Catalytic Enantioselective Synthesis of anti‐Vicinal Silylboronates by Conjunctive Cross‐Coupling

Chiral 1,2‐bimetallic reagents are useful motifs in synthetic chemistry. Although syn‐1,2‐bimetallic compounds can be prepared by alkene dimetallation, anti‐1,2‐bimetallics are still rare. The stereospecific 1,2‐metallate shift that occurs during conjunctive cross‐coupling is shown to enable a practical and modular approach to the catalytic synthesis of enantioenriched anti‐1,2‐borosilanes. In addition to reaction development, the synthetic utility of anti‐1,2‐borosilanes was investigated, including applications to the synthesis of anti‐1,2‐diols and anti‐1,2‐amino alcohols     

Catalytic,Enantioselective Synthesis of 1,2‐anti‐Diols by Asymmetric Ring‐Opening/Cross‐Metathesis

An enantioselective method for the synthesis of 1,2‐anti‐diols has been developed. A cyclometalated chiral‐at‐ruthenium complex catalyzes the asymmetric ring‐opening/cross‐metathesis of dioxygenated cyclobutenes, thus resulting in functionally rich synthetic building blocks. Syntheses of the insect pheromone (+)‐endo‐brevicomin and monosaccharide ribose demonstrate the synthetic utility of the 1,2‐anti‐diol fragments generated in the title reaction.     

Synthesis of γ‐Boryl‐Substituted Homoallylic Alcohols with anti Stereochemistry Based on a Double‐Bond Transposition

The stereoselective synthesis of anti isomers of γ‐boryl‐substituted homoallylic alcohols is disclosed. (E)‐1,2‐Di(boryl)alk‐1‐enes undergo Ru‐catalyzed double‐bond transposition with control of the geometry. The in situ generated (E)‐1,2‐di(boryl)alk‐2‐enes add to aldehydes in a stereospecific manner. The alkenylboron group within the product is amenable to a variety of synthetic derivatizations.     

Conformational Analysis of 1,2‐Di‐O‐Octanoyl‐Ethylene‐Glycerol During Aggregation

Conformational analysis of 1,2‐di‐O‐octanoyl‐ethylene‐glycerol during aggregation by 600 MHz ¹H NMR is described. In monomeric states, 1,2‐di‐O‐octanoyl‐ethylene‐glycerol exists in 75% anti‐conformer and 25% gauche‐conformer. The first critical micelle concentration of 1,2‐di‐O‐octanoyl‐ethylene‐glycerol is calculated to be 4.5 mM. In micellar states, 1,2‐di‐O‐octanoyl‐ethylene‐glycerol exists in 25% anti‐conformer and 75%) gauche‐conformer. When the concentration is greater than 10 mM, 1,2‐di‐O‐octanoyl‐ethylene‐glycerol probably aggregates to become the larger micelle, micelle II. In the second micellar state, 1,2‐di‐O‐octanoylethylene‐glycerol only exists in gauche‐conformer.     

Asymmetric Nucleophilic Monofluorobenzylation of Carbonyl Compounds: Synthesis of Enantiopure vic‐Fluorohydrins and α‐Fluorobenzylketones

Asymmetric nucleophilic monofluoroalkylation of a broad range of aldehydes with an α‐fluoro‐γ‐sulfinylbenzyl carbanion takes place with complete control of the facial selectivity at the carbanion and good to high anti‐diastereoselectivity to give easily separable mixtures of two optically pure 1,2‐fluorohydrin derivatives (up to 24:1 anti/syn). Separation and removal of the p‐tolylsulfinyl group with tBuLi provides enantiomerically pure anti‐1,2‐disubstituted‐1,2‐fluorohydrins, whereas α‐fluorobenzylketones can be obtained by desulfinylation of the mixture followed by pyridinium chlorochromate oxidation (one‐pot process).     

Cyclotrimerization of ‘Oxabenzonorbornadiene’: Synthesis of syn‐ and anti‐5,6,11,12,17,18‐Hexahydro‐5,18:6,11:12,17‐triepoxytrinaphthylene

An efficient synthetic route to the concave‐shaped, potentially ionophoric syn‐ and anti‐isomers of 5,6,11,12,17,18‐hexahydro‐5,18:6,11:12,17‐triepoxytrinaphthylene ( 4 ) was elaborated. Starting from ‘oxabenzonorbornadiene’ ( 5 ), the stannylated precursor 9 was prepared in three steps, followed by cyclotrimerization catalyzed by copper(I) thiophene‐2‐carboxylate (CuTC) , which afforded 4 in a syn/anti ratio of 5 : 4.     

Silver(I)‐Catalyzed Diastereoselective Synthesis of anti‐1,2‐Hydroxyboronates

A catalytic protocol for the diastereoselective synthesis of anti‐1,2‐hydroxyboronates is described. The process provides access to secondary alkyl organoborons. The deborylative 1,2‐addition reactions of alkyl 1,1‐diborons proceed in the presence of a silver(I) salt with either KOtBu or nBuLi as an activator. The catalytic diastereoselective protocol can be extended to aryl, alkenyl, and alkyl aldehydes with up to 99:1 d.r.     

