Synthesis of Valuable Chiral Intermediates by Isolated Ketoreductases: Application in the Synthesis of α‐Alkyl‐β‐hydroxy Ketones and 1,3‐Diols

Regio‐ and stereoselective reductions of α‐substituted 1,3‐diketones to the corresponding β‐keto alcohols or 1,3‐diols by using commercially available ketoreductases (KREDs) are described. A number of α‐monoalkyl‐ or dialkyl‐substituted symmetrical as well as non‐symmetrical diketones were reduced in high optical purities and chemical yields, in one or two enzymatic reduction steps. In most cases, two or even three out of the four possible diastereomers of α‐alkyl‐β‐keto alcohols were synthesized by using different enzymes, and in two examples both ketones were reduced to the 1,3‐diol. By replacing the α‐alkyl substituent with the OAc group, 1‐keto‐2,3‐diols, as well as 1,2,3‐triols were synthesized in high optical purities. These enzymatic reactions provide a simple, highly stereoselective and quantitative method for the synthesis of different diastereomers of valuable chiral synthons from non‐chiral, easily accessible 1,3‐diketones.     

Cyclohexa‐3,5‐diene‐1,2‐trans‐diols – Synthesis and Application in Target‐Oriented Syntheses

An exhaustive overview of the field of cyclohexa‐3,5‐diene‐1,2‐trans‐diols is given. Early and recent methods for the formation of the compounds are reviewed and the various syntheses in which the title compounds have been applied are presented. Special emphasis is given to naturally occurring epoxides, which have been the dominant target molecules since the 1970s. Finally, recent advances in biotechnology are highlighted; with the increased availability of the enantiomerically pure cyclohexa‐3,5‐diene‐1,2‐trans‐diols, new synthetic endeavours were initiated.     

Preparation of cis‐1,4‐Polyisoprene Electrospun Microfibers

cis‐1,4‐Polyisoprene, a significant industrial elastomer, is electrospun into different nanostrucutures. Cis‐1,4‐polyisoprene electrospun fibers are prepared from cis‐1,4‐polyisoprene solutions in dichloromethane or chloroform and characterized by environmental scanning electron microscope and Fourier‐transform infrared spectroscopy. ESEM observation reveals that the cis‐1,4‐polyisoprene fibers show a bamboo‐like morphology with a nearly constant node distance, a diameter of 20–60 µm and a length of about 300 µm. In addition, within the individual nodes parallel grooves are clearly seen, which is very promising for their use in microprinting in the field of microelectronics. Smooth cis‐1,4‐polyisoprene fibers with a diameter of 5–8 µm can be obtained via electrospinning its chloroform solutions. In contrast to most polymers, the jet of cis‐1,4‐polyisoprene does not split during the electrospinning processes, which facilitates the collection of highly aligned fibers by using a rotating mandrel as a ground target.

     

Highly Selective Synthetic Method for 1,6‐Diols Bearing Enyne Functions: Development of 3,6‐Dianion Reagent of 1,2‐Hexadien‐4‐yne Using 1,6‐Dibromo‐2,4‐hexadiyne and Indium

The reaction of aldehydes and ketones with an organoindium reagent generated in situ from indium and 1,6‐dibromo‐2,4‐hexadiyne in the presence of lithium iodide in tetrahydrofuran (THF) selectively produced 1,6‐diols linked to an allenyne unit with complete regioselectivity and chemoselectivity through 1,2‐hexadien‐4‐yn‐3,6‐ylation, indicating that the organoindium acted as the 3,6‐dianion reagent of 1,2‐hexadien‐4‐yne.     

