Amine‐Catalyzed Asymmetric Epoxidation of α,β‐Unsaturated Aldehydes

The direct organocatalytic enantioselective epoxidation of α,β‐unsaturated aldehydes with different peroxides is presented. Proline, chiral pyrrolidine derivatives, and amino acid‐derived imidazolidinones catalyze the asymmetric epoxidation of α,β‐unsaturated aldehydes. In particular, protected commercially available α,α‐diphenyl‐ and α,α‐di(β‐naphthyl)‐2‐prolinols catalyze the asymmetric epoxidation reactions of α,β‐unsaturated aldehydes with high diastereo‐ and enantioselectivities to furnish the corresponding 2‐epoxy aldehydes in high yield with up to 97:3 dr and 98 % ee. The use of non‐toxic catalysts, water and hydrogen peroxide, urea hydroperoxide or sodium percarbonate as the oxygen sources could make this reaction environmentally benign. In addition, one‐pot direct organocatalytic asymmetric tandem epoxidation‐Wittig reactions are described. The reactions were highly diastereo‐ and enantioselective and provide a rapid access to 2,4‐diepoxy aldehydes. Moreover, a highly stereoselective one‐pot organocatalytic asymmetric cascade epoxidation‐Mannich reaction, which proceeds via the combination of iminium and enamine activation, is presented. The mechanism and stereochemistry of the amino acid‐ and chiral pyrrolidine‐catalyzed direct asymmetric epoxidation of α,β‐unsaturated aldehydes are also discussed.     

One‐Pot Cascade Reactions using Fructose‐6‐phosphate Aldolase: Efficient Synthesis of D‐Arabinose 5‐Phosphate,D‐Fructose 6‐Phosphate and Analogues

One‐pot multienzymatic reactions have been performed for the synthesis of 1‐deoxy‐D ‐fructose 6‐phosphate, 1,2‐dideoxy‐D ‐arabino‐hept‐3‐ulose 7‐phosphate, D ‐fructose 6‐phosphate and D ‐arabinose 5‐phosphate. The whole synthetic strategy is based on an aldol addition reaction catalysed by fructose‐6‐phosphate aldolase (FSA) as a key step of a three or four enzymes‐catalysed cascade reaction. The four known donors for FSA – dihydroxyacetone (DHA), hydroxyacetone (HA), 1‐hydroxy‐2‐butanone (HB) and glycolaldehyde (GA) – were used with D ‐glyceraldehyde 3‐phosphate as acceptor substrate. The target phosphorylated sugars were obtained in good to excellent yields and high purity.     

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.     

Base‐Catalyzed Condensation of 2‐Hydroxybenzaldehydes with α,β‐Unsaturated Aldehydes – Scope and Limitations

The base‐catalyzed condensation of α,β‐unsaturated carbonyl compounds with 2‐hydroxybenzaldehydes yielding tetrahydroxanthones and dihydrobenzopyrans has been investigated. A novel access to highly functionalized dihydrobenzopyrans via a mild generation of the dienol of senecialdehyde and subsequent conjugated aldol reaction has been reported.     

Organocatalytic Asymmetric Sulfa‐Michael Addition to α,β‐Unsaturated Ketones

The highly enantioselective organocatalytic sulfa‐Michael addition to α,β‐unsaturated ketones has been accomplished using benzyl and tert‐butyl mercaptans as the sulfur‐centered nucleophiles. Optically active products are obtained in high yields and good to excellent stereocontrol (up to 96 % ee) from a large variety of enones. Central to these studies has been the use of the catalytic primary amine salt A , derived from 9‐amino‐(9‐deoxy)‐epi‐hydroquinine and D ‐N‐Boc‐phenylglycine, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis with enones.     

Organocatalysis in Natural Product Synthesis: A Simple One‐Pot Approach to Optically Active β‐Diols

Optically active β‐diols have been prepared using an organocatalytic one‐pot approach from α,β‐unsaturated aldehydes using (E)‐benzaldehyde oxime as nucleophile in an oxa‐Michael reaction with subsequent in situ reduction or Grignard addition. With this protocol at hand, two biologically active compounds, an insect sex pheromone and a glycerol kinase substrate have been synthesized.     

