Search

A palladium-catalyzed enantioselective Heck cyclization/dearomatization cascade via capturing the cyclized Heck π-allylpalladium intermediate by β-naphthols is reported, which provides a new strategy for the construction of chiral indole-terpenoid frameworks. This method affords indole-functionalized β-naphthalenone compounds bearing an all-carbon-substituted quaternary chiral center in excellent yields (up to 92%) and enantioselectivities (up to 94% ee). In addition, the utility of this method is showcased by the gram-scale syntheses and diverse transformations of the dearomatized products.

In this study, an environmentally benign electrochemical protocol for intramolecular oxidative amination is developed, which offers an efficient and sustainable route to access diverse fused tricyclic systems of pyrido[1,2-e]purine-2,4-dione derivatives with pharmacological interest, exhibiting broad scope and generality (>50 examples, yields up to 99%). This electrochemical strategy features good functional group tolerance and permits access to compounds that were previously not achievable under thermal conditions. The photoluminescence properties of the representative N9-fused tricyclic xanthines have also been investigated.

The first ring-opening of D–A oxiranes with N-heteroaromatics in a chemoselective C–C bond cleavage manner was achieved. In the presence of 5 mol% of Y(OTf)3 as the catalyst, diverse N-heteroaromatics, including benzotriazoles, purines, substituted benzimidazole, imidazole and pyrazole, reacted well with various D–A oxiranes, providing acyclic nucleoside analogues containing a N-glycosidic bond in up to 97% yield and up to >95 : 5 regioselectivity. Through simple transformation, the Ganciclovir analogue could also be obtained.

Highly enantioselective allylation of a vinylethylene carbonate by asymmetric palladium catalysis has been developed for a variety of N-heteroaromatic substrates. The employed procedure allows for the efficient synthesis of various acyclic nucleoside analogs in good yields (up to 96%) and with high enantioselectivities (up to 99%) at the Pd catalyst amount of 0.5 mol%. In addition, these acyclic nucleosides are demonstrated to undergo rapid transformation to a variety of interesting structurally diverse chiral acyclic nucleosides and isonucleosides.

A generally useful Ni(II)/trisoxazoline-catalyzed asymmetric sulfa-Michael/Aldol cascade reaction is introduced to access chiral 3-amine-tetrahydrothiophene derivatives containing a quaternary stereocenter (32 examples, up to 93% yield, > 20:1 dr and 92% ee). Moreover, the novel strategy offers an efficient and convenient approach to construct chiral thionucleoside analogues.

A novel concept that conversion of chiral 2-substituted DMAP into its DMAP-N-oxide could significantly enhance the catalytic activity and still be used as an acyl transfer catalyst is presented. A new type of chiral 2-substituted DMAP-N-oxides, derived from l-prolinamides, has been rationally designed, facilely synthesized, and applied in the dynamic kinetic resolution of azlactones. Using simple MeOH as the nucleophile, various l-amino acid derivatives were produced in high yields (up to 98% yield) and enantioselectivities (up to 96% ee). Furthermore, α-deuterium labeled l-phenylalanine derivative was also obtained. Experiments and DFT calculations revealed that in 2-substituted DMAP-N-oxide, the oxygen atom acted as the nucleophilic site and the N-H bond functioned as the H-bond donor. High enantioselectivity of the reaction was governed by steric factors, and the addition of benzoic acid reduced the activation energy by participating in the construction of a H-bond bridge. The theoretical chemical study indicated that only when attack directions of the chiral catalyst were fully considered could the correct calculation results be obtained. This work paves the way for the utilization of the C2 position of the pyridine ring and the development of chiral 2-substituted DMAP-N-oxides as efficient acyl transfer catalysts.

Highly enantioselective [5 + 4] annulation of ortho-quinone methides with vinylethylene carbonates has been developed by asymmetric palladium catalysis. The reaction allows for efficient synthesis of various nine-membered benzodioxonines in good yields (up to 88%) with high enantioselectivity (up to 98%). Mechanistic studies indicate that the [5 + 4] annulation occurs through an unusual action of chiral phosphine and achiral palladium catalysts.

