1.36–1.23 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.0, 163.4, 160.3, 148.2, 134.1, 132.2, 131.9, 131.4, 128.4, 127.4, 124.6, 114.5, 71.7, 62.5, 55.5, 52.6, 48.6, 40.4, 29.6, 20.2, 13.7. HRMS (ESI) m/z: [M + H]+ Calcd for C23H28N3O8S+ 506.1592; found 506.1593.

4.1.20. Methyl N-((2RS,3RS)-1-Butyl-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-N-(methylsulfonyl)glycinate (12d)

Yield 94 mg, 53%; dr 94:6, light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 4.75 (d, J = 2.0 Hz, 1H), 4.39 (d, J = 1.9 Hz, 1H), 4.24 (d, J = 18.6 Hz, 1H), 4.09 (d, J = 18.6 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.47 (dt, J = 14.0, 7.6 Hz, 1H), 3.05 (s, 3H), 2.75 (dt, J = 13.7, 6.7 Hz, 1H), 1.47–1.39 (m, 2H), 1.34–1.23 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 170.2, 164.3, 160.2, 128.0, 127.6, 114.6, 72.7, 62.8, 55.4, 52.6, 49.0, 41.3, 40.2, 29.6, 20.2, 13.7. HRMS (ESI) m/z: [M + H]+ Calcd for C18H27N2O6S+ 399.1584; found 399.1590.

4.1.21. Methyl 2-(((3RS,4RS)-1-Ethyl-2-oxo-4-(p-tolyl)azetidin-3-yl)thio)acetate (12e)

Yield 189 mg, 50%; dr > 95:5, orange oil. 1H NMR (400 MHz, CDCl3) δ 7.20 (s, 4H), 4.46 (d, J = 2.1 Hz, 1H), 3.98 (d, J = 2.3 Hz, 1H), 3.67 (s, 3H), 3.56–3.44 (m, 2H), 3.38 (d, J = 15.3 Hz, 1H), 2.92 (dq, J = 14.3, 7.2 Hz, 1H), 2.35 (s, 3H), 1.08 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.5, 165.5, 139.0, 133.6, 129.8, 126.6, 62.9, 58.6, 52.6, 35.9, 32.6, 21.3, 12.9. HRMS (ESI) m/z: [M + H]+ Calcd for C15H20NO3S+ 294.1158; found 294.1163.

4.1.22. 2-(((3RS,4RS)-1-Ethyl-2-oxo-4-(p-tolyl)azetidin-3-yl)thio)acetonitrile (12f)

Yield 120 mg, 47%; dr > 95:5, light brown oil. 1H NMR (500 MHz, CDCl3) δ 7.29–7.19 (m, 4H), 4.66 (d, J = 2.0 Hz, 1H), 4.06 (d, J = 1.6 Hz, 1H), 3.63–3.45 (m, 3H), 2.99 (dqd, J = 14.5, 7.2, 0.9 Hz, 1H), 2.39 (s, 3H), 1.14 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 164.3, 139.4, 133.0, 130.0, 126.6, 116.8, 62.4, 58.1, 36.2, 21.3, 15.6, 12.8. HRMS (ESI) m/z: [M + Na]+ Calcd for C14H16N2NaOS+ 283.0876; found 283.0877.

4.1.23. 2-(((2RS,3RS)-1-Butyl-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)thio)-N-(4-fluorophenyl)acetamide (12g)

Yield 102 mg, 60%; dr > 95:5, light brown oil. 1H NMR (500 MHz, CDCl3) δ 9.23 (s, 1H), 7.63–7.54 (m, 2H), 7.23–7.18 (m, 2H), 7.06–6.97 (m, 2H), 6.95–6.87 (m, 2H), 4.37 (d, J = 2.1 Hz, 1H), 3.91 (dd, J = 2.1, 0.8 Hz, 1H), 3.81 (s, 3H), 3.63 (d, J = 15.5 Hz, 1H), 3.51–3.41 (m, 1H), 3.37 (d, J = 15.6 Hz, 1H), 2.85 (dt, J = 13.7, 6.7 Hz, 1H), 1.45 (dt, J = 14.5, 7.3 Hz, 2H), 1.39–1.21 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 167.2, 166.8, 160.5, 160.5, 159.5 (d, J = 243.2 Hz), 134.2 (d, J = 2.6 Hz), 127.9, 127.5, 121.7 (d, J = 8.0 Hz), 115.6 (d, J = 22.4 Hz), 114.7, 62.8, 58.3, 55.5, 41.0, 36.1, 29.6, 20.2, 13.6. 19F NMR (376 MHz, CDCl3) δ-118.1. HRMS (ESI) m/z: [M + Na]+ Calcd for C22H25FN2NaO3S+ 439.1462; found 439.1462.

