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1. Catalytic Stereoselective 1,2- cis -Furanosylations Enabled by Enynal-Derived Copper Carbenes

   https://doi.org/10.1021/acscatal.3c05237  

   Ghosh, Bidhan; Alber, Adam; Lander, Chance W; Shao, Yihan; Nicholas, Kenneth M; Sharma, Indrajeet (January 2024, ACS Catalysis)

   Chang, Sukbok (Ed.)

   1,2-cis-Furanosides are present in various biomedically relevant glycosides, and their stereoselective synthesis remains a significant challenge. In this vein, we have developed a stereoselective approach to 1,2-cis-furanosylations using earth-abundant copper catalysis. This protocol proceeds under mild conditions at room temperature and employs readily accessible benchtop stable enynalderived furanose donors. This chemistry accommodates a variety of alcohols, including primary, secondary, and tertiary, as well as mannosyl alcohol acceptors, which have been incompatible with most known methods of furanosylation. The resulting 1,2-cisfuranoside products exhibit high yields and anomeric selectivity with both the ribose and arabinose series. Furthermore, the anomeric selectivity is independent of the C2 oxygen-protecting group and the anomeric configuration of the starting donor. Experimental evidence and computational studies support our hypothesis that copper chelation between the C2 oxygen of the furanose donor and an incoming alcohol nucleophile is responsible for the observed 1,2-cisstereoselectivity. 

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2. Protoglobin‐Catalyzed Formation of cis ‐Trifluoromethyl‐Substituted Cyclopropanes by Carbene Transfer

   https://doi.org/10.1002/anie.202208936  

   Schaus, Lucas; Das, Anuvab; Knight, Anders M.; Jimenez‐Osés, Gonzalo; Houk, K. N.; Garcia‐Borràs, Marc; Arnold, Frances H.; Huang, Xiongyi (December 2022, Angewandte Chemie International Edition)

   Abstract Trifluoromethyl‐substituted cyclopropanes (CF₃‐CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis oftrans‐CF₃‐CPAs, stereoselective production of correspondingcis‐diastereomers remains a formidable challenge. We report a biocatalyst for diastereo‐ and enantio‐selective synthesis ofcis‐CF₃‐CPAs with activity on a variety of alkenes. We found that an engineered protoglobin fromAeropyrnum pernix(ApePgb) can catalyze this unusual reaction at preparative scale with low‐to‐excellent yield (6–55 %) and enantioselectivity (17–99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron‐carbenoid and substrates to adopt a pro‐cisnear‐attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF₃‐CPAs for drug discovery. 

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3. Regio- and enantioselective synthesis of acyclic quaternary carbons via organocatalytic addition of organoborates to (Z)-Enediketones

   https://doi.org/10.1038/s41467-024-44744-y  

   Peng, Po-Kai; Isho, Andrew; May, Jeremy A. (January 2024, Nature Communications)

   Abstract The chemical synthesis of molecules with closely packed atoms having their bond coordination saturated is a challenge to synthetic chemists, especially when three-dimensional control is required. The organocatalyzed asymmetric synthesis of acyclic alkenylated, alkynylated and heteroarylated quaternary carbon stereocenters via 1,4-conjugate addition is here catalyzed by 3,3´-bisperfluorotoluyl-BINOL. The highly useful products (31 examples) are produced in up to 99% yield and 97:3 er using enediketone substrates and potassium trifluoroorganoborate nucleophiles. In addition, mechanistic experiments show that the (Z)–isomer is the reactive form, ketone rotation at the site of bond formation is needed for enantioselectivity, and quaternary carbon formation is favored over tertiary. Density functional theory-based calculations show that reactivity and selectivity depend on a key n→π* donation by the unbound ketone’s oxygen lone pair to the boronate-coordinated ketone in a 5-exo-trig cyclic ouroboros transition state. Transformations of the conjugate addition products to key quaternary carbon-bearing synthetic building blocks proceed in good yield. 

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4. Why is thiol unexpectedly less reactive but more selective than alcohol in phenanthroline-catalyzed 1,2- cis O - and S -furanosylations?

   https://doi.org/10.1039/d4ob01593b  

   Ramakrishna, Boddu S; Rani, Neha; Xu, Hengfu; Alan-Lee, Cyrus; Schlegel, H Bernhard; Nguyen, Hien M (January 2025, Organic & Biomolecular Chemistry)

   The lack of catalytic stereoselective approaches for producing 1,2-cis S-furanosides emphasizes the critical need for further research in this area. Herein, we present a stereoselective S-furanosylation method, utilizing a 4,7-dipiperidine-substituted phenanthroline catalyst. This developed protocol fills a gap in the field, enabling the coupling of cysteine residues and thiols with furanosyl bromide electrophiles. The process allows for stereoselective access to 1,2-cis S-furanosides. Through computational and experimental investigations, thiol is found to be less reactive than alcohol but exhibits greater stereoselectivity. The 1,2-cis stereoselectivity of O-products depends on the nature of the electrophile, while S-products are obtained with excellent 1,2-cis stereoselectivity, irrespective of the furanose structure. The displaced bromide ion from the glycosyl electrophile influences the reaction’s reactivity and stereoselectivity. Alcohol-OH forms a stronger hydrogen bond with bromide ion than thiol-SH, contributing to the difference in their reactivity. The energy difference between forming S-furanoside and O-furanoside transition states is 3.7 kcal/mol, supporting the increased reactivity of alcohol over thiol. The difference in transition state energies between the major and minor S-product is greater than that for the major and minor O-product. This is consistent with experimental data showing how thiol is more stereoselective than alcohol. The catalyst and reaction conditions utilized for the generation of 1,2-cis O-furanosides in our prior studies are found to be unsuitable for the synthesis of 1,2-cis S-furanosides. In the present study, a highly reactive phenanthroline catalyst and specific reaction conditions have been developed to achieve stereoselective S-linked product formation. 

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5. Highly stereoselective syntheses of ( E )-δ-boryl- anti -homoallylic alcohols via allylation with α-boryl-( E )-crotylboronate

   https://doi.org/10.1039/d1cc04058h  

   Liu, Jiaming; Chen, Ming (October 2021, Chemical Communications)

   A highly stereoselective synthesis of ( E )-δ-boryl- anti -homoallylic alcohols is developed. In the presence of a Lewis acid, aldehyde allylation with α-boryl-( E )-crotylboronate gave δ-boryl- anti -homoallylic alcohols in good yields with excellent E -selectivity. The E -vinylboronate group in the products provides a useful handle for cross-coupling reactions as illustrated in the fragment synthesis of chaxamycins. 

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