Organocatalytic Enantioselective Synthesis of Pyrazoles Bearing a Quaternary Stereocenter

An efficient one‐pot asymmetric synthesis of pyrazoles bearing a chiral quaternary stereocenter has been developed. Quinine‐derived thiourea catalyzed the enantioselective addition of pyrazolones to isatin‐derived ketimines, providing the corresponding acetylated pyrazoles after in situ treatment with Ac₂O/Et₃N. The corresponding pyrazoles were afforded in high yields and excellent enantioselectivities.     

Organocatalytic and Scalable Synthesis of the Anti‐Influenza Drugs Zanamivir,Laninamivir, and CS‐8958

Zanamivir, laninamivir, and CS‐8958 are three neuraminidase inhibitors that have been clinically used to combat influenza. We report herein a novel organocatalytic route for preparing these agents. Only 13 steps are needed for the assembly of zanamivir and laninamivir from inexpensive D ‐araboascorbic acid by this synthetic route, which relies heavily on a thiourea‐catalyzed enantioselective Michael addition of acetone to tert‐butyl (2‐nitrovinyl)carbamate and an anti‐selective Henry reaction of the resulting Michael adduct with an aldehyde prepared from D ‐araboascorbic acid. The synthetic procedures are scalable, as evident from the preparation of more than 3.5 g of zanamivir.     

Organocatalytic Enantioselective Synthesis of Chiral Diarylmethylamines from Racemic Alcohols

An organocatalytic approach for direct conversion of racemic diarylmethanols to valuable chiral diarylmethylamines is described. Different from the previously reported elegant “borrowing hydrogen” approach, the present process employs a distinct complementary formal S_N1 strategy. This approach enjoys excellent enantioselectivity, mild conditions, broad scope, and easy product derivatization. Mechanistically, control experiments also provided important insights into some notable features, such as substrate kinetic resolution and reversibility as well as the critical role of the ortho‐ hydroxy group in the substrate.     

Organocatalytic Strategies for the Development of the Enantioselective Inverse-electron-demand Hetero-Diels-Alder Reaction

Cycloaddition reactions, in particular Diels-Alder reactions, have attracted a lot of attention from organic chemists since they represent one of the most powerful methodologies for the construction of carbon-carbon bonds. In particular, inverse-electron-demand hetero-Diels-Alder reactions have been an important breakthrough for the synthesis of heterocyclic compounds. Among all their variants, the organocatalytic enantioselective version has been widely explored since the asymmetric construction of diversely functionalized scaffolds under reaction conditions encompassed within the green chemistry field is of great interest. In this review, a profound revision on the latest advances on the organocatalytic asymmetric inverse-electron demand hetero-Diels-Alder reaction is shown.     

Short,Enantioselective Total Synthesis of Chatancin

An enantioselective total synthesis of the polycyclic diterpene (+)‐chatancin, a potent PAF antagonist, is reported. Proceeding in seven steps from dihydrofarnesal, this synthetic route was designed to circumvent macrocyclization‐based strategies to complex, cyclized cembranoids. The described synthesis requires only six chromatographic purifications, is high yielding, and avoids protecting‐group manipulations. An X‐ray crystal structure of this fragile marine natural product was obtained.     

Highly Efficient Enantioselective Construction of Bispirooxindoles Containing Three Stereocenters through an Organocatalytic Cascade Michael–Cyclization Reaction

Bispirooxindole derivatives containing three stereocenters, including two spiro quaternary centers, were synthesized in a high‐yielding, atypically rapid, and stereocontrolled cascade Michael–cyclization reaction between methyleneindolinones and isothiocyanato oxindoles catalyzed by a bi‐ or multifunctional organocatalyst. Mild conditions were used to construct bispirooxindoles with excellent enantio‐ and diastereomeric purities within less than 1 min. Catalyst reconfiguration offered access to the opposite enantiomer. This exceptionally highly efficient procedure will allow diversity‐oriented syntheses of this intriguing class of compounds with potential biological activities.     

Organocatalytic,Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

An unprecedented enantioselective oxa‐Michael reaction of α‐tertiary alcohols using cinchona‐alkaloid‐based chiral bifunctional squaramide catalysts is reported. An oxidative dearomatization of phenol followed by an enantioselective oxa‐Michael addition sequence provided a broad array of chiral sterically hindered tetrahydrofurans and tetrahydropyrans attached to a cyclohexadienone moiety in spiro fashion. In general, good yields and excellent enantioselectivities (up to 99 %) were observed. The chiral oxo‐cycles obtained have easily been transformed into chromans without disturbing the enantioselectivity.     

Organocatalytic Asymmetric Synthesis of Organophosphorus Compounds

240 Years have passed since the discovery of elemental phosphorus. During that time organophosphorus chemistry has emerged as an interesting and exciting field of research. Recently organophosphorus chemistry has been raised to a new level. Organophosphorus compounds have found applications in asymmetric organocatalysis for the synthesis of optically active compounds of synthetic or biological importance. The aim of this review article is to present recent contributions to this developing field of chemistry and to point out synthetic advantages of methodologies developed so far.     

Short,Enantioselective Total Synthesis of Highly Oxidized Taxanes

In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol ( 1 ) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E ( 2 ) and taxabaccatin III ( 3 ), have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The strategy holistically mimics nature's approach (two‐phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox‐isomerization to set the key trans‐diol present in 2 and 3 . This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion, thus empowering a medicinal chemistry campaign that is not wedded to semi‐synthesis.     

