Computer-aided design of chiral ligands. Part III. A novel ligand for asymmetric allylation designed using computational techniques

[reaction: see text] Computer-aided design protocols to identify new chiral ligands for reactions proceeding through well-defined transition states are outlined. Ligand families are discovered via computational screening of large structural databases such as the Cambridge Structural Database. Using this method, a novel cis-decalin ligand has been identified as a chiral auxiliary for the allylboration of aldehydes. Synthesis, resolution, and evaluation revealed that this new auxiliary provided the aldehyde facial approach upon which the design was predicated.     

Diastereoselective Ru-catalyzed cross-metathesis-dihydroxylation sequence. an efficient approach toward enantiomerically enriched syn-diols

Sequential catalysis has evolved as a powerful concept within the past years and allows the more efficient use of catalytically active expensive transition metals in organic synthesis. In this paper we present the stereoselective cross-metathesis-dihydroxylation of various olefins with chiral auxiliary substituted acrylamides. The chiral information (i.e., the auxiliary) introduced in the metathesis reactions allows for a stereoselective subsequent RuO4-catalyzed dihydroxylation. The sequence is concluded by an unusual kinetic resolution of the diastereomeric diols obtained in the oxidation reaction. As a consequence a variety of structurally diverse enantiomerically enriched diols are obtained. To the best of our knowledge the results summarized in this paper represent the first highly efficient diastereoselective RuO4-catalyzed oxidation.     

Nonlinear Effects in Asymmetric Catalysis

There is a need for the preparation of enantiomerically pure compounds for various applications. An efficient approach to achieve this goal is asymmetric catalysis. The chiral catalyst is usually prepared from a chiral auxiliary, which itself is derived from a natural product or by resolution of a racemic precursor. The use of non‐enantiopure chiral auxiliaries in asymmetric catalysis seems unattractive to preparative chemists, since the anticipated enantiomeric excess (ee) of the reaction product should be proportional to the ee value of the chiral auxiliary (linearity). In fact, some deviation from linearity may arise. Such nonlinear effects can be rich in mechanistic information and can be synthetically useful (asymmetric amplification). This Review documents the advances made during the last decade in the use of nonlinear effects in the area of organometallic and organic catalysis.     

Design of Selenium‐Based Chiral Chemical Probes for Simultaneous Enantio‐ and Chemosensing of Chiral Carboxylic Acids with Remote Stereogenic Centers by NMR Spectroscopy

Selenium‐based enantiopure chiral chemical probes have been designed in a modular way starting from available amino alcohols. The probes developed were found to be efficient in chemoselective interaction with carboxylic functions of chiral substrates leading to diastereomeric amide formation and in sensing α‐, β‐, and remote (up to seven bonds away from the carboxylic group) chiral centers by using ⁷⁷Se NMR spectroscopy. As a result, it was possible to determine the enantiomeric ratio of structurally diverse individual chiral acids including polyfunctional compounds and drugs with high accuracy. An approach to analyzing the crude reaction mixtures has been successfully developed by using bifunctional selenium‐ and fluorine‐containing chiral probes. More importantly, it was revealed that, based on the ⁷⁷Se NMR data obtained, it is possible to obtain primary information about the location and nature of the substituents at the chiral center (chemo‐ and enantiosensing), which can simplify the structural elucidation of complex compounds. The derivatization procedure takes as little as 5 min and can be performed directly in an NMR tube followed by NMR measurements without any isolation and purification steps.     

Chiral Photochemistry in a Confined Space: Torquoselective Photoelectrocyclization of Pyridones within an Achiral Hydrophobic Capsule

Chiral induction during the photoelectrocyclization of pyridones included within octa acid (OA) capsule has been established. Chiral induction is brought about by a chiral auxiliary appended to the reactive pyridone moiety. Importantly, the same chiral auxiliary while ineffective in acetonitrile solution is found to be effective within the confined space of OA capsule. The diastereomeric excess of 92% obtained here is comparable only to that in solid state. OA capsule, we believe, provides restriction to the rotational motions of the reactant pyridone and chiral auxiliary and thus places the chiral auxiliary in a selective conformation with respect to the reactive pyridone part. A correlation between the position of the methyl group on the pyridone ring and diastereoselectivity was noted. Structures of the host-guest complexes were examined by ¹H NMR and the data were used to obtain preliminary information concerning the mechanism of chiral induction within the confined spaces of OA capsule.     

