Abstract
Ten β-lactam derivatives (6a–j) with an O-phenyl group at C-2, a glycoside at C-3 and various substituted phenyl rings on the nitrogen, were formed via a series of reactions starting with the glycoside precursors, functionalizing this to the aldehyde, forming the imines and finally the lactams, which were modified, removing the benzyl group on the glycoside producing a further set of lactams (7a–j) and converting them to the β2,3 amino acids (8a–j) in the final stage of the synthesis. The synthesis and structural elucidation of the three sets of compounds are discussed here. In addition, the crystal structure of 6e is also discussed, which shows the absolute configuration of the molecule to be 2S,3R. The Hirshfeld interactions are calculated to be Cl···H (11.1 %), O···H (8.0 %) and N···H (0.4 %). The reaction mechanism for the formation of the β-lactam is also proposed. The three sets of compounds were evaluated for their antibacterial activity against three gram-positive (Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus) and one gram-negative strain (Escherichia coli). The β2,3-amino acids 8a, 8b and 8h showed good antibacterial activity against all strains with MIC values between 0.17 and 1.44 mM, comparable to the standard ampicillin. All three compounds showed better activity to E. coli than ampicillin. Interestingly, molecular docking to the penicillin-binding protein (PBP 2X) showed the same three compounds 8a, 8b and 8h to have a better MolDock score than ampicillin and the free carboxyl groups in the β-amino acid to bind to Ser337, blocking it from further binding with peptidoglycan for cross-linking and subsequent transpeptidation.
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Introduction
The overuse of antibiotics resulting in antibiotic resistance is a topic of great concern. There is thus a need to develop new antimicrobials with higher potency and less toxicity (Fisher et al., 2005; Ritter and Wong, 2001). One such approach is molecular hybridization, where two or more different classes of biologically active compounds are linked to create a hybrid molecule with enhanced therapeutic effects (Mehta and Singh, 2002). Glycofuranose and other sugar derivatives have demonstrated significant anticancer (Tripathi et al., 2001), and antimycobacterial activity (Maddry et al., 1998; Tripathi et al., 2002), enhanced drug delivery (Namane et al., 1992; Negre et al., 1992) and improved aqueous solubility and oral activity (Fisher et al., 1991), while enantiomerically pure β-amino acids (hydrolysis products of β-lactams) have received great attention due to their interesting pharmacological properties and occurrence in natural products (Juaristi and Soloshonok, 1997).
β2,3-Amino acids have a three carbon core skeleton with side chains at C-2 and C-3. Examples of compounds with these core skeletons are the natural products: majusculamide-C (Carter et al., 1984), onchidin (Rodriguez et al., 1994), guineamide-C (Tan et al., 2003), malevamide D (Horgen et al., 2002) and ulongapeptin (Williams et al., 2003). Peptides containing β-amino acids are known to display interesting biological properties and are increasingly finding applications in medicinal chemistry (Juaristi and Lopez-Ruiz, 1999; Aguilar et al., 2007; Ruf et al., 2012). In addition, these β-amino acids have shown antibacterial (Hicks et al., 2013), anticancer (Hansen et al., 2012), proteasome inhibiting activity (Zhu et al., 2010) and anti-HIV activity (Hamada et al., 2002). A number of natural products possess a β-amino acid core, namely taxol or taxotere with anticancer activity (Wani et al., 1971), cryptophycin (Smith et al., 1994) and microginin (Tatsufumi et al., 1993) with angiotensin-converting-enzyme-inhibiting activity, amastatin, an aminopeptidase inhibitor (Aoyagi et al., 1978) and jasplakinolide with antifungal activity (Scott et al., 1988).
Several attractive asymmetric catalytic methods for the synthesis of enantiomerically pure β-amino acids have been reviewed in the literature (Ma, 2003; Sewald, 2003; Weiner et al., 2010). Furthermore, a significant amount of work with respect to methodology and synthesis has been reported for sugar β-lactams and β-amino acid derivatives (Ramesh et al., 2012; Shaikh et al., 2007; Chincholkar et al., 2007; Sanap et al., 2010; Deshmukh et al., 2004); however, to the best of our knowledge, there have been no reports on the synthesis of glycosylated β2,3-amino acids, with side chains at C-2 and C-3. Herein, we report a non-catalytic method for the stereo-selective synthesis of sugar β-lactams and glycosylated β2,3-amino acid derivatives, their structural elucidation with NMR and single crystal X-ray diffraction and their antibacterial activity along with molecular docking studies.
Results and discussion
Chemistry
In our synthetic approach, we have used the methodologies of Agrofoglio et al. (1997) and Arun et al. (2003) with modifications. The synthesis started with formation of the furanose ring from d-glucose, together with selective acetal protection forming 1 (Fig. 1). The free hydroxy group on 1 was then protected with a benzyl group in 2, before selectively removing the acetal group at C-5 and C-6 resulting in 3. Oxidation with sodium periodate produced the aldehyde intermediate 4, from which the imines 5a–j were formed from several substituted anilines. The β-lactams 6a–j were then formed from the imines with phenoxyacetyl chloride. The position of the substituent on aniline was important as the yields were best with substituents at the para position and poorer with the meta substituted anilines. The reaction did not occur with ortho substituted anilines due to steric hindrance between the ortho substituents on the imine and phenoxyacetyl chloride. The structures of 6a–j were confirmed by NMR spectroscopy. Single crystal X-ray diffraction and coupling constants (J H-2/H-3 = 5.6 Hz) indicated that only the cis 2S,3R diastereomer formed in the reaction.
Synthetic scheme for the synthesis of the β-amino acids 8a–j via hydrolysis of the β-lactams. Reagents and conditions: i CuSO4, acetone, H2SO4, rt, 30 h; ii NaH, TBAI, benzyl bromide, THF, 2 h; iii 70 % acetic acid in water, rt, 16 h; iv NaIO4, 0 °C, 2 h; v: substituted ArNH2, MgSO4, CH2Cl2, reflux 8–9 h; vi PhOCH2COCl, Et3N, CH2Cl2, 0 °C to rt, 15 h; vii Pd/C, MeOH, rt; viii LiOH/THF, 0–10 °C, 2 h
Using 6b as an example of a benzyl-protected β-lactam, the IR spectrum showed an amide carbonyl absorption at 1750 cm−1. The 1H NMR spectrum showed the β-lactam protons H-2 and H-3 as a doublet and double doublet at δ 5.28 (J = 5.6 Hz) and δ 4.73 (J = 8.9, 5.6 Hz), respectively. The β-lactam carbonyl resonance was observed at δ 164.1. The glycoside proton resonances appeared at δ 4.60–4.61 (m, H-5), δ 4.39 (d, J = 3.3 Hz, H-6), δ 4.67 (d, J = 3.8 Hz, H-7) and δ 6.06 (d, J = 3.8 Hz, H-8). The acetonide tertiary carbon C-9 appeared at δ 111.9 and C-10 and C-11 appeared at δ 26.8 and 26.3 in the 13C NMR spectrum.
The benzyl-protected group was indicated by the diastereotopic protons H-7a1 and H-7a2 as two doublets at δ 4.27 and δ 4.60 each with J = 11.4 Hz and the aromatic protons as a multiplet at δ 7.14–7.21. The oxygenated phenyl ring on the β-lactam core structure was indicated by the presence of multiplets at δ 7.00–7.07 (H-2c/4c/6c) and δ 7.25–7.23 (H-3c/5c). For the N-substituted 3-fluorophenyl ring, the H-2b and H-4b resonances appeared as a doublet of triplets at δ 7.47 (J = 10.6, 2.2 Hz) and triplet of doublets at δ 6.79 (J = 8.4, 2.3 Hz). H-6b occurred as a double doublet at δ 7.54 with J = 8.1 and 1.4 Hz and H-5b overlapped with H-3c/5c at δ 7.25–7.30.
The COSY correlation between H-3 and H-5 indicated that the glycoside was attached to C-3 of the lactam ring. The HMBC correlation from H-2 to the aromatic singlet resonance of C-1c confirms the attachment of the phenoxy group to the lactam ring. HMBC correlations from H-2 and H-3 to the carbonyl carbon C-1 confirmed the formation of the lactam ring. The HMBC correlation from H-6 to C-7a confirmed that the hydroxy at C-6 was benzyl-protected and the acetonide methyl groups H-10 and H-11 showed HMBC correlations to C-9, allowing this carbon to be assigned. Weak NOESY interactions between H-3 and H-2b and H-6b confirmed that the 3-fluorophenyl group was attached to the nitrogen of the lactam ring. NOESY interactions between H-10 and both H-5 and H-6 indicate that these protons are on the same side of the plane, and likewise, NOESY interactions between H-11 and both H-7 and H-8 indicate that these protons are on the other side of the plane. This allowed us to differentiate H-10 from H-11. Selected HMBC and NOESY interactions are given in Figs. 2 and 3.
Selected NOESY interactions for 6b
Selected HMBC correlations for 6b
There are two possible conformations for the attachment of the sugar to the β-lactam ring in the synthesized derivatives 6a–j. The crystal structure of 6e (Fig. 4) shows that H-3 and H-5 are anti. The coupling constant (J) between these two protons was found to be 8.9 ± 0.2 Hz for all the derivatives. This coupling constant was consistent with a dihedral angle of 171.69° observed between H-3 and H-5 in the crystal structure of 6e. Likewise, the coupling constant J H2,H3 of 5.6 Hz was consistent with the almost eclipsed protons which had a dihedral angle of 0.5° from the crystal structure.
Ortep diagrams for 6e
Debenzylation of 6a–j with hydrogen on a palladium–carbon catalyst resulted in 7a–j with a free hydroxy group at C-6. This was indicated by the OH absorption at 3477 cm−1 in the IR spectrum as well as the loss of the five proton multiplet at δ 7.14–7.21 for the benzyl group and the two H-7a proton resonances in the 1H NMR spectrum. The C-6 carbon resonance to which the benzyl group was attached was also observed more upfield in 7b at δ 75.6 as opposed to δ 83.1 in 6b.
In the last step of the reaction, the lactams 7a–j were hydrolysed to the β-amino acids using lithium hydroxide in THF to produce 8a–j. This was indicated by the change in carbonyl resonance from δ 164.0 in the lactam (7b) to δ 173.1 in 8b. The H-2 and H-3 resonances also shifted to δ 5.07 (d, J = 2.2 Hz) and δ 4.54 (dd, J = 8.8, 2.2 Hz) in 8b, respectively, from δ 5.46 (d, J = 5.6 Hz) and δ 4.69 (dd, J = 8.6, 5.6 Hz) in 7b. The change in J H2,H3 from 5.6 to 2.2 Hz is evident from the fact that the lactam ring was hydrolysed and from the fact that the dihedral angle between H-2 and H-3 approached 90°. Final confirmation was obtained by the HRMS of each of the synthesized compounds 8a–j.
The proposed mechanism for the stereo-selective synthesis of the sugar-based β-lactams (6a–j) is illustrated in Fig. 5. The reaction can occur either via an endo or exo attack by the pi electrons of the imine on the LUMO of the ketene. However, due to the bulky sugar moiety, causing steric hindrance, only the exo attack occurs resulting in the intermediate INT1 and transition state TS1. It is important to note that the exo attack in INT1 results in the electron donor of the ketene occupying the outward position at C-3 with lower-energy conrotatory transition state structures resulting in the 2S,3R diastereomer (Tang et al., 2010; Lopez et al., 1993).
Proposed reaction mechanism for the Staudinger reaction
Crystal structure
Crystal and structure refinement data for 6e are shown in Table 1. 6e crystallizes in the orthorhombic P212121 space group with two molecules in the asymmetric unit. The benzyl and phenyl rings are pointed away from each other at opposite ends of the lactam ring, with the sugar moiety situated orthogonal to the phenyl moiety on the nitrogen. The two benzyl rings on the sugar and the lactam are almost parallel to each other. Bond distances in the lactam rings all display single-bond characters with the N–C bond lengths being 1.368(3) and 1.370(3) for the amide bond and 1.493(3) and 1.490(5) for the other N–C-bond for the two molecules (Table 2). The two sets of C–C bond distances for the two molecules are 1.538(3) and 1.552(3), and 1.536(3) and 1.558(3) Å. The difference in the lactam ring bond distances causes some strain in the ring; thus, the bond angles of the lactam ring lie between 86.4(2)° and 99.2(2)° for both molecules. As explained in the NMR section, H(25) and H(8) are antiperiplanar with a dihedral angle of above 170.0° and H(8) and H(9) are eclipsed with a dihedral angle of 0.5°. In the crystal, weak C–H…O hydrogen bonding interactions (Table 3) link the molecules in a 3D network (Fig. 6). Figure 7 represents fingerprint plots corresponding to Hirshfeld surface–surface interactions and percentage contribution of interactions. The Hirshfeld interactions for 6e are Cl···H (11.1 %) > O···H (8.0 %) > N···H (0.4 %).
