Carbohydrate-based pseudo-dipeptides: New ligands for the highly enantioselective Ru-catalyzed transfer hydrogenation reaction

Article abstract of DOI:10.1039/c1cc15024c

Ruthenium-complexes of novel carbohydrate based pseudo-dipeptide ligands effectively and selectively catalyze the reduction of a broad range of aryl-alkyl ketones under ATH conditions. Excellent enantioselectivities (>99% ee) are obtained using aminosugars as the sole source of chirality. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc15024c

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COMMUNICATION
Carbohydrate-based pseudo-dipeptides: new ligands for the highly
enantioselective Ru-catalyzed transfer hydrogenation reactionw
a
a
b
a
´
Mercedes Coll, Oscar Pamies, Hans Adolfsson* and Montserrat Dieguez*
Received 12th August 2011, Accepted 20th September 2011
DOI: 10.1039/c1cc15024c
Ruthenium-complexes of novel carbohydrate based pseudo-
dipeptide ligands effectively and selectively catalyze the reduction
of a broad range of aryl–alkyl ketones under ATH conditions.
Excellent enantioselectivities (499% ee) are obtained using
aminosugars as the sole source of chirality.
difference between previously described successful catalysts and
these pseudo-dipeptide counterparts is the lack of a basic NH
group in the latter’s ligand structure. The main features of ligands
1 are that: (i) the presence of a chiral a-amino acid is crucial if
significant levels of enantioselectivity are to be achieved. How-
ever, the enantioselectivity value is dictated by the combination
of substituents/configurations in both the amino acid and the
amino alcohol parts;9 and (ii) the sense of enantioselectivity is
controlled by the configuration in the amino acid part. Catalysts
based on L-amino acids, then, predominantly gave S configu-
ration products while the use of ligands based on D-amino
acids resulted in the formation of the R alcohols as the major
enantiomer.9 Despite all these important contributions, there
is still a lack of a catalyst able to provide the desired secondary
alcohols in enantiopure form (499% ee) for a broad range of
substrates as the enzymes do. The most successful catalysts
developed to date afford the desired alcohols in a range of
95–99% ee.2 Therefore, the development of extremely enantio-
selective ATH catalysts containing ligands based on simple
starting materials and that have high modularity still need to
be further explored.
The value of enantiopure secondary alcohols lies mainly in their
use as important building blocks for the synthesis of natural,
pharmaceutical and agricultural products.1 The enantioselective
reduction of prochiral ketones has emerged as an efficient and
direct synthetic tool for preparing these compounds. In this
context, asymmetric metal-catalyzed transfer hydrogenation
(ATH) is an alternative method that is operationally simpler
and significantly safer than direct hydrogenation with molecular
hydrogen.2 The most commonly used catalysts in transfer hydro-
genations are based on transition metal catalysts (i.e. ruthenium,
rhodium, or iridium complexes) modified with monosulfonated
diamines,3,4 b-amino alcohols,5 or 2-(aminomethyl)pyridines6 as
chiral ligands.7 Recently, iron-based catalysts have also shown
useful activity and selectivity.8
Adolfsson et al. have reported the use of a new type of
ligand 1—pseudo-dipeptides—(Fig. 1) for the enantioselective
transfer hydrogenation of a broad range of aryl–alkyl ketones.9
These ligands are based on the combination of different N-Boc-
protected a-amino acids and b-amino alcohols. The fundamental
One of the simplest ways to synthesize chiral ligands is
to rely on nature to provide appropriate chiral synthons. For
this purpose, carbohydrates are particularly useful because
they are cheap, they have several stereogenic centers and their
modular constructions are easy. In this respect, carbohydrates
have become an important natural source for preparing chiral
ligand libraries, which have been successfully applied in several
metal-catalyzed asymmetric transformations.10,11 Despite this
success, carbohydrate-based ligands have hardly been used for
this transformation and in all the examples low-to-moderate
enantioselectivities (o78% ee) have been reported.12
In this communication, we describe a new class of pseudo-
dipeptide ligands, derived from carbohydrates, for the highly
enantioselective Ru-catalyzed transfer hydrogenation of a broad
range of substrates (Fig. 2). The main benefit of incorporating
the sugar core is that excellent enantioselectivities (typically
499% ee) can be obtained using the sugar amino alcohol part
as a sole source of chirality. This feature allows for the use
of non-enantiopure a-amino acid derivatives (even achiral or
racemic ones).
