Enantiodifferentiating Photodimerization of a 2,6-Disubstituted Anthracene Assisted by Supramolecular Double-Helix Formation with Chiral Amines

A novel 2,6-anthrylene-linked bis(m-terphenylcarboxylic acid) strand ( 1 ) self-associates into a racemic double-helix. In the presence of chiral mono- and diamines, either a right- or left-handed double-helix was predominantly induced by chiral amines sandwiched between the carboxylic acid strands with accompanying stacking of the two prochiral anthracene linker units in an enantiotopic face-selective way, as revealed by circular dichroism and NMR spectral analyses. The photoirradiation of the optically active double helices complexed with chiral amines proceeded in a diastereo- (anti or syn) and enantiodifferentiating way to afford the chiral anti-photodimer with up to 98 % enantiomeric excess when (R)-phenylethylamine was used as a chiral double-helix inducer. The resulting optically active anti-photodimer can recognize the chirality of amines and diastereoselectively complex with chiral amines.     

Unexpected Thermally Stable,Cholesteric Liquid‐Crystalline Helical Polyisocyanides with Memory of Macromolecular Helicity

The achiral sodium salt of poly(4‐carboxyphenyl isocyanide) (poly‐ 1 –Na) folds into a one‐handed helix induced by optically active amines in water. The induced helicity remains when the optically active amines are completely removed, and further modification of the side groups to amide residues is possible without loss of memory of macromolecular helicity. Although the helical poly‐ 1 –Na loses its chiral memory at high temperature, helical polyisocyanides modified with achiral primary amines, which no longer have any chiral components, keep their memory perfectly even at 100 °C in N,N‐dimethylformamide in some cases and exhibit cholesteric liquid‐crystalline phases, thus providing a robust scaffold with heat resistance to which a variety of functional groups can be introduced.     

Homo‐double helix formation of an optically active conjugated polymer bearing carboxy groups and amplification of the helicity upon complexation with achiral and chiral amines

An optically active, m‐terphenyl‐based π‐conjugated polymer bearing carboxy groups was synthesized by the copolymerization of the diethynyl monomer bearing a carboxy group with (S,S)‐2,5‐bis(2‐methylbutoxy)‐1,4‐dibromobenzene using Sonogashira reaction. The copolymer showed a weak circular dichroism (CD) in the main‐chain chromophore region due to a homo‐double helix formation with an excess helical handedness biased by the chiral alkoxy substituents through self‐association. However, upon complexation with achiral amines, such as piperidine, the CD intensity of the polymer significantly increased resulting in the formation of a greater excess one‐handed homo‐double helix via hydrogen‐bonded inclusion complexation with the achiral amines between each strand, leading to the amplification of the helicity. A preferred‐handed homo‐double helix was also induced in the polymer in the presence of nonracemic amines. The effect of the achiral and chiral amines on the homo‐double helix formation was investigated by comparing the CD spectra of the polymer to those of its model dimer. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 990–999     

Helicene‐Grafted Silica Nanoparticles Capture Hetero‐Double‐Helix Intermediates during Self‐Assembly Gelation

A mixture of a pseudoenantiomeric ethynylhelicene (M)‐tetramer and a (P)‐pentamer forms a hetero‐double‐helix in a solution, which self‐assembles and gelates solvents. When gelation was conducted in the presence of chiral silica (P)‐nanoparticles grafted with (P)‐helicene, the resulting hetero‐double‐helix intermediate was adsorbed on the (P)‐nanoparticles, and was removed from the solution by aggregation and precipitation. The resulting precipitates contained only the hetero‐double‐helix, not random coil or clusters of the hetero‐double‐helix. (P)‐Nanoparticles did not extract the hetero‐double‐helix from the self‐assembly gels. The hetero‐double‐helix was then isolated by liberating it from the precipitates in 2‐bromopropionic acid, and was crystallized from the solution. The crystalline hetero‐double‐helices were isolated for several other combinations of pseudoenantiomeric ethynylhelicene oligomers.     

Diastereo‐ and Enantioselective anti‐Selective Hydrogenation of α‐Amino‐β‐keto Ester Hydrochlorides and Related Compounds Using Transition‐Metal–Chiral‐Bisphosphine Catalysts

This review describes our recent works on the diastereo‐ and enantioselective synthesis of anti‐β‐hydroxy‐α‐amino acid esters using transition‐metal–chiral‐bisphosphine catalysts. A variety of transition metals, namely ruthenium (Ru), rhodium (Rh),iridium (Ir), and nickel (Ni), in combination with chiral bisphosphines, worked well as catalysts for the direct anti‐selective asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides, yielding anti‐β‐hydroxy‐α‐amino acid esters via dynamic kinetic resolution (DKR) in excellent yields and diastereo‐ and enantioselectivities. The Ru‐catalyzed asymmetric hydrogenation of α‐amino‐β‐ketoesters via DKR is the first example of generating anti‐β‐hydroxy‐α‐amino acids. Complexes of iridium and axially chiral bisphosphines catalyze an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides via dynamic kinetic resolution. A homogeneous Ni–chiral‐bisphosphine complex also catalyzes an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides in an anti‐selective manner. As a related process, the asymmetric hydrogenation of the configurationally stable substituted α‐aminoketones using a Ni catalyst via DKR is also described.     

