“Dutch”拆分研究进展

本文综述了第一代Dutch拆分、第二代Dutch拆分及反义Dutch拆分的拆分机理和研究进展,并展望了Dutch拆分的应用前景。Dutch拆分能以高收率和近于100％ee值与所有的实验消旋体迅速形成非对映体的结晶。第一代Dutch拆分中Family拆分试剂在形成非对映体晶体过程是典型的固溶体行为。在第二代Dutch拆分中,成核抑制剂改变了非对映异构体的亚稳区宽度,溶解度较大的非对映体盐比溶解度较小的非对映体盐的结晶温度下降得更多,使溶解度较小的非对映体盐更容易析出。     

动力学拆分法的研究进展

综述了光活性化合物动力学拆分法的研究进展及其在不对称合成中的应用。     

用循环拆分法制备手性萘乙胺

研究了1-(1-萘基)乙胺[(RS)-1]和1-(2-萘基)乙胺[(RS)-2]的循环拆分方法。以D-酒石酸为拆分剂,分别拆分(RS)-1和(RS)-2得到了(R)-1-(1-萘基)乙胺(收率31%,98%ee)和(R)-1-(2-萘基)乙胺(收率30%,98%ee),并对母液中的非目标对映异构体成功的进行了消旋化,实现了循环拆分。     

化学拆分的新方法研究

主要介绍了近年来发展起来的两种化学拆分新方法,包括拆分和组合拆分;并简要论述了化学拆分中的手性识别现象,以及化学拆分方法在手性药物制备中的应用。     

The Family Approach to the Resolution of Racemates

The resolution of racemates is revolutionized with the method presented here, in which mixtures (“families”) of structurally and stereochemically related resolving agents are used to precipitate salts of acidic or basic racemates rapidly and dependably. The racemate is usually separated in a single operation into enantiomers—the enantiomeric excesses and yields are good to excellent. Reagent mixtures with racemic or achiral components have also been developed.     

Efficiency in nonenzymatic kinetic resolution

The Walden memorial at the Technical University in Riga is pictured in the frontispiece to mark the recent centennial of the Walden inversion. This is a rare public monument to key events from the first era of exploration in stereocontrolled synthesis, and may be the only such monument to use the language of organic chemistry expressed at the molecular level. The reaction of racemic substrates with chiral nucleophiles is one of many methods currently known to achieve kinetic resolution, a phenomenon that ranks as the oldest and most general approach for the synthesis of highly enantioenriched substances. The first nonenzymatic kinetic resolutions as well as the original forms of the Walden inversion were studied in the 1890s. All of these investigations were conducted within the first generation following the demonstration that carbon is tetrahedral, and provided abundant evidence that the principles and importance of enantiocontrolled syntheses were understood. However, a reliable, rapid technique to quantify results and guide the optimization process was still lacking. Many decades passed before this problem was solved by the advent of HPLC and GLPC assays on chiral supports, which stimulated explosive growth in the synthesis of nonracemic substances by kinetic resolution. The Walden monument is accessible to passers-by for hands-on inspection as well as for contemplation and learning. In a similar way, kinetic resolution is experimentally accessible and can be thought-provoking at several levels. We follow the story of kinetic resolution from the early discoveries through fascinating historical milestones and conceptual developments, and close with a focus on modern techniques that maximize efficiency.     

From Racemic Compound to Spontaneous Resolution: A Linker‐Imposed Evolution of Chiral [MnMo9O32]6−‐Based Polyoxometalate Compounds

Five compounds based on [MnMo₉O₃₂]^6?: (Himi)₆[MnMo₉O₃₂] ( 1 ) (imi=imidazole), Na₂(Himi)₄[MnMo₉O₃₂] ? 2 H₂O ( 2 ), Na₃(Himi)₃[MnMo₉O₃₂] ( 3 ), D ‐NH₄Mn_2.5[MnMo₉O₃₂] ? 11 H₂O ( 4 a ), and L ‐NH₄Mn_2.5[MnMo₉O₃₂] ? 11 H₂O ( 4 b ) were prepared and characterized. X‐ray crystallographic analysis revealed that compounds 1 and 2 with imidazole molecules as linkers are racemic compounds; compound 3 is a racemic solid solution of Na⁺ cations and the polyoxoanion [MnMo₉O₃₂]^6?; and compounds 4 a and 4 b are enantiomers. In compound 4 , the homochiral polyoxoanions [MnMo₉O₃₂]^6? are connected by Mn²⁺ cations to form a unique (4⁵ ? 6)(4⁷ ? 6⁸) topology net framework. By adjusting the linkers from imidazole molecules to Na⁺ and finally Mn²⁺ cations, the chiral polyoxoanions [MnMo₉O₃₂]^6? were changed from a racemic compound to a conglomerate. This means that spontaneous resolution can be efficiently realized by connecting homochiral polyoxoanions into one‐dimensional (1D), 2D, and 3D structures, with an emphasis on using appropriate linkers with substantial interaction strength, directionality, and enantioselectivity.     

