Carbohydrate-based N-heterocyclic carbenes for enantioselective catalysis

Article abstract of DOI:10.1039/c4ob02056a

Versatile syntheses of C2-linked and C₂-symmetric carbohydrate-based imidazol(in)ium salts from functionalised 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.

Full text of DOI:10.1039/c4ob02056a

Organic &
Biomolecular Chemistry
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Carbohydrate-based N-heterocyclic carbenes for
enantioselective catalysis†
Cite this: Org. Biomol. Chem., 2014,
12, 9180
Alexander S. Henderson, John F. Bower* and M. Carmen Galan*
Received 1st August 2014,
Accepted 29th September 2014
Versatile syntheses of C2-linked and C2-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.
DOI: 10.1039/c4ob02056a
www.rsc.org/obc
N-heterocyclic carbenes (NHCs) have been extensively exploited
over the last few decades as ligands in transition-metal cataly-
sis.1,2 However, the use of chiral NHCs in enantioselective cata-
lysis remains underdeveloped.2 A 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. functionalised
arenes, amino acids) as N-substituents.1–3 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 tran-
sition-metal catalysis.2,4 Within this area, the design of NHC-
based 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 dis-
closed.5b,e,h In most cases, application to enantioselective tran-
sition-metal catalysis has not been pursued.5a–c,e–g A C1-linked
carbohydrate-functionalized Ru catalyst was evaluated in asym-
metric 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 co-
workers has demonstrated that C6-linked NHC-capped cyclo-
dextrins provide chiral “cavities” that mediate enantioselective
gold-catalysed alkene cyclopropanation in up to 59% ee.5h
Fig. 1 Carbohydrate NHCs in asymmetric catalysis.
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 C2-
linked and C2-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 imidazo-
lium core via the C1, C3 or C6 positions.5 To prepare moder-
ately 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
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK.
E-mail: john.bower@bris.ac.uk, m.c.galan@bris.ac.uk
†Electronic supplementary information (ESI) available: Experimental procedures
and data, NMR spectra and X-ray data for 12c. CCDC 1017544. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c4ob02056a
9180 | Org. Biomol. Chem., 2014, 12, 9180–9183
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Scheme 1 Synthesis of β-glucosamine based NHC·HCl salts.
Scheme 2 Synthesis of mannosamine based NHC·HCl salts.
eventual NHC. Therefore, and given the availability of C2
amino-carbohydrates, we have targeted a series C2-linked hindrance of the axial amine (vs. equatorial amine as in
imidazol(in)ium salts (Fig. 1B).
4a–e).9 Consequently, we elected to explore conversion to the
Commercially available D-glucosamine hydrochloride, corresponding imidazolinium salts. To this end, mannos-
which bears an equatorial amine at C2, was initially chosen for amine derivative 9 was reacted with oxalyl chloride to yield the
this study (Scheme 1). Treatment of amine 1 with p-anisalde- corresponding bis-amide. Carbonyl reduction with LiAlH4 fol-
hyde under basic conditions provided imine 2 in 95% yield lowed by thermal condensation/cyclization with CH(OEt)3 in
(1 : 6 α : β mixture). Alkylation of the remaining hydroxyl the presence of NH4Cl afforded imidazolinium 7b.
groups with either methyl iodide, allyl bromide, benzyl
β-D-Mannosamine 11 was obtained from known β-D-gluco-
bromide, 1-(bromomethyl)-2-methylbenzene, or 2-(bromo- side 10 (Scheme 2),10 which is accessible from commercial
methyl)naphthalene in the presence of NaH gave compounds 1,2 : 5,6-di-O-isopropylidene-α-D-glucofuranose (see ESI† for
3a–e in 64–73% yield. Imine hydrolysis (5 M HCl) afforded details). Triflation of the C2 OH was followed by displacement
differentially protected amino building blocks 4a–e (51–94% with azide (NaN3) to install the synthetically challenging β-D-
yield). Bidirectional condensation with glyoxal then generated mannosamine scaffold. Sequential acetal hydrolysis, permethyl-
bis-iminoethylidene derivatives 5a–e in 82–96% yield. Ring- ation and azide reduction then afforded amine 11 in a 46%