Tungsten‐Catalyzed Regio‐ and Enantioselective Aminolysis of trans‐2,3‐Epoxy Alcohols: An Entry to Virtually Enantiopure Amino Alcohols

The first catalytic enantioselective aminolysis of trans‐2,3‐epoxy alcohols has been accomplished. This stereospecific ring‐opening process was efficiently promoted by a tungsten/bis(hydroxamic acid) catalytic system, furnishing various anti‐3‐amino‐1,2‐diols with excellent regiocontrol and high enantioselectivities (up to 95 % ee). Moreover, virtually enantiopure 3‐amino‐1,2‐diols could be obtained by the sequential combination of two reactions that both involve the use of a chiral catalyst.     

Catalytic Enantioselective Synthesis of anti-Vicinal Silylboronates by Conjunctive Cross-Coupling

Chiral 1,2-bimetallic reagents are useful motifs in synthetic chemistry. Although syn-1,2-bimetallic compounds can be prepared by alkene dimetallation, anti-1,2-bimetallics are still rare. The stereospecific 1,2-metallate shift that occurs during conjunctive cross-coupling is shown to enable a practical and modular approach to the catalytic synthesis of enantioenriched anti-1,2-borosilanes. In addition to reaction development, the synthetic utility of anti-1,2-borosilanes was investigated, including applications to the synthesis of anti-1,2-diols and anti-1,2-amino alcohols     

Convenient Synthesis of Various Substituted Homotaurines from Alk‐2‐enamides

Various substituted homotaurines (=3‐aminopropane‐1‐sulfonic acids) 6 were readily synthesized in satisfactory to good yields via the Michael addition of thioacetic acid to alk‐2‐enamides 3 (→ 4 ), followed by LiAlH₄ reduction (→ 5 ) and performic acid oxidation (Scheme 1). The configuration of ‘anti’‐disubstituted homotaurine ‘anti’‐ 6h was deduced from the 3‐(acetylthio)alkanamide (=S‐(3‐amino‐1,2‐dimethyl‐3‐oxopropyl) ethanethioate)‘anti’‐ 4h formed in the Michael addition, which was identified via the Karplus equation analysis, and confirmed by X‐ray diffraction analysis. The current route is an efficient method to synthesize diverse substituted homotaurines, including 1‐, 2‐, and N‐monosubstituted, as well as 1,2‐, 1,N‐, 2,N‐, and N,N‐disubstituted homotaurines (Table).     

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.     

Chiral Ammonium Betaine‐Catalyzed Highly Stereoselective Aza‐Henry Reaction of α‐Aryl Nitromethanes with Aromatic N‐Boc Imines

A highly stereoselective aza‐Henry reaction of α‐aryl nitromethanes with aromatic N‐Boc imines was established by using C₁‐symmetric chiral ammonium betaine as a bifunctional organic base catalyst. Various substituted aryl groups for both imines and nitromethanes were tolerated in the reaction, and a series of precursors for the synthesis of unsymmetrical anti‐1,2‐diaryl ethylenediamines was provided.     

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

α‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.     

A Mild Approach to the Synthesis of sn‐Glycerol 1,2‐Di‐γ‐linolenate 3‐Palmitate

A synthetic approach comprising several studied modifications was applied to the preparation of sn‐glycerol 1,2‐di‐γ‐linolenate 3‐palmitate ( 4 ). Thereby, a convenient and mild synthetic method was elaborated, affording 4 from 1,2‐O‐isopropylidene‐sn‐glycerol ( 1 ) in an average yield of 65 – 75% and analytically acceptable purity.     

1,N6‐Etheno derivative of 7‐de­aza‐2,8‐di­aza­adenosine

In the tricyclic nucleoside 7‐(β‐d ‐ribo­furan­osyl)‐7H‐imidazo­[1,2‐c]­pyrazolo­[4,3‐e][1,2,3]­triazine, C₁₁H₁₂N₆O₄, the con­formation of the N‐gly­cosyl bond is intermediate between anti and high anti [χ = −103.5 (3)°]. The ribo­furan­ose moiety adopts a ₃T² sugar pucker (S‐type sugar) and the conformation at the exocyclic C—C bond is ap (gauche–trans). Molecules of the title compound form a three‐dimensional network via three medium–strong intermolecular hydrogen bonds (one O—H⋯N and two O—H⋯O bonds).     

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.     

Tandem Z‐Selective Cross‐Metathesis/Dihydroxylation: Synthesis of anti‐1,2‐Diols

A stereoselective synthesis of anti‐1,2‐diols has been developed using a multitasking Ru catalyst in an assisted tandem catalysis protocol. A cyclometalated Ru complex catalyzes first a Z‐selective cross‐metathesis of two terminal olefins, followed by a stereospecific dihydroxylation. Both steps are catalyzed by Ru, as the Ru complex is converted to a dihydroxylation catalyst upon addition of NaIO₄. A variety of olefins were transformed into valuable, highly functionalized, and stereodefined molecules. Mechanistic experiments were performed to probe the nature of the oxidation step and catalyst inhibition pathways. These experiments point the way to more broadly applicable tandem catalytic transformations.     