Preparation and Reactions of Amino Acid Ester Sulfones as New Remote Asymmetrical Induced Reagents

The development of chiral auxiliary-controlled asymmetric synthesis has been receiving increasing interest in recent yearsfi,2] Various chiral auxiliary reagents have been observed[3] and a lot of results showed that variation of the chiral auxiliary could influence asymmetric induction. Recently, it has been reported the reaction of the aminated sulfones as a remote chiral auxiliary with α,β-unsaturated carbonyl compounds.[4] Here we would like to report the preparation of amino acid ester sulfones as new remote asymmetrical induced reagents and their reactions with α,β-unsaturated esters.     

Aziridine ring-opening reactions with chiral enolates. Stereocontrolled synthesis of 5-substituted-3-methyl-pyrrolidin-2-ones

A procedure for performing stereocontrolled aziridine ring-opening reactions with chiral enolates derived from (S,S)-(+)-pseudoephedrine amides has been developed leading to gamma-aminoamides in good yields. The diastereoselectivity of the reaction becomes controlled by the presence of the chiral auxiliary on the enolate, although the stereogenic center contained in the structure of the aziridine has a striking influence on the stereochemical course of the reaction which results in the presence of the corresponding matched and mismatched combinations. Besides, the sense of the asymmetric induction of the chiral auxiliary has resulted to be the opposite to the one found with other type of electrophiles, although it is in good agreement with the trend observed in the reaction of the same kind of enolates with epoxides. Finally, the obtained gamma-aminoamide adducts were converted into enantiopure gamma-amino acids, gamma-aminoesters, and pyrrolidin-2-ones using easy to perform and high yielding reactions.     

Fumarate of (S,S)-alpha,alpha'-bis(trifluoromethyl)-1,8-anthracenedimethanol. A chiral macrocycle for the Diels-Alder reaction with cyclopentadiene

The synthesis and structural study of the fumarate of (S,S)-alpha,alpha'-bis(trifluoromethyl)-1,8-anthracenedimethanol by NMR spectroscopy are reported. The conformational study of the 13-membered macrocycle is presented. The cited alcohol is assayed as a chiral auxiliary in a Diels-Alder reaction with cyclopentadiene, and after methanolysis, provides the norbornene derivative with high enantioselectivity.     

1,1,1,3,3,3‐Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide‐Directed Fujiwara–Moritani Reaction with Acrylates and Styrenes

Axially chiral biaryls are ubiquitous structural motifs of biologically active molecules and privileged ligands for asymmetric catalysis. Their properties are due to their configurationally stable axis, and therefore, the control of their absolute configuration is essential. Efficient access to atropo‐enantioenriched biaryl moieties through asymmetric direct C?H activation, by using enantiopure sulfoxide as both the directing group (DG) and chiral auxiliary, is reported. The stereoselective oxidative Heck reactions are performed in high yields and with excellent atropo‐stereoselectivities. The pivotal role of 1,1,1,3,3,3‐hexafluoropropanol (HFIP) solvent, which enables a drastic increase in yield and stereoselectivity of this transformation, is evidenced and investigated. Finally, the synthetic usefulness of the herein disclosed transformation is showcased because the traceless character of the sulfoxide DG allows straightforward conversions of the newly accessed, atropopure sulfoxide‐biaryls into several differently substituted axially chiral scaffolds.     

