Preparation of pyrrolidine-oxazoline containing ligands and their application in asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.tet.2004.02.038

Nine members of a new ligand class incorporating both an oxazoline ring and a pyrrolidine unit were prepared in an efficient four-step synthesis starting from readily available chiral amino alcohols and proline. A study of these ligands in the asymmetric transfer hydrogenation of acetophenone showed that the catalysts formed from [Ir(cod)Cl]₂ were the most active while those derived from [Ru(p-cymene)Cl₂]₂ gave the highest enantioselectivities (up to 61% ee).

Full text of DOI:10.1016/j.tet.2004.02.038

Tetrahedron 60 (2004) 3405–3416
Preparation of pyrrolidine–oxazoline containing ligands and their
application in asymmetric transfer hydrogenation
Helen A. McManus,a Sarah M. Barry,a Pher G. Anderssonb and Patrick J. Guirya
,
*
aDepartment of Chemistry, Centre for Synthesis and Chemical Biology, Conway Institute for Biomolecular and Biomedical Research,
University College Dublin, Belfield, Dublin 4, Ireland
bDepartment of Organic Chemistry, Uppsala University, Box 531, SE-751 21 Uppsala, Sweden
Received 2 January 2004; revised 10 February 2004; accepted 19 February 2004
Abstract—Nine members of a new ligand class incorporating both an oxazoline ring and a pyrrolidine unit were prepared in an efficient
four-step synthesis starting from readily available chiral amino alcohols and proline. A study of these ligands in the asymmetric
transfer hydrogenation of acetophenone showed that the catalysts formed from [Ir(cod)Cl]2 were the most active while those derived from
[Ru(p-cymene)Cl2]2 gave the highest enantioselectivities (up to 61% ee).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
bis(oxazolinylmethyl)amine ligand 1 gives up to 97% ee for
the ruthenium-catalysed reduction of a variety of aromatic
ketones with excellent conversions.11 The catalyst formed
from [Ru(p-cymene)Cl2]2 and the chiral 1,2,3,4-tetrahydro-
quinolinyl-oxazoline ligand 2 gave 83% ee for the reduction
of acetophenone at 220 8C using 5 mol% ruthenium in
moderate yield (46% after 21 h).12
The preparation of enantiopure secondary alcohols by the
catalytic enantioselective reduction of prochiral ketones is
an important transformation in organic synthesis.1 In recent
years, extensive research has been carried out in this area
with the development of asymmetric transfer hydrogen-
ation.2 This process offers an attractive alternative and/or
complement to the use of molecular hydrogen and hydride
reduction due to its operational simplicity and use of a safe,
inexpensive and easy to handle hydrogen source.
a-Amino acids and their derivatives have also attracted
attention as ligands for asymmetric transfer hydrogenation
because they are relatively cheap and easily accessible.13
Proline-derived ligands have recently been investigated and
[Ru(p-cymene)Cl2]2 complexes of prolinamide 3 with a
4 mol% catalyst loading gave enantioselectivities in the
range of 60–93% ee at 224 8C for a variety of ketone
substrates.14 (S)-2-Anilinomethylpyrrolidine 4 and (S)-2-
naphthylaminomethyl-pyrrolidine 5 form highly active
complexes with [Ru(p-cymene)Cl2]2 giving high enantio-
selectivities (74–96% ee) for the reduction of aromatic
ketones in good to excellent yields (59–99%) with a
catalyst loading of 0.2–0.5 mol% ruthenium.15
Rhodium,3,4c iridium4 and ruthenium5 are the most
commonly used metals for transfer hydrogenation with
2-propanol being the hydrogen source of choice.
