Carbohydrate-based N-heterocyclic carbenes for enantioselective catalysis †

Versatile syntheses of C2-linked and C 2 -symmetric carbohydrate-based imidazol(in)ium salts from func-tionalised amino-carbohydrate derivatives are reported. The novel NHCs were ligated to [Rh(COD)Cl] 2 and evaluated in Rh-catalysed asymmetric hydrosilylation of ketones with good yields and promising enantioselectivities.

N-heterocyclic carbenes (NHCs) have been extensively exploited over the last few decades as ligands in transition-metal catalysis. 1,2However, the use of chiral NHCs in enantioselective catalysis remains underdeveloped. 2A key challenge resides in the development of systems that are able to relay efficiently ligand chirality to the coordination sphere of the metal centre.Most efforts in this area have been devoted to modification of the NHC backbone or the use of chiral motifs (e.g.2][3] Complementary methodologies that enable the incorporation of cheap and diversifiable chiral building blocks onto NHC scaffolds will likely accelerate the development of efficient ligand systems.1d Carbohydrates are one of the most diverse and important classes of biomolecule.Nature provides in carbohydrates a toolkit of well-defined chirality that is primed for modification.It is not surprising then, that carbohydrate scaffolds have been employed successfully as ligands for enantioselective transition-metal catalysis. 2,4Within this area, the design of NHCbased systems has received relatively little attention (Fig. 1A). 5 Anomeric reactivity has been exploited to append the NHC unit (via nitrogen) to C1 of the carbohydrate.5a,c,d,f,g Related C3-and C6-linked monosaccharide systems have also been disclosed.5b,e,h In most cases, application to enantioselective transition-metal catalysis has not been pursued.5a-c,e-g A C1-linked carbohydrate-functionalized Ru catalyst was evaluated in asymmetric ring-opening cross-metathesis (AROCM) but high yields could only be achieved with modest enantioselectivities (up to 26 ee).5d More recently, elegant work by Sollogoub and coworkers has demonstrated that C6-linked NHC-capped cyclodextrins provide chiral "cavities" that mediate enantioselective gold-catalysed alkene cyclopropanation in up to 59% ee.5h Nevertheless, applications of carbohydrate-based NHCs to enantioselective transition-metal catalysis remain underexplored.5d As part of our ongoing interest in imidazolium-linked sugar building blocks for oligosaccharide synthesis, 6 we became interested in their application as carbene ligands for catalysis.Herein we report flexible synthetic entries to a series of C2linked and C 2 -symmetric carbohydrate-based NHCs (Fig. 1B).As a proof of concept, we demonstrate the complexation of these to afford a series of neutral Rh(I) catalysts, that show promising activity for enantioselective ketone hydrosilylation.
Previous reports have linked carbohydrates to the imidazolium core via the C1, C3 or C6 positions. 5To prepare moderately rigid NHC complexes that might allow the chirality of the glycan to be propagated to the substrate during catalysis, attachment via C6 was deemed as suboptimal.Anomeric (C1) attachment was also discounted to avoid problems associated with diastereocontrol at this centre and the stability of the eventual NHC.Therefore, and given the availability of C2 amino-carbohydrates, we have targeted a series C2-linked imidazol(in)ium salts (Fig. 1B).
To study the effects of sugar ring substituent configuration (C2 axial vs. equatorial) on overall catalytic efficiency and selectivity, mannosamine scaffolds were also targeted (Scheme 2).Azido-containing mannopyranoside 8, 8 which can be prepared in 3 steps from commercial 1-O-methyl-α-D-mannopyranoside, was subjected to acetal hydrolysis (TsOH), followed by permethylation with methyl iodide and NaH.Subsequent Pd-catalysed hydrogenation of the azide furnished amine 9 in 89% yield over 3 steps.
