Alcohol Dehydrogenase Triggered Oxa‐Michael Reaction for the Asymmetric Synthesis of Disubstituted Tetrahydropyrans and Tetrahydrofurans

An alcohol dehydrogenase‐mediated asymmetric reduction and subsequent intramolecular oxa‐Michael reaction has been developed for the preparation of tetrahydropyrans (or oxanes) and tetrahydrofurans, in excellent conversion, yield and high enantiomeric and diastereomeric excess. To highlight the utility of the methodology, we report the synthesis of an analogue of the fungal antioxidant brocaketone A. Also described is the preparation of the (‐)‐(R,R)‐enantiomer of the natural product, (+)‐(S,S)‐(cis‐6‐methyltetrahydropyran‐2‐yl)acetic acid

Transaminase triggered aza-Michael approach for the enantioselective synthesis of piperidine scaffolds

The expanding “toolbox” of biocatalysts opens new opportunities to redesign synthetic strategies to target molecules by incorporating a key enzymatic step into the synthesis. Herein, we describe a general biocatalytic approach for the enantioselective preparation of 2,6-disubstituted piperidines starting from easily accessible pro-chiral ketoenones. The strategy represents a new biocatalytic disconnection, which relies on an ω-TA-mediated aza-Michael reaction. Significantly, we show that the reversible enzymatic process can power the shuttling of amine functionality across a molecular framework, providing access to the desired aza-Michael products

Asymmetric Construction of Alkaloids Employing a Key ω-Transaminase Cascade

An ω‐transaminase triggered intramolecular aza‐Michael reaction has been employed for the preparation of cyclic β‐enaminones in good yield and excellent enantio‐ and diastereoselectivity, starting from easily accessible prochiral ketoynones and commercially available enzymes. The powerful thermodynamic driving force associated with the spontaneous aza‐Michael reaction effectively displaces the transaminase reaction equilibrium towards product formation, using only two equivalents of isopropylamine. To demonstrate the potential of this methodology, we have combined this biocatalytic aza‐Michael step with annulation chemistry, affording unique stereo‐defined fused alkaloid architectures

mCRP-Induced Focal Adhesion Kinase-Dependent Monocyte Aggregation and M1 Polarization, which was partially blocked by the C10M Inhibitor

Monomeric C-reactive protein (mCRP) has recently been implicated in the abnormal vascular activation associated with development of atherosclerosis, but it may act more specifically through mechanisms perpetuating damaged vessel inflammation and subsequent aggregation and internalization of resident macrophages. Whilst the direct effects of mCRP on endothelial cells have been characterized, the interaction with blood monocytes has, to our knowledge, not been fully defined. Here we showed that mCRP caused a strong aggregation of both U937 cell line and primary peripheral blood monocytes (PBMs) obtained from healthy donors. Moreover, this increase in clustering was dependent on focal adhesion kinase (FAK) activation (blocked by a specific inhibitor), as was the concomitant adhesive attachment to the plate, which was suggestive of macrophage differentiation. Confocal microscopy confirmed the increased expression and nuclear localization of p-FAK, and cell surface marker expression associated with M1 macrophage polarization (CD11b, CD14, and CD80, as well as iNOS) in the presence of mCRP. Inclusion of a specific CRP dissociation/mCRP inhibitor (C10M) effectively inhibited PBMs clustering, as well as abrogating p-FAK expression, and partially reduced the expression of markers associated with M1 macrophage differentiation. mCRP also increased the secretion of pro-inflammatory cytokines Interleukin-8 (IL-8) and Interleukin-1β (IL-1β), without notably affecting MAP kinase signaling pathways; inclusion of C10M did not perturb or modify these effects. In conclusion, mCRP modulates PBMs through a mechanism that involves FAK and results in cell clustering and adhesion concomitant with changes consistent with M1 phenotypical polarization. C10M has potential therapeutic utility in blocking the primary interaction of mCRP with the cells—for example, by protecting against monocyte accumulation and residence at damaged vessels that may be predisposed to plaque development and atherosclerosis

Stereoselective synthesis of 1,3-disubstituted dihydroisoquinolines vial-phenylalanine-derived dihydroisoquinoline N-oxides.

The preparation of chiral pool-derived nitrone 3 and its use in the protecting-group free, stereoselective synthesis of a range of 1,3-disubstituted tetrahydroisoquinolines is described. Grignard reagent additions to nitrone 3 yielded trans-1,3-disubstituted N-hydroxytetrahydroisoquinolines 6 with good levels of selectivity, while 1,3-dipolar cycloadditions to this nitrone provided access to 3-(2-hydroxyalkyl)isoquinolines 12 as single diastereomers

Pyridine-3-carboxaldehyde O-methyloxime

The general part of the experimental section [1] has been presented elsewhere. Methoxylamine hydrochloride (858 mg, 10.3 mmol) and potassium carbonate (2.58 g, 18.7 mmol) were added to a solution of pyridine-3-carboxaldehyde (1 g, 9.34 mmol) in ethanol (15 mL) under nitrogen at room temperature and the mixture was stirred for 2 h [2]. Water (20 mL) and dichloromethane (20 mL) were then added and the organic and aqueous phases separated. The aqueous phase was extracted with dichloromethane (3 x 15 mL) and the organic extracts were combined. The organic extract was dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography using ethyl acetate a

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10.8 mmol) was added to a solution of propargyl alcohol 1 (0.35 mL, 4.9 mmol) in THF (10 mL) under nitrogen at 20°C and the mixture stirred for 10 min. The reaction was then cooled to-78°C and a solution of pyridine-3-carboxaldehyde 2 (500 mg, 4.9 mmol) in THF (1 mL) was added dropwise. The resultant mixture was stirred for 1 h at-78°C, warmed to 0°C then stirred for 1 h. Saturated aqueous ammonium chloride (15 mL) was added and then the mixture was warmed to room temperature. The orange-yellow solution was extracted with diethyl ether (3 x 20 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford a yellow oil. Further purification by flash chromatography using ethy