Rhodium‐Catalyzed Enantioselective Arylation of Aliphatic Imines

Chiral rhodium(I)‐catalyzed highly enantioselective arylation of aliphatic N‐sulfonyl aldimines with arylboronic acids has been developed. This transformation is achieved by the use of a rhodium/bis(phosphoramidite) catalyst to give enantiomerically enriched α‐branched amines (up to 99 % ee). In addition, this system enables efficient synthesis of (+)‐NPS R‐568 and Cinacalcet which are calcimimetic agents.     

Me‐bipam for Enantioselective Ruthenium(II)‐Catalyzed Arylation of Aldehydes with Arylboronic Acids

Ligand design by‐pam : A ruthenium‐catalyzed asymmetric arylation of aldehydes with arylboronic acids has been developed, giving chiral diarylmethanols in good yields. The use of a chiral bidentate phosphoramidite ligand ((R,R)‐Me‐bipam) led to excellent enantioselectivities.

     

Rhodium‐Catalyzed Formation of Stereocontrolled Trisubstituted Alkenes from Baylis–Hillman Adducts

Efficient and general conditions for the formation of stereodefined trisubstituted alkenes by using the rhodium‐catalyzed reaction of unactivated Baylis–Hillman adducts with either organoboronic acids or potassium trifluoro(organo)borates are reported (see scheme).

     

Highly Enantioselective Rhodium‐Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram

Highly enantioselective additions of arylboroxines to simple aryl ketones have been achieved for the first time with a Rh/(R,R,R,R)‐WingPhos catalyst, thus providing a range of chiral diaryl alkyl carbinols with excellent ee values and yields. (R,R,R,R)‐WingPhos has been proven to be crucial for the high reactivity and enantioselectivity. The method has enabled a new, concise, and enantioselective synthesis of the antidepressant drug escitalopram.     

Regio‐ and Enantioselective Synthesis of N‐Substituted Pyrazoles by Rhodium‐Catalyzed Asymmetric Addition to Allenes

The rhodium‐catalyzed asymmetric N‐selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)‐ruxolitinib.     

Enantioselective Rhodium‐Catalyzed Atom‐Economical Macrolactonization

A highly attractive route toward macrolactones, which form the cyclic scaffold of a multitude of diverse natural compounds, is described. Although many chemical approaches to this structural motif have been explored, an asymmetric variant of the cyclization is unprecedented. Herein we present an enantioselective macrolactonization through an intramolecular atom‐economical rhodium‐catalyzed coupling of ω‐allenyl‐substituted carboxylic acids. The use of a modified diop ligand, chiral DTBM‐diop, led to high enantioselectivity (up to 93 % ee). The reaction tolerated a large variety of functionalities, including α,β‐unsaturated carboxylic acids and depsipeptides, and provided the desired macrocycles with very high enantio‐ and diastereoselectivity.     

Rhodium‐Catalyzed Cascade Reaction of 1,6‐Enynes Involving Addition,Cyclization, and β‐Oxygen Elimination

The reaction of arylboronic acids with 1,6‐enynes that contain an allylic ether moiety is catalyzed by a rhodium(I) complex to produce cyclopentanes with a tetrasubstituted exo olefin and a pendant vinyl group. The reaction is initiated by the regioselective addition of an arylrhodium(I) species to the carbon–carbon triple bond of the 1,6‐enyne. The resulting alkenylrhodium(I) compound subsequently undergoes intramolecular carborhodation of the allylic double bond in a 5‐exo‐trig mode. β Elimination of the methoxy group affords the cyclization product and the catalytically active methoxorhodium(I) species. The use of alkyl Grignard reagents instead of arylboronic acids as organometallic nucleophiles was also examined.     

