Development of a novel chemoenzymatic route to enantiomerically enriched ß-adrenolytic agents. A case study toward propranolol, alprenolol, pindolol, carazolol, moprolol, and metoprolol.

Efficient chemoenzymatic routes toward the synthesis of both enantiomers of adrenergic ß-blockers were accomplished by identifying a central chiral building block, which was first prepared using lipase-catalyzed kinetic resolution (KR, Amano PS-IM) as the asymmetric step at a five gram-scale (209 mM conc.). The enantiopure (R)-chlorohydrin (>99% ee) subsequently obtained was used for the synthesis of a series of model (R)-(+)-ß-blockers (i.e., propranolol, alprenolol, pindolol, carazolol, moprolol, and metoprolol), which were produced with enantiomeric excess in the range of 96-99.9%. The pharmaceutically relevant (S)-counterpart, taking propranolol as a model, was synthesized in excellent enantiomeric purity (99% ee) via acetolysis of the respective enantiomerically pure (R)-mesylate by using cesium acetate and a catalytic amount of 18-Crown-6, followed by acidic hydrolysis of the formed (S)-acetate. Alternatively, asymmetric reduction of a prochiral ketone, namely 2-(3-chloro-2-oxopropyl)-1H-isoindole-1,3(2H)-dione, was performed using lyophilized E. coli cells harboring overexpressed recombinant alcohol dehydrogenase from Lactobacillus kefir (E. coli/Lk-ADH-Lica) giving the corresponding chlorohydrin with >99% ee. Setting the stereocenter early in the synthesis and performing a 4-step reaction sequence in a 'one-pot two-step' procedure allowed the design of a 'step-economic' route with a potential dramatic improvement in process efficiency. The synthetic method can serve for the preparation of a broad scope of enantiomerically enriched ß-blockers, the chemical structures of which rely on the common α-hydroxy-N-isopropylamine moiety, and in this sense, might be industrially attractive.

Heavy-Atom Free spiro Organoboron Complexes As Triplet Excited States Photosensitizers for Singlet Oxygen Activation.

Herein, we present a new strategy for the development of efficient heavy-atom free singlet oxygen photosensitizers based on rigid borafluorene scaffolds. Physicochemical properties of borafluorene complexes can be easily tuned through the choice of ligand, thus allowing exploration of numerous organoboron structures as potent 1O2 sensitizers. The singlet oxygen generation quantum yields of studied complexes vary in the range of 0.55-0.78. Theoretical calculations reveal that the introduction of the borafluorene moiety is crucial for the stabilization of a singlet charge transfer state, while intersystem crossing to a local triplet state is facilitated by orthogonal donor-acceptor molecular architecture. Our study shows that quantitative oxidation of selected organic substrates can be achieved in 20-120 min of irradiation with only 0.05 mol % loading of a photocatalyst.