Bacillus subtilis epoxide hydrolase-catalyzed preparation of enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether and its application to expeditious synthesis of (R)-bicalutamide

Expeditious synthesis of (R)-bicalutamide (1), a synthetic antiandrogen, from enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether (4) was achieved. An engineered Bacillus subtilis epoxide hydrolase worked enantioselectively on the racemic epoxide (7) to provide the above starting material in highly enantiomerically enriched state.     

Stereocontrolled Total Synthesis of Polygalolide A

The total synthesis of polygalolide A, a secondary metabolite that was isolated from a Chinese medicinal plant, is reported. A key issue in this synthesis was construction of an oxabicyclo[3.2.1] skeleton, which was solved by the development of an intramolecular Ferrier‐type C‐glycosylation of a glucal with siloxyfuran as an internal nucleophile. The substrate was prepared from D ‐glucal by the introduction of trimethylsilylacetylene and siloxyfuran groups. Although C‐glycosylation did not occur under the conditions found from model experiments, further examination revealed that the combination of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,4,6‐collidine successfully afforded the desired product as a single diastereomer. The siloxy group at the C3 position played a crucial role in the stereocontrol of this reaction. The product was further transformed into a tetracyclic compound as follows: The vinyl ether and acetylenic moieties were reduced and the siloxy group was removed with a Barton–McCombie reaction. The construction of the six‐membered ether and the γ‐lactone provided the tetracyclic compound. Finally, a phenolic moiety was introduced by using a Mukaiyama aldol reaction to furnish polygalolide A.     

Biosynthesis‐Assisted Structural Elucidation of the Bartolosides,Chlorinated Aromatic Glycolipids from Cyanobacteria

The isolation of the bartolosides, unprecedented cyanobacterial glycolipids featuring aliphatic chains with chlorine substituents and C‐glycosyl moieties, is reported. Their chlorinated dialkylresorcinol (DAR) core presented a major structural‐elucidation challenge. To overcome this, we discovered the bartoloside (brt) biosynthetic gene cluster and linked it to the natural products through in vitro characterization of the DAR‐forming ketosynthase and aromatase. Bioinformatic analysis also revealed a novel potential halogenase. Knowledge of the bartoloside biosynthesis constrained the DAR core structure by defining key pathway intermediates, ultimately allowing us to determine the full structures of the bartolosides. This work illustrates the power of genomics to enable the use of biosynthetic information for structure elucidation.     

Synthesis and optical properties of σ–π conjugated organic–inorganic hybrid gels

Organic–inorganic hybrid gels containing Si‐vinylene units have been synthesized by a hydrosilylation reaction of tri‐ or tetra‐ethynyl aryl compounds, 1,3,5‐triethynylbenzene (TEB), 3,3′,5,5′‐tetraethynylbiphenyl (TEBP), or tetrakis(4‐ethynylphenyl)methane (TEPM), and bisdimethylsilyl compounds, 1,1,3,3‐tetramethyldisiloxane (TMDS) or 1,4‐bisdimetylsilylbenzene (BDMSB), in toluene. Network structure of the resulting gels was quantitatively characterized by a scanning microscopic light scattering. The reactions yielded the gels having homogeneous network structure of 1.5–2.9 nm mesh size under the monomer concentrations that were relatively higher than the critical gelation concentration. The gels obtained from TEB showed broad absorption in the range from 340 to 370 nm, and emission in the range from 440 to 490 nm. The TEB–BDMSB gels showed remarkable red shift of the emission in comparison with that of the corresponding reaction solutions derived from the network formed by σ–π conjugation. The TEPM–TMDS, BDMSB gels exited by 280 nm showed not only the emission peak at around 360 nm derived from TEPM, but the broad peak at around 420 nm, which should be derived from interaction between phenyl groups of TEPM in the gels. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1360–1368     

Biofunctionalized Hydrogel Microscaffolds Promote 3D Hepatic Sheet Morphology

Development of artificial tissues providing the proper geometrical, mechanical, and environmental cues for cells is highly coveted in the field of tissue engineering. Recently, microfabrication strategies in combination with other chemistries have been utilized to capture the architectural complexity of intricate organs, such as the liver, in in vitro platforms. Here it is shown that a biofunctionalized poly (ethylene glycol) (PEG) hydrogel scaffold, fabricated using a sphere‐template, facilitates hepatic sheet formation that follows the microscale patterns of the scaffold surface. The design takes advantage of the excellent diffusion properties of porous, uniform 3D hydrogel platforms, and the enhanced‐cell–extracellular matrix interaction with the display of conjugated collagen type I, which in turn elicits favorable Huh‐7.5 response. Collectively, the experimental findings and corresponding simulations demonstrate the importance of biofunctionalized porous scaffolds and indicate that the microscaffold shows promise in liver tissue engineering applications and provides distinct advantages over current cell sheet and hepatocyte spheroid technologies.