4.1.24. Methyl 2-(2-((2RS,3SR)-1-Butyl-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-1,3-dithian-2-yl)acetate (12m)

Yield 18 mg, 35%; light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.87 (d, J = 2.2 Hz, 1H), 3.93 (d, J = 2.0 Hz, 1H), 3.81 (s, 3H), 3.60 (s, 3H), 3.46 (d, J = 14.5 Hz, 1H), 3.35 (d, J = 14.5 Hz, 1H), 3.08 (ddd, J = 14.3, 12.1, 2.0 Hz, 2H), 2.88 (dt, J = 14.5, 3.9 Hz, 1H), 2.76–2.62 (m, 2H), 2.12 (dtd, J = 13.5, 5.4, 2.9 Hz, 1H), 1.96–1.84 (m, 1H), 1.47 (ddt, J = 11.7, 9.7, 3.4 Hz, 2H), 1.41–1.30 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.2, 165.7, 159.8, 129.5, 128.3, 114.4, 65.8, 57.4, 55.4, 51.9, 49.1, 42.9, 40.1, 29.9, 26.3, 26.3, 24.5, 20.4. HRMS (ESI) m/z: [M + H]+ Calcd for C21H30NNaO4S2+ 424.1611; found 424.1615.

4.1.25. 2,2,2-Trifluoroethyl N-((3RS,4RS)-1-butyl-2-oxo-4-(p-tolyl)azetidin-3-yl)-N-(phenylsulfonyl)glycinate (16)

Yield 109 mg, 70%; dr > 95:5, light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7 7.61–7.51 (m, 3H), 7.45–7.37 (m, 2H), 7.21 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.77 (d, J = 2.0 Hz, 1H), 4.58–4.41 (m, 2H), 4.38 (d, J = 18.6 Hz, 1H), 4.37 (d, J = 1.8 Hz, 1H), 4.30 (d, J = 18.6 Hz, 1H), 3.85 (s, 3H), 3.43 (dt, J = 14.8, 7.6 Hz, 1H), 2.73 (dt, J = 13.6, 6.8 Hz, 1H), 1.41 (p, J = 7.5 Hz, 2H), 1.32–1.20 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 168.2, 163.6, 160.2, 138.0, 133.5, 129.3, 128.4, 127.6, 127.4, 122.8 (q, J = 277.0 Hz), 114.5, 71.4, 62.9, 61.1 (q, J = 37.0 Hz), 55.5, 47.8, 40.4, 29.6, 20.2, 13.6. 19F NMR (376 MHz, CDCl3) δ-73.6. HRMS (ESI) m/z: [M+H]+ Calcd for C24H28F3N2O6S+ 529.1615; found 529.1619.

4.2. N-((2RS,3RS)-1-Butyl-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl)-N-(phenylsulfonyl)glycine (18)

Compound 16 (37 mg, 0.07 mmol) or 6p (55 mg, 0.12 mmol) was dissolved in a mixture of MeOH and water (3 + 3 mL), followed by addition of NaOH (5 equiv.). After stirring for 24 h at room temperature, MeOH was removed in vacuo, and the residue was acidified with HCl conc to pH 1 and partitioned between water (5 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give pure title compound. Yield 27 mg, 90% (from hydrolysis of compound 16), light yellow oil. Yield 44 mg, 80% (from hydrolysis of compound 6p), light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 4.78 (d, J = 2.0 Hz, 1H), 4.39 (d, J = 1.8 Hz, 1H), 4.26 (d, J = 18.5 Hz, 1H), 4.19 (d, J = 18.6 Hz, 1H), 3.85 (s, 3H), 3.44 (dt, J = 14.7, 7.6 Hz, 1H), 2.75 (dt, J = 14.2, 7.0 Hz, 1H), 1.43 (p, J = 7.6 Hz, 2H), 1.28 (dq, J = 15.6, 4.3, 3.7 Hz, 2H), 0.86 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.0, 164.2, 160.3, 138.1, 133.5, 129.3, 128.4, 127.7, 127.4, 114.5, 71.7, 63.0, 55.5, 48.0, 40.5, 29.6, 20.3, 13.7. HRMS (ESI) m/z: [M + Na]+ Calcd for C22H26N2O6NaS+ 469.1404; found 469.1413. IR (KBr): ῦ = 1760 (vs) cm−1 (C=O).

