Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

2‐Diazo‐2H‐indoles

2‐Diazo‐2H‐indoles were prepared by diazotization of the corresponding 1H‐indol‐2‐amines and subsequent neutralization. On the basis of NMR data and ab initio and semiempirical calculations, we suggest that the zwitterionic form A is the most representative structure for 2‐diazo‐2H‐indoles. In fact, spectral data are compatible with a 1H‐indole structure, and the fully optimized molecules gave distances in agreement with those reported for the anion obtained from 1H‐indole. The calculated charges are compatible with a zwitterionic structure in which the negative charge is mainly located at the ring N‐atom at variance with the case of diazopyrroles and 3‐diazo‐3H‐indoles where the negative charge is essentially located on the ipso C‐atom.     

Thiadiazole-based Thioglycosides as Sodium-glucose Co-transporter 2(SGLT2)Inhibitors

A series of thiadiazole‐based thioglycosides were synthesized as SGLT2 inhibitors from D‐glucose, D‐galactose and a variety of phenylacetic acids via a convenient protocol in 8 steps and evaluated in vivo with an oral glucose tolerance test (OGTT), and 5‐benzyl‐1,3,4‐thiadiazol‐2‐yl 1‐thio‐β‐D‐glucopyranoside ( 1a ) was the most efficacious to suppress the blood glucose excursion during OGTT.     

[2+2] Photocycloaddition of 2‐Morpholinoprop‐2‐enenitrile to Perinaphthenone

Perinaphthenone (=1H‐phenalen‐1‐one), known for efficient population of its T₁ (π,π*) state and suggested as a standard sensitizer for singlet oxygen (¹Δg) formation, forms a single stereoisomer of a head‐to‐tail [2+2] photoadduct across its C(2)=C(3) bond with 2‐morpholinoprop‐2‐enenitrile in benzene by broad band UV excitation (λ≥280 nm). The reaction is advantageously run to low conversion of starting materials only. The structure of the adduct, especially the relative configuration at C(9), has been derived from ¹H‐NMR data including NOE signal enhancement studies.     

Zoledronate complexes. III. Two zoledronate complexes with alkaline earth metals: [Mg(C5H9N2O7P2)2(H2O)2] and [Ca(C5H8N2O7P2)(H2O)]n

Diaquabis[dihydrogen 1‐hydroxy‐2‐(imidazol‐3‐ium‐1‐yl)ethylidene‐1,1‐diphosphonato‐κ²O,O′]magnesium(II), [Mg(C₅H₉N₂O₇P₂)₂(H₂O)₂], consists of isolated dimeric units built up around an inversion centre and tightly interconnected by hydrogen bonding. The Mg^II cation resides at the symmetry centre, surrounded in a rather regular octahedral geometry by two chelating zwitterionic zoledronate(1−) [or dihydrogen 1‐hydroxy‐2‐(imidazol‐3‐ium‐1‐yl)ethylidene‐1,1‐diphosphonate] anions and two water molecules, in a pattern already found in a few reported isologues where the anion is bound to transition metals (Co, Zn and Ni). catena‐Poly[[aquacalcium(II)]‐μ₃‐[hydrogen 1‐hydroxy‐2‐(imidazol‐3‐ium‐1‐yl)ethylidene‐1,1‐diphosphonato]‐κ⁵O:O,O′:O′,O′′], [Ca(C₅H₈N₂O₇P₂)(H₂O)]_n, consists instead of a Ca^II cation in a general position, a zwitterionic zoledronate(2−) anion and a coordinated water molecule. The geometry around the Ca^II atom, provided by six bisphosphonate O atoms and one water ligand, is that of a pentagonal bipyramid with the Ca^II atom displaced by 0.19 Å out of the equatorial plane. These Ca^II coordination polyhedra are `threaded' by the 2₁ axis so that successive polyhedra share edges of their pentagonal basal planes. This results in a strongly coupled rhomboidal Ca₂–O₂ chain which runs along [010]. These chains are in turn linked by an apical O atom from a –PO₃ group in a neighbouring chain. This O‐atom, shared between chains, generates strong covalently bonded planar arrays parallel to (100). Finally, these sheets are linked by hydrogen bonds into a three‐dimensional structure. Owing to the extreme affinity of zoledronic acid for bone tissue, in general, and with calcium as one of the major constituents of bone, it is expected that this structure will be useful in modelling some of the biologically interesting processes in which the drug takes part.     

