Versatile Chiral Building Blocks Research Articles

Remote C-H Amination and Alkylation of Camphor at C8 through Hydrogen-Atom Abstraction.

Camphor continues to serve as a versatile chiral building block for chemical synthesis. We have developed a novel method to functionalize the camphor skeleton at C8 using an intramolecular hydrogen atom abstraction. The key advance involves the use of a camphor-derived aminonitrile, which is converted to the corresponding nitrogen-centered radical under photoredox conditions to effect the 1,5-hydrogen atom transfer at C8. The resulting carbon-centered radical at C8 was utilized in a C-H amination to access topologically complex proline derivatives. Furthermore, the total synthesis of several sesquiterpenoids was accomplished by engaging the radical generated at C8 in alkylation reactions.

Organocatalytic Conjugate Hydroazidation and Hydrocyanation: A Metal-Free Approach to Synthetically Versatile Chiral Building Blocks

Chiral β-azido- and β-cyanocarbonyl compounds are extremely useful building blocks in asymmetric synthesis, thanks to the manyfold reactivity of their functional groups. The enantioselective synthesis of such compounds, until the beginning of the 21st century, has been mostly achieved using transition-metal chiral catalysts. The explosion of enantioselective organocatalysis, however, has enabled the development of efficient metal-free methodologies with significant benefits in terms of costs and environmental safety. An overview of the advances made in recent years in this field is herein presented.

Nitrene-Mediated Enantioselective Intramolecular Olefin Oxyamination to Access Chiral γ-Aminomethyl-γ-Lactones.

Attaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral-at-ruthenium catalysts, chiral γ-aminomethyl-γ-lactones containing a quaternary carbon in γ-position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ-Aminomethyl-γ-lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ-lactams, 2-oxazolidinones, and tetrahydrofurans.

Nitrene‐Mediated Enantioselective Intramolecular Olefin Oxyamination to Access Chiral γ‐Aminomethyl‐γ‐Lactones

AbstractAttaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral‐at‐ruthenium catalysts, chiral γ‐aminomethyl‐γ‐lactones containing a quaternary carbon in γ‐position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ‐Aminomethyl‐γ‐lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ‐lactams, 2‐oxazolidinones, and tetrahydrofurans.

From Cell-Free Protein Synthesis to Whole-Cell Biotransformation: Screening and Identification of Novel α-Ketoglutarate-Dependent Dioxygenases for Preparative-Scale Synthesis of Hydroxy-l-Lysine

The selective hydroxylation of non-activated C-H bonds is still a challenging reaction in chemistry. Non-heme Fe2+/α-ketoglutarate-dependent dioxygenases are remarkable biocatalysts for the activation of C-H-bonds, catalyzing mainly hydroxylations. The discovery of new Fe2+/α-ketoglutarate-dependent dioxygenases with suitable reactivity for biotechnological applications is therefore highly relevant to expand the limited range of enzymes described so far. In this study, we performed a protein BLAST to identify homologous enzymes to already described lysine dioxygenases (KDOs). Six novel and yet uncharacterized proteins were selected and synthesized by cell-free protein synthesis (CFPS). The subsequent in vitro screening of the selected homologs revealed activity towards the hydroxylation of l-lysine (Lys) into hydroxy-l-lysine (Hyl), which is a versatile chiral building block. With respect to biotechnological application, Escherichia coli whole-cell biocatalysts were developed and characterized in small-scale biotransformations. As the whole-cell biocatalyst expressing the gene coding for the KDO from Photorhabdus luminescens showed the highest specific activity of 8.6 ± 0.6 U gCDW−1, it was selected for the preparative synthesis of Hyl. Multi-gram scale product concentrations were achieved providing a good starting point for further bioprocess development for Hyl production. A systematic approach was established to screen and identify novel Fe2+/α-ketoglutarate-dependent dioxygenases, covering the entire pathway from gene to product, which contributes to accelerating the development of bioprocesses for the production of value-added chemicals.

γ-Hydroxy Amides from Tartaric Acid: Versatile Chiral Building Blocks for the Total Synthesis of Natural Products.

"Chiral pool" compounds possessing well defined stereocenters and suitable functionality serve as excellent building blocks for the synthesis of natural products and therapeutically important compounds. Tartaric acid is a C2 -symmetric molecule available in both enantiomeric forms. It was extensively utilized in the synthesis of privileged chiral ligands/catalysts such as TADDOLs, and as a start point in the synthesis of plethora of compounds. The advent of several new C-C bond forming reactions offers opportunity for the development of novel synthetic strategies based on chiral pool compounds. We found that the desymmetrization of the bis-dimethyl amide/Weinreb amide derived from tartaric acid can be accomplished by controlled addition of Grignard /organolithium reagents leading to the mono keto amides, the reduction of which affords the γ-hydroxy amides. This account describes our research efforts of more than a decade on the synthesis and application of diverse γ-hydroxy amides derived from tartaric acid in the total synthesis of structurally simple to complex bio-active natural products.