Absolute asymmetric synthesis of stereochemically labile aldehyde helicates and subsequent chirality transfer reactions

Helical complexes formed between aluminum tris(2,6-diphenylphenoxide) (ATPH) and five different aldehydes have been prepared and structurally characterized by X-ray diffraction. It was found that [Al(OC6H3Ph2)3PhCHO] (2), [Al(OC6H3Ph2)3(4-CH3C6H4CHO)] (3), [Al(OC6H3Ph2)3(4-tBuC6H4CHO)] (4), and [Al(OC6H3Ph2)3(p-CH3OC6H4CHO)] (5) all crystallize as conglomerates, while crystals of [Al(OC6H3Ph2)3(o-CH3OC6H4CHO)] (6) are racemic. Supramolecular CH/pi interactions between molecules in crystals of 2-5 that enable stereochemical information to be mediated in three dimensions have been identified and explain the high frequency of conglomerate formation among ATPH helicates. Since 2-5 are stereochemically labile and thus enantiomerize rapidly in solution, the conglomerates can be resolved by crystallization-induced asymmetric transformation. The determination of the enantiomeric excess (ee) in solid samples of stereochemically labile molecules is not trivial, but solid-state CD spectroscopic data, anomalous dispersion data, and the ee values in alkylation reactions all indicate that preferential crystallization of 2-5 yields an essentially enantiopure product. Thus the preparation of 2-5 constitute new examples of absolute asymmetric synthesis. The helical chirality can be transferred (and thus trapped) to alcohols (with ee values of up to 16%) in crystal-to-crystal reactions with achiral organometallic reagents.     

Dynamic Kinetic Resolution of 2,3‐Dihydrobenzo[b]furans: Chemoenzymatic Synthesis of Analgesic Agent BRL 37959

An efficient asymmetric synthesis of (S)‐2,3‐dihydrobenzo[b]furan‐3‐carboxylic acid ( 8 a ) and (S)‐5‐chloro‐2,3‐dihydrobenzo[b]furan‐3‐carboxylic acid ( 8 b ) was established. Key to the success was the highly stereoselective enzymatic kinetic resolution of the corresponding methyl or ethyl esters that was further developed into a dynamic process. As a reliable and fast tool for analysing the enantiomeric excess, HPLC coupled with a CD detector was utilized. The route was completed by a Friedel–Crafts acylation of ethyl (S)‐5‐chloro‐2,3‐dihydrobenzo[b]furan‐3‐carboxylate ( 7 c ) followed by saponification leading to (S)‐5‐chloro‐2,3‐dihydrobenzo[b]furan‐3‐carboxylic acid ( 2 ), an analgesic agent.     

One‐Pot Resolution of trans‐2‐Iodo‐cyclohexanol with O,O′‐Dibenzoyl‐(2R,3R)‐tartaric Acid in Solid Phase

A one‐pot, solid‐state resolution of racemic‐trans‐2‐iodo‐cyclohexanol by O,O′‐dibenzoyl‐(2R,3R)‐tartaric acid was performed. By mixing the solid racemate with half an equivalent resolving agent, the (1R,2R)‐isomer of the alcohol remains uncomplexed and can be sublimated at lower temperature. By increasing the temperature, the complex decomposes and the (1S,2S)‐isomer can be gained as a second fraction of the sublimation and the resolving agent remains back.     

结晶诱导不对称转化在拆分手性化合物中的研究进展

结晶诱导动态拆分(CIDR)是对映异构体(或非对映异构体)的原位外消旋作用和选择性结晶过程的耦合.结晶诱导不对称转化(CIAT)包括了CIDR过程,也包括了结晶诱导分离具有单个或多个非对映异构体中心的异构体、顺反式烯烃的过程.概述了CIAT和CIDR在拆分手性化合物中的研究进展.     

Practical Tactics in Resolution of Racemates via Diastereomeric Salt Formation

A practical tactics in the classical resolutions was illustrated for affording the desired isomers in maximum yields. According to the practical tactics resolution of racemic ethyl nipecotate, Corey lactone and huperzine A intermediate was successfully practiced. The basis of this practicability is the well-known Marckwald principle.     

Dynamic kinetic resolution of 2-methyl-2-nitrocyclohexanol: Combining the intramolecular nitroaldol (Henry) reaction & lipase-catalysed resolution

Efforts to combine the intramolecular nitroaldol reaction with lipase-catalysed resolution of the resulting nitroaldol adduct in a one-pot dynamic kinetic resolution (DKR) are described. Significant challenges were encountered in the combination of the two systems. trans-2-Methyl-2-nitrocyclohexyl acetate (±)-3b was isolated in excellent enantiopurity (>98% ee) via a sequential DKR sequence where the lipase-mediated resolution and base-mediated interconversion of 2-methyl-2-nitrocyclohexanol 2 were effected alternately, demonstrating the feasibility of this approach initially. Further work showed, for the first time, evidence that a DKR-type system is possible for 2. Reaction engineering allowed the design of a sequential one-pot reaction system which furnished the products with excellent enantioselectivity, and good diastereoselectivity.     