Crystal packing diagram of 6e
Hirshfeld analysis of 6e
In vitro antibacterial activity
All the above-mentioned synthesized compounds (6a–j, 7a–j and 8a–j) were evaluated for antibacterial activity against four bacterial strains (three gram-positive (+) and one gram-negative). Disc diffusion assays were initially used to gauge whether or not the compounds had activity and to select compounds on which to determine the MIC values. The results are presented in Tables 4 and 5. Compounds 6a–j with an O-benzyl group at C-6 on the sugar moiety were the least active in the disc diffusion assay. By removing the benzyl group at C-6 resulting in the free hydroxy group, the activity of the resultant compounds 7a–j increased, having a broader spectrum of activity in that some of the compounds were now also active against Escherichia coli and Staphylococcus aureus. E. coli and S. aureus were resistant to 6a–j. However, the highest activity was shown by the glycosyl β2,3-amino acid derivatives (8a–j) with all compounds having a broad spectrum of activity and only 8i and 8j (the 3,4-dimethoxy and unsubstituted derivatives) being inactive against S. aureus.
Amongst the glycosyl β2,3-amino acid derivatives (8a–j), the highest activity was shown by 8h, followed by 8b and 8a. These were all the fluoro derivatives substituted at the 3,4-position, 3-position and 4-position, respectively. These results indicate that the fluorine atom substituted on the N-phenyl ring is essential for antibacterial activity and that both C-3 and C-4 substitutions are equally important, with fluorine substitution at both positions showing the best activity. The MIC values of these three compounds (8a, 8b and 8h) were then determined to further evaluate their antibacterial activity. These results also indicated that 8h was the best antibacterial compound overall and 8a, 8b and 8h all showed good-to-moderate activity against the bacterial strains tested against. All three compounds 8a, 8b and 8h showed at least twofold better activity (0.17 mM) than ampicillin (0.37 mM) against E. coli. In addition, 8h showed slightly better activity (0.33 mM) than ampicillin (0.37 mM) against P. aeruginosa.
These results indicate that the β2,3 amino acid core is better than the lactam moiety in these molecules with regard to antibacterial activity. These results also showed the importance of the free hydroxy group at C-6 and fluorine substitution at the 3- and 4-positions on the N-phenyl ring.
Docking studies
To validate these results, molecular docking studies for 8a, 8b and 8h were carried out using Molegro Virtual Docker (MVD-2013, 6.0). Recently, Nagarajan et al. (2012) reported the synthesis and antimicrobial activity of sugar-based azetidin-2-one derivatives of which many compounds displayed great affinity towards penicillin-binding protein (PBP) and inactivate PBPs by interfering with the process of transpeptidation. It was also reported that Ser337, Ser395, Ser548 and Thr550 are important residues of PBP 2X for the binding of β-lactam glycosides to the target PBP (Nagarajan et al., 2012). β-Lactam antibiotics such as cefditoren (CDS) exhibit potent antimicrobial activity by targeting PBPs, which are membrane-associated enzymes that catalyse polymerization and cross-linking of peptidoglycan precursors in bacterial cell wall biosynthesis. The involvement of the active-site serine residue of PBPs is found to be crucial during the cross-link formation and subsequent transpeptidation (Mcdonough et al., 2002).
The trypsin-digested PBP 2X is composed of a short cytoplasmic region, a transmembrane region and a periplasmic unit containing three domains: the N-terminal, transpeptidase and C-terminal domains. The crystal structure of CDS-acylated PBP 2X from Streptococcus pneumonia (2Z2M) exists as a homodimeric assembly, and the inhibitor CDS is bound to two chains (B and E) of the structure, but none of the binding sites come in the interface of two domains or two different chains (Yamada et al., 2007). The protein data bank (PDB) structure 2Z2M bound to the inhibitor CDS shows a true binding site for each of the subunits and was considered as the centre of search space for docking. Hence, to identify other residual interactions of the tested compounds, a grid box (including residues within a 10.0 Å radius) large enough to accommodate the active site was constructed. An essential feature of the binding site is the conservation of hydrogen bonds and aromatic π–π stacking interactions.
The molecular docking results for 8a, 8b and 8h are summarized in Table 6. The MolDock score ranged from −142.7 to −147.7 kcal mol−1, while the MolDock score of standard drugs AMP (Ampicillin) and CDS was −139.5 and −196.6 kcal mol−1, respectively. Based on the MolDock score, the conformations were ranked with the criteria that the lower the MolDock score, the higher the binding affinity. Thus, all the test compounds exhibited better affinities compared to ampicillin (AMP) towards PBP 2X. Compounds 8h and 8a (MolDock score: −147.7 and −147.8 kcal mol−1, respectively) displayed similar affinity towards PBP 2X followed by 8b (−142.7 kcal mol−1). MVD could predict the correct pose of the ligand. The docked pose displays the proper conformation and better interaction than the co-crystallized ligand. The best poses (orientations) of the docked compounds and of standard drugs (AMP and CDS) are represented in Fig. 8. Compounds 8a, 8b and 8h exhibited well-conserved interactions with PBP 2X such as hydrogen bonding, hydrophobic bonding and van der Waal’s interactions with one or more amino acid residues in the active pocket. Compound 8h displayed the highest number (8) of conserved hydrogen bond interactions (−22.6 kcal mol−1) with amino acid residues Ser337, Ser395, Asn397 and Thr550, while compound 8a exhibited three hydrogen bond interactions (−12.5 kcal mol−1) with Ser337, Ser395 and Asn397. In compound 8b (−8.7 kcal mol−1), prominent hydrogen bonding interactions were observed with Ser337 and Gln552 residues.
The docked pose of compounds in the active site of PBP 2X; Hydrogen bonds are represented by broken lines (blue). a Cefdfitoren, b Ampicillin, c 8a, d 8h, e 8b (Color figure online)
Besides hydrogen bonding interactions, steric and aromatic π–π stacking interactions were also evident with the various amino acid residues in the active site of 2Z2M. These are essential for the inhibition of PBP 2X. The present study indicated that in general, free carboxyl groups in the β-amino acid bind to Ser337, blocking it from further binding with peptidoglycan for cross-linking and subsequent transpeptidation. Thus, the in silico results provide strong evidence that 8a, 8b and 8h play a vital role in binding with 2Z2M, which could eventually lead to effective inhibition of PBPs.
Materials and methods
Reagents and chemicals were purchased from Sigma-Aldrich via Capital Laboratories, South Africa. Organic solvents were purified by re-distillation and dried according to standard procedures. Melting points were determined on a Thermonik Campbell melting point apparatus and are uncorrected. Optical rotations were recorded on a Perkin-Elmer 341 digital polarimeter under standard conditions. Infrared spectra were recorded on a Bruker infrared spectrophotometer, Model 599-B. The purity of the compounds was determined on an analytical HPLC (Shimadzu-20A5) fitted with a C8 (150 mm × 5 μm) column using a mobile phase (A) (25 %) with 0.1 % formic acid buffer and (B) acetonitrile (75 %) in an isocratic system over a period of 30–60 min. 1H, 13C and 19F NMR spectra were recorded in CDCl3 or CD3OD at room temperature using a Bruker Avance 400 MHz instrument. Chemical shifts (δ) are noted against the internal standard tetramethylsilane. 2D NMR (COSY, NOESY, HSQC and HMBC) was used to confirm the structure of the synthesized compounds. ESI-MS analysis was carried out in the positive mode on a Shimadzu mass spectrometer 2020, and HRMS was recorded on a Waters Synapt G2 quadrupole time-of-flight mass spectrometer, also in the positive mode (Milford, MA, USA).
Crystals suitable for X-ray diffraction were obtained by slow evaporation in a combination of dichloromethane, acetone and n-hexane at room temperature. The data collection and cell refinement was done using Bruker APEX2 and SAINT-Plus software packages, respectively. Data reduction was performed with SAINT-Plus and XPREP. SHELXS-97 (Sheldrick, 2008) was used to solve and refine the structure. ORTEP-3 (Farrugia, 1999) and WinGX (Farrugia, 1999) were used to prepare the graphics for publication. Crystallographic data (excluding structure factors) for the structure in this paper have been deposited with the Cambridge Crystallographic Data Centre, CCDC, 12 Union Road, Cambridge CB21EZ, UK. Copies of the data can be obtained free of charge on quoting the depository number CCDC-1035534 (Fax: +44-1223-336-033; E-Mail: deposit@ccdc.cam.ac.uk, http://www.ccdc.cam.ac.uk).
Hirshfeld analysis
Crystal Explorer 3.0 software was used to determine the Hirshfeld surface in the crystal structure and its associated fingerprint analysis and to view the molecular contacts between the molecules (Spackman and McKinnon, 2002). The different colour intensities presented indicate the strength of interactions for short and long contacts. The program was run with the cif file. Bond lengths to hydrogen atoms were set to typical neutron values of C–H = 1.083 Å. The Hirshfeld surface mapped with d norm of the molecule, and Cl···H, O···H and N···H contacts are coloured with white-to-blue, indicating that the molecular contacts are close to van der Waals separations in the structures. Accordingly, at each point on the iso-surface, two distances are defined: d e and d i . The distance from a point to the nearest nucleus external to the surface is denoted as d e , while the distance from a point to the nearest nucleus internal to the surface is denoted as d i (Mckinnon et al., 2004, 2007). The normalized distance (d norm) based on d e and d i is given by:
where r vdw i and r vdw e are the van der Waals radii of the atoms.
The parameter d norm defines a surface with a red–white–blue colour scheme, where red is used to highlight short contacts, white for contacts around the van der Waals separation and blue for long contacts. Hirshfeld surface fingerprint plots were generated using d i and d e as 2D histograms.
Docking methodology
Chemdraw10.0 was used to construct the compounds 8a, 8b and 8h, and the 2D structures converted into energy-minimized 3D structures which were saved as MDL MolFiles (.mol2). The coordinate file and crystal structure of trypsin-digested PBP 2X (PDB ID: 2M2Z) were obtained from the protein data bank (http://www.rscb.org/pdb). The protein file was prepared by the removal of water molecules, addition of polar hydrogens and removal of other bound ligands. In the present study, the binding site was selected based on the amino acid residues of the prepared protein as obtained from the protein data bank which are involved in binding with CDS. This binding site would be considered as the most probable region based on crystallographic data. The docking protocol was carried out for the synthesized compounds as listed in Table 6 using MVD-2013 (6.0) software and standard operating procedures.
The MolDock scoring function is used by the MVD program and is defined by E score = E inter + E intra, where, E score = MolDock score, E inter = ligand–Protein interaction and E intra = internal energy of the ligand. MolDock is based on a heuristic search algorithm that combines differential evolution with a cavity prediction algorithm. The docking scoring function of MolDock is an extension of the piecewise linear potential (PLP) including new hydrogen bonding and electrostatic terms. To further improve docking accuracy, a re-ranking scoring function was introduced, which identifies the most promising docking explanation from the results obtained by the docking algorithm (Thomsen and Christensen, 2006).
Antibacterial assay
The synthesized compounds 6a–j, 7a–j and 8a–j were evaluated for antibacterial activity using the disc diffusion method (Clinical and Laboratory Standards Institute, 2007) against gram-positive and gram-negative bacteria, Staphylococcus aureus 29263, Pseudomonas aeruginosa 2758, Escherichia coli 25922 and Bacillus subtilis 6623. The standard antibiotic ampicillin was used as a control for comparison. Briefly, Mueller Hilton agar was prepared (38 g in 1 L of water) and poured into sterile prelabeled petri dishes, which were then allowed to set and dry at room temperature. The bacterial organisms were standardized using a 0.5 McFarland standard turbidity and then swabbed onto the agar plates. Paper discs were dissolved in sample and control discs were placed onto the agar plates which were inverted and incubated at 35–37 °C for 24 h. The diameter of the zone of inhibition was measured in mm. Based on these results, the most active compounds, 8a, 8b and 8h, were selected to determine their MIC values using the broth microdilution assay with ampicillin as the control and following the method in Andrews (2001).
