Rhodium(I)/organoboron-catalyzed site-selective functionalization

Site-selective functionalization is a powerful strategy with broad applications in organic synthesis. Compared with enantioselective synthesis, site/regioselective methods focus more on regiocontrol and have broader relevance in biological reactions. Carbohydrates are one of the four major biomolecules, but their structures and stereochemistry are often complex. Obtaining carbohydrates with stereoselectivity is still a challenge to a large extent. Recently, researchers used chiral Rhodium(I)/organoboron synergistic catalytic strategy to realize the synthesis of carbohydrate with high stereoselectivity.

First, the researchers chose mannosyl triol derivative and oxanorbornadiene as model substrates to screen the reaction conditions, and obtained the best reaction conditions: 1.0 equiv and 2.0 equiv substrates were in Rh(cod)₂OTf (5 mol%) as catalyst, 2-cyclohexylethylene boronic acid (30 mol%) as cocatalyst, (R,S)-PPF-P^tBu₂ (6 mol%) as ligand, THF (2 mL) as solvent under the conditions of 50 °C for 24 h, the C3 regioisomer can be obtained in 92% yield, >20:1 r.r. and >20:1 d.r..

With the optimal reaction conditions in hand, the researchers investigated the substrate scope of the reaction. The results show that mannose, galactose, rhamnose, arabinose, galactaldehyde, trehalose, lyxose, 1,6-anhydromannose, sedoheptulose and other sugar compounds are compatible with the reaction, in moderate to good (45-92%) yield and good steric control. In addition, the researchers confirmed the absolute and regioisomer configurations of these products by X-ray diffraction analysis and vibrational circular dichroism analysis. Altogether, these results suggest that the chirality of the ligand, the three-dimensional structure of the carbohydrate polyol, and the electronic effects of the organoboron reagent jointly determine the stereoselectivity and yield of the reaction.

Secondly, the researchers investigated the substrate range of electrophilic reagents, and the results showed that oxanorbornadiene derivatives substituted with different groups (such as methyl, methoxy, dioxolane, fluorine, bromine, etc.) could successfully achieve this conversion, and the corresponding products were obtained with good yield and stereocontrol. In addition, researchers have extended this strategy to structurally related aliphatic, cyclic aliphatic, and aromatic substituted allylic carbonate substrates. By optimizing the ligand ((S) - NPN) and solvent (CH₃CN), corresponding products can be obtained with a yield of 60-81% and good regioselectivity and diastereoselectivity.

To demonstrate the utility of this transformation, the researchers also performed a series of transformations for synthetic applications.

1) 1 mmol-scale reaction was achieved at a reduced rhodium catalyst loading (4 mol%), and the product was obtained in 90% yield, >20:1 r.r. and >20:1 d.r.;
2) This product was reduced by Pd/C at room temperature to obtain the hydrogenated product in an equivalent yield, or the TBS protecting group was removed under the action of TBAF, and the corresponding product was obtained in a yield of 92%;
3) Alkyne-linked sugar products and azides were used to synthesize sugar triazole derivatives through click chemistry;
4) Galactose derivatives can undergo acid-catalyzed 2-deoxyglycosylation and give disaccharide products in a highly α-selective manner.

Reference

1. A synergistic Rh(I)/organoboron-catalysed site-selective carbohydrate functionalization that involves multiple stereocontrol
   V. U. Bhaskara Rao, Caiming Wang, Daniel P. Demarque, Corentin Grassin, Felix Otte, Christian Merten, Carsten Strohmann, Charles C. J. Loh