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Thus, a range of para-substituted ketones were reduced with
high enantioselectivities (Table 2, entries 3–10). However, the
highest enantioselectivity of the series was achieved in the re-
duction of p-tolyl methyl ketone (S2; Table 2, entries 3 and 4).
This behavior is in contrast to the observed electronic effects
of the substrate on the catalytic performance of thioamide li-
gands 2.[8j,10a–c] The catalytic performance of the reaction, how-
ever, was influenced by steric factors on the aryl substituent.
Both the activity and enantioselectivity decreased considerably
upon using ortho-substituted aryl ketones (i.e., substrate S8;
Table 2, entries 17 and 18). Nevertheless, the use of several
meta-substituted ketones led to activities and enantioselectivi-
ties that were as high as those achieved with the use of para-
substituted ketones (up to 98% ee; Table 2, entries 13–16). In
contrast, the enantioselectivities were not affected by the
steric bulk of the alkyl substituent (Table 2, entries 1 and 2
versus entries 19 and 20). As observed with the previous thioa-
mide ligands, the reduction of alkyl/alkyl ketones proceeded
with low conversions and enantioselectivities (Table 2,
entries 21 and 22).
gands under similar reaction conditions.[15] In general, for 2-
acetylthiophene (S14), Rh/L1–L4a–f catalysts follow the same
trend as that for the ATH of S1. Again, the catalyst precursors
containing ligands L1a,f and L3a,f provided the best enantio-
selectivities of the reduced product (up to 99% ee; Table 3, en-
tries 1, 4, 6, and 7). However, for pyridyl-containing substrates
S12 and S13, the effect of the substituents/configuration of
the thioamide moiety and at C-3 of the furanoside backbone
was dependent on the substitution pattern of the substrate,
and it was different from that of substrate S1. For 2-acetylpyri-
dine (S12), high enantioselectivities were only achieved by
using the Rh/L1 f and Rh/L3 f catalytic systems (up to 97% ee;
Table 3, entries 4 and 7), whereas for 3-acetylpyridine (S13) the
enantioselectivity was excellent and independent of the con-
figuration and steric bulk of the thioamide substituent and the
substituent/configuration at C-3 of the furanoside backbone.
Ligands L1–L3a–d,f therefore afforded enantioselectivities in
the range of 98–99% ee in the ATH of S13 (Table 3, entries 1, 2,
and 4–7). These results are among the best reported for this
type of challenging substrate,[15] and more important, they
overcome one of the limitations encountered with the use of
the previous successful first-generation sugar-based pseudodi-
peptide ligands 3–5 (Figure 2), which were unable to reduce
this substrate class (Table 3, entry 8).[13]
We next decided to evaluate the new ligand library in the
ATH of a more challenging class of substrates, that is, heteroar-
omatic ketones. Enantiopure alcohols with heteroaromatic sub-
stituents are one of the key motifs used in the preparation of
biologically active compounds, and developing new methods
for their preparation is therefore of great importance for the
pharmaceutical and agrochemical industries. Unfortunately, co-
ordination of the heteroaromatic moiety to metal catalysts has
to be avoided to achieve high enantioselectivities. There are
therefore very few catalytic systems able to reduce heteroaro-
matic ketones with high enantioselectivities under transfer hy-
drogenation conditions.[15] Table 3 shows the most notable re-
sults in the reduction of heteroaromatic substrates S12–S14 by
using thioamide ligands L1–L4a–f. We were again able to fine-
tune the ligands to obtain both enantiomers with excellent
enantioselectivities (up to 99% ee). Although, as expected, the
activities were lower than those in the reduction of S1, they
were similar to those obtained by using other successful li-
Conclusions
To obtain both enantiomers of the alcohol products with high
enantioselectivity and to expand the scope of the substrates
to include very challenging heteroaromatic ketones, we ex-
panded the ligand design of one of the most successful pseu-
dodipeptide ligands (i.e., 3–5) used in the ATH of ketones by
replacing the carbonyl oxygen atom with a sulfur atom.
Changing the substituents/configurations at C-3 of the furano-
side backbone and of the amino acid part of the ligand led to
a highly modular carbohydrate-based thioamide ligand library.
This library has the advantage that it can be efficiently pre-
pared from commercial a-amino acids and d-glucose; hence,
the ligands can be prepared
from inexpensive and readily
Table 3. Selected results for the Rh-catalyzed ATH reaction of several heteroaromatic ketones using thioamide
ligands L1L4a–f.[a]
available natural chiral feed-
stocks. Excellent enantioselectivi-
ties (up to 99% ee) were ach-
ieved for a wide range of aryl
alkyl ketones, including less-
studied heteroaromatic ketones.
Interestingly, both enantiomers
of the alcohol products could be
obtained with high enantioselec-
tivities by simply changing the
absolute configuration of the
thioamide substituent. We have
therefore been able to identify
a library of sugar-based thioa-
mide ligands, and these ligands
are some of only a few examples
that can provide high enantiose-
Entry Ligand Conv.[b] [%] ee[c] [%]
(configuration)
Conv.[b] [%] ee[c] [%]
(configuration)
Conv.[b] [%] ee[c] [%]
(configuration)
1
2
3
4
5
6
7
8
L1a
L1d
L1e
L1 f
L2a
L3a
L3 f
5 f
71
88
80
54
98
83
48
<1
65 (S)
77 (S)
7 (S)
97 (R)
60 (S)
66 (S)
96 (R)
–
39
52
75
26
28
27
24
<1
99 (S)
99 (S)
5 (S)
98 (R)
99 (S)
99 (S)
98 (R)
–
42
58
38
37
<5
14
99 (R)
69 (R)
16 (R)
99 (S)
nd[d]
98 (R)
98 (S)
–
24
<1
[a] Reaction conditions: ketone (0.2m in 2-propanol/THF, 1:1; 1 equiv.), [RhCl2Cp*]2 (1 mol%), ligand (2.2 mol%),
NaOiPr (10 mol%), LiCl (10 mol%), RT. [b] Conversion determined by analysis of the reaction mixture by
1H NMR spectroscopy after 3 h. [c] Determined by HPLC on a chiral stationary phase. [d] nd=not determined.
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