Brown Allylation: Application to the Synthesis of Natural Products

AbstractAsymmetric allylation represents an important reaction applied in the natural product synthesis. The stereoselective introduction of an allyl group allows to obtain versatile chiral building blocks, which may further undergo various transformations due to the presence of the carbon–carbon double bond. In this review, we address the Brown allylation, which involves the conversion of aldehydes into homoallylic alcohols using B‐allyldiisopinocampheylborane as a chiral reagent. We provide a comprehensive overview of the reaction and highlight its application in the synthesis of natural products, while assessing its performance in comparison to other approaches. The total of 17 syntheses have been described, including the synthesis of biologically active macrolides disciformycin B, biselyngbyolide B, peloruside A, and gliomasolide A, bis‐piperidine alkaloid (−)‐anaferine and dysoxylactam A.

Malic acid——A Versatile Chiral Building Block in the Enantioselective Total Synthesis of Natural Products and in Synthetic Methodologies

Malic acid——A Versatile Chiral Building Block in the Enantioselective Total Synthesis of Natural Products and in Synthetic Methodologies

Asymmetric Synthesis of α-Quaternary γ-Lactams through Palladium-Catalyzed Asymmetric Allylic Alkylation.

The synthesis of chiral unsaturated γ-lactams is reported featuring a highly enantioselective palladium-catalyzed asymmetric allylic alkylation of α,γ-disubstituted 2-silyloxypyrroles. This method allows a straightforward access to optically active γ-lactams bearing an α-quaternary stereogenic center in high yields (up to 93%), high regioselectivities (up to >20:1), and excellent enantioselectivities (up to 95% ee). To further demonstrate the synthetic utility of the method, the resulting allylated products were converted to various versatile chiral building blocks, such as pyrrolidines and pyrrolidinones.

Asymmetric Carboxycyanation of Aldehydes by Cooperative AlF/Onium Salt Catalysts: from Cyanoformate to KCN as Cyanide Source.

Asymmetric 1,2-additions of cyanide yield enantioenriched cyanohydrins as versatile chiral building blocks. Next to HCN, volatile organic cyanide sources are usually used. Among them, cyanoformates are more attractive on technical scale than TMSCN for cost reasons, but catalytic productivity is usually lower. Here, the development of a new strategy for cyanations is described, in which this activity disadvantage is overcome. A Lewis acidic Al center cooperates with an aprotic onium moiety within a remarkably robust bifunctional Al-F-salen complex. This allowed for unprecedented turnover numbers of up to 104 . DFT studies suggest an unexpected unique trimolecular pathway in which the ammonium bound cyanide attacks the aldehyde, which itself is activated by the carbonyl group of the cyanoformate binding to the Al center. In addition, a novel practical carboxycyanation method was developed that makes use of KCN as the sole cyanide source. The use of a pyrocarbonate as carboxylating reagent provided the best results.

Regioselective and Enantioselective Synthesis of β-Indolyl Cyclopentenamides by Chiral Anion Catalysis.

The regioselective and enantioselective synthesis of β-indolyl cyclopentenamides, a versatile chiral building block, by asymmetric addition of indoles to α,β-unsaturated iminium intermediates has been achieved through chiral anion catalysis. Key to the success of this methodology is the generation of a chiral anion-paired ketone-type α,β-unsaturated iminium intermediate from α-hydroxy enamides. Preliminary mechanistic studies and DFT calculations are consistent with a mechanism involving multiple, concurrent pathways for isomerization of the initially formed azaallylcation into the key α,β-unsaturated iminium intermediate, all mediated by the phosphoric acid catalyst.

Regioselective and Enantioselective Synthesis of β‐Indolyl Cyclopentenamides by Chiral Anion Catalysis

AbstractThe regioselective and enantioselective synthesis of β‐indolyl cyclopentenamides, a versatile chiral building block, by asymmetric addition of indoles to α,β‐unsaturated iminium intermediates has been achieved through chiral anion catalysis. Key to the success of this methodology is the generation of a chiral anion‐paired ketone‐type α,β‐unsaturated iminium intermediate from α‐hydroxy enamides. Preliminary mechanistic studies and DFT calculations are consistent with a mechanism involving multiple, concurrent pathways for isomerization of the initially formed azaallylcation into the key α,β‐unsaturated iminium intermediate, all mediated by the phosphoric acid catalyst.

Quercitol: From a Taxonomic Marker of the Genus Quercus to a Versatile Chiral Building Block of Antidiabetic Agents.

Quercitol is a cyclohexanepentol that has been recognized as a biomarker of plants in genus Quercus, which includes oak. As a result of its glucose-like structure, it has been introduced as an alternative chiral building block in the synthesis of several bioactive compounds. Our continuing investigations on the synthesis of antidiabetic agents from quercitol have demonstrated that this chiral synthon can generate diverse structural features with improved hypoglycemic activity.

Highly Enantioselective, Base-Free Synthesis of α-Quaternary Succinimides through Catalytic Asymmetric Allylic Alkylation.