Understanding the Signatures of Secondary‐Structure Elements in Proteins with Raman Optical Activity Spectroscopy

A prerequisite for the understanding of functional molecules like proteins is the elucidation of their structure under reaction conditions. Chiral vibrational spectroscopy is one option for this purpose, but provides only indirect access to this structural information. By first‐principles calculations, we investigate how Raman optical activity (ROA) signals in proteins are generated and how signatures of specific secondary‐structure elements arise. As a first target we focus on helical motifs and consider polypeptides consisting of twenty alanine residues to represent α‐helical and 3₁₀‐helical secondary‐structure elements. Although ROA calculations on such large molecules have not been carried out before, our main goal is the stepwise reconstruction of the ROA signals. By analyzing the calculated ROA spectra in terms of rigorously defined localized vibrations, we investigate in detail how total band intensities and band shapes emerge. We find that the total band intensities can be understood in terms of the reconstructed localized vibrations on individual amino acid residues. Two different basic mechanisms determining the total band intensities can be established, and it is explained how structural changes affect the total band intensities. The band shapes can be rationalized in terms of the coupling between the localized vibrations on different residues, and we show how different band shapes arise as a consequence of different coupling patterns. As a result, it is demonstrated for the chiral variant of Raman spectroscopy how collective vibrations in proteins can be understood in terms of well‐defined localized vibrations. Based on our calculations, we extract characteristic ROA signatures of α helices and of 3₁₀‐helices, which our analysis directly relates to differences in secondary structure.     

Understanding the catalytic role of flexible chiral δ-amino alcohols: the 1-(2-aminoethyl)norbornan-2-ol model

An empiric first approach to the knowledge about the structural factors influencing the catalytic behavior of conformationally flexible δ-amino-alcohol-based ligands, for the enantioselective addition of dialkylzincs to prochiral carbonyl groups, has been applied using the 1-(2-aminoethyl)norbornan-2-ol moiety as the model chiral system, and the asymmetrically catalyzed addition of diethylzinc to benzaldehyde as the test reaction. For this purpose, a selected small library of seven norbornane-based chiral ligands, bearing well-defined structural variations to allow a comparative study, that is, variation of the relative configuration and steric hindrance at the C(2), C(3) and/or C(7) norbornane positions, has been synthesized and probed in the mentioned test reaction. The experimental results obtained have been rationalized empirically using diastereomeric Noyori-like transition states, demonstrating that the conformational flexibility of the δ-amino-alcohol ligands, contrary to the more studied and rigid β-amino-alcohols, plays a crucial role on the catalytic behavior of such ligands (stereochemical sense and degree of the stereodifferentiation in the asymmetric process), which makes such structural factors, important for the improved design of new related chiral catalysts. In this sense, a robust crude empirical model for the prediction of the catalytic behavior of such δ-amino-alcohol-based ligands is proposed.     

TADDOLate complexes of zinc

TADDOL (alpha,alpha,alpha',alpha'-Tetraaryl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol) and its derivatives have been used as a chiral auxiliary in a huge number of enantioselective syntheses mediated by transition metals. Herein we report for the first time on the synthesis and structural characterization of Zn-TADDOLate complexes. The homo trinuclear zinc complex, [Me2Zn3{(S,S)-TADDOLate}2(THF)2], was obtained by reaction of TADDOL with dimethylzinc, whereas the hetero trinuclear complex, [Li2Zn{(S,S)-TADDOLate}2(THF)2], was synthesized from dilithium TADDOLate with zinc dichloride. Both structures reveal a non-linear trimetallic M...Zn...M setup, which is surrounded by two TADDOLate ligands.     

