基于杯[4]芳烃和S-联萘酚的荧光传感器的合成及其对N-Boc保护谷氨酸阴离子的对应选择性识别性能研究

合成了一种基于杯[4]芳烃和S-联萘酚单元的新型手性大环受体4,并用荧光光谱和核磁氢谱研究了该受体与阴离子的键合性质。非线性曲线拟合结果表明受体4与N-Boc保护L-和D-谷氨酸阴离子都能通过多重氢键形成1:1的络合物,而且对N-Boc保护谷氨酸阴离子对映体显示了较好的对应选择性识别性能（Kass(L) / Kass(D) = 4.65）。不同的荧光响应表明受体4可以用作N-Boc保护谷氨酸阴离子的对应选择性的荧光化学传感器。     

Bifunctional‐Thiourea‐Catalyzed Diastereo‐ and Enantioselective Aza‐Henry Reaction

Bifunctional thiourea 1 a catalyzes aza‐Henry reaction of nitroalkanes with N‐Boc‐imines to give syn‐β‐nitroamines with good to high diastereo‐ and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N‐protecting groups of the imines have a determining effect on the chirality of the products, that is, the reaction of N‐Boc‐imines gives R adducts as major products, whereas the same reaction of N‐phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP‐99,994.     

Synthesis of 1‐Substituted Tetrahydroisoquinolines by Lithiation and Electrophilic Quenching Guided by In Situ IR and NMR Spectroscopy and Application to the Synthesis of Salsolidine,Carnegine and Laudanosine

The lithiation of N‐tert‐butoxycarbonyl (N‐Boc)‐1,2,3,4‐tetrahydroisoquinoline was optimized by in situ IR (ReactIR) spectroscopy. Optimum conditions were found by using n‐butyllithium in THF at ?50 °C for less than 5 min. The intermediate organolithium was quenched with electrophiles to give 1‐substituted 1,2,3,4‐tetrahydroisoquinolines. Monitoring the lithiation by IR or NMR spectroscopy showed that one rotamer reacts quickly and the barrier to rotation of the Boc group was determined by variable‐temperature NMR spectroscopy and found to be about 60.8 kJ mol^?1, equating to a half‐life for rotation of approximately 30 s at ?50 °C. The use of (?)‐sparteine as a ligand led to low levels of enantioselectivity after electrophilic quenching and the “poor man’s Hoffmann test” indicated that the organolithium was configurationally unstable. The chemistry was applied to N‐Boc‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline and led to the efficient synthesis of the racemic alkaloids salsolidine, carnegine, norlaudanosine and laudanosine.     

Disulfonimide‐Catalyzed Asymmetric Reduction of N‐Alkyl Imines

A chiral disulfonimide (DSI)‐catalyzed asymmetric reduction of N‐alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O has been developed. The reaction delivers Boc‐protected N‐alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross‐coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)‐Rivastigmine, NPS R‐568 Hydrochloride, and (R)‐Fendiline.     

Dynamic thermodynamic resolution of lithiated N-Boc-N′-alkylpiperazines

Deprotonation of N-Boc-N′-alkylpiperazines with sec-BuLi in Et₂O-TMEDA gave the 2-lithio derivatives which were resolved in the presence of a chiral ligand. The best ligands for the asymmetric substitution were diamino-alkoxides that promoted a dynamic thermodynamic resolution (DTR) of the organolithium at −30 °C. Electrophilic quench gave enantiomerically enriched 2-substituted piperazines. Of a selection of piperazines, the N′-t-butyl derivative gave the best results, with the product N-Boc-N′-t-butyl-2-substituted piperazines being formed with enantiomer ratios up to 81:19.     

Dual Stereocontrol for Enantioselective Hydrogenation of Dihydroisoquinolines Induced by Tuning the Amount of N‐Bromosuccinimide

An efficient dual stereocontrol in iridium‐catalyzed hydrogenation of 1‐substituted 3,4‐dihydroisoquinolines was realized by tuning the amount of N‐bromosuccinimide using chiral ligand of single configuration, providing both enantiomers of 1‐substituted 1,2,3,4‐tetrahydroisoquinolines with up to 89% ee (S) and 98% ee (R), respectively. Dual activation role of N‐bromosuccinimide is proposed to be responsible for the reversal of enantioselectivity under two hydrogenation conditions.     

Asymmetric Synthesis of Hydrocarbazoles Catalyzed by an Octahedral Chiral‐at‐Rhodium Lewis Acid

A bis‐cyclometalated chiral‐at‐metal rhodium complex catalyzes the Diels–Alder reaction between N‐Boc‐protected 3‐vinylindoles (Boc=tert‐butyloxycarbonyl) and β‐carboxylic ester‐substituted α,β‐unsaturated 2‐acyl imidazoles with good‐to‐excellent regioselectivity (up to 99:1) and excellent diastereoselectivity (>50:1 d.r.) as well as enantioselectivity (92–99 % ee) under optimized conditions. The rhodium catalyst serves as a chiral Lewis acid to activate the 2‐acyl imidazole dienophile by two‐point binding and overrules the preferred regioselectivity of the uncatalyzed reaction.     

