Modular hydroxyamide and thioamide pyranoside-based ligand library from the sugar pool: New class of ligands for asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1002/adsc.201301112

A large library of pyranoside-based hydroxyamide and thioamide ligands has been synthesized for asymmetric transfer hydrogenation in an attempt to expand the scope of the substrates to cover a broader range of challenging heteroaromatic and aryl/fluoroalkyl ketones. These ligands have the advantage that they are prepared from commercial D-glucose, D-glucosamine and α-amino acids, inexpensive natural chiral feedstocks. By carefully selecting the ligand components (substituents/configurations at the amide/thioamide moiety, the position of amide/thioamide group and the configuration at C-2), we found that pyranoside-based thioamide ligands provided excellent enantioselectivities (in the best cases, ees of >99% were achieved) in a broad range of ketones, including the less studied heteroaromatics and challenging aryl/fluoroalkyls. Note that both enantiomers of the reduction products can be obtained with excellent enantioselectivities by simply changing the absolute configuration of the thioamide substituent.

Full text of DOI:10.1002/adsc.201301112

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DOI: 10.1002/adsc.201301112
Modular Hydroxyamide and Thioamide Pyranoside-Based
Ligand Library from the Sugar Pool: New Class of Ligands for
Asymmetric Transfer Hydrogenation of Ketones
Mercꢀ Coll,a Oscar Pꢁmies,a,* and Montserrat Diꢂgueza,*
a
Departament de Quꢃmica Fꢃsica i Inorgꢁnica, Universitat Rovira i Virgili, C/Marcel·lꢃ Domingo s/n, 43007 Tarragona,
Spain
Fax : (+34)-97-755-9563; phone: (+34)-97-755-8780; e-mail: oscar.pamies@urv.cat or montserrat.dieguez@urv.cat
Received: December 10, 2013; Revised: February 5, 2014; Published online: June 20, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301112.
Abstract: A large library of pyranoside-based hy- 2), we found that pyranoside-based thioamide li-
droxyamide and thioamide ligands has been synthe- gands provided excellent enantioselectivities (in the
sized for asymmetric transfer hydrogenation in an at- best cases, ees of >99% were achieved) in a broad
tempt to expand the scope of the substrates to cover range of ketones, including the less studied hetero-
a broader range of challenging heteroaromatic and
ACHTUNGTRENaNGNU romatics and challenging aryl/fluoroalkyls. Note
aryl/fluoroalkyl ketones. These ligands have the ad- that both enantiomers of the reduction products can
vantage that they are prepared from commercial d- be obtained with excellent enantioselectivities by
glucose, d-glucosamine and a-amino acids, inexpen- simply changing the absolute configuration of the
sive natural chiral feedstocks. By carefully selecting thioamide substituent.
the ligand components (substituents/configurations
at the amide/thioamide moiety, the position of Keywords: asymmetric catalysis; carbohydrates; ke-
amide/thioamide group and the configuration at C- tones; rhodium; ruthenium; transfer hydrogenation
Introduction
sonꢄs group reported that amino acid-derived
hydroxyamides 1 and thioamides 2 (Figure 1) in com-
AHCTUNGTRENNUNG
Over the last four decades, transition metal-based bination with Ru or Rh half-sandwich complexes are
asymmetric catalysis has been a powerful strategy for excellent catalysts for the ATH of aryl alkyl ketone-
accessing a wide range of optically pure compounds.[1] s.[8h,i,9] These ligands are based on the combination of
In particular, considerable effort has been made in different N-Boc-protected a-amino acids and b-amino
the enantioselective reduction of prochiral ketones alcohols (for type 1)[8h,9a–g] or on thioamides (for type
because the alcohols formed have important uses in
the pharmaceutical, agrochemical, fragrance and
flavor industries.[1] Asymmetric transfer hydrogena-
tion (ATH) is an alternative, sustainable, efficient and
mild method that is operationally simpler and signifi-
cantly safer than direct hydrogenation with molecular
hydrogen.[2] The most commonly used asymmetric
transfer hydrogenation catalysts are based on transi-
tion metals (i.e., ruthenium,[3] rhodium,[4] iridium[4a–c,5]
and more recently iron[6] and osmium[7]). In the mid
1990s, Noyori and co-workers disclosed that Ru-arene
complexes modified with chiral b-amino alcohols or
monosulfonated diamines (i.e., TSDPEN, which con-
stitutes one of the widely used ligands in this transfor-
mation) are efficient catalysts for reducing ketones
and ketimines.[2f,i,3a,b] Since then the range of ligand
classes has been expanded.[8] In this respect, Adolfs-
Figure 1. General structure of hydroxyamide ligands 1, thio-
amide ligands 2 and sugar-based hydroxyamide 3 and thio-
AHCTUNGTREGaNNUN mide ligands 4.