Briefly, the cultures were grown overnight on TSA and diluted to an equivalent of a 0.5 McFarland standard. 96-well microtiter plates were inoculated with 100 µL of cell suspension, 100 μL of Mueller-Hinton (MH) broth and twofold serial dilutions of compounds 8a, 8b and 8h dissolved in DMSO (2500–39 μg mL−1) and the antimicrobial agent ampicillin (128–4 μg mL−1). The plates were then incubated at 30 °C for 24 h without shaking. The negative control wells contained MH broth only, and the positive control wells contained the respective cell suspensions with no compound/antimicrobial agents added. This was done in duplicate. The MIC was the lowest concentration of antimicrobial agent, which inhibited the visible growth of the bacteria.
Synthesis of intermediate 4
The synthesis of compound 4 was carried out following the procedures reported in Agrofoglio et al. (1997) and Arun et al. (2003). This involved acetonide protection of glucose, benzyl protection of the free hydroxyl group, subsequent acetonide deprotection and oxidation to the aldehyde (4).
Synthesis of the imines (5a–j)
Anhydrous MgSO4 (2.0 g) was added to a solution of substituted anilines (2.0 mmol) and aldehyde 4 (556.0 mg, 2.0 mmol) in dichloromethane (DCM) (30 mL), and the mixture was stirred under reflux for 8 h. The solution was filtered and the solvent removed under reduced pressure to afford the imines 5a–j as brown or colourless oils, which were used immediately for the next step.
Synthesis of the β-lactams (6a–j)
A solution of phenoxyacetyl chloride (255.0 mg, 1.5 mmol) in dry DCM was added to a solution of the respective imine (5a–j) (1 mmol) and triethylamine (454.0 mg, 4.5 mmol) in dry DCM (20 mL) at 0–5 °C under nitrogen. Upon completion, the mixture was allowed to attain room temperature and stirred overnight. Completion of the reaction was monitored by TLC. On completion, the solvent was concentrated under reduced pressure to afford the crude β-lactams (6a–j) as white solids, which were purified by column chromatography using silica gel and 20 % ethyl acetate in n-hexane.
(6a) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(4-fluorophenyl)-3-phenoxyazetidin-2-one)
White solid (60 % yield); mp 120–122 °C; [α] 20D = −4.32° (c 0.02, MeOH); IR υ max 2934 (C–H), 1744 (C=O); 1590, 1511, 1493 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.70 (2H, dd, J = 9.1, 4.8 Hz, H-2b/6b), 7.26–7.30 (2H, m, H-3c/5c), 7.14–7.19 (5H, m, H-2a-H-6a), 7.03–7.08 (3H, m, H-2c/4c/6c), 6.98 (2H, t, J = 8.8 Hz, H-3b/5b), 6.04 (1H, d, J = 3.8 Hz, H-8), 5.28 (1H, d, J = 5.6 Hz, H-2), 4.71 (1H, dd, J = 8.8, 5.6 Hz, H-3), 4.65 (1H, d, J = 3.9 Hz, H-7), 4.60 (2H, d, J = 11.8 Hz, H-7a2, H-5), 4.39 (1H, d, J = 3.3 Hz, H-6), 4.29 (1H, d, J = 11.4 Hz, H-7a1), 1.47 (3H, s, H-10), 1.31 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.7(C, C-1), 159.6 (C, d, J = 242.3 Hz, C-4b), 157.3(C, C-1c), 137.0 (C, C-1a), 133.6 (C, C-1b), 129.7 (CH, C-3c/5c), 128.5 (CH, C-3a/5a), 128.1 (CH, C-4a), 127.6 (CH, C-2a/6a), 122.6 (CH, C-4c), 119.9 (CH, d, J = 7.9 Hz, C-2b/6b), 115.6 (CH, C-2c/6c), 115.5 (CH, d, J = 22.4 Hz, C-3b/5b), 111.9 (C, C-9), 105.0 (CH, C-8), 83.1(CH, C-6), 81.9 (CH, C-7), 81.3 (CH, C-5), 79.2 (CH, C-2), 72.0 (CH2, C-7a), 58.5 (CH, C-3), 26.8 (CH3, C-11), 26.3 (CH3, C-10); 19F NMR (CDCl3, 376.5 MHz) δ −117.49; MS (m/z) (pos): 506 (M+).
(6b) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(3-fluorophenyl)-3-phenoxyazetidin-2-one)
White solid (45 % yield); mp 108–109 °C; [α] 20D = −3.80° (c 0.02, MeOH); IR υ max 2990 (C–H), 2934 (C–H), 1750 (C=O), 1613, 1591, 1494 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.54 (1H, dd, J = 8.1, 1.4 Hz, H-6b), 7.47 (1H, dt, J = 10.6, 2.2 Hz, H-2b), 7.25–7.30 (3H, m, H-3c/5c, H-5b), 7.14–7.21 (5H, m, H-2a-H-6a), 7.01–7.07 (3H, m H-2c/4c/6c), 6.78 (1H, td, J = 8.4, 2.3 Hz, H-4b), 6.05 (1H, d, J = 3.8 Hz, H-8), 5.28 (1H, d, J = 5.7 Hz, H-2), 4.73 (1H, dd, J = 8.9, 5.6 Hz, H-3), 4.66 (1H, d, J = 3.8 Hz, H-7), 4.60* (1H, d, J = 11.4 Hz, H-7a2), 4.60–4.61* (1H, m, H-5), 4.39 (1H, d, J = 3.3 Hz, H-6), 4.27 (1H, d, J = 11.4 Hz, H-7a1), 1.48 (3H, s, H-10), 1.32 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 164.1 (C, C-1), 162.8 (C, d, J = 243.5 Hz, C-3b), 157.3 (C, C-1c), 139.0 (C, d, J = 10.8 Hz, C-1b), 137.0 (C, C-1a), 130.0 (CH, d, J = 9.0 Hz, C-5b) 129.7 (CH, C-3c/5c), 128.5 (CH, C-3a/5a), 128.1 (CH, C-4a), 127.6 (CH, C-2a/6a), 122.6 (CH, C-4c), 115.6 (CH, C-2c/6c), 114.0 (CH, d, J = 3.0 Hz, C-6b), 111.9 (C, C-9), 111.4 (CH, d, J = 21.2 Hz, C-4b), 105.9 (CH, d, J = 26.7 Hz, C-2b), 105.0 (CH, C-8), 83.1(CH, C-6), 81.9 (CH, C-7), 81.2 (CH, C-5), 79.1 (CH, C-2), 72.0 (CH2, C-7a), 58.6 (CH, C-3), 26.8 (CH3, C-11), 26.3 (CH3, C-10); 19F NMR (CDCl3, 376.5 MHz) δ −111.50; MS (m/z) (pos): 506 (M+). * resonances overlap.
(6c) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-2-one)
White solid (75 % yield); mp 130–132 °C; [α] 20D = −5.95° (c 0.02, MeOH); IR υ max 2958 (C–H), 2936 (C–H), 1747 (C=O), 1598, 1590, 1512, 1494 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.67 (2H, d, J = 9.0, Hz, H-2b/6b), 7.28 (2H, t, J = 7.7 Hz, H-3c/5c), 7.16–7.18 (5H, m, H-2a-H-6a), 7.08 (2H, d, J = 8.0 Hz, H-2c/6c), 7.02 (1H, t, J = 7.3 Hz, H-4c), 6.83 (2H, t, J = 9.0 Hz, H-3b/5b), 6.04 (1H, d, J = 3.8 Hz, H-8), 5.28 (1H, d, J = 5.5 Hz, H-2), 4.69 (1H, dd, J = 8.8, 5.5 Hz, H-3), 4.65 (1H, d, J = 3.8 Hz, H-7), 4.60* (1H, d, J = 11.5 Hz, H-7a2), 4.59–4.62* (1H, m, H-5), 4.41 (1H, d, J = 3.3 Hz, H-6), 4.28 (1H, d, J = 11.5 Hz, H-7a1), 3.77 (3H, s, H-7b), 1.47 (3H, s, H-10), 1.31 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.5 (C, C-1), 157.4 (C, C-1c), 156.6 (C, C-4b), 137.1 (C, C-1a), 131.2 (C, C-1b), 129.7 (CH, C-3c/5c), 128.5 (CH, C-3a/5a), 128.0 (CH, C-4a), 127.6 (CH, C-2a/6a), 122.5 (CH, C-4c), 119.8 (CH, d, C-2b/6b), 115.6 (CH, C-2c/6c), 114.0 (CH, C-3b/5b), 111.9 (C, C-9), 105.0 (CH, C-8), 83.2(CH, C-6), 81.9 (CH, C-7), 81.4 (CH, C-5), 79.2 (CH, C-2), 72.0 (CH2, C-7a), 58.5 (CH, C-3), 55.5 (CH3, C-7b), 26.9 (CH3, C-11), 26.3 (CH3, C-10); MS (m/z) (pos): 518 (M+). * resonances overlap.
(6d) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(3-methoxyphenyl)-3-phenoxyazetidin-2-one)
White solid (50 % yield); mp 80–81 °C; [α] 20D = −5.26° (c 0.02, MeOH); IR υ max 2955 (C–H), 2930 (C–H), 1755 (C=O), 1599, 1591, 1491 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.38 (1H, t, J = 2.1 Hz, H-5b), 7.34–7.36 (1H, m, H-4b), 7.26–7.30 (3H, m, H-2b/3c/5c), 7.14–7.21 (5H, m, H-2a-H-6a), 7.08 (2H, d, J = 7.8 Hz, H-2c/6c), 7.02 (1H, t, J = 7.2 Hz, H-4c), 6.65 (1H, dd, J = 8.5, 2.6 Hz, H-6b), 6.05 (1H, d, J = 3.9 Hz, H-8), 5.29 (1H, d, J = 5.6 Hz, H-2), 4.72 (1H, dd, J = 8.7, 5.6 Hz, H-3), 4.67 (1H, d, J = 4.0 Hz, H-7), 4.67 (1H, d, J = 4.0 Hz, H-7), 4.60–4.67 (2H, m, H-7a2/H-5), 4.43 (1H, d, J = 3.3 Hz, H-6), 4.29 (1H, d, J = 11.4 Hz, H-7a1), 3.78 (3H, s, H-7b), 1.48 (3H, s, H-10), 1.32 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 164.1 (C, C-1), 159.9 (C, C-3b), 157.3 (C, C-1c), 138.8 (C, C-1b), 137.1 (C, C-1a), 129.7 (CH, C-3c/5c), 129.5 (CH, C-5b), 128.5 (CH, C-3a/5a), 128.0 (CH, C-4a), 127.6 (CH, C-2a/6a), 122.5 (CH, C-4c), 115.6 (CH, C-2c/6c), 111.9 (C, C-9), 111.0 (CH, C-6b), 110.8 (CH, C-4b), 105.0 (CH, C-8), 103.8 (CH, C-2b), 83.2 (CH, C-6), 82.0 (CH, C-7), 81.3 (CH, C-5), 79.0 (CH, C-2), 72.0 (CH2, C-7a), 58.7 (CH, C-3), 55.3 (CH3, C-7b), 26.8 (CH3, C-11), 26.3 (CH3, C-10); MS (m/z) (pos): 518 (M+).
(6e) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(4-chlorophenyl)-3-phenoxyazetidin-2-one)
White solid (65 % yield); mp 110–112 °C; [α] 20D = −7.72°(c 0.02, MeOH); IR υ max 2969 (C–H), 2927 (C–H), 1744 (C=O), 1595, 1491 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.66 (2H, d, J = 8.8 Hz, H-2b/6b), 7.24–7.29 (4H, m, H-3b/5b, H-3c/5c), 7.13–7.20 (5H, m, H-2a-H-6a), 7.00–7.06 (3H, m, H-2c/4c/6c), 6.03 (1H, d, J = 3.8 Hz, H-8), 5.28 (1H, d, J = 5.6 Hz, H-2), 4.71 (1H, dd, J = 8.8, 5.6 Hz, H-3), 4.65 (1H, d, J = 3.8 Hz, H-7), 4.58–4.61 (2H, m, H-5/7a2), 4.38 (d, J = 3.3 Hz, H-6), 4.25 (1H, d, J = 11.5 Hz, H-7a1), 1.46 (3H, s, H-10), 1.32 (3H, s, H-11). 13C NMR (CDCl3, 100 MHz) δ 163.9 (C, C-1), 157.3 (C, C-1c), 137.0 (C, C-1a), 136.2 (C, C-4b), 129.7 (CH, C-3c/5c), 128.8 (CH, C-2b/6b), 128.5 (CH, C-3a/5a), 128.1 (CH, C-4a), 127.6 (CH, C-2a/6a), 122.6 (CH, C-4c), 119.7 (CH, C-3b/5b), 115.6 (CH, C-2c/6c), 112.0 (C, C-9), 105.0 (CH, C-8), 83.1 (CH, C-6), 81.9 (CH, C-7), 81.3 (CH, C-5), 79.2 (CH, C-2), 72.0 (CH2, C-7a), 58.5 (CH, C-3), 26.8 (CH3, C-11), 26.3 (CH3, C-10); MS (m/z) (pos): 522 (M+).
