Crystal Structure of HydG from Carboxydothermus hydrogenoformans: A Trifunctional [FeFe]‐Hydrogenase Maturase

The structure of the radical S‐adenosyl‐L ‐methionine (SAM) [FeFe]‐hydrogenase maturase HydG involved in CN^?/CO synthesis is characterized by two internal tunnels connecting its tyrosine‐binding pocket with the external medium and the C‐terminal Fe₄S₄ cluster‐containing region. A comparison with a tryptophan‐bound NosL structure suggests that substrate binding causes the closing of the first tunnel and, along with mutagenesis studies, that tyrosine binds to HydG with its amino group well positioned for H‐abstraction by SAM. In this orientation the dehydroglycine (DHG) fragment caused by tyrosine Cα?Cβ bond scission can readily migrate through the second tunnel towards the C‐terminal domain where both CN^? and CO are synthesized. Our HydG structure appears to be in a relaxed state with its C‐terminal cluster CysX₂CysX₂₂Cys motif exposed to solvent. A rotation of this domain coupled to Fe₄S₄ cluster assembly would bury its putatively reactive unique Fe ion thereby allowing it to interact with DHG.     

(S)‐Selectivity in Phenylacetyl Carbinol Synthesis Using the Wild‐Type Enzyme Acetoin:Dichlorophenolindophenol Oxidoreductase from Bacillus licheniformis

Thiamine diphosphate (ThDP)‐dependent enzymes are well known biocatalysts for the asymmetric synthesis of α‐hydroxy ketones with preferential (R)‐selectivity. Pharmaceutically relevant phenylacetyl carbinol (PAC) has been prepared with absolute (S)‐configuration only on a few occasions using enzyme variants suitably designed through rational site‐directed mutagenesis approaches. Herein, we describe the synthesis of (S)‐phenylacetyl carbinol products with extended reaction scope employing the readily available wild‐type ThDP‐dependent enzyme acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) from Bacillus licheniformis. On a semipreparative scale, cross‐benzoin‐like condensations of methylacetoin (donor) and differently substituted benzaldehydes proceed with almost complete chemoselectivity yielding the target (S)‐1‐hydroxy‐1‐phenylpropan‐2‐one derivatives with high conversion efficiencies (up to 95%) and good enantioselectivities (up to 99%). Ao:DCPIP OR accepts hydroxy‐ and nitrobenzaldehydes and also sterically demanding substrates such as 1‐naphthaldehyde and 4‐(tert‐butyl)benzaldehyde, which are typically poor acceptors in enzymatic transformations. The explorative synthesis of (S)‐phenylpropionyl carbinol mediated by Ao:DCPIP OR via carboligation of benzaldehyde with 3,4‐hexanedione is also reported.

     

Pneumocandin Biosynthesis: Involvement of a trans‐Selective Proline Hydroxylase

Echinocandins are cyclic nonribosomal hexapeptides based mostly on nonproteinogenic amino acids and displaying strong antifungal activity. Despite previous studies on their biosynthesis by fungi, the origin of three amino acids, trans‐4‐ and trans‐3‐hydroxyproline, as well as trans‐3‐hydroxy‐4‐methylproline, is still unknown. Here we describe the identification, overexpression, and characterization of GloF, the first eukaryotic α‐ketoglutarate/Fe^II‐dependent proline hydroxylase from the pneumocandin biosynthesis cluster of the fungus Glarea lozoyensis ATCC 74030. In in vitro transformations with L ‐proline, GloF generates trans‐4‐ and trans‐3‐hydroxyproline simultaneously in a ratio of 8:1; the latter reaction was previously unknown for proline hydroxylase catalysis. trans‐4‐Methyl‐L ‐proline is converted into the corresponding trans‐3‐hydroxyproline. All three hydroxyprolines required for the biosynthesis of the echinocandins pneumocandins A₀ and B₀ in G. lozoyensis are thus provided by GloF. Sequence analyses revealed that GloF is not related to bacterial proline hydroxylases, and none of the putative proteins with high sequence similarity in the databases has been characterized so far.     