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Figure 2. Pyranoside-based a-amino acid hydroxyamide/thioamide ligands L1–L6a–h.
2),[8i,9h–j] respectively. Both showed the advantage of potential thioamide L4–L6a–h ligands (Figure 2). The
possessing a modular ligand building block – the combination of commercially available ligand building
amino acid part. Despite all these important contribu- blocks (d-glucose or d-glucosamine and a-amino
tions, further improvement in terms of substrate acids) creates a highly modular ligand library, in
scope, selectivity and turnover frequency was required which several ligand parameters can easily be tuned
to make the process competitive with conventional so that catalyst performance can be maximized for
hydrogenations. Therefore, enantioselective ATH cat- each substrate type. With this ligand library, we inves-
alysts containing modular ligands based on simple tigated the effect of systematically varying the
starting materials needed to be developed.[10,11] In this substituents/configurations at the amide/thioamide
context, in 2011 we developed new hydroxyamide li- moiety (a–h), the replacement of the hydroxyamide
gands 3 (Figure 1) in which the b-amino alcohol part functionality (ligands L1–L3) with thioamide (ligands
was replaced by a readily available sugar b-amino al- L4–L6), the position of the amide/thioamide group at
cohol moiety.[12] The introduction of a furanoside either C-2 (ligands L1 and L2, L4 and L5) or C-3 (li-
amino sugar moiety into the ligand design represent- gands L3 and L6) of the pyranoside backbone and the
ed an important breakthrough. Ru-catalysts modified configuration at C-2 (L1 and L2, L4 and L5). By care-
with carbohydrate hydroxyamide ligands 3 (Figure 1) fully selecting the ligand components we achieved
therefore proved to efficiently catalyze the reduction both enantiomers of the desired alcohols in high-to-
of a wide range of aryl alkyl ketones. The secondary excellent enantioselectivities and yields for a wide
alcohols formed were obtained in excellent enantiose- range of substrates, including the more challenging
lectivities (typically 99% ee) surpassing the enantiose- aryl/fluoroalkyl and heteroaromatic ketones.
lectivities obtained with previously successful
hydroxyACHTUNGTRENNUNGamide ligands 1. However the latter catalytic
systems cannot reduce industrially relevant heteroaro- Results and Discussion
matic ketones and only one of the enantiomers of the
product can be accessed. To overcome these limita- Ligand Synthesis
tions, we recently prepared a second generation of
the furanoside-based ligand library containing the thi- Pyranoside ligands L1–L6 were synthesized from the
oamide functionality (4, Figure 1), based on previous corresponding sugar amino alcohols 1–3, easily made
sugar hydroxyamide ligands 3.[13] Although the in few steps from d-glucose (compounds 1 and 3)[15]
number and type of substrates that can be successfully and d-glucosamine (compound 2),[16] following
reduced with these systems has increased, greater a straightforward methodology in a parallel way
effort is still needed in the design of ligands to discov- (Scheme 1). Compounds 1–3 were chosen as inter-
er a catalytic system that can efficiently reduce mediates for preparing ligands because the various el-
a broader range of heteroaromatic ketones and other ements that make it possible to study the position at
more challenging substrates such as aryl/fluoroalkyl which the amide/thioamide is coupled (at either C-2
ketones.[14]
or C-3) and the configuration of C-2 of the sugar
To address all these points, in this study, we pre- amino alcohol can be easily incorporated. We first
pared and evaluated a new carbohydrate-based li- synthesized the a-amino acid hydroxyamide ligands
brary of 24 potential hydroxyamide L1–L3a–h and 24 L1–L3 from intermediates 1–3 in a single step by cou-
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Modular Hydroxyamide and Thioamide Pyranoside-Based Ligand Library
Scheme 1. Synthesis of pyranoside-based a-amino acid hydroxyamide/thioamide ligands L1–L6a–h. (a) N-Boc-protected a-
amino acid/i-BuOCOCl/NMM/THF/À158C; (b) BzCl/Py/CH2Cl2/08C to room temperature; (c) Lawessonꢄs reagent/THF/
608C.
