Development of the first and practical method for enantioselective synthesis of B-enriched p-borono-l-phenylalanine

At present p-(¹⁰B)borono-l-phenylalanine (l-¹⁰Bpa) is used clinically as an excellent ¹⁰B carrier for BNCT; however, its enantioselective synthesis has not been reported yet. The present Letter describes the first and practical method for enantioselective synthesis of ¹⁰B-enriched l-Bpa using Z-l-Ser-OMe as the chiral synthon in good total yield and high optical purity.     

Highly enantioselective preparation of tricyclo[4.4.0.0]decene derivatives via catalytic asymmetric intramolecular cyclopropanation reactions of α-diazo-β-keto esters

The enantioselective preparation of the tricyclo[4.4.0.0^5,7]dec-2-ene derivatives via the catalytic asymmetric intramolecular cyclopropanation (CAIMCP) reactions of α-diazo-β-keto esters with excellent ee (95-98% ee) is described. The chiral building blocks reported herein would be versatile intermediates for enantioselective natural products synthesis.     

Synthesis and Configuration of Neomaclafungin A

The relative and absolute configuration of neomaclafungins were impossible to establish by spectroscopic analyses alone because of the lack of exploitable ¹H‐¹H couplings and nOes between the upper and the lower subunits. This very difficult task now is finally completed by an enantioselective total synthesis of neomaclafungin A (revised) and its diastereomer (reported). The results also provided a key reference for the complete structures for other neomaclafungins and the long‐known closely related natural product maclafungin.     

Intermolecular Enantioselective Benzylic C(sp3)−H Amination by Cationic Copper Catalysis**

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp³)−H functionalization by hydrogen-atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp³)−H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp³)−H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen-atom transfer.     

Experimental and Theoretical Investigations of the Stereoselective Synthesis of P‐Stereogenic Phosphine Oxides

An efficient enantioselective strategy for the synthesis of variously substituted phosphine oxides has been developed, incorporating the use of (1S,2S)‐2‐aminocyclohexanol as the chiral auxiliary. The method relies on three key steps: 1) Highly diastereoselective formation of P^V oxazaphospholidine, rationalized by a theoretical study; 2) highly diastereoselective ring‐opening of the oxazaphospholidine oxide with organometallic reagents that takes place with inversion of configuration at the P atom; 3) enantioselective synthesis of phosphine oxides by cleavage of the remaining P?O bond. Interestingly, the use of a P^III phosphine precursor afforded a P‐epimer oxazaphospholidine. Hence, the two enantiomeric phosphine oxides can be synthesized starting from either a P^V or a P^III phosphine precursor, which constitutes a clear advantage for the stereoselective synthesis of sterically hindered phosphine oxides.     

Enantioselective Silylation of Aliphatic C−H Bonds for the Synthesis of Silicon-Stereogenic Dihydrobenzosiloles

A rhodium(I)-catalyzed enantioselective silylation of aliphatic C−H bonds for the synthesis of silicon-stereogenic dihydrobenzosiloles is demonstrated. This reaction involves a highly enantioselective intramolecular C(sp³)−H silylation of dihydrosilanes, followed by a stereospecific intermolecular alkene hydrosilylation leading to the asymmetrically tetrasubstituted silanes. A wide range of dihydrosilanes and alkenes displaying various functional groups are compatible with this process, giving access to a variety of highly functionalized silicon-stereogenic dihydrobenzosiloles in good to excellent yields and enantioselectivities.     

Synthesis of enantiopure β2-homoalanine derivatives via rhodium catalyzed asymmetric hydrogenation

The stereoselective synthesis of chiral β²-homoalanine derivatives with 99% ee by the Rh-catalyzed enantioselective hydrogenation of prochiral 2-aminomethyl acrylates is described. The subsequent transformation to chiral 3-amino-2-methylpropanols is also demonstrated.     

New Catalysts for the Asymmetric Hydrophosphonylation of Aldehydes1

Abstract

Chiral α-hydroxyphosphonates are biologically active² and are flexible precursors for other α and γ substituted phosphonates ³ The fact that the biological activity is oRen dependent on the absolute configuration of the a-position has resulted in a growing interest in methods for the asymmetric synthesis of hydroxyphosphonates ¹Potentially, the most efficient and economic route to these compounds involves enantioselective catalvsis.     

Catalytic Enantioselective Synthesis of Helicenes

Helicenes and helicene-like molecules, usually containing multiple ortho-fused aromatic rings, possess unique helical chirality. These compounds have found a wide range of important applications in many research fields, such as asymmetric catalysis, molecular recognition, sensors and responsive switches, circularly polarized luminescence materials and others. However, the catalytic enantioselective synthesis of helicenes was largely underexplored, when compared with the enantioselective synthesis of molecules bearing other stereogenic elements (e.g. central chirality and axial chirality). Since the pioneer work of asymmetric synthesis of helicenes via enantioselective [2+2+2] cycloaddition of triynes by Stará and Starý, last two decades have witnessed the tremendous development in the catalytic enantioselective synthesis of helicenes. In this review, we comprehensively summarized the advances in this field, which include methods enabled by both transition metal catalysis and organocatalysis, and provide our perspective on its future development.     

Asymmetric synthesis of suitably protected γ-hydroxy-aza-β3-homothreonine building blocks

An efficient and easily applicable method for the enantioselective synthesis of γ-Hydroxy aza-β³-homothreonine (aza-β³-Hyht) has been established. The method involves stereoselective reductive amination of glyoxylic acid and the corresponding Fmoc protected chiral hydrazine. A stereoselectivity of 99% was achieved for each step using (R)-2,3-O-isopropylideneglyceraldehyde as the chiral auxiliary. This new synthetic monomer is a useful building block for the solid-phase synthesis of new peptidomimetics.     