(NH4)3[VO2(SO4)2(H2O)2]·1.5H2O

The title compound, tri­ammonium cis‐di­aqua‐cis‐dioxo‐trans‐disulfatovanadate 1.5‐hydrate, was obtained by oxidizing V^IV to V^V in a 2 M sulfuric acid solution of vanadyl­ sulfate and adding ammonium sulfate. Here, the V atom is sandwiched by two sulfate groups by corner‐sharing to form a discrete [VO₂(SO₄)₂(OH₂)₂]^3? anion. The water mol­ecules occupy cis positions in the equatorial plane of the vanadium octahedron.     

Preparation of β2‐Homotryptophan Derivatives for β‐Peptide Synthesis

In view of the prominent role of the 1H‐indol‐3‐yl side chain of tryptophan in peptides and proteins, it is important to have the appropriately protected homologs H‐β² HTrp OH and H‐β³ HTrp OH (Fig.) available for incorporation in β‐peptides. The β²‐HTrp building block is especially important, because β²‐amino acid residues cause β‐peptide chains to fold to the unusual 12/10 helix or to a hairpin turn. The preparation of Fmoc and Z β²‐HTrp(Boc) OH by Curtius degradation (Scheme 1) of a succinic acid derivative is described (Schemes 2–4). To this end, the (S)‐4‐isopropyl‐3‐[(N‐Boc‐indol‐3‐yl)propionyl]‐1,3‐oxazolidin‐2‐one enolate is alkylated with Br CH₂CO₂Bn (Scheme 3). Subsequent hydrogenolysis, Curtius degradation, and removal of the Evans auxiliary group gives the desired derivatives of (R)‐H β²‐HTrp OH (Scheme 4). Since the (R)‐form of the auxiliary is also available, access to (S)‐β²‐HTrp‐containing β‐peptides is provided as well.     

K2[Mo2O4(C2O4)2(H2O)2]·3H2O

The crystal and molecular structure of dipotassium di‐μ‐oxo‐bis[aqua(oxalato‐O¹,O²)oxomolybdenum(III)] trihydrate, K₂­[Mo₂O₄(C₂O₄)₂(H₂O)₂]·3H₂O, has been determined from X‐ray diffraction data. In the dimeric anion, which has approximate twofold symmetry, each Mo atom is in a distorted octahedral coordination, being bonded to one terminal oxo‐O atom, two bridging O atoms, two O atoms from the oxalato ligand and one from the water mol­ecule. Bond lengths trans to the multiple‐bonded terminal oxo ligand are larger than those in the cis position, confirming the trans influence as a generally valid rule.     

Enantioselective Synthesis of 2‐(2‐Arylcyclopropyl)glycines: Conformationally Restricted Homophenylalanine Analogs

Starting from simple aromatic aldehydes and acetylfuran, (E)‐1‐(furan‐2‐yl)‐3‐arylprop‐2‐en‐1‐ones ( 2 ) were synthesized in high yields. Cyclopropanation of the C?C bond with trimethylsulfoxonium iodide (Me₃SO⁺I^?) furnished (furan‐2‐yl)(2‐arylcyclopropyl)methanones 3 in 90–97% yields. Selective conversion of cyclopropyl ketones to their (E)‐ and (Z)‐oxime ethers 5 and oxazaborolidine‐catalyzed stereoselective reduction of the C?N bond followed by separation of the formed diastereoisomers, furnished (2‐arylcyclopropyl)(furan‐2‐yl)methanamines 6 in optically pure form and high yield. Oxidation of the furan ring of (S,S,S)‐, (S,R,R)‐, (R,S,S)‐, and (R,R,R)‐ 6a afforded the four stereoisomers of α‐(2‐phenylcyclopropyl) glycine ( 1a ).     

Three isomeric forms of hydroxyphenyl‐2‐oxazoline: 2‐(2‐hydroxyphenyl)‐2‐oxazoline, 2‐(3‐hydroxyphenyl)‐2‐oxazoline and 2‐(4‐hydroxyphenyl)‐2‐oxazoline

Crystal structures are reported for three isomeric compounds, namely 2‐(2‐hydroxy­phenyl)‐2‐oxazoline, (I), 2‐(3‐hydroxy­phenyl)‐2‐oxazoline, (II), and 2‐(4‐hydroxy­phenyl)‐2‐oxazoline, (III), all C₉H₉NO₂ [systematic names: 2‐(4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenol, (I), 3‐(4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenol, (II), and 4‐(4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenol, (III)]. In these compounds, the deviation from coplanarity of the oxazoline and benzene rings is dependent on the position of the hydroxy group on the benzene ring. The coplanar arrangement in (I) is stabilized by a strong intra­molecular O—H⋯N hydrogen bond. Surprisingly, the 2‐oxazoline ring in mol­ecule B of (II) adopts a ³T₄ (^C2T_C3) conformation, while the 2‐oxazoline ring in mol­ecule A, as well as that in (I) and (III), is nearly planar, as expected. Tetra­mers of mol­ecules of (II) are formed and they are bound together via weak C—H⋯N hydrogen bonds. In (III), strong inter­molecular O—H⋯N hydrogen bonds and weak intra­molecular C—H⋯O hydrogen bonds lead to the formation of an infinite chain of mol­ecules perpendicular to the b direction. This paper also reports a theoretical investigation of hydrogen bonds, based on density functional theory (DFT) employing periodic boundary conditions.     

