Achiral Aldehydes Research Articles

Quantitative Difference in Solubility of Diastereomeric (2H/1H)-Isotopomers.

Many achiral organic compounds become chiral by an isotopic substitution of one of the enantiotopic moieties in their structures. Although spectroscopic methods can recognize the molecular chirality due to an isotopic substitution, the effects of isotopically chiral compounds in enantioselective reactions have remained unsolved because the small chirality arises only from the difference between the number of neutrons in the atomic nuclei. The difference between the diastereomeric isotopomers of reactive sources should be the key to these effects. However, the energy difference between them is difficult to calculate, even using present computational methods, and differences in physical properties have not yet been reported. Here, we demonstrate that the small energy difference between the diastereomeric isotopomers at the molecular level can be enhanced to appear as a solubility difference between the diastereomeric (2H/1H) isotopomers of α-aminonitriles, synthesized from an isotopically chiral amine, achiral aldehyde, and HCN. This small, but measurable, difference induces the chiral (d/l) imbalance in the suspended α-aminonitrile; therefore, a second enhancement in the solid-state chirality proceeds to afford a highly stereoimproved aminonitrile (>99% selectivity) whose handedness arises completely from the excess enantiomer of isotopically chiral amine, even in a low enantiomeric excess and low deuterium-labeling ratio. Because α-aminonitriles can be hydrolyzed to chiral α-amino acids with the removal of an isotope-labeling moiety, the current sequence of reactions represents a highly enantioselective Strecker amino acid synthesis induced by the chiral hydrogen (2H/1H) isotopomer. Thus, hydrogen isotopic chirality links directly with the homochirality of α-amino acids via a double enhancement of α-aminonitrile, the chiral intermediate of a proposed prebiotic mechanism.

Stereoselective Aldol Additions of Glycolic Acid and Its Derivatives

This review gives a comprehensive overview of aldol additions of glycolic acid derivatives to achiral aldehydes and acetals affording α,β-dihydroxycarboxylic acids or derivatives thereof. The focus is on simple diastereoselectivity. A selection of related aldol additions is also presented: aldol additions of glycolic acid derivatives to ketones with two different substituents and aldol additions of α-substituted glycolic acid derivatives.1 Introduction1.1 Organization of this Review1.2 Outside the Scope of this Review: Aldol Additions Giving α,β-Dihydroxyaldehydes and α,β-Dihydroxyketones Diastereoselectively1.3 Non-Aldol Routes to Diastereomerically Pure α,β-Dihydroxycarboxylic Acid Derivatives2 Aldol Additions of Glycolic Acid (Derivative) Enolates to Aldehydes2.1 Aldol Additions of Glycolate Enolates (‘Glycolic Acid Dianions’)2.2 Aldol Additions of Glycolic Ester Enolates2.3 Aldol Additions of Glycolic Thioester Enolates2.4 Aldol Additions of Glycolimide Enolates2.5 Aldol Additions of Glycolamide Enolates2.6 Mukaiyama Aldol Additions of Silyl Ketene Acetals of Glycolic Esters­ and Thioesters2.7 Aldol Additions of Glycoloyl Chlorides via Acyl Ammonium Enolates3 Aldol-Providing Substitutions of Glycolimide Enolates in Acetals4 Additions Related to Aldol Additions of Glycolic Acid Derivative Enolates to Aldehydes4.1 Selected Simply Diastereoselective Aldol Additions of Enolates of Glycolic Acid Derivatives to Ketones with Two Different Substituents4.2 Simply Diastereoselective Aldol Additions of Enolates of Glycolic Acid Derivatives with a Methyl Substituent at C-α (Lactic Acid Derivatives)5 Conclusion

Chirality transfer based on dynamic covalent chemistry: from small chiral molecules to supramolecules.

Single-tailed and gemini-type supra-gelators were facilely fabricated via the conjugation of the d- or l-enantiomeric dihydrazide TDH with single-tailed achiral aldehyde C12BAD through dynamic acylhydrazone bonding. Chirality transfer from small molecules to supramolecules was successfully achieved via the spontaneous assembly of the formed supra-gelators into supramolecular chiral hydrogels.

Role of Association in Chiral Catalysis: From Asymmetric Synthesis to Spin Selectivity.