Enzymatic transformations. Part 55: Highly productive epoxide hydrolase catalysed resolution of an azole antifungal key synthon

A highly productive bioprocess for the preparation of enantiopure azole antifungal chirons is described. These are key building blocks for the synthesis of new triazole drug derivatives known to display valuable activity against such infections as for instance fluconazole-resistant oro-oesophageal candidiasis. Using commercially available recombinant Aspergillus niger epoxide hydrolase under optimised experimental conditions, the hydrolytic kinetic resolution of 1-chloro-2-(2,4-difluorophenyl)-2,3-epoxypropane was performed in plain water, at room temperature, using a two-phase reactor. This methodology allowed the process to be run at a substrate concentration as high as 500 g/L (i.e., 2.5 M) and afforded the (unreacted) epoxide and the corresponding vicinal diol, both in nearly enantiopure form and quantitative yield.     

Chemometrics applied to unravel multicomponent processes and mixtures: Revisiting latest trends in multivariate resolution

Progress in the analysis of multicomponent processes and mixtures relies on the combination of sophisticated instrumental techniques and suitable data analysis tools focused on the interpretation of the multivariate responses obtained. Despite the differences in compositional variation, complexity and origin, the raw measurements recorded in a multicomponent chemical system can be very often described with a simple model consisting of the composition-weighted sum of the signals of their pure compounds.

Multivariate resolution methods have been the tools designed to unravel this pure compound information from the non-selective mixed original experimental output. The evolution of these chemometric approaches through the improvement of exploratory tools, the adaptation to work with complex data structures, the ability to introduce chemical and mathematical information in the algorithms and the better quality assessment of the results obtained is revisited. The active research on these chemometric area has allowed the successful application of these methodologies to chemical problems as complex and diverse as the interpretation of protein folding processes or the resolution of spectroscopic images.     

Optical isomer separation of flavanones and flavanone glycosides by nano-liquid chromatography using a phenyl-carbamate-propyl-β-cyclodextrin chiral stationary phase

In this paper a phenyl-carbamate-propyl-β-cyclodextrin stationary phase was employed for the enantioseparation of several flavonoids, including flavanones and methoxyflavanones by using nano-liquid chromatography (nano-LC). The same stationary phase was also used for the diastereoisomeric separation of two flavanone glycosides. The compounds: flavanone, 2′-hydroxyflavanone, 4′-hydroxyflavanone, 6-hydroxyflavanone, 7-hydroxyflavanone, 4′-methoxyflavanone, 6-methoxyflavanone, 7-methoxyflavanone, hesperetin, hesperidin, naringenin and naringin were studied using reversed, polar organic and normal elution modes. The effect of the nature and composition of the mobile phase (organic modifier type, buffer and water content in the reversed phase mode) on the enantioresolution (R_s), retention factor (k) and enantioselectivity (α) were investigated. Baseline resolution of all studied flavonoids, with the exception of 2′-hydroxyflavanone and naringin, was achieved in reversed phase mode using a mixture of MeOH/H₂O at different ratios as mobile phase. Good results, in terms of peak efficiency and short analysis time, were obtained adding 1% triethylammonium acetate pH 4.5 buffer to MeOH/H₂O mixture. The separation of the studied compounds was also performed in polar organic mode. By using 100% of MeOH as mobile phase, the resolution was achieved for the studied analytes, except for 7-hydroxyflavanone, 2′-hydroxyflavanone, naringenin, hesperidin and naringin. Normal mode was tested employing a mixture of EtOH/hexane/TFA as mobile phase achieving the enantiomeric and diastereomeric separation of only hesperetin and hesperidin, respectively. The use of nano-LC technique for the resolution of flavanones optical isomers allowed to achieve good resolutions in shorter analysis time compared to the results reported in literature with conventional HPLC.     

Catalytic Kinetic Resolution of Biaryl Compounds

Biaryl compounds with axial chirality are very common in synthetic chemistry, especially in catalysis. Axially chiral biaryls are important due to their biological activities and extensive applications in asymmetric catalysis. Thus the development of efficient enantioselective methods for their synthesis has attracted considerable attention. This Minireview discusses the progress made in catalytic kinetic resolution of biaryl compounds and chronicles significant advances made recently in catalytic kinetic resolution of biaryl scaffolds.     

Characterization of an energy dispersive X-ray fluorescence imaging system based on a Micropattern Gaseous Detector

An energy dispersive X-ray fluorescence (EDXRF) imaging system based on a Micropattern Gas Detector has already shown good results for different applications. An X-ray tube, a pinhole camera and a Micro-Hole and Strip Plate (MHSP) based detector are the main components of the experimental system. The detector uses an MHSP in a Xe atmosphere at 1 bar, and acting as a photon counting device, i.e., it is capable to record each single event retaining the energy and the interaction position (2D-sensitive detector) information of the incident photon, demonstrating to be a promising device for EDXRF imaging applications. This work presents studies of energy resolution, energy linearity and spatial resolution/elemental mapping as a function of image magnification of the system.