Pyroglutamate-derived hydroxyamide ligands: Synthesis and application to asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2010.04.055

The synthesis of a series of chiral hydroxy amide ligands is described. These ligands were used in a ruthenium-catalysed transfer hydrogenation reaction where one ligand gave the product in 72% ee. The ligands were also used in two titanium-catalysed reac

Full text of DOI:10.1016/j.tetasy.2010.04.055

Tetrahedron: Asymmetry 21 (2010) 867–870
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Pyroglutamate-derived hydroxyamide ligands: synthesis and application
to asymmetric catalysis
*
Paul Geoghegan, Patrick O’Leary
˙
National University of Ireland, Galway, School of Chemistry, Synthetic Methods: Asymmetric Catalytic Transformations (SMACT), Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a series of chiral hydroxy amide ligands is described. These ligands were used in a
ruthenium-catalysed transfer hydrogenation reaction where one ligand gave the product in 72% ee.
The ligands were also used in two titanium-catalysed reactions, an alkylation where ee’s of up to 74%
were achieved and a phenyl acetylene addition where more modest selectivities were observed.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 April 2010
Accepted 28 April 2010
Available online 1 June 2010
1. Introduction
cyclo[4.4.0]dec-5-ene (TBD)18 to give the target ligands directly in
reasonable yield.
Chiral b-hydroxyamides are commonly prepared as intermedi-
ates in the synthesis of, amongst others, oxazoline or bis-oxazoline
ligands.1–3 They may be synthesised in a relatively facile manner
from an amino alcohol and a carboxylic acid derivative. Despite
the large number that have been reported and their synthetic
availability, their utilisation as ligands in their own right is under-
explored.
A relatively small number of individual reports have appeared
in the literature indicating that ligands of this type form the basis
of selective catalysts in borane reductions,4,5 transfer hydrogena-
tions,6 alkylation7 and alkynylation8,9 of carbonyl compounds, ally-
lation10 and Michael addition reactions.11 The ligands have been
used in complexes with titanium,12,8,9 chromium10 and ruthe-
nium.6 They have also been used as organocatalysts in reactions
such as the kinetic resolution of alcohols via selective esterifica-
tion13,14 and the reduction of imines with silanes.15
2.2. Ruthenium-catalysed hydrogenation
We initially applied these ligands to the ruthenium-catalysed
transfer hydrogenation reduction of a ketone to a secondary alco-
hol. Enantioselective reductions of this type which employ very
mild conditions are widely used from small to large scale synthe-
sis. We thought our ligands may be particularly suited to this reac-
tion because Adolfsson had found that his ‘pseudo’ dipeptide
ligands (Fig. 1) needed to have their N terminus protected by a
Boc group for the reaction to be successful.19,6 In our case the
amide of the pyroglutamate would not need to be protected.
The transfer hydrogenation reactions did indeed work, giving
the reduced product, albeit, in modest yield (Table 1). The enanti-
oselectivity of the reaction was found to be very dependent on the
nature of the substituent on the ligand. The phenyl and benzyl
substituted ligands 1 and 3 giving enantioselectivities of 50% and
72%, respectively, which, in the context of this reaction, represents
a significant starting point for further ligand development.20
We have an ongoing interest in the use of amide-based ligands
in asymmetric catalysis and the amide functionality is the key to
our UNIFIDE and CROSIDE ligands.16 We have in the past and again
herein used the cyclic amide
L-pyroglutamic acid as a readily avail-
able source of chirality.17
2.3. Alkylation of benzaldehyde
We next used the ligands in the titanium-catalysed alkylation of
benzaldehyde with diethylzinc. This reaction is a typical catalytic
asymmetric benchmark reaction that has been has been carried
out in an enantioselective manner using many different ligands.21
Titanium-based catalyst systems have been found to be both effi-
cient and selective.
The alkylation reaction was again conducted using all four li-
gands (Table 2). In all cases conversion was high but we only
achieved a significant enantioselectivity in the case of ligand 1
where an ee of 74% was achieved. Hydroxyamides have been used
as ligands in this reaction in the past. In that case a wide variety of
bishydroxyamides were used and the highest enantioselectivity
2. Results and discussion
2.1. Synthesis of ligands
We have synthesised four new hydroxyamide ligands from the
methyl ester of pyroglutamic acid and four different amino alco-
hols (Scheme 1). The reaction was conducted using 1,5,7-triazabi-
* Corresponding author. Tel.: +353 (0)91 492476; fax: +353 (0)91 525700.