Boronic Acid‐Catalyzed Selective Oxidation of 1,2‐Diols to α‐Hydroxy Ketones in Water

The activation of 1,2‐diols through formation of boronate esters was found to enhance the selective oxidation of 1,2‐diols to their corresponding α‐hydroxy ketones in aqueous medium. The oxidation step was accomplished using dibromoisocyanuric acid (DBI) as a terminal chemical oxidant or an electrochemical process. The electrochemical process was based on the use of platinum electrodes, methylboronic acid [MeB(OH)₂] as a catalyst and bromide ion as a mediator. Electro‐generated OH⁻ ions (EGB) at the cathode acted as a base and “Br⁺” ion generated at the anode acted as an oxidant. Various cyclic and acyclic 1,2‐diols as substrates were selectively oxidized to the corresponding α‐hydroxy ketones via their boronate esters by the two oxidative methods in good to excellent yields.

     

Regioselective Addition of Organometallic Reagents to 2‐(1‐Alkynyl)‐2‐alken‐1‐ones for an Efficient Synthesis of Substituted 1,2‐Allenyl Ketones

Highly substituted 1,2‐allenyl ketones can be easily and efficiently prepared from organometallic reagents and readily available 2‐(1‐alkynyl)‐2‐alken‐1‐ones. The synthetic application of 1,2‐allenyl ketone products was also showcased by palladium‐catalyzed further transformation.     

Efficient Synthesis of Chiral Isoquinoline and Pyrido[1,2‐b]‐isoquinoline Derivatives via Intramolecular Heck Reactions

The palladium(0)‐catalyzed reaction of derivatives of γ‐amino‐α,β‐unsaturated esters bearing an N‐(2‐iodobenzoyl) substituent results in an intramolecular Heck reaction, the outcome of which depends on the structure of the substrate as well as on the experimental conditions. The methodology developed has been applied to the efficient syntheses of chiral isoquinoline and pyrido[1,2‐b]–isoquinoline derivatives.     

Facile Synthesis of Enantiopure 4‐Substituted 2‐Hydroxy‐4‐ butyrolactones using a Robust Fusarium Lactonase

A facile chemo‐enzymatic process has been developed for producing stereoisomers of 4‐substituted 2‐hydroxy‐4‐butyrolactones with good to excellent enantioselectivity. This process involves an easy separation of the diastereoisomers by column chromatography and efficient enzymatic resolution by whole cells of Escherichia coli JM109 expressing Fusarium proliferatum lactonase gene. This biocatalyst shows strong tolerance towards different substrate structures and at least three out four possible isomers could be obtained in excellent enantiomeric purity. Different substrate concentrations (10 mM–200 mM) were examined, giving a substrate to catalyst ratio of up to 26:1. This general and efficient enzymatic process provides access to stereoisomers of 4‐substituted 2‐hydroxy‐4‐butyrolactones readily and cost‐effectively. The stereochemical assignments were conducted systematically based on NMR, X‐ray diffraction and circular dichroism, leading to further understanding of the enzyme’s stereoselectivity.     

Stereoselective Synthesis of 3‐Hydroxy‐4‐arylcyclopentanones and 4‐Arylcyclopentenones through a Heck–Matsuda Desymmetrization of meso cis‐4‐Cyclopentene‐1,3‐diol

A new palladium‐catalyzed route to 3‐hydroxy‐4‐arylcyclopentanones and 4‐arylcyclopentenones in a diastereo‐ and enantioselective manner by a Heck–Matsuda desymmetrization was achieved from the commercially available meso cis‐4‐cyclopentene‐1,3‐diol. This method is highly practical, mild, high yielding and is carried out under “open vessel” conditions. Protected and unprotected substrates provide distinct products bearing considerable value as synthetic scaffolds for the synthesis of natural and unnatural bioactive compounds containing a five‐membered ring.

     

Gold‐Catalyzed Redox Synthesis of Imidazo[1,2‐a]pyridines using Pyridine N‐Oxide and Alkynes

A mild, catalytic, atom economical synthesis of imidazo[1,2‐a]pyridines has been developed: catalytic dichloro(2‐pyridinecarboxylato)gold [PicAuCl₂] in the presence of an acid produces a range of imidazo[1,2‐a]pyridines in good yields starting from alkynes and 2‐aminopyridine N‐oxides. This strategy is mild and foreseen to be of particular use for the installation of stereogenic centers adjacent to the imidazo[1,2‐a]pyridine ring without loss of enantiomeric excess.

