More Like this

1. Crystal structure of a seven-substitution mutant of hydroxynitrile lyase from rubber tree

   https://doi.org/10.1107/S2053230X25007034  

   Pierce, Colin T; Greenberg, Lauren R; Walsh, Meghan E; Shi, Ke; Magee, Drenen J; Aihara, Hideki; Gordon, Wendy; Evans, Robert L; Kazlauskas, Romas J (September 2025, Acta Crystallographica Section F Structural Biology Communications)

   The α/β-hydrolase fold superfamily includes esterases and hydroxynitrile lyases which, despite catalyzing different reactions, share a Ser–His–Asp catalytic triad. We report a 1.99 Å resolution crystal structure of HNL6V, an engineered variant of hydroxynitrile lyase fromHevea brasiliensis(HbHNL) containing seven amino-acid substitutions (T11G, E79H, C81L, H103V, N104A, G176S and K236M). The structure reveals that HNL6V maintains the characteristic α/β-hydrolase fold while exhibiting systematic shifts in backbone and catalytic atom positions. Compared with wild-typeHbHNL, the C^αpositions in HNL6V differ by a mean of 0.2 ± 0.1 Å, representing a statistically significant displacement. Importantly, the catalytic triad and oxyanion-hole atoms have moved 0.2–0.8 Å closer to their corresponding positions in SABP2, although they remain 0.3–1.1 Å from fully achieving the configuration of SABP2. The substitutions also increase local flexibility, particularly in the lid domain covering the active site. This structural characterization demonstrates that targeted amino-acid substitutions can systematically shift catalytic geometries towards those of evolutionarily related enzymes. 

   more » « less
2. Scope and Mechanistic Probe into Asymmetric Synthesis of α-Trisubstituted-α-Tertiary Amines by Rhodium Catalysis

   https://doi.org/10.1021/jacs.3c04211  

   Arachchi, Madhawee K.; Schaugaard, Richard N.; Schlegel, H. Bernhard; Nguyen, Hien M. (September 2023, Journal of the American Chemical Society)

   Asymmetric reactions that convert racemic mixtures into enantioenriched amines are of significant importance due to the prevalence of amines in pharmaceuticals, with about 60% of drug candidates containing tertiary amines. Although transition metal catalyzed allylic substitution processes have been developed to provide access to enantioenriched α-disubstituted allylic amines, enantioselective synthesis of sterically demanding α-tertiary amines with a tetrasubstituted carbon stereocenter remains a major challenge. Herein, we report a chiral diene-ligated rhodium catalyzed asymmetric substitution of racemic tertiary allylic trichloroacetimidates with aliphatic secondary amines to afford α-trisubstituted-α-tertiary amines. Mechanistic investigation is conducted using synergistic experimental and computational studies. Density functional theory calculations show that the chiral diene-ligated rhodium promotes the ionization of tertiary allylic substrates to form both anti and syn π-allyl intermediates. The anti π-allyl pathway proceeds through a higher energy than the syn π-allyl pathway. The rate of conversion of the less reactive π-allyl intermediate to the more reactive isomer via π−σ−π interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin−Hammett conditions are met in the amination reaction, leading to dynamic kinetic asymmetric transformation. Computational studies also show that hydrogen bonding interactions between β-oxygen of allylic substrate and amine-NH greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the π-allyl intermediate. The synthetic utility of the current methodology is showcased by efficient preparation of α-trisubstituted-α-tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched−linear >99:1, up to 99% enantiomeric excess). 

   more » « less
3. Lewis-Base-Catalyzed Reductive Aldol Reaction To Access Quaternary Carbons

   https://doi.org/doi.org/10.1021/acs.orglett.8b00507  

   DePorre, Y.C.; Annand, J.R.; Bar, S.; Schindler, C.S. (April 2018, Organic letters)

   A synthetic method for the efficient construction of β-hydroxylactones and lactams bearing α-quaternary carbon centers is described. This transformation relies on an electronically differentiated Lewis base catalyst, which is uniquely capable of promoting a reductive aldol reaction of α,α-disubstituted and α,α,β-trisubstituted enones. This approach provides a valuable synthetic alternative for carbon–carbon bond formation in complex molecular settings due to its orthogonal reactivity compared to that of traditional aldol reactions. Based on this method described herein, lactones, lactams, and morpholine amides bearing α-quaternary carbon centers are accessible in yields up to 85% and 50:1 dr. 

   more » « less
4. Lewis Acid-Catalyzed 2,3-Dihydrofuran Acetal Ring-Opening Benzannulations toward Functionalized 1-Hydroxycarbazoles

   https://doi.org/10.3390/molecules27238344  

   Yuan, Shaoren; Guerra Faura, Gabriel; Areheart, Hailey E.; Peulen, Natalie E.; France, Stefan (December 2022, Molecules)

   The development of a Lewis acid-catalyzed, intramolecular ring-opening benzannulation of 5-(indolyl)2,3-dihydrofuran acetals is described. The resulting 1-hydroxycarbazole-2-carboxylates are formed in up to 90% yield in 1 h. The dihydrofuran acetals are readily accessed from the reactions of enol ethers and α-diazo-β-indolyl-β-ketoesters. To highlight the method’s synthetic utility, a formal total synthesis of murrayafoline A, a bioactive carbazole-containing natural product, was undertaken. 

   more » « less
5. Generation of Diazomethyl Radicals by Hydrogen Atom Abstraction and Their Cycloaddition with Alkenes

   https://doi.org/10.1002/anie.202105472  

   Su, Yong‐Liang; Dong, Kuiyong; Zheng, Haifeng; Doyle, Michael P. (July 2021, Angewandte Chemie International Edition)

   Abstract A general catalytic methodology for the synthesis of pyrazolines from α‐diazo compounds and conjugated alkenes is reported. The direct hydrogen atom transfer (HAT) process of α‐diazo compounds promoted by thetert‐butylperoxy radical generates electrophilic diazomethyl radicals, thereby reversing the reactivity of the carbon atom attached with the diazo group. The regiocontrolled addition of diazomethyl radicals to carbon‐carbon double bonds followed by intramolecular ring closure on the terminal diazo nitrogen and tautomerization affords a diverse set of pyrazolines in good yields with excellent regioselectivity. This strategy overcomes the limitations of electron‐deficient alkenes in traditional dipolar [3+2]‐cycloaddition of α‐diazo compounds with alkenes. Furthermore, the straightforward formation of the diazomethyl radicals provides umpolung reactivity, thus opening new opportunities for the versatile transformations of diazo compounds. 

   more » « less