E-mail address: patrick.oleary@nuigalway.ie (P. O’Leary).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.055

868
P. Geoghegan, P. O’Leary / Tetrahedron: Asymmetry 21 (2010) 867–870
Ph
O
Ph
H2N
N
H
OH
OH
NH
O
TBD
O
70%
1
OMe
NH
O
TBD
OH
O
R
R
N
H
OH
NH
H2N
O
R = iPr 2
CH2Ph 3 67%
iBu 4
78%
74%
Scheme 1. Synthesis of the ligands 1–4 used in this study.
3. Conclusions
O
R'
R
N
H
We have succeeded in generating new ligands in a facile man-
ner from the readily available -pyroglutamic acid and a variety
OH
HN
Boc
L
of amino alcohols. These hydroxyamide ligands were successfully
used to induce enantioselectivity in three asymmetric transforma-
tions. Though the selectivities achieved were good, at 74% ee, there
is still quite some scope for improvement. We are currently inves-
tigating other applications of these ligands. In addition by estab-
lishing the structure–activity relationships in the transformations
we have studied to date we hope to deduce the nature of the active
species.
Figure 1. Boc-protected ligands reported by Adolfsson.
achieved was 58%.7 These bishydroxyamides were found to give
better selectivities with other aldehydes particularly aliphatic
aldehydes and we are currently exploring our ligands’ behaviour
with a wide variety of starting materials. It is interesting to note
that the most selective catalyst is that derived from the (R)-amino
alcohol and the (S)-pyroglutamic acid. We are continuing to inves-
tigate if ligands with this stereochemistry are generally more
selective in this reaction.
4. Experimental
4.1. General information
All reactions were conducted under a nitrogen atmosphere.
Methyl (2S)-5-oxopyrrolidine-2-carboxylate16 and the amino alco-
hols22 were synthesised using literature procedures. All other
chemicals were purchased from Aldrich Chemical Company and
generally used without further purification. Any necessary reagent
purification, along with the drying and distillation of solvents, was
carried out according to literature procedures.23 Melting points
were measured on a Stuart Scientific SMP3 apparatus. IR spectra
were measured on a Perkin–Elmer Spectrum 1000 FT-IR, or a Per-
kin–Elmer Spectrum One FT-IR. Optical rotations were measured
2.4. Alkynylation of benzaldehyde
The final reaction we report here is the alkynylation reaction of
benzaldehyde using phenylacetylene as reported by Hui et al.
(Table 3).8,9
In this reaction the activity was again quite good with high
yields being obtained. The enantioselectivity achieved in this reac-
tion was quite poor regardless of the ligand used. The benzyl-
substituted ligand gave the highest selectivity at 34% ee.
Table 1
Ruthenium-catalysed hydrogen transfer using hydroxyamide ligands 1–4
OH
OH
O
[{RuCl2(p-cymene)}2] (0.5 mol%)
+
Ligand (1.1 mol%)
NaOH (5 mol%)
2-propanol, RT, 24h
(S)
(R)
Entry
Ligand
% Conversion
% ee (R)
1
2
3
4
1 R = Ph
2 R = iPr
3 R = Bn
4 R = iBu
30
28
35
27
50
27
72
18

P. Geoghegan, P. O’Leary / Tetrahedron: Asymmetry 21 (2010) 867–870
869
Table 2
4.1.2. (2S)-N-[(1S)-1-(Hydroxymethyl)-2-methyl-propyl]-5-oxo-
pyrrolidine-2-carboxamide 2
Titanium-catalysed alkylation using hydroxyamide ligands 1–4
The reaction was conducted as for the synthesis of 1 men-
tioned above using methyl (2S)-5-oxopyrrolidine-2-carboxylate
(2.00 g, 14 mmol), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (0.49 g,
3.5 mmol) and (S)-valinol (1.52 g, 14.7 mmol). The product 2
(2.22 g, 74 %) was isolated as a white solid; mp 144.1–145.9 °C;
OH
OH
Ti(OiPr)4, DCM
O
+
RT,
Zn
(S)
(R)
½
a 2D0
ꢂ
¼ ꢃ14:1 (c 0.8, H2O) 1H NMR (DMSO-d6) 0.81 (d, J 6.8, 3H,),
Entry
Ligand
% Conversion
% ee (R)
0.85 (d, J 6.8, 3H), 1.75–1.94 (m, 2H), 2.01–2.21 (m, 3H), 3.29–3.41
(m, 2H) 3.51–3.60 (m, 1H,), 4.04 (dd, J 8.2, 3.9, 1H), 4.60 (br s, 1H),
7.59 (br d, J 8.9, 1H), 7.82 (br s, 1H); 13C NMR (DMSO-d6) 18.8, 20.2,
26.0, 28.7, 29.8, 56.3, 61.7, 62.9, 172.8, 178.0; IR (solid) 3396, 3323,
3215, 1680, 1640; m/z (ESI) 213 ([M]ꢃ, 100%), HRMS (ESꢃ): found
[MꢃH]ꢃ 213.1238, C10H17N2O3 requires 213.1239.