Ruthenium(arene) complexes bearing chiral 1,2-amino
alcohol,6 monotosylated diamine7 and 1,2-diamine
ligands8,7c are some of the most effective catalysts for
asymmetric transfer hydrogenation of aromatic ketones in
terms of both enantioselectivity and catalytic activity. It is
thought that the NH group in these ligands plays a crucial
role in achieving high enantioselectivity via a six-membered
cyclic transition state brought about by hydrogen bonding
between it and the ketone substrate.9
Encouraged by the results obtained by the use of both
proline-derived and oxazoline-containing ligands, we have
designed and prepared a new class of ligands 6a-i for
asymmetric transfer hydrogenation, which incorporate both
of these structural units. These ligands contain the important
NH moiety thought to be crucial for high enantio-
selectivities and the 1,2 arrangement of coordinating
nitrogen atoms present in ligands 1 and 3-5. In this paper,
we describe the synthesis of nine members of this new class
of ligands and discuss the results obtained in the reduction
of acetophenone. As these ligands contain two chiral
Chiral oxazoline-containing ligands have also been success-
ful in asymmetric transfer hydrogenation using 2-propanol
as the hydrogen donor.10 For example, Zhang’s tridentate
Keywords: Pyrrolidine–oxazoline; Hydrogenation; Proline-derived
ligands.
*
Corresponding author. Tel.: þ35-317-162-309; fax: þ35-317-162-127;
e-mail address: p.guiry@ucd.ie
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.038

3406
H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
centres, diastereomeric ligand pairs (6b and 6c, 6d and 6e
and 6f and 6g) were investigated in order to determine the
role of each chiral centre in enantioselection.
Table 1. Yields obtained for the reaction steps in the synthesis of ligands
6a-ia
R
Hydroxyamide
formation
Cyclisation
Deprotection
9
Yield (%)
10
Yield (%)
6
Yield (%)
49
2. Results and discussion
2.1. Ligand synthesis
H
9a
9b
9c
9d
9e
9f
87
92
86
57
57
81
82
60
87
10a
10b
10c
10d
10e
10f
86
92
87
81
94
88
75
93
98
6a
(S)-iPr
(R)-iPr
(S)-Ph
(R)-Ph
(S)-tBu
(S)-tBu
(S)-Me
(S)-Bn
6b
6c
6d
6e
6f
89
67
46
40
48
55
55
68
We envisaged that ligands 6a-i could be prepared by means
of a four-step synthesis starting from readily available chiral
amino alcohols and proline (Scheme 1, Table 1). First,
N-carbobenzyloxy(CBZ)-protected proline 7a-b was chlori-
nated with thionyl chloride16 and then reacted without
purification with a chiral amino alcohol 8a-i in the presence
of triethylamine to give b-hydroxyamides 9a-i in moderate
to good yields (57–92%). We have recently reported that
diethylaminosulfur triflouride (DAST) is a useful reagent
for the cyclisation of b-hydroxyamides to oxazolines giving
better results compared to the usual protocol of chlorination
followed by base-induced cyclisation.17 Cyclodehydration
of 9a-i by treatment with DAST afforded excellent yields
(75–98%) of the CBZ-protected pyrrolidine–oxazolines
10a-i, which were then deprotected in a transfer hydro-
genolysis reaction using Pd/C and cyclohexene18 yielding
9gb
9h
9i
10gb
10h
10i
6gb
6h
6i
a
(S)-Configuration of the pyrrolidine chiral centre.
(R)-Configuration of the pyrrolidine chiral centre.
b
the required pyrrolidine–oxazoline ligands 6a-i in moderate
yields (40–89%). It was found that both 10a-i and the final
ligands were subject to ring-opening to the corresponding
b-hydroxyamide after prolonged storage at room tempera-
ture. However, these compounds can be stored under
nitrogen without significant decomposition at 26 8C.