Asymmetric Photochemical Synthesis of Chiral 5‐(R)‐(l)‐Menthyloxy‐4‐Cycloaminobutyrolactones

Through photocatalysed regiospecific and stereoselective additions of cycloamines to 5‐(R)‐(l)‐menthyloxy‐2 (5H)‐furanone (3), chiral 5‐(R)‐(l)‐menthyloxy‐4‐cycloaminobutyrolactones were synthesized. In the new asymmetric photoaddition of compound 3, the N‐methyl cyclic amines (4) gave novel chiral C? C photoadducts (5) in 24–50% isolated yields with d. e. ≥ 98%. However, the secondary cyclic amines (6) afforded optically active N? C photoadducts (7) in 34–58% isolated yields with d. e. ≥ 98% under the same condition. All the synthesized optically active compounds were identified on the basis of their analytical data and spectroscopic data, such as [α]₅₈₉²⁰, IR, ¹H NMR, ¹³C NMR, MS and elementary analysis. The photosynthesis of chiral butyrolactones and its mechanism were discussed in detail.     

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.     

Isosteviol‐amino Acid Conjugates as Highly Efficient Organocatalysts for the Asymmetric One‐pot Three‐component Mannich Reactions

Isosteviol‐amino acid conjugates were synthesized and used as chiral catalysts for the asymmetric three‐component Mannich reaction with hydroxyacetone as donor molecule. Good yields (up to 98%) and excellent stereoselectivities (up to 97:3 dr and 99% ee) were achieved in a short reaction time. In addition, syn‐ or anti‐configurations of α‐hydroxy‐β‐amino carbonyl compounds were obtained as main products with different chiral catalysts.     

A Highly Efficient Synthesis of Optically Active Ferrocenylethylamines via Hydride Reduction of Chiral Ferrocenylketimines

Due to using (R)‐ or (S)‐α‐methylbenzylamine as a chiral auxiliary, and low‐temperature regime for reduction of the intermediate ferrocenyl‐mono‐ or 1,1′‐bis‐ketimines, the corresponding secondary mono‐ or 1,1′‐bis‐amines were prepared with high diastereoselectivity. Removal of the α‐methylbenzyl group afforded the optically active primary mono‐ and bis‐ferrocenylethylamines in high yields. The absolute configuration of (R,R)‐ 3a and (S,S)‐ 3b was determined by X‐ray single crystal diffraction.     

One‐Handed Single Helicates of Dinickel(II) Benzenehexapyrrole‐α,ω‐diimine with an Amine Chiral Source

Benzenehexapyrrole‐α,ω‐dialdehyde, composed of a pair of formyltripyrrole units with a 1,3‐phenylene linker, was metallated to give dinuclear single‐stranded helicates. X‐ray studies of the bis‐nickel(II) complex showed a helical C₂ form with a pair of helical–metal coordination planes of a 3N+O donor set. The terminal aldehyde was readily converted into the imine by optically active amines, whereby helix‐sense bias was induced. Bis‐nickel(II) and bis‐palladium(II) complexes of the benzenehexapyrrole‐α,ω‐diimines were studied to show that an enantiomer pair of the helical C₂ form are interchanged by slow flipping of each coordination plane and fast rotation around the C(benzene)?C(pyrrole) bond. The helical screw in the bis‐nickel(II) complexes was biased to one side in more than 95 % diastereoselectivity, which was achieved by using a variety of optically active amines, such as (R)‐1‐cyclohexylethylamine, (S)‐1‐ phenylethylamine, L ‐Phe(OEt) (Phe=phenylalanine), and (R)‐valinol. The nickel complexes showed much better diastereoselectivity than the corresponding palladium complexes.     

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.     

One Stone for Three Birds‐Rhodium‐Catalyzed Highly Diastereoselective Intramolecular [4+2] Cycloaddition of Optically Active Allene‐1,3‐dienes

RhCl(PPh₃)₃‐catalyzed [4+2] intramolecular cycloaddition of optically active axially chiral allene‐dienes afforded cis‐fused [3.4.0]‐bicyclic products with three chiral centers in good yields with an excellent chemo‐ and diastereoselectivity. A pair of enantiomers of such products was generated highly selectively from both enantiomers of starting allene‐dienes, indicating that the axial chirality dictated the absolute configurations of the three in situ generated chiral centers with a very high efficiency of chirality transfer.     