pling a series of N-Boc-protected amino acids using Asymmetric Transfer Hydrogenation of
isobutyl chloroformate in the presence of N-methyl- Acetophenone
morpholine (Scheme 1, step a). In this step the de-
sired diversity in the substituents and configuration of In the initial set of experiments we evaluated pyrano-
the amino acid part was also attained (a–h). We next side-based hydroxyamide/thioamide ligands L1–L6a–
synthesized thioamide ligands L4–L6, in a two-step h in the asymmetric Ru- and Rh-catalyzed transfer
procedure, from hydroxyamide compounds L1–L3 by hydrogenation of acetophenone S1. Acetophenone
first protecting the free hydroxy group with benzoyl was chosen as a model substrate because the reaction
chloride (Scheme 1, step b). The subsequent reaction was performed with a wide range of ligands, which
with Lawessonꢄs reagent (Scheme 1, step c) provided enabled the efficiency of the various ligand systems to
direct access to pyranoside-based thioamide ligands be compared directly.[2–9] In all cases, the catalysts
L4–L6.
were generated in situ from the corresponding ligand
2A(p-cymene)]2 or [RhCl2Cp*]2 in the
The ligands were characterized by elemental analy- and either [RuCl CTHGNUTRENNUNG
ses and H and 13C{1H} NMR spectra (see the Sup- presence of base.
1
porting Information). The elemental analyses were in We first investigated the effect of the catalyst pre-
agreement with the assigned structures. The spectral cursor using ligands L1–L6a (Table 1). In contrast to
1
assignments were based on information from H-1H, previously reported furanoside-based hydroxyamide
1
and H-13C correlation measurements. The expected ligands 3 (Figure 1),[12] the use of ligands L1–L3 led to
1H and 13C NMR patterns for the pyranoside nucleus poor catalytic activity when both types of catalyst pre-
(positions 1–7) were observed (see the Experimental cursors were used (Table 1, entries 1–6). Previous
Section). The vicinal 1H-1H couplings in the sugar mechanistic studies with successful hydroxyamide li-
ring were in the normal range (0–7 Hz). As expected, gands 1 showed that this type of ligand coordinates to
ligands L1 and L4, with an S configuration at C-2, dis- the metal in a tridentate fashion, through both nitro-
played the anomeric proton (H-1) as a singlet, while gen atoms and the oxygen atom.[9h] The lower activity
for compounds L2, L3 and L5, L6, with an opposite found with hydroxyamide ligands L1–L3 can there-
configuration at C-2, the anomeric proton appears as fore be attributed to the higher rigidity of the pyrano-
a doublet due to the coupling with H-2. The expected side backbone which hinders its coordination to the
signals for the different amide/thioamide groups were metal center in contrast to the less steric environment
also observed.
generated by the furanoside backbone. Note that for
furanoside ligands 3, the amido group was attached to
the flexible primary carbon (C-6), which allows the
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Table 1. Ru- and Rh-catalyzed asymmetric transfer hydroge-
nation reaction of S1 using ligands L1–L6a–h[a]
Table 2. Rh-catalyzed asymmetric transfer hydrogenation re-
action of S1 using thioamide ligands L4–L6a–h.[a]
Entry
Ligand
% Conv. (% Yield)[b]
% ee[b]
1
2
3
4
5
6
7
8
L4a
L4b
L4c
L4d
L4e
L4f
L4g
L4h
L5a
L5e
L5f
L5g
L5h
L6a
L6e
L6g
L4a
L4g
L4a
L4g
88 (81)[c]
91 (87)
76 (72)
92 (85)
88 (81)
86 (82)
76 (69)
72 (67)
82 (77)
84 (76)
79 (74)
72 (68)
69 (61)
19 (15)
38 (34)
18 (13)
100 (91)
100 (95)
99 (94)
100 (93)
99 (R)
97 (R)
90 (R)
96 (R)
86 (R)
33 (S)
98 (S)
89 (S)
98 (R)
86 (R)
8 (R)
95 (S)
89 (S)
84 (R)
93 (R)
83 (S)
98 (R)
98 (S)
98 (R)
98 (S)
Entry Ligand Catalyst precursor
% Conv.[b] % ee[b]
1
2
3
4
5
6
7
8
L1a
L2a
L3a
L1a
L2a
L3a
L4a
L5a
L6a
L4a
L5a
L6a
N
(p-cymene)]2
0
0
1
6
5
4
nd
nd
nd
9
19 (S)
16 (S)
11 (S)
90 (R)
87 (R)
70 (R)
99 (R)
98 (R)
84 (R)
10
11
12
13
14
15
16
17[d]
18[d]
19[d,e]
20[d,e]
9
7
10
11
12
88
82
19
[a]
[b]
Reaction conditions: S1 (1 equiv., 0.2M in 2-propanol/
THF: 1/1), [RuCl2A(p-cymene)]2 (0.25 mol%) or
[RhCl2Cp*]2 (0.25 mol%), ligand (0.55 mol%), NaO-i-Pr
(5 mol%), LiCl (10 mol%) and at room temperature, 3 h.
Conversion and enantiomeric excess were determined by
GC (CP Chirasil DEX CB).