(6f) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(3-chlorophenyl)-3-phenoxyazetidin-2-one)
White solid (45 % yield); mp 112–114 °C; [α] 20D = −4.80° (c 0.02, MeOH); IR υ max 2986 (C–H), 2943 (C–H), 1752 (C=O), 1595, 1485 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.75 (1H, t, J = 1.7 Hz, H-2b), 7.50 (1H, dd, J = 8.2, 1.7 Hz, H-6b), 7.28 (2H, t, J = 8.5 Hz, H-3c/5c), 7.23 (1H, d, J = 10.2 Hz, H-5b), 7.14–7.21 (5H, m, H-2a-H-6a), 7.01–7.06 (4H, m, H-4b, H-2c/4c/6c), 6.06 (1H, d, J = 3.9 Hz, H-8), 5.28(1H, d, J = 5.7 Hz, H-2), 4.74 (1H, dd, J = 8.9, 5.7 Hz, H-3), 4.67 (1H, d, J = 3.9 Hz, H-7), 4.60–4.63 (2H, m, H-5/H-7a2), 4.38 (1H, d, J = 3.3 Hz, H-6), 4.27 (1H, d, J = 11.5 Hz, H-7a1), 1.48 (3H, s, H-10), 1.32 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 164.2 (C, C-1), 157.4 (C, C-1c), 138.8 (C, C-1b), 137.1 (C, C-1a), 134.6 (C, C-3b), 130.0 (CH, C-5b), 129.8 (CH, C-3c/5c), 128.7 (CH, C-3a/5a), 128.2 (CH, C-4a), 127.6 (CH, C-2a/6a), 124.8 (CH, C-4b), 122.8 (CH, C-4c), 118.6 (CH, C-6b), 116.6 (CH, C-2b), 115.7 (CH, C-2c/6c), 112.0 (C, C-9), 105.1 (CH, C-8), 83.2 (CH, C-6), 82.0 (CH, C-7), 81.4 (CH, C-5), 79.3(CH, C-2), 72.2 (CH2, C-7a), 58.6 (CH, C-3), 27.0 (CH3, C-11), 26.4 (CH3, C-10); MS (m/z) (pos): 522 (M+).
(6g) (3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(3,4-dichlorophenyl)-3-phenoxyazetidin-2-one)
White solid (40 % yield); mp 109–110 °C; [α] 20D = −3.15° (c 0.02, MeOH); IR υ max 2922 (C–H), 1746 (C=O), 1592, 1477 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.86 (1H, d, J = 2.4 Hz, H-2b), 7.59 (1H, dd, J = 8.7, 2.4 Hz, H-6b), 7.34 (1H, d, J = 8.8 Hz, H-5b), 7.28 (2H, t, J = 7.7 Hz, H-3c/5c), 7.14–7.21 (5H, m, H-2a-H-6a), 7.02–7.06 (3H, m, H-2c/4c/6c), 6.05 (1H, d, J = 3.9 Hz, H-8), 5.28 (1H, d, J = 5.6 Hz, H-2), 4.72 (1H, dd, J = 9.0, 5.7 Hz, H-3), 4.67 (1H, d, J = 3.9 Hz, H-7), 4.58–4.63 (2H, m, H-5/H-7a2), 4.37 (1H, d, J = 3.3 Hz, H-6), 4.27 (1H, d, J = 11.4 Hz H-7a1), 1.47 (3H, s, H-10), 1.32 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 164.0 (C, C-1), 157.2 (C, C-1c), 136.93 (C, C-4b), 136.90 (C, C-1a), 132.6 (C, C-1b), 130.4 (CH, C-6b), 129.7 (CH, C-3c/5c), 128.5 (CH, C-3a/5a), 128.1 (CH, C-4a), 127.9 (C, C-3b), 127.6 (CH, C-2a/6a), 122.7 (CH, C-4c), 120.1 (CH, C-5b), 117.8 (CH, C-2b), 115.6 (CH, C-2c/6c), 112.0 (C, C-9), 105.0 (CH, C-8), 83.0 (CH, C-6), 81.9 (CH, C-7), 81.2 (CH, C-5), 79.3 (CH, C-2), 72.0 (CH2, C-7a), 58.6 (CH, C-3), 26.8 (CH3, C-11), 26.3 (CH3, C-10), MS (m/z) (pos): 556 (M+).
(6h) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(3,4-difluorophenyl)-3-phenoxyazetidin-2-one)
White solid (40 % yield); mp 134–135 °C; [α] 20D = −3.14° (c 0.02, MeOH); IR υ max 2986 (C–H), 2943 (C–H), 1752 (C=O), 1595, 1485 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.62 (1H, ddd, J = 11.9, 7.0, 2.5 Hz, H-2b), 7.46–7.51 (1H, m, H-6b), 7.26–7.30 (2H, m, H-3c/5c), 7.13–7.20 (5H, m, H-2a-H-6a), 7.02–7.11 (4H, m, H-5b, H-2c/4c/6c), 6.05 (1H, d, J = 3.9 Hz, H-8), 5.28 (1H, d, J = 5.6 Hz, H-2), 4.66–4.71 (2H, m, H-3/H-7), 4.58–4.63 (2H, m, H-5/H-7a2), 4.38 (1H, d, J = 3.6 Hz, H-6), 4.27 (1H, d, J = 11.4 Hz, H-7a1), 1.48 (3H, s, H-10), 1.32 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.9 (C, C-1), 157.2 (C, C-1c), 149.6 (C, dd, J = 259.3, 13.5 Hz, C-3b), 149.6 (C, dd, J = 257.3, 13.0 Hz, C-4b), 137.0 (C, C-1a), 134.0 (C, C-1b), 129.7 (CH, C-3c/5c), 128.5 (CH, C-3a/5a), 128.1 (CH, C-4a), 127.6 (CH, C-2a/6a), 122.7 (CH, C-4c), 117.2 (CH, d, J = 17.9 Hz, C-5b), 115.6 (CH, C-2c/6c), 114.3 (CH, dd, J = 5.9, 3.8 Hz, C-6b), 112.0 (C, C-9), 108.1 (CH, d, J = 21.8 Hz, C-2b), 105.0 (CH, C-8), 83.0 (CH, C-6), 81.6 (CH, C-7), 81.2 (CH, C-5), 79.3 (CH, C-2), 72.0 (CH2, C-7a), 58.8 (CH, C-3), 26.8 (CH3, C-11), 26.3 (CH3, C-10); 19F NMR (CDCl3, 376.5 MHz) δ −135.79; −142.25; MS (m/z) (pos): 524 (M+).
(6i) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(3,4-dimethoxyphenyl)-3-phenoxyazetidin-2-one)
White solid (65 % yield); mp 120–121 °C; [α] 20D = −2.88° (c 0.02, MeOH); IR υ max 2961 (C–H), 1754 (C=O), 1590, 1510, 1454 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.49 (1H, d, J = 2.4 Hz, H-2b), 7.26–7.30 (3H, m, H-6b, H-3c/5c), 7.13–7.20 (5H, m, H-2a-H-6a), 7.08–7.10 (2H, m, H-2c/6c), 7.00–7.04 (1H, t, J = 7.4 Hz, H-4c), 6.79 (1H, d, J = 8.7, H-5b), 6.03 (1H, d, J = 3.8 Hz, H-8), 5.29 (1H, d, J = 5.4 Hz, H-2), 4.66–4.70 (2H, m, H-3/H-7), 4.59–4.63 (2H, m, H-5/H-7a2), 4.46 (1H, d, J = 3.2 Hz, H-6), 4.29 (1H, d, J = 11.4 Hz, H-7a1), 3.84 (3H, s, H-7b), 3.87 (3H, s, H-8b), 1.47 (3H, s, H-10), 1.32 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.7 (C, C-1), 157.5 (C, C-1c), 149.0 (C, C-3b), 146.2 (C, C-4b), 137.2 (C, C-1a), 131.6 (C, C-1b), 129.8 (CH, C-3c/5c), 128.6 (CH, C-3a/5a), 128.2 (CH, C-4a), 127.8 (CH, C-2a/6a), 122.6 (CH, C-4c), 115.8 (CH, C-2c/6c), 112.1 (C, C-9), 111.3 (CH, C-5b), 110.5 (CH, C-6b), 105.1 (CH, C-8), 103.3 (CH, C-2b), 83.4 (CH, C-6), 82.1 (CH, C-7), 81.4 (CH, C-5), 79.3 (CH, C-2), 72.2 (CH2, C-7a), 59.2 (CH, C-3), 56.2 (CH3, C-7b), 56.0 (CH3, C-8b), 27.0 (CH3, C-11), 26.5 (CH3, C-10); MS (m/z) (pos): 548 (M+).
(6j) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-phenoxy-1-phenylazetidin-2-one)
White solid (65 % yield); mp 118–119 °C; [α] 20D = −3.68° (c 0.02, MeOH); IR υ max 2928 (C–H), 1753 (C=O), 1597, 1489 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.72 (2H, d, J = 7.8 Hz, H-2b/6b), 7.26–7.32 (4H, m, H-3b/5b, H-3c/5c), 7.15–7.20 (5H, m, H-2a-H-6a), 7.07–7.11 (3H, m, H-4b, H-2c/6c), 7.03 (1H, t, J = 7.2 Hz, H-4c), 6.05 (1H, d, J = 3.9 Hz, H-8), 5.28 (1H, d, J = 5.6 Hz, H-2), 4.76 (1H, dd, J = 8.9, 5.6 Hz, H-3), 4.66 (1H, d, J = 3.9 Hz, H-7), 4.60–4.64 (2H, m, H-5/H-7a2), 4.41 (1H, d, J = 3.4 Hz, H-6), 4.28 (1H, d, J = 11.4 Hz, H-7a1), 1.47 (3H, s, H-10), 1.31 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 164.2(C, C-1), 157.5 (C, C-1c), 137.8 (C, C-1b), 137.3 (C, C-1a), 129.8 (CH, C-3c/5c), 128.9 (CH, C-3b/5b), 128.7 (CH, C-3a/5a), 128.2 (CH, C-4a), 127.7 (CH, C-2a/6a), 124.8 (CH, C-4b), 122.7 (CH, C-4c), 118.5 (CH, C-2b/6b), 115.8 (CH, C-2c/6c), 112.0 (C, C-9), 105.1 (CH, C-8), 83.3 (CH, C-6), 82.0 (CH, C-7), 81.5 (CH, C-5), 79.2 (CH, C-2), 72.1 (CH2, C-7a), 58.5 (CH, C-3), 27.0 (CH3, C-11), 26.4 (CH3, C-10); MS (m/z) (pos): 488 (M+).
Debenzylation of 6a–j to produce the lactams 7a–j
The β-lactams (6a–j) (2.0 mmol) in 20 mL MeOH were treated with 10 % Pd/C (0.06 g), under hydrogen pressure for 2 h. Completion of the reaction was monitored by TLC, and on completion, the catalyst was removed by filtration and the solvent evaporated under reduced pressure to afford the crude compounds (7a–j) as white solids, which was then purified by column chromatography using silica gel and 35 % ethyl acetate in n-hexane.
(7a) ((3S,4R)-1-(4-fluorophenyl)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-phenoxyazetidin-2-one)
White solid (80 % yield); mp 165–167 °C; [α] 20D = −3.99° (c 0.02, MeOH); IR υ max 3477 (O–H), 1757 (C=O) cm−1, 1600, 1509, 1496; 1H NMR (CDCl3, 400 MHz) δ 7.73 (2H, dd, J = 6.9, 4.7 Hz, H-2b/6b), 7.31 (2H, t, J = 8.5 Hz, H-3c/5c), 7.14 (2H, d, J = 8.0 Hz, H-2c/6c), 6.98–7.06 (3H, m, H-3b/5b, H-4c), 6.03 (1H, d, J = 3.7 Hz, H-8), 5.46 (1H, d, J = 5.6 Hz, H-2), 4.67 (1H, dd, J = 8.6, 5.6 Hz, H-3), 4.59 (1H, d, J = 2.9 Hz, H-6), 4.54 (1H, dd, J = 8.7 Hz, 2.9 Hz, H-5), 4.48 (1H, d, J = 3.7 Hz, H-7), 1.45 (3H, s, H-10), 1.29 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.7 (C, C-1), 159.6 (C, d, J = 242.4 Hz, C-4b), 157.5 (C, C-1c), 133.8 (C, C-1b), 129.8 (CH, C-3c/5c), 122.8 (CH, C-4c), 120.0 (CH, d, J = 7.9 Hz, C-2b/6b), 115.7 (CH, C-2c/6c), 115.6 (CH, d, J = 22.4 Hz, C-3b/5b), 112.0 (C, C-9), 104.6 (CH, C-8), 85.6 (CH, C-7), 81.6 (CH, C-5), 79.4 (CH, C-2), 75.6 (CH, C-6), 58.9 (CH, C-3), 26.8 (CH3, C-11), 26.2 (CH3, C-10); 19F NMR (CDCl3, 376.5 MHz) δ −117.32; MS (m/z) (pos): 416 (M+).
