Asymmetric aldol reaction via memory of chirality

Asymmetric aldol reactions of α-amino acid derivatives via memory of chirality were developed. Chiral oxazolidones with contiguous tetra- and trisubstituted chiral centers were obtained in 78-94% ee by the asymmetric aldol reaction followed by intramolecular acylation.     

Stereochemical diversity in asymmetric cyclization via memory of chirality

An enantiodivergent asymmetric cyclization of N-Boc-N-omega-bromoalkyl-alpha-amino acid derivatives has been developed. With potassium amide bases in DMF, cyclization proceeds with retention of configuration, while inversion of configuration was observed with lithium amide bases in THF. Chirality of the parent amino acids was preserved during enolate formation and cyclization to give aza-cyclic amino acids in up to 98% ee with retention of configuration or inversion of configuration, depending on the reaction conditions. Thus, both enantiomers of cyclic amino acids with a tetrasubstituted stereocenter were prepared in high enantiomeric purity from readily available l-alpha-amino acids. This protocol is also applicable to a spirocyclization and an intramolecular conjugate addition of alpha-amino acid derivatives, giving either of the enantiomers of a diazaspiro compound and a tetrahydroisoquinoline derivative, respectively, in up to 99% ee.     

Quantitative chirality/enantioselectivity relations in large random supramolecular structures

We study the relationship between shape and enantioselectivity, employing quantitative geometric chirality measurements. The model we use comprises of the boundary surfaces of two-dimensional (2D) chiral, large, random selectors (diffusion limited aggregates), interacting with homologous series of small 2D-chiral S-shaped probes (the selectands). We show how the enantioselectivity of the selectors depends on the chirality of the selectands and report the following findings: I) The enantioselectivity of a chiral selector can switch preference from the "right" to the "left" enantiomer within a homologous series of selectands. II) At this switch point the chiral selector is functionally achiral. III) Within a homologous series of chiral selectands, there is a "resonance of recognition", namely, the classical key-lock concept is replaced by a picture of various degrees of recognition. IV) The degree of enantioselectivity and the switch in handedness preference are the outcome of a complex interplay between the details of the specific geometry of the selector and the selectand, and the global shape parameter of chirality measure. V) It is shown that isochiral selectands, namely selectands of the same chirality value, may be recognized differently by a chiral selector. VI) It is proposed that a more realistic way to treat the issue of minimal points needed for chiral interaction is resolution based. VII) It is shown how to attach handedness to purely random objects.     

Highly efficient induction of chirality in intramolecular

Highly stereocontrolled, intramolecular [2 + 2] cycloadditions between ketenimines and imines leading to 1,2-dihydroazeto[2, 1-b]quinazolines have been achieved. The source of stereocontrol is a chiral carbon atom adjacent either to the iminic carbon or nitrogen atom. In the first case, the stereocontrol stems from the preference for the axial conformer in the first transition structure. In the second case, the origin of the stereocontrol lies on the two-electron stabilizing interaction between the C-C bond being formed and the sigma orbital corresponding to the polar C-X bond, X being an electronegative atom. These models can be extended to other related systems for predicting the stereochemical outcome in this intramolecular reaction.     

Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality

Glycine-derived 1,4-benzodiazepine-2-ones such as diazepam are chiral by virtue of the boat-shaped conformation of the diazepine ring and exist as a racemic mixture of conformational enantiomers. However, the presence of a chiral center at C-3 of the benzodiazepine perturbs this equilibrium and preferentially stabilizes one ring conformer. We report that N-i-Pr 1,4-benzodiazepine-2-ones derived from (S)-Ala and (S)-Phe can be deprotonated and alkylated in 86-99% ee, despite the fact that the original chiral center is destroyed in the deprotonation step. We attribute this highly enantioselective alkylation to the chiral memory of the benzodiazepine ring. This protocol provides easy access to the previously unexplored "quaternary" 1,4-benzodiazepine-2-ones.     