CTHUNGTRENNUNG
[a]
Reaction conditions: S1 (1 equiv., 0.2M in 2-propanol/
THF: 1/1), [RhCl2Cp*]2 (0.25 mol%), ligand
(0.55 mol%), NaO-i-Pr (5 mol%), LiCl (10 mol%), at
room temperature, 3 h.
Conversion and enantiomeric excess were determined by
GC (CP Chirasil DEX CB). Isolated yields are shown in
parenthesis.
This reaction was also carried out at a 0.1 mol scale, af-
fording the reduced product in 85% yield and 98% ee.
Reaction carried out at 408C.
[b]
[c]
perfect coordination of the three groups. The results
in Table 1 also showed that both activity and enantio-
selectivity were best when the thioamide ligands and
[RhCl2Cp*]2 were used as the catalyst precursor (en-
tries 10–12).[17] These results are in line with those
previously observed when related thioamide-based li-
gands 4 were used.[13] Interestingly, these pyranoside
[d]
[e]
Reaction carried out using 0.1 mol% of [RhCl2Cp*]2.
thioamide ligands displayed higher activities and present (i.e., i-Pr>i-Bu>Bn>Ph>Me@H; Table 2,
enantioselectivities than the previously reported fura- entries 1–6). In addition, as observed for other thio-
noside-based thioamide ligands 4.
ACHTUNGTRENaNGNU mide ligands, the sense of the enantioselectivity is
We then moved on to investigate the effect of the governed by the absolute configuration of the sub-
ligand parameters on the catalytic performance. For stituent in the thioamide moiety (Table 2, entries 1 vs.
purposes of comparison, we evaluated the remaining 7). Both enantiomers of the reduction products can
thioamide ligands using [RhCl2Cp*]2 as the catalyst therefore be accessed in high enantioselectivity
precursor. The results, which are summarized in simply by changing the absolute configuration of the
Table 2, indicated that catalytic performance (activity thioamide substituent.
and enantioselectivity) is mainly affected by the sub-
Varying the configuration of the pyranoside carbon
stituents/configurations at the thioamide moiety (a–h) in which the thioamide is coupled has little impact on
and the position of the thioamide group at either C-2 the activity and stereochemical outcome of the reac-
or C-3 of the pyranoside backbone while the effect of tion. Thus, the use of ligands L4 and L5, with opposite
the configuration of C-2 is less pronounced.
We first investigated the effect on catalytic per- to similar catalytic results (i.e., Table 2, entry 1 vs. 9).
formance of the substituents/configuration of the thio- Finally we studied the effect of the position of the
configuration at C-2 of the pyranoside backbone, led
amide moiety with ligands L4a–h (Table 2, entries 1– thioamide group at either C-2 (ligands L4 and L5) or
6). Systematic variation of the electronic and steric C-3 (ligands L6) of the pyranoside backbone. Ligands
properties of the thioamide substituents indicated that L4 and L5, which contain the thioamide group at the
enantioselectivities were mainly controlled by the C-2 position, produced better activities and enantiose-
steric properties of these substituents and were higher lectivities than ligands L6, with the thioamide group
when more sterically demanding substituents were at C-3. The lower catalytic activity can be attributed
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Modular Hydroxyamide and Thioamide Pyranoside-Based Ligand Library
to the higher steric congestion around the metal the previously reported successful furanoside-based
center exerted using this L6 pyranoside backbone. thioamide ligands 4.
This is further supported by the fact that the highest
Our results using several para-substituted aryl ke-
activity when ligands L6 are used is achieved with the tones (S1–S6) indicated that enantioselectivity is rela-
less sterically demanding methyl thioamide substitu- tively insensitive to the electronic effects in the aryl
ent (ligand L6e; entry 15 vs. 16). Note that in contrast ring (Table 3, entries 1–12). However, enantioselectiv-
to L4 and L5, ligand L6e also afforded the highest ities (up to 99%) were highest with electron-rich ke-
enantioselectivity of the L6 series.
tones S4 and S6 (Table 3, entries 7, 8, 11 and 12), and
To sum up, the enantioselectivities (ees up to 99%) lowest (up to 96%) with the electron-deficient ketone
were highest when thioamide ligands with bulky iso- S5 (Table 3, entries 9 and 10). The catalytic per-
propyl groups were used (ligands L4 and L5a, g). formance of the reaction, however, was influenced by
Both enantiomers of the alcohol product were steric factors on the aryl substituent. Both activity
achieved in excellent enantioselectivity by simply and enantioselectivity decreased considerably when
changing the configuration of the thioamide substitu- ortho-substituted aryl ketones were used (i.e., sub-
ent. These results clearly show the efficiency of using strate S10; Table 3, entries 19 and 20). Nevertheless,
highly modular scaffolds in the ligand design. Activity the use of several meta-substituted ketones (S7–S9)
can be improved by controlling not only the structural led to activities and enantioselectivities as high as
but also the reaction parameters. In this case, activity those achieved using para-substituted substrates.
was further improved (up to 100% conversion in 2 h) Therefore, several para- and meta-substituted aryl ke-
by performing the reaction at a higher temperature tones, including those containing 2-naphthyl groups,
(408C) and, interestingly, the high enantioselectivities can be efficiently reduced using Rh-L4, L5a, g.
were maintained (ees up to 98%, entries 17 and 18).