(7b) ((3S,4R)-1-(3-fluorophenyl)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-phenoxyazetidin-2-one)
White solid (82 % yield); mp 156–157 °C; [α] 20D = −3.61° (c 0.02, MeOH); IR υ max 3421(O–H), 1757 (C=O), 1610, 1589, 1493 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.54 (1H, dd, J = 8.0, 1.1 Hz, H-6b), 7.50 (1H, dt, J = 10.6, 2.2 Hz, H-2b), 7.31 (2H, t, J = 8.5 Hz, H-3c/5c), 7.25–7.27 (1H, m, H-5b), 7.15 (2H, d, J = 8.8, H-2c/6c), 7.05 (1H, t, J = 7.4, H-4c), 6.80 (1H, td, J = 8.5, 2.3 Hz, H-4b), 6.05 (1H, d, J = 3.7, H-8), 5.46 (1H, d, J = 5.6 Hz, H-2), 4.69 (1H, dd, J = 8.6, 5.6 Hz, H-3), 4.59 (1H, d, J = 2.9, H-6), 4.55(1H, dd, J = 8.6, 3.0 Hz, H-5), 4.49 (1H, d, J = 3.8 Hz, H-7), 1.45 (3H, s, H-10), 1.29 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 164.0 (C, C-1), 161.6 (C, d, J = 243.5 Hz, C-3b), 157.5 (C, C-1c), 138.9 (C, d, J = 10.6 Hz, C-1b), 130.1 (CH, d, J = 9.2 Hz, C-5b), 129.8 (CH, C-3c/5c), 122.9 (CH, C-4c), 115.7 (CH, C-2c/6c), 114.0 (CH, d, J = 2.9 Hz, C-6b), 112.9 (C, C-9), 111.5 (CH, d, J = 21.2 Hz, C-4b), 105.9 (CH, d, J = 26.3 Hz, C-2b), 104.6 (CH, C-8), 85.6 (CH, C-7), 81.5 (CH, C-5), 79.3 (CH, C-2), 75.6 (CH, C-6), 59.0 (CH, C-3), 26.8 (CH3, C-11), 26.2 (CH3, C-10); 19F NMR (CDCl3, 376.5 MHz) δ −111.33; MS (m/z) (pos): 416 (M+).
(7c) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-2-one)
White solid (85 % yield); mp 148–150 °C; [α] 20D = −4.58° (c 0.02, MeOH); IR υ max 3477 (O–H), 1757 (C=O) cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.66 (2H, d, J = 9.0, Hz, H-2b/6b), 7.31 (2H, t, J = 8.3, H-3c/5c), 7.13 (2H, d, J = 8.0 Hz, H-2c/6c), 7.02 (1H, t, J = 7.3 Hz, H-4c), 6.84 (2H, d, J = 9.0 Hz, H-3b/5b), 6.02 (1H, d, J = 3.7 Hz, H-8), 5.39 (1H, d, J = 5.5 Hz, H-2), 4.63 (1H, dd, J = 8.6, 5.5 Hz, H-3), 4.57–4.58 (1H, m, H-6), 4.52 (1H, dd, J = 8.6, 2.8 Hz, H-5), 4.47 (1H, d, J = 3.7 Hz, H-7), 3.76 (3H, s, H-7b), 2.15 (1H, s, H-12), 1.44 (3H, s, H-10), 1.27 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.4 (C, C-1), 157.6 (C, C-1c), 156.7 (C, C-4b), 131.1 (C, C-1b), 129.8 (CH, C-3c/5c), 122.7 (CH, C-4c), 119.9 (CH, C-2b/6b), 115.7 (CH, C-2c/6c), 114.0 (CH, C-3b/5b), 111.9 (C, C-9), 104.6 (CH, C-8), 85.6 (CH, C-7), 81.6 (CH, C-5), 79.3 (CH, C-2), 75.6 (CH, C-6), 58.9 (CH, C-3), 55.5 (CH3, C-7b), 26.8 (CH3, C-11), 26.3 (CH3, C-10); MS (m/z) (pos): 428 (M+).
(7d) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(3-methoxyphenyl)-3-phenoxyazetidin-2-one)
White solid (79 % yield); mp 169–170 °C; [α] 20D = −3.27° (c 0.02, MeOH); IR υ max 3420(O–H), 1755 (C=O), 1599, 1586, 1494 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.29–7.38 (4H, m, H-2b/6b, H-3c/5c), 7.22 (1H, t, J = 8.2 Hz, H-5b), 7.15 (2H, d, J = 8.2 Hz, H-2c/6c), 7.04 (1H, t, J = 7.3 Hz, H-4c), 6.66 (1H, dd, J = 8.0, 1.8 Hz, H-4b), 6.04 (1H, d, J = 3.7 Hz, H-8), 5.44 (1H, d, J = 5.6 Hz, H-2), 4.69 (1H, dd, J = 8.5, 5.6 Hz, H-3), 4.62 (1H, d, J = 2.9 Hz, H-6), 4.55 (1H, dd, J = 8.5, 2.9 Hz, H-5), 4.49 (1H, d, J = 3.8 Hz, H-7), 3.79 (3H, s, H-7b), 1.45 (3H, s, H-10), 1.29 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 164.0 (C, C-1), 159.9 (C, C-3b), 157.5 (C, C-1c), 138.7 (C, C-1b), 129.8 (CH, C-3c/5c), 129.7 (CH, C-5b), 122.8 (CH, C-4c), 115.7 (CH, C-2c/6c), 112.0 (C, C-9), 111.1 (CH, C-6b), 110.8 (CH, C-4b), 104.6 (CH, C-8), 103.8 (CH, C-2b), 85.6 (CH, C-7), 81.6 (CH, C-5), 79.2 (CH, C-2), 75.7 (CH, C-6), 59.0 (CH, C-3), 55.3 (CH3, C-7b), 26.8 (CH3, C-11), 26.3 (CH3, C-10); MS (m/z) (pos): 428 (M+).
(7e) ((3S,4R)-1-(4-chlorophenyl)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-phenoxyazetidin-2-one)
White solid (78 % yield); mp 184–185 °C; [α] 20D = −4.62° (c 0.02, MeOH); IR υ max 3454 (O–H), 1754(C=O), 1595, 1491 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.68 (2H, d, J = 8.8 Hz, H-2b/6b), 7.29–7.33 (2H, m, H-3c/5c), 7.27 (2H, d, J = 8.8 Hz, H-3b/5b), 7.13 (2H, d, J = 8.2 Hz, H-2c/6c), 7.04 (1H, t, J = 7.4 Hz, H-4c), 6.03 (1H, d, J = 3.7 Hz, H-8), 5.45 (1H, d, J = 5.6 Hz, H-2), 4.68 (1H, dd, J = 8.7, 5.7 Hz, H-3), 4.58 (1H, d, J = 2.8 Hz, H-6), 4.53 (1H, dd, J = 8.7, 2.9 Hz, H-5), 4.48 (1H, d, J = 3.7 Hz, H-7), 1.44 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.8 (C, C-1), 157.5 (C, C-1c), 136.1 (C, C-1b), 129.8 (CH, C-3c/5c), 129.0 (CH, C-2b/6b), 122.8 (CH, C-4c), 119.6 (CH, C-3b/5b), 115.7 (CH, C-2c/6c), 112.0 (C, C-9), 104.6 (CH, C-8), 85.6 (CH, C-7), 81.6 (CH, C-5), 79.4 (CH, C-2), 75.6 (CH, C-6), 58.8 (CH, C-3), 26.8 (CH3, C-11), 26.2 (CH3, C-10); MS (m/z) (pos): 432 (M+).
(7f) ((3S,4R)-1-(3-chlorophenyl)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-phenoxyazetidin-2-one)
White solid (83 % yield); mp 160–161 °C; [α] 20D = −5.01° (c 0.02, MeOH); IR υ max 3422 (O–H), 1752 (C=O), 1594, 1484 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.76 (1H, t, J = 2.0 Hz, H-2b), 7.64 (1H, ddd, J = 8.0, 1.9, 0.7 Hz, H-6b), 7.32 (2H, t, J = 8.5 Hz, H-3c/5c), 7.20–7.26 (1H, m, H-5b), 7.14 (2H, d, J = 8.6 Hz, H-2c/6c), 7.03-7.09 (2H, m, H-4b, H-4c), 6.05 (1H, d, J = 3.8 Hz, H-8), 5.45 (1H, d, J = 5.6 Hz, H-2), 4.70 (1H, dd, J = 8.6, 5.6 Hz, H-3), 4.56 (1H, d, J = 3.0 Hz, H-6), 4.53 (1H, dd, J = 8.6, 3.0 Hz, H-5), 4.49 (1H, d, J = 3.8 Hz, H-7), 1.69 (1H, s, H-12), 1.45 (3H, s, H-10), 1.29 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 164.0 (C, C-1), 157.5 (C, C-1c), 138.6 (C, C-1b), 134.6 (C, C-3b), 129.0 (CH, C-5b), 129.8 (CH, C-3c/5c), 124.8 (CH, C-4c), 122.9 (CH, C-2b), 118.5 (CH, C-4b), 116.5 (CH, C-6b), 115.7 (CH, C-2c/6c), 112.0 (C, C-9), 104.6 (CH, C-8), 85.6 (CH, C-7), 81.5 (CH, C-5), 79.3 (CH, C-2), 75.6 (CH, C-6), 58.8 (CH, C-3), 26.8 (CH3, C-11), 26.2 (CH3, C-10); MS (m/z) (pos): 432 (M+).
(7g) ((3S,4R)-1-(3,4-dichlorophenyl)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d][1,3]dioxol-5-yl)-3-phenoxyazetidin-2-one)
White solid (86 % yield); mp 165–167 °C; [α] 20D = −4.02° (c 0.02, MeOH); IR υ max 3464 (O–H), 2990 (C–H), 2977 (C–H), 2928 (C–H), 1762 (C=O), 1590, 1478, 1468 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.88 (1H, d, J = 2.5 Hz, H-2b), 7.60 (1H, dd, J = 8.7, 2.4 Hz, H-6b), 7.35 (1H, d, J = 8.7 Hz, H-5b), 7.32 (2H, t, J = 8.5 Hz, H-3c/5c), 7.13 (2H, d, J = 7.8 Hz, H-2c/6c), 7.04 (1H, t, J = 7.4 Hz, H-4c), 6.04 (1H, d, J = 3.8 Hz, H-8), 5.47 (1H, d, J = 5.6 Hz, H-2), 4.69 (1H, dd, J = 8.7, 5.7 Hz, H-3), 4.56 (1H, br s, H-6), 4.53 (1H, dd, J = 8.7, 2.9 Hz, H-5), 4.48 (1H, d, J = 3.8 Hz, H-7), 1.83 (1H, s, H-12), 1.45 (3H, s, H-10), 1.29 (3H, s, H-11); 13C NMR (CDCl3, 400 MHz) δ 163.9 (C, C-1), 157.4 (C, C-1c), 136.8 (C, C-4b), 132.7 (C, C-1b), 130.5 (CH, C-6b), 129.8 (CH, C-3c/5c), 128.0 (C, C-3b), 122.7 (CH, C-4c), 120.1 (CH, C-5b), 117.7 (CH, C-2b), 115.7 (CH, C-2c/6c), 112.1 (C, C-9), 104.6 (CH, C-8), 85.6 (CH, C-7), 81.4 (CH, C-5), 79.4 (CH, C-2), 75.6 (CH, C-6), 58.9 (CH, C-3), 26.8 (CH3, C-11), 26.2 (CH3, C-10); MS (m/z) (pos): 466 (M+).
