Enantioselective synthesis of chiral carbocyclic pyrimidine nucleosides via asymmetric cyclopropanation

An efficient method to construct chiral cyclopropyl pyrimidine carbocyclic nucleoside analogues bearing a quaternary center was developed via asymmetric Michael-initiated cyclopropanation. The axis chirality was observed in cyclopropyl pyrimidine carbocyclic nucleoside analogues for the first time, which was caused by the rotationally restricted NC bond in N-COPh moiety. Using (DHQD)₂AQN as the organocatalyst, diverse cyclopropyl pyrimidine carbocyclic nucleoside analogues were generated in 76–93% yields and 73–96% ee.     

Catalytic asymmetric synthesis of glycidic amides via chiral sulfur ylides

Reaction of diazoacetamides with aromatic aldehydes in the presence of 20 mol% of chiral binaphthylsulfide and 10 mol% of copper(II) acetylacetonate gave chiral glycidic amides with up to 64% ee.     

Enantioselective synthesis of planar chiral azaferrocenes via chiral ligand-mediated ring- and lateral-lithiations

Lithiation of 1′,2′,3′,4′,5′-pentamethylazaferrocene (1) with sec-BuLi/(−)-sparteine (3) in Et₂O at −78°C followed by quenching with electrophiles gave the ring-substituted products 2 in 74-81% ee. On the other hand, lithiation of 1′,2,2′,3′,4′,5,5′-heptamethylazaferrocene (6) with sec-BuLi in the presence of S-valine-derived bis(oxazoline) 5 in Et₂O at −55°C and subsequent reaction with electrophiles afforded the laterally functionalized products 7 in excellent enantioselectivity (96-99% ee).     

Enantioselective synthesis of vinylcyclopropanes and vinylepoxides mediated by camphor-derived sulfur ylides: rationale of enantioselectivity, scope, and limitation

By a sidearm approach, camphor-derived sulfur ylides 1 were designed and synthesized for the cyclopropanation of electron-deficient alkenes and epoxidation of aldehydes. Under the optimal conditions, the exo-type sulfonium salts 4a and 4b reacted with beta-aryl-alpha,beta-unsaturated esters, amides, ketones, and nitriles to give 1,3-disubstituted-2-vinylcyclopropanes with high diastereoselectivities and enantioselectivities. When the endo-type sulfonium salts 5a and 5b were used, the diastereoselectivities were not changed, whereas the absolute configurations of the products became the opposite to those of the reactions of 4a and 4b. An ylide cyclopropanation of chalcone derivatives with phenylvinyl bromide in the presence of catalytic amount of chiral sulfonium salts 4b and 5b has been developed. The sidearmed hydroxyl group was found to play a key role in the control of enantioselectivity and diastereoselectivity. The origins of the high diastereoselectivity and enantioselectivity were also studied by density functional theory calculations, which reveal the importance of the hydrogen-bonding between the sidearmed hydroxyl group and the substrate in determining the diastereoselectivity and enantioselectivity. The ylides 1 were also successfully applied for the epoxidation of aromatic aldehydes.     

Ammonium ylides for the diastereoselective synthesis of glycidic amides

A highly trans-selective protocol for the synthesis of glycidic amides was developed. This approach gave access to oxiranes by reacting stabilised ammonium ylides bearing an α-carbonyl group and aromatic aldehydes in moderate to good yields.     

Enantioselective copper-catalyzed cyclopropanation of styrene by means of chiral bispidine ligands

Enantiopure C₁- and C₂-symmetric bispidine ligands have been synthesized and screened in the asymmetric copper-catalyzed cyclopropanation of styrene. In order to improve the enantiomeric excesses (ee) of the cyclopropane derivatives, the best performing C₁-symmetric diamine ligand was selected for studies on the reaction conditions. The optimized procedure allowed us to obtain up to 91% ee for the cis-cyclopropane derivative and up to 79% ee for the trans one.     

Controllable stereoinversion in DNA-catalyzed olefin cyclopropanation via cofactor modification

The assembly of DNA with metal-complex cofactors can form promising biocatalysts for asymmetric reactions, although catalytic performance is typically limited by low enantioselectivities and stereo-control remains a challenge. Here, we engineer G-quadruplex-based DNA biocatalysts for an asymmetric cyclopropanation reaction, achieving enantiomeric excess (ee_trans) values of up to +91% with controllable stereoinversion, where the enantioselectivity switches to −72% ee_trans through modification of the Fe-porphyrin cofactor. Complementary circular dichroism, nuclear magnetic resonance, and fluorescence titration experiments show that the porphyrin ligand of the cofactor participates in the regulation of the catalytic enantioselectivity via a synergetic effect with DNA residues at the active site. These findings underline the important role of cofactor modification in DNA catalysis and thus pave the way for the rational engineering of DNA-based biocatalysts.

Cofactor modification in a DNA-catalyzed olefin cyclopropanation reaction enables controllable stereoinversion and achieves enantioselectivities of up to +91% and −72% ee_trans.     

