Advanced Synthesis & Catalysis

A mild photocatalyzed approach to achieve the α-alkylation of esters via formation of an α -radical is disclosed here. Cesium enolates of esters were generated in situ using Cs2 CO3 as a base. A subsequent photocatalyzed oxidation at the α-carbon of these enolates produced an α-radical that was added into activated alkenes. This is the first example accessing the α-carbon radical of esters in photoredox catalyed transformations.

The electron donor-acceptor complex-enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α-alkylated aldehydes without an external photoredox catalyst. The photosensitizer-free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales. Inspired by these limitations, a protocol was developed for the enantioselective α-alkylation of aldehydes based on the synergistic combination of visible light-driven asymmetric organocatalysis and a controlled continuous flow reaction environment...

Although optical pure amino alcohols are in high demand due to their widespread applicability, they still remain challenging to synthesize, since commonly elaborated protection strategies are required. Here, a multi-enzymatic methodology is presented that circumvents this obstacle furnishing enantioenriched 1,3-amino alcohols out of commodity chemicals. A Type I aldolase forged the carbon backbone with an enantioenriched aldol motif, which was subsequently subjected to enzymatic transamination. A panel of 194 TAs was tested on diverse nine aldol products prepared through different nucleophiles and electrophiles...

Various widely applied compounds contain cyano-groups, and this functional group serves as a chemical handle for a whole range of different reactions. We report a cyanide free chemoenzymatic cascade for nitrile synthesis. The reaction pathway starts with a reduction of carboxylic acid to aldehyde by carboxylate reductase enzymes (CARs) applied as living cell biocatalysts. The second - chemical - step includes in situ oxime formation with hydroxylamine. The final direct step from oxime to nitrile is catalyzed by aldoxime dehydratases (Oxds)...

Saturated N-heterocycles are prominent motifs found in various natural products and pharmaceuticals. Despite the increasing interest in this class of compounds, the synthesis of saturated bicyclic azacycles requires tedious multi-step syntheses. Herein, we present a one-pot protocol for the synthesis of octahydroindoles, decahydroquinolines, and octahydroindolizines through a cascade reaction.

N -heterocyclic carbenes (NHCs) have emerged as catalysts for the construction of C-C bonds in the synthesis of substituted ketones under single-electron processes. Despite these recent reports, there still remains a need to increase the utility and practicality of these reactions by exploring new radical coupling partners. Herein, we report the synthesis of γ-aryloxyketones via combined NHC/photoredox catalysis. In this reaction, an α-aryloxymethyl radical is generated via oxidation of an aryloxymethyl potassium trifluoroborate salt, which is then added into styrene derivatives to provide a stabilized benzylic radical...

A methodology is reported for visible-light-promoted synthesis of unsymmetrical chalcogenides enabled by dimsyl anion in the absence of transition-metals or photoredox catalysts. The cross-coupling reaction between aryl halides and diaryl dichalcogenides proceeds with electron-rich, electron-poor, and heteroaromatic moieties. Mechanistic investigations using UV-Vis spectroscopy, time-dependent density functional theory (TD-DFT) calculations, and control reactions suggest that dimsyl anion forms an electron-donor-acceptor (EDA) complex capable of absorbing blue light, leading to a charge transfer responsible for generation of aryl radicals from aryl halides...

Several manganese-PNP pincer catalysts for the formal hydroamination of allylic alcohols are presented. The resulting γ-amino alcohols are selectively obtained in high yields applying Mn-1 in a tandem process under mild conditions.

Phenanthroline, a rigid and planar compound with two fused pyridine rings, has been used as a powerful ligand for metals and a binding agent for DNA/RNA. We discovered that phenanthroline could be used as a nucleophilic catalyst to efficiently access high yielding and diastereoselective α-1,2- cis glycosides through the coupling of hydroxyl acceptors with α-glycosyl bromide donors. We have conducted an extensive investigation into the reaction mechanism, wherein the two glycosyl phenanthrolinium ion intermediates, a 4 C1 chair-liked β-conformer and a B2,5 boat-like α-conformer, have been detected in a ratio of 2:1 (β:α) using variable temperature NMR experiments...

The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel-Crafts-type 1,4-addition using a Jørgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used to generate both 'normal' and 'abnormal' cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity...

A catalyst- and additive-free decarbonylative trifluoromethylthiolation of aldehyde feedstocks has been developed. This operationally simple, scalable, and open-to-air transformation is driven by the selective photoexcitation of electron donor-acceptor (EDA) complexes, stemming from the association of 1,4-dihydropyridines (donor) with N -(trifluoromethylthio)phthalimide (acceptor), to trigger intermolecular single-electron transfer events under ambient- and visible light-promoted conditions. Extension to other electron acceptors enables the synthesis of thiocyanates and thioesters, as well as the difunctionalization of [1...