(7h) ((3S,4R)-1-(3,4-difluorophenyl)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d][1,3]dioxol-5-yl)-3-phenoxyazetidin-2-one)
White solid (77 % yield); mp 159–160 °C; [α] 20D = −2.85° (c 0.02, MeOH); IR 3472 (O–H), 2986 (C–H), 2926 (C–H), 1759 (C=O),1611, 1600, 1515, 1496 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.65 (1H, ddd, J = 11.8, 7.1, 2.5 Hz, H-2b), 7.68 (1H, d, J = 9.0 Hz, H-6b), 7.32 (2H, t, J = 8.3 Hz, H-3c/5c), 7.13 (2H, d, J = 7.9 Hz, H-2c/6c), 7.03–7.11 (1H, m, H-5b/H-4c), 6.05 (1H, d, J = 3.8 Hz, H-8), 5.47 (1H, d, J = 5.6 Hz, H-2), 4.67 (1H, dd, J = 8.6, 5.6 Hz, H-3), 4.58 (1H, br s, H-6), 4.53 (1H, dd, J = 8.7, 2.9 Hz, H-5), 4.49 (1H, d, J = 3.8 Hz, H-7), 1.47 (3H, s, H-10), 1.29 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.8 (C, C-1), 157.4 (C, C-1c), 150.0 (C, dd, J = 245.9, 13.4 Hz, C-3b), 150.0 (C, dd, J = 244.5, 12.6 Hz, C-4b), 134.0 (C, C-1b), 129.8 (CH, C-3c/5c), 122.9 (CH, C-4c), 117.9 (CH, d, J = 18.4 Hz, C-5b), 115.7 (CH, C-2c/6c), 114.2 (CH, dd, J = 6.0, 3.9 Hz, C-6b), 112.1 (C, C-9), 108.1 (CH, d, J = 21.8 Hz, C-2b), 104.6 (CH, C-8), 85.6 (CH, C-7), 81.5 (CH, C-5), 79.4 (CH, C-2), 75.6 (CH, C-6), 59.1 (CH, C-3), 26.8 (CH3, C-11), 26.2 (CH3, C-10); 19F NMR (CDCl3, 376.5 MHz) δ −135.64, −142.06; MS (m/z): 434 (M+).
(7i) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-1-(3,4-dimethoxyphenyl)-3-phenoxyazetidin-2-one)
White solid (82 % yield); mp 145–146 °C; [α] 20D = −4.26° (c 0.02, MeOH); IR υ max 3463 (O–H), 1740 (C=O), 1598, 1517, 1458 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.48 (1H, d, J = 2.4 Hz, H-2b), 7.27–7.33 (3H, m, H-6b, H-3c/5c), 7.15 (2H, d, J = 8.0 Hz, H-2c/6c), 7.03 (1H, t, J = 7.4 Hz, H-4c), 6.80 (1H, d, J = 8.8 Hz, H-5b), 6.02 (1H, d, J = 3.7 Hz, H-8), 5.43 (1H, d, J = 5.5 Hz, H-2), 4.62–4.66 (2H, m, H-3, H-6), 4.54 (1H, dd, J = 8.4, 2.9 Hz, H-5), 4.49 (1H, d, J = 3.7 Hz, H-7), 3.87 (3H, s, H-8b), 3.84 (3H, s, H-7b), 1.79 (1H, br s, H-12), 1.44 (3H, s, H-10), 1.29 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.5 (C, C-1), 157.5 (C, C-1c), 148.9 (C, C-3b), 146.1 (C, C-4b), 131.3 (C, C-1b), 129.8 (CH, C-3c/5c), 122.7 (CH, C-4c), 115.7 (CH, C-2c/6c), 112.0 (C, C-9), 111.3 (CH, C-5b), 110.4 (CH, C-2b), 104.6 (CH, C-8), 103.1 (CH, C-6b), 85.6 (CH, C-7), 81.6 (CH, C-5), 79.3 (CH, C-2), 75.6 (CH, C-6), 59.4 (CH, C-3), 56.1 (CH3, C-7b), 55.9 (CH3, C-8b), 26.8 (CH3, C-11), 26.3 (CH3, C-10); MS (m/z) (pos): 458 (M+).
(7j) ((3S,4R)-4-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-phenoxy-1-phenylazetidin-2-one)
White solid (84 % yield); mp 167–168 °C; [α] 20D = −4.04° (c 0.02, MeOH); IR υ max 3454 (O–H), 1749 (C=O), 1597, 1492 cm−1; 1H NMR (CDCl3, 100 MHz) δ 7.74 (2H, d, J = 7.8, 4.7 Hz, H-2b/6b), 7.31 (4H, t, J = 7.8 Hz, H-3c/5c, H-3b/5b), 7.15 (2H, d, J = 8.1 Hz, H-2c/6c), 7.11 (1H, t, J = 7.4 Hz, H-4b), 7.04 (1H, t, J = 7.3 Hz, H-4c), 6.04 (1H, d, J = 3.7 Hz, H-8), 5.45 (1H, d, J = 5.6 Hz, H-2), 4.71 (1H, dd, J = 8.6, 5.6 Hz, H-3), 4.61 (1H, d, J = 2.9 Hz, H-6), 4.55 (1H, dd, J = 8.6, 2.9 Hz, H-5), 4.49 (1H, d, J = 3.7 Hz, H-7), 1.66 (1H, br s, H-12), 1.44 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CDCl3, 100 MHz) δ 163.9 (C, C-1), 157.5 (C, C-1c), 137.6 (C, C-1b), 129.8 (CH, C-3c/5c), 128.8 (CH, C-3b/5b), 124.7 (CH, C-4b), 122.8 (CH, C-4c), 118.3 (CH, C-2b/6b), 115.7 (CH, C-2c/6c), 112.0 (C, C-9), 104.6 (CH, C-8), 85.6 (CH, C-7), 81.6 (CH, C-5), 79.2 (CH, C-2), 75.7 (CH, C-6), 58.7 (CH, C-3), 26.8 (CH3, C-11), 26.3 (CH3, C-10); MS (m/z) (pos): 398 (M+).
Hydrolysis of the lactams 7a–j to the β-amino acids 8a–j
LiOH (48.0 mg, 2.0 mmol) in 5 mL water was added to a solution of 7a–j (1.0 mmol) in THF (20 mL), and the mixture stirred at 0–10 °C for 2 h. On completion, the solvent was removed under reduced pressure and the pH of the residue adjusted to 2–3 using aqueous HCl at 0–5 °C to afford white solids (8a–j).
(8a) ((2S,3R)-3-(4-fluorophenylamino)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d][1,3]dioxol-5-yl)-2-phenoxypropanoic acid)
White solid (83 % yield); mp 109–110 °C; [α] 20D = 33.25° (c 0.02, MeOH); IR υ max 3491 (O–H), 3412 (N–H), 2989 (C–H), 2920 (C–H), 1684 (C=O), 1590, 1492 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.30 (2H, t, J = 7.6 Hz, H-3c/5c), 7.00 (1H, t, J = 7.2 Hz, H-4c), 6.93 (2H, d, J = 8.1 Hz, H-2c/6c), 6.76–6.84 (4H, m, H-2b/3b/5b/6b), 5.90 (1H, d, J = 3.7 Hz, H-8), 5.05 (1H, d, J = 2.0 Hz, H-2), 4.49 (1H, d, J = 3.8 Hz, H-7), 4.41–4.46 (2H, m, H-3, H-5), 3.89 (1H, d, J = 2.2 Hz, H-6), 1.47 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CD3OD, 100 MHz) δ 173.2 (C, C-1), 159.4 (C, C-1c), 157.2 (C, d, J = 231.7 Hz, C-4b), 146.0 (C, C-1b), 130.7 (CH, C-3c/5c), 122.9 (CH, C-4c), 116.2 (CH, C-2c/6c), 116.0 (CH, d, J = 7.2 Hz, C-2b/6b), 115.9 (CH, d, J = 22.3 Hz, C-3b/5b), 112.7 (C, C-9), 106.0 (CH, C-8), 87.0 (CH, C-7), 83.2 (CH, C-5), 78.1 (CH, C-2), 75.4 (CH, C-6), 57.5 (CH, C-3), 27.1(CH3, C-10), 26.5 (CH3, C-11); 19F NMR (CD3OD, 376.5 MHz) δ −130.50; HRMS (m/z) (pos): 434.1612 [M + H]+ (calculated for C22H25NO7F: 434.1615).
(8b) ((2S,3R)-3-(3-fluorophenylamino)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d][1,3]dioxol-5-yl)-2-phenoxypropanoic acid)
White solid (88 % yield); mp 115–117 °C; [α] 20D = 28.25° (c 0.02, MeOH); IR υ max 3390 (O–H), 1730 (C=O), 1616, 1590, 1492 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.31 (2H, t, J = 7.8 Hz, H-3c/5c), 6.99–7.05 (2H, m, H-5b, H-4c), 6.95 (2H, d, J = 8.1 Hz, H-2c/6c), 6.56 (1H, d, J = 8.2 Hz, H-6b), 6.51 (1H, d, J = 12.2 Hz, H-2b), 6.26 (1H, td, J = 8.5, 2.0 Hz, H-4b), 5.90 (1H, d, J = 3.7, H-8), 5.07 (1H, d, J = 2.2 Hz, H-2), 4.54 (1H, dd, J = 8.8, 2.2 Hz, H-3), 4.49 (1H, d, J = 3.7 Hz, H-7), 4.43 (1H, dd, J = 8.9, 2.6 Hz, H-5), 3.87 (1H, d, J = 2.5 Hz, H-6), 1.47 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CD3OD, 100 MHz) δ 173.1 (C, C-1), 164.2 (C, d, J = 243.5 Hz, C-3b), 159.4 (C, C-1c), 151.8 (C, d, J = 10.8 Hz, C-1b), 130.8 (CH, d, J = 9.0 Hz, C-5b), 130.7 (CH, C-3c/5c), 123.0 (CH, C-4c), 116.2 (CH, C-2c/6c), 112.7 (C, C-9), 110.6 (CH, d, J = 3.0 Hz, C-6b), 106.0 (CH, C-8), 103.9 (CH, d, J = 21.2 Hz, C-4b), 101.1 (CH, d, J = 26.7 Hz, C-2b), 87.0 (CH, C-7), 83.2 (CH, C-5), 78.1 (CH, C-2), 75.3 (CH, C-6), 56.3 (CH, C-3), 27.0 (CH3, C-10), 26.5 (CH3, C-11); 19F NMR (CD3OD, 376.5 MHz) δ −115.90; HRMS (m/z) (pos): 434.1615 [M + H]+ (calculated for C22H25NO7F: 434.1615).
(8c) ((2S,3R)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-(4-methoxyphenylamino)-2-phenoxypropanoic acid)
White solid (87 % yield); mp 113–115 °C; [α] 20D = 23.04° (c 0.02, MeOH); IR υ max 3400 (O–H), 1727 (C=O), 1619, 1590, 1511, 1493 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.30 (2H, t, J = 7.9 Hz, H-3c/5c), 7.00 (1H, t, J = 7.4 Hz, H-4c), 6.92 (1H, d, J = 8.2 Hz, H-2c/6c), 6.81 (2H, d, J = 8.5 Hz, H-3b/5b), 6.73 (2H, d, J = 8.9 Hz, H-2b/6b), 5.90 (1H, d, J = 3.6 Hz, H-8), 4.97 (1H, d, J = 1.8 Hz, H-2), 4.49 (1H, d, J = 3.7 Hz, H-7), 4.44 (1H, dd, J = 8.1, 2.0 Hz, H-3), 4.39 (1H, d, J = 7.4 Hz, H-5), 3.95 (1H, d, J = 2.2 Hz, H-6), 3.72 (3H, s, H-7b), 1.47 (3H, s, H-10), 1.29 (3H, s, H-11); 13C NMR (CD3OD, 100 MHz) δ 173.5 (C, C-1), 159.4 (C, C-1c), 154.1 (C, C-4b), 143.1 (C, C-1b), 130.6 (CH, C-3c/5c), 122.9 (CH, C-4c), 117.3 (CH, C-3b/5b),116.2 (CH, C-2c/6c), 115.6 (CH, C-2b/6b), 112.8 (C, C-9), 106.0 (CH, C-8), 87.0 (CH, C-7), 82.7 (CH, C-5), 78.0 (CH, C-2), 75.8 (CH, C-6), 58.3 (CH3, C-7b), 56.3 (CH, C-3), 27.1 (CH3, C-10), 26.5 (CH3, C-11); HRMS (m/z) (pos): 446.1808 [M + H]+ (calculated for C23H28NO8: 446.1815).