Enantio- and diastereoselective synthesis of syn-beta-hydroxyallylsilanes via a chiral (Z)-gamma-silylallylboronate

syn-beta-Hydroxyallylsilanes of general structure 11 and 28 are prepared in 50-86% yield and 91-95% ee (for aliphatic aldehydes; 50% ee for benzaldehyde) via the BF(3).Et(2)O-promoted gamma-silylallylboration reactions, using reagents 14 and 15.     

Synthesis of chiral 3-substituted hexahydropyrroloindoline via intermolecular cyclopropanation

[Structure: see text] A new and efficient synthetic route to chiral 3-substituted hexahydropyrroloindoline 18 possessing absolute configurations in accordance with indole alkaloids has been developed from readily available L-tryptophan. The key step relies on the one-pot cascade reaction of oxazolidinone 17 with diazoester, which proceeds through intermolecular cyclopropanation, ring opening, and cyclization.     

A novel chiral sulfonium yilde: highly enantioselective synthesis of vinylcyclopropanes

A newly designed chiral sulfonium allylide, generated in situ from the corresponding sulfonium salt in the presence of KOBu(t), reacted with alpha,beta-unsaturated esters, ketones, amides, and nitriles to afford trans-2-silylvinyl-trans-3-substituted cyclopropyl esters, ketones, amides, and nitriles with outstanding diastereoselectivity and excellent enantioselectivity in good to high yields. A mechanistic rationale is proposed.     

Enantioselective synthesis of a chiral fluoropiperidine via asymmetric hydrogenation of a vinyl fluoride

Asymmetric hydrogenation of a vinyl fluoride derivative gives efficient access to enantioenriched 1,3,4-trisubstituted piperidine 1 with a stereogenic alkyl fluoride center. Extensive catalyst screening across transition metals and chiral ligands identified only one catalyst, a Rh/Walphos complex, that gives high conversion, enantioselectivity and chemoselectivity for olefin reduction over defluorination. The presence of acid additives in the hydrogenation exerts a profound effect on reaction outcome. The results of deuterium labeling studies demonstrate that significant olefin isomerization accompanies the undesired defluorination side-reaction.     

Highly diastereoselective Simmons-Smith cyclopropanation of allylic amines

[reaction: see text] Cyclopropanation of allylic tertiary amines using the Simmons-Smith reagent has been achieved by employing chelating groups in close proximity to the amine. The chelating groups promote cyclopropanation at the expense of N-ylide formation. Using pseudoephedrine as the chelating group, high diastereoselectivity is observed.     

First diastereoselective chiral synthesis of (-)-securinine

[reaction: see text] A diastereoselective total synthesis of securinine in optically pure form was achieved by employing ring-closing metathesis of the corresponding dienyne compound as a key step.     

硫叶立德途径立体控制合成乙烯基型环氧化合物

在相转移条件下(CH3CN/KOH/RT)乙烯基型硫叶立德和醛反应高产率地得到以反式为主的产物,而在低温溴化锂存在下(LiBr/KHMDS/THF/-90℃)得到以顺式为主的产物,对于通过反应条件的变换而改变反应产物立体化学的机理,给出了一个初步的解释。     

Enantioselective synthesis of spirooxoindoles via chiral auxiliary (bicyclic lactam) controlled SNAr reactions

A highly efficient enantioselective S(N)Ar reaction of chiral acyl bicyclic lactam with substituted-2,4-dinitrobenzenes was developed, affording products containing quarternary stereogenic centers. They are further utilized towards an enantioselective synthesis of spirooxoindoles.     

Enantioselective synthesis of homoallylic alcohols via a chiral In(III)-PYBOX complex

In the presence of 20 mol% of a chiral catalytic complex prepared from In(OTf)(3) and chiral PYBOX, allyltributylstannane reacted with aldehydes to afford the corresponding homoallylic alcohols in moderate to high enantioselectivities (60-93% ee).     

Bromoporphyrins as versatile synthons for modular construction of chiral porphyrins: cobalt-catalyzed highly enantioselective and diastereoselective cyclopropanation

5,10-Bis(2',6'-dibromophenyl)porphyrins bearing various substituents at the 10 and 20 positions were demonstrated to be versatile synthons for modular construction of chiral porphyrins via palladium-catalyzed amidation reactions with chiral amides. The quadruple carbon-nitrogen bond formation reactions were accomplished in high yields with different chiral amide building blocks under mild conditions, forming a family of D2-symmetric chiral porphyrins. Cobalt(II) complexes of these chiral porphyrins were prepared in high yields and shown to be active catalysts for highly enantioselective and diastereoselective cyclopropanation under a practical one-pot protocol (alkenes as limiting reagents and no slow addition of diazo reagents).     

Enantioselective and diastereoselective synthesis of fluorinated dipeptides by late electrophilic fluorination

A series of optically enriched monofluorinated dipeptides incorporating an α-fluoro-α-amino acid were prepared by enantio- and diastereoselective electrophilic fluorination. This previously unsuccessful approach to fluorinated dipeptides can now be achieved with up to 73:27 enantiomeric ratio and high >98:2 diastereomeric ratio.