We next studied several aryl/alkyl ketones bearing
We also performed the reaction at low catalyst load- increasingly sterically demanding alkyl substituents
ing using ligands L4a, g. The excellent enantioselec- (S11–S13). The results indicated that increasing the
tivity (98% ee) and activity (up to 100% conversion steric bulk has a negative effect on catalytic per-
after 4 h) were maintained. Interestingly, when these formance (i.e., MeꢀEt>i-Bu@Cy; entries 1, 2 and
results are compared with the catalytic performance 21–26). It should be pointed out that the reduction of
obtained with their corresponding furanoside-based the more hindered cyclohexyl-containing ketone S13
thioamide 4 and hydroxyamide 1 systems, we can con- followed a different trend than previous substrates.
clude that introducing a pyranoside moiety into li- The enantioselectivity was therefore highest with
gands L4, L5a, g is advantageous. We therefore ligand L4e, which contained the smallest methyl thio-
obtain enantioselectivities as high as those reported amide substituent (Table 3, entry 25 vs. 26).
with the best catalytic systems reported for this pro-
Finally, we investigated the asymmetric transfer hy-
cess but our new thioamides L4, L5a, g provided drogenation of aryl/fluoroalkyl ketones S14 and S15.
higher activities than previous furanoside-based ana- Enantioenriched a-trifluoromethyl alcohols are im-
logues 4.
portant intermediates in the development of medi-
cines, agrochemicals, and materials owing to the
unique properties of the fluorine atom.[18] The forma-
tion of optically active a-trifluoromethyl alcohols
relies mainly on the use of biocatalysts, metal-cata-
lyzed asymmetric hydrogenation and hydrobora-
tion.[19] Few reports have been published on the use
of asymmetric transfer hydrogenation of fluoroalkyl
ketones.[20] Catalyst precursors Rh/L4a and Rh/L4g
Asymmetric Transfer Hydrogenation of Other
Ketones: Scope and Limitations
Asymmetric Transfer Hydrogenation of Aryl Alkyl
and Aryl Fluoroalkyl Ketones
To further study the potential of the readily available proved to be the most selective, giving the corre-
thioamide ligands, we evaluated them in the asym- sponding a-trifluoromethyl alcohols in high enantiose-
metric Rh-catalyzed transfer hydrogenation of other lectivities (ees up to 89%). It should be noted that
aryl alkyl/trifluoroalkyl ketones S2–S15 (Table 3). The these results compete favorably with the results ob-
ATH results indicated that the general trends were tained using the Ru/R2NSO2DPEN catalyst (38% ee),
the same as for the ATH of S1 (see the Supporting which is considered the state of art in ATH reac-
Information for a full set of results). Results were tions.[14]
therefore best with ligands L4, L5a, g, giving access to
In summary, the modular ligand design (substitu-
both enantiomers of the secondary alcohol products ents/configurations at the thioamide moiety, position
in high-to-excellent enantioselectivities (ees up to of thioamide group at either C-3 or C-2 of the pyra-
99%). Again, pyranoside-based thioamide ligands dis- noside backbone and the configuration at C-2 of the
played higher activities and enantioselectivities than pyranoside backbone) has been shown to be extreme-
ly successful at finding highly selective ligands for
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Table 3. Selected results for the Rh-catalyzed asymmetric transfer hydrogenation reaction of ketones S1–S15 using thioamide
ligands L4–L6a–h.[a]
Entry Substrate
Ligand % Conv.
%
Entry Substrate
Ligand % Conv.