(S,S)-(+)-pseudoephedrine as chiral auxiliary in asymmetric aza-Michael reactions. Unexpected selectivity change when manipulating the structure of the auxiliary

[reaction: see text] The asymmetric aza-Michael reaction of metal benzylamides to alpha,beta-unsaturated amides derived from the chiral amino alcohol (S,S)-(+)-pseudoephedrine has been studied in detail. A deep study of the most important experimental parameters (solvent, temperature, nucleophile structure, influence of additives) has been carried out, showing that the reaction usually proceeds with good yields and diastereoselectivities, although the experimental conditions have to be modified depending on the substitution pattern of the conjugate acceptor. Additionally, a very interesting facial selectivity inversion has been observed when manipulating the structure of the chiral auxiliary, which has allowed a diastereodivergent procedure to be set up for performing asymmetric aza-Michael reactions using the same chirality source. Finally, the adducts obtained in the asymmetric aza-Michael reaction have proven to be very versatile synthetic intermediates in the preparation of other interesting compounds such as beta-amino esters, gamma-amino alcohols, and beta-amino ketones in highly enantioenriched form.     

3D Enantiomorphic Mg‐Based Metal–Organic Frameworks as Chemical Sensor of Nitrobenzene and Efficient Catalyst for CO2 Cycloaddition

Two enantiomorphic Mg^II‐based metal‐organic frameworks, {MgL(H₂O)₂}_n ( 1‐D and 1‐L ) (where H₂L=2,2′‐bipyridyl‐4,4′‐dicarboxylic acid) have been synthesized by solvothermal reaction without any chiral auxiliary. The single‐crystal X‐ray measurement and the structural analysis indicate that both 1‐D and 1‐L possess 2‐fold interpenetrated frameworks with different left‐ and right‐handed helical chains simultaneously, which serve as chiral source, thus transmitting chirality over the whole frameworks. The fluorescence measurements reveal that they exhibit a strong quenching response to nitrobenzene and could be potentially used as a chemical sensor. Owing to the accessible Lewis acidic sites in channels, they display high catalytic efficiency for cycloaddition reaction of CO₂ with epoxides and could be reused five times without losing activity.     

Asymmetric Total Synthesis of (−)‐Stenine and 9a‐epi‐Stenine

A route for the asymmetric synthesis of (?)‐stenine, a member of the Stemona alkaloid family used as folk medicine in Asian countries, is described. The key features of the sequence employed include stereoselective transformations on a cyclohexane ring controlled by a chiral auxiliary unit and an intramolecular Mitsunobu reaction to construct the perhydroindole ring system. By using an intermediate in the route to (?)‐stenine, an asymmetric synthesis of 9a‐epi‐stenine was also executed. The C(9a) stereocenter in 9a‐epi‐stenine was installed by using a Staudinger/aza‐Wittig reaction of a keto–azide precursor followed by reduction of the resulting imine. The results of this effort demonstrate the applicability of the chiral auxiliary based strategy to the preparation of naturally occurring alkaloids that contain highly functionalized cyclohexane cores.     

Chiral Inductions in Excited State Reactions: Photodimerization of Alkyl 2‐Naphthoates as a Model

Enantioselectivity in organic transformations continues to be a topic major interest in organic photochemistry. In the last decade, synergistic combination of photocatalysis and organocatalysis has emerged as a powerful strategy to gain enantioselectivity in photochemical reactions, and remarkable achievements have been obtained. In this strategy, the asymmetric induction is provided in ground state. In contrast, in the conventional enantioselective photochemistry, the chiral induction is controlled in electronic excited state, and to achieve high stereoselectivity is still a formidable challenge. Because the reactions of excited states often yield strained products with unique structures in single step that are difficult to form by thermal reactions, the development of new strategies attempted to achieve enantioselectivity in excited state reactions is still highly desired. Since the short excited state lifetime and low activation energy for reaction in excited state leave little room for manipulating the chiral induction, in order to gain enantioselectivity the substrate molecule has to already reside in a chiral environment during the excitation step. Chiral auxiliaries and chiral supramolecular hosts can provide such environments. In this presentation, we summarize the studies employing chiral auxiliary and chiral microreactor approaches to achieve high asymmetric inductions in excited state reactions performed in our laboratory. We chose the photodimerization of alkyl 2‐naphthoates as a reaction model to give deeper insights into the basic factors controlling chiral induction in excited state.     

