Search

Metallo-β-lactamase (MBL) production in Gram-negative bacteria is an important contributor to β-lactam antibiotic resistance. Combining β-lactams with β-lactamase inhibitors (BLIs) is a validated route to overcoming resistance, but MBL inhibitors are not available in the clinic. On the basis of zinc utilization and sequence, MBLs are divided into three subclasses, B1, B2, and B3, whose differing active-site architectures hinder development of BLIs capable of “cross-class” MBL inhibition. We previously described 2-mercaptomethyl thiazolidines (MMTZs) as B1 MBL inhibitors (e.g., NDM-1) and here show that inhibition extends to the clinically relevant B2 (Sfh-I) and B3 (L1) enzymes. MMTZs inhibit purified MBLs in vitro (e.g., Sfh-I, Ki 0.16 μM) and potentiate β-lactam activity against producer strains. X-ray crystallography reveals that inhibition involves direct interaction of the MMTZ thiol with the mono- or dizinc centers of Sfh-I/L1, respectively. This is further enhanced by sulfur-π interactions with a conserved active site tryptophan. Computational studies reveal that the stereochemistry at chiral centers is critical, showing less potent MMTZ stereoisomers (up to 800-fold) as unable to replicate sulfur-π interactions in Sfh-I, largely through steric constraints in a compact active site. Furthermore, in silico replacement of the thiazolidine sulfur with oxygen (forming an oxazolidine) resulted in less favorable aromatic interactions with B2 MBLs, though the effect is less than that previously observed for the subclass B1 enzyme NDM-1. In the B3 enzyme L1, these effects are offset by additional MMTZ interactions with the protein main chain. MMTZs can therefore inhibit all MBL classes by maintaining conserved binding modes through different routes. Metallo-β-lactamase (MBL) production in Gram-negative bacteria is an important contributor to β-lactam antibiotic resistance. Combining β-lactams with β-lactamase inhibitors (BLIs) is a validated route to overcoming resistance, but MBL inhibitors are not available in the clinic. On the basis of zinc utilization and sequence, MBLs are divided into three subclasses, B1, B2, and B3, whose differing active-site architectures hinder development of BLIs capable of “cross-class” MBL inhibition. We previously described 2-mercaptomethyl thiazolidines (MMTZs) as B1 MBL inhibitors (e.g., NDM-1) and here show that inhibition extends to the clinically relevant B2 (Sfh-I) and B3 (L1) enzymes. MMTZs inhibit purified MBLs in vitro (e.g., Sfh-I, Ki 0.16 μM) and potentiate β-lactam activity against producer strains. X-ray crystallography reveals that inhibition involves direct interaction of the MMTZ thiol with the mono- or dizinc centers of Sfh-I/L1, respectively. This is further enhanced by sulfur-π interactions with a conserved active site tryptophan. Computational studies reveal that the stereochemistry at chiral centers is critical, showing less potent MMTZ stereoisomers (up to 800-fold) as unable to replicate sulfur-π interactions in Sfh-I, largely through steric constraints in a compact active site. Furthermore, in silico replacement of the thiazolidine sulfur with oxygen (forming an oxazolidine) resulted in less favorable aromatic interactions with B2 MBLs, though the effect is less than that previously observed for the subclass B1 enzyme NDM-1. In the B3 enzyme L1, these effects are offset by additional MMTZ interactions with the protein main chain. MMTZs can therefore inhibit all MBL classes by maintaining conserved binding modes through different routes.

Polycyclic xanthones are secondary metabolites from actinomycetes and cervinomycin A and B are bioactive 26-membered polycyclic xanthones from Streptomyces sp. CPCC 204980. Herein, we report cervinomycins C1-4 (1–4) from the same strain. The structures of 1–4 were determined by 1D- and 2D-NMR, or single-crystal X-ray diffraction. Compounds 1–4 feature the open or loss of A (oxazolidine) ring in their angular polycyclic framework compared with cervinomycin B. Compounds 1–4 showed potent cytotoxicity against human cancer cell lines HCT116 and BxPC-3, with IC50 at 0.9–801.0 nM and strong anti-Gram-positive bacterial activity.

