Enantioenriched Methylene‐Bridged Benzazocanes Synthesis by Organocatalytic and Superacid Activations

Achieving in a straightforward way the synthesis of enantioenriched elaborated three‐dimensional molecules related to bioactive natural products remains a long‐standing quest in organic synthesis. Enantioselective organocatalysis potentially offers a unique opportunity to solve this problem, especially when combined with complementary modes of activation. Here, we report the sequential association of organocatalytic and superacid activations of simple linear achiral readily available precursors to promote the formation of unique highly elaborated chiral methylene‐bridged benzazocanes exhibiting three to five fully‐controlled stereocenters. This peculiar backbone, difficult to assemble by standard synthetic approaches, is closely related to bioactive natural and synthetic morphinans and benzomorphans. The formation of a highly reactive chiral 7‐membered ring N‐acyl iminium superelectrophilic ion, evidenced by low‐temperature in situ NMR experiments, triggers a challenging stereoselective Friedel–Crafts‐type cyclization.     

Rhodium(III)/Copper(II)‐Promoted trans‐Selective Heteroaryl Acyloxylation of Alkynes: Stereodefined Access to trans‐Enol Esters

Enol esters are versatile synthetic building blocks which can be elaborated by a wide variety of transformations. The classical synthesis by O‐selective enolate acylation often hampers control of the E/Z selectivity with highly substituted substrates. A rhodium(III)/copper(II)‐mediated process is reported to provide tetrasubstituted enol esters in a trans‐selective fashion. Overall, the reaction consists of a heteroaryl acyloxylation of alkynes. The process is initiated by a rhodium(III)‐catalyzed C2‐selective activation of electron‐rich heteroarenes, such as benzofuran, furan, and thiophene. Upon addition across an alkyne, a transmetalation to copper(II) enables reductive C? O bond formation. The transformation allows the three‐component couplings of heteroarenes, alkynes, and carboxylic acids. Application of the method in the functionalization of bioactive furocoumarin natural products is also described.     

Catalytic Atroposelective C7 Functionalisation of Indolines and Indoles

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry. In particular, axially chiral indole- and indoline-based frameworks have been recognised as important heterobiaryl classes because they are the core units of bioactive natural alkaloids, chiral ligands and bioactive compounds. Among them, the synthesis of C7-substituted indole biaryls and the analogous indoline derivatives is particularly challenging, and methods for their efficient synthesis are in high demand. Transition-metal catalysis is considered one of the most efficient methods to construct atropisomers. Here, we report the enantioselective synthesis of C7-indolino- and C7-indolo biaryl atropisomers by means of C−H functionalisation catalysed by chiral RhJasCp complexes.     

Catalytic Enantioselective Aza-pinacol Rearrangement

The first catalytic enantioselective asymmetric aza-pinacol rearrangement is reported. The reactions are catalyzed by a chiral phosphoric acid and proceed via a highly organized transition state involving a cyclic aza-ortho-xylylene intermediate to afford the indoline structures with good to excellent enantioselectivity. The synthetic utility of this method is demonstrated by the asymmetric synthesis of a key intermediate to the natural product minfiensine and the identification of a chiral lead compound to repress antibiotic resistance.     

Catalytic Enantioselective Aza‐pinacol Rearrangement

The first catalytic enantioselective asymmetric aza‐pinacol rearrangement is reported. The reactions are catalyzed by a chiral phosphoric acid and proceed via a highly organized transition state involving a cyclic aza‐ortho ‐xylylene intermediate to afford the indoline structures with good to excellent enantioselectivity. The synthetic utility of this method is demonstrated by the asymmetric synthesis of a key intermediate to the natural product minfiensine and the identification of a chiral lead compound to repress antibiotic resistance.     

Boron‐Catalyzed Regioselective Deoxygenation of Terminal 1,2‐Diols to 2‐Alkanols Enabled by the Strategic Formation of a Cyclic Siloxane Intermediate

The selective deoxygenation of polyols is a frontier in our ability to harness the stereochemical and structural complexity of natural and synthetic feedstocks. Herein, we describe a highly active and selective boron‐based catalytic system for the selective deoxygenation of terminal 1,2‐diols at the primary position, a process that is enabled by the transient formation of a cyclic siloxane. The method provides an ideal complement to well‐known catalytic asymmetric reactions to prepare synthetically challenging chiral 2‐alkanols in nearly perfect enantiomeric excess, as illustrated in a short synthesis of the anti‐inflammatory drug (R)‐lisofylline.     