The substrate scope of the asymmetric allylation with zinc organyls catalyzed by 3,3-bis(2,4,6-triisopropylphenyl)-1,1-binaphthyl-2,2-diyl hydrogenphosphate (TRIP) has been extended to non-cyclic ester organozinc reagents and ketones. Tertiary chiral alcohols are obtained with ee's up to 94% and two stereogenic centers can be created. Compared to the previous lactone reagent the stereopreference switches almost completely, proving the fact that the nature of the organometallic compound is of immense importance for the asymmetry of the product...

Enzyme discovery for use in the manufacture of chemicals, requiring high stereoselectivities, continues to be an important avenue of research. Here, a sequence directed metagenomics approach is described to identify short chain carbonyl reductases. PCR from a metagenomic template generated 37 enzymes, with an average 25% sequence identity, twelve of which showed interesting activities in initial screens. Six of the most productive enzymes were then tested against a panel of 21 substrates, including bulkier substrates that have been noted as challenging in biocatalytic reductions...

A two-enzyme cascade reaction plus in situ oxidative decarboxylation for the transformation of readily available canonical and non-canonical L-α-amino acids into 2-substituted 3-hydroxy-carboxylic acid derivatives is described. The biocatalytic cascade consisted of an oxidative deamination of L-α-amino acids by an L-α-amino acid deaminase from Cosenzaea myxofaciens , rendering 2-oxoacid intermediates, with an ensuing aldol addition reaction to formaldehyde, catalyzed by metal-dependent ( R )- or ( S )-selective carboligases namely 2-oxo-3-deoxy-l-rhamnonate aldolase (YfaU) and ketopantoate hydroxymethyltransferase (KPHMT), respectively, furnishing 3-substituted 4-hydroxy-2-oxoacids...

Among aromatic compounds, borazarenes represent a significant class of isosteres in which carbon-carbon bonds have been replaced by B-N bonds. Described herein is a summary of the selective reactions that have been developed for known systems, as well as a summary of computationally-based predictions of selectivities that might be anticipated in reactions of yet unrealized substructures.

Regioselective cobalt-catalyzed [2+2+2] cycloaddition using fluorine-containing diynes with nitriles was described. Cycloaddition of fluorinated diynes with nitriles under the influence of CoCl2 (phen), zinc bromide, and zinc dust in dichloroethane at 80°C for 3 h took place smoothly, exclusively affording the corresponding α -fluoroalkylated pyridines in excellent yields. In addition, dinitriles as substrate were also found to be suitable for this reaction, giving the corresponding fluoroalkylated bipyridine derivatives in excellent yields...

We herein report the ammonium salt-catalyzed synthesis of chiral 3,3-disubstituted isoindolinones bearing a heteroatom functionality in the 3-position. A broad variety of differently substituted CF3 S- and RS-derivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proof-of-concept for the racemic synthesis of the analogous F-containing products was obtained as well, giving access to one of the rare examples of a fairly stable α-F-α-amino acid derivative...

Chiral 2-alkylquinazolinones are key synthetic intermediates, but their preparation in high optical purity is challenging. Thus, a multicomponent procedure integrating anthranilic acids, N -Boc-amino acids, and amines in the presence of methanesulfonyl chloride, N -methylimidazole, and copper(II) chloride was developed to mildly afford N -Boc-2-alkylaminoquinazolin-4(3 H )-ones with excellent preservation of enantiomeric purity (>99% ee). Copper(II) chloride was essential to retaining enantiopurity, and reaction component structural changes were well tolerated, resulting in an efficient, all-in-one procedure that promotes sequential coupling, lactonization, aminolysis, and cyclization in good yields...

Transition metal-catalyzed reactions in aqueous media are experiencing a constant increase in interest. In homogenous catalysis the use of water as a solvent offers advantages in cost, safety, the possibility of two-phase catalysis and simplified separation strategies. In the life sciences, transition metal catalysis in aqueous systems enables the ligation or modification of biopolymers in buffer systems or even in their cellular environment. In biocatalysis, aqueous systems allow the simultaneous use of enzymes and transition metal catalysts in cascade reactions...

Palladium(II) precatalysts are used extensively to facilitate cross-coupling reactions because they are bench stable and give high activity. As a result, precatalysts such as Buchwald's palladacycles, Organ's PEPPSI species, Nolan's allyl-based complexes, and Yale's 1- tert -butylindenyl containing complexes, are all commercially available. Comparing the performance of the different classes of precatalysts is challenging because they are typically used under different conditions, in part because they are reduced to the active species via different pathways...