Fig. 1 General structure of pseudo-dipeptide ligands 1.
a
´
Departament de Quımica Fısica i Inorganica, Universitat Rovira i
Virgili, Campus Sescelades, C/Marcellı Domingo, s/n,
´
`
´
43007 Tarragona, Spain. E-mail: montserrat.dieguez@urv.cat;
Fax: +34-977559563; Tel: +34-977558780
b Department of Organic Chemistry, Stockholm University,
SE-10691 Stockholm, Sweden. E-mail: hansa@organ.su.se;
Fax: +46-815498; Tel: +46-8162484
w Electronic supplementary information (ESI) available: (i) Experi-
mental procedures and characterization of new ligands L1–L10 and
sugar intermediates 2–4; and (ii) ATH results using ligands L2 and L7.
See DOI: 10.1039/c1cc15024c
The synthesis of the carbohydrate-based pseudo-dipeptide
ligands L1–L10 is straightforward (Scheme 1). They were effici-
ently prepared by coupling a series of N-Boc protected amino
c
12188 Chem. Commun., 2011, 47, 12188–12190
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Table 1 Ru-catalyzed asymmetric transfer hydrogenation reaction of
S1 using ligands L1–L10a
Entry
Ligand
mol% Ru
T/1C
% Convb/h
% eeb
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L6
L7
L1 + L6
L8
L9
L10
L1
0.25
0.25
0.25
0.25
0.25
0.25
1
0.25
0.25
0.25
0.25
0.25
0.25
0.25
1
25
25
25
25
25
25
25
25
25
25
25
25
50
25
25
80 (3)
80 (3)
81 (3)
49 (3)
42 (3)
1 (3)
499 (S)
499 (S)
499 (S)
499 (S)
499 (S)
n.d.
6 (R)
99 (S)
99 (S)
499 (S)
499 (S)
99 (S)
499 (S)
98.7 (S)
4 (R)
6 (3)
56 (3)
48 (3)
78 (3)
79 (3)
51 (3)
98 (0.5)
21 (3)
2 (3)
9
10
11
12
13
14c
15c
Fig. 2 Carbohydrate-based pseudo-dipeptide ligands L1–L10.
L1
L6
a
Reaction conditions: S1 (1 equiv., 0.2 M in 2-propanol/THF (1 : 1),
[RuCl2(p-cymene)]2 (0.25 mol% in Ru), ligand (0.55 mol%), NaOiPr
b
(5 mol%), LiCl (10 mol%) and at room temperature. Conversion
c
and enantiomeric excess was determined by GC. No LiCl added.
the enantioselectivity is dictated by the sugar amino alcohol
part. The results contrast with the ‘‘cooperative’’ effect between
the substituents/configurations at both the aminoalcohol and
the a-amino acid moieties previously observed for other success-
ful pseudo-dipeptide ligands.9 On the other hand, the configu-
ration of the amino acid has an impact on the conversion,
therefore, it has to be matched to the configuration of the
carbohydrate part for constructing efficient ligands.
Scheme 1 Synthesis of ligands L1–L10. (i) iBuOCOCl/NMM/THF/-
15 1C.
acids with the corresponding sugar amino-alcohols 2–4 by using
isobutyl chloroformate in the presence of N-methylmorpholine
(Scheme 1).9b,c Sugar amino-alcohols 2–4 are readily prepared
on a large scale from inexpensive D-glucose (see ESIw for
experimental details).
The use of ligand L8, with opposite configuration at C-3 of
the furanoside backbone in comparison to L1, has no effect on
activity and enantioselectivity (Table 1, entry 1 vs. 10). This
result encouraged us to study whether high ee’s can also be
achieved using 3-benzyl aminoalcohol 4 derived ligands (L9
and L10), which are synthesized in fewer steps than corres-
ponding ligands derived from aminoalcohols 2 and 3. We were
pleased to find out that again excellent enantioselectivities were
obtained using ligands L9 and L10 (Table 1, entries 11 and 12).
We also performed the reaction at a higher temperature
(50 1C) using ligand L1 (entry 13). Activity increased con-
siderably (up to 98% conversion in 30 minutes), and the
excellent enantioselectivity was maintained (499% ee (S)).
Finally, we evaluated the efficiency of these catalysts with-
out the addition of LiCl (entries 14 and 15). The results are
in line with the decrease in activity and enantioselectivity
previously observed using pseudo-dipeptides 1, which suggest
a similar coordination mode, and mechanism for the ATH-
reaction.9f The reason for the change in enantiocontrol is most
likely due to interactions between the ligand and the p-cymene
when the Ru-hydride complex is formed.
