Recent Advances in π-Stacking Interaction-Controlled Asymmetric Synthesis.

The π-stacking interaction is one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry. It plays an important role in stabilizing some structures and transition states in certain reactions via both intramolecular and intermolecular interactions, facilitating different selectivities, such as chemo-, regio-, and stereoselectivities. This minireview focuses on the recent examples of the π-stacking interaction-controlled asymmetric synthesis, including auxiliary-induced asymmetric synthesis, kinetic resolution, asymmetric synthesis of helicenes and heterohelicenes, and multilayer 3D chiral molecules.

Novel Strategies for Enantio- and Site-Selective Molecular Transformations.

A strategy for symmetric synthesis based on dynamic chirality of enolates (memory of chirality) has been developed. Asymmetric alkylation, conjugate addition, aldol reaction, and arylation via C-N axially chiral enolate intermediates are described. Asymmetric alkylation and conjugate addition via C-O axially chiral enolate intermediates with a half-life of racemization as short as approx. 1 s. at -78 °C have been accomplished. Organocatalysts for asymmetric acylation and site-selective acylation have been developed. Kinetic resolution of racemic alcohols via remote asymmetric induction by the catalyst is shown. Catalyst-controlled site-selective acylation of carbohydrates and its application to total synthesis of natural glycoside are described. Chemo-selective monoacylation of diols and selective acylation of secondary alcohols with reversal of inherent reactivity are also discussed. Geometry-selective acylation of tetrasubstituted alkene diols is achieved, where acylation takes place independent from the steric environments of the substrates.

Simultaneous Kinetic Resolution and Asymmetric Induction within a Borrowing Hydrogen Cascade Mediated by a Single Catalyst.

The mechanistic uniqueness and versatility of borrowing hydrogen catalysis provides an opportunity to investigate the controllability of a cascade reaction, and more importantly, to realize either one or both of chiral recognition and chiral induction simultaneously. Here we report that, in a borrowing hydrogen cascade starting from racemic allylic alcohols, one of the enantiomers could be kinetically resolved, while the other enantiomer could be purposely converted to various targeted products, including α,ß-unsaturated ketones, ß-functionalized ketones and γ-functionalized alcohols. By employing a robust Ru-catalyst, both kinetic resolution and asymmetric induction were achieved with remarkable levels of efficiency and enantioselectivity. Density functional theory (DFT) calculations suggest that corresponding catalyst-substrate π-π interactions are pivotal to realize the observed stereochemical diversity.

Turning the Nitrogen Atoms of an Ar2 P-CH2 -N-N-CH2 -PAr2 Motif into Uniquely Configured Stereocenters: A Novel Diphosphane Design for Asymmetric Catalysis.

Hexahydropyridazines with CH2 PAr2 groups at both N atoms are newly designed 1,4-diphosphanes and were synthesized for the first time. Their N atoms assume a single configuration under the influence of stereocenters at C-5 and C-6. In the solid state, these N-atoms bind the CH2 PAr2 substituents axially. Combined with Pd0 , N,N'-chiral diphosphanes of this kind catalyzed Tsuji-Trost type allylations of dialkyl malonates with racemic 1,3-diphenylallyl acetate efficiently and with up to 91 % ee.

Reducing Diastereomorphous Bis(phosphane oxide) Atropisomers to One Atropisomerically Pure Diphosphane: A New Ligand and a Novel Ligand-Preparation Design.

1,1'-Biphenyl-2,2'-diphosphanes with an achiral bridge spanning C-5 and C-5' form atropisomers that are enantiomers. Accessing them in an atropisomerically pure form requires resolving a racemic mixture thereof or of a bis(phosphane oxide) precursor. 1,1'-Biphenyl-2,2'-diphosphanes with a homochiral bridge spanning C-5 and C-5' form atropisomers that are diastereomers. We synthesized the first compound of this kind 1) atropselectively and 2) under thermodynamic control-seemingly a first-time exploit in diphosphane synthesis. The selectivity-inducing step was a high-temperature reduction of two non-interconverting bis(phosphane oxide) atropisomers (60:40 mixture). It furnished the desired diphosphane atropisomerically pure (and atropconvergently because the yield was 67 %). This diphosphane proved worthwhile in Tsuji-Trost allylations, the Hayashi addition of phenylboronic acid to cyclohexenone, and the asymmetric hydrogenation of methyl acetoacetate (up to 95 % yield and 95 % ee).

Studies on Cycloalkane-Based Bisamide Organogelators: A New Example of Stochastic Chiral Symmetry-Breaking Induced by Sonication.

Enantiomerically pure C16 -alkyl amides derived from cis and trans cycloalkane-1,2-dicarboxylic acids, respectively, have been synthesized and their behavior as organogelators has been investigated. These compounds include cis/trans diastereomeric cyclobutane and cyclohexane derivatives with the aim to explore the influence of the ring size as well as the relative configuration in their hierarchical self-assembly to form gels. High resolution 1 H NMR spectroscopy studies allowed the determination of the dynamics of the gelation process in [D8 ]toluene and the sol-gel transition temperature. The morphology and size of the aggregates have been investigated and results have shown that, in the case of cyclobutane derivatives, the cis/trans stereochemistry is not relevant for the gelation behavior and the properties of the soft-materials obtained, but it is remarkable for cyclohexane diamides, which are better organogelators. The four compounds produce chiral aggregates despite that two of them are meso achiral molecules. We show herein that this fact is an example of stochastic symmetry breaking induced by sonication. The self-assembly of these molecules has been modelled providing information and support about the structure and the chirality of the aggregates.

Point-to-Point Ultra-Remote Asymmetric Control with Flexible Linker.