The synthesis of diversely substituted five-membered ring succinimide derivatives is reported featuring a direct, base-free, palladium-catalyzed asymmetric allylic alkylation. The method allows a straightforward access to the desired heterocyclic scaffold bearing an all-carbon α-quaternary stereogenic center in high yields and good to excellent enantioselectivities. To further demonstrate the synthetic utility of the method, the allylated products were further converted to various versatile chiral building blocks, including a chiral pyrrolidine and a spirocyclic derivative, using selective transformations.

Enantioselective Bromocyclization of Allylic Amides Mediated by Phosphorus Catalysis

Halocyclization of alkenes is commonly employed to increase molecular complexity during organic synthesis because it enables double installation of heteroatoms on a carbon–carbon double bond. Moreover, stereodefined halogenated compounds are widely found among naturally occurring compounds and can serve as versatile chiral building blocks. Therefore, the development of asymmetric halocyclization reactions is of great interest and, in recent years, there has been remarkable progress in catalytic asymmetric halogenation reactions. This account summarizes recent progress made by our group on phosphorus-­catalyzed enantioselective bromocyclization of allylic amides. Building on a comprehensive study of the reaction mechanism, we discovered an intriguing catalytic reaction in which P+Br species serves as a fine-tuning element for substrate fixation. We also describe the application of this bromocyclization to asymmetric desymmetrization of 1,4-diene substrates and a concise synthesis of the HIV-protease inhibitor ­nelfinavir using the newly developed desymmetrization reaction as a key step.1 Introduction2 Enantioselective Bromocyclization of Allylic Amides with a BINAP Catalyst2.1 Bromocyclization with a P/P Catalyst2.2 Bromocyclization with a P/P=O Catalyst3 Desymmetrization of Bisallylic Amides through Enantioselective Bromocyclization3.1 Desymmetrization of Bisallylic Amides3.2 Enantioselective Synthesis of Nelfinavir4 Summary

Synthesis of Enantioenriched γ-Amino-α,β-unsaturated Esters Utilizing Palladium-Catalyzed Rearrangement of Allylic Carbamates for Direct Application to Formal [3 + 2] Cycloaddition.

An efficient synthesis of enantioenriched γ-amino-α,β-unsaturated esters was developed by utilizing the palladium-catalyzed decarboxylative rearrangement of enantioenriched allylic carbamates possessing an ester moiety at the allylic position. The reaction proceeded in good yield with a high degree of chirality transfer by making use of Xantphos as a superior ligand for the catalyst. The products directly participated in the formal [3 + 2] cycloaddition reaction with tosyl isocyanate under Brønsted base catalysis to afford enantioenriched β,γ-diamino acid derived imidazolidin-2-ones as versatile chiral building blocks.

Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β-Fluorinated Amides.

The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C-C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, α- and β-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Brønsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chemistry.

ChemInform Abstract: Asymmetric Synthesis of δ‐Chloro‐β‐amino‐N‐sulfinyl Imidates as Versatile Chiral Building Blocks for the Synthesis of 2,3‐Disubstituted Piperidines.

AbstractNew β‐amino‐δ‐chloro carboximidates bearing a chiral sulfoxide auxiliary are prepared and used as building blocks for the synthesis of enantio‐ and diastereomeric pure 2,3‐disubstituted piperidines (similar reactions based on the minor diastereomer are not shown).

Asymmetric Synthesis of δ‐Chloro‐β‐amino‐N‐sulfinyl Imidates as Versatile Chiral Building Blocks for the Synthesis of 2,3‐Disubstituted Piperidines

AbstractMannich‐type reactions of chiral δ‐chloro‐N‐tert‐butanesulfinyl‐substituted imidates across N‐sulfonyl aldimines resulted in the efficient and anti‐stereoselective synthesis of new β‐(sulfonylamino)‐N‐sulfinyl imidates (dr > 99:1). These compounds were then successfully cyclized to give 2‐aryl‐N‐sulfonylpiperidine‐3‐(N‐sulfinyl)carbimidates in high yields. These proved to be useful intermediates for the synthesis of chiral methyl 2‐arylpiperidine‐3‐carboxylates as well as cis‐3‐amino‐2‐aryl‐N‐sulfonylpiperidines.

Synthesis of Bromo‐Substituted 4‐Hydroxy[2.2]paracyclophanes and [2.2]Paracyclophane‐4,7‐quinones as Versatile Chiral Building Blocks

AbstractApproaches to a number of bromo‐substituted derivatives of 4‐hydroxy[2.2]paracyclophane, including the regioselective mono‐ and dibromination of this phenol, were investigated. The applicability of the regioisomeric monobromo‐substituted phenols for the synthesis of substituted [2.2]paracyclophane‐4,7‐quinones through a one‐pot diazonium coupling/reduction/oxidation sequence was demonstrated. The compounds obtained possess various substitution patterns and could be used for the synthesis of a wide range of [2.2]paracyclophane derivatives by transformation of the bromine, hydroxy, and quinoid fragments.