The origin of biomolecules in the pre-biological period is still a matter of debate, as is the unclarified nature of the differences in enantiomer properties, especially for the medically important activity of chiral drugs. With regards to the first issue, significant progress was made in the last decade of the 20th century through experimental confirmation of Frank's popular theory on chiral catalysis in spontaneous asymmetric synthesis. Soai examined the chiral catalysis of the alkylation of achiral aldehydes by achiral reagents. Attempts to model this process demonstrated the key role of chiral compounds associates as templates for chiral synthesis. However, the elementary mechanism of alkylation and the role of free radicals in this process are still incompletely understood. Meanwhile, the influence of external magnetic fields on chiral enrichment in the radical path of alkylation has been predicted. In addition, the role of chiral dyad association in another radical process, electron transfer (ET), has been recently demonstrated by the following methods: chemically induced dynamic nuclear polarisation (CIDNP), NMR spectroscopy, XRD and photochemistry. The CIDNP analysis of ET in two dyads has revealed a phenomenon first observed for chiral systems, spin selectivity, which results in the difference between the CIDNP enhancement coefficients of dyad diastereomers. These dyads are linked systems consisting of the widespread drug (S)-naproxen (NPX) or its R analogue and electron donors, namely, (S)-tryptophan and (S)-N-methylpyrrolidine. Because NPX is one of the most striking examples of the difference in the therapeutic properties of enantiomers, the appearance of spin selectivity in dyads with (S)- and (R)-NPX and S donors can shed light on the chemical nature of these differences. This review is devoted to discussing the chemical nature of spin selectivity and the role of chiral associates in the chiral catalysis of an elementary radical reaction: ET in chiral dyads.

Highly Stereoselective Strecker Synthesis Induced by a Slight Modification of Benzhydrylamine from Achiral to Chiral.

2-Methylbenzhydrylamine is a chiral variant of achiral benzhydrylamine; however, the chirality formed from the small difference between the phenyl and o-tolyl groups is not expected to induce sufficient stereoselectivity in conventional homogeneous reactions. Initiated by the spontaneous formation and asymmetric amplification of the enantioenriched N-benzhydryl-α-aminonitrile forming conglomerate, we here report that (S)- and (R)-configured title amine, upon the Strecker reaction with achiral aldehydes and HCN, afford the corresponding α-aminonitriles with up to >99.5 % diastereomeric excess, in conjunction with an enhancement of chirality in the solid state. l-Alanine with 98 % ee was synthesized from the (S)-amine by using the method discussed here. Achiral aromatic and heteroaromatic aldehydes could also be successfully utilized to afford chiral α-aminonitriles in a highly stereoselective manner. The stereodivergent synthesis of styrylglycine nitriles has also been accomplished by using racemic and enantioenriched 2-methylbenzhydrylamine. Thus, accompanied with a small rearrangement of the common substrate from achiral toward chiral, the present reactions induce an enhancement of chirality, and expands the concept of stereoselective synthesis to increase the opportunity to access highly enantioenriched compounds such as α-amino acids.

Kinetic Resolution of Aromatic β‐Amino Acids Using a Combination of Phenylalanine Ammonia Lyase and Aminomutase Biocatalysts

AbstractAn enzymatic strategy for the preparation of (R)‐β‐arylalanines employing phenylalanine aminomutase and ammonia lyase (PAM and PAL) enzymes has been demonstrated. Candidate PAMs with the desired (S)‐selectivity from Streptomyces maritimus (EncP) and Bacillus sp. (PabH) were identified via sequence analysis using a well‐studied template sequence. The newly discovered PabH could be linked to the first ever proposed biosynthesis of pyloricidin‐like secondary metabolites and was shown to display better β‐lyase activity in many cases. In spite of this, a method combining the higher conversion of EncP with a strict α‐lyase from Anabaena variabilis (AvPAL) was found to be more amenable, allowing kinetic resolution of five racemic substrates and a preparative‐scale reaction with >98% (R) enantiomeric excess. This work represents an improved and enantiocomplementary method to existing biocatalytic strategies, allowing simple product separation and modular telescopic combination with a preceding chemical step using an achiral aldehyde as starting material.magnified image

KetoABNO/NOx Cocatalytic Aerobic Oxidation of Aldehydes to Carboxylic Acids and Access to α-Chiral Carboxylic Acids via Sequential Asymmetric Hydroformylation/Oxidation.

A method for aerobic oxidation of aldehydes to carboxylic acids has been developed using organic nitroxyl and NOx cocatalysts. KetoABNO (9-azabicyclo[3.3.1]nonan-3-one N-oxyl) and NaNO2 were identified as the optimal nitroxyl and NOx sources, respectively. The mildness of the reaction conditions enables sequential asymmetric hydroformylation of alkenes/aerobic aldehyde oxidation to access α-chiral carboxylic acids without racemization. The scope, utility, and limitations of the oxidation method are further evaluated with a series of achiral aldehydes bearing diverse functional groups.