Asymmetric Aza‐Morita–Baylis–Hillman‐Type Reactions: The Highly Enantioselective Reaction between Unmodified α,β‐ Unsaturated Aldehydes and N‐Acylimines by Organo‐co‐catalysis

The highly enantioselective organo‐co‐catalytic aza‐Morita–Baylis–Hillman (MBH)‐type reaction between N‐carbamate‐protected imines and α,β‐unsaturated aldehydes has been developed. The organic co‐catalytic system of proline and 1,4‐diazabicyclo[2.2.2]octane (DABCO) enables the asymmetric synthesis of the corresponding N‐Boc‐ and N‐Cbz‐protected β‐amino‐α‐alkylidene‐aldehydes in good to high yields and up to 99% ee. In the case of aza‐MBH‐type addition of enals to phenylprop‐2‐ene‐1‐imines, the co‐catalytic reaction exhibits excellent 1,2‐selectivity. The organo‐co‐catalytic aza‐MBH‐type reaction can also be performed by the direct highly enantioselective addition of α,β‐unsaturated aldehydes to bench‐stable N‐carbamate‐protected α‐amidosulfones to give the corresponding β‐amino‐α‐alkylidene‐aldehydes with up to 99% ee. The organo‐co‐catalytic aza‐MBH‐type reaction is also an expeditious entry to nearly enantiomerically pure β‐amino‐α‐alkylidene‐amino acids and β‐amino‐α‐alkylidene‐lactams (99% ee). The mechanism and stereochemistry of the chiral amine and DABCO co‐catalyzed aza‐MBH‐type reaction are also discussed.     

Engineering a Promiscuous Tautomerase into a More Efficient Aldolase for Self‐Condensations of Linear Aliphatic Aldehydes

The enzyme 4‐oxalocrotonate tautomerase (4‐OT) from Pseudomonas putida mt‐2 takes part in a catabolic pathway for aromatic hydrocarbons, where it catalyzes the conversion of 2hydroxyhexa‐2,4‐dienedioate into 2‐oxohexa‐3‐enedioate. This tautomerase can also promiscuously catalyze carbon–carbon bond‐forming reactions, including various types of aldol reactions, by using its amino‐terminal proline as a key catalytic residue. Here, we used systematic mutagenesis to identify two hotspots in 4‐OT (Met45 and Phe50) at which single mutations give marked improvements in aldolase activity for the self‐condensation of propanal. Activity screening of a focused library in which these two hotspots were varied led to the discovery of a 4‐OT variant (M45Y/F50V) with strongly enhanced aldolase activity in the self‐condensation of linear aliphatic aldehydes, such as acetaldehyde, propanal, and butanal, to yield α,β‐unsaturated aldehydes. With both propanal and benzaldehyde, this double mutant, unlike the previously constructed single mutant F50A, mainly catalyzes the self‐condensation of propanal rather than the cross‐condensation of propanal and benzaldehyde, thus indicating that it indeed has altered substrate specificity. This variant could serve as a template to create new biocatalysts that lack dehydration activity and possess further enhanced aldolase activity, thus enabling the efficient enzymatic self‐coupling of aliphatic aldehydes.     

A Simple Organocatalytic Enantioselective Cyclopropanation of α,β‐Unsaturated Aldehydes

A highly chemo‐ and enantioselective organocatalytic cyclopropanation of α,β‐unsaturated aldehydes with bromomalonate and 2‐bromoacetoacetate esters is presented. The reaction is catalyzed by chiral amines and gives access to 2‐formylcyclopropanes in high yields and up to 99 % ee.     

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.     

Organocatalytic Asymmetric Formal [3+3] Cycloaddition Reactions of α,β‐Unsaturated Aldehydes with Nazarov Reagents

An organocatalytic asymmetric formal [3+3] cycloaddition reaction of α,β‐unsaturated aldehydes with Nazarov reagents promoted by prolinol derivatives afforded, after oxidation, 3,4‐dihydropyranones in good yields with high enantioselectivities of up to 97% ee.     