An ultra-remote intramolecular (point-to-point) asymmetric control through 38 bonds (1,39-asymmetric induction) has been achieved by using the principle of direct supramolecular orientation of catalytic and reactive moieties in asymmetric autocatalysis. We found the highly stereoselective diisopropylzinc addition reaction using designed molecules possessing pyrimidine sites at each terminal of a conformationally flexible simple methylene chain.

Double Asymmetric Induction During the Addition of (RP)-Menthyl Phenyl Phosphine Oxide to Chiral Aldimines.

P,C-Stereogenic α-amino phosphine oxides were prepared from the addition of (RP )-menthyl phenyl phosphine oxide to chiral aldimines under neat condition at 80 °C in up to 91:9 drC and 99% yields. The diastereoselectivity was mainly induced by chiral phosphorus that showed matched or mismatched induction with (S)- or (R)-aldimines, respectively.

Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool α-Amino Acids for Natural Product Synthesis.

Chiral pool α-amino acids have been used as powerful tools for the total synthesis of structurally diverse natural products. Some common naturally occurring α-amino acids are readily available in both enantiomerically pure forms. The applications of the chiral pool in asymmetric synthesis can be categorized prudently as chiral sources, devices, and inducers. This review specifically examines recent advances in substrate-controlled asymmetric reactions induced by the chirality of α-amino acid templates in natural product synthesis research and related areas.

Iridium(III)-catalyzed C-H amidation of arylphosphoryls leading to a P-stereogenic center.

Direct CH amidation of arylphosphoryl compounds has been developed by using an Ir(III) catalyst system under mild conditions. A wide range of substrates could be employed with high functional-group tolerance. This procedure was successfully applied for the first time to the asymmetric reaction giving rise to a P-chirogenic center with a high diastereomeric ratio of up to 19:1 (90 % de).

Foldamer-mediated remote stereocontrol: >1,60 asymmetric induction.

An N-terminal L-α-methylvaline dimer induces complete conformational control over the screw sense of an otherwise achiral helical peptide foldamer formed from the achiral quaternary amino acids Aib and Ac6 c. The persistent right-handed screw-sense preference of the helix enables remote reactive sites to fall under the influence of the terminal chiral residues, and permits diastereoselective reactions such as alkene hydrogenation or iminium ion addition to take place with 1,16-, 1,31-, 1,46- and even 1,61-asymmetric induction. Stereochemical information may be communicated in this way over distances of up to 4 nm.

Studies for the enantiocontrolled preparation of substituted tetrahydropyrans: Applications for the synthesis of leucascandrolide A macrolactone.

Strategies for the stereocontrolled preparations of 2,6-cis-and 2,6-trans-substituted tetrahydropyrans have been devised. These studies have explored methodology for asymmetric induction in SE' reactions using chiral 1,3,2-diazaborolidine controllers. Reactions with aldehydes at -78 °C yield nonracemic 1,5-diols for chemoselective internal backside displacements. This concept is developed as a flexible and reliable strategy in studies toward leucascandrolide A macrolactone 2 via the sequential applications of SE' reactions leading to the C1-C9 aldehyde 14, and the bis-tetrahydropyran 59, respectively.

Chloroalkene dipeptide isosteres as peptidomimetics.

To date various biologically active peptides have been discovered, characterized and modified for drug discovery. However, the utilization of peptides as therapeutics involves some limitation due to several factors, including low metabolic stability owing to proteolysis and non-specific interactions with multiple off-target molecules. Hence, the development of "peptidomimetics," in which a part or whole of a molecule is modified, is a desirable strategy to enhance the stability or bioactivity of peptide-based drugs. In this situation, we have designed and developed a synthetic method for chloroalkene dipeptide isosteres (CADIs), which involves replacement of an amide bond in peptides with a chloroalkene structure and are classified as peptidomimetics. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI can be obtained utilizing diastereoselective allylic alkylation with organocopper reagents as a key reaction. This CADI can be transformed into an N-fluorenylmethoxycarbonyl protected CADI in short steps. In addition, CADIs are used in Fmoc-based solid-phase peptide synthesis and introduced into a bioactive peptide. Protocols for practical preparation of some CADIs and peptide mimetics containing a CADI are described as detailed recipes.

Spontaneous mirror symmetry breaking and origin of biological homochirality.

Recent reports on both theoretical simulations and on the physical chemistry basis of spontaneous mirror symmetry breaking (SMSB), that is, asymmetric synthesis in the absence of any chiral polarizations other than those arising from the chiral recognition between enantiomers, strongly suggest that the same nonlinear dynamics acting during the crucial stages of abiotic chemical evolution leading to the formation and selection of instructed polymers and replicators, would have led to the homochirality of instructed polymers. We review, in the first instance, which reaction networks lead to the nonlinear kinetics necessary for SMSB, and the thermodynamic features of the systems where this potentiality may be realized. This could aid not only in the understanding of SMSB, but also the design of reliable scenarios in abiotic evolution where biological homochirality could have taken place. Furthermore, when the emergence of biological chirality is assumed to occur during the stages of chemical evolution leading to the selection of polymeric species, one may hypothesize on a tandem track of the decrease of symmetry order towards biological homochirality, and the transition from the simple chemistry of astrophysical scenarios to the complexity of systems chemistry yielding Darwinian evolution.

Tandem Intramolecular Alkyne Silylformylation-Allylsilylation: A Case of Remote 1,5-Asymmetric Induction.

Two new C-C bonds as well as a remote stereocenter are formed in the title reaction. With remarkable efficiency, this new reaction provides, through remote 1,5-asymmetric induction, anti-1,5 diols that are useful synthons for polyol synthesis (see scheme; Hacac=acetylacetone).