closure to the corresponding imidazolium chlorides 6a–e was over 5 steps. In an identical fashion to 9, the imidazolinium
achieved in 60–74% yield using TMSCl and paraformalde- moiety was constructed by formation of bis-amide, reduction
hyde.7 1H NMR data unambiguously confirmed the formation to the secondary amine and then thermal cyclisation with
of the C2 derived glucoside-imidazolium structures (singlet at HC(OEt)3 and NH4Cl. 1H NMR data confirmed the formation of
δ: 12.31–11.96 ppm corresponding to the C2H imidazolium, the glycan-imidazolinium structures (singlet at δ: 9.96–9.69 ppm
and carbohydrate anomeric signals (d, J1,2 = 8.0–8.5 Hz at corresponding to the C2H imidazolinium and carbohydrate
δ: 6.40–5.52 ppm). Additionally, glucosamine derived imidazoli- (H-1) signals (d, J1,2 = 1.5 (7b) and 2.0 (7c) Hz) at δ: 5.12 (7b)
nium 7a was prepared by reduction of 5a to the corresponding and 4.47 (7c) ppm).
diamine (LiAlH4), and subsequent condensation with triethyl
orthoformate. This allowed access to a comparable imidazoli- from imidazol(in)iums 6a–e and 7a–c to Rh(I) was pursued.
nium ligand.
Pleasingly, base-promoted complexation (NaOt-Bu or KOt-Bu)
To demonstrate utility, ligation of the carbenes derived
To study the effects of sugar ring substituent configuration to [Rh(COD)Cl]2 proceeded smoothly and the target Rh-NHCs
(C2 axial vs. equatorial) on overall catalytic efficiency and 12a–e and 13a–c were isolated in moderate to good yield.
selectivity, mannosamine scaffolds were also targeted These complexes were purified by flash column chromato-
(Scheme 2). Azido-containing mannopyranoside 8,8 which can graphy and show good stability in the solid state (Scheme 3).11
be prepared in 3 steps from commercial 1-O-methyl-α-D-manno- Complex 12c was characterized by X-ray diffraction
pyranoside, was subjected to acetal hydrolysis (TsOH), followed (Scheme 3A) and this revealed an N–C–N angle of 103.2° and a
by permethylation with methyl iodide and NaH. Subsequent C–Rh bond length of 2.03 Å; these values are in line with other
Pd-catalysed hydrogenation of the azide furnished amine 9 in reported Rh-NHC complexes.12
89% yield over 3 steps.
As a benchmark reaction, we investigated the application of
Attempts to condense 9 following the same conditions as [Rh(NHC)]-based catalysts 12–13 to enantioselective ketone
described for the glucose series (Scheme 1), proceeded with hydrosilylation, a process that is sensitive to the electronic and
low efficiency, probably due to decreased reactivity and steric steric demands of the substrate.13 Complex 12a catalysed the
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Scheme 4 Exploration of ketone scope with complex 12a.
gave lower levels of enantiocontrol (entries 5–7).16 Changing
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). Interest-
ingly, a switch in preference from R to S was observed for the
formation of 15a when changing from an α to a β configur-
ation at C1 (13b vs. 13c). These results highlight the impor-
tance 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 C2-symmetric carbohydrate-based NHCs. Suit-
able 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 3 Complexation of NHC ligands to [Rh(COD)Cl]2.
1,2-additon of diphenylsilane to acetophenone 14a14 and, fol-
lowing 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 (K2CO3, MeOH) provided an
increased yield of 15a but no change in er (entry 2).15 Complex
13a, which is the imidazolinium analogue of 12a, provided
similar levels of enantioselectivity (80 : 20 R : S), (entry 3). Ally-
lated and benzylated complexes 12b–e, which possess bulkier
modifying groups on the carbohydrate unit compared to 12a,
Table 1 Initial screen of carbohydrate-NHC complexes in Rh-catalysed
hydrosilylation of acetophenone
Entry
Complex
Yielda (%)
er (R : S)b
Acknowledgements
1
2
3
4
5
6
7
8
9
12a
12a
13a
12b
12c
12d
12e
13b
13c
62
80 : 20
81 : 19
80 : 20
65 : 35
67 : 33
68 : 32
60 : 40
56 : 44
43 : 57
We thank the EPSRC Bristol Chemical Synthesis CDT (ASH),
EPSRC (EP/J007455/1) and the Royal Society (JFB) and
the EPSRC (EP/J002542/1 and EP/L001926/1) (MCG). Dr
M. Haddow (University of Bristol) is thanked for XRDS of 12c.
89c
85c
76
19
29
23
56c
51c
Notes and references
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: K2CO3, MeOH, 2 h.
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