Because the pyrrolidine–oxazoline ligands have two chiral
centres, it was necessary to prepare diastereomers to
examine the effect of match and mismatch chiral centres
on enantioselection. Initially, five ligands 6b,d,f,h,i were
prepared from (S)-proline 7a and the corresponding
naturally occurring (S)-amino alcohol. Using (R)-amino
alcohols, diastereomers 6c and 6e of the iso-propyl- and
phenyl-substituted ligands 6b and 6d, respectively, were
synthesised. Since (R)-tert-leucinol is more expensive than
its enantiomer, a diastereomer 6g of the tert-butyl
substituted ligand 6f was accessed using (S)-tert-leucinol
and (R)-proline 7b. In total, nine members of this new ligand
class 6a-i, including three diastereomeric pairs were
prepared in good overall yield for application in asymmetric
transfer hydrogenation.
2.2. Metal screening and reaction optimisation
Using Chemspeedw ASW 2000 equipment, ligands 6a-i
were evaluated in the asymmetric transfer hydrogenation of
Scheme 1. Synthesis of pyrrolidine–oxazoline ligands 6a-i.

H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
Table 2. Optimisation of reaction conditions for transfer hydrogenation of acetophenonea
3407
Entry
Metal complex
Ligand
Lig/Met
Conv. (%)b
10 h
ee (%)b
Conf.c
1 h
1 h
10 h
1
2
3
4
[Ru(p-cymene)Cl2]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
6b
6b
6b
6b
6b
6b
6c
6c
6c
2.0
1.2
2.0
3.0
4.0
2.0
2.0
2.0
2.0
2
62
43
43
42
42
41
42
49
41
R
R
R
R
R
R
S
10
13
13
17
79
80
78
84
65
63
19
88
36
44
43
41
5
6d
7
9
5
18
45
45
43
8e
9f
S
S
a
Acetophenone:KOiPr:Metal¼200:5:1.
b
c
d
e
f
Determined by GC analysis on a CP-Chirasil-Dex CB column (25 m, 0.25 (diam.), 0.25 mm).
Determined by reference to literature values.20
Acetophenone:KOiPr:Metal¼20:5:1, reaction conducted at 0 8C.
Acetophenone:KOiPr:Metal¼200:2.5:1.
Acetophenone:KOiPr:Metal¼100:5:1.
Table 3. Transfer hydrogenation of acetophenone using [Ir(cod)Cl]2 and
ligands 6a-ia
acetophenone (Table 2). Six metal complexes of rhodium,
iridium and ruthenium were screened with ligand 6b in an
attempt to find the optimal metal for transfer hydrogenation.
Ruthenium [RuCl2(PPh3)3 and RuCl2(DMSO)4] and
rhodium [RhCl(PPh3)3 and [Rh(cod)Cl]2] complexes
showed no catalytic activity when tested with ligand 6b.
[Ru(p-cymene)Cl2]2 gave a slight conversion (2%)
accompanied by a moderate ee of 62% (entry 1). The best
results were achieved with the catalyst formed from ligand
6b and [Ir(cod)Cl]2 which afforded moderate enantio-
selectivity (43% ee) and good conversion (79%) after 10 h
at room temperature (entry 2). The reaction was optimised
by varying the reaction temperature, catalyst loading of the
[Ir(cod)Cl]2 pre-catalyst and the equivalents of ligand and
base used. Changing the number of equivalents of ligand 6b
used (up to 4 equiv. lig/metal) had very little effect on both
conversion and enantioselectivity (entries 2–5). In an
attempt to increase enantioselectivities, the reaction was
carried out at 0 8C using the iridium source and ligand 6b.
At this temperature, the reaction was sluggish affording
65% conversion after 10 h with a ten-fold increase in
catalyst loading (5 mol%) but the enenatioselectivity did not
change (entry 6). With the diastereomeric (S)-proline-(R)-
iso-propyl ligand 6c, the enantioselectivity increased (49%
vs. 42%) when the amount of base used was halved,
however this was accompanied by a significant decrease in
catalytic activity (19% vs. 63% conversion after 10 h)
(entries 7–8). Not surprisingly, increasing the catalyst
loading by a factor of 2–1 mol% iridium resulted in
increased conversion but little change in enantioselectivity
(entry 9).