ChemInform Abstract: Aldol Additions of Titanium and Boron Enolates of Achiral and Chiral δ‐Lactones to Achiral Model Aldehydes: Simple and Induced Diastereoselectivities.

AbstractIt is found that titanium enolates in most cases syn‐selectively react with achiral aldehydes, whereas boron enolates react anti‐selectively in all cases.

ChemInform Abstract: Enantioselective Hydroformylation of 1‐Alkenes with Commercial Ph‐BPE Ligand.

A rhodium complex, in conjunction with commercially available Ph-BPE ligand, catalyzes the branch-selective asymmetric hydroformylation of 1-alkenes and rapidly generates α-chiral aldehydes. A wide range of terminal olefins including 1-dodecene were examined, and all delivered high enantioselectivity (up to 98:2 er) as well as good branch:linear ratios (up to 15:1).

Enantioselective Hydroformylation of 1-Alkenes with Commercial Ph-BPE Ligand.

A rhodium complex, in conjunction with commercially available Ph-BPE ligand, catalyzes the branch-selective asymmetric hydroformylation of 1-alkenes and rapidly generates α-chiral aldehydes. A wide range of terminal olefins including 1-dodecene were examined, and all delivered high enantioselectivity (up to 98:2 er) as well as good branch:linear ratios (up to 15:1).

ChemInform Abstract: Complementary Catalytic Strategies to Access α‐Chiral Aldehydes

AbstractReview: 79 refs.

Synthesis of Two Subunits of the Macrolide Domain of the Immunosuppressive Agent Sanglifehrin A and Assembly of a Macrolactone Precursor. Application of Masamune anti-Aldol Condensation

Asymmetric anti-aldol coupling of a norephedrine-derived ester with an α-chiral aldehyde was used to synthesize a carboxylic acid representing the C13-C19 segment of the macrocyclic domain present in the immunosuppressive agent sanglifehrin A. Felkin addition set configuration at the C14-C17 stereotetrad in this unit in which hydroxyl functions at C15 and C17 were masked as an internal ketal. The carboxyl group of this segment was coupled to the N-terminus of the tripeptide portion (C1-N12) of sanglifehrin A macrolactone to assemble the C1-C19 domain. Synthesis of the C20-C25 subunit of sanglifehrin A containing a (23S) alcohol was completed via asymmetric allylation of (E)-3-iodo-2-methylprop-2-enal followed by oxidative cleavage of the terminal vinyl appendage and a Takai olefination with pinacol dichloromethylboronate. Esterification of this alcohol with a C1-C19 carboxylic acid furnished an open C1-C25 macrolactone precursor, but this substance failed to undergo macrocyclization via intramolecular Suzuki-Miyaura coupling.

Stereoselective Aldol Reaction in Aqueous Solution Using Prolinamido-Glycosides as Water-Compatible Organocatalyst

Prolinamido-glycoside catalyzed asymmetric aldol reaction in aqueous media is reported. The reactions are rapid and highly stereoselective when water is used as solvent. The stereoselectivities were under influence of configurations of a prolyl residue of the catalyst and α-chiral aldehydes. Water soluble prolinamido-glycoside catalysts are easily separable from reaction mixture and can be recycled and re-used several times.

ChemInform Abstract: Diastereoselection During 1,2‐Addition of 3‐Bromomethyl‐5H‐furan‐2‐one to α‐Chiral Aldehydes Mediated by Indium in Aqueous and Organic Solvent Systems: Direct Route to Obtain Optically Active α‐Methylene‐γ‐butyrolactones.

The stereochemical course of indium-promoted allylations to α-chiral aldehydes with 3-bromomethyl-5H-furan-2-one was investigated in anhydrous THF and pure H2O. High levels of 3,4-syn;4,5-syn diastereomers were produced with free hydroxyl derivatives whether in THF or pure H2O, reflecting the promising synthetic potential of this chemistry. This stereo-differentiation was attributed to the strong geometric bias exercised by our allylindium reagent and adherence to a chelation control transition-state alignment. Meanwhile, heightened levels of 3,4-anti;4,5-anti diastereomers were obtained with the rigid aldehydes 1h and 1i.

Asymmetric autocatalysis of pyrimidyl alkanol and its application to the study on the origin of homochirality.