A Highly Enantioselective Catalytic Domino Aza‐Michael/Aldol Reaction: One‐Pot Organocatalytic Asymmetric Synthesis of 1,2‐Dihydroquinolidines

The highly enantioselective organocatalytic domino aza‐Michael/aldol reaction is presented. The unprecedented, chiral amine‐catalyzed asymmetric domino reactions between 2‐aminobenzaldehydes and α,β‐unsaturated aldehydes proceed with excellent chemo‐ and enantioselectivity to give the corresponding pharmaceutically valuable 1,2‐dihydroquinolines derivatives in high yields with 90 to >99 % ee.     

Assembly of 4‐Substituted 3‐Nitro‐1,2,3,4‐tetrahydropyridines via Organocatalytic Michael Addition

An organocatalytic Michael addition of protected 2‐amino‐1‐nitroethanes to α,β‐unsaturated aldehydes followed by treatment with TFA afforded 4‐substituted 3‐nitro‐1,2,3,4‐tetrahydropyridines with good diastereoselectivity and excellent enantioselectivity. Good yields were observed in the case of β‐aryl‐substituted α,β‐unsaturated aldehydes as the substrates, while moderate yields were obtained when β‐alkyl‐substituted α,β‐unsaturated aldehydes were used.     

Aldehyde‐Catalyzed Transition Metal‐Free Dehydrative β‐Alkylation of Methyl Carbinols with Alcohols

Different to the borrowing hydrogen strategy in which alcohols were activated by transition metal‐catalyzed anaerobic dehydrogenation, the direct addition of aldehydes was found to be an effective but simpler way of alcohol activation that can lead to efficient and green aldehyde‐catalyzed transition metal‐free dehydrative C‐alkylation of methyl carbinols with alcohols. Mechanistic studies revealed that the reaction proceeds via in situ formation of ketones by Oppenauer oxidation of the methyl carbinols by external aldehydes, aldol condensation, and Meerwein–Ponndorf–Verley (MPV)‐type reduction of α,β‐unsatutated ketones by substrate alcohols, affording the useful long chain alcohols and generating aldehydes and ketones as the by‐products that will be recovered in the next condensation to finish the catalytic cycle.     

Organocatalytic and Stereoselective [3 + 2] Cycloadditions of Azomethine Imines with α,β‐Unsaturated Aldehydes

Bipyrazolidin‐3‐one derivatives are biologically significant compounds and their importance has increased in the past decades. In this paper, the first stereoselective [3 + 2] dipolar cycloadditions of azomethine imines with α,β‐unsaturated aldehydes catalyzed by readily available α,α‐diarylprolinol salts are reported, providing a facile route to the synthesis of various chiral bipyrazolidin‐3‐one derivatives under mild conditions. The organocatalyst 1 g with strongly electron‐withdrawing groups exhibited the best stereoselectivity (exo:endo up to 98:2, for exo product up to 97 % ee), in the combination with trifluoroacetic acid.     

Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays

We investigated the reactions between substituted α,β‐unsaturated carbonyl compounds (Michael systems) and thiols by computations as well as chemoassays. The results give insight into variations in the underlying mechanisms as a function of the substitution pattern. This is of interest for the mechanisms of inhibition of the SARS coronavirus main protease (SARS‐CoV M^pro) by etacrynic acid derivatives as well as for the excess toxicity of substituted α,β‐unsaturated carbonyl compounds. This study compares possible reaction courses including 1,4‐addition followed by a ketonization step, and underscores the importance of a base‐catalyzed step for the reactivity of thiol groups in enzymes. Phenyl and methyl substituents at the Michael system decrease the reactivity of the electrophilic compound, but chlorophenyl substituents partly recover the reactivity. Computations also indicate that electron‐pushing substituents lead to a change in the reaction mechanism. The conformation of the Michael system is also found to significantly influence reactivity: the s‐cis conformation leads to higher reactivity than the s‐trans conformation. The computed data explain the trends in measured inhibition potencies of substituted α,β‐unsaturated carbonyl compounds and of reaction rates in chemical assays. They also indicate that the reversibility of inhibition does not stand in contrast to the formation of a new covalent bond between inhibitor and protease.     