%
A
ACHTUNGTRENNUNG
1
2
L4a
L4g
88 (81)
76 (70)
99 (R)
97 (S)
17
18
L4a
L4g
99 (94)
96 (92)
99 (R)
99 (S)
3
4
L4a
L4g
64 (59)
61 (54)
98 (R)
97 (S)
19
20
L4a
L4g
40 (35)
34 (31)
56 (S)
55 (R)
5
6
L4a
L4g
87 (82)
72 (67)
98 (R)
98 (S)
21
22
L4a
L4g
82 (78)
77 (71)
97 (R)
96 (S)
7
8
L4a
L4g
92 (87)
84 (78)
99 (R)
99 (S)
23
24
L4a
L4g
64 (57)
68 (59)
91 (R)
90 (S)
9
10
L4a
L4g
99 (93)
97 (92)
96 (R)
95 (S)
25[c]
26[c]
L4e
L4g
18 (14)
15 (12)
79 (R)
70 (S)
11
12
L4a
L4g
74 (67)
68 (63)
99 (R)
98 (S)
27
28
L4a
L4g
81 (74)
79 (71)
89 (S)
88 (R)
13
14
L4a
L4g
92 (84)
87 (81)
98 (R)
98 (S)
29
30
L4a
L4g
92 (81)
93 (82)
87 (S)
87 (R)
15
16
L4a
L4g
98 (94)
92 (87)
99 (R)
98 (S)
[a]
Reaction conditions: ketone (1 equiv., 0.2M in 2-propanol/THF: 1/1), [RhCl2Cp*]2 (0.25 mol%), ligand (0.55 mol%),
NaO-i-Pr (5 mol%), LiCl (10 mol%), at room temperature, 3 h.
[b]
[c]
Conversion and enantiomeric excess were determined by GC (CP Chirasil DEX CB). Isolated yields are shown in paren-
thesis.
1
Conversion determined by H NMR and enantiomeric excess determined by HPLC (Chiralcel OD-H).
almost every substrate and identifying four general li- strates: the heteroaromatic ketones. The preparation
gands L4 and L5a, g with good performance over the of chiral heteroaromatic alcohols is of great impor-
entire range of substrates (ees up to 99%). The results tance for the pharmaceutical and agrochemical indus-
obtained so far are among the best reported and, tries because they are found in many biologically
more importantly, they overcome one of the limita- active compounds. The ATH can be a more efficient
tions encountered with the use of previously success- approach for preparing these compounds. Unfortu-
ful furanoside-based thioamide and hydroxyamide nately, due to the coordination ability of the hetero-
ligand libraries, which were unable to reduce aryl/flu-
ACHTUNGTRENaNGNU romatic moiety, the ATH of heteroaryl alkyl ketones
oroalkyl ketones in high enantiomeric excesses.[21]
is extremely difficult. Coordination to the metal cata-
lysts has to be avoided if activities and enantioselec-
tivities are to be high. There are therefore very few
catalytic systems that can reduce heteroaromatic ke-
tones under transfer hydrogenation conditions in high
enantioselectivities.[22] Table 4 shows the most notable
Asymmetric Transfer Hydrogenation of Heteroaryl
Alkyl Ketones
Encouraged by the excellent results obtained up to results in the reduction of a wide range of heteroaro-
this point, we decided to go one step further and eval- matic substrates S16–S22 using thioamide ligands L4–
uate the new ligand library in the asymmetric transfer L6a–h (for a full set of results see the Supporting In-
hydrogenation of a more challenging class of sub- formation). The results indicated again that the sense
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Modular Hydroxyamide and Thioamide Pyranoside-Based Ligand Library
Table 4. Selected results for the Rh-catalyzed asymmetric
transfer hydrogenation reaction of several heteroaromatic
ketones using thioamide ligands L4–L6a–h.[a]
of enantioselectivity is dictated by the configuration
at the thioamide moiety. Both enantiomers of the het-
eroaromatic alcohol products can therefore be ob-
tained by simply changing the configuration at the
Entry
Substrate
Ligand
% Conv.
AHCTUNGTRENNUNG
(% Yield)[b]
%
ee[c]
thioACTHNUTRGENUaGN mide group (i.e., Table 4, entry 1 vs. 3). Howev-
er, the effect of the ligand parameters on the catalytic
performance depends on the substrate type. Never-
theless, we were again able to fine tune the ligand pa-
rameters to obtain high-to-excellent enantioselectivi-
ties for each heteroaromatic substrate.
1
2
3
4
5
L4a
L4e
L4g
L5a
L6a
100 (92)[e]
100 (94)
100 (93)
79 (71)
>99 (R)[d]
93 (R)[d]
98 (S)[d]
98 (R)[d]
51 (R)[d]
21 (15)
For pyridine-based substrates, we found that the re-
duction of 4-acetylpyridine S16 (Table 4, entries 1–5)
follows the same trend as for aryl/alkyl ketones S1–
S12. Thus, full conversions and excellent enantioselec-
tivities (in the best cases, ees of >99% were achieved)
were obtained with ligand L4a, g (Table 4, entries 1
and 3). On the other hand, the ATH of 3-acetylpyri-
dine S17 and 3-propionylpyridine S18 behaves slightly
differently regarding the ligand backbone (Table 4,
entries 6–14). Excellent enantioselectivities are there-
fore achieved using ligands L4–L6a, g regardless of
the ligand backbone (ees up to 99%; Table 4, en-
tries 6, 9, 10, 11, 13 and 14). As observed for aceto-
phenone, the use of the more sterically demanding
pyranoside ligand backbone L6 led to low activity.