Entry
Ligand
R
Conv. (%)b
ee (%)b
Conf.c
1 h
15 h
1 h
15 h
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
42
30
32
40
21
96
60
27
19
94
91
81
79
55
97
86
79
74
Rac.
38
39
33
41
20
16
10
29
Rac.
37
38
32
34
17
16
13
32
—
R
S
R
S
R
R
S
iPr
iPr
Ph
Ph
iBu
iBu
Me
Bn
S
a
Acetophenone:KOiPr:ligand:Ir¼200:5:2:1, reactions conducted at room
temperature.
Determined by GC analysis on a Supelco b-Dex 120 column (30 m,
0.25 mm (diam.), 0.25 mm).
b
c
Determined by reference to literature values.20
transfer hydrogenation (Table 3). Firstly, all catalysts
formed from [Ir(cod)Cl]2 and ligands 6a-i demonstrated
high catalytic activity in the reaction giving up to 94%
conversion after 15 h. Of these the (S)-proline-(S)-tert-
butyl-substituted ligand 6f proved particularly active
affording 96% conversion after just 1 h. However, the
enantioselctivity obtained using this ligand was poor (20%
ee after 1 h) (entry 6). Similar levels of enantioselectivity
were afforded using the tert-butyl diastereomer 6g and the
methyl-substituted ligand 6h (entries 7–8). The iso-propyl-
(6b and 6c), phenyl- (6d and 6e) and benzyl- (6i) substituted
ligands gave the best levels of enantioselection but these
were modest at best (32–38% ee) (entries 2–5 and 9).
2.3. Iridium catalysed asymmetric transfer
hydrogenation
Examining the results obtained using the three diastereo-
meric ligand pairs (6b and 6c, 6d and 6e and 6f and 6g)
reveals an interesting trend. In the case of the iso-propyl-
and phenyl-substituted ligands, changing the configuration
of the chiral centre at the oxazoline ring results in very
similar levels of enantioselectivity but different enantiomers
Having determined the optimal reaction conditions
([Ir(cod)Cl]2 (0.25 mol%), 5 equiv. KOiPr/Ir, 2 equiv.
lig/Ir, room temp.), isolated experiments were carried out
to evaluate the pyrrolidine–oxazoline ligands 6a-i in

3408
H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
of the 1-phenylethanol product (entries 2–5). The tert-
butyl-substituted diastereomers (6f and 6g) with the same
chiral centre at the oxazoline ring but with opposite
configurations of the pyrrolidine chiral centre both gave
(R)-1-phenylethanol with almost identical enantio-
selectivities after 15 h (entries 6 and 7). These results
suggest that only the chiral centre on the oxazoline ring is
important in controlling the stereochemical outcome of the
reaction. This was confirmed by the racemic product
obtained when ligand 6a, which comprises of an
unsubstituted oxazoline ring, was used (entry 1).
that quite high catalyst loadings (4–5 mol% Ru) were used
for ruthenium-catalysed transfer hydrogenation with some
oxazoline and pyrrolidine containing ligands.12,14
Encouraged by this and in an attempt to increase the
enantioselectivites obtained with this ligand class, we tested
ligands 6a-i in the transfer hydrogenation of acetophenone
using a ten-fold increase in catalyst loading (2.5 mol% of
[Ru(p-cymene)Cl2]2). Gratifyingly, for the majority of
ligands tested moderate catalytic activity was recorded
accompanied by improved enantioselectivity in some cases
(Table 4). The best results were obtained using the iso-
propyl-substituted ligands 6b and 6c, giving much improved
enantioselectivities (51 (R) and 61 (S)% ee, respectively)
compared to those afforded by iridium catalysis (37 (R) and
38 (S)% ee, respectively). The catalysts formed from these
ligands and [Ru(p-cymene)Cl2]2 were also the most active
giving 73–76% conversion after 15 h (entries 3 and 4). A
much increased catalytic activity was obtained when the
reaction was conducted at reflux temperature (98% conver-
sion after 2 h) but the enantioselectivity decreased dramati-
cally (16% ee) using 6b as the ligand (entry 2). The
remaining ligands afforded poor to moderate conversions
(8–51% after 15 h) and enantioselectivites (4–25% ee)
which were no better and in some cases lower than those
obtained in the Ir-catalysed reaction. By comparing the
results obtained with the diastereomeric ligand pairs (entries
3–8), it can be seen that the sense of asymmetric induction
achieved was similar to that observed with iridium, i.e. the
chiral centre on the oxazoline was dominant.
