Stereodivergent Organocatalytic Intramolecular Michael Addition/Lactonization for the Asymmetric Synthesis of Substituted Dihydrobenzofurans and Tetrahydrofurans

A stereodivergent asymmetric Lewis base catalyzed Michael addition/lactonization of enone acids into substituted dihydrobenzofuran and tetrahydrofuran derivatives is reported. Commercially available (S)‐(?)‐tetramisole hydrochloride gives products with high syn diastereoselectivity in excellent enantioselectivity (up to 99:1 d.r._syn/anti, 99 % ee_syn), whereas using a cinchona alkaloid derived catalyst gives the corresponding anti‐diastereoisomers as the major product (up to 10:90 d.r._syn/anti, 99 % ee_anti).     

Dihydroxyacetone Phosphate Aldolase Catalyzed Synthesis of Structurally Diverse Polyhydroxylated Pyrrolidine Derivatives and Evaluation of their Glycosidase Inhibitory Properties

The chemoenzymatic synthesis of a collection of pyrrolidine‐type iminosugars generated by the aldol addition of dihydroxyacetone phosphate (DHAP) to C‐α‐substituted N‐Cbz‐2‐aminoaldehydes derivatives, catalyzed by DHAP aldolases is reported. L ‐Fuculose‐1‐phosphate aldolase (FucA) and L ‐rhamnulose‐1‐phosphate aldolase (RhuA) from E. coli were used as biocatalysts to generate configurational diversity on the iminosugars. Alkyl linear substitutions at C‐α were well tolerated by FucA catalyst (i.e., 40–70 % conversions to aldol adduct), whereas no product was observed with C‐α‐alkyl branched substitutions, except for dimethyl and benzyl substitutions (20 %). RhuA was the most versatile biocatalyst: C‐α‐alkyl linear groups gave the highest conversions to aldol adducts (60–99 %), while the C‐α‐alkyl branched ones gave moderate to good conversions (50–80 %), with the exception of dimethyl and benzyl substituents (20 %). FucA was the most stereoselective biocatalyst (90–100 % anti (3R,4R) adduct). RhuA was highly stereoselective with (S)‐N‐Cbz‐2‐aminoaldehydes (90–100 % syn (i.e., 3R,4S) adduct), whereas those with R configuration gave mixtures of anti/syn adducts. For iPr and iBu substituents, RhuA furnished the anti adduct (i.e., FucA stereochemistry) with high stereoselectivity. Molecular models of aldol products with iPr and iBu substituents and as complexes with the RhuA active site suggest that the anti adducts could be kinetically preferred, while the syn adducts would be the equilibrium products. The polyhydroxylated pyrrolidines generated were tested as inhibitors against seven glycosidases. Among them, good inhibitors of α‐L ‐fucosidase (IC₅₀=1–20 μM ), moderate of α‐L ‐rhamnosidase (IC₅₀=7–150 μM ), and weak of α‐D ‐mannosidase (IC₅₀=80–400 μM ) were identified. The apparent inhibition constant values (K_i) were calculated for the most relevant inhibitors and computational docking studies were performed to understand both their binding capacity and the mode of interaction with the glycosidases.     

Diastereodivergent Asymmetric Michael Addition of Cyclic Azomethine Ylides to Nitroalkenes: Direct Approach for the Synthesis of 1,7‐Diazaspiro[4.4]nonane Diastereoisomers

The first highly diastereoselective and enantioselective catalytic asymmetric Michael addition of cyclic azomethine ylides with nitroalkenes have been developed to diastereodivergently generate either the syn or anti adducts by employing N,O‐ligand/Cu(OAc)₂ and N,P‐ligand/Cu(OAc)₂ catalytic systems. Both catalytic systems exhibit broad substrate applicability to afford the corresponding Michael adducts in good to excellent yields, with excellent levels of diastereo‐ (up to 99:1 diastereomeric ratio) and enantioselectivities (up to >99 % enantiomeric excess). Importantly, the chiral 1,7‐diazaspiro[4.4]nonane diastereomer derivatives can be easily obtained in good yields through facile NaBH₄ reduction of the Michael adducts.     

A Highly anti‐Selective Asymmetric Henry Reaction Catalyzed by a Chiral Copper Complex: Applications to the Syntheses of (+)‐Spisulosine and a Pyrroloisoquinoline Derivative

A highly anti‐selective asymmetric Henry reaction has been developed, affording synthetically versatile β‐nitroalcohols in a predominately anti‐selective manner (mostly above 15:1) and excellent ee values (mostly above 95 %). Moreover, the anti‐selective Henry reaction was carried out in the presence of water for the first time with up to 99 % ee. The catalytic mechanism was proposed based on the detection of the intermediates by extractive electrospray ionization mass spectrometry (EESI‐MS). Furthermore, the anti adducts have been successfully transformed into the biochemically important (+)‐spisulosine and a pyrroloisoquinoline derivative.     