Spectroscopic characterizations of key reaction intermediates are often considered the final confirmation of a reaction mechanism. This proof‐of‐principle study showcases the application of vibrational circular dichroism (VCD) spectroscopy for the characterization of in situ generated reaction intermediates using the key intermediates of enamine catalysis of Jørgensen–Hayashi‐type prolinol ether catalysts as model system. By comparison of experimental and computed spectra, the enamines are shown to preferentially adopt an anti‐conformation with E‐configured C=C bond. For the parent prolinol catalyst, the structure and stereochemistry of the oxazolidine side product is determined as well. This study thus demonstrates that VCD spectra can provide insights into structural preferences of organocatalysts that utilize a covalent activation mechanism. Thereby it outlines new fields of applications for VCD spectroscopy and finally adds the technique to the toolbox of physical organic chemistry for in‐depth mechanistic studies., Before it reacts: The enamine and oxazolidine intermediates are characterized by in situ IR and VCD spectroscopy. The study demonstrates the proof‐of‐principle for such analysis of asymmetric catalysts employing a covalent substrate activation mechanism by VCD spectroscopy.Stereochemistry of the reaction intermediates of prolinol ether catalyzed reactions characterized by vibrational circular dichroism spectroscopy (Merten and Golub @MertenLab @ruhrunibochum)

Efforts towards the first total synthesis of (-)-oxazolomycin B and (+)-oxazolomycin C from the intermediate of our previous synthesis of (+)-neoxazolomycin are reported. The syntheses were achieved in a longest linear sequence of 25 steps from the amino acid serine in 3.6 and 2.7 % overall yields, respectively. The efficiency of our approach is derived from silyl triflate-mediated reductive oxazolidine ring-opening and Fürstner's Ru-catalyzed hydrosilylation and protodesilylation reactions. The obtained spectra and optical rotations were in good agreement with those of natural products, thus confirming the structures.

(E)-3,3,3-Trichloro-1-nitroprop-1-ene undergoes [3+2] cycloaddition reaction with N-aryl(pyridin-3-yl) nitrones under mild conditions. The reaction is fully regio- and stereoselective and gives expected nitro-substituted nicotine analogs with 3,4-cis-4,5-trans-stereoconfiguration.

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O2, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.

A straightforward synthesis of enantiopure α-trifluoromethyl aziridine-2-carboxylic acid (α-TfmAzy) is reported from a trifluoropyruvate derived enantiopure oxazolidine. A key Strecker-type synthetic step and a late cyanide basic hydrolysis gave the target compounds in six steps and 41% yield. A final peptide coupling was performed to demonstrate the usefulness of this highly constrained fluorinated unnatural amino acid.

A library of steviol-based trifunctional chiral ligands was developed from commercially available natural stevisoide and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The key intermediate steviol methyl ester was prepared according to literature procedure. Depending on the epoxidation process, both cis- and trans-epoxyalcohols were obtained. Subsequent oxirane ring opening with primary and secondary amines afforded 3-amino-1,2-diols. The ring opening with sodium azide followed by a &ldquo, click&rdquo, reaction with alkynes resulted in dihydroxytriazoles. The regioselective ring closure of N-substituted aminodiols with formaldehyde was also investigated. The resulting steviol-type aminodiols were tested against a panel of human adherent cancer cell lines (A2780, SiHa, HeLa, and MDA-MB-231). It was consistently found that the N-benzyl substituent is an essential part within the molecule and the ring closure towards N-benzyl substituted oxazolidine ring system increased the antiproliferative activity to a level comparable with that of cisplatine. In addition, structure&ndash, activity relationships were examined by assessing substituent effects on the aminodiol systems.

A short and efficient strategy for the synthesis of (−)-cytoxazone, (−)-4- epi -cyoxazone and their analogues by using DDQ mediated diastereoselective intermolecular benzylic amination has been described. Immunological evaluation of their cytokine modulating activity revealed that the change of hydroxy methyl to methyl group increased the cellular immunity in in-vitro cultures. Changes in the stereochemistry of oxazolidine haven't influenced the biological activity.

To gain further knowledge of the structure-activity relationship and druggability of novel oxazolidinone-based UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) inhibitors as Gram-negative antibacterial agents, compounds containing the hydrophobic tails with different lengths and terminal substitutions were synthesized and their antibacterial activities against standard and clinically isolated Gram-negative strains were evaluated. We summarized their structure-activity relationships and found that oxazolidinone-based compounds exhibited a narrower antibacterial spectrum compared with threonine-based compounds. Furthermore, we parallelly compared the metabolic stabilities of the compounds with the classic threonine scaffold and the novel oxazolidinone scaffold in liver microsomes. The results indicated that the druggability of the oxazolidinone scaffold may be inferior to the classic threonine scaffold in the design of LpxC inhibitors.