Conversely, the chiral centre of the pyrrolidine ring, appears
to play some part in determining catalyst activity. This is
evident by examining the conversions obtained by the
catalysts formed from the diastereomeric ligand pairs. In all
three cases, the ligand derived from (S)-proline and the (S)-
amino alcohol gave higher conversions than those obtained
with their respective diastereomers. This is best seen with
the tert-butyl-substituted ligands, where the (S)-pyrrolidine-
(S)-tert-butyl ligand 6d gives (R)-1-phenylethanol in 96%
conversion after 1 h while its diastereomer 6g afforded
product in only 60% conversion (entries 6 vs 7). Also,
ligand 6a which contains only the pyrrolidine chiral centre
gives high conversions (94% after 15 h). This effect where
one chiral centre, of the two in the ligand, dictates the
stereochemistry of the product has been previously reported
by Adolfsson in his study of transfer hydrogenation
employing ligands of type 11.19
3. Conclusions
A new class of ligands 6a-i, comprising chiral pyrrolidine
and oxazoline rings, was prepared in four steps starting from
readily available enantiopure proline and chiral amino
alcohols. These were screened with a number of metal
complexes and it was found that only those catalysts derived
from [Ir(cod)Cl]2 and [Ru(p-cymene)Cl2]2 were successful.
The catalysts formed from ligands 6a-i and [Ir(cod)Cl]2
(0.25 mol%) proved to be very active in this reaction (up to
96% conversion after 1 h at room temperature) but gave
only modest enantioselectivities (up to 38% ee). Much
improved enantioselectivities (61% ee with ligand 6c) were
achieved using [Ru(p-cymene)Cl2]2 (2.5 mol%) as the pre-
catalyst. The results obtained using diastereomeric ligand
pairs revealed that the stereochemical outcome of the
reaction was controlled only by the oxazoline chiral centre.
2.4. Ruthenium-catalysed asymmetric transfer
hydrogenation
As shown in Table 2 (entry 1), when ligand 6b was screened
with [Ru(p-cymene)Cl2]2 (0.25 mol%), slight catalytic
activity was observed. It has been reported in the literature,
Table 4. Transfer hydrogenation of acetophenone using [Ru(p-
cymene)Cl2]2 and ligands 6-8a
Entry
Ligand
R
Conv. (%)b
ee (%)b
1 h
15 h
8
1 h
15 h
4
Conf.c
1
2
3
4
5
6
7
8
9
10
6a
6bd
6b
6c
6d
6e
6f
6g
6h
6i
H
6
98e
8
8
3
1
5
5
2
7
R
R
R
S
R
S
R
R
R
R
iPr
iPr
iPr
Ph
16e
52
63
14
10
25
34
14
18
4. Experimental
4.1. General
76
73
30
24
43
37
51
40
51
61
15
14
20
25
16
17
Ph
tBu
tBu
Me
Bn
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Varian Oxford 300 spectrometer at room
temperature in CDCl3 or d 6-DMSO using tetramethylsilane
as an internal standard. Chemical shifts (d) are given in parts
per million and coupling constants are given as absolute
values expressed in Hertz. Low resolution electron-impact
MS spectra were measured at an ionization potential of
70 eV. Isomers were assumed to have the same response
factors. Electro-spray mass spectrometric analysis was
5
a
Acetophenone:KOiPr:ligand:Ru¼20:5:2:1, reactions conducted at room
temperature.
b
c
d
e
Determined by GC ananlysis on a Supelco chiral b-dex column.