A new type of amino amide organocatalyzed enantioselective crossed aldol reaction of ketones with aromatic aldehydes

A new type of amino amide organocatalysts was designed and synthesized from commercially available amino acids in easy steps. Their catalytic activities were examined in enantioselective crossed aldol reaction of various acyclic and cyclic ketones with aromatic aldehydes to afford the corresponding chiral anti-aldol adducts with good to excellent chemical yields, diastereoselectivities and enantioselectivities (up to 99%, up to syn:anti?=?1:99, up to 97% ee).     

A Powerful Chiral Phosphoric Acid Catalyst for Enantioselective Mukaiyama–Mannich Reactions

A new BINOL‐derived chiral phosphoric acid bearing 2,4,6‐trimethyl‐3,5‐dinitrophenyl substituents at the 3,3′‐positions was developed. The utility of this chiral phosphoric acid is demonstrated by a highly enantioselective (ee up to >99 %) and diastereoselective (syn/anti up to >99:1) asymmetric Mukaiyama–Mannich reaction of imines with a wide range of ketene silyl acetals. Moreover, this method was successfully applied to the construction of vicinal tertiary and quaternary stereogenic centers with excellent diastereo‐ and enantioselectivity. Significantly, BINOL‐derived N‐triflyl phosphoramide constitutes a complementary catalyst system that allows the title reaction to be applied to more challenging imines without an N‐(2‐hydroxyphenyl) moiety.     

Asymmetric iodoamination of chalcones and 4-aryl-4-oxobutenoates catalyzed by a complex based on scandium(III) and a N,N'-dioxide ligand

Highly diastereo‐ and enantioselective iodoamination of chalcones, 4‐aryl‐4‐oxobutenoates, and a trifluoro‐substituted enone has been accomplished in the presence of a chiral N,N′‐dioxide/[Sc(OTf)₃] complex (0.5–2 mol %), delivering the desired vicinal anti‐α‐iodo‐β‐amino carbonyl compounds regioselectively in high yields (up to 97 %) and with excellent diastereoselectivities (>99:1 d.r.) and enantioselectivities (up to 99 % ee). Enantiopure syn‐α‐iodo‐β‐amino products could also be obtained from the isomerization of particular iodo compounds. TsNHX species (X=Cl, Br, I), generated from the reactions between the halo sources and TsNH₂, were further confirmed as the active species in the haloamination reactions involved in the formation of the key halonium ion intermediates. A typical haloamination dependency was observed, with reactivity decreasing in the order NBS>NIS?NCS.     

Asymmetric Henry reactions of aldehydes with various nitroalkanes catalyzed by copper(II) complexes of novel chiral N‐monoalkyl cyclohexane‐1,2‐diamines

A number of novel chiral diamines 3 , (1R,2R)‐N‐monoalkylcyclohexane‐1,2‐diamines, were designed and synthesized from trans‐cyclohexane‐1,2‐diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane to provide β‐nitroalcohol in high yield (up to 99%) and good enantiomeric excess (up to 89%). By using ligand (1R,2R)‐N¹‐(4‐methylpentan‐2‐yl)cyclohexane‐1,2‐diamine ( 3g ), the reaction was optimized in terms of the metal ion, temperature, solvent and base. Further experiments indicated that the complex, 3g –Cu(OAc)₂, was an efficient catalyst in the asymmetric Henry reaction between different aldehydes and nitromethane, and the desired products have been obtained with high chemical yields (up to 99%) and high enantiomeric excess (up to 93%). The optimized catalyst promoted the diastereoselective Henry reaction of various aldehyde substrates and nitroalkane, which gave the corresponding anti‐selective adduct with up to 99% yield and 83:17 anti/syn selectivity. Upon scaling up to gram quantities, the β‐nitroalcohol was obtained in good yield (96%) with excellent selectivities (93% ee). The chiral induction mechanism was tentatively explained on the basis of a previously proposed transition‐state model. Copyright © 2014 John Wiley & Sons, Ltd.     

Diastereoselectively Switchable Asymmetric Haloaminocyclization for the Synthesis of Cyclic Sulfamates

An asymmetric synthesis of cyclic sulfamates by catalytic haloaminocyclization of primary sulfamate ester derivatives is described. The remarkable reversal of diastereoselectivity was found to be dependent on the halogen source and the chiral catalyst. By using privileged complexes of N,N′‐dioxides with Sc(OTf)₃ or Lu(OTf)₃ as the catalyst, a variety of enantioenriched syn‐ and anti‐cyclic sulfamates or related trans‐aziridines could be obtained in 92–99 % ee and up to 97 % yield.     

