Copper-Catalyzed Radical Enantioselective Synthesis of γ-Butyrolactones with Two Non-vicinal Carbon Stereocenters

Chiral heterocycles with two or more carbon stereocenters are quite important skeletons in many fields. However, powerful strategies for the construction of such synthetically valuable heterocycles, especially with two or more remote carbon stereocenters, have largely lagged behind. We report here a powerful method for the synthesis of chiral γ-butyrolactones with two non-vicinal carbon stereocenters from readily available chemical feedstocks under mild conditions. Both of the two diastereoisomers can be obtained with good to excellent enantioselectivities. The well-designed copper/PyBox catalytic system overrides the intrinsic stereoinduction of the close chirality center generated by the previous innocent radical addition step. Nevertheless, this work has the power to selectively provide one single diastereoisomer by taking advantage of the epimerization effect but also to synthesize all four diastereoisomers with the pair of chiral ligands L2 and L2′ having opposite chirality. The obtained useful chiral γ-butyrolactones can be synthetically transformed into acyclic or cyclic molecules with two non-vicinal carbon stereocenters. Mechanistic studies reveal that this radical reaction follows a linear relationship and can be well performed with a less loading amount of ligand compared to that of the copper catalyst.     

Stereospecific Reactions Leading to Allylboronic Esters Within Acyclic Systems Bearing Distant Stereocenters

The preparation of acyclic molecules featuring congested stereocenters in a 1,4-relationship in only three catalytic steps from commercially available building blocks is reported. This approach involves a diastereoselective diboration of alkenyl cyclopropyl methanol derivatives followed by a regioselective exergonic ring fragmentation. The starting materials can be prepared enantiomerically enriched and all substituents can be interconverted, therefore, this strategy allows a large variety of diversely functionalized allylboronic esters possessing distant tetrasubstituted stereocenters with high diastereoselectivity.     

Stereodivergent Construction of 1,3-Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction

Herein, we report a synthesis of cyclohexanones bearing multi-continuous stereocenters by combining copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridium-catalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2-position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3-position) by a proper combination of two chiral catalysts with different enantiomers.     

Enantioselective Construction of Quaternary Stereocenters

The stereoselective formation of C-C bonds is of great importance for the synthesis of enantiomerically pure natural products and pharmaceuticals. A broad repertoire of chiral auxiliaries, reagents, and catalysts can be utilized for the reliable generation of tertiary stereocenters. In contrast, the synthesis of organic compounds with quaternary stereocenters is a much more demanding and challenging task. Every enantioselective synthetic method can demonstrate its value through the generation of a fully substituted carbon center. In this Minireview examples of newer stoichiometric and catalytic methods are summarized which have proved their suitability for the enantioselective construction of quaternary stereocenters.     

Control of Vicinal Stereocenters through Nickel-Catalyzed Alkyl–Alkyl Cross-Coupling

Vicinal stereocenters are found in many natural and unnatural compounds. Although metal-catalyzed cross-coupling reactions of unactivated alkyl electrophiles are emerging as a powerful tool in organic synthesis, there have been virtually no reports of processes that generate, much less control, vicinal stereocenters. In this investigation, we establish that a chiral nickel catalyst can mediate doubly stereoconvergent alkyl–alkyl cross-coupling, specifically, reactions of a racemic pyrrolidine-derived nucleophile with cyclic alkyl halides (as mixtures of stereoisomers) to produce vicinal stereocenters with very good stereoselectivity.     

The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters

A long-standing challenge to synthesis can now be met through the use of new and powerful catalytic asymmetric reactions for the assembly of complex chiral molecules with quaternary stereocenters from achiral building blocks. The reaction sequence shown below is just one example discussed in this review.     

A stereoselective hydroamination transform to access polysubstituted indolizidines

Stereoselective, intramolecular, formal hydroamination of dienamines via directed hydroboration is reported. Four stereocenters are set in the process. Natural and unnatural indolizidine alkaloids can be synthesized from simple unsaturated amines using the title process.     

Solid-phase synthesis of constrained terminal and internal lactam peptidomimetics

Lactams are key components of many peptidomimetic structures. Five- and six-membered lactam peptidomimetics with hydrogen or amino acid side chains at the alpha-position can be constructed from peptide precursors during a solid-phase synthesis. There is no significant racemization of remote stereocenters during synthesis.     