A highly enantioselective cyclopropanation to synthesize pyrimidine-substituted diester D–A cyclopropanes is reported. Various N1-vinylpyrimidines react well with phenyliodonium ylides, delivering chiral cyclopropanes in up to 97% yield with up to 99% ee. Through simple [3+2] annulation with benzaldehyde or ethyl glyoxylate, different chiral pyrimidine nucleoside analogues with a sugar ring could be obtained.

A straight synthetic approach to fused polycyclic tropane scaffold formation through an asymmetric dearomatization cycloaddition process of 2-nitrobenzofurans with cyclic azomethine ylides was successfully developed. In the presence of a chiral copper complex, derived from Cu(OAc)

Electrochemically driven, Cp*Ir(III)-catalyzed regioselective annulative couplings of benzoic acids with alkynes have been established herein. The combination of iridium catalyst and electricity not only circumvents the need for stoichiometric amount of chemical oxidant, but also ensures broad reaction compatibility with a wide array of sterically and electronically diverse substrates. This electrochemical approach represents a sustainable strategy as an ideal alternative and supplement to the oxidative annulations methodology to be engaged in the synthesis of isocoumarin derivatives.

A DMAP-N-oxide, featuring an α-amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O-acylated azlactones afforded C-acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP-N-oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP-N-oxides for asymmetric acyl transfer reactions.

Bifunctional chiral DMAP-N-oxides have been reported for the highly enantioselective rearrangement of indolyl carbonates. Using 2.5 mol% of chiral DMAP-N-oxide, diverse oxindoles containing an all-carbon quaternary stereocenter were obtained in excellent yields (up to 98% yield) with high enantioselectivities (up to 96% ee). Compared to the widespread use of chiral DMAP and isothiourea catalysts, in which the nitrogen atom serves as a nucleophilic site, we found that chiral DMAP-N-oxides, which utilize the oxygen atom as a nucleophilic site, were also efficient organocatalysts in this rearrangement.

Intermolecular asymmetric dearomative 1,3-dipolar cycloaddition of 2-nitrobenzofurans with azomethine ylides was enabled by using a chiral Cu(i)/(S,Sp)-iPr-Phosferrox catalyst. As a result, a series of highly stereoselective chiral [2,3]-fused hydrobenzofurans possessing four contiguous stereogenic centers were obtained with good to high yields, diastereoselectivities and enantioselectivities. The reaction has broad substrate scope tolerating various functional groups.

Chemoselective asymmetric [3 + 2] cycloaddition reactions of purines with aminocyclopropanes for the dearomatization of purines have been successfully developed. In the presence of a copper complex, derived from Cu(OTf)2 and bisoxazoline, a series of hydropyrrolo-purine compounds were obtained in high yields (up to 98%) with excellent enantioselectivities (up to 99% ee). The chemoselectivity in current cycloaddition reactions has been explained by density functional theory calculations.

Summary Heterocycles are a very important class of compounds that exist extensively as structural cores in natural products and biologically active molecules. Catalytic asymmetric dearomatization (CADA) is an efficient strategy for the construction of chiral fused- or spiro-heterocycles from simple planar aromatic compounds. Herein, we report the development of enantioselective dearomative [3 + 2] cycloaddition reactions of benzazoles with aminocyclopropanes via kinetic resolution. In the presence of a copper complex, derived from Cu(OTf)2 and bisoxazoline, a series of hydropyrrolo-benzazole derivatives containing quaternary stereogenic centers were obtained in high yields (up to 99%) with excellent enantioselectivity (up to 99% enantiomeric excess [ee]). With the same catalytic system, 2-amino cyclopropane-1,1-dicarboxylates with a high enantiomeric purity (up to 98% ee) were also obtained by an efficient kinetic resolution (s values of up to 95). In addition, the utility of this method was showcased by the facile transformation of products into several important heterocyclic frameworks, including pyrrolo-benzothiazine and 1,5-benzothiazepine.