To initially evaluate these new ligands (L1–L10), we chose
the Ru-catalyzed ATH of acetophenone S1. As this reaction
was carried out with a wide variety of ligands bearing different
donor groups, we were able to compare the efficacy of the
various ligand systems. The results are summarized in Table 1.
We first investigated the effect of the a-amino acid substi-
tuents on the catalytic performance with ligands L1–L5. We
found that enantioselectivities were excellent (499% ee) in all
cases (Table 1, entries 1–5). The results indicate that varying
the a-amino acid substituent does not affect enantioselectivity.
However, our results also indicate that activity is affected by
these a-amino acid substituents. The highest activities were
obtained with catalysts based on ligands L1–L3.
Interestingly, changing the configuration of the a-amino
acid from S (ligand L1) to R (ligand L6) inhibits the catalytic
activity almost completely (Table 1, entries 1 vs. 6 and 7). This
result prompted us to study whether high levels of enantio-
selectivity can be maintained by introducing an achiral or
racemic a-amino acid moiety into the ligand design. For this
purpose we evaluated ligand L7, derived from glycine, and a
1 : 1 mixture of L1 and L6 ligands (Table 1, entries 8 and 9),
respectively. In both cases enantioselectivities were excellent
(99% ee). This is unprecedented behavior which confirms that
Encouraged by the excellent results obtained up to this
point, and in order to study the potential of these readily
available ligands further, we evaluated them in the ATH of
other ketones (S2–S11). The results are summarized in Fig. 3.
We found that the combination of [RuCl2(p-cymene)]2 and L1
c
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(2009SGR116) Governments, and the ICREA Foundation for
financial support.
Notes and references
1 Modern Reduction Methods, ed. P. G. Andersson and I. J. Munslow,
Wiley-VCH, Weinheim, 2008.
2 See for example: (a) C. Wang, X. Wu and J. Xiao, Chem.–Asian J.,
2008, 3, 1750; (b) S. Gladiali and E. Alberico, Chem. Soc. Rev.,
2006, 35, 226; (c) K. Everaere, A. Mortreux and J.-F. Carpentier,
Adv. Synth. Catal., 2003, 345, 67; (d) T. Ohkuma and R. Noyori, in
Comprehensive Asymmetric Catalysis I–III, ed. E. N. Jacobsen,
A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, vol. 1, p. 199;
(e) M. J. Palmer and M. Wills, Tetrahedron: Asymmetry, 1999,
10, 2045.
3 S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya and R. Noyori,
J. Am. Chem. Soc., 1995, 117, 7562.
Fig. 3 Selected asymmetric transfer hydrogenation results. Reaction
conditions: 0.25 mol% [RuCl2(p-cymene)]2, 0.55 mol% L1, 1 mmol
substrate, 3 h at room temperature. a1 mol% of [RuCl2(p-cymene)]2, 24 h.
4 Selected recent examples: (a) F. K. Cheung, C. Lin, F. Minissi,
A. L. Criville, M. A. Graham, D. J. Fox and M. Wills, Org. Lett.,
2007, 9, 4659; (b) N. A. Cortez, G. Aguirre, M. Parra-Hake and
R. Somanathan, Tetrahedron Lett., 2007, 48, 4335; (c) J. Canivet
and G. Suss-Fink, Green Chem., 2007, 9, 391; (d) L. Li, J. Wu,
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Chem., 2007, 9, 23; (e) D. S. Matharu, D. J. Morris, G. J. Clarkson
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or L9, respectively, efficiently catalyze the ATH of several
other aryl–alkyl ketones. The results show that the catalytic
performance (activity and enantioselectivity) is not affected
by the steric and electronic properties of the aryl group, except
for substrates S5, S9 and S12, which required higher catalyst
loadings (1 mol% of [RuCl2(p-cymene)]2) to achieve good
conversions. This behavior contrasts with the electronic and
steric effect on enantioselectivity observed for previous pseudo-
dipeptide ligands.9 Furthermore, enantioselectivities were
excellent (499%) in all cases, surpassing the enantioselectivities
obtained with previous successful pseudo-dipeptide ligands.9 The
carbohydrate-functionalized pseudo-dipeptides represent a power-
ful ligand library that provides the highest levels of enantio-
selectivity (499%) for a wide range of aryl–alkyl ketones.