Complete relative stereochemistry of multiple stereocenters using only residual dipolar couplings

Residual dipolar couplings (RDCs), in combination with molecular order matrix calculations, were used to unambiguously determine the complete relative stereochemistry of an organic compound with five stereocenters. Three simple one-dimensional experiments were utilized for the measurements of (13)C-(1)H, (13)C-(19)F, (19)F-(1)H, and (1)H-(1)H RDCs. The order matrix calculation was performed on each chiral isomer independently. The fits were evaluated by the comparison of the root-mean-square deviation (rmsd) of calculated and measured RDCs. The order tensor simulations based on two different sets of RDC data collected with phage and bicelles are consistent. The resulting stereochemical assignments of the stereocenters obtained from using only RDCs are in perfect agreement with those obtained from the single-crystal X-ray structure. Six RDCs are found to be necessary to run the simulation, and seven are the minimum to get an acceptable result for the investigated compound. It was also shown that (13)C-(1)H and (1)H-(1)H RDCs, which are the easiest to measure, are also the most important and information-rich data for the order matrix calculation. The effect of each RDC on the calculation depends on the location of the corresponding vector in the structure. The direct RDC of a stereocenter is important to the configuration determination, but the configuration of stereocenters devoid of protons can also be obtained from analysis of nearby RDCs.     

Construction of Acyclic All-Carbon Quaternary Stereocenters and 1,3-Nonadjacent Stereoelements via Organo/Metal Dual Catalyzed Asymmetric Allenylic Substitution of Aldehydes

A method for the asymmetric construction of functionalized acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements has been developed via organo/metal dual catalyzed asymmetric allenylic substitution of branched and linear aldehydes, by developing an unknown acyclic secondary-secondary diamine as the enabling organocatalyst. Although it is believed that secondary-secondary diamines are difficult to be used as the organocatalysts in organo/metal dual catalysis, this study demonstrates that such diamines can be successfully combined with a metal catalyst in organo/metal dual catalysis. Our study enables the asymmetric construction of two important classes of motifs which were previously difficult to access, axially chiral allene-containing acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements bearing allenyl axial chirality and central chirality, in good yields with high enantio- and diastereoselectivity.     

Control of absolute helicity in single-stranded abiotic metallofoldamers

Described is the design, synthesis, and characterization of abiotic, single-stranded metallofoldamers that adopt helical secondary structures upon metal complexation. The absolute helicity is determined by stereocenters at the ends of the structures and is enforced by the steric influence and hydrogen bonding ability of esters in the backbone of the foldamer. Folding of the structures is characterized in the solid state by X-ray crystallography and in solution by specific rotation, CD spectroscopy, and NMR spectroscopy.     

Highly diastereoselective and enantioselective Michael addition of 5H-oxazol-4-ones to α,β-unsaturated ketones catalyzed by a new bifunctional organocatalyst with broad substrate scope and applicability

A new thiourea-tertiary amine bifunctional catalyst derived from L-tert-leucine was developed and provides excellent stereocontrol in a novel and direct Michael addition of 5H-oxazol-4-ones to α,β-unsaturated ketones with much broad substrate scope. The conjugate addition products with chiral vicinal quaternary and tertiary stereocenters can be easily transformed to structurally interesting compounds or building blocks.     

Small ring constrained peptidomimetics. Synthesis of epoxy peptidomimetics, inhibitors of cysteine proteases.

Different dipeptide analogues containing an oxirane ring in the place of the peptidic bond were prepared starting from naturally occurring amino acids. N-Fmoc-amino aldehydes were transformed into the corresponding methoxyvinyl derivatives through a Wittig reaction, and the addition of PhSeCl gave a series of different alpha-phenylselenyl aldehydes. Mukajiama reaction with silylketene acetals gave an intermediate product that was finally transformed into the desired oxiranyl peptidomimetics. Following this strategy we were able to control three new contiguous stereocenters starting from the enantiomerically pure amino acid. The dipeptide analogues could be used in SPPS on a SASRIN resin as the final epoxides were relatively unstable under acidic conditions. Moreover the synthesis of the single dipeptide mimetics was carried out on solid phase to generate a small library of epoxy peptidomimetics. Some of the products prepared in this work resulted as time-dependent reversible inhibitors of cysteine protease.     