4.3. (2RS,3SR)-4-Butyl-3-(4-methoxyphenyl)-5-oxo-1-(phenylsulfonyl)piperazine-2-carboxylic Acid (19)

Preparation 1 (Scheme 6b). In a screw-cap vial equipped with a magnetic stir bar, N-butyl-1-(4-methoxyphenyl)methanimine (40 mg, 0.21 mmol) and compound 14 (80 mg, 0.19 mmol) were mixed in chlorobenzene (5 mL). Then, acetic anhydride (21 mg, 0.21 mmol) was added. The resulting mixture was placed in a bath pre-heated to 80 °C. After 16 h, the reaction mixture was cooled to RT and concentrated. The residue was dissolved in a mixture of MeOH and water (6 + 6 mL) followed by the addition of NaOH (19 mg, 0.49 mmol, 5 equiv.). After stirring for 24 h at room temperature, MeOH was removed in vacuo and the residue was diluted with water (5 mL) and extracted with ethyl acetate (5 mL). The aqueous layer was separated and acidified with HCl conc to pH 1 and extracted with ethyl acetate (2 × 10 mL). Combined organic layers were dried over sodium sulfate, filtered and concentrated to give pure compound 19. Yield 45 mg, 56%, dr > 95:5, light orange oil.
1H NMR (400 MHz, CDCl3) δ 7.50 (tt, J = 7.0, 1.4 Hz, 1H), 7.41 (dd, J = 8.5, 1.4 Hz, 2H), 7.37–7.29 (m, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 5.07 (d, J = 2.3 Hz, 1H), 4.84 (d, J = 2.1 Hz, 1H), 4.24 (d, J = 17.1 Hz, 1H), 4.06 (d, J = 17.1 Hz, 1H), 3.90 (dt, J = 13.6, 7.6 Hz, 1H), 3.83 (s, 3H), 2.58 (dt, J = 13.9, 7.1 Hz, 1H), 1.51–1.34 (m, 2H), 1.31–1.12 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.7, 165.0, 160.0, 138.4, 133.0, 129.0, 129.0, 127.5, 127.3, 114.7, 61.2, 61.2, 55.5, 46.2, 45.7, 29.1, 20.0, 13.8. HRMS (ESI) m/z: [M + Na]+ Calcd for C22H26N2O6NaS+ 469.1404; found 469.1411. IR (KBr): ῦ = 1738 (s), 1611 (s) cm−1 (C=O).
Preparation 2 (Scheme 7b). A mixture of N-(phenylsulfonyl)iminodiacetic acid (123 mg, 0.45 mmol), N-butyl-1-(4-methoxyphenyl)methanimine (95 mg, 0.5 mmol) and acetic anhydride (50 mg, 0.5 mmol) in PhCl (1 mL) was placed in a pre-heated bath (150 °C) and stirred for 16h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (5 mL) and saturated sodium bicarbonate solution (5 mL). The aqueous layer was separated, cooled to 0 °C and acidified with HCl concentrated to pH 1, followed by extraction with ethyl acetate (2 × 5 mL). Combined organic layers were dried over sodium sulfate, filtered and concentrated to give pure compound 19. Yield 90 mg, 47%; dr > 95:5, light orange oil.

Supplementary Materials

The following supporting information can be downloaded at: www.mdpi.com/article/10.3390/molecules27082469/s1. Synthesis of starting materials and their analytical data, crystallographic data, copies of NMR spectra, Table S1 (diastereomeric ratios from crude reaction mixtures and after purification). References [30,31,32,33,34,35,36] are cited in the supplementary materials.

Author Contributions

Conceptualization, O.B., D.D. and M.K.; methodology, O.B.; investigation, A.A., G.K. and O.B.; data curation, O.B. and A.A.; writing—original draft preparation, M.K.; writing—review and editing, D.D. and O.B.; supervision, O.B.; funding acquisition, O.B. All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge financial support of this work by the Russian Science Foundation (project grant 20-73-10078).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We are grateful to the Research Centre for Magnetic Resonance, the Centre for Chemical Analysis and Materials Research, the Research Centre for X-ray Diffraction Studies and The Center for Study of Extreme States of Materials and Constructions of Saint Petersburg State University Research Park for the analytical data.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