On the Reactivity of the Platina‐β‐diketone [Pt2{(COMe)2H}2(μ‐Cl)2] Towards Ph2PCH2CH2CH2SOxPh (x = 0, 2)

The reaction of the electronically unsaturated platina‐β‐diketone [Pt₂{(COMe)₂H}₂(μ‐Cl)₂] ( 1 ) with Ph₂PCH₂CH₂CH₂SPh ( 2 ) leads selectively to the formation of the acetyl(chlorido) platinum(II) complex (SP‐4‐3)‐[Pt(COMe)Cl(Ph₂PCH₂CH₂CH₂SPh‐κP,κS)] ( 4 ) having the γ‐phosphinofunctionalized propyl phenyl sulfide coordinated in a bidentate fashion (κP,κS). In boiling benzene complex 4 undergoes decarbonylation yielding the methyl(chlorido) platinum(II) complex (SP‐4‐3)‐[PtMeCl(Ph₂PCH₂CH₂CH₂SPh‐κP,κS)] ( 6 ). However, the reaction of 1 with the analogous γ‐diphenylphosphinofunctionalized propyl phenyl sulfone Ph₂PCH₂CH₂CH₂SO₂Ph ( 3 ) affords the acetyl(chlorido) platinum(II) complex (SP‐4‐4)‐[Pt(COMe)Cl(Ph₂PCH₂CH₂CH₂SO₂Ph‐κP)₂] ( 5 ). In boiling benzene complex 5 undergoes a CO extrusion yielding (SP‐4‐4)‐[PtMeCl(Ph₂PCH₂CH₂CH₂SO₂Ph‐κP)₂] ( 8 ) whereas in presence of 1 the formation of the carbonyl complex (SP‐4‐3)‐[PtMeCl(CO)(Ph₂PCH₂CH₂CH₂SO₂Ph‐κP)] ( 7 ) is observed. Addition of Ag[BF₄] to complex 5 leads to the formation of the cationic methyl(carbonyl) platinum(II) complex (SP‐4‐1)‐[PtMe(CO)(Ph₂PCH₂CH₂CH₂SO₂Ph‐κP)₂][BF₄] ( 9 ). All complexes were characterized by microanalysis and NMR spectroscopy (¹H, ¹³C, ³¹P) and complexes 4 and 6 additionally by single‐crystal X‐ray diffraction analyses.     

Tuning the LCST of poly(2‐cyclopropyl‐2‐oxazoline) via gradient copolymerization with 2‐ethyl‐2‐oxazoline

Poly(2‐propyl‐oxazoline)s can be prepared by living cationic ring‐opening polymerization of 2‐oxazolines and represent an emerging class of biocompatible polymers exhibiting a lower critical solution temperature in aqueous solution close to body temperature. However, their usability is limited by the irreversibility of the transition due to isothermal crystallization in case of poly(2‐isopropyl‐2‐oxazoline) and the rather low glass transition temperatures (T_g < 45 °C) of poly(2‐n‐propyl‐2‐oxazoline)‐based polymers. The copolymerization of 2‐cyclopropyl‐2‐oxazoline and 2‐ethyl‐2‐oxazoline presented herein yields gradient copolymers whose cloud point temperatures can be accurately tuned over a broad temperature range by simple variation of the composition. Surprisingly, all copolymers reveal lower T_gs than the corresponding homopolymers ascribed to suppression of interchain interactions. However, it is noteworthy that the copolymers still have T_gs > 45 °C, enabling convenient storage in the fridge for future biomedical formulations. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3118–3122     

New Supramolecular Complex Assembled through Hydrogen Bonds. Crystal Structure of Co(PMBP-tsc)_2 ·2DMF·2H_2O

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Synthesis and Reactivity towards DIBAL‐H of Cyclo‐Siloxanes cyclo‐[R2SiOSi(Ot‐Bu)2O]2, cyclo‐(t‐BuO)2Si(OSiR2)2O,and cyclo‐R2Si[OSi(Ot‐Bu)2]2O (R = Me,Ph)