     

Synthesis of Fully Substituted 3‐Formyl‐4‐iodofurans via a Gold(I)‐Catalyzed Oxidation/1,2‐Alkynyl Migration/Cyclization/Iodination Cascade

A highly efficient gold(I)‐catalyzed cascade reaction for the synthesis of fully substituted 3‐formyl‐4‐iodofurans has been developed. Mechanistic investigations indicate a reaction pathway that involves a direct iodination reaction of the organogold intermediate via functionalization of the Au C(sp²) bond, instead of a direct iodination of the 3‐formylfurans.

     

New Trifluoromethyl Substituted 1,2, 3‐Triazoles Linked to D‐Galactose and D‐Gulose

The title compounds were synthesized by 1,3‐dipolar cycloaddition of 3,3,3‐trifluoropropinyl benzene ( 2 ) to the azido sugars 2,3,4,6‐tetra‐O‐acetyl‐β‐D ‐galactopyranosyl azide ( 1 ), 6‐O‐acetyl‐4‐O‐cyclohexylcarbamoyl‐2,3‐O‐(2,2,2‐trichloroethylidene)‐β‐D ‐gulopyranosyl azide ( 6 ), 6‐azido‐6‐deoxy‐1,2:3,4‐di‐O‐isopropylidene‐α‐D ‐galactopyranose ( 12 ), and methyl 6‐azido‐4‐O‐cyclohexylcarbamoyl‐6‐deoxy‐2,3‐O‐(2,2,2‐trichloroethylidene)‐β‐D ‐gulopyranoside ( 16 ), respectively. Because of the dissymmetry of the dipolarophile 2 , always two regioisomeric products were obtained, the nucleoside‐analogous compounds 3/4 (from 1 ) and 7/8 (from 6 ), respectively, and the reversed nucleosides 13/14 (from 12 ) and 17/18 (from 16 ), respectively. Protecting group chemistry like transesterification, deacetalation, hydrodechlorination is demonstrated in some cases. Thus, the trichloroethylidene derivatives 7, 8, 17, and 18 were converted into the corresponding ethylidene derivatives ( 9, 10, 19, 20 ) by treatment with tributylstannane/AIBN. An X‐ray analysis is given for the 1‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D ‐galactopyranosyl)‐4‐trifluoromethyl‐5‐phenyl‐1,2,3‐triazole ( 4 ) and for the 1‐[6‐O‐acetyl‐4‐O‐cyclohexylcarbamoyl‐2,3‐O‐(2,2,2‐trichloroethylidene)‐β‐D ‐gulopyranosyl]‐4‐trifluoromethyl‐5‐phenyl‐1,2,3‐triazole ( 7 ).     

Regioselective Copper‐Catalyzed Oxidative Cross‐Coupling of Imidazo[1,2‐a]pyridines with Methyl Ketones: An Efficient Route for Synthesis of 1,2‐Diketones

An efficient copper‐catalyzed oxidative coupling of imidazo[1,2‐a]pyridines with methyl ketones to directly generate structurally sophisticated 1,2‐dicarbonyl imidazo[1,2‐a]pyridine derivatives under oxidative conditions is described. The reaction proceeds in good yields using the environmental friendly molecular oxygen as the oxidant. ¹⁸O‐Labelling experiments unambiguously established that the oxygen of the dicarbonyl products originated from oxygen rather than from water.

     

Preparation and swelling properties of solution crosslinked poly(cis‐1,4‐butadiene) gels

Poly(cis‐1,4‐butadiene) (PCB) gels were prepared by the crosslinking polymerization of 4‐tert‐butylstyrene (tBS) and divinylbenzene (DVB) onto unvulcanized butadiene rubber with a solution polymerization technique with benzoyl peroxide (BPO) as an initiator. The effects of the reaction conditions, such as the amount of the solvent, the amount of DVB and tBS, and the initiator (BPO), on the equilibrium swelling ratio (Q_e) were also investigated. The highest oil absorbencies of crosslinked gels in xylene and cyclohexane were 51.35 and 32.98 g/g, respectively. A swelling kinetic equation was proposed for this system: Q_t = Q_e ? {Kt + [1/(Q_e ? Q₀)]}^?1, where Q_t is the swelling ratio at time t, Q₀ is the initial swelling ratio, and K is the swelling kinetic constant. This equation fit the experimental results quite well. The diffusion of organic solvents in PCB gels was Fickian. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 2241–2245, 2003     