Recent progress in a chiral multinucleating system utilizing tartaric acid esters

In order to develop a practical method for the construction of chiral molecules, we have designed a novel chiral reaction system possessing multi‐metal centers utilizing tartaric acid ester as a chiral auxiliary. Based on this concept, we have developed an asymmetric 1,3‐dipolar cycloaddition reaction of azomethine imines, an asymmetric hetero Diels‐Alder reaction of nitroso compounds, an asymmetric Diels‐Alder reaction of o‐quinodimethanes. Furthermore, an asymmetric nucleophilic addition of alkynylzinc reagents, prepared in situ from dialkylzinc and 1‐alkynes, to nitrones was achieved with high level of stereocontrol. In the last case, the addition of methylzinc salt of a product‐like racemic hydroxylamine was found to be effective for unprecedented enhancement of enantioselectivity. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 173–187; 2010: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.201000002     

Chemoenzymatic synthesis and application of a new,easily chiral auxiliary for the synthesis of peptidomimetics via an Ugi reaction

A new chiral auxiliary derived from α-phenylethylamine, α-(2,4-dimethoxyphenyl)ethylamine is presented. It significantly expands upon the application of α-phenylethylamine derivatives used as chiral auxiliaries. A straightforward, chemoenzymatic synthesis of non-racemic α-(2,4-dimethoxyphenyl)ethylamine is described and the new chiral auxiliary applied to an asymmetric Ugi reaction. The mild conditions used for the cleavage of the auxiliary allowed to obtain chiral, non-racemic peptidomimetics possessing reactive α,β-unsaturated double bonds.     

Total Synthesis of (+)‐Asteriscanolide: Further Exploration of the Rhodium(I)‐Catalyzed [(5+2)+1] Reaction of Ene‐Vinylcyclopropanes and CO

The total synthesis of (+)‐asteriscanolide is reported. The synthetic route features two key reactions: 1) the rhodium(I)‐catalyzed [(5+2)+1] cycloaddition of a chiral ene‐vinylcyclopropane (ene‐VCP) substrate to construct the [6.3.0] carbocyclic core with excellent asymmetric induction, and 2) an alkoxycarbonyl‐radical cyclization that builds the bridging butyrolactone ring with high efficiency. Other features of this synthetic route include the catalytic asymmetric alkynylation of an aldehyde to synthesize the chiral ene‐VCP substrate, a highly regioselective conversion of the [(5+2)+1] cycloadduct into its enol triflate, and the inversion of the inside–outside tricycle to the outside–outside structure by an ester‐reduction/elimination to enol‐ether/hydrogenation procedure. In addition, density functional theory (DFT) rationalization of the chiral induction of the [(5+2)+1] reaction and the diastereoselectivity of the radical annulation has been presented. Equally important is that we have also developed other routes to synthesize asteriscanolide using the rhodium(I)‐catalyzed [(5+2)+1] cycloaddition as the key step. Even though these routes failed to achieve the total synthesis, these experiments gave further useful information about the scope of the [(5+2)+1] reaction and paved the way for its future application in synthesis.     

Enecarbamates as selective substrates in oxidations: chiral-auxiliary-controlled mode selectivity and diastereoselectivity in the [2+2] cycloaddition and ene reaction of singlet oxygen and in the epoxidation by DMD and mCPBA

The stereochemical course of the oxidation of chiral oxazolidinone-substituted enecarbamates has been studied for singlet oxygen ((1)O(2)), dimethyldioxirane (DMD), and m-chloroperbenzoic acid (mCPBA) by examining of the special structural and stereoelectronic features of the enecarbamates. Valuable mechanistic insight into these selective oxidations is gained. Whereas the R(1) substituent on the chiral auxiliary is responsible for the steric shielding of the double bond and determines the sense of the pi-facial diastereoselectivity, structural characteristic such as the Z/E configuration and the nature of the R(2) group on the double bond are responsible for the extent of the diastereoselectivity. Stereoelectronic steering by the vinylic nitrogen functionality controls the mode selectivity (ene reaction vs [2+2] cycloaddition) in the case of (1)O(2).