1
2
3
4
1 R = Ph
2 R = iPr
3 R = Bn
4 R = iBu
90
88
82
79
74
5
24
6
4.1.3. (2S)-N-[(1S)-1-Benzyl-2-hydroxy-ethyl]-5-oxo-
pyrrolidine-2-carboxamide 3
Table 3
Titanium-catalysed alkynylation using hydroxyamide ligands 1–4
The reaction was conducted as for the synthesis of 1 mentioned
above using methyl (2S)-5-oxopyrrolidine-2-carboxylate (1.43 g,
10 mmol), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (0.28 g,
2.1 mmol) and (S)-phenylalaninol (1.51 g, 10 mmol). The product
3 (1.76 g, 67%) was isolated as a white solid; mp 170.6–171.2 °C;
OH
O
Ti(OiPr)4, DCM
+
RT,
Zn
½
a 2D0
ꢂ
¼ ꢃ32:9 (c 1, MeOH); 1H NMR (DMSO-d6) 1.63–1.72 (m,
1H), 1.94–2.07 (m, 2H), 2.07–2.19 (m, 1H), 2.61 (dd, J 13.5, 8.3,
1H), 2.80 (dd, J 13.5, 5.7, 1H,), 3.27–3.39 (m, 2H), 3.83–3.92 (m,
2H), 4.77 (t, J 5.5, 1H), 7.13–7.27 (m, 5H), 7.72 (br s, 1H), 7.76 (br
s, 1H); 13C NMR (DMSO-d6) 25.5, 29.1, 36.4, 52.4, 55.7, 62.4,
125.9, 128.1, 129.1, 139.1, 172., 177.4; IR (solid) 3299, 3228,
1686, 1645; m/z (ESI) 261 ([M]ꢃ, 100%), HRMS (ESꢃ): found
[MꢃH]ꢃ 261.1240, C14H17N2O3 requires 261.1239.
Entry
Ligand
% Conversion
% ee (R)
1
2
3
4
1 R = Ph
2 R = iPr
3 R = Bn
4 R = iBu
88
79
89
78
11
20
34
16
4.1.4. (2S)-N-[(1S)-1-(Hydroxymethyl)-3-methyl-butyl]-5-oxo-
pyrrolidine-2-carboxamide 4
on a Schmidt + Haensch L1000 polarimeter at 589 nm (Na) in a
10 cm cell. Thin layer chromatography (TLC) was carried out on
precoated silica gel plates (Merck 60 F254); column chromatogra-
phy was conducted using Merck Silica Gel 60 or Apollo Scientific
The reaction was conducted as for the synthesis of 1 mentioned
above using methyl (2S)-5-oxopyrrolidine-2-carboxylate (1.66 g,
11.6 mmol), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.49 g, 3.5 mmol)
and (S)-leucinol (1.36 g, 11.6 mmol). The product 4 (2.07 g, 78 %)
Silica Gel 40–63 l. Elemental analysis was performed on a Per-
kin–Elmer 2400 analyser. 1H NMR (400 MHz) and 13C NMR
(100 MHz) were recorded on a JEOL ECX-400 NMR spectrometer.
All spectra were recorded at probe temperatures (ꢀ20 °C) using
tetramethylsilane as internal standard. All chiral liquid–liquid
chromatography (HPLC) was carried out on a Varian instrument,
with an UV–vis detector at the specified wavelength, with a Daicel
CHIRALCEL OD 0.46 cm ꢁ 25 cm column, using isopropanol/hexane
as the solvent, under conditions described for each experiment.
was isolated as a white solid; mp 122.4–123.9 °C; ½a D20
¼ ꢃ21:9
ꢂ
(c 1, H2O); 1H NMR (DMSO-d6) 0.79 (d, J 6.7, 3H), 0.83 (d, J 6.6,
3H), 1.21–1.29 (m, 2H), 1.49–1.59 (m, 1H), 1.77–1.86 (m, 1H),
1.98–2.24 (m, 3H), 3.17–3.30 (m, 2H), 3.70–3.80 (m, 1H), 3.93
(dd, J 8.0, 3.7, 1H), 4.61 (t, J 5.7, 1H), 7.57 (d, J 8.7, 1H), 7.74 (br s,
1H); 13C NMR (DMSO-d6) 22.4, 23.9, 24.7, 26.1, 29.8, 39.9, 49.2,
56.3, 64.2, 172.6, 177.9; IR (solid) 3224, 3093, 1686, 1654; m/z
(ESI) 227 ([M]ꢃ, 100%), HRMS (ESꢃ): found [M-H]ꢃ 227.1394,
C11H19N2O3 requires 247.1396.