     

Correlation of spin states and spin delocalization with the dioxygen reactivity of catecholatoiron(III) complexes

A series of catecholatoiron(III) complexes, [Fe(III)L(4Cl-cat)]BPh4 (L = (4-MeO)2TPA (1), TPA (2), (4-Cl)2TPA (3), (4-NO2)TPA (4), (4-NO2)2TPA (5); TPA = tris(pyridin-2-ylmethyl)amine; 4Cl-cat = 4-chlorocatecholate), have been characterized by magnetic susceptibility measurements and EPR, 1H NMR, and UV-vis-NIR spectroscopies to clarify the correlation of the spin delocalization on the catecholate ligand with the O2 reactivity as well as the spin-state dependence of the O2 reactivity. EPR spectra in frozen CH3CN at 123 K clearly showed that introduction of electron-withdrawing groups effectively shifts the spin equilibrium from a high-spin to a low-spin state. The effective magnetic moments determined by the Evans method in a CH3CN solution showed that 5 contains 36% of low-spin species at 243 K, while 1-4 are predominantly in a high-spin state. Evaluation of spin delocalization on the 4Cl-cat ligand by paramagnetic 1H NMR shifts revealed that the semiquinonatoiron(II) character is more significant in the low-spin species than in the high-spin species. The logarithm of the reaction rate constant is linearly correlated with the energy gap between the catecholatoiron(III) and semiquinonatoiron(II) states for the high-spin complexes 1-3, although complexes 4 and 5 deviate negatively from linearity. The lower reactivity of the low-spin complex, despite its higher spin density on the catecholate ligand compared with the high-spin analogues, suggests the involvement of the iron(III) center, rather than the catecholate ligand, in the reaction with O2.     

Design, synthesis and antiinflammatory activity of a new indomethacin ester. 2-[N-[3-(3-(piperidinomethyl)phenoxy)propyl]carbamoylmethylthio]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole-3-acetate

A novel indomethacin ester prodrug, 2-[N-[3-(3-(piperidinomethyl)phenoxy)propyl]carbamoylmethylthio ]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (1) was prepared from a new histamine H2-receptor antagonist, N-[3-(3-(piperidinomethyl)phenoxy)propyl]-2-(2-hydroxyethylthio )acetamide (2) and indomethacin (3). The compound 1 was shown to be essentially similar to 3 in its antiinflammatory action and to almost completely inhibit carrageenin-induced hind-paw edema in the rat at a very high dose of 230 mg/kg (280 mumol/kg), which is comparable to that of 100 mg/kg (280 mumol/kg) of 3, without producing gastric lesions. On a molar basis, the acute gastric lesioning properties of 1 were near one-hundred times less than those of 3, resulting in over a twenty-fold improvement in the ratio of antiedema activity to ulcerogenicity. The effect of the co-administration of histamine H2-receptor antagonists on antiedema activity and ulcerogenicity caused by 3 is also discussed.     

Synthesis, Reactivity, and Spectroscopic Properties of meso-Triaryl-5-oxaporphyrins

[meso-Triaryl-21,23-didehydro-23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) was prepared by the reaction of meso-triarylbilindione with acetic anhydride and zinc acetate, and it was isolated as a trifluoroacetate salt. The X-ray crystallographic study demonstrated that the trifluoroacetate anion was coordinated to the zinc ion. [21,23-Didehydro-10,15,20-tris(4-methoxycarbonylphenyl)-23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) 3a was dissolved in various organic solvents such as toluene, chloroform, diethyl ether, ethyl acetate, acetone, acetonitrile, methanol, DMSO, and DMF, although it readily reacted with alcohols and DMF to yield linear tetrapyrroles. The solubility of 3a in toluene was 4.2 ± 0.1 g dm(-3) at room temperature. 3a showed characteristic UV-vis absorption at 649 nm and fluorescence emission at 657 nm in chloroform. The fluorescence quantum yields of 3a, [21,23-didehydro-10,15,20-triphenyl-23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) (3c), and [21,23-didehydro-10,15,20-tris(4-methoxyphenyl)-23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) (3b) were 0.071, 0.071, and 0.050, respectively. Reaction of 3a with EtOH afforded the zinc complex of 19-ethoxybilinone, and it proceeded 2 orders of magnitude faster than that of [β-octaalkyl-21,23-didehydro-23H-5-oxaporphyrinato]zinc(II). The reaction with alcohols was sensitive to steric bulk of the alcohols; the rate of reaction with i-PrOH was 2700 times faster than that of t-BuOH at 303 K. The reaction of [meso-triaryl-21,23-didehydro-23H-5-oxaporphyrinato]zinc(II) with water proceeded 3 orders of magnitude slower than that with EtOH.     

Structure–activity relationship of dihydroimidazo-, dihydropyrimido,tetrahydrodiazepino-[2,1-b]-thiazoles,and -benzothiazoles as an acylation catalyst

Cyclic isothioureas 1, 2, 3, and 4 were synthesized through a four-step procedure from the corresponding ortho-bromoanilines 10 via Pd- or Cu-catalyzed cyclization–benzothiazole formation. Nonbenzo analogues 7, 8, and 9 were synthesized by a condensation reaction of cyclic thioureas 15 and α-bromoacetophenones 14. Investigations of the acylation reactions of 1-phenylethanol with acid anhydrides in the presence of these cyclic isothiourea catalysts revealed their structure–activity relationships. Remarkable electronic effects resulting from substituent(s) on a benzo or phenyl moiety and the influence of the size of the annulating ring were observed. Introduction of an electron-donating substituent(s) enhanced the reaction rate. A few substitution effects on chiral catalysts of type 3 and 7 were also studied.