CONSPECTUS: Amplification of enantiomeric excess (ee) is a key feature for the chemical evolution of biological homochirality from the origin of chirality. We describe the amplification of ee in the asymmetric autocatalysis of 5-pyrimidyl alkanols in the reaction between diisopropylzinc (i-Pr2Zn) and pyrimidine-5-carbaldehydes. During the reaction, an extremely low ee (ca. 0.00005% ee) can be amplified to >99.5% ee, and therefore, the initial slightly major enantiomer is automultiplied by a factor of ca. 630000, while the initial slightly minor enantiomer is automultiplied by a factor of less than 1000. In addition, pyrimidyl alkanols with various substituents at the 2-position of the pyrimidine ring, 3-quinolyl alkanol, 5-carbamoyl-3-pyridyl alkanol, and large multifunctionalized pyrimidyl alkanols also act as highly efficient asymmetric autocatalysts in the addition of i-Pr2Zn to the corresponding aldehydes. The asymmetric autocatalysis of pyrimidyl alkanol can discriminate the chirality of various compounds. Chiral substances such as alcohols, amino acids, hydrocarbons, metal complexes, and heterogeneous chiral materials can act as chiral triggers for asymmetric autocatalysis to afford pyrimidyl alkanols with the corresponding absolute configuration of the initiator. This recognition ability of chiral compounds is extremely high, and chiral discrimination of a cryptochiral quaternary saturated hydrocarbon was established by applying asymmetric autocatalysis. By using the large amplification effect of the asymmetric autocatalysis, we can link various proposed origins of chirality with highly enantioenriched organic compounds in conjunction with asymmetric autocatalysis. Thus, a statistical fluctuation in ee of racemic compounds can be amplified to high ee by using asymmetric autocatalysis. Enantiomeric imbalance induced by irradiation of circularly polarized light can affect the enantioselectivity of asymmetric autocatalysis. The asymmetric autocatalysis was also triggered by the morphology of inorganic chiral crystals such as quartz, sodium chlorate, and cinnabar. Chiral organic crystals of achiral compounds also act as chiral initiators, and during the study of a crystal of cytosine, enantioselective chiral crystal phase transformation of the cytosine crystal was achieved by removal of the water of crystallization in an achiral monohydrate crystal. Enantioselective C-C bond formation was realized on the surfaces of achiral single crystals based on the oriented prochirality of achiral aldehydes. Furthermore, asymmetric autocatalysis of pyrimidyl alkanols is a highly sensitive reaction that can recognize and amplify the significantly small effect of a chiral compound arising solely from isotope substitution of hydrogen, carbon, and oxygen (D/H, (13)C/(12)C, and (18)O/(16)O). These examples show that asymmetric autocatalysis with an amplification of chirality is a powerful tool for correlating the origin of chirality with highly enantioenriched organic compounds. Asymmetric autocatalysis using two β-amino alcohols reveals a reversal of enantioselectivity in the addition of i-Pr2Zn to aldehyde and is one approach toward understanding the mechanism of asymmetric dialkylzinc addition, where heteroaggregates act as the catalytic species.

Self-replication and amplification of enantiomeric excess of chiral multifunctionalized large molecules by asymmetric autocatalysis.

Self-replication of large chiral molecular architectures is one of the great challenges and interests in synthetic, systems, and prebiotic chemistry. Described herein is a new chemical system in which large chiral multifunctionalized molecules possess asymmetric autocatalytic self-replicating and self-improving abilities, that is, improvement of their enantioenrichment in addition to the diastereomeric ratio. The large chiral multifunctionalized molecules catalyze the production of themselves with the same structure, including the chirality of newly formed asymmetric carbon atoms, in the reaction of the corresponding achiral aldehydes and reagent. The chirality of the large multifunctionalized molecules controlled the enantioselectivity of the reaction in a highly selective manner to construct multiple asymmetric stereogenic centers in a single reaction.

Self‐Replication and Amplification of Enantiomeric Excess of Chiral Multifunctionalized Large Molecules by Asymmetric Autocatalysis

AbstractSelf‐replication of large chiral molecular architectures is one of the great challenges and interests in synthetic, systems, and prebiotic chemistry. Described herein is a new chemical system in which large chiral multifunctionalized molecules possess asymmetric autocatalytic self‐replicating and self‐improving abilities, that is, improvement of their enantioenrichment in addition to the diastereomeric ratio. The large chiral multifunctionalized molecules catalyze the production of themselves with the same structure, including the chirality of newly formed asymmetric carbon atoms, in the reaction of the corresponding achiral aldehydes and reagent. The chirality of the large multifunctionalized molecules controlled the enantioselectivity of the reaction in a highly selective manner to construct multiple asymmetric stereogenic centers in a single reaction.

Rapid optical methods for enantiomeric excess analysis: from enantioselective indicator displacement assays to exciton-coupled circular dichroism.