Determined by reference to literature values.20
Reaction carried out at 82 8C.
Results after 2 h.

H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
3409
performed on a Waters Micromass Quattro Ultima mass
spectrometer. Elemental analyses were performed by Ms
Anne Connolly, Department of Chemistry, University
College Dublin. Infra-red spectra were recorded on a
Perkin–Elmer Infra-red FT spectrometer. Optical rotation
values were measured on a Perkin–Elmer 343 polarimeter.
Melting points were determined in open capillary tubes in a
Gallenkamp melting point apparatus and are uncorrected.
Thin layer chromatography (TLC) was carried out on plastic
sheets pre-coated with silica gel 60 F254 (Merck). Column
chromatography separations were performed using Merck
Kieselgel 60 (0.040–0.063 mm). GC analysis was per-
formed using (a) a Varian 3400 instrument equipped with a
CP-Chirasil-Dex CB column (25 m, 0.25 mm (diam.),
0.25 mm) with nitrogen as a carrier gas at 15 psi and a
flame-ionizing detector or (b) a Shimadzu GC-17A gas
chromatograph equipped with a Shimadzu C-R3A chroma-
topac integrator and a Supelco b-Dex 120 chiral capillary
column (30 m, 0.25 mm (diam.)£0.25 mm) with helium as a
carrier gas at 1.0 mL/min and a flame-ionizing detector.
Solvents were dried immediately before use by distillation
from standard drying agents. Amino alcohols were prepared
from their corresponding amino acids using a standard
reduction procedure.21 N-Carbobenzyloxy-(S)-proline and
N-carbobenzyloxy-(R)-proline were prepared from the
corresponding amino acids following the procedure
reported by Corey.22 It should be noted that for the majority
of compounds prepared, the 1H NMR and 13C NMR spectra
obtained showed two signals for most protons and carbons
and such signals are given in square brackets.
4H, pyr-H2C(5), CH2O, OH), 4.19–4.26 (m, 1H, pyr-
HC(2)), 4.68 (app t, J¼5.3 Hz, 1H, CH2O), 5.01–5.18 (m,
2H, CH2Ph(CBZ)), 7.36–7.44 (m, 5H, Ar-HC(CBZ)),
7.93–7.97 (m, 1H, NH); 13C NMR (75 MHz, DMSO-d6):
d [23.8, 24.6] (pyr-H2C(4)), [30.9, 32.0] (pyr-H2C(3)), 42.1
(CH2N), [47.2, 47.8] (pyr-H2C(5)), [60.3, 60.8] (pyr-
HC(2)), 60.5 (CH2O), [66.4, 66.6] (CH2Ph(CBZ)), [127.7,
128.5], [128.16, 128.23], [128.9, 129.1] (Ar-HC(CBZ)),
137.7 (ipso-Ph(CBZ)), [154.6, 154.8] (CvO(CBZ)),
[172.6, 172.9] (CONH)); IR (KBr): n 3428, 3292, 1689,
1646, 1548, 1431, 1363, 1138, 1093, 735 cm21; MS-ESþ
(CH3CN): m/z 293 (MþHþ, 100%). Anal. Calcd for
C15H20N2O4: C, 61.61; H, 6.89; N, 9.62. Found: C, 61.25;
H, 6.88; N, 9.50.