Asymmetric Yttrium-Catalyzed C(sp3)−H Addition of 2-Methyl Azaarenes to Cyclopropenes

An enantioselective C−H addition to a C=C bond represents the most atom-efficient route for the construction of chiral carbon–carbon skeletons, a central research topic in organic synthesis. We herein report the enantioselective yttrium-catalyzed C(sp³)−H bond addition of 2-methyl azaarenes, such as 2-methyl pyridines, to various substituted cyclopropenes and norbornenes. This process efficiently afforded a new family of chiral pyridylmethyl-functionalized cyclopropane and norbornane derivatives in high yields and high enantioselectivities (up to 97 % ee).     

Forming All-Carbon Quaternary Stereocenters by Organocatalytic Aminomethylation: Concise Access to β2,2-Amino Acids

The asymmetric synthesis of β^2,2-amino acids remains a formidable challenge in organic synthesis. Here a novel organocatalytic enantioselective aminomethylation of ketenes with stable and readily available N,O-acetals is reported, providing β^2,2-amino esters bearing an all-carbon quaternary stereogenic center in high enantiomeric ratios with a catalytic amount of chiral phosphoric acid. Typically, this transformation probably proceeds through an asymmetric counter-anion-directed catalysis. As a result, a concise, practical, and atom-economic protocol toward rapidly access to β^2,2-amino acids has been developed.     

Asymmetric Yttrium‐Catalyzed C(sp3)−H Addition of 2‐Methyl Azaarenes to Cyclopropenes

An enantioselective C−H addition to a C=C bond represents the most atom‐efficient route for the construction of chiral carbon–carbon skeletons, a central research topic in organic synthesis. We herein report the enantioselective yttrium‐catalyzed C(sp³)−H bond addition of 2‐methyl azaarenes, such as 2‐methyl pyridines, to various substituted cyclopropenes and norbornenes. This process efficiently afforded a new family of chiral pyridylmethyl‐functionalized cyclopropane and norbornane derivatives in high yields and high enantioselectivities (up to 97 % ee ).     

Enantioselective Iridium‐Catalyzed Allylic Substitution with 2‐Methylpyridines

An enantioselective iridium‐catalyzed allylic substitution with a set of highly unstabilized nucleophiles generated in situ from 2‐methylpyridines is described. Enantioenriched 2‐substituted pyridines, which are frequently encountered in natural products and pharmaceuticals, could be easily constructed by this simple method in good yields and excellent enantioselectivity. The synthetic utility of the pyridine products is demonstrated through the synthesis of a key intermediate of a reported Na⁺/H⁺ exchanger inhibitor and the total synthesis of (−)‐lycopladine A.     

An Efficient Synthesis of Optically Active [4-13C] Labelled Quorum Sensing Signal Autoinducer-2

A new synthetic route for the quorum sensing signal Autoinducer-2 (AI-2) is described and used for the preparation of [4-¹³C]-AI-2 starting from [1-¹³C]-bromoacetic acid. The key step in this process was the enantioselective reduction of an intermediate ketone. This synthesis provides, selectively, both enantiomers of the labelled or unlabelled parent compound, (R) or (S)-4,5-dihydroxypentane-2,3-dione (DPD) and was used for an improved synthesis of [1-¹³C]-AI-2.     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols by Sequential Metal-Free Diene Aziridination/Kinetic Resolution

A general protocol for the enantioselective synthesis of 3-heterosubstituted-2-amino-1-ols was developed based on metal- free intramolecular regio- and stereoselective diene aziridination and regioselective opening. Kinetic resolution of the resulting (1′-NR¹R² and 1′-SR)-4-oxazolidinones was performed using ABCs organocatalysts, expanding the application of this methodology.     

Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P−H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P−H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner. The key to the success lies in not only the implementation of dialkyl phosphites with a strong bond dissociation energy to promote the desired chemoselectivity but also the utilization of an anionic chiral N,N,N-ligand to forge the chiral C(sp³)−P bond. The developed Cu/N,N,N-ligand catalyst has enriched our library of single-electron transfer catalysts in the enantioselective radical transformations.     

Improved Synthesis of Cyclic Tertiary Allylic Alcohols by Asymmetric 1,2‐Addition of AlMe3 to Enones

The development of an improved protocol for the enantioselective Rh^I/binap‐catalysed 1,2‐addition of AlMe₃ to cyclic enones is reported. ³¹P NMR analysis of the reaction revealed that the catalyst in its resting state is a chloride‐bridged dimer. This insight led to the use of AgBF₄ as an additive for in situ activation of the dimeric precatalyst. Thus, the catalyst loading can now be reduced to only 1 mol % with respect to rhodium. Various 5–7‐membered cyclic enones can be transformed into tertiary allylic alcohols with excellent levels of enantioselectivity and high yields. The obtained products are versatile synthetic building blocks, shown by a highly enantioselective formal total synthesis of the pheromone (?)‐frontalin as well as formation of a bicyclic lactone that has the core structure of the natural flavour component “wine lactone”.     

Spiroleucettadine: synthetic studies and investigations towards structural revision

Synthetic efforts towards spiroleucettadine are described, including the enantioselective synthesis of the presumed biosynthetic precursor. High level density functional theory calculations were used to predict the ¹³C NMR shifts of possible alternative structures and, along with a re-evaluation of the available NMR data, allow the proposal of revised structures for this spirocyclic alkaloid.