Unusual CC Bond Isomerization of an α,β‐Unsaturated γ‐Butyrolactone Catalysed by Flavoproteins from the Old Yellow Enzyme Family

An unexpected, redox‐neutral C?C bond isomerization of a γ‐butyrolactone bearing an exo‐methylene unit to the thermodynamically more favoured endo isomer (k_cat=0.076 s^?1) catalysed by flavoproteins from the Old Yellow Enzyme family was discovered. Theoretical calculations and kinetic data support a mechanism through which the isomerization proceeds through FMN‐mediated hydride addition onto exo‐Cβ, followed by hydride abstraction from endo‐Cβ′, which is in line with the well‐established C?C bond bioreduction of OYEs. This new isomerase activity enriches the catalytic versatility of ene‐reductases.     

Copper‐Catalyzed Asymmetric Allylic Alkylation of Halocrotonates: Efficient Synthesis of Versatile Chiral Multifunctional Building Blocks

The highly enantioselective synthesis of α‐methyl‐substituted esters is reported in up to 90% yield and up to 99% ee using copper‐TaniaPhos as chiral catalyst. The transformation proved scalable to at least 6.6 mmol (1.7 g scale). The products of this transformation have been further elaborated to multifunctional building blocks with a single (branched esters and acids) or multiple stereogenic centers (vicinal dimethyl esters, as well as, hydroxy‐ or iodo‐substituted lactones).     

Enantioselective Phase‐Transfer Catalytic α‐Benzylation and α‐Allylation of α‐tert‐Butoxycarbonyllactones

A new enantioselective α‐benzylation and α‐allylation of α‐tert‐butoxycarbonyllactones was devloped. α‐Benzylation and α‐allylation of α‐tert‐butoxycarbonylbutyrolactone and α‐tert‐butoxycarbonylvalerolactone under phase‐transfer catalytic conditions (50% cesium hydroxide, toluene, −60 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐NAS bromide (1 mol%) afforded the corresponding α‐substituted α‐tert‐butoxycarbonyllactones in very high chemical yields (up to 99%) and optical yields (up to 99% ee). The synthetic potential of this method has been successfully demonstrated by the asymmetric synthesis of unnatural α‐quaternary homoserines, 3‐alkyl‐3‐carboxypyrrolidine and 3‐alkyl‐3‐carboxypiperidine.     

Nitrile as Activating Group in the Asymmetric Bioreduction of β‐Cyanoacrylic Acids Catalyzed by Ene‐Reductases

Asymmetric bioreduction of an (E)‐β‐cyano‐2,4‐dienoic acid derivative by ene‐reductases allowed a shortened access to a precursor of pregabalin [(S)‐3‐(aminomethyl)‐5‐methylhexanoic acid] possessing the desired configuration in up to 94% conversion and >99% ee. Deuterium labelling studies showed that the nitrile moiety was the preferred activating/anchor group in the active site of the enzyme over the carboxylic acid or the corresponding methyl ester.

     

Copper‐Catalyzed Allenylation‐Isomerization Sequence of Penta‐1,4‐diyn‐3‐yl Acetates with P(O)H Compounds: Facile Synthesis of 1‐Phosphonyl 2,4‐Diynes

The copper‐catalyzed reaction of 5‐substituted penta‐1,4‐diyn‐3‐yl acetates with P(O)H compounds to efficiently give a new class of phosphonyl diynes is reported. The reaction may take place through a regioselective nucleophilic attack of phosphorus nucleophiles on Cu‐allenylidene intermediates to form allenyl intermediates followed by a rapid allene‐alkyne isomerization process. The synthetic utility of the obtained products is demonstrated.

     

Highly Enantioselective Co‐Catalytic Direct Aldol Reactions by Combination of Hydrogen‐Bond Donating and Acyclic Amino Acid Catalysts

Highly enantioselective co‐catalytic direct aldol reactions by a combination of simple hydrophobic acyclic amino acid and hydrogen‐bond donating catalysts are presented. The corresponding aldol products are formed in high yields with high regio‐, diastereo‐ (anti or syn) and enantioselectivity (up to 99.5:0.5 er). The catalyst loadings can be decreased to as little as 2 mol%.     