Highly diastereo- and enantioselective tandem reaction toward functionalized pyrrolidines with multiple stereocenters

An efficient asymmetric tandem dual Michael reaction that constructs three contiguous stereocenters in acyclic open-chain systems with very high enantioselectivity and diastereoselectivity has been developed. This protocol provides a reliable and rapid approach for synthesis of chiral pyrrolidines with multiple stereocenters.     

Stereocontrolled Syntheses of Seven‐Membered Carbocycles by Tandem Allene Aziridination/[4+3] Reaction

A tandem allene aziridination/[4+3]/reduction sequence converts simple homoallenic sulfamates into densely functionalized aminated cycloheptenes, where the relative stereochemistry at five contiguous asymmetric centers can be controlled through the choice of the solvent and the reductant. The products resulting from this chemistry can be readily transformed into complex molecular scaffolds which contain up to seven contiguous stereocenters.     

Diastereoselective Alkene Hydroesterification Enabling the Synthesis of Chiral Fused Bicyclic Lactones

Palladium-catalysed diastereoselective hydroesterification of alkenes assisted by the coordinative hydroxyl group in the substrate afforded a variety of chiral γ-butyrolactones bearing two stereocenters. Employing the carbonylation-lactonization products as the key intermediates, the route from the alkenes with single chiral center to chiral THF-fused bicyclic γ-lactones containing three stereocenters was developed.     

Dual-function cinchona alkaloid catalysis: catalytic asymmetric tandem conjugate addition-protonation for the direct creation of nonadjacent stereocenters

Catalytic tandem asymmetric reactions constitute a powerful strategy for the asymmetric construction of nonadjacent stereocenters in acyclic molecules directly from achiral precursors. In this Communication, we report a highly enantioselective and diastereoselective addition of trisubstituted carbon donors to 2-chloroacrylonitrile catalyzed by bifunctional cinchona alkaloid catalysts. This represents the first asymmetric tandem conjugate addition-protonation with efficient catalytic control of two nonadjacent stereocenters. As demonstrated in a concise and highly stereoselective formal total synthesis of (-)-manzacidin A, this asymmetric tandem reaction establishes a new and versatile catalytic approach for the enantioselective and diastereoselective creation of 1,3-tertiary-quaternary stereocenters.     

Implementation of Stereochemistry in Automatic Kinetic Model Generation

The kinetic model generation code Genesys is extended by the addition of algorithms for the detection of stereocenters and for the detection of stereoisomers. To make this possible, a so‐called 2.5D representation of molecules that accounts for the presence of stereocenters and that keeps track of the associated stereoconfiguration of the stereocenters is introduced. A novel algorithm for the detection of steric relations between substituents allows the automated assignment of rate coefficients to stereoselective reactions. The functionality of the algorithms is illustrated for the thermal rearrangement of the monoterpenoid 2‐pinanol, an intermediate in the fragrance industry. Accounting for stereochemistry proves to be essential in explaining the reactive behavior of 2‐pinanol and the selectivity to its products. Good agreement with experimental data from the literature was obtained. CBS‐QB3 calculations for (R)‐cis‐ and (R)‐trans‐2‐pinanol support the experimentally observed differences for the suggested stereoselective and stereospecific reactions.     

Highly enantioselective amination of alpha-substituted alpha-cyanoacetates with chiral catalysts accessible from both quinine and quinidine

[Reaction: see text] The catalytic construction of nitrogen-substituted quaternary stereocenters is an important and challenging task in asymmetric synthesis. In this paper, we describe the use of 6'-OH-modified cinchona alkaloids that are accessible from either quinine or quinidine for the development of a highly enantioselective amination of alpha,alpha-disubstituted carbonyl compounds that is suitable for the creation of nitrogen-substituted quaternary stereocenters in either the R or S configuration.     

Enantioselective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction

A new electron-deficient chiral triazolium salt has been shown to catalyze the formation of quaternary stereocenters by an asymmetric intramolecular Stetter reaction. Pentafluorophenyl substitution on an aminoindanol-derived catalyst affords tertiary ether, thioether, and quaternary stereocenters in typically greater than 90% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction proceeds at room temperature under mild conditions to provide quaternary stereocenters with functional group relationships that are particularly difficult to access by other methods.