A novel series of thiourea, carbamimidothioic acid, 4, 5-dihydrooxazole-2-thiol, oxazolidine-2thine, and 2-amino-1-phenylpropyl-2-chloroacetate derivatives was designed and synthesized using 2-amino-1-phenylpropan-1-ol (L-norephedrine) as a strategic starting material. The structures of the newly synthesized compounds were established by elemental analyses, IR, and 1H NMR and 13C NMR spectral data. The compounds were evaluated for their in vitro anticancer activity against various cancer cell lines. The corresponding acetamide, carbamimidothioic acid, and 2-2-amino-1-phenylpropyl-2-chloroacetate derivatives showed almost the same activity as the standard drug doxorubicin against human breast cancer cell line (MCF-7). Also, the acetamide and 2-thioxoimidazolidin-4-one derivatives exhibited higher activity than the reference drug doxorubicin against human colon cancer cell line (HCT 116).

Pyrolysis of azido- meta -meconine yields only a single product 1D, which has been characterized spectroscopically ( 1 H NMR, 13 C NMR, HSQC, DEPT & MS). These results reveal that the fused five-member lactone ring can influence the product selectivity. The DFT calculations suggest the formation of favourable oxazolidine intermediate compared to azirine ( 1Z ) and ketenimine ( 1H ) intermediates. The isodesmic analysis showed that the fused lactone aryl nitrene ( 1N ) would have more strain to form azirine ( 1Z ) intermediate than the corresponding aryl nitrene ( 1M ).

A variety of (R)-phenylglycinol-derived oxazolopiperidone lactams 1–14 were converted to linear-chain enantiopure amino diols 15–26 by reduction with LiNH2BH3 in an unprecedented process involving the simultaneous reductive opening of the oxazolidine and lactam rings. Subsequent removal of the phenylethanol moiety gave enantiopure 5-amino-1-pentanols bearing substituents at the 2-, 3-, 4-, 2,2-, 2,3- 2,4- and 3,4-positions (28–36), which were isolated as their N-Boc derivatives.

In the title compound, known also as (S)-4-[4-(benz­yloxy)benz­yl]oxazolidine-2,5-dione, the benz­yloxy and benzyl rings are almost coplanar, making a dihedral angle of 0.078 (10)°, and are inclined to the oxazolidine ring by 59.16 (11) and 58.42 (11)°, respectively., In the title compound, C17H15NO4 (alternative name; O-benzyl-l-tyrosine N-carb­oxy anhydride), the oxazolidine ring is planer, with an r.m.s. deviation of 0.039 Å. The benz­yloxy and benzyl rings are almost coplanar, making a dihedral angle of 0.078 (10)°, and are inclined to the oxazolidine ring by 59.16 (11) and 58.42 (11)°, respectively. In the crystal, mol­ecules are linked by N—H⋯O and C—H⋯O hydrogen bonds, forming ribbons propagating along [010]. The ribbons are linked by C—H⋯π inter­actions, forming a three-dimensional supra­molecular structure. The oxazolidine rings of adjacent ribbons are arranged into a layer parallel to the ab plane. This arrangement is favourable for the polymerization of the compound in the solid state.

In the title racemic compound, C12H11NO5[systematic name: benzyl 2-(2,5-dioxooxazolidin-4-yl)acetate], the oxazolidine ring is planar, with an r.m.s. deviation of 0.03 Å. The benzyl ring is almost normal to the oxazolidine ring, making a dihedral angle of 80.11 (12)°. In the crystal, inversion dimers are formed between the L- and D-enantiomersviapairs of N—H...O hydrogen bonds. This arrangement is favourable for the polymerization of the compound in the solid state. The dimers are linked by C—H...O hydrogen bonds, forming layers parallel to theabplane.

A novel fluorescent probe possessing the two different functional groups of bromoacetyl ester and aldehyde functionality was designed as a selective chemodosimeter for cysteine (Cys). The initially nonfluorescent bromoacetyl-fluorescein monoaldehyde (3) was rapidly transformed into a strongly fluorescent molecule through the first nucleophilic substitution followed by the subsequent ester bond cleavage reactions by one Cys and the second oxazolidine formation reaction with another Cys. The molecular probe exhibited a rapid response toward Cys over homocysteine or glutathione owing to the favorable kinetic processes with Cys, of which property was successfully applied for live cell imaging with tunicamycin, an inducer of cytosolic Cys.