Synthesis of an Enantiomerically Pure 1,3‐Thiazole‐5(4H)‐thione and Its Stereoselective 1,3‐Dipolar Cycloaddition with an Azomethine Ylide

Starting from the enantiomerically pure 2H‐azirin‐3‐amines (R,S)‐ 4 and (S,S)‐ 4 , the enantiomeric, optically active 4‐benzyl‐4‐methyl‐2‐phenyl‐1,3‐thiazole‐5(4H)‐thiones (R)‐ 1 and (S)‐ 1 , respectively, have been prepared (Schemes 2 and 3). In each case, the reaction of 1 with N‐(benzylidene)[(trimethylsilyl)methyl]amine ( 2 ) in HMPA in the presence of CsF and trimethylsilyl triflate gave a mixture of four optically active spirocyclic cycloadducts (Scheme 4). Separation by preparative HPLC yielded two pure diastereoisomers, e.g., (4R,5R,9S)‐ 10 and (4R,5R,9R)‐ 10 . The regioisomeric compounds 11 were obtained as a mixture of diastereoisomers. The products were formed by a 1,3‐dipolar cycloaddition of 1 with in situ generated azomethine ylide 3 , which attacks 1 stereoselectively from the sterically less‐hindered side, i.e., with (R)‐ 1 the attack occurs from the re‐side and in the case of (S)‐ 1 from the si‐side.     

Helicity Induction and Its Static Memory of Poly(biphenylylacetylene)s Bearing Pyridine N‐Oxide Groups and Their Use as Asymmetric Organocatalysts

Novel poly(biphenylylacetylene) derivatives carrying different types of pyridine N‐oxide units with a bulky or less‐bulky substituent at a different position as the functional pendant groups (poly‐ 2a and poly‐ 2b ) were synthesized by the rhodium‐catalyzed polymerization of the corresponding monomers. The influence of the steric environment around the catalytically active pyridine N‐oxide sites on the helicity induction and its static memory as well as the asymmetric catalytic activities of the resulting helical polymers with a macromolecular helicity memory was investigated. The polyacetylenes formed an excess one‐handed helical conformation upon noncovalent interactions with optically active alcohols and the induced macromolecular helicities of the polyacetylenes were efficiently memorized after the removal of the chiral inducers. Poly‐ 2b with the macromolecular helicity memory showed an enantioselectivity for the catalytic asymmetric allylation of benzaldehydes, producing optically active allyl alcohols, although their enantioselectivities were low. On the other hand, poly‐ 2a exhibited a negligible catalytic activity probably due to the bulky substituent at the o‐position of the pyridine N‐oxide residues, while poly‐ 2a underwent a unique helix‐inversion with the increasing concentration of chiral alcohols and the opposite helicity of poly‐ 2a was further successfully memorized. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2481–2490     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines

The synthesis of novel 2,2‐disubstituted 2H‐azirin‐3‐amines with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers (1′R,2R)‐ 4a – e and (1′R,2S)‐ 4a – e (Scheme 1, Table 1), which are synthons for the (R)‐ and (S)‐isomers of isovaline, 2‐methylvaline, 2‐cyclopentylalanine, 2‐methylleucine, and 2‐(methyl)phenylalanine, respectively. The configuration at C(2) of the synthons was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group. The reaction of 4 with thiobenzoic acid, benzoic acid, and the dipeptide Z‐Leu‐Aib‐OH ( 12 ) yielded the monothiodiamides 10 , the diamides 11 (Scheme 2, Table 3), and the tripeptides 13 (Scheme 3, Table 4), respectively.     

Desymmetrization of 1,4‐Pentadien‐3‐ol by the Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Imines

Desymmetrization of the divinyl carbinol 1,4‐pentadien‐3‐ol was accomplished by the asymmetric 1,3‐dipolar cycloaddition of azomethine imines based on a magnesium‐mediated, multinucleating chiral reaction system utilizing diisopropyl (R,R)‐tartrate as the chiral auxiliary. The corresponding optically active trans‐pyrazolidines, each with three contiguous stereogenic centers, were obtained with excellent regio‐, diastereo‐, and enantioselectivity, with results as high as 99 % ee. This reaction was shown to be applicable to both aryl‐ and alkyl‐substituted azomethine imines. The use of a catalytic amount of diisopropyl (R,R)‐tartrate was also effective when accompanied by the addition of MgBr₂.     