The binding selectivity of an adenine-monofunctionalized pillar[5]arene (H) with a series of pyrimidine derivatives were investigated through 1H NMR experiments and density functional theory (DFT) study. High binding-selectivity was demonstrated. Typically, H displayed very strong binding strength with 6-(2,4-dioxo-3, 4-dihydropyrimidin-1 (2H)-yl)hexanenitrile (G1) [Ka >105 M−1], up to about 3000-fold as compared with 1-hexylpyrimidine-2,4(1H, 3H)-dione (G5) [Ka = 31 M−1]. The strong binding ability of H with G1 was due to the cooperative multiple hydrogen bond, dipole-dipole, C-H···π and π···π interactions. The high binding-selectivity was also verified by calculation results. The calculated interaction energy (ΔEi) of G1⊂H was −12.92 Kcal·mol−1 while that of G5⊂H was −2.85 Kcal·mol−1.

A direct route to chiral six-membered carbocyclic purine nucleoside analogues with three chiral stereocenters, including a chiral tetrasubstituted carbon center, via a highly enantioselective [3 + 3] annulation has been established. With the application of Takemoto's catalyst, various chiral six-membered carbocyclic purine nucleoside analogues were obtained in high yields (up to 89%) with moderate to good diastereoselectivities (up to 90:10 dr) and excellent enantioselectivities (92-98% ee). Furthermore, diverse chiral six-membered carbocyclic purine nucleoside analogues were generated by simple transformations.

Diversity-oriented synthesis of pyrazoline derivatives that contain a quaternary carbon center has been achieved via the 1,3-dipolar cycloaddition between N-purine-substituted allenes and α-alkyl/aryl diazoesters. Using Pd2(dba)3 as a catalyst, only 1-pyrazoline derivatives are produced in a regioselective manner. When DPPB is used as a catalyst, diverse 1-pyrazolines and 2-pyrazolines are obtained in moderate to good total yields.

Optical ratio two-photon probe utilizing fluorescent responses for the imaging and detecting of hypochlorite (ClO − ) require smart molecular systems able to operate selectively in the weak alkaline watery environment. Herein, we report a three-input “AND-type” fluorescent logic gate (NPA-CN) that demonstrates effective quantification of ClO − in the weak alkaline watery environment. NPA-CN with high signal-to-noise ratio provides a linear response to the three-input (ClO − , OH − and H 2 O) in rough endoplasmic reticulum (RER) of living cells on ratio-mode. More inportantly, NPA-CN can be used to whilst simultaneously image and quantify the changes of three-input.

An efficient route to chiral carbocyclic nucleoside analogues containing a quaternary stereocenter and a C═C double bond has been established via a highly enantioselective [3 + 2] annulation of Morita-Baylis-Hillman (MBH) carbonates with α-purine-substituted acrylates. With 20 mol % (S)-SITCP as the catalyst, various chiral carbocyclic nucleoside analogues with a quaternary stereocenter and a C═C double bond were obtained in high yields (up to 92%) with good diastereoselectivities (up to 10:1 dr) and excellent enantioselectivities (up to 96% ee). Furthermore, the corresponding products were subjected to diverse transformations to afford interesting and potentially useful chiral carbocyclic nucleosides.

An efficient route to construct 2,5-disubstituted tetrazole hemiaminal silyl ethers via one-pot three-component hemiaminal silylation of 5-substituted tetrazoles, aldehydes, and silyl triflates was developed. Diverse 2,5-disubstituted tetrazole hemiaminal silyl ethers were obtained with 37 : 63–>99 : 1 regioisomeric ratios. The regioselectivities of this reaction were significantly affected by steric hindrance and the conjugation effects of substitutions on the 5-position of tetrazoles.