The six‐, eight‐ and twelve‐membered cyclo‐siloxanes, cyclo‐[R₂SiOSi(Ot‐Bu)₂O]₂ (R = Me ( 1 ), Ph ( 2 )), cyclo‐(t‐BuO)₂Si(OSiR₂)₂O (R = Me ( 3 ), Ph ( 4 )), cyclo‐R₂Si[OSi(Ot‐Bu)₂]₂O (R = Me ( 5 ), Ph ( 6 )) and cyclo‐[(t‐BuO)₂Si(OSiMe₂)₂O]₂ ( 3a ) were synthesized in high yields by the reaction of (t‐BuO)₂Si(OH)₂ and [(t‐BuO)₂SiOH]₂O with R₂SiCl₂ and (R₂SiCl)₂O (R = Me, Ph). Compounds 1 — 6 were characterized by solution and solid‐state ²⁹Si NMR spectroscopy, electrospray mass spectrometry and osmometric molecular weight determination. The molecular structure of 4 has been determined by single crystal X‐ray diffraction and features a six‐membered cyclo‐siloxane ring that is essentially planar. The reduction of 1 — 6 with i‐Bu₂AlH (DIBAL‐H) led to the formation of the metastable aluminosiloxane (t‐BuO)₂Si(OAli‐Bu₂)₂ ( 7 ) along with Me₂SiH₂ and Ph₂SiH₂.     

Iron‐Catalyzed Highly Enantioselective cis‐Dihydroxylation of Trisubstituted Alkenes with Aqueous H2O2

Reliable methods for enantioselective cis‐dihydroxylation of trisubstituted alkenes are scarce. The iron(II) complex cis‐α‐[Fe^II(2‐Me₂‐BQPN)(OTf)₂], which bears a tetradentate N₄ ligand (Me₂‐BQPN=(R,R)‐N,N′‐dimethyl‐N,N′‐bis(2‐methylquinolin‐8‐yl)‐1,2‐diphenylethane‐1,2‐diamine), was prepared and characterized. With this complex as the catalyst, a broad range of trisubstituted electron‐deficient alkenes were efficiently oxidized to chiral cis‐diols in yields of up to 98 % and up to 99.9 % ee when using hydrogen peroxide (H₂O₂) as oxidant under mild conditions. Experimental studies (including ¹⁸O‐labeling, ESI‐MS, NMR, EPR, and UV/Vis analyses) and DFT calculations were performed to gain mechanistic insight, which suggested possible involvement of a chiral cis‐Fe^V(O)₂ reaction intermediate as an active oxidant. This cis‐[Fe^II(chiral N₄ ligand)]²⁺/H₂O₂ method could be a viable green alternative/complement to the existing OsO₄‐based methods for asymmetric alkene dihydroxylation reactions.     

Synthesis of 4‐fluoroalkyl‐2H‐pyrido [1, 2‐a] pyrimidin‐2‐ones from 2, 2‐dihydropolyfluoroalkanoic acids

In the presence of N, N′‐dicyclohexylcarbodiimide, 2‐aminopyridine and its derivatives (2) condensed with 2, 2‐di‐hydropolyfluoroalkanoic adds (1) to give the corresponding amides. Subsequent intramolecular Micheal addition‐elimination reactions of the fluorine‐containing amides under basic conditions gave 4‐fluoroalkyl‐2H‐pyrido[1,2‐a]pyrimidin‐2‐ones (3) in good yields.     

Stereocontrolled Synthesis of (2R,3S)‐2‐Methylisocitrate,a Central Intermediate in the Methylcitrate Cycle

2‐Methylisocitrate (=3‐hydroxybutane‐1,2,3‐tricarboxylic acid) is an intermediate in the oxidation of propanoate to pyruvate (=2‐oxopropanoate) via the methylcitrate cycle in both bacteria and fungi (Scheme 1). Stereocontrolled syntheses of (2R,3S)‐ and (2S,3R)‐2‐methylisocitrate (98% e.e.) were achieved starting from (R)‐ and (S)‐lactic acid (=(2R)‐ and (2S)‐2‐hydroxypropanoic acid), respectively. The dispiroketal (6S,7S,15R)‐15‐methyl‐1,8,13,16‐tetraoxadispiro[5.0.5.4]hexadecan‐14‐one ( 2a ) derived from (R)‐lactic acid was deprotonated with lithium diisopropylamide to give a carbanion that was condensed with diethyl fumarate (Scheme 3). The configuration of the adduct diethyl (2S)‐2‐[(6S,7S,14R)‐14‐methyl‐15‐oxo‐1,8,13,16‐tetraoxadispiro[5.0.5.4]hexadec‐14‐yl]butanedioate ( 3a ) was assigned by consideration of possible transition states for the fumarate condensation (cf. Scheme 2), and this was confirmed by a crystal‐structure analysis. The adduct was subjected to acid hydrolysis to afford the lactone 4a of (2R,3S)‐2‐methylisocitrate and hence (2R,3S)‐2‐methylisocitrate. Similarly, (S)‐lactic acid led to (2S,3R)‐2‐methylisocitrate. Comparison of 2‐methylisocitrate produced enzymatically with the synthetic enantiomers established that the biologically active isomer is (2R,3S)‐2‐methylisocitrate.     