In summary, we have successfully designed and evaluated a
new pseudo-dipeptide ligand library in the Ru-catalyzed ATH
of several ketones. The ligand library is based on the combi-
nation of various N-Boc-protected a-amino acids and a sugar
amino alcohol unit. Interestingly, we have demonstrated that
the introduction of a furanoside aminosugar moiety into the
ligand design is highly advantageous and it efficiently transfers
the chiral information to the products (ee’s ranging from 98%
to 499% in the reduction of a range of ketones). In contrast
to previous successful pseudo-dipeptides, the enantioselectivity
is exclusively controlled by the sugar moiety which enables the
use of inexpensive achiral or racemic a-amino acid derivatives.
Moreover, catalysts formed with the carbohydrate-based pseudo-
dipeptides showed a higher degree of substrate versatility than
the corresponding pseudo-dipeptide analogues 1. These novel
carbohydrate pseudo-dipeptide compounds constitute there-
fore an exceptional ligand system that favorably competes
in terms of enantioselectivity with other successful catalytic
systems including enzymatic kinetic resolution (KR) and
dynamic kinetic resolution (DKR).2,13 Because of the modular
construction of these carbohydrate-based ligands, structural
diversity is easy to achieve, so activities and enantioselectivities
can be maximized for other substrates as required. Further
studies of this kind, as well as mechanistic studies, are currently
underway.
6 W. Baratta, M. Bosco, G. Chelucci, A. Del Zotto, K. Siega,
M. Toniutti, E. Zangrando and P. Rigo, Organometallics, 2006,
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7 For a recent example of a phosphine-based catalyst, see; M. T. Reetz
and X. Li, J. Am. Chem. Soc., 2006, 128, 1044.
8 (a) C. P. Casey and H. Guan, J. Am. Chem. Soc., 2007, 129, 5816;
(b) S. Zhou, S. Fleischer, K. Junge, S. Das, D. Addis and M. Beller,
Angew. Chem., Int. Ed., 2010, 49, 8121; (c) A. Naik, T. Maji and
O. Reiser, Chem. Commun., 2010, 46, 4475; (d) A. Mikhailine,
A. L. Lough and R. H. Morris, J. Am. Chem. Soc., 2009, 131, 1394.
9 (a) I. M. Pastor, P. Vastila and H. Adolfsson, Chem. Commun.,
2002, 2046; (b) I. M. Pastor, P. Vastila and H. Adolfsson,
Chem.–Eur. J., 2003, 9, 4031; (c) A. Bøgevig, I. M. Pastor and
H. Adolfsson, Chem.–Eur. J., 2004, 10, 294; (d) P. Vastila,
J. Wettergren and H. Adolfsson, Chem. Commun., 2005, 4039;
(e) P. Vastila, A. B. Zaitsev, J. Wettergren, T. Privalov and
H. Adolfsson, Chem.–Eur. J., 2006, 12, 3218; (f) J. Wettergren,
E. Buitrago, P. Ryberg and H. Adolfsson, Chem.–Eur. J., 2009,
15, 5709.
10 For recent reviews, see: (a) M. Dieguez, O. Pamies and C. Claver,
Chem. Rev., 2004, 104, 3189; (b) M. M. K. Boysen, Chem.–Eur. J.,
2007, 13, 8648; (c) V. Benessere, R. Del Litto, A. De Roma and
F. Ruffo, Coord. Chem. Rev., 2010, 254, 390; (d) S. Woodward,
M. Dieguez and O. Pamies, Coord. Chem. Rev., 2010, 254, 2007.
11 One of the limitations of using sugars as precursors for ligands
is that often only one of the enantiomers is readily available.
However, this limitation can be overcome by the rational design
of pseudo-enantiomeric ligands. See ref. 10d.
12 (a) S. Guillarme, T. X. Mai Nguyen and C. Saluzzo, Tetrahedron:
Asymmetry, 2008, 19, 1450; (b) K.-D. Huynh, H. Ibrahim,
M. Toffano and G. Vo-Thanh, Tetrahedron: Asymmetry, 2010,
21, 1542.
13 See for example: B. Martin-Matute and J.-E. Backvall, Curr. Opin.
Chem. Biol., 2007, 11, 226.
We thank the Swedish Research Council and The Carl
Trygger Foundation, the Spanish (CTQ2010-15835) and Catalan
c
12190 Chem. Commun., 2011, 47, 12188–12190
This journal is The Royal Society of Chemistry 2011