Asymmetric Allylic Substitution-Isomerization for the Modular Synthesis of Axially Chiral N-Vinylquinazolinones

Axially chiral N-substituted quinazolinones are important bioactive molecules, which are presented in many synthetic drugs. However, most strategies toward their atroposelective synthesis are mainly limited to the axially chiral arylquinazolinone frameworks. The development of modular synthetic methods to access diverse quinazolinone-based atropisomers remains scarce and challenging. Herein, we report the regio- and atroposelective synthesis of axially chiral N-vinylquinazolinones via the strategy of asymmetric allylic substitution-isomerization. The catalysis system utilized both asymmetric transition-metal catalysis and organocatalysis to efficiently afford trisubstituted and tetrasubstituted N-vinylquinazolinone atropisomers, respectively. With the meticulous design of β-substituted allylic substrates, both Z- and E-tetrasubstituted axially chiral N-vinylquinazolinones were obtained in good yields and high enantioselectivities.     

Cascade Biocatalysis for Sustainable Asymmetric Synthesis: From Biobased l‐Phenylalanine to High‐Value Chiral Chemicals

Sustainable synthesis of useful and valuable chiral fine chemicals from renewable feedstocks is highly desirable but remains challenging. Reported herein is a designed and engineered set of unique non‐natural biocatalytic cascades to achieve the asymmetric synthesis of chiral epoxide, diols, hydroxy acid, and amino acid in high yield and with excellent ee values from the easily available biobased l ‐phenylalanine. Each of the cascades was efficiently performed in one pot by using the cells of a single recombinant strain over‐expressing 4–10 different enzymes. The cascade biocatalysis approach is promising for upgrading biobased bulk chemicals to high‐value chiral chemicals. In addition, combining the non‐natural enzyme cascades with the natural metabolic pathway of the host strain enabled the fermentative production of the chiral fine chemicals from glucose.     

A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine,and (+)‐1‐epi‐Castanospermine

The asymmetric total synthesis of natural azasugars (+)‐castanospermine, (+)‐7‐deoxy‐6‐epi‐castanospermine, and synthetic (+)‐1‐epi‐castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)‐ 8 . The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama‐type reaction with either chiral or achiral aldehydes (≥95 % de; de=diastereomeric excess) and a diastereodivergent reduction of tetramic acids, which allows formation of three continuous stereogenic centers with high diastereoselectivities. The method also provides a flexible access to structural arrays of 5‐(α‐hydroxyalkyl)tetramic acids, such as 17/34 , and 5‐(α‐hydroxyalkyl)‐4‐hydroxyl‐2‐pyrrolidinones, such as 18 and 25/35 a . The method constitutes the first realization of the challenging chiral synthons A and D and thus of the conceptually attractive retrosynthetic analysis shown in Scheme 1 in a highly enantioselective manner.     

Catalytic Asymmetric Crotylation of Aldehydes: Application in Total Synthesis of (−)‐Elisabethadione

A new, highly efficient Lewis base catalyst for a practical enantio‐ and diastereoselective crotylation of unsaturated aldehydes with E‐ and Z‐crotyltrichlorosilanes has been developed. The method was employed as a key step in a novel asymmetric synthesis of bioactive serrulatane diterpene (?)‐elisabethadione. Other strategic reactions for setting up the stereogenic centers included anionic oxy‐Cope rearrangement and cationic cyclization. The synthetic route relies on simple, high yielding reactions and avoids use of protecting groups or chiral auxiliaries.     

An Enantioselective Approach to Heteroatom-Containing Bicyclic Derivatives via Inverse-Electron-Demand Diels−Alder Reactions

Chiral heteroatom-containing bicyclic scaffolds are important pharmacophores and prevalent in bioactive natural products and drug molecules. Herein, we report a unified approach for the divergent synthesis of chiral heteroatom-containing bicyclic derivatives by lanthanide (III)-catalyzed asymmetric inverse-electron-demand Diels–Alder reactions of 2-pyrones. These reactions occur with various readily available dihydropyrroles and dihydrofurans as dienophiles, providing a step-economical synthetic platform for densely functionalized cis-hydroindoles and cis-hydrobenzofurans with excellent yields and enantioselectivities. The synthetic utility of this approach is demonstrated by the concise synthesis of (–)-α-lycorane and (–)-lycorine alkaloids.     

Synthetic Studies toward C‐Glucosidic Ellagitannins: A Biomimetic Total Synthesis of 5‐O‐Desgalloylepipunicacortein A

C‐glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C‐glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open‐chain glucose core by a C‐aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP‐containing 5‐O‐desgalloylepipunicacortein A ( 1 β ) was achieved by either using the natural ellagic acid bis‐lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C‐aryl glucosidic bond in the title compound.     

Total Synthesis of (−)‐Apratoxin A, 34‐Epimer,and Its Oxazoline Analogue

A concise and convergent total synthesis of the highly cytotoxic marine natural product apratoxin A is accomplished by an 18‐step linear sequence. The high sensitivity of the thiazoline, bearing an adjacent β‐hydroxyl group at the C35‐position, results in the assembly process requiring the inclusion of appropriate protecting groups and the careful optimization of all individual transformations. In the synthesis of 3,7‐dihydroxy‐2,5,8,8‐tetramethylnonanoic acid (Dtena), the three reagent‐controlled asymmetric reactions enables us to introduce four chiral carbon centers in a dihydroxylated fatty acid moiety. Formation of the hindered ester and sterically‐unfavorable N‐methylamide bonds were successfully demonstrated. The thiazoline in apratoxin A was constructed by Tf₂O and Ph₃PO‐mediated dehydrative cyclization, and final macrocyclization was achieved between N‐methylisoleucine and proline residues. Moreover, an oxazoline analogue and a C34 epimer of apratoxin A have also been elaborated in a similar approach. This synthetic route would enable assembly of other analogues differing in stereocenters of Dtena and their amino acids.     