Palladium‐Catalyzed Regio‐ and Stereoselective Chlorothiolation of Terminal Alkynes with Sulfenyl Chlorides

Chlorothiolation of terminal alkynes with sulfenyl chlorides yields anti‐adducts without transition‐metal catalysts. In sharp contrast, transition‐metal‐catalyzed chlorothiolation has not been developed to date, possibly because organosulfur compounds can poison catalyst. Herein, the regio‐ and stereoselective palladium‐catalyzed chlorothiolation of terminal alkynes with sulfenyl chlorides is described. syn‐Chlorothiolation offers a complementary synthetic route to chloroalkenyl sulfides. 2‐Chloroalkenyl sulfides can easily be transformed into various sulfur‐containing products, most of which are often found in natural products and pharmaceuticals.     

A Solid‐Supported Organocatalyst for Highly Stereoselective,Batch, and Continuous‐Flow Mannich Reactions

The fast and highly stereoselective Mannich reaction of aldehydes and ketones with the N‐(p‐methoxyphenyl) ethyl glyoxylate imine catalyzed by polystyrene resins functionalized with (2S,4R)‐hydroxyproline is reported. The effect of the nature of the linker connecting proline with the polymeric backbone has been studied, and a 1,2,3‐triazole linker constructed from azidomethyl polystyrene and O‐propargyl hydroxyproline turns out to be optimal for catalytic activity and enantioselectivity. With aldehyde donors, fast reactions leading to complete conversion in 1–3 h are recorded in DMF. With ketone donors, the reactions tend to be slower, but can be efficiently accelerated (six‐membered ring cycloalkanones) by low‐power microwave irradiation. This approach, which greatly facilitates product isolation since the catalyst is removed by simple filtration, has allowed the implementation of the reactions of aldehyde substrates in a continuous‐flow, single‐pass system. In this manner, the continuous synthesis of the enantiomerically and diastereomerically pure adducts (syn/anti>97:3; ee>99 %) has been achieved at room temperature with residence times of 6.0 min. This methodology has allowed for the preparation of up to 7.8 mmol of the desired Mannich adduct through the use of 0.46 mmol of catalytic resin (5.9 mol %), in a greatly simplified experimental protocol that avoids purification steps.     

A Concise and Highly Enantioselective Total Synthesis of (+)‐anti‐ and (−)‐syn‐Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines

A concise asymmetric (>99:1 e.r.) total synthesis of (+)‐anti‐ and (?)‐syn‐mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless‐derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)‐anti‐ and (?)‐syn‐mefloquine, respectively. The synthetic (+)‐anti‐ and (?)‐syn‐mefloquine samples were derivatized with (S)‐(+)‐mandelic acid tert‐butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X‐ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)‐anti‐ as well as (?)‐syn‐mefloquine.     

Development of a Simple Adjustable Zinc Acid/Base Hybrid Catalyst for C−C and C−O Bond‐Forming and C−C Bond‐Cleavage Reactions

A newly designed zinc Lewis acid/base hybrid catalyst was developed. By adjusting the Lewis acidity of the zinc center, aldol‐type additions of 2‐picolylamine Schiff base to aldehydes proceeded smoothly to afford syn‐aldol adduct equivalents, trans‐N,O‐acetal adducts, in high yields with high selectivities. NMR experiments, including microchanneled cell for synthesis monitoring (MICCS) NMR analysis, revealed that anti‐aldol adducts were formed at the initial stage of the reactions under kinetic control, but the final products were the trans‐(syn)‐N,O‐acetal adducts that were produced through a retro‐aldol process under thermodynamic control. In the whole reaction process, the zinc catalyst played three important roles: i) promotion of the aldol process (C?C bond formation), ii) cyclization process to the N,O‐acetal product (C?O bond formation), and iii) retro‐aldol process from the anti‐aldol adduct to the syn‐aldol adduct (C?C bond cleavage and C?C bond formation).     

Asymmetric Palladium‐Catalyzed Alkene Carboamination Reactions for the Synthesis of Cyclic Sulfamides

The synthesis of cyclic sulfamides by enantioselective Pd‐catalyzed alkene carboamination reactions between N‐allylsulfamides and aryl or alkenyl bromides is described. High levels of asymmetric induction (up to 95:5 e.r.) are achieved using a catalyst composed of [Pd₂(dba)₃] and (S)‐Siphos‐PE. Deuterium‐labelling studies indicate the reactions proceed through syn‐aminopalladation of the alkene and suggest that the control of syn‐ versus anti‐aminopalladation pathways is important for asymmetric induction.     