N‐tert‐butoxycarbonyl‐N‐substituted hydrazines in SNAr displacements. Synthetic pathways to N‐1‐substituted anthrapyrazoles,aza‐anthrapyrazoles and aza‐benzothiopyranoindazoles

The synthesis of several N‐tert‐butoxycarbonyl(Boc)‐protected‐N‐substituted hydrazines has been accomplished. The use of these protected hydrazines in S_NAr substitutions leads to products in which the most nucleophilic nitrogen displaces the leaving group. Treatment of these compounds with trifluoroacetic acid readily removes the Boc‐protecting group and the intermediates readily undergo cyclizations to yield N‐1‐substituted aza‐benzothiopyranoindazoles, anthrapyrazoles and aza‐anthrapyrazoles. Side chain buildup was employed in the synthesis of several aza‐anthrapyrazoles.     

Chiral separation of amides of amino acid on a (S)‐N‐(3,5‐dinitrobenzoyl)leucine‐N‐phenyl‐N‐propylamide‐bonded silica using nonaqueous capillary electrochromatography

(S)‐N‐(3,5‐dinitrobenzoyl)leucine‐N‐phenyl‐N‐propylamine‐bonded silica was used as a chiral stationary phase for separation of a set of racemic π‐acidic and π‐basic α‐amino acid amides in electrolyteless ACN‐water eluents by CEC in the RP and polar organic (PO) modes. The effect of the amount of water in the ACN‐water eluent on chiral separation was examined. As water is added to ACN, retention was shortened but resolution and selectivity deteriorated severely. Retention, enantioselectivity, and resolution factors obtained in 100% ACN were compared with those in an n‐hexane‐isopropanol eluent with a small amount of water by normal phase (NP) CEC. Much shorter retention times with comparable enantioselectivities were observed with 100% ACN, demonstrating the advantage of separation on (S)‐N‐(DNB)leucine‐N‐phenyl‐N‐propylamine‐bonded silica in PO‐CEC over NP‐CEC.     

Dynamic thermodynamic and dynamic kinetic resolution of 2-lithiopyrrolidines

Dynamic resolution has been studied as a method for the asymmetric synthesis of 2-substituted pyrrolidines. Highly enantioselective electrophilic substitutions of racemic 2-lithiopyrrolidines in the presence of a chiral ligand have been achieved. The organolithium compounds were prepared by tin-lithium exchange from the corresponding tributylstannanes and n-butyllithium or by deprotonation of N-(tert-butyloxycarbonyl)pyrrolidine with sec-butyllithium. A range of N-substituents and chiral ligands were investigated for the dynamic resolution. Electrophilic quench of the resolved diastereomeric 2-lithiopyrrolidine-chiral ligand complexes provided the enantiomerically enriched 2-substituted pyrrolidines. With N-alkyl derivatives, the resolution occurs conveniently at (or just below) room temperature and either enantiomer of the product can be formed by appropriate choice of the chiral ligand. The asymmetric induction occurs as a result of a thermodynamic preference for one of the diastereomeric complexes. The minor complex was found to have a faster rate of reaction with the electrophile. The use of N-allylic derivatives provides a means to prepare the N-unsubstituted pyrrolidine products. Best results were obtained with the N-2,3-dimethylbut-2-enyl derivative, and this N-substituent could be cleaved using 1-chloroethyl chloroformate. With N-Boc-2-lithiopyrrolidine, the enantioselectivity arises by a kinetic resolution and high levels of asymmetric induction in the presence of excess n-butyllithium can be obtained. Dynamic kinetic resolution of the N-Boc derivative is limited in the scope of electrophile that can be used.     

Chiral‐Organotin‐Catalyzed Kinetic Resolution of Vicinal Amino Alcohols

A highly efficient kinetic resolution of racemic amino alcohols has been achieved for the first time with a chiral tin catalyst. A chiral organotin compound with 3,4,5‐trifluorophenyl groups at the 3,3′‐positions of the binaphthyl framework enabled this transformation with excellent yield and high enantioselectivity. The process tolerates aryl‐ and alkyl‐substituted amino alcohols and a variety of other substrates, affording the corresponding products in high enantioselectivity and with s factors up to >500.     

Dynamic kinetic resolution of N-Boc-2-lithiopyrrolidine

Asymmetric substitution of the organolithium derived either from N-Boc-2-tributylstannylpyrrolidine by tin-lithium exchange or from N-Boc-pyrrolidine by deprotonation occurs in the presence of a commercially available chiral diamine ligand with high levels of enantioselectivity by a dynamic kinetic resolution pathway.     