A convergent strategy was developed for the stereoselective synthesis of four unusual N-acylated monosaccharides (5-8), which are fragments of lipooligosaccharide IV (LOS-IV) from Mycobacterium marinum. A critical substrate-controlled asymmetric cyclization of an amino acid derived oxazolidine provided a key lactam intermediate 11, which was successfully converted to targets 5-7. The key step in the synthesis of 8 was a one-pot cascade oxidation-cyclization-oxidation reaction of a Boc-protected amino alcohol, prepared from 3-butynol, which led to the formation of lactam 15. The five-membered ring lactam intermediates in these synthetic routes were sensitive to elimination side reactions, but careful manipulation of the reaction sequence allowed for the stereoselective synthesis of the targets. This work represents the first synthesis of these unusual motifs, which have been shown to be essential to the bioactivity of LOS-IV.

In this work, the synthesis of a new class of trans-oxazolidines by the regio- and stereocontrolled reaction of NH-ketoaziridines with phenylisocyanate is reported. A plausible mechanism has been proposed.

(R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol (TBPT), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product [(R)-3-(piperidin-4-ylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazole (M1)] and a cyclized oxazolidine structure [7-(((4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)octahydro-3H (M2)]. After administration of TBPT to humans the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent (M/P) ratios for M1 and M2 was attempted using in vitro metabolism, binding, and permeability data in static and dynamic physiologically based pharmacokinetic (PBPK) models. In the static model, the fraction of parent clearance yielding the metabolite (which also required taking into account secondary metabolites of M1 and M2), the clearance of the metabolites and parent, and an estimate of the availability of the metabolites from the liver were combined to yield estimated parent/metabolite ratios of 0.32 and 23 for M1 and M2, respectively. PBPK modeling that used in vitro and physicochemical data input yielded estimates of 0.26 and 20, respectively. The actual values were 0.12 for M1/TBPT and 58 for M2/TBPT. Thus, the ratio for M1 was overpredicted, albeit at values less than unity. The ratio for M2/TBPT was underpredicted, and the high ratio of 58 may exceed a limiting ceiling of the approach. Nevertheless, when considered in the context of determining whether a potential circulating metabolite may be quantitatively important prior to administration of a drug for the first time to humans, the approaches succeeded in highlighting the importance of M2 (M/P ratio >> 1) relative to M1, despite M1 being much greater than M2 in vitro.

Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans-androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields. Title compounds were tested in vitro against a panel of six human tumor cell lines, named A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon), and the results were compared with steroidal chemotherapeutic agents (abiraterone and galeterone); the A-ring of the steroidal backbone, the nature of the heterocycle and the N-substituents proved to be essential motifs for establishing structure-activity relationships concerning not only the potency but also the selectivity against tumor cell lines. Estrone derivatives, particularly those bearing a spiranic 2-aminooxazoline scaffold were found to be the most active compounds, with GI50 values ranging from the low micromolar to the submicromolar level (0.34–1.5 μM). Noteworthy, the lead compounds showed a remarkable increase in activity against the resistant cancer cell lines (T-47D and WiDr) compared to the anticancer reference drugs (up to 120-fold).

In the title compound, C20H19N3O3S, the conformation of the oxazolidine ring is characterized as twisted on the C—C bond. In the crystal, zigzag chains parallel to [101] are formed by N—H...O hydrogen bonds and are connected by C—H...O and C—H...π(ring) interactions.

In the title molecule, C20H17ClN2O3S, the oxazolidine ring is oriented towards the benzothiazine moiety so that the centroid of the former isca5.05 Å from the sulfur atom of the latter. In the crystal, the molecules are arranged in layers parallel to (101) and held together by the aid of C—H...O interactions, resulting in a three-dimensional network structure.

International audience; The design of constrained peptides is of prime importance in the development of bioactive compounds and for applications in supramolecular chemistry. Due to its nature, the peptide bond undergoes a spontaneous cis–trans isomerism, and the cis isomers are much more difficult to stabilize than the trans forms. By using oxazolidine-based pseudoprolines (ΨPro) substituted by a trifluoromethyl group, we show that the cis peptide bond can be readily switched from 0% to 100% in Xaa-ΨPro dipeptides. Our results prove that changing the configuration of the Cα in Xaa or in ΨPro is sufficient to invert the cis:trans populations while changing the nature of the Xaa side chain finely tuned the conformers ratio. Moreover, a strong correlation is found between the puckering of the oxazolidine ring and the peptide bond conformation. This finding highlights the role of the trifluoromethyl group in the stabilization of the peptide bond geometry. We anticipate that such templates will be very useful to constrain the backbone geometry of longer peptides.