4.1.1. (2S)-N-[(1S)-2-Hydroxy-1-phenyl-ethyl]-5-oxo-
pyrrolidine-2-carboxamide 1
4.1.5. Asymmetric addition of diethylzinc to benzaldehyde
To a stirred mixture of methyl (2S)-5-oxopyrrolidine-2-carbox-
ylate (2.14 g, 15 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD) (0.60 g, 4.5 mmol) at 50 °C was added R-phenylglycinol
(2.27 g, 16.5 mmol). The reaction mixture was warmed to 75 °C
and stirred for 12 h, allowed to cool to ambient temperature and
concentrated in vacuo. The residue obtained was chromatographed
on silica gel using 8% methanol/ethyl acetate as eluent to afford 1
as a solid which was then triturated with cold acetonitrile to give
the pure product (2.60 g, 70%) as a white solid; mp 189.8–
To a solution of ligand (0.1 mmol) in dichloromethane (1 mL)
was added titanium tetraisopropoxide (72 lL, 0.20 mmol) and
the resulting solution was stirred for 1 h and it was then cooled
to 0 °C. Diethylzinc (2 mL, 2 mmol, 1.0 M in hexane) was added
and the mixture was stirred for 0.5 h. The aldehyde (1 mmol) in
dichloromethane (1 mL) was added and the mixture was stirred
for an additional 18 h, allowing the reaction mixture to slowly
reach ambient temperature. The reaction was quenched with
saturated ammonium chloride solution (2 mL), the reaction
mixture was extracted with dichloromethane (3 ꢁ 5 mL) and the
combined extracts dried over anhydrous magnesium sulfate. After
removal of the solvent under reduced pressure, the residue was
purified by column chromatography (pet./EtOAc, gradient elution)
to afford the pure chiral 1-phenyl-1-propanol as a colourless oil.
The enantioselectivity was determined by HPLC analysis [Daicel
Chiralcel OD column, hexane/2-propanol 98.0:2.0, 0.5 mL/min,
254 nm (tR 24.4 min, tS 31.8 min)].
191.1 °C; ½a 2D0
ꢂ
¼ ꢃ81:6 (c 1, MeOH); 1H NMR (DMSO-d6) 1.72–
1.81 (m, 1H), 1.99–2.11 (m, 2H), 2.18–2.28 (m, 1H), 3.53 (t, J 5.9,
2H), 4.06 (dd, J 8.7, 4.5, 1H), 4.77–4.84 (m, 1H), 4.88 (t, J 5.8,
1H,), 7.17–7.23 (m, 1H), 7.24–7.32 (m, 4H), 7.85 (br s, 1H,), 8.29
(br d, J 8.2, 1H); 13C NMR (DMSO-d6) 25.8, 29.8, 55.1, 56.2, 65.1,
127.3, 128.6, 139.5, 172.5, 177.9; IR (solid) 3372, 3287, 1655,
1638; m/z (ESI) 247 ([M]ꢃ, 100%), HRMS (ESꢃ): found [MꢃH]ꢃ
247.1082, C13H15N2O3 requires 247.1083.

870
P. Geoghegan, P. O’Leary / Tetrahedron: Asymmetry 21 (2010) 867–870
4.1.6. Asymmetric addition of phenylacetylene to benzaldehyde
The ligand (0.20 mmol) and titanium tetraisopropoxide
(0.4 mmol) were mixed in dry DCM (3.0 mL) at room temperature.
Diethylzinc (2.0 mL, 1.0 M solution in hexane) was added. After the
mixture was stirred at room temperature for 2 h, phenylacetylene
(3.3 mL, 3 mmol) was added and the mixture was stirred for 1 h.
Acknowledgement
We thank Westmeath County Council and Science Faculty, NUI,
Galway for supporting this work.
References
Then the solution was treated with benzaldehyde (102 lL,
1. Denmark, S. E.; Nakajima, N.; Nicaise, O. J. C.; Faucher, A. M.; Edwards, J. P. J.
Org. Chem. 1995, 60, 4884–4892.
2. Carreiro, E. P.; Burke, A. J.; Ramalho, J. P. P.; Rodrigues, A. I. Tetrahedron:
Asymmetry 2009, 20, 1272–1278.