Desymmetrisations of 1‐Alkylbicyclo[3.3.0]octane‐2,8‐diones by Enzymatic Retro‐Claisen Reaction Yield Optically Enriched 2,3‐Substituted Cyclopentanones

A series of 1‐alkylbicyclo[3.3.0]octane‐2,8‐diones was transformed by enzymatic retro‐Claisen reaction using recombinant 6‐oxocamphor hydrolase (OCH) overexpressed in Escherichia coli, to yield optically active 2,3‐substituted cyclopentanones with enantiomeric excesses of up to >95 %. Whilst the parent substrate, bicyclo[3.3.0]octane‐2,8‐dione 12 , was transformed only very slowly, derivatives 13, 14, 15, 16 and 30 with alkyl chains of varying length in the 1‐position were converted rapidly to optically active products with typically 82 % de and up to >95 % enantiomeric excess. The results confirm the apparent requirement of OCH for non‐enolisable diketone substrates, and offer a potential route to decorated cyclopentanone derivatives of multiple chiral centres. Computer modelling of 1‐methylbicyclo[3.3.0]octane‐2,8‐dione into the active site of OCH suggested that the bicyclic [3.3.0] series substrates were accommodated in the active site in similar orientation with the natural enzyme substrate, 6‐oxocamphor, and would thus yield the (2S,3S)‐product series.     

Diversity‐Oriented Synthesis of Functionalized 1‐Aminopyrroles by Regioselective Zinc Chloride‐Catalyzed,One‐Pot ‘Conjugate Addition/Cyclization’ Reactions of 1,3‐Bis(silyl enol ethers) with 1,2‐Diaza‐1,3‐butadienes

In a convenient one‐pot process, the easily accessible 1,2‐diaza‐1,3‐butadienes and 1,3‐bis(silyl enol ethers) are converted into the previously unknown functionalized 1‐aminopyrroles and 1‐amino‐4,5,6,7‐tetrahydroindoles. The domino reaction proceeds through a zinc chloride‐catalyzed ‘conjugate addition/cyclization’ sequence.     

A Novel Assembly of Substituted Pyrroles by Acid‐Catalyzed Sequential Three‐Component Reaction of Amines,Alkynoates, and 1,2‐Diaza‐1,3‐dienes

A novel protocol for the assembly of polysubstituted pyrroles has been developed through the acid‐catalyzed, sequential three‐component reaction of primary aliphatic amines, alkynoates and 1,2‐diaza‐1,3‐dienes (DDs). This methodology proceeds with complete chemo‐/regioselectivity involving first formation of an enamino ester intermediate, in situ Michael addition with azo‐ene compounds and subsequent intramolecular ring closure.     

Catalytic Hydrogenation of Chiral α‐Amino and α‐Hydroxy Esters at Room Temperature with Nishimura Catalyst without Racemization

The hydrogenation of carboxylic acid derivatives at room temperature was investigated. With a mixed Rh/Pt oxide (Nishimura catalyst), low to medium activity was observed for various α‐amino and α‐hydroxy esters. At 100 bar hydrogen pressure and 10% catalysts loading, high yields of the desired amino alcohols and diols were obtained without racemization. The most suitable α‐substituents were NH₂, NHR, and OH, whereas β‐NH₂ were less effective. Usually, aromatic rings were also hydrogenated, but with the free bases of amino acids as substrates, some selectivity was observed. No reaction was found for α‐NR₂, α‐OR, and unfunctionalized esters; acids and amides were also not reduced under these conditions. A working hypothesis for the mode of action of the catalyst is presented.