An atom-economic addition of pyrimidines to allenes has been developed for the diverse synthesis of branched or linear N-allylpyrimidine analogues. With [Rh(COD)Cl]2/chiral MeOBIPHEP as the catalyst, the asymmetric allylation reaction proceeded well and afforded the branch selective adducts in good yields, with high regio- and enantioselectivities. Meanwhile, when [Pd(η3-allyl)Cl]2/DPPF was used as the catalyst, the linear-selective allylation of pyrimidines could be carried out in good yields. Here, the configuration of the CC bond in the side chain of the products was mainly found to be the E-form.

Palladium-catalyzed regio- and enantioselective allylic amination of aliphatic Morita-Baylis-Hillman (MBH) adducts with N-heteroaromatic nucleophiles (e.g., benzimidazole, 4,5-diphenylimidazole, benzotriazole, and purines) was achieved by using a spiroketal-based diphosphine (SKP) ligand, and afforded a range of chiral, branched N-allyl products with high selectivity.

An efficient route to construct chiral cyclopropyl purine nucleoside analogues has been established via the catalytic asymmetric Michael-initiated ring-closure reactions of α-purine acrylates with α-bromo-carboxylic esters. Using (DHQD)2AQN as the catalyst, various chiral cyclopropyl purine nucleoside analogues with a chiral quaternary stereocenter were obtained in 72-98% yields, excellent diastereoselectivities, and 93-97% ee. Through simple functional group transformations, diverse chiral cyclopropyl purine nucleosides with hydroxymethyl group or carboxyl group were obtained.

A direct route to chiral pyrimidine acyclic nucleoside analogues with a sulfur-contained side chain has been reported via enantioselective tandem conjugated addition-protonation reactions of thioacetic acid to α-pyrimidine substituted acrylates. In the presence of quinine-derived thiourea as the catalyst, diverse chiral sulfur-contained pyrimidine acyclic nucleoside analogues were given in excellent yields (95-99% yields) and moderate to excellent enantioselectivities (up to 99% ee).

A combined palladium- and photoredox-catalyzed monoselective arylation of 6-arylpurine nucleosides has been developed by employing purine as a directing group via the photoredox reaction, and many functional groups are well tolerated in this direct C-H arylation condition. Various of functionalized purines (nucleosides) which are potentially of great importance in medicinal chemistry could be obtained under visible light irradiation at room temperature within 4 h.

A highly efficient Pd-catalyzed asymmetric formal [3+2] cycloaddition using α-N-heterocyclic acrylates to react with vinyl epoxides has been achieved for the first time to access chiral functionalized tetrahydrofuran skeletons (34 examples, up to 93% yield, >20 : 1 dr and 99% ee). Meanwhile, using a palladium/(S,S)-tBu-FOXAP catalyst or a palladium/(R)-Segphos catalyst, purine or pyrimidine isonucleoside analogs are constructed in high yields and stereoselectivity, respectively. The commercial availability of the catalysts, broad substrate scope and easy transformation of the products make this methodology an attractive method in asymmetric synthesis.

An asymmetric transfer hydrogenation via dynamic kinetic resolution of a broad range of rac- α-(purin-9-yl)cyclopentones was first developed. A series of cis-β-(purin-9-yl)cyclopentanols were obtained with up to 97% yield,20/1 dr, and99% ee. This also provides an efficient synthetic route to a variety of chiral carbocyclic nucleosides.

The synthesis of chiral cyclopropyl carbocyclic purine nucleoside analogues via the highly enantioselective intramolecular cyclopropanation reactions has been reported. With a chiral ruthenium(II)-phenyloxazoline complex as the catalyst, cyclopropyl carbocyclic purine nucleoside analogues containing three contiguous stereocenters were obtained with up to 99% yield and 99% ee. Furthermore, a chiral cyclopropyl carbocyclic adenosine nucleoside having anti-BLV activity could be synthesized in a concise manner using this strategy.