We describe a new synthesis of the 5-(aminomethyl)oxazolidin-3-one core of linezolid in enantiomerically pure form. The expedient cyclization of the α-hydroxy amide derived from isoserine and 3-fluoro-4-morpholinoaniline to give the corresponding (aminomethyl)oxazolidine-2,4-dione, followed by its mild selective reduction at the C(4)-position, gave linezolid in almost quantitative overall yield.

We have previously reported on a study of the structure–activity relationship in a series of 2,3,4-substituted oxazolidines recently discovered by our group varying the substituent at the ring or stereochemistry of the oxazolidine ring. We discovered the cytotoxic and pro-apoptotic potential of compounds 1 and 2 with good selectivity against cancer cell lines. In the present study we describe the synthesis and cytotoxic evaluation against cancer cell lines (HL60, JURKAT, MDA-MB-231 and LNCaP) of a series of oxazolidines designed by isosteric replacement or rigidification of the oxymethylene spacer of compounds 1 and 2. Alkenes 3 and 4 retained the activity against MDA-MB-231 cells and they were more active on HL60, JURKAT and LNCaP cells. Considering LNCaP cells, E-isomer 4 was at least 7 times and about 3 times more potent than lead 1 and Z-isomer 3, respectively. Compound 4 exerted significant activity against LNCaP with IC50 in the low micromolar range (11 μM) without affecting VERO cells and PBMC proliferation (IC50 > 100 μM) indicating its low toxicity to normal cells.

A facile and catalytic asymmetric synthesis of the pentacyclic core of (-)-nakadomarin A, containing all the stereogenic centers of the natural product was achieved. The key intermediate involves the oxazolidine moiety as an iminium cation equivalent. An efficient method for the removal of the N-hydroxyethyl group is also described.

Naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of highly potent antitumor antibiotics, isolated from various streptomycin species. PBDs covalently bond and cross-link with discrete sequences of base pairs in the minor groove of DNA. A wide range of synthetic PBDs and PBD dimers have been shown to be highly potent cytotoxic agents, and have been used as payloads in antibody drug conjugates (ADCs). However, all PBDs as stand-alone agents or as delivered via small molecule drug conjugates (SMDCs), cause undesired off-target toxicity. Recently, we designed folate conjugated pro-PBDs, masking the imine moiety with its synthetic precursors: namely, 1,3-oxazolidine carbamate and an aromatic amine. The 1,3-oxazolidine carbamate provided a conjugation site for attachment of pro-PBD to a targeting ligand. After delivery to the targeted cell and internalization, reductive cleavage of the linker system results in the generation of a 1,3-oxazolidine. The oxazolidine reacts with water to form an aldehyde which subsequently reacts intramolecularly to ultimately form the PBD diazepine ring. Herein, we report the design and synthesis of folate conjugates of pro-PBDs and self-immolative sterically hindered disulfide linker systems, which pave the way toward novel, highly-specific therapeutics which have the potential to minimize off-target toxicities. One of the so designed conjugates, EC2629, satisfied all of our criteria for selection for pre-clinical development: • EC2629 shows high affinity towards FR mediated binding. • Cross-links DNA only following self-immolative release of free drug. • Picomolar potency against FR-expressing cells. • Curative activity with no weight loss in animal models. • Active against drug resistant tumor xenograft models in-vivo. • EC2629 is active against patient derived xenograft models in-vivo. • Based on high cytotoxicity and minimal off target toxicity (in-vitro & in-vivo), EC2629 is selected for pre-clinical development. • Biological evaluation of EC2629 was presented at World ADC, Berlin, Germany (March, 2018). Citation Format: Iontcho Vlahov, Longwu Qi, Hari K. Santhapuram, Garth Parham, Kevin Wang, Jeremy F. Vaughn, Spencer J. Hahn, Marilynn Vetzel, Melissa Nelson, Joseph A. Reddy, Christopher P. Leamon. pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, the legacy: Design and synthesis of pro-PBD conjugates containing self-immolative substituted disulfide linkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 216.