(8d) ((2S,3R)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-(3-methoxyphenylamino)-2-phenoxypropanoic acid)
White solid (86 % yield); mp 99–100 °C; [α] 20D = 22.08° (c 0.02, MeOH); IR υ max 3394 (O–H), 1730(C=O), 1620, 1597, 1511, 1494 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.30 (2H, t, J = 7.6 Hz, H-3c/5c), 6.93–7.02 (4H, m, H-5b, H-2c/4c/6c), 6.38–6.40 (2H, m, H-2b/4b), 6.18 (1H, dd, J = 7.7, 1.8 Hz, H-6b), 5.90 (1H, d, J = 3.7 Hz, H-8), 5.04 (1H, s, H-2), 4.52 (1H, dd, J = 8.5, 2.1 Hz, H-3), 4.49 (1H, d, J = 3.8 Hz, H-7), 4.43 (1H, dd, J = 8.6, 2.6 Hz, H-5), 3.89 (1H, d, J = 2.6 Hz, H-6), 3.73 (3H, s, H-7b), 1.47 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CD3OD, 400 MHz) δ 162.0 (C, C-1), 159.4 (C, C-1c), 150.9 (C, C-1b), 150.9 (C, C-3b), 130.7 (CH, C-3c/5c), 130.5 (CH, C-5b), 122.9 (CH, C-4c), 116.2 (CH, C-2c/6c), 112.7 (C, C-9), 107.9 (CH, C-6b), 106.0 (CH, C-8), 104.0 (CH, C-4b), 100.6 (CH, C-2b), 87.0 (CH, C-7), 83.1 (CH, C-5), 78.1 (CH, C-2), 75.4 (CH, C-6), 56.5 (CH, C-3), 55.5 (CH3, C-7b), 27.0 (CH3, C-10), 26.5 (CH3, C-11); HRMS (m/z) (pos): 446.1812 [M + H]+ (calculated for C23H28NO8: 446.1815).
(8e) ((2S,3R)-3-(4-chlorophenylamino)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d][1,3]dioxol-5-yl)-2-phenoxypropanoic acid)
White solid (90 % yield); mp 129–130 °C; [α] 20D = 17.25° (c 0.02, MeOH); IR υ max 3508 (O–H), 3410 (N–H), 1681 (C=O), 1603, 1588, 1513, 1492 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.32 (2H, dd, J = 8.2 Hz, 7.6 Hz, H-3c/5c), 6.99–7.04 (3H, m, H-2c/4c/6c), 6.94 (2H, d, J = 8.1 Hz, H-3b/5b), 6.75 (2H, d, J = 8.8 Hz, H-2b/6b), 5.89 (1H, d, J = 3.7 Hz, H-8), 5.06 (1H, d, J = 2.4 Hz, H-2), 4.49–4.53 (2H, m, H-3, H-7), 4.42 (1H, dd, J = 8.7, 2.6 Hz, H-5), 3.88 (1H, d, J = 2.6 Hz, H-6), 1.47 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CD3OD, 100 MHz) δ 173.1 (C, C-1), 159.4 (C, C-1c), 148.5 (C, C-1b), 130.7 (CH, C-3c/5c), 129.5 (CH, C-3b/5b), 123.0 (CH, C-4c), 122.4 (C, C-4b), 116.2 (CH, C-2c/6c), 115.9 (CH, C-2b/6b), 112.7 (C, C-9), 106.0 (CH, C-8), 87.0 (CH, C-7), 83.3 (CH, C-5), 78.1 (CH, C-2), 75.3 (CH, C-6), 56.6 (CH, C-3), 27.0 (CH3, C-11), 26.5 (CH3, C-10); HRMS (m/z) (pos): 450.1305 [M + H]+ (calculated for C22H25ClNO7: 450.1320).
(8f) ((2S,3R)-3-(3-chlorophenylamino)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d][1,3]dioxol-5-yl)-2-phenoxypropanoic acid)
White solid (85 % yield); mp 100–102 °C; [α] 20D = 19.08° (c 0.02, MeOH); IR υ max 3395 (O–H), 1731(C=O), 1595, 1492 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.31 (2H, t, J = 8.2 Hz, H-3c/5c), 7.01 (2H, t, J = 7.8 Hz, H-4c, H-5b), 6.95 (2H, d, J = 8.1 Hz, H-2c/6c), 6.80 (1H, t, J = 1.8 Hz, H-2b), 6.69 (1H, dd, J = 8.1, 1.9 Hz, H-4b), 6.56 (1H, dd, J = 7.8, 0.7 Hz, H-6b), 5.90 (1H, d, J = 3.8 Hz, H-8), 5.08 (1H, d, J = 2.4 Hz, H-2), 4.54 (1H, dd, J = 8.9, 2.4 Hz, H-3), 4.50 (1H, d, J = 3.8 Hz, H-7), 4.43 (1H, dd, J = 8.8, 2.6 Hz, H-5), 3.88 (1H, d, J = 2.6 Hz, H-6), 1.47 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CD3OD, 100 MHz) δ 173.1 (C, C-1), 159.4 (C, C-1c), 151.2 (C, C-1b), 135.6 (C, C-3b), 130.9 (CH, C-5b), 130.7 (CH, C-3c/5c), 123.0 (CH, C-4c), 117.6 (CH, C-4b), 116.2 (CH, C-2c/6c), 114.1 (CH, C-2b), 113.1 (CH, C-6b), 112.7 (C, C-9), 106.0 (CH, C-8), 87.0 (CH, C-7), 83.2 (CH, C-5), 78.1 (CH, C-2), 75.3 (CH, C-6), 56.3 (CH, C-3), 27.0 (CH3, C-10), 26.5 (CH3, C-11); HRMS (m/z) (pos): 450.1323 [M + H]+ (calculated for C22H25ClNO7: 450.1320).
(8g) ((2S,3R)-3-(3,4-dichlorophenylamino)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d][1,3]dioxol-5-yl)-2-phenoxypropanoic acid)
White solid (83 % yield); mp 135–137 °C; [α] 20D = 18.50° (c 0.02, MeOH); IR υ max 3480 (N–H), 3416 (N–H), 1676 (C=O), 1596, 1493 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.31 (2H, t, J = 8.5 Hz, H-3c/5c), 7.12 (1H, d, J = 8.9 Hz, H-5b), 7.01 (1H, t, J = 7.4 Hz, H-4c), 6.96 (1H, s, H-2b), 6.93 (2H, d, J = 4.5 Hz, H-2c/6c), 6.70 (1H, dd, J = 8.8, 2.7 Hz, H-6b), 5.90 (1H, d, J = 3.7 Hz, H-8), 5.07 (2H, d, J = 2.4 Hz, H-2), 4.49–4.52 (2H, m, H-3, H-7), 4.42 (1H, dd, J = 9.0, 2.6 Hz, H-5), 3.87 (1H, d, J = 2.6 Hz, H-6), 1.47 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CD3OD, 400 MHz) δ 173.0 (C, C-1), 159.4 (C, C-1c), 149.9 (C, C-1b), 133.2 (C, C-3b), 131.2 (CH, C-5b), 130.7 (CH, C-3c/5c), 123.0 (CH, C-4c), 119.7 (C, C-4b), 116.2 (CH, C-2c/6c), 115.6 (CH, C-2b), 114.6 (CH, C-6b), 112.7 (C, C-9), 106.0 (CH, C-8), 87.0 (CH, C-7), 83.2 (CH, C-5), 78.0 (CH, C-2), 75.2 (CH, C-6), 56.5 (CH, C-3), 27.0 (CH3, C-10), 26.5 (CH3, C-11); HRMS (m/z): 484.0941 [M + H]+ (calculated for C22H24Cl2NO7: 484.0930).
(8h) ((2S,3R)-3-(3,4-difluorophenylamino)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro [3,2-d][1,3]dioxol-5-yl)-2-phenoxypropanoic acid)
White solid (81 % yield); mp 103–104 °C; [α] 20D = 17.25° (c 0.02, MeOH); IR υ max 3477 (O–H), 3412 (N–H), 1685 (C=O), 1527, 1493 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.31 (2H, d, J = 8.5 Hz, H-3c/5c), 7.00 (1H, t, J = 7.2 Hz, H-4c), 6.96 (2H, d, J = 6.8 Hz, H-2c/6c), 6.87–6.89 (1H, m, H-5b), 6.65 (1H, ddd, J = 13.6, 6.8, 2.5 Hz, H-2b), 6.50 (1H, d, J = 8.9 Hz, H-6b), 5.89 (1H, d, J = 3.8 Hz, H-8), 5.06 (2H, s, H-2), 4.48 (1H, d, J = 3.7 Hz, H-7), 4.42 (2H, s, H-3, H-5), 3.86 (1H, s, H-6), 1.46 (3H, s, H-10), 1.27 (3H, s, H-11); 13C NMR (CD3OD, 400 MHz) δ 173.1 (C, C-1), 159.9 (C, C-1c), 151.8 (C, dd, J = 240.5, 13.4 Hz, C-3b), 147.2 (C, d, J = 9.0 Hz, C-1b), 143.8 (C, dd, J = 232.7, 13.1 Hz, C-4b), 130.7 (CH, C-3c/5c), 123.0 (CH, C-4c), 117.8 (CH, d, J = 17.7 Hz, C-5b), 116.2 (CH, C-2c/6c), 112.7 (C, C-9), 110.0 (CH, C-6b), 105.9 (CH, C-8), 103.1 (CH, d, J = 21.0 Hz, C-2b), 87.0 (CH, C-7), 83.3 (CH, C-5), 78.1 (CH, C-2), 75.3 (CH, C-6), 57.1 (CH, C-3), 27.0 (CH3, C-10), 26.5 (CH3, C-11); 19F NMR (CD3OD, 376.5 MHz) δ −140.86, −156.61; HRMS (m/z) (pos): 452.1528 [M + H]+ (calculated for C22H24F2NO7: 452.1521).
(8i) ((2S,3R)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-3-(3,4-dimethoxyphenylamino)-2-phenoxypropanoic acid)
White solid (80 % yield); mp 114–115 °C; [α] 20D = 27.50° (c 0.02, MeOH); IR υ max 3391(O–H), 2937 (C–H), 1728 (C=O), 1597, 1515, 1492 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.30 (2H, d, J = 8.5 Hz, H-3c/5c), 7.00 (1H, t, J = 7.3 Hz, H-4c), 6.92 (2H, d, J = 8.0 Hz, H-2c/6c), 6.74 (1H, dd, J = 4.5, 4.5 Hz, H-5b), 6.55 (1H, s, H-2b), 5.91 (1H, d, J = 3.7 Hz, H-8), 5.01 (1H, s, H-2), 4.49 (1H, d, J = 3.7 Hz, H-7), 4.43 (2H, s, H-3, H-5), 3.90 (1H, s, H-6), 3.80 (3H, s, H-7b), 3.74 (3H, s, H-8b), 1.47 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CD3OD, 400 MHz) δ 173.4 (C, C-1), 159.4 (C, C-1c), 151.3 (C, C-3b), 144.4 (C, C-1b), 142.8 (C, C-4b), 130.7 (CH, C-3c/5c), 122.9 (CH, C-4c), 117.3 (CH, C-6b), 116.2 (CH, C-2c/6c), 115.4 (CH, C-5b), 112.8 (C, C-9), 106.0 (CH, C-8), 101.8 (CH, C-2b), 87.0 (CH, C-7), 82.8 (CH, C-5), 78.0 (CH, C-2), 75.6 (CH, C-6), 57.8* (CH, CH3, C-3, C-8b), 56.3 (CH3, C-7b), 27.1 (CH3, C-10), 26.5 (CH3, C-11); HRMS (m/z) (pos): 476.1917 [M + H]+ (calculated for C24H30NO9: 476.1921). * overlapping resonances.