Biocatalysis in ionic liquids: markedly enhanced enantioselectivity of lipase

[reaction: see text] Lipase-catalyzed transesterifications in ionic liquids proceeded with markedly enhanced enantioselectivity. It was observed that lipases were up to 25 times more enantioselective in ionic liquids than in conventional organic solvents.     

Metal ions dramatically enhance the enantioselectivity for lipase-catalysed reactions in organic solvents

We propose a simple and a powerful method to enhance the enantioselectivity for lipase-catalysed transformations in organic solvents by an addition of metal ion-containing water to the reaction mixture. In this paper, various metal ions such as LiCl or MgCl2 are tested to improve the enantioselectivity for the model reactions. The enantioselectivities obtained are dramatically enhanced, the E values of which are about 100-fold as compared with the ordinary conditions without a metal ion, for example, E = 200 by addition of LiCl. Furthermore, lowering the reaction temperature led to an almost perfect enantioselectivity of lipase in the presence of a metal ion, for example, E = 1,300 by addition of LiCl. Also, a mechanism for the drastic enhancement by metal ions is discussed briefly on the basis of the EPR spectroscopic study and the initial rate for each enantiomer of the substrate.     

Axially chiral amidinium ions as inducers of enantioselectivity in Diels-Alder reactions

[reaction: see text] Enantioselective catalysis of Diels-Alder reactions is mostly achieved by coordinating the dienophile to relatively strong chiral Lewis acids. Here we report on a novel approach employing the hydrogen-bond-mediated association of dienophiles to chiral host molecules. In a reaction forming the steroid skeleton of norgestrel, chiral amidinium ions induce 5:ent-5 ratios of up to 2.5:1. Improved and simplified amidinium catalysts may become interesting candidates to perform stereoselective transformations.     

Powdered KOH in DMSO: an efficient base for asymmetric cyclization via memory of chirality at ambient temperature

Enolate chemistry has been extensively used for stereoselective C-C bond formation, in which metal amide bases are frequently employed in strictly anhydrous solvents at low temperatures. However, we found that asymmetric intramolecular C-C bond formation via axially chiral enolate intermediates proceeded in up to 99% ee at 20 degrees C using powdered KOH in dry or wet DMSO as a base. The enantioselectivity was even higher than that of the corresponding reactions with potassium hexamethyldisilazide in DMF at -60 degrees C. The racemization barrier of the axially chiral enolate intermediate was estimated to be approximately 15.5 kcal/mol. On the basis of the barrier, the chiral enolate intermediate was supposed to undergo cyclization within approximately 10(-3) sec at 20 degrees C after it is generated to give the product in >or=99% ee. Thus, enolates generated with powdered KOH in DMSO were expected to be extremely reactive.     

First example of memory of chirality in carbenium ion chemistry

The non-Kolbe reaction of N-benzoyloxazolidine derivatives 6 derived from L-serine gave optically active N,O-acetals 7 when graphite was used as an anode material. This reaction represents the first example of "memory of chirality" in carbenium ion chemistry. The material used for the anode was critical for the memory of chirality. The substitution of carboxyl group with methoxyl group was found to proceed with an inversion mechanism.     

Asymmetric cyclization via memory of chirality: a concise access to cyclic amino acids with a quaternary stereocenter

N-(omega-Bromoalkyl)-amino acid derivatives, readily prepared from natural alpha-amino acids, gave cyclic amino acids with a quaternary stereocenter by treatment with potassium hexamethyldisilazaide in DMF. The chirality of parent amino acids was almost completely preserved during an enolate-formation and cyclization process, giving aza-cyclic amino acids in up to 98% ee in retention of configuration. This method is applicable to the asymmetric synthesis of azetidine, pyrrolidine, piperidine, and azepane derivatives. The asymmetric cyclization seems to proceed via an axially chiral enolate intermediate and not through a concerted SEi process.     