A Phosphine‐Catalyzed Regioselective [3+2] Cycloaddition of Ethyl 5,5‐Diarylpenta‐2,3,4‐trienoate with Aromatic Aldehydes and α,β‐Unsaturated Carbonyl Compounds

Tributylphosphine‐catalyzed regioselective [3+2] cycloadditions between ethyl 5,5‐diarylpenta‐2,3,4‐trienoate 1 and various aromatic aldehydes 2 to produce a wide variety of polysubstituted 2,5‐dihydrofurans 3 , and between 1 and β‐unsubstituted α,β‐unsaturated carbonyl compounds 5 to give polysubstituted cyclopentenes 6 with a quaternary carbon center, are reported. In both cases the reaction partners approach each other via the sterically less hindered orientation to afford the target products in excellent regioselectivity. The reaction mechanism involved first the generation of a zwitterionic intermediate between the butatriene 1 and PBu₃. For the formation of 2,5‐dihydrofurans 3 , the preferred cyclization mode encompassed the nucleophilic attack of the α‐position of butatriene to the aldehydic carbon of 2 , followed by the ring closure between the aldehydic oxygen of 2 and the γ‐position of butatriene, which is the first report of a normal [3+2] cycloaddition between cumulenes and aldehydes. For the formation of cyclopentenes 6 , the reaction involved attack of the γ‐position of the butatriene to the electron‐deficient β‐position of the α,β‐unsaturated carbonyl compounds 5 , followed by the ring closure between the α‐position of 5 and the α‐position of butatriene, which shows a different regioselectivity to the previously reported [3+2] cycloadditions between butatriene and olefins.

     

Organocatalytic Enantioselective Aza‐Michael Addition of Purine Bases to α,β‐Unsaturated Ketones

The first organocatalytic enantioselective aza‐Michael addition of purine bases to α,β‐unsaturated ketones has been developed, affording Michael adducts in moderate to high yields (up to 96% yield) and high to excellent enantioselectivities (up to >99% ee). A wide range of α,β‐unsaturated ketones including aliphatic and aromatic enones are tolerated in this process, generally demonstrating good reactivity, regioselectivity and enantioselectivity. The aromatic α,β‐unsaturated ketones showing quite low reactivity in the reported catalytic systems, were first successfully employed as Michael acceptors in this transformation, yielding high enantioselectivities (up to 94% ee). The utility of this method was also applied for the synthesis of enantioenriched non‐natural nucleoside analogues with potential biological activities.     

Iterative One‐Pot α‐Glycosylation Strategy: Application to Oligosaccharide Synthesis

Based on the combined use of dimethylformamide (DMF) modulation and neighboring group participation, three iterative one‐pot α‐glycosylation methods, i.e., one‐pot (α,α)‐, one‐pot (β,α)‐, and one‐pot (α,β)‐glycosylations, were developed. These methods are applicable to a range of thioglycosyl donors, confer stereocontrol in α‐/β‐glycosidic bond formation, and thus provide for rapid access to oligosaccharides with various permutations of anomeric configurations. The utility of these one‐pot glycosylation methods is demonstrated in the synthesis of eight non‐natural and natural oligosaccharide targets, including the core 1 serine conjugate, core 8 serine conjugate, the D ‐Gal‐α(1→3)‐D ‐Glc‐α(1→3)‐L ‐Rha trisaccharide unit of the cell wall component in Streptococcus pneumoniae, and the D ‐Glc‐α(1→2)‐D ‐Glc‐α(1→3)‐D ‐Glc trisaccharide terminus of the N‐linked glycan precursor. Confirmation of the anomeric configurations of these oligosaccharides is evidenced by ¹H, ¹³C, ¹³C‐non‐proton decoupling, and heteronuclear correlation 2D NMR experiments. Global deprotection of selected oligosaccharide targets is illustrated.     

3‐ and 4‐Uloses Derived from N‐Acetyl‐D‐glucosamine: A Unique Pair of Complementary Organocatalysts for Asymmetric Epoxidation of Alkenes

The 4‐ulose and the 3‐ulose, both derived in two steps from the α‐methyl glycoside of N‐acetyl‐D ‐glucosamine (GlcNAc), act as organocatalysts in the asymmetric epoxidation of alkenes, with unprecedented complementary enantioselectivity. The best results are found with α,β‐unsaturated esters as substrates, with enantiomeric ratios up to 90:10 and 11:89, respectively.