(8j) ((2S,3R)-3-((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-5-yl)-2-phenoxy-3-(phenylamino)propanoic acid)
White solid (90 % yield); mp 117–118 °C; [α] 20D = 27.25° (c 0.02, MeOH); IR υ max 3508 (O–H), 3410 (N–H), 1682 (C=O), 1588, 1513, 1493 cm−1; 1H NMR (CD3OD, 400 MHz) δ 7.31 (2H, t, J = 7.7, Hz, H-3c/5c), 7.11 (2H, t, J = 8.3 Hz, H-3b/5b), 7.00 (1H, t, J = 7.4 Hz, H-4c), 6.94 (2H, d, J = 8.1 Hz, H-2c/6c), 6.85 (2H, d, J = 8.0 Hz, H-2b/6b), 6.67 (1H, t, J = 7.2 Hz, H-4b), 5.91 (1H, d, J = 3.7 Hz, H-8), 5.06 (1H, d, J = 2.5 Hz, H-2), 4.57 (1H, dd, J = 8.5, 2.5 Hz, H-3), 4.50 (1H, d, J = 3.7 Hz, H-7), 4.45 (1H, dd, J = 8.4, 2.6 Hz, H-5), 3.94 (1H, d, J = 2.6, H-6), 1.47 (3H, s, H-10), 1.28 (3H, s, H-11); 13C NMR (CD3OD, 100 MHz) δ 173.0 (C, C-1), 159.3 (C, C-1c), 148.5 (C, C-1b), 130.7 (CH, C-3c/5c), 129.9 (C, C-3b/5b), 123.0 (CH, C-4c), 119.3 (CH, C-4b), 116.3 (CH, C-2c/6c), 115.7 (CH, C-2b/6b), 112.8 (C, C-9), 106.1 (CH, C-8), 87.0 (CH, C-7), 82.8 (CH, C-5), 77.8 (CH, C-2), 75.5 (CH, C-6), 57.1 (CH, C-3), 27.1 (CH3, C-10), 26.5 (CH3, C-11); HRMS (m/z) (pos): 416.1711 [M + H]+ (calculated for C22H26NO7: 416.1709).
References
Agrofoglio LA, Jacquinet J-C, Lancelot G (1997) A multigram, stereoselective synthesis of d-[13C5]ribose from d-[13C6]glucose and its conversion into [13C5]nucleosides. Tetrahedron Lett 38:1411–1412
Aguilar M-I, Purcell AW, Devi R, Lew R, Rossjohn J, Smith AI, Perlmutter P (2007) β-Amino acid-containing hybrid peptides—new opportunities in peptidomimetics. Org Biomol Chem 5:2884–2890
Andrews JA (2001) Determination of inhibitory concentrations. J Antimicrob Chemother 48:5–16
Aoyagi T, Tobe H, Kojima F, Hamada M, Takeuchi T, Umezawa H (1978) Amastatin, an inhibitor of aminopeptidase A, produced by actinomycetes. J Antibiot 31:636–638
Arun M, Joshi SN, Puranik VG, Bhawal BM, Deshmukh ARAS (2003) Asymmetric synthesis of azetidin-2-ones by [2 + 2] cycloaddition using chiral imines derived from d-(+)-glucose. Tetrahedron 59:2309–2316
Carter DC, Moore RE, Mynderse JS, Niemczura WP, Todd JS (1984) Structure of Majusculamide C, a cyclic depsipeptide from Lyngbya majuscule. J Org Chem 49:236–241
Chincholkar PM, Puranik VG, Deshmukh ARAS (2007) Stereoselective synthesis of spiro-β-lactams using d-(+)-glucose derived chiral pool: remarkable influence of the torquoelectronic effect. Tetrahedron 63:9179–9187
Clinical and Laboratory Standards Institute (2007) M100-S17. In: Performance standards for antimicrobial susceptibility testing, 17th Informational Supplement, vol 27, no. 1, Wayne, PA
Deshmukh ARAS, Jayanthi A, Thiagarajan K, Puranik VG, Bhawal BM (2004) Synthesis of polycyclic β-lactams from d-glucose derived chiral template via substrate-controlled radical cyclization. Synthesis 18:2965–2974
Farrugia LJ (1999) WinGX suite for small-molecule single crystal crystallography. J Appl Cryst 32:837–838
Fisher JF, Harrison AW, Bundy GL, Wilkonsin KF, Rush BD, Ruwart MJ (1991) Peptide to glycopeptide: glycosylated oligopeptide renin inhibitors with attenuated in vivo clearance properties. J Med Chem 34:3140–3143
Fisher JF, Meroueh SO, Mobashery S (2005) Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity. Chem Rev 105:395–424
Hamada Y, Ohtake J, Sohma Y, Kimura T, Hayashi Y, Kiso Y (2002) New water-soluble prodrugs of HIV protease inhibitors based on O → N intramolecular acyl migration. Bioorg Med Chem 10:4155–4167
Hansen T, Ausbacher D, Zachariassen ZG, Anderssen T, Havelkova M, Strom MB (2012) Anticancer activity of small amphipathic β2,2-amino acid derivatives. Eur J Med Chem 58:22–29
Hicks RP, Abercrombie JJ, Wong RK, Leung KP (2013) Antimicrobial peptides containing unnatural amino acid exhibit potent bactericidal activity against ESKAPE pathogens. Bioorg Med Chem 21:205–214
Horgen FD, Kazmierski EB, Westenburg HE, Yoshida WY, Scheuer PJ (2002) Malevamide D: isolation and structure determination of an Isodolastatin H analogue from the marine cyanobacterium Symploca hydnoides. J Nat Prod 66:155–156
Juaristi E, Lopez-Ruiz H (1999) Recent advances in the enantioselective synthesis of beta-amino acids. Curr Med Chem 6:983–1004
Juaristi E, Soloshonok VA (eds) (1997) Enantioselective synthesis of β-amino acids. Wiley-VCH, New York
Lopez R, Sordo TL, Sordo JA, Gonzalez J (1993) Torquoelectronic effect in the control of the stereoselectivity of ketene-imine cycloaddition reactions. J Org Chem 58:7036–7037
Ma J-A (2003) Recent developments in the catalytic asymmetric synthesis of α- and β-amino acids. Agew Chem Int Ed 42:4290–4299
Maddry JA, Bansal N, Bermudez LE, Comber RN, Orme IM, Suling WJ, Wilson LN, Reynolds RC (1998) Homologated aza analogs of arabinose as antimycobacterial agents. Bioorg Med Chem Lett 8:237–242
McDonough MA, Anderson JW, Silvaggi NR, Pratt RF, Knox JR, Kelly JA (2002) Structures of two kinetic intermediates reveal species specificity of penicillin-binding proteins. J Mol Biol 322:111–122
McKinnon JJ, Spackman MA, Mitchell AS (2004) Novel tools for visualizing and exploring intermolecular interactions in molecular crystals. Acta Cryst Sect B 60:627–668
McKinnon JJ, Jayatilaka D, Spackman MA (2007) Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces. Chem Commun 38:3814–3816
Mehta G, Singh V (2002) Hybrid systems through natural product leads: an approach towards new molecular entities. Chem Soc Rev 31:324–334
Nagarajan S, Arjun P, Raaman N, Shah A, Sobhia ME, Das TM (2012) Stereoselective synthesis of sugar-based β-lactam derivatives: docking studies and its biological evaluation. Tetrahedron 68:3037–3045
Namane A, Gouyette C, Fillion M-P, Fillion G, Huynh-Dinh T (1992) Improved brain delivery of AZT using a glycosyl phosphotriester prodrug. J Med Chem 35:3039–3044
Negre E, Chance ML, Hanboula SY, Monsigny M, Roche A-C, Mayer RM, Hommel M (1992) Antileishmanial drug targeting through glycosylated polymers specifically internalized by macrophage membrane lactins. Antimicrob Agents Chemother 36:2228–2232
Ramesh VVE, Puranik VG, Sanjayan GJ (2012) Carbohydrate-derived conformationally restricted bicyclic dipeptides as potential hetero foldamer building blocks. Tetrahedron Asymmetry 23:1400–1404
Ritter TK, Wong C-H (2001) Carbohydrate-based antibiotics: a new approach to tackling the problem of resistance. Angew Chem Int Ed 40:3508–3533
Rodriguez J, Fernandez R, Quinoa E, Riguera R, Debitus C, Bouchet P (1994) Onchidin: a cytotoxic depsipeptide with C-2 symmetry from a marine mollusk. Tetrahedron Lett 35:9239–9242
Ruf S, Buning C, Schreuder H, Horstick G, Linz W, Olpp T, Pernerstorfer J, Hiss K, Kroll K, Kannt A, Kohlmann M, Linz D, Hubschle T, Rutten H, Wirth K, Schmidt T, Sadowski T (2012) Novel β-amino acid derivatives as inhibitors of cathepsin A. J Med Chem 55:7636–7649
Sanap SP, Ghosh S, Jabgunde AM, Pinjari RV, Gejji SP, Singh S, Chopade BA, Dhavale DD (2010) Synthesis, computational study and glycosidase inhibitory activity of polyhydroxylated conidine alkaloids—a bicyclic iminosugar. Org Biomol Chem 8:3307–3315
Scott VR, Boehme R, Matthews TR (1988) New class of antifungal agents: jasplakinolide, a cyclodepsipeptide from the marine sponge, Jaspis species. Antimicrob Agents Chemother 32:1154–1157
Sewald N (2003) Synthetic routes towards enantiomerically pure β-amino acids. Angew Chem Int Ed 42:5794–5795
Shaikh AL, Kale AS, Shaikh MA, Puranik VG, Desmukh ARAS (2007) Asymmetric synthesis of β-lactams by [2 + 2] cycloaddition using 1,4:3,6-dianhydro-d-glucitol (isosorbide) derived chiral pools. Tetrahedron 63:3380–3388
Sheldrick GM (2008) A short history of SHELX. Acta Cryst Sect A 64:112–122
Smith CD, Zhang X, Mooberry SL, Patterson GML, Moore RE (1994) Cryptophycin: a new antimicrotuble agent active against drug-resistant cells. Cancer Res 54:3779–3784
Spackman MA, McKinnon JJ (2002) Fingerprinting intermolecular interactions in molecular crystals. Cryst Eng Commun 4:378–392
Tan LT, Sitachitta N, Gerwick WH (2003) The Guineamides, novel cyclic depsipeptides from a Papua New Guinea collection of the marine Cyanobacterium Lyngbya majuscula. J Nat Prod 66:764–771
Tang K, Wang J, Cheng X, Hou Q, Liu Y (2010) Theoretical investigations towards the Staudinger reaction catalyzed by N-heterocyclic carbene: mechanism and stereoselectivity. Eur J Org Chem 2010:6249–6255
Tatsufumi O, Hisashi M, Masahiro M, Katsumi Y (1993) Microginin, an angiotensin-converting enzyme inhibitor from the blue-green alga Microcystis aeruginosa. Tetrahedron Lett 34:501–504
Thomsen R, Christensen MH (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem 49:3315–3321
Tripathi RP, Rastogi SK, Kundu B, Saxena JK, Reddy VJM, Srivastava S, Chandra S, Bhanduri AP (2001) Identification of inhibitors of DNA topoisomerase II from a synthetic library of glycoconjugates. Comb Chem High Throughput Screen 4:237–244
Tripathi RP, Tripathi R, Tiwari VK, Bala L, Sinha S, Srivastava A, Srivastava R, Srivastava BS (2002) Synthesis of glycosylated β-amino acids as a new class of antitubercular agents. Eur J Med Chem 37:773–781
Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT (1971) Plant antitumor agents. VI. The isolation and structure of Taxol, a novel antileukemic and antitumor agent form Taxus brevifolia. J Am Chem Soc 93:2325–2327
Weiner B, Szymanski W, Janssen DB, Minaard AJ, Feringa BL (2010) Recent advances in the catalytic asymmetric synthesis of β-amino acids. Chem Soc Rev 39:1656–1691
Williams PG, Yoshida WY, Quon MK, Moore RE, Paul VJ (2003) Ulongapeptin, a cytotoxic cyclic depsipeptide from a Palauan marine cyanobacterium Lyngbya sp. J Nat Prod 66:651–654
Yamada M, Watanabe T, Miyara T, Baba N, Saito J, Takeuchi Y, Ohsawa F (2007) Crystal structure of cefditoren complexed with Streptococcus pneumoniae penicillin-binding protein 2X: structural basis for its high antimicrobial activity. Antimicrob Agents Chemother 51:3902–3907
Zhu Y, Zhu X, Wu G, Ma Y, Li Y, Zhao X, Yuan Y, Yang J, Yu S, Shao F, Li R, Ke Y, Lu A, Liu Z, Zhang L (2010) Synthesis, in vitro and in vivo biological evaluation, docking studies, and structure-activity relationship (SAR) discussion of dipeptidyl boronic acid proteasome inhibitors composed of β-amino acids. J Med Chem 53:1990–1999
Acknowledgments
This research was supported by Grants from the National Research Foundation (NRF), South Africa, and was supported by the South African Research Chairs Initiative of the Department of Science and Technology. We thank Dr Mahesh Palkel for assisting with molecular docking studies.
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Kadam, P., Karpoormath, R., Omondi, B. et al. Stereo-selective synthesis, structural and antibacterial studies of novel glycosylated β2,3-amino acid analogues. Med Chem Res 24, 3174–3193 (2015). https://doi.org/10.1007/s00044-015-1370-4
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DOI: https://doi.org/10.1007/s00044-015-1370-4