A memory of chirality approach to the stereoselective synthesis of 4-hydroxy-alpha-methylprolines

To extend the memory of chirality (MOC) methodology to structurally more diverse compounds, the synthesis of 4-hydroxy-alpha-methylprolines was undertaken. Yield and selectivity were very good, with an unexpected reversal in selectivity observed for the cyclization of one adduct with an unprotected hydroxyl.     

A facile three-step synthesis of (±)-crispine A via an acyliminium ion cyclisation

A high yielding cyclisation of the readily available N-(4,4-diethoxybutyl)-2-(3,4-dimethoxyphenyl)acetamide to 8,9-bis(methyloxy)-2,3,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-5(1H)-one is described. The latter can be reduced with either AlH₃ or BH₃ to (±)-crispine A in an overall yield of 55%.     

Selection of horseradish peroxidase variants with enhanced enantioselectivity by yeast surface display

We report a method for in vitro selection of catalytically active enzymes from large libraries of variants displayed on the surface of the yeast S. cerevisiae. Two libraries, each containing approximately 2 x 10(6) variants of horseradish peroxidase (HRP), were constructed; one involved error-prone PCR that sampled mutations throughout the coding sequence, whereas the other involved complete combinatorial enumeration of five positions near the active site to non-cysteine residues. The enzyme variants displayed on the yeast surface were allowed to modify it with a fluorescently labeled substrate. A combination of positive and negative selection applied to the active-site-directed library resulted in variants with up to an 8-fold altered enantioselectivity, including its reversal, toward L/D-tyrosinol. In contrast, the library constructed by using error-prone PCR yielded no HRP variants with a significantly improved enantioselectivity.     

Inverting the enantioselectivity of a carbonyl reductase via substrate-enzyme docking-guided point mutation

Substrate-enzyme docking-guided point mutation of a carbonyl reductase from Sporobolomyces salmonicolor led to mutant enzymes, which reversed the enantiopreference and enhanced the enantioselectivity toward the reduction of para-substituted acetophenones. Such a dramatic change in the enantioselectivity indicates that the 245 residue in the catalytic site plays a critical role in determining the enantioselectivity of these ketone reductions, providing valuable insight into our understanding of how residues involved in substrate binding affect the orientation of bound substrate and thus control the reduction stereoselectivity.     

Highly selective fluorescence turn-on determination of fluoride ions via chromogenic aggregation of a silyloxy-functionalized salicylaldehyde azine

A novel fluorescent chemsensor TBS-protected salicylaldehyde azine (TSAA) for fluoride ion was developed based on aggregation-induced emission (AIE). The probe TSAA was prepared by the reaction of salicylaldehyde azine (SAA) with tert-butyldimethylsilyl chloride (TBS-Cl) via an unusual synthetic methodology and shows only non-emission. Upon treatment with fluoride in aqueous MeCN solution, the TBS protective group of probe TSAA was removed readily and the fluorescence of the probe was switched on, which resulted in a new fluorescence peak around 543 nm. The fluorescent intensity at 543 nm increases linearly with fluoride ion concentration in the range 1–50 μmol L^?1. This proposed probe shows excellent selectivity toward fluoride ion over other common anions and cations.     

On the memory of chirality in gold(I)-catalyzed intramolecular carboalkoxylation of alkynes

A computational study of the mechanism of the intramolecular carboalkoxylation of alkynes reported by Toste et al. allows the characterization of the chirality transfer process that makes this reaction enantioselective. Memory of chirality is preserved up until the stereocenter-generating iso-Nazarov cyclization through the synergy between the helicity of a pentadienyl cation intermediate and the control in the conformation of the allyl group, both elements defined upon alkoxy migration. The high barriers to conformational scrambling relative to those corresponding to chemical steps ensure the robustness of the chirality transfer mechanism and result in an unusual importance of conformational changes in reactivity that seems to be common in gold-catalyzed transformations.