Stereoselective Aldol Reactions Catalyzed by Acyclic Amino Acids in Aqueous Micelles

The catalytic properties of all proteinogenic, acyclic amino acids for direct aldol reaction in H₂O, assisted by various surfactants, were investigated. The basic and neutral amino acids were shown to be efficient catalysts, giving rise to good‐to‐excellent yields of adducts (up to 95%), with moderate‐to‐good diastereoselectivities (up to 86%), L ‐arginine being the most‐effective catalyst. The syn/anti diastereoisomer ratio could be readily tuned by proper choice of the amino acid used. Also, the range of substrates that underwent the reaction was extended to less‐reactive aldehydes carrying electron‐donating Br substituents.     

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

A minimalist active site redesign of the L ‐fuculose‐1‐phosphate aldolase from E. coli FucA was envisaged, to extend its tolerance towards bulky and conformationally restricted N‐Cbz‐amino aldehyde acceptor substrates (Cbz=benzyloxycarbonyl). Various mutants at the active site of the FucA wild type were obtained and screened with seven sterically demanding N‐Cbz‐amino aldehydes including N‐Cbz‐prolinal derivatives. FucA F131A showed an aldol activity of 62 μmol h^?1 mg^?1 with (R)‐N‐Cbz‐prolinal, whereas no detectable activity was observed with the FucA wild type. For the other substrates, the F131A mutant gave aldol activities from 4 to about 25 times higher than those observed with the FucA wild type. With regard to the stereochemistry of the reactions, the (R)‐amino aldehydes gave exclusively the anti configured aldol adducts whereas their S counterparts gave variable ratios of anti/syn diastereoisomers. Interestingly, the F131A mutant was highly stereoselective both with (R)‐ and with (S)‐N‐Cbz‐prolinal, exclusively producing the anti and syn aldol adducts, respectively. Molecular models suggest that this improved activity towards bulky and more rigid substrates, such as N‐Cbz‐prolinal, could arise from a better fit of the substrate into the hydrophobic pocket created by the F131A mutation, due to an additional π–cation interaction with the residue K205′ and to efficient contact between the substrate and the mechanistically important Y113′ and Y209′ residues. An expedient synthesis of novel polyhydroxylated pyrrolizidines related to the hyacinthacine and alexine types was accomplished through aldol additions of dihydroxyacetone phosphate (DHAP) to hydroxyprolinal derivatives with the hyperactive FucA F131A as catalyst. The iminocyclitols obtained were fully characterised and found to be moderate to weak inhibitors (relative to 1,4‐dideoxy‐1,4‐imino‐L ‐arabinitol (LAB) and 1,4‐dideoxy‐1,4‐imino‐D ‐arabinitol (DAB)) against glycosidases and rat intestinal saccharidases.     

Anti-selective direct asymmetric Mannich reaction catalyzed by protease

The anti-selective direct asymmetric Mannich reaction of (hetero) aromatic aldehydes, 4-anisidine and O-protected hydroxyacetones for the synthesis of stereodefined anti-β-amino-α-hydroxycarbonyl compounds was developed. Protease type XIV from Streptomyces griseus (SGP) was used as a biocatalyst in 1,4-dioxane/phosphate buffer under mild reaction conditions. The excellent diastereoselectivities of up to >99:1 (anti/syn) and good enantioselectivities of up to 90% ee were achieved. This method provides a more sustainable complement to chemically catalyzed anti-selective direct asymmetric Mannich reactions.     

Controlling Stereoselectivity in the Aminocatalytic Enantioselective Mannich Reaction of Aldehydes with In Situ Generated N‐Carbamoyl Imines

A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N‐carbamoyl imines has been developed. Both α‐imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N‐tert‐butoxycarbonyl (Boc) or N‐carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configuration and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N‐carbamate‐protected imines are generated in situ from stable and easily handled α‐amido sulfones.     

Felkin-Anh selectivity in Rh(bisoxazolinylphenyl)-catalyzed reductive aldol coupling reaction: asymmetric synthesis of stereotriads

The catalytic reductive aldol coupling of 2-phenylpropionaldehyde and acrylate derivatives with rhodium-bisoxazolinyl catalysts resulted in high Felkin-Anh selectivity (β,γ-syn) up to 98% accompanied by α,β-anti diastereoselectivity and high enantiomeric excesses up to 99%.     

Pyrrolidine-linker-camphor assembly: bifunctional organocatalysts for efficient Michael addition of cyclohexanone to nitroolefins under neat conditions

A simple and convenient strategy was developed to synthesize a new class of pyrrolidinyl-camphor based bifunctional organocatalysts possessing varying functional linkers. Catalytic screening of these camphor-pyrrolidine linked derivatives for asymmetric Michael reaction of cyclohexanone with β-nitrostyrene was carried out. Various aryl- and heteroaryl-nitroolefins, ketones as well as aldehydes gave the corresponding Michael adducts in high chemical yields (up to 95%) and exceptionally high diastereo-(syn/anti up to 99:1) and enantioselectivity (up to 95%) using catalyst 6 under solvent-free conditions.