Enantioselective Organocatalytic Conjugate Addition of Aldehydes to Vinyl Sulfones and Vinyl Phosphonates as Challenging Michael Acceptors

Chiral framework : Chiral amines with pyrrolidine frameworks catalyze the enantioselective conjugate addition of a wide range of aldehydes to various vinyl sulfones and vinyl phosphonates in high yields and with enantioselectivities up to >99 % ee (see scheme). The high versatility of the Michael adducts is exemplified by various functionalizations with conservation of the optical purity.

     

Organocatalytic Asymmetric Synthesis of an Advanced Intermediate of (+)-Sarain A

The first organocatalytic asymmetric synthesis of an advanced intermediate of (+)-sarain A was achieved. This approach featured the employment of an organocatalytic asymmetric Michael addition reaction and a nitrogen-to-carbon chirality transfer to forge three chiral centers, as well as a catalytic hydrosilylation for the chemoselective reduction of a key lactam intermediate. The tricyclic intermediate contained all the required functionalities for elaborating into (+)-sarain A.     

Organocatalytic Asymmetric Cascade Reactions of 7‐Vinylindoles: Diastereo‐ and Enantioselective Synthesis of C7‐Functionalized Indoles

The first catalytic asymmetric cascade reaction of 7‐vinylindoles has been established by the rational design of such substrates. Cascade reactions with isatin‐derived 3‐indolylmethanols in the presence of a chiral phosphoric acid derivative allow the diastereo‐ and enantioselective synthesis of C7‐functionalized indoles as well as the construction of cyclopenta[b]indole and spirooxindole frameworks (all >95:5 d.r., 94–>99 % ee). This approach not only addresses the great challenge of the catalytic asymmetric synthesis of C7‐functionalized indoles, but also provides an efficient method for constructing biologically important cyclopenta[b]indole and spirooxindole scaffolds with excellent optical purity. Investigation of the reaction pathway and activation mode has suggested that this cascade reaction proceeds through a vinylogous Michael addition/Friedel–Crafts process, in which dual H‐bonding activation of the two reactants plays a crucial role.     

A Direct,Concise, and Enantioselective Synthesis of 2‐Substituted 4,4,4‐Trifluorobutane‐1,3‐diols Based on the Organocatalytic In Situ Generation of Unstable Trifluoroacetaldehyde

A direct, concise, and enantioselective synthesis of 2‐substituted 4,4,4‐trifluorobutane‐1,3‐diols based on the organocatalytic asymmetric direct aldol reaction of an ethyl hemiacetal of trifluoroacetaldehyde with various aldehydes was examined. A catalytic amount (30 mol %) of commercially available and inexpensive l ‐prolinamide is quite effective as an organocatalyst for the catalytic in situ generation of gaseous and unstable trifluoroacetaldehyde from its hemiacetal, and a successive asymmetric direct aldol reaction with various aldehydes in dichloromethane at 0 °C, followed by reduction with sodium borohydride, gives 2‐substituted 4,4,4‐trifluorobutane‐1,3‐diols in moderate to good yields (31–84 %) with low diastereoselectivities and good to excellent enantioselectivities (64–97 % ee).     

Stereoselective Organocatalytic Synthesis of Oxindoles with Adjacent Tetrasubstituted Stereocenters

Oxindoles with adjacent tetrasubstituted stereocenters were obtained in high yields and stereoselectivities by organocatalyzed conjugate addition reactions of monothiomalonates (MTMs) to isatin‐derived N‐Cbz ketimines. The method requires only a low catalyst loading (2 mol %) and proceeds under mild reaction conditions. Both enantiomers are accessible in good yields and excellent stereoselectivities by using either Takemoto’s catalyst or a cinchona alkaloid derivative. The synthetic methodology allowed establishment of a straightforward route to derivatives of the gastrin/cholecystokinin‐B receptor antagonist AG‐041R.     

Enantioselective Organocatalytic Michael/Aldol Sequence: Anticancer Natural Product (+)‐trans‐Dihydrolycoricidine

A total synthesis of the anticancer natural product (+)‐trans‐dihydrolycoricidine is reported from α‐azidoacetone and cinnamaldehyde precursors. Key elements include an asymmetric organocatalytic sequence proceeding by a regiospecific secondary‐amine‐catalyzed syn Michael addition followed by an intramolecular aldol reaction. The sequence results in the formation of an advanced intermediate, containing three stereogenic centers, in one step which and was converted into the title compound in eight steps.     

Highly Efficient,Convergent, and Enantioselective Synthesis of Phthioceranic Acid

A new strategy for highly concise, convergent, and enantioselective access to polydeoxypropionates has been developed. ZACA‐Pd‐catalyzed vinylation was used to prepare smaller deoxypropionate fragments, and then two key sequential Cu‐catalyzed stereocontrolled sp³–sp³ cross‐coupling reactions allowed convergent assembly of smaller building blocks to build‐up long polydeoxypropionate chains with excellent stereoselectivity. We employed this strategy for the synthesis of phthioceranic acid, a key constituent of the cell‐wall lipid of Mycobacterium tuberculosis, in just 8 longest linear steps with full stereocontrol.     

Highly Enantioselective Organocatalytic Addition of Aldehydes to N‐(Phenylmethylene)benzamides: Asymmetric Synthesis of the Paclitaxel Side Chain and Its Analogues

Easily side‐tracked : A simple route to the paclitaxel side chain and its analogues is based on the (R)‐proline‐catalyzed addition of aldehydes to N‐(phenylmethylene)benzamides, followed by oxidation of the resulting protected α‐hydroxy‐β‐benzoylaminoaldehydes (92–99 % ee). Esterification of the subsequent phenylisoserine derivatives with baccatin III gives paclitaxel analogues (see scheme).