Synthesis of Optically Active P‐Chiral and Optically Inactive Oligophosphines

A series of optically active P‐chiral oligophosphines (S,R,R,S)‐ 2 , (S,R,S,S,R,S)‐ 3 , (S,R,S,R,R,S,R,S)‐ 4 , and (S,R,S,R,S,R,R,S,R,S,R,S)‐ 5 with four, six, eight, and 12 chiral phosphorus atoms, respectively, were successfully synthesized by a step‐by‐step oxidative‐coupling reaction from (S,S)‐ 1 . The corresponding optically inactive oligophosphines 1′ – 5′ were also prepared. Their properties were characterized by DSC, XRD, and optical‐rotation analyses. While optically active bisphosphine (S,S)‐ 1 and tetraphosphine (S,R,R,S)‐ 2 behaved as small molecules, octaphosphine (S,R,S,R,R,S,R,S)‐ 4 and dodecaphosphine (S,R,S,R,S,R,R,S,R,S,R,S)‐ 5 exhibited the features of a polymer. Furthermore, DSC and XRD analyses showed that hexaphosphine (S,R,S,S,R,S)‐ 3 is an intermediate between a small molecule and a polymer. Comparison of optically active oligophosphines 1 – 5 with the corresponding optically inactive oligophosphines 1′ – 5′ revealed that the optically active phosphines have higher crystallinity than the optically inactive counterparts. It is considered that the properties of oligophosphines depend on the enantiomeric purity as well as the oligomer chain length.     

Diastereo‐ and Enantioselective Synthesis of (E)‐δ‐Boryl‐Substituted anti‐Homoallylic Alcohols in Two Steps from Terminal Alkynes

We report the highly diastereo‐ and enantioselective preparation of (E)‐δ‐boryl‐substituted anti‐homoallylic alcohols in two steps from terminal alkynes. This method consists of a cobalt(II)‐catalyzed 1,1‐diboration reaction of terminal alkynes with B₂pin₂ and a palladium(I)‐mediated asymmetric allylation reaction of the resulting 1,1‐di(boryl)alk‐1‐enes with aldehydes in the presence of a chiral phosphoric acid. Propyne, which is produced as the byproduct during petroleum refining, could be used as the starting material to construct homoallylic alcohols that are otherwise difficult to synthesize with high stereocontrol.     

One‐Handed Helical Screw Direction of Homopeptide Foldamer Exclusively Induced by Cyclic α‐Amino Acid Side‐Chain Chiral Centers

Chiral cyclic α,α‐disubstituted amino acids, (3S,4S)‐ and (3R,4R)‐1‐amino‐3,4‐(dialkoxy)cyclopentanecarboxylic acids ((S,S)‐ and (R,R)‐Ac₅c^dOR; R: methyl, methoxymethyl), were synthesized from dimethyl L ‐(+)‐ or D ‐(?)‐tartrate, and their homochiral homoligomers were prepared by solution‐phase methods. The preferred secondary structure of the (S,S)‐Ac₅c^dOMe hexapeptide was a left‐handed (M) 3₁₀ helix, whereas those of the (S,S)‐Ac₅c^dOMe octa‐ and decapeptides were left‐handed (M) α helices, both in solution and in the crystal state. The octa‐ and decapeptides can be well dissolved in pure water and are more α helical in water than in 2,2,2‐trifluoroethanol solution. The left‐handed (M) helices of the (S,S)‐Ac₅c^dOMe homochiral homopeptides were exclusively controlled by the side‐chain chiral centers, because the cyclic amino acid (S,S)‐Ac₅c^dOMe does not have an α‐carbon chiral center but has side‐chain γ‐carbon chiral centers.     

Synthesis of Both Enantiomers of Nine‐Membered CF3‐Substituted Heterocycles Using a Single Chiral Ligand: Palladium‐Catalyzed Decarboxylative Ring Expansion with Kinetic Resolution

The two enantiomers of trifluoromethyl‐benzo[c][1,5]oxazonines, (R)‐ 4 and (S)‐ 4 , can be selectively accessed with high enantiopurity by the Pd‐catalyzed ring‐expansion reaction of trifluoromethyl‐benzo[d][1,3]oxazinones ( 1 ) with vinyl ethylene carbonates ( 3 ) using one antipode of a chiral ligand. Initially, the reaction proceeds by a double decarboxylative ring‐expansion with kinetic resolution of 1 in the presence of a Pd‐catalyst/chiral ligand to provide (R)‐ 4 with high enantiopurity. At the same time, the nonreactive antipode of 1 , (S)‐ 1 , which was recovered with an impeccable s factor of up to 713 and an ideal chemical yield, was transferred into the antipode of the products, (S)‐ 4 , with high enantiopurity by a second run of the Pd‐catalyzed double decarboxylation reaction, but this time without any chiral auxiliary. Thus, both antipodes of the chiral trifluoromethyl heterocycles 4 can be obtained in excellent enantiopurity using only a single antipode of the chiral catalyst.