The results achieved in the reduction of 2-acetylpyri-
dine S19 indicated that the thioamide substituent had
a different effect on enantioselectivity than S16–S18.
Enantioselectivity was therefore best with ligand L4e,
with a methyl thioamide substituent (ees up to 86%;
Table 4, entry 17). Similarly, the effect on enantiose-
lectivity of the thioamide substituent is also different
in the reduction of 2-acetylfuran S20. Enantioselectiv-
ity was therefore best using ligand L4c, containing
a phenyl thioamide substituent (entry 22). Finally, for
acetylthiophenes S21 and S22, enantioselectivities
were excellent with ligands L6 regardless of the
nature of the thioamide substituent (Table 4, en-
tries 27–29 and 32–34). These excellent results again
showed that the presence of a pyranoside backbone
in the ligand design of these thioamide ligands is
highly advantageous. Our new Rh/pyranoside-based
thioamide systems can therefore expand the scope to
a broad range of heteroaromatic ketones. Again, the
modular ligand design has been shown to be crucial
in finding highly selective catalytic systems for each
substrate.
6
7
8
9
L4a
L4e
L4g
L5a
L6a
100 (91)
100 (91)
100 (90)
86 (74)
41 (36)
99 (S)
94 (S)
97 (R)
98 (S)
99 (S)
10
11
12
13
14
L4a
L4g
L5a
L6a
99 (90)
100 (93)
96 (89)
73 (62)
99 (S)
98 (R)
97 (S)
98 (S)
15
16
17
18
19
20
L4a
L4d
L4e
L4g
L5e
L6e
100 (90)
97 (91)
86 (80)
100 (92)
100 (93)
92 (84)
28 (S)
46 (S)
86 (S)
29 (R)
84 (S)
34 (S)
21
22
23
24
L4a
L4c
L5a
L6a
90 (81)
100 (93)
93 (85)
36 (21)
42 (R)
88 (R)
21 (R)
54 (R)
25
26
27
28
29
L4a
L5a
L6a
L6e
L6h
89 (81)
74 (64)
84 (76)
64 (59)
80 (72)
94 (R)
86 (R)
>99 (R)
>99 (R)
97 (S)
30
31
32
33
34
L4a
L5a
L6a
L6e
L6h
98 (93)
86 (81)
49 (42)
30 (17)
43 (39)
93 (S)
84 (S)
>99 (S)
>99 (S)
95 (R)
[a]
Reaction conditions: ketone (1 equiv., 0.2M in 2-propa-
nol/THF: 1/1), [RhCl2Cp*]2 (1 mol%), ligand
(2.2 mol%), NaO-i-Pr (10 mol%), LiCl (10 mol%), at
room temperature, 3 h.
[b]
Conversion measured by 1H NMR. Isolated yields are
shown in parenthesis.
[c]
[d]
[e]
Enantiomeric excess was determined by chiral HPLC.
Enantiomeric excess was determined by chiral GC.
This reaction was also carried out at a 0.1 mol scale, af-
fording the reduced product in almost enantiopure form
(99% ee) in 98% yield.
Conclusions
A large library of pyranoside-based hydroxyamide
and thioamide ligands L1–L6a–h has been synthesized
for ATH in an attempt to expand the scope of the
substrates to cover a broader range of challenging
heteroaromatic and aryl/fluoroalkyl ketones. These li-
gands have the advantage that they are prepared
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Mercꢀ Coll et al.
tion of the desired amino alcohol (2 mmol, 379.4 mg), previ-
ously azeotropically dried with toluene, in THF (4 mL) was
added and the resulting mixture was stirred at room temper-
ature for 2 h. The crude mixture was purified by flash chro-
matography to produce the corresponding ligands as white
solids.
from commercial d-glucose, d-glucosamine and a-
amino acids, inexpensive natural chiral feedstocks.