Triple ring contraction of a [2+2] macrocyclic ligand

Schiff base condensation of 2,6‐diformylpyridine and 1,3‐diaminopropan‐2‐ol in the presence of a Ba^II template ion yields a complex containing a [2+2] macrocycle, [Ba₂(μ_1,2‐ClO₄)₂(H₂L1)₂], where H₂L1 is 3,7,15,19,25,26‐hexaazatricyclo[19.3.1.1^9,13]hexacosa‐1(25),2,7,9(26),10,12,14,19,21,23‐decaene‐5,17‐diol. On transmetallation with Cu^II cations, the macrocycle undergoes three successive ring contractions, yielding crystals of (acetato‐κO)[26,28‐dioxa‐3,7,15,19,25,27‐hexaazahexacyclo[19.3.1.1^2,5.1^9,13.1^17,10.0^3,8]octacosa‐1(25),9(27),10,12,14,21,23‐heptaene‐κ⁵N]copper(II) perchlorate, [Cu(CH₃COO)(C₂₀H₂₂N₆O₂)]ClO₄ or [Cu(CH₃COO)(L2)]ClO₄, in which the macrocycle ring size has been reduced from 20 members in H₂L1 to 16 in L2.     

Two isomers of Pd2(S2NC7H4)4

The dichloromethane solvates of the isomers tetrakis(μ‐1,3‐benzothiazole‐2‐thiolato)‐κ⁴N:S;κ⁴S:N‐dipalladium(II)(Pd—Pd), (I), and tetrakis(μ‐1,3‐benzothiazole‐2‐thiolato)‐κ⁶N:S;κ²S:N‐dipalladium(II)(Pd—Pd), (II), both [Pd₂(C₇H₄NS₂)₄]·CH₂Cl₂, have been synthesized in the presence of (o‐isopropylphenyl)diphenylphosphane and (o‐methylphenyl)diphenylphosphane. Both isomers form a lantern‐type structure, where isomer (I) displays a regular and symmetric coordination and isomer (II) an asymmetric and distorted structure. In (I), sitting on an centre of inversion, two 1,3‐benzothiazole‐2‐thiolate units are bonded by a Pd—N bond to one Pd atom and by a Pd—S bond to the other Pd atom, and the other two benzothiazolethiolate units are bonded to the same Pd atoms by, respectively, a Pd—S and a Pd—N bond. In (II), three benzothiazolethiolate units are bonded by a Pd—N bond to one Pd atom and by a Pd—S bond to the other Pd atom, and the fourth benzothiazolethiolate unit is bonded to the same Pd atoms by, respectively, a Pd—S bond and a Pd—N bond.     

Synthesis and Antifungal Bioactivity of Methyl 2-Methoxyimino-2-{2-[(substituted benzylidene)aminooxymethyl]phenyl}acetate and 2-Methoxyimino-2-{2-[(substituted benzylidene)aminooxy-methyl]phenyl}-N-methylacetamide Derivatives

Ten methyl 2‐methoxyimino‐2‐{2‐[(substituted benzylidene)aminooxymethyl]phenyl}acetate and 2‐methoxy‐ imino‐2‐{2‐[(substituted benzylidene)aminooxymethyl]phenyl}‐N‐methylacetamide derivatives were synthesized. Structures of the new compounds were characterized by IR, ¹H NMR and GC‐MS data. These compounds at 10 µg/mL were tested in vitro against five pathogenic fungi, namely, Sclerotonia, Botrytis cinerea Pers, Gibberella zeae, Rhizoctorua solani and Pyricularia oryzae. Compounds G₅ , G₆ , G₇ and G₈ showed potent antifungal activities against Botrytis cinerea Pers, G₇ against Gibberella zeae and G₇ , G₈ against Rhizoctorua solani, respectively.