Attempts to condense 9 following the same conditions as described for the glucose series (Scheme 1), proceeded with low efficiency, probably due to decreased reactivity and steric hindrance of the axial amine (vs.equatorial amine as in 4a-e). 9Consequently, we elected to explore conversion to the corresponding imidazolinium salts.To this end, mannosamine derivative 9 was reacted with oxalyl chloride to yield the corresponding bis-amide.Carbonyl reduction with LiAlH 4 followed by thermal condensation/cyclization with CH(OEt) 3 in the presence of NH 4 Cl afforded imidazolinium 7b.
To demonstrate utility, ligation of the carbenes derived from imidazol(in)iums 6a-e and 7a-c to Rh(I) was pursued.Pleasingly, base-promoted complexation (NaOt-Bu or KOt-Bu) to [Rh(COD)Cl] 2 proceeded smoothly and the target Rh-NHCs 12a-e and 13a-c were isolated in moderate to good yield.These complexes were purified by flash column chromatography and show good stability in the solid state (Scheme 3). 11omplex 12c was characterized by X-ray diffraction (Scheme 3A) and this revealed an N-C-N angle of 103.2°and a C-Rh bond length of 2.03 Å; these values are in line with other reported Rh-NHC complexes. 12s a benchmark reaction, we investigated the application of [Rh(NHC)]-based catalysts 12-13 to enantioselective ketone hydrosilylation, a process that is sensitive to the electronic and steric demands of the substrate. 13Complex 12a catalysed the 1,2-additon of diphenylsilane to acetophenone 14a 14 and, following acid promoted (HCl) cleavage of the silyl ether, alcohol 15a was isolated in 62% yield and 80 : 20 er (Table 1, entry 1).Hydrolysis under basic conditions (K 2 CO 3 , MeOH) provided an increased yield of 15a but no change in er (entry 2). 15Complex 13a, which is the imidazolinium analogue of 12a, provided similar levels of enantioselectivity (80 : 20 R : S), (entry 3).Allylated and benzylated complexes 12b-e, which possess bulkier modifying groups on the carbohydrate unit compared to 12a, gave lower levels of enantiocontrol (entries 5-7). 16Changing the configuration of the C2 amine in the glycan from equatorial (glucos-) to axial (mannos-) (13b/c) had a detrimental effect in both yield and enantioselectivity (entries 9 and 10).Interestingly, a switch in preference from R to S was observed for the formation of 15a when changing from an α to a β configuration at C1 (13b vs. 13c).These results highlight the importance of substituent configuration and size on the carbohydrate scaffold and show that these factors can affect the enantioselectivity of the reaction.
To explore scope further, hydrosilylation of structurally diverse ketones 14b-d was explored using complex 12a (Scheme 4).Pleasingly, reaction yields were uniformly high (84-96% yield) and the products were formed with similar levels of enantioselectivity (71 : 29-75 : 25; R : S) across the range of alkyl-alkyl (15b), aryl-alkyl (15c), and bicyclic (15d) ketone motifs.Evidently further optimisation is required, but these results demonstrate that the carbohydrate-based NHC ligand of 12a is effective at relaying chiral information to the "active" coordination sites of the Rh-complex.
In conclusion, we outline flexible routes to a family of novel C2-linked and C 2 -symmetric carbohydrate-based NHCs.Suitable selection and modification of the carbohydrate unit is readily achieved and this provides "tunable" access to a diverse range of derivatives.The corresponding Rh(I)-complexes are accessed easily and display promising enantioselectivities in ketone hydrosilylation.Overall, the results described here highlight the potential of this family of simple and modifiable carbohydrate derived NHCs as ligands for enantioselective transition metal catalysis.The development and application of related classes of chiral NHC will be reported in due course.Scheme 4 Exploration of ketone scope with complex 12a.

Table 1
Initial screen of carbohydrate-NHC complexes in Rh-catalysed hydrosilylation of acetophenone a Isolated yields.b R : S ratios were determined by chiral HPLC using the corresponding racemate as a standard.c Optimised silyl ether cleavage conditions: K 2 CO 3 , MeOH, 2 h.