Moreover, the modular nature of the ligand library
enables the substituents/configurations at the amide/
thioamide moiety, the position of amide/thioamide
group and the configuration at C-2 of the pyranoside
backbone to be easily and systematically varied, so
that activities and enantioselectivities can be maxi-
mized for each substrate as required. By carefully se-
lecting the ligand components, we found that pyrano-
side-based thioamide ligands provided excellent enan-
tioselectivities (in the best cases, ees of >99% were
achieved) in a broad range of ketones, including the
less studied heteroaromatics and challenging aryl/flu-
oroalkyls. Note that both enantiomers of the reduc-
tion products can be obtained with excellent enantio-
selectivities by simply changing the absolute configu-
ration of the thioamide substituent. In addition, the
efficiency of this ligand design is also corroborated by
the fact that these Rh-pyranoside-based thioamide
catalysts provided higher activity and enantioselectivi-
ty and a broader substrate scope than their furano-
side-based thioamide analogues. The results of our
pyranoside-based thioamide catalyst library compare
very well with the ones achieved using the furanoside-
based thioamide and hydroxyamide ligands which
have recently emerged as some of the most successful
catalysts developed for this process, with the added
advantage that our Rh/pyranoside-thioamide systems
are able to expand the scope to a broad range of het-
eroaromatic substrates and to the successful reduction
of aryl/fluoroalkyl ketones. These findings represent
an improvement on the previously reported furano-
side-derived hydroxyamide and thioamide ligands and
open up a new type of ligand for the highly enantiose-
lective reduction of industrially relevant heteroaro-
matic and aryl/fluoroalkyl ketones.
Typical Procedure for the Benzoylation of L1–L3a–h
A solution of benzoyl chloride (1.1 mmol, 130 mL) in di-
chloromethane (0.4 mL) was slowly added to a cooled solu-
tion (08C) of the desired pseudo-dipeptide (1 mmol) in pyri-
dine (1 mL). The reaction mixture was stirred overnight.
Then ice was added and the product was extracted with di-
chloromethane (3ꢆ20 mL), dried over MgSO4, evaporated
to dryness and purified by flash chromatography (pentane/
ethyl acetate: 2/1) to produce the corresponding benzoylat-
ed product as white solids.
Typical Procedure for the Preparation of Thioamide
Ligands L4–L6a–h
To a cooled solution of the desired benzoylated product
(0.5 mmol) in THF (2 mL) Lawessonꢄs reagent (0.4 mmol,
158 mg) was added. The reaction mixture was stirred over-
night at 608C. Then, the reaction mixture was evaporated
and chromatographed (pentane/ethyl acetate: 3/1) to pro-
duce the corresponding thioamides as white solids.
Typical Procedure for the ATH of Ketones
The desired ligand (0.0055 mmol), the catalyst precursor
ACHUNTGRENUN{G [RuCl2ACHTUNGTRENN(UGN p-cymene)]2 or [RhCl2Cp*]2; 0.0025 mmol)}, and
LiCl (4.2 mg, 0.1 mmol) were treated under vacuum for
10 min. Under argon, substrate (1 mmol), propan-2-ol
(2 mL) and THF (2.5 mmol) were sequentially added. The
reaction was initiated by adding i-PrONa (0.1M, 0.5 mL,
0.05 mmol) to the solution. After completion of the reaction
the reaction mixture was evaporated and the product was
purified by column chromatography (SiO2). For substrates
S1–S12,[9b,d,k] S14 and S15,[14] the alcohol products were ana-
lyzed by GC (CP Chirasil DEX CB). For substrate S16, the
alcohol products were analyzed by GC (Chiraldex b-
DM).[6d] For substrates S13[23] and S19,[6d] conversions were
measured by 1H NMR and enantioselectivity by HPLC
(Chiralcel OD-H). For substrates S17, S18 and S20–S22,
conversions were measured by 1H NMR and enantioselectiv-
ity by HPLC (Chiralcel OJ-H).[6d]
Experimental Section
General Considerations
All reactions were carried out using standard Schlenk tech-
niques under an atmosphere of argon. Solvents were puri-
fied and dried by standard procedures. Compound 2 was
prepared as previously described.[15] 1H and 13C{1H} NMR
Acknowledgements
spectra were recorded using
a 400 MHz spectrometer.
Chemical shifts were relative to SiMe4 as internal standard.
1H and 13C assignments were made on the basis of H-1H
1
We would like to thank Spanish Government for providing
grant CTQ2010-15835, the Catalan Government for grant
2009SGR116, and the ICREA Foundation for providing M.
Diꢀguez and O. Pꢁmies with financial support through the
ICREA Academia awards.
gCOSY and 1H-13C gHSQC experiments.
Typical Procedure for the Preparation of Hydroxy-
amide Ligands L1–L3a–h
To a cooled solution (À158C) of the desired N-Boc-protect-
ed amino acid (2 mmol) in THF (4 mL), N-methylmorpho-
line (NMM, 2.3 mmol, 252 mL) and isobutyl chloroformate
(2.3 mmol, 300 mL) were slowly added. After 45 min, a solu-
2300
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[Rh
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led to very low catalytic activity (<5%).
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