Intramolecular Formal anti‐Carbopalladation/Heck Reaction: Facile Domino Access to Carbo‐ and Heterooligocyclic Dienes

An intramolecular domino process consisting of a formal anti‐carbopalladation followed by Heck reaction is realized. Complex oligo(hetero)cyclic scaffolds are efficiently obtained in one synthetic step from easily obtainable enyne precursors. In contrast to common syn‐carbopalladation reactions of alkyne units, the carbopalladation employed here is designed to afford an anti‐arrangement of the two new substituents across the emerging double bond. A prerequisite is that the residues next to the alkyne should lack any β‐hydrogen atoms. The method paves the way to tri‐ and tetrasubstituted double‐bond systems that have not been accessible by conventional Pd catalysis.     

Binuclear trans‐Bis(β‐iminoaryloxy)palladium(II) Complexes Doubly Linked with Pentamethylene Spacers: Structure‐Dependent Flapping Motion and Heterochiral Association Behavior of the Clothespin‐Shaped Molecules

The synthesis, structure, and solution‐state behavior of clothespin‐shaped binuclear trans‐bis(β‐iminoaryloxy)palladium(II) complexes doubly linked with pentamethylene spacers are described. Achiral syn and racemic anti isomers of complexes 1 – 3 were prepared by treating Pd(OAc)₂ with the corresponding N,N′‐bis(β‐hydroxyarylmethylene)‐1,5‐pentanediamine and then subjecting the mixture to chromatographic separation. Optically pure (100 % ee) complexes, (+)‐anti‐ 1 , (+)‐anti‐ 2 , and (+)‐anti‐ 3 , were obtained from the racemic mixture by employing a preparative HPLC system with a chiral column. The trans coordination and clothespin‐shaped structures with syn and anti conformations of these complexes have been unequivocally established by X‐ray diffraction studies. ¹H NMR analysis showed that (±)‐anti‐ 1 , (±)‐anti‐ 2 , syn‐ 2 , and (±)‐anti‐ 3 display a flapping motion by consecutive stacking association/dissociation between cofacial coordination planes in [D₈]toluene, whereas syn‐ 1 and syn‐ 3 are static under the same conditions. The activation parameters for the flapping motion (ΔH^≠ and ΔS^≠) were determined from variable‐temperature NMR analyses as 50.4 kJ mol^?1 and 60.1 J mol^?1 K^?1 for (±)‐anti‐ 1 , 31.0 kJ mol^?1 and ?22.7 J mol^?1 K^?1 for (±)‐anti‐ 2 , 29.6 kJ mol^?1 and ?57.7 J mol^?1 K^?1 for syn‐ 2 , and 35.0 kJ mol^?1 and 0.5 J mol^?1 K^?1 for (±)‐anti‐ 3 , respectively. The molecular structure and kinetic parameters demonstrate that all of the anti complexes flap with a twisting motion in [D₈]toluene, although (±)‐anti‐ 1 bearing dilated Z‐shaped blades moves more dynamically than I‐shaped (±)‐anti‐ 2 or the smaller (±)‐anti‐ 3 . Highly symmetrical syn‐ 2 displays a much more static flapping motion, that is, in a see‐saw‐like manner. In CDCl₃, (±)‐anti‐ 1 exhibits an extraordinary upfield shift of the ¹H NMR signals with increasing concentration, whereas solutions of (+)‐anti‐ 1 and the other syn/anti analogues 2 and 3 exhibit negligible or slight changes in the chemical shifts under the same conditions, which indicates that anti‐ 1 undergoes a specific heterochiral association in the solution state. Equilibrium constants for the dimerizations of (±)‐ and (+)‐anti‐ 1 in CDCl₃ at 293 K were estimated by curve‐fitting analysis of the ¹H NMR chemical shift dependences on concentration as 26 M ^?1 [K_D(racemic)] and 3.2 M ^?1 [K_D(homo)], respectively. The heterochiral association constant [K_D(hetero)] was estimated as 98 M ^?1, based on the relationship K_D(racemic)=1/2 K_D(homo)+1/4 K_D(hetero). An inward stacking motif of interpenetrative dimer association is postulated as the mechanistic rationale for this rare case of heterochiral association.     

Structural Fluctuation of Disilanyl Double‐Pillared Bisheteroarenes

Silacyclophanes possessing two disilanyl pillars were synthesized from tricyclic heteroarenes in one‐pot synthetic procedures. The step‐like anti structures of three congeners bearing two heteroarene units were revealed in single crystals by X‐ray crystallographic analysis. Depending on the structures of aromatic units, torsion angles at the disilanyl pillars altered to maintain the overall step‐like molecular structures. The structure, however, fluctuated between anti and syn conformers in a solution phase despite the presence of eight methyl groups on the ring periphery. The analysis of the coalescence temperature with NMR spectroscopy showed the fundamental energetics of the dynamics. The subtle structural differences affected the dynamic behavior of the silacyclophanes.