Catalytic Asymmetric Alkynylation and Arylation of Aldehydes by an H8‐Binaphthyl‐Based Amino Alcohol Ligand

A novel chiral H₈‐1,1′‐binaphthyl‐based amino alcohol ligand (1R_a,2S,3R)‐ 2 has been synthesized and applied in the direct nucleophilic addition of organozincs (alkynylzinc and arylzinc prepared in situ) to aldehydes, yielding the corresponding optically active propargylic alcohols and diarylmethanols in high yields and good to excellent enantioselectivities. For the asymmetric arylation reaction, one catalyst (1R_a,2S,3R)‐ 2 can afford both enantiomers of many pharmaceutically interesting diarylmethanols by a proper combination of various arylzinc reagents and aldehydes.     

Catalytic Enantioselective Arylative Dearomatization of 3‐Methyl‐2‐vinylindoles Enabled by Reactivity Switch

The first catalytic asymmetric dearomatization of 3‐methyl‐2‐vinylindoles has been established by using quinone monoimides as suitable electrophiles in the presence of chiral phosphoric acid, which afforded chiral indole derivatives bearing a quaternary stereogenic center in a chemospecific and highly enantioselective fashion (up to 81% yield, >99% ee). The success of this reaction was enabled by the reactivity switch of 3‐methyl‐2‐vinylindoles, which has not been reported before. This reaction also represents the first catalytic asymmetric arylative dearomatization of vinylindoles, which will help confront the challenges in catalytic asymmetric arylative dearomatization and dearomatization of vinylindoles.

     

Catalytic Performance of Nanoscopic,Aluminium Trifluoride‐Based Catalysts in the Synthesis of (all‐rac)‐α‐Tocopherol

A novel nanoscopic, partly hydroxylated aluminium fluoride was prepared in a sol‐gel fluorination synthesis and characterised by IR probe molecules. It was shown that this material has, in contrast to high surface area aluminium fluoride (HS‐AlF₃) which is one of the strongest Lewis acids, a low amount of strong Lewis acid sites combined with weak and medium strength Brønsted sites. Both materials were tested in the synthesis of (all‐rac)‐α‐tocopherol through the condensation of 2,3,6‐trimethylhydroquinone (TMHQ) with isophytol (IP). The activity data indicate the partly hydroxylated aluminium fluoride to be a very efficient and highly selective catalyst for (all‐rac)‐α‐tocopherol (>99.9%, for an IP conversion of 100%) whereas high surface area aluminium fluoride is a poor catalyst for this reaction.     

One‐Step Catalytic Enantioselective α‐Quaternary 5‐Hydroxyproline Synthesis: An Asymmetric Entry to Highly Functionalized α‐Quaternary Proline Derivatives

The highly enantioselective cascade reaction between N‐protected α‐cyanoglycine esters and α,β‐unsaturated aldehydes is disclosed. The reaction represents a one‐step entry to polysubstituted 5‐hydroxyproline derivatives having a quaternary α‐stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two‐step entry to functionalized α‐quaternary proline derivatives.     

Practical Synthesis of Chiral N,N′‐Bis(2′‐pyridinecarboxamide)‐1,2‐cyclohexane Ligands

A simple and scalable procedure for the preparation of chiral ligands 1 and 2 from trans‐1,2‐diaminocyclohexane and 2‐picolinic acid is described.     

Optically Pure 1,2‐Bis[(o‐alkylphenyl)phenylphosphino]ethanes and Their Use in Rhodium‐Catalyzed Asymmetric Hydrogenations of α‐(Acylamino)acrylic Derivatives