A series of 23 racemic mefloquine-oxazolidine derivatives, 4-[3-(aryl)hexahydro[1,3]oxazolo[3,4-a]pyridin-1-yl]-2,8-bis(trifluoromethyl)quinolines, derived from (R*, S*)-(±)-mefloquine and arenealdehydes, have been evaluated for their activity against four cancer cell lines (HCT-8, OVCAR-8, HL-60, and SF-295). Good cytotoxicities have been determined with IC50 values ranging from 0.59 to 4.79 μg/mL. In general compounds with aryl groups having strong electron-releasing substituents, such as HO and MeO, or electron-rich heteroaryl groups, for example imidazol-2-y-l, are active. However, other factors such as steric effects may play a role. As both the active and non-active conformations of the mefloquine-oxazolidine derivatives are similar, it is concluded that molecular conformations do not play a significant role either. This study is the first to evaluate mefloquine derivatives as antitumor agents. The mefloquine-oxazolidine derivatives are considered to be useful leads for the rational design of new antitumor agents.

Aryl and alkyl chiral oxazolidine sulfonium salts with cis and trans dispositions derived from (–)-(R)-2-phenylglycinol were demonstrated to be good to excellent chiral auxiliaries for the diastereoselective synthesis of (2R,3S)-trans-epoxyamides. Interestingly, the diastereoselective outcome depends on the stereochemistry of the chiral center at the C-4 position of the oxazole moiety. The stereoselectivities were consistent even for aliphatic aldehydes.

In order to optimize Mukaiyama reagent-induced cyclization of vicinal sec-amino alcohols of desosamine origin towards exclusive formation of N′-substituted-2-imino-1,3-thiazolidines via a thiocarbamoyl intermediate, the influence of reaction conditions was studied. A novel, mild, one-pot, two-step method was developed, and the formation of N′-substituted-2-imino-1,3-oxazolidines as side products was minimized. The inversion of configuration at C-2′ was unambiguously established using NMR-based conformational analysis. A reaction mechanism was proposed. A test series of novel desosamine-modified 14- and 15-membered macrolides, bearing N′-alkyl-2-imino-1,3-thiazolidines fused to the desosamine sugar were prepared.

An expedient regio-, stereo- and product-selective synthesis of novel hybrid heterocyclic systems comprising [1,2-c]oxazolidine, pyrrolidine and piperidine units, in good to excellent yields, has been developed via three-component 1,3-dipolar cycloaddition/annulation domino reactions and concomitant trifluoroacetic acid mediated condensative annulation with paraformaldehyde. These novel structurally complex heterocyclic hybrids, accessed by a two-step protocol, possess seven rings and seven contiguous stereocentres.

Two chiral bidentate C1-symmetric 1,3-oxazolidine ligands (1 and 2) and coordination complexes with copper(II) chloride (Cu2Cl4(C15H14N2O)2 (3) and [Cu2Cl4(C16H16N2O)2]·CH3OH (4)) were synthesized and characterized by X-ray crystallographic techniques. The ligands maintain the same stereochemistry within all structures, resulting in an anti-relationship between the 2,4-substituents. Structures 3 and 4 dimerized through bridging chlorides and 3 has an extended hydrogen bonding network resulting in an infinite 1D chain.

A novel trinuclear zinc(II) complex, [Zn3L2(NCS)2], where L is the deprotonated form of 2-(3-(2-(2-hydroxy-3-methoxybenzylideneamino)ethyl)oxazolidin-2-yl)-6-methoxyphenol (H2L), has been unexpectedly prepared from the reaction of Schiff base ligand 2-((2-(2-hydroxyethylamino)ethylimino)methyl)-6-methoxyphenol (HL′) with 3-methoxysalicylaldehyde, ammonium thiocyanate, and zinc nitrate in methanol. The complex has been characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction studies. It is interesting that the Schiff base ligand HL′ used to prepare the complex was transferred to a novel ligand H2L, bearing newly formed oxazolidine ring. Zinc ion and thiocyanate anion may be the essential factors for the cyclorization. Thermal stability and fluorescent property of the complex were also studied.

The synthesis of substituted [4.3.0] bicyclic lactams derived from 6-oxo-2-hydroxymethylpiperidine is described. The enolate derived from these systems can be alkylated with a range of reactive electrophiles; the diastereoselectivity which can be achieved depends on the substitution pattern of the oxazolidine ring system and the nature of the alkylating reagent, and can vary from 1:1 to as much as 10:1.