亚胺及其类似物的催化不对称炔基化反应新进展

手性炔丙胺是天然产物和药物活性分子不对称全合成中常用的关键中间体,亚胺及其类似物的不对称炔基化反应可以为该砌块提供高效高对映选择性的合成路径;此外通过合理的底物和反应设计,亚胺的不对称炔基化反应还能作为一系列串联反应的起点,来合成多种结构新颖的含氮杂环化合物.因此,亚胺及其类似物的高效高对映选择性炔基化反应得到合成化学家们持续关注.按照底物类型,主要分为醛亚胺的不对称炔基化和酮亚胺的不对称炔基化两大部分,介绍了亚胺及其类似物的不对称炔基化反应在过去十年中的研究进展.对这些反应的机理、优势与不足之处以及该反应在合成中的应用进行简要讨论,从而为拓展该反应在合成中的应用提供一些有益参考和借鉴.     

Studies of a Diazo Cyclopropanation Strategy for the Total Synthesis of (−)‐Lundurine A

The bioactive Kopsia alkaloids lundurines A–D are the only natural products known to contain indolylcyclopropane. Achieving their syntheses can provide important insights into their biogenesis, as well as novel synthetic routes for complex natural products. Asymmetric total synthesis of (?)‐lundurine A has previously been achieved through a Simmons–Smith cyclopropanation strategy. Here, the total synthesis of (?)‐lundurine A was carried out using a metal‐catalyzed diazo cyclopropanation strategy. In order to avoid a carbene C?H insertion side reaction during cyclopropanation of α‐diazo‐ carboxylates or cyanides, a one‐pot, copper‐catalyzed Bamford–Stevens diazotization/diazo decomposition/cyclopropanation cascade was developed, involving hydrazone. This approach simultaneously generates the C/D/E ring system and the two chiral quaternary centers at C2 and C7.     

Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

β‐Substituted chiral γ‐aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β‐substituted γ‐aminobutyric acid derivatives through visible‐light‐induced photocatalyst‐free asymmetric radical conjugate additions is reported. Various β‐substituted γ‐aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42–89 %) and with excellent enantioselectivity (90–97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)‐pregabalin, (R)‐baclofen, (R)‐rolipram, and (S)‐nebracetam.     

The first example of a diastereoselective thio-Ugi reaction: a new synthetic approach to chiral imidazole derivatives

The first example of a diastereoselective thio-Ugi reaction with chiral alpha-methylbenzylamine is described. The reaction results in formation of two diastereomers of thioamides, the major of which was isolated. We have found that under similar conditions stereochemical results of the thio-Ugi reaction are opposite to stereochemical results of the Ugi reaction. Several chiral thioamides were synthesized. The reaction of thioamides with ammonia results in substituted amidines, which can be cyclized to imidazole derivatives in aqueous HCl. The synthesis of chiral imidazole derivatives was elaborated. Using certain approaches, both isomers of a key synthon in the synthesis of SB203386 (an orally bioactive HIV-1 protease inhibitor) were prepared. The scope, limitations, and stereochemistry of the approach are discussed.     

Enantioselective Double Manipulation of Tetrahydroisoquinolines with Terminal Alkynes and Aldehydes under Copper(I) Catalysis

Tetrahydroisoquinoline alkaloids with a C1 stereogenic center are a common unit in many natural and non‐natural compounds of biological importance. Herein we describe a novel Cu^I‐catalyzed highly chemo‐ and enantioselective synthesis of chiral tetrahydroisoquinoline‐alkaloid derivatives from readily available unsubstituted tetrahydroisoquinolines, aldehydes, and terminal alkynes in the presence of the ligand (R,R)‐N‐pinap. This synthetic operation installs two substituents in the 1‐ and 2‐positions.     

Organoselenium Chemistry in Stereoselective Reactions

Selenium-based methods have developed rapidly over the past few years asnd organoselenium chemistry has become a very useful tool in the hands of synthetic chemists. The different reactivity of selenium-containing compounds in contrast to the sulfur analogues has led to versatile and new synthetic methods in organic chemistry. Various functionalities can be selectively introduced into complex molecules under very mild reaction conditions. In this review, the principles of organoselenium chemistry are traced back to their origins and are highlighted with respect to stereoselective synthesis. The unique properties of selenium allow the development of new and highly selective transformations, which can be employed subsequently in new routes for the synthesis of versatile chiral building blocks and for natural product synthesis.