Optically pure (S,S)‐1,2‐bis[(o‐alkylphenyl)phenylphosphino]ethanes 1a–d were prepared in four steps from phenyldichlorophosphine via phosphine‐boranes as the intermediates. The rhodium complexes 5a–d of these diphosphines were used for the asymmetric hydrogenations of α‐(acylamino)acrylic derivatives including β‐disubstituted derivatives. Markedly high enantioselectivity (78–>99%) was observed for the reduction of β‐monosubstituted derivatives. β‐Disubstituted derivatives were also reduced in considerably high enantioselectivity (up to 90%). The single crystal X‐ray analysis of the rhodium complex 5c of (S,S)‐1,2‐bis[phenyl(5′,6′,7′,8′‐tetrahydronaphthyl)phosphino]ethane ( 1c) revealed its δ‐type structure with face orientation of the two tetrahydronaphthyl groups and edge orientation of the two phenyl groups. This conformation corresponds to that of the rhodium complex of 1,2‐bis[(o‐methoxyphenyl)phenylphosphino]ethane (DIPAMP); the rhodium complex of (R,R)‐DIPAMP, whose chirality at phosphorus is opposite that of 5c , exhibits a λ‐type structure with the face orientation of the two o‐methoxyphenyl groups and the edge orientation of the two phenyl groups. The conformational similarity of these rhodium complexes as well as the stereochemical outcome in the asymmetric hydrogenations means that the coordinative interaction of the methoxy group of DIPAMP with rhodium metal is not the main factor that affects asymmetric induction.     

Catalytic Asymmetric Epoxidation of 2‐Cyclopentenones

The first highly efficient asymmetric epoxidation of 2‐cyclopentenones has been developed. Using a newly designed and readily available Cinchona amine catalyst, 2‐cyclopentenones are reacted with hydrogen peroxide to give the corresponding epoxycyclopentanones in high yields and excellent enantioselectivities.     

Brønsted Acid‐Catalyzed [3+2] Cyclodimerization of 3‐Alkyl‐ 2‐vinylindoles Leading to the Diastereoselective Construction of a Pyrroloindole Framework

A Brønsted acid‐catalyzed [3+2] cyclodimerization of 3‐alkyl‐2‐vinylindoles has been established, which led to the diastereoselective construction of pyrroloindole frameworks in high yields (up to 98% yield, all >95:5 dr). This reaction not only represents the first application of 3‐alkyl‐2‐vinylindoles as nitrogen‐carbon‐carbon (NCC) building blocks, but also reveals a new [3+2] cyclodimerization of 2‐vinylindoles. Control experiments demonstrated that both the free N H group and the C‐3 alkyl group in the indole moiety play a crucial role in performing the [3+2] cyclodimerization. A preliminary attempt also demonstrated the feasibility of performing heterodimerization.

     

Simple Chiral Diaminobinaphthyl Dilithium Salts for Intramolecular Catalytic Asymmetric Hydroamination of Amino‐1,3‐dienes

Simple and easily accessible chiral lithium amide salts are reported as efficient (pre)catalysts for the diastereo‐ [up to (E:Z)=92:8] and enantioselective [up to 72% ee (E)] hydroamination/cyclisation of conjugated primary aminodienes. These chiral lithium salts are straightforwardly prepared by in situ combination of an N‐substituted (R)‐(+)‐1,1′‐binaphthyl‐2,2′‐diamine ligand and a commercial methyllithium solution. Information on the solid‐state structure of these salts was obtained by X‐ray analysis of a single crystal.     

Catalytic Asymmetric β‐Peroxidation of Nitroalkenes

The first example of an asymmetric β‐peroxidation of nitroalkenes is disclosed. The reaction is promoted by catalytic loadings of a commercially available diaryl‐2‐pyrrolidinemethanol derivative and tert‐butyl hydroperoxide as the oxidant. A synthetically useful class of peroxides is obtained in good yield and enantioselectivity (up to 84% ee).     

Redesign of the Phosphate Binding Site of L‐Rhamnulose‐ 1‐Phosphate Aldolase towards a Dihydroxyacetone Dependent Aldolase

The aldol addition of unphosphorylated dihydroxyacetone (DHA) to aldehydes catalyzed by L ‐rhamnulose‐1‐phosphate aldolase (RhuA), a dihydroxyacetone phosphate‐dependent aldolase, is reported. Moreover, a single point mutation in the phosphate binding site of the RhuA wild type, that is, substitution of aspartate for asparagine at position N29, increased by 3‐fold the of aldol addition reactions of DHA to other aldehyde acceptors rather than the natural L ‐lactaldehyde. The RhuA N29D mutant modified the optimum enzyme design for the natural substrate and changed its catalytic properties making the aldolase more versatile to other aldol additions of DHA.