Stereoselective Synthesis and Modelling‐Driven Optimisation of Carane‐Based Aminodiols and 1,3‐Oxazines as Catalysts for the Enantioselective Addition of Diethylzinc to Benzaldehyde

The reductive amination of (?)‐2‐carene‐3‐aldehyde, prepared in two steps from (?)‐perillaldehyde, furnished 2‐carene‐based allylamines. tert‐Butyloxycarbonyl (Boc) or carbobenzyloxy (Cbz) protection of the resulting amines, followed by stereoselective dihydroxylation in highly stereospecific reactions with OsO₄ and subsequent deprotection, resulted in N‐benzylaminodiols, which were transformed to primary and tertiary aminodiols. The reactions of the N‐benzyl‐ and N‐(1‐phenylethyl)‐substituted derivatives with formaldehyde led to highly regioselective ring closure, resulting in carane‐fused 1,3‐oxazines. The aminodiols and their 1,3‐oxazine derivatives were applied as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. The best (R) enantioselectivity was observed in the case of the N‐((R)‐1‐phenylethyl)‐substituted aminodiol, whereas the opposite chiral direction was preferred when the 1,3‐oxazines were applied. Through the use of molecular modelling at an ab initio level, this phenomenon was interpreted in terms of competing reaction pathways. Molecular modelling at the RHF/LANL2DZ level of theory was successfully applied for a mechanism‐based interpretation of the stereochemical outcome of the reactions leading to the development of further 1,3‐oxazine‐based ligands, which display excellent (S) enantioselectivity (95 and 98 % ee) in the examined transformation.     

Enantioselective Reactions of 2‐Sulfonylalkyl Phenols with Allenic Esters: Dynamic Kinetic Resolution and [4+2] Cycloaddition Involving ortho‐Quinone Methide Intermediates

We report herein a dynamic kinetic resolution (DKR) involving ortho ‐quinone methide (o ‐QM) intermediates. In the presence of Et₃N and the cinchonine‐derived nucleophilic catalyst D , the DKR of 2‐sulfonylalkyl phenols with allenic esters afforded chiral benzylic sulfones in 57–79 % yield with good to excellent enantioselectivity (85–95 % ee ). Furthermore, with 2‐(tosylmethyl)sesamols or 2‐(tosylmethyl)naphthols, from which stable o ‐QM substrates can be generated, a formal [4+2] cycloaddition delivered 4‐aryl‐ or alkyl‐substituted chromans with excellent enantioselectivity (88–97 % ee ).     

Approach to Fully Substituted Cyclic Nitrones from N‐Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C

An approach to cyclic nitrones from N‐hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N‐OSEM [SEM=2‐(trimethylsilyl)ethoxymethyl] lactam forms a five‐membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one‐pot process. When combined with the N‐oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio‐pure form, enabling the concise total synthesis of cylindricine C.     

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.     

A pipecolic acid (Pip)‐containing dipeptide,Boc‐d‐Ala‐l‐Pip‐NHiPr

The title dipeptide, 1‐(tert‐butoxy­carbonyl‐d ‐alanyl)‐N‐iso­propyl‐l ‐pipecol­amide or Boc‐d ‐Ala‐l ‐Pip‐NHⁱPr (H‐Pip‐OH is pipecolic acid or piperidine‐2‐carboxylic acid), C₁₇H₃₁N₃­O₄, with a d –l heterochiral sequence, adopts a type II′β‐­turn conformation, with all‐trans amide functions, where the C‐terminal amide NH group interacts with the Boc carbonyl O atom to form a classical i+3 i intramolecular hydrogen bond. The C^α substituent takes an axial position [H^α (Pip) equatorial] and the trans pipecolamide function is nearly planar.     

Enantioselective Alkylation of N‐Arylhydrazones Derived from α‐Keto Esters and Isatin Derivatives through Asymmetric Phase‐Transfer Catalysis

The phase‐transfer‐catalyzed asymmetric alkylation reactions of N‐arylhydrazones derived from α‐keto‐esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra‐substituted carbon stereocenter in good yields with high chemo‐ and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza‐β‐lactams without loss of enantiopurity.     

Chiral N‐Heterocyclic Carbene Ligands Bearing a Pyridine Moiety for the Copper‐Catalyzed Alkylation of N‐Sulfonylimines with Dialkylzinc Reagents

Amino acid‐derived chiral imidazolium salts, each bearing a pyridine ring, were developed as N‐heterocyclic carbene ligands. The copper‐catalyzed asymmetric alkylation of various N‐sulfonylimines with dialkylzinc reagents in the presence of these chiral imidazolium salts afforded the corresponding alkylated products with high enantioselectivity (up to 99 % ee). The addition of HMPA to the reaction mixture as a co‐solvent is critical in terms of chemical yield and enantioselectivity. A wide range of N‐sulfonylimines and dialkylzinc reagents were found to be applicable to this reaction.     

Asymmetric Synthesis of 2,3‐Dihydropyrroles by Ring‐Opening/Cyclization of Cyclopropyl Ketones Using Primary Amines

The asymmetric ring‐opening/cyclization of cyclopropyl ketones with primary amine nucleophiles was catalyzed by a chiral N,N′‐dioxide/scandium(III) complex through a kinetic resolution process. A broad range of cyclopropyl ketones and primary amines are suitable substrates of this reaction. The corresponding products were afforded in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield) under mild reaction conditions. This method provides a promising access to chiral 2,3‐dihydropyrroles as well as an effective procedure for the kinetic resolution of 2‐substituted cyclopropyl ketones.