The synthesis of nebularine and its analogs has been achieved via oxidative desulfuration in H2O for the first time. With 50% HNO3 as an oxidant and solvent, 18 products were obtained in good yields (70%–94%). The oxidative desulfuration system could tolerate different functional groups including fluoro, chloro, amino, alkyl, allyl, ribosyl, deoxyribosyl, and arabinofuranosyl groups. More importantly, the drug nebularine could be obtained successfully on a 20 g scale, which made this route more attractive for industrial applications.

The organocatalytic asymmetric allylic etherification reaction of Morita–Baylis–Hillman carbonates and silanols was reported for the first time. With modified cinchona alkaloid (DHQD)2PYR as the catalyst, a series of aromatic, heterocyclic, or aliphatic Morita–Baylis–Hillman carbonates (25 examples) worked well with triphenylsilanol, affording the corresponding products in moderate to good yields (up to 98%), high regioselectivities (>20:1), and good enantioselectivities (up to 92%). When dimethylphenylsilanol was used as the nucleophile, the product was obtained in 60% yield and 87% ee.

Diarylethene photoswitches based on the natural nucleoside deoxyadenosine were designed and synthesized. In aqueous solution, some of them exhibited good photochromic properties, including clear changes in color upon irradiation at 365 nm, red-shifts of the absorption wavelength, with good fatigue resistance, thermal stability, conversion efficiency, and base-pairing properties.

The first asymmetric hydrogenation of α-purine nucleobase-substituted α,β-unsaturated esters, catalyzed by a chiral rhodium (R)-Synphos catalyst, has been developed. A wide range of mono- and disubstituted acrylates were successfully hydrogenated under very mild conditions in high yields with good to excellent enantioselectivities (up to 99% ee). This method provides a convenient approach to the synthesis of a new kind of optically pure acyclic nucleoside and Tenofovir analogues.

The Yb(OTf)3-catalyzed [3+2] cycloaddition of donor-acceptor cyclopropanes with thiourea offers an efficient route to diverse 2-amino-4,5-dihydrothiophenes (up to 92% yield), in which optically active 2-amino-dihydrothiophenes can be produced from enantiomerically pure cyclopropanes. Thiourea, which is an odorless and cheap reagent, provides a C[double bond, length as m-dash]S double bond, serves as an amino source, and functions as a decarbalkoxylation reagent in this reaction. Preliminary mechanistic studies demonstrate that the reaction undergoes a sequential [3+2] cycloaddition/deamination/decarboxylation process.

An efficient route to construct chiral acyclic purine nucleoside analogues via dynamic kinetic resolution of α-purine substituted alkanoic acids is reported. Using ( S)-BTM as the catalyst, diverse chiral acyclic purine nucleoside analogues were obtained in moderate to good yields (up to 93%) and high enantioselectivities (up to 98% ee). Chiral acyclic purine nucleosides could be obtained from the esterified products via reduction reaction, which could then be transferred into Tenofovir analogues.

A Sc(OTf)3-catalyzed dearomative [3 + 2] cycloaddition of benzazoles with donor–acceptor oxiranes through chemoselective C–C bond cleavage of oxiranes was developed under mild conditions. This reaction provides an efficient method to construct benzazolo[3,2-c]oxazole compounds in good yields and with high diastereoselectivity. The reaction has a general substrate scope, and the donor–acceptor oxiranes with electron-donating and electron-withdrawing groups on the aromatic ring afforded the desired cycloadducts.

An efficient method to construct chiral acyclic nucleosides via Sharpless asymmetric dihydroxylation of N-allylpyrimidines or N-alkenylpurines is reported. A range of chiral acyclic nucleosides with two adjacent hydroxyl groups present on the side chains could be produced in good yields (up to 97% yield) and excellent enantioselectivities (90-99% ee). The synthetic utility of the reaction was demonstrated by the catalytic asymmetric synthesis of ( S)-Cidofovir and ( R)-Buciclovir.