3. Frain, D.; Kirby, F.; McArdle, P.; O’Leary, P. Synlett 2009, 1261–1264.
4. Fang, T.; Xu, J.; Du, D.-M. Synlett 2006, 1559–1563.
5. Wang, J.; Liu, H.; Du, D.-M. Tetrahedron: Asymmetry 2009, 20, 605–609.
6. Wettergren, J.; Bøgevig, A.; Portier, M.; Adolfsson, H. Adv. Synth. Catal. 2006,
348, 1277–1282.
7. Blay, G.; Fernández, I.; Marco-Aleixandre, A.; Pedro, J. R. Tetrahedron:
Asymmetry 2005, 16, 1207–1213.
8. Chen, Z.-C.; Hui, X.-P.; Yin, C.; Huang, L.-N.; Xu, P.-F.; Yu, X.-X.; Cheng, S.-Y. J.
Mol. Catal. A: Chem. 2007, 269, 179–182.
9. Huang, L.-N.; Hui, X.-P.; Chen, Z.-C.; Yin, C.; Xu, P.-F.; Yu, X.-X.; Cheng, S.-Y. J.
Mol. Catal. A: Chem. 2007, 275, 9–13.
1.0 mmol). After the reaction was completed (TLC, 18 h), the reac-
tion solution was cooled to 0 °C and the reaction was quenched by
5% aqueous HCl. The mixture was extracted with diethyl ether
(3 ꢁ 10 mL). The extract was washed with brine (3 ꢁ 15 mL), dried
over anhydrous MgSO4 and concentrated under vacuum. The crude
product was purified by flash column chromatography (silica gel,
12.5% EtOAc in petroleum ether) to give 1,3-diphenyl-prop-2-yn-
1-ol as a colourless oil. The enantioselectivity was determined by
HPLC analysis [Daicel Chiralcel OD column, hexane/2-propanol
90.0: 10.0, 1.0 mL/min, 254 nm (tR 10.0 min, tS 17.8 min)].
4.1.7. Hydrogen-transfer to acetophenone
10. Sugimoto, K.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1997, 62, 2322–2323.
11. Fuerte, A.; Corma, A.; Sánchez, F. Catal. Today 2005, 107–108, 404–409.
12. Fang, T.; Du, D.-M.; Lu, S.-F.; Xu, J. Org. Lett. 2005, 7, 2081–2084.
13. Ó Dálaigh, C.; Hynes, S. J.; Maher, D. J.; Connon, S. J. Org. Biomol. Chem. 2005,
981.
14. Ó Dálaigh, C.; Hynes, S. J.; O Brien, J. E.; McCabe, T.; Maher, D. J.; Watson, G. W.;
Connon, S. J. Org. Biomol. Chem. 2006, 2785.
15. Onomura, O.; Kouchi, Y.; Iwasaki, F.; Matsumura, Y. Tetrahedron Lett. 2006, 47,
3751–3754.
16. Bateman, L.; Breeden, S. W.; O’Leary, P. Tetrahedron: Asymmetry 2008, 19, 391–
396.
17. Panday, S. K.; Prasad, J.; Dikshit, D. K. Tetrahedron: Asymmetry 2009, 20, 1581–
1632.
18. Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetrahedron Lett. 2007, 48,
3863–3866.
19. Bøgevig, A.; Pastor, I. M.; Adolfsson, H. Chem. Eur. J. 2004, 10, 294–302.
20. Mao, J.; Guo, J. Chirality 2010, 173–181.
Ligand (0.022 mmol) and [RuCl2(-cymene)]2 (6.1 mg, 0.01 mmol)
were dried under vacuum in a dry Schlenck tube for 15 min. 2-
Propanol (degassed, 10 mL) and NaOH (4 mg, 0.1 mmol) were
added under a nitrogen atmosphere. The solution was stirred for
30 min and acetophenone (2 mmol) was added. The reaction
mixture was stirred at room temperature for 24 h. The reaction
was quenched by addition of aqueous NH4Cl, the reaction mixture
extracted with EtOAc and the organic phase was subsequently
passed through a short pad of silica (washed through with a little
EtOAc) and evaporated under vacuum. The product was purified
using SiO2 column chromatography and was isolated as a colour-
less oil. The enantioselectivity was determined by HPLC analysis
[Daicel Chiralcel OD column, hexane/isopropanol 95:5, 1 ml/min;
254 nm (tR 11.3 min, tS 13.6 min)]. The configuration was assigned
by comparison with the sign of specific rotation of the known
compounds.
21. Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757–824.
22. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993, 58,
3568–3571.
23. Armarego, W. L.; Perrin, D. D. Purification of Laboratory Chemicals, 4th ed.;
Buttersworth-Heinemann: Oxford, 1998.