CONSPECTUS: The advent of high-throughput screening (HTS) for chiral catalysts has encouraged the development of fast methods for determining enantiomeric excess (ee). Traditionally, chromatographic methods such as chiral HPLC have been used for ee determination in HTS. These methods, however, are not optimal because of high duty cycle. Their long analysis time results in a bottleneck in the HTS process. A more ideal method for HTS that requires less analysis time such as chiroptical methods are thus of interest. In this Account, we summarize our efforts to develop host-guest systems for ee determination. The first part includes our enantioselective indicator displacement assays (eIDAs), and the second part focuses on our circular dichroism based host-guest systems. Our first eIDA utilizes chiral boronic acid receptors, along with prescreened indicators, to determine ee for chiral α-hydroxyacids and vicinal diols with ±7% average error (AE). To further the practicality for this system, a HTS protocol was developed. Our second eIDA uses diamino chiral ligands and Cu(II) as the receptor for the ee determination of α-amino acids. The system reported ±12% AE, and a HTS protocol was developed for this system. Our first CD based host-guest system uses metal complexes composed of Cu(I) or Pd(II) with enantiopure 2,2'-diphenylphosphino-1,1'-binaphthyl (BINAP) as host to determine the ee of chiral vicinal diamines (±4% AE), primary amines (±17% AE), and cyclohexanones (±7% AE). Primary amines and cyclohexanones were derivatized to form chiral imines or chiral hydrazones to allow coordination with the metal complex. Upon coordination of chiral analytes, the metal-to-ligand (BINAP) charge transfer band was modulated, thus allowing the discrimination of chiral analytes. As an effort to improve the accuracy for chiral primary amine ee determination, a system with a host composed of o-formylphenyl boronic acid (FPBA) and enantiopure 1,1'-bi-2-naphthol (BINOL) was used to reduce the AE to ±5.8%. In the presence of amines, the FPBA-BINOL host forms an imine-coordinated boronic ester, thus affecting the CD signal of the boron complex. Another chiral primary amine ee determination system was developed with Fe(II) and 3-hydroxy-2-pyridinecarbaldehyde. The chiral imines, formed by the pyridinecarbaldehyde and chiral amines, would coordinate to the Fe(II) ion yielding exciton-coupled circular dichroism (ECCD) active metal complexes. This system was able to determine the ee of chiral amines with ±5% AE. Furthermore, this imine-Fe(II) complex system also successfully determined the ee of α-chiral aldehydes with ±5% AE. Other ECCD based hosts were subsequently developed; one with bisquinolylpyridylamine and Cu(II) for chiral carboxylates and amino acids and another multicomponent system with pyridine chromophores for chiral secondary alcohol ee determination. Both of the systems were able to determine ee of the chiral analytes with ±3% AE. Overall, our group has developed ee determining host-guest systems that target various functionalities. To date, we are able to determine the ee of vicinal diols, α-hydroxyacids, vicinal diamines, cyclohexanones, amines, α-chiral aldehydes, carboxylates, amino acids, and secondary alcohols with ±7% or lower average error. Future development will involve improving the average error and employing the current systems to analyze real-life samples resulting from parallel syntheses.

Phosphine-catalyzed asymmetric synthesis of β-lactones from disubstituted ketenes and aldehydes.

In this article we describe a general catalytic procedure for the formation of β-lactones bearing two stereogenic centers, from disubstituted ketenes and achiral aldehydes. BINAPHANE was found to display excellent enantioselectivity (≥90% ee for eight examples) and good diastereoselectivity (≥90:10 for 13 examples) in catalyzing the formation of β-lactones bearing two stereogenic centers from achiral aldehydes (both aromatic and aliphatic) and alkylarylketenes or dialkylketenes. A preference for formation of the trans diastereomer was observed in these reactions. For those reactions where BINAPHANE failed as a catalyst, tri-n-butylphosphine was found to be an effective achiral nucleophilic catalyst, effecting good yield and diastereoselectivity in racemic β-lactone formation. Evidence for the involvement of phosphonium enolate intermediates in the reaction mechanism was obtained through reaction monitoring by (31)P NMR spectroscopy and by comparison with previously characterized intermediates observed in the phosphine-catalyzed ketene homodimerization reaction.

ChemInform Abstract: Development and Applications of Remote Stereocontrol Using Allylic Organobismuth Reagents.

AbstractThe investigations reveal that BiI3‐mediated couplings of bromides (I) and (VI) as well as stannane (IV) with achiral aldehydes (II) proceed with useful levels of (E)‐1,5‐stereocontrol.