A variety of (R)-phenylglycinol-derived oxazolopiperidone lactams 1–14 were converted to linear-chain enantiopure amino diols 15–26 by reduction with LiNH2BH3 in an unprecedented process involving the simultaneous reductive opening of the oxazolidine and lactam rings. Subsequent removal of the phenylethanol moiety gave enantiopure 5-amino-1-pentanols bearing substituents at the 2-, 3-, 4-, 2,2-, 2,3- 2,4- and 3,4-positions (28–36), which were isolated as their N-Boc derivatives.

1.The first generation 5HT-4 partial agonist, 4-{4-[4-Tetrahydrofuran-3-yloxy)-benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol, PF-4995274 (TBPT), was metabolized to N-dealkylated (M1) and an unusual, cyclized oxazolidine (M2) metabolites. M1 and M2 demonstrated pharmacological activity at 5HT receptor subtypes warranting further investigation into their dispositional properties in humans; M2 was a minor component in vitro but was the pre-dominant metabolite identified in human plasma. 2.To shift metabolism away from the piperidine ring of TBPT, a series of heterocyclic replacements were designed, synthesized, and profiled. Groups including azetidines, pyrrolidines, as well as functionalized piperidines were evaluated with the goal of identifying an alternative group that maintained the desired potency, functional activity, and reduced turnover in human hepatocytes. 3.Activities of 4-substituted piperidines or pyrrolidine analogs at the pharmacological target were not significantly altered, but the same metabolic pathways of N-dealkylation and oxazolidine formation were still observed. Altering these to bridged ring systems lowered oxazolidine metabolite formation, but not N-dealkylation. 4.The effort concluded with identification of azetidines as second-generation 5HT4 partial agonists. These were neither metabolized via N-dealkylation nor converted to cyclized oxazolidine metabolites rather oxidized on the isoxazole ring. The use of azetidine as a replacement for aliphatic aza-heterocyclic rings in drug design to alter drug metabolism and pharmacology is discussed.

A synthetic route to enantiopure cis-1,3-dimethyltetrahydroisoquinolines, synthetic precursors of naphthylisoquinoline alkaloids, has been developed. The synthesis relies on the use of a phenylglycinol-derived lactam as the starting enantiopure scaffold. After stereoselective opening of the oxazolidine ring, the C-3 methyl substituent was installed, taking advantage of the lactam carbonyl group by stereoselective hydrogenation of an α-methylenamide generated via a vinyl triflate.

Protected enantiopure 2-pyrrolylalanine was synthesized for application in peptide science as an electron-rich arylalanine (histidine) analog with π-donor capability. (2S)-N-(Boc)-N'-(Phenylsulfonyl)-, (2S)-N,N'-bis-(phenylsulfonyl)-, and (2S)-N,N'-bis-(Boc)-3-(2-pyrrolyl)alanines (10, 3, and 14, respectively) were made in 13-17% overall yields and six to seven steps from oxazolidine β-methyl ester 4. Homoallylic ketone 5 was prepared by a copper-catalyzed cascade addition of vinylmagnesium bromide to ester 4 and converted to pyrrolyl amino alcohol 7 by olefin oxidation and Paal-Knorr condensation. Protecting group shuffle and oxidation of the primary alcohol enabled the synthesis of pyrrolylalanines. The bis-Boc analog 14 proved useful in peptide chemistry and was employed to make N-acetyl-pyrrolylalaninyl-proline N''-methylamide 25. A study of the influence of the pyrrole moiety on the prolyl amide isomer equilibrium of 25 using (1)H NMR spectroscopy in chloroform, DMSO, and water demonstrated that the pyrrolylalanine peptide exhibited behavior and conformations different from those of other arylalanine analogs.

In situ formation of ligands is an efficient approach to synthesizing novel complexes with unique coordinating moieties. Oxazolidines and oxazinanes are 1,3-N,O-containing five-membered and six-membered heterocycles, respectively. Metal complexes of ligands derived from these two heterocycles are rather rare. In this work, we designed and synthesized a novel multihydoxy ligand, 2-((2,3-dihydroxypropylamino)methyl)phenol (H3L1). It contains both aminoethanol and aminopropanol units, which may be employed to react with aldehydes to afford oxazolidines and oxazinanes, respectively. Thus, H3L1 was reacted with metal salts in the absence or presence of aldehydes to afford complexes [Cu(HL1)]2 (1), [CuL2]4·4CH3OH (2) [Zn5Na2(L3)4(DMSO)2.65(DMF)1.35]·DMF (3), and [Ni(HL4)]2 (4). Complex 1 is a dialkoxo-bridged binuclear Cu(II) complex. The coordination moieties are linked by intermolecular C–H···O hydrogen bonds to afford a 1D double-chain supramolecular structure. Interestingly, in complexes 2–4, H3L1 has been ...