Rhodium‐Catalyzed Sequential Allylic Amination and Olefin Hydroacylation Reactions: Enantioselective Synthesis of Seven‐Membered Nitrogen Heterocycles

Dynamic kinetic asymmetric amination of branched allylic acetimidates has been applied to the synthesis of 2‐alkyl‐dihydrobenzoazepin‐5‐ones. These seven‐membered‐ring aza ketones are prepared in good yield with high enantiomeric excess by rhodium‐catalyzed allylic substitution with 2‐amino aryl aldehydes followed by intramolecular olefin hydroacylation of the resulting alkenals. This two‐step procedure is amenable to varied functionality and proves useful for the enantioselective preparation of these ring systems.     

Enantioselective Rhodium‐Catalyzed Cycloisomerization of (E)‐1,6‐Enynes

An enantioselective rhodium(I)‐catalyzed cycloisomerization reaction of challenging (E)‐1,6‐enynes is reported. This novel process enables (E)‐1,6‐enynes with a wide range of functionalities, including nitrogen‐, oxygen‐, and carbon‐tethered (E)‐1,6‐enynes, to undergo cycloisomerization with excellent enantioselectivity, in a high‐yielding and operationally simple manner. Moreover, this Rh^I‐diphosphane catalytic system also exhibited superior reactivity and enantioselectivity for (Z)‐1,6‐enynes. A rationale for the striking reactivity difference between (E)‐ and (Z)‐1,6‐enynes using Rh^I‐BINAP and Rh^I‐TangPhos is outlined using DFT studies to provide the necessary insight for the design of new catalyst systems and the application to synthesis.     

Direct Synthesis of Chiral 3‐Arylsuccinimides by Rhodium‐Catalyzed Enantioselective Conjugate Addition of Arylboronic Acids to Maleimides

Chiral rhodium catalysts comprising 2,5‐diaryl‐ substituted bicyclo[2.2.1]diene ligands L1 – L10 were utilized in the enantioselective 1,4‐addition reaction of arylboronic acids to N‐substituted maleimides. In the presence of 2.5 mol % of Rh^I/ L2 , enantioenriched conjugate addition adducts were isolated in 72–99 % yields with 86–98 % ee. This protocol offers a convenient method to access a variety of 3‐arylsuccinimides in a highly enantioselective manner. Maleimides with readily cleavable N‐protecting groups were tolerated enabling the synthesis of useful synthetic intermediates. Pyrrolidine 4 , a biologically active compound, and pyrrolidine 5 , an ent‐precursor to an HSD‐1 inhibitor, were synthesized to demonstrate the utility of this method.     

Enantioselective Reactions of N‐Acyliminium Ions Using Chiral Organocatalysts

N‐acyliminium ions are reactive intermediates that can act as electron‐deficient electrophiles toward weak or soft nucleophiles, thereby providing useful methods for both intermolecular‐ and intramolecular carbon–carbon and carbon–heteroatom bond formation. Nucleophilic additions to N‐acyliminium ions constitute an important method for providing α‐functionalized amino compounds and many other biologically active nitrogen‐containing heterocycles. The development of efficient catalytic asymmetric reactions is a key objective in modern organic chemistry and is very important for the synthesis of natural products, pharmaceuticals, and agrochemicals. Various methods are available for this purpose and mostly rely on the use of chiral catalysts for enantioselective synthesis. This review deals with one aspect of such catalysis, which has emerged only in the past few years, and its applications in enantioselective reactions of N‐acyliminium ions to provide various nitrogen‐containing heterocycles.     

Regioconvergent and Enantioselective Rhodium‐Catalyzed Hydroamination of Internal and Terminal Alkynes: A Highly Flexible Access to Chiral Pyrazoles

The rhodium‐catalyzed asymmetric N‐selective coupling of pyrazole derivatives with internal and terminal alkynes features an utmost chemo‐, regio‐, and enantioselective access to enantiopure allylic pyrazoles, readily available for incorporation in small‐molecule pharmaceuticals. This methodology is distinguished by a broad substrate scope, resulting in a remarkable compatability with a variety of different functional groups. It furthermore exhibits an intriguing case of regio‐, position‐, and enantioselectivity in just one step, underscoring the sole synthesis of just one out of up to six possible products in a highly flexible approach to allylated pyrazoles by emanating from various internal and terminal alkynes.