An unprecedented cyclization reaction of donor–acceptor oxiranes with N,N′-disubstituted thioureas to construct trans-dihydropyrimidines is presented. Preliminary reaction mechanism studies demonstrated that the reaction underwent sequential cycloaddition/amine ester exchange/oxygen–sulfur exchange/desulfuration/Michael addition process. A wide range of trans-dihydropyrimidines were produced with high yields up to 94% by using this method.

The enantioselective Friedel-Crafts alkylation reaction of β-naphthols with donor-acceptor aminocyclopropane was developed. In the presence of a copper complex derived from Cu(OTf)2 and bisoxazoline, a series of γ-substituted γ-aminobutyric acid derivatives were obtained with good yields (up to 98 %) and excellent enantioselectivities (up to 98 %). Using this catalytic system, the 2-amino cyclopropane-1,1-dicarboxylate was obtained with high enantiomeric excess (up to 98 %) by an efficient kinetic resolution (s values of up to 90). The Friedel-Crafts alkylation product could be transformed into a tetracyclic 1,3-oxazine derivative.

An efficient route to synthesize cycloalkyl substituted purine nucleosides was developed. This metal-free C-H activation was accomplished by a tBuOOtBu initiated radical reaction. By adjusting the amount of tBuOOtBu and reaction time, the selective synthesis of C6-monocycloalkyl or C6,C8-dicycloalkyl substituted purine nucleosides could be realized. Furthermore, uracil and related nucleosides were also suitable substrates, giving the C5-cyclohexyl substituted uracil derivatives in good yields with excellent regioselectivities.

An efficient route to construct chiral acyclic purine nucleosides containing a hemiaminal ester moiety is reported via three-component dynamic kinetic resolution of purines, aldehydes, and acid anhydrides. The procedure provides diverse chiral acyclic purine nucleoside analogues in a regioselective manner with good yields (up to 93% yield) and excellent enantioselectivities (up to 95% ee). Furthermore, the chiral (acyloxyalkyl)-5-fluorouracil could also be generated as a potential prodrug of 5-fluorouracil.

A straightforward entry to chiral carbocyclic nucleoside analogues has been realized via the enantioselective [3+2] cycloaddition of α-nucleobase substituted acrylates to vinyl cyclopropanes for the first time. With Pd2(dba)3-L5 as the catalyst, carbocyclic purine, uracil, and thymine nucleoside analogues with quaternary stereocenters were obtained in excellent yields (up to 99% yield) and good enantioselectivities (up to 92% ee).

A mono-adenine-functionalized pillar[5]arene and a guest including uracil were prepared. They formed a novel four-unit [c2]daisy chain both in the solid state and in a chloroform solution. As far as we know, this [c2]daisy chain is the first one without a covalently bound linear thread. This unique assembly behavior is mainly induced by hydrogen-bond interactions between A and U in the A-U base pairs.

The diversity-oriented synthesis of acyclic nucleosides has been achieved via ring-opening of vinyl cyclopropanes with purines. With Pd2(dba)3·CHCl3 as a catalyst, the 1,5-ring-opening reaction proceeded well and afforded N9 adducts as the major form, in which the C=C bonds in the side chain were exclusively E-form. In the presence of AlCl3, the 1,3-ring-opening reaction occurred smoothly, giving N9 adducts as the dominate products. Meanwhile, when MgI2 was used as the catalyst, the 1,3-ring-opening reaction also worked well to form N7 adducts.

A direct route to branched N-allylpyrimidine analogues is herein reported via the highly regio- and enantioselective asymmetric allylation of pyrimidines with racemic allylic carbonates. With [Rh(COD)Cl]2/chiral diphosphine as the catalyst, a range of chiral pyrimidine acyclic nucleosides could be obtained under neutral conditions in good yields (up to 95% yield) with high levels of regio- and enantioselectivities (15:1 to >40:1 B/L and up to 99% ee). Furthermore, chiral pyrimidine acyclic nucleoside bearing two adjacent chiral centers has been successfully synthesized by asymmetric dihydroxylation.