Jadomycin A and related jadomycin M and W aglycons were synthesized. Easy re-construction of 4-(hydroxymethyl)-1,3-oxazolidin-5-one system into an isomeric 1,3-oxazolidine-4-carboxylic acid system during the synthetic trial of jadomycin S aglycon requests us to more precisely re-examine the structures proposed for jadomycins S and T, derived from hydroxyl-containing amino acids of l -serine and l -threonine, respectively.

The 3-phenyl-2-(pyridin-2-yl)oxazolidine ligand (ppo) was synthesised and its coordination behaviour regarding Ni(II) and Pd(II) centres was studied. The reaction with K(2)PdCl(4) affords [Pd(N,N'-ppo)Cl(2)] (1), in which ppo binds to palladium via the pyridyl nitrogen and the oxazolyl nitrogen atoms. On the contrary, reaction with NiCl(2)·6H(2)O produces [Ni(N,O-ppo)(2)Cl(2)] (2), in which two ppo ligands are coordinated via the pyridyl nitrogen and the oxygen atom of the oxazolidine ring. The X-ray diffraction analysis of the complexes confirms a square planar geometry for Pd(II) in 1 and an octahedral configuration around Ni(II) in 2, which, to the best of our knowledge, represents the first reported example of a structurally characterised nickel-oxazolidine compound. In addition, both complexes prove to be active catalysts under mild conditions in the aza-Michael reaction of (E)-4-phenylbut-3-en-2-one (benzalacetone) with aliphatic amines.

The cytochrome bc₁ complex (EC 1.10.2.2, bc₁) is one of the most promising targets for new drugs and agricultural fungicides. Among the existing bc₁ complex inhibitors specifically binding to the Q(o) site, oxazolidinedione derivatives have attracted great attention. With the aim to understand the substituent effects of oxazolidinedione derivatives on the inhibition activity against the bc₁ complex, a series of new oxazolidinedione derivatives were designed, synthesized, and biologically evaluated. The further inhibitory kinetics studies against porcine succinate-cytochrome c reductase (SCR) revealed that the representative compound 8d and famoxadone are both non-competitive inhibitors with respect to the substrate cytochrome c, but competitive inhibitors with respect to substrate decylubiquinol (DBH₂). In addition, compound 8d and famoxadone showed, respectively, 35-fold and 15-fold greater inhibitory activity against the porcine SCR than the porcine bc₁ complex, indicating that these two inhibitors not only inhibited the activity of the bc₁ complex, but possibly affect the interaction between the complex II and the bc₁ complex. To our knowledge, this is the first report that famoxadone and its analogs have effects on the interaction between the complex II and the bc₁ complex.

A number of compounds have been prepared in order to improve pharmacological roles of antihyperglycemic activity. In the present paper, a series of 3-benzyl-2-(4'-substituted phenyl)-4(5H)-(4″-nitrophenyl amino)-1,3-oxazolidines (6a-e) were tested against hyperglycemia. Their antihyperglycemic activity was evaluated by streptozotocin (STZ) and sucrose-loaded (SLM) models. Compounds 6a, b, c, d, and e displayed significant reductions in blood glucose in the streptozotocin and sucrose loaded rat models. The purity of the synthesized compounds was characterized by means of IR, (1)H-NMR, mass spectral and elemental analysis.

A simple and facile stereoselective formal total synthesis of (―)-swainsonine has been reported starting from Garner's L -serine derived oxazolidine aldehyde. Our synthetic strategy involves stereoselective allylation and Still olefination as key intermediary reaction steps.

S N 2' sequences have been employed for the synthesis of β-branched α-amino acids using 1,2-diastereocontrol for forming C―C bonds. An oxazolidine fragment derived from Garner's aldehyde provides the handle for facial discrimination and acts as a masked amino acid functionality. This study encompasses directed and non-directed allylic substitution reactions. The stereocontrol of the oxazolidine appendage during terminal olefin hydroformylation was also studied. Efforts to understand the diastereochemical outcome of the reactions as well as synthetic applications are disclosed.