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Molecules 27 02469 g001
Figure 1. Selected examples of biologically active compounds comprising lactams rings of various sizes.
Figure 1. Selected examples of biologically active compounds comprising lactams rings of various sizes.
Molecules 27 02469 g001
Molecules 27 02469 sch001
Scheme 1. (a) The Castagnoli–Cushman reaction; (b) The use of HPA monoester in the Castagnoli–Cushman reaction [20]; (c) Reaction investigated in this work and initially proposed structure of the reaction product.
Scheme 1. (a) The Castagnoli–Cushman reaction; (b) The use of HPA monoester in the Castagnoli–Cushman reaction [20]; (c) Reaction investigated in this work and initially proposed structure of the reaction product.
Molecules 27 02469 sch001
Molecules 27 02469 sch002
Scheme 2. The actual outcome of the reaction of monoester 4 with (E)-N-ethyl-1-(p-tolyl)methanimine.
Scheme 2. The actual outcome of the reaction of monoester 4 with (E)-N-ethyl-1-(p-tolyl)methanimine.
Molecules 27 02469 sch002
Molecules 27 02469 sch003
Scheme 3. Plausible mechanistic pathways for the reaction of mono ester 4, imines and acetic anhydride.
Scheme 3. Plausible mechanistic pathways for the reaction of mono ester 4, imines and acetic anhydride.
Molecules 27 02469 sch003
Molecules 27 02469 g002
Figure 2. Examples of antibiotics comprising 3-amino-2-azetidinone scaffold.
Figure 2. Examples of antibiotics comprising 3-amino-2-azetidinone scaffold.
Molecules 27 02469 g002
Molecules 27 02469 sch004
Scheme 4. The developed novel protocol for synthesis of polysubstituted 3-amino-2-azetidinones 6a–o.
Scheme 4. The developed novel protocol for synthesis of polysubstituted 3-amino-2-azetidinones 6a–o.
Molecules 27 02469 sch004
Molecules 27 02469 sch005
Scheme 5. The developed novel protocol for synthesis of polysubstituted 3-amino-2-azetidinones 12.
Scheme 5. The developed novel protocol for synthesis of polysubstituted 3-amino-2-azetidinones 12.
Molecules 27 02469 sch005
Molecules 27 02469 sch006
Scheme 6. TFE (a) and HFIP (b) monoesters 13 and 14 in Ac2O-promoted reactions with imine 15.
Scheme 6. TFE (a) and HFIP (b) monoesters 13 and 14 in Ac2O-promoted reactions with imine 15.
Molecules 27 02469 sch006
Molecules 27 02469 g003
Figure 3. Key HMBC correlations (red arrows) displayed by compounds 18 and 19.
Figure 3. Key HMBC correlations (red arrows) displayed by compounds 18 and 19.
Molecules 27 02469 g003
Molecules 27 02469 sch007
Scheme 7. Alternative synthesis of compounds (a) 18 and (b) 19.
Scheme 7. Alternative synthesis of compounds (a) 18 and (b) 19.
Molecules 27 02469 sch007
Table 1. Condition findings for the reaction of monoester 4 with (E)-N-ethyl-1-(p-tolyl)methanimine.
Table 1. Condition findings for the reaction of monoester 4 with (E)-N-ethyl-1-(p-tolyl)methanimine.
Molecules 27 02469 i001 
EntryReagentT (°C)SolventYield (% a,b)
1CDI130PhCl (chlorobenzene)0
2(COCl)2130/25PhCl0
3(CF3CO)2O130PhCl0
4Ac2O80PhCl0
5110PhCl36
6130PhCl66, 64 c
7150PhCl26
81301,4-dioxane66
9130o-xylene51
10130PhCl23 d
a Reactions were conducted with ratio 4:imine:activating agent = 1/1.1/1.1, at 0.06 M concentration using dry solvent. b Isolated yields. c Conducted with 1.3 equiv. of imine and 1.3 equiv. of Ac2O. d 1 equiv. of N,N-diisopropylethylamine was added.
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Ananeva, A.; Bakulina, O.; Dar’in, D.; Kantin, G.; Krasavin, M. Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis. Molecules 2022, 27, 2469. https://doi.org/10.3390/molecules27082469

AMA Style

Ananeva A, Bakulina O, Dar’in D, Kantin G, Krasavin M. Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis. Molecules. 2022; 27(8):2469. https://doi.org/10.3390/molecules27082469

Chicago/Turabian Style

Ananeva, Anna, Olga Bakulina, Dmitry Dar’in, Grigory Kantin, and Mikhail Krasavin. 2022. "Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis" Molecules 27, no. 8: 2469. https://doi.org/10.3390/molecules27082469

APA Style

Ananeva, A., Bakulina, O., Dar’in, D., Kantin, G., & Krasavin, M. (2022). Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis. Molecules, 27(8), 2469. https://doi.org/10.3390/molecules27082469

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