4.2.2. (2S)-2-((1S)-1-Hydroxymethyl-2-methyl-propyl-
carbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester
(9b). Yield: 6.17 g, 92%. White solid; mp: 114–116 8C;
1
[a]D¼261.0 (c 0.46, EtOH); H NMR (300 MHz, DMSO-
d6): d[0.73 (d, J¼6.7 Hz), 0.77 (d, J¼6.7 Hz) and 0.84 (app
t, J¼7.1 Hz)] (6H, CH(CH3)2, ratio 1.3:1.0), 1.73–1.90 (m,
4H, CH(CH3)2, pyr-H2C(4), pyr-H2C(3)), 2.07–2.15 (m,
1H, pyr-H2C(3)), 3.37–3.46 (m, 3H, pyr-H2C(5), CH2O),
3.51–3.58 (m, 1H, CHN), [4.23 (dd, J¼8.8, 2.7 Hz) and
4.29 (dd, J¼8.8, 2.5 Hz)] (1H, pyr-HC(2), ratio 1.0:1.4),
4.47–4.54 (m, 1H, CH2O), [4.95 (d, J¼12.8 Hz), 5.04 (d,
J¼12.8 Hz) and 5.07 (d, J¼10.3 Hz), 5.11 (d, J¼10.3 Hz)]
(2H, CH2Ph(CBZ), ratio 1.3:1.0), 7.28–7.38 (m, 5H, Ar-
HC(CBZ)), 7.52 (app t, J¼9.0 Hz, 1H, CONH); 13C NMR
(75 MHz, DMSO-d6): d [18.7, 18.8] (CH(CH3)2), [20.2,
20.4] (CH(CH3)2), [23.7, 24.6] (pyr-H2C(4)), [28.8, 29.0]
(CH(CH3)2), [30.8, 32.2] (pyr-H2C(3)), [47.3, 47.9] (pyr-
H2C(5)), 56.3 (CHN), [60.0, 60.6] (pyr-HC(2)), [62.0, 62.1]
(CH2O), 66.4 (CH2Ph(CBZ)), [127.8, 128.4], [128.15,
128.2], [128.9, 129.1] (Ar-HC(CBZ)), 137.7 (ipso-
Ph(CBZ)), [154.6, 154.7] (CvO(CBZ)), [172.4, 172.7]
(CONH); IR (KBr): n 3455, 3299, 1666, 1656, 1544, 1441,
1357, 1171, 1119, 699, 668 cm21; MS-ESþ (CH3CN): m/z
335 (MþHþ, 100%). Anal. Calcd for C18H26N2O4: C,
64.63; H, 7.83; N, 8.41. Found: C, 64.28; H, 7.83; N, 8.27.
4.2. Synthesis of hydroxyamides
Thionyl chloride (2.6 mL, 35.64 mmol) was added dropwise
to a solution of carbobenzyloxy-(S)-proline (5.00 g,
20.06 mmol) in dry benzene (40 mL). The resulting clear
solution was heated at reflux for 2 h. After cooling to room
temperature, the yellow reaction mixture was concentrated
in vacuo to give the acid chloride as a yellow oil. Yield: 99%
(5.37 g), IR (neat): n¼1783 cm21 (COCl) (lit.16
1780 cm21), 1709 cm21 (CBZ).
4.2.3. (2S)-2-((1R)-1-Hydroxymethyl-2-methyl-propyl-
carbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester
(9c). Yield: 5.84 g, 86%. White solid; mp: 118–122 8C;
[a]D¼221.6 (c 0.61, EtOH); H NMR (300 MHz, DMSO-
The acid chloride (5.370 g, 20.05 mmol) was dissolved in
dry CH2Cl2 (160 mL) in an oven-dried Schlenk tube and the
resulting solution was cooled to 0 8C in an ice/water bath.
To this was added dropwise a solution of the amino alcohol
(22.06 mmol) and triethylamine (22.06 mmol) in dry
CH2Cl2 (30 mL). A cloudy reaction mixture was obtained
and this was allowed to stir at room temperature overnight
(15 h) under an atmosphere of nitrogen. The reaction
mixture was reduced in volume to approx. 50 mL, washed
successively with aq. NH4Cl (3£50 mL) and water
(2£50 mL), dried over anhyd. sodium sulfate and concen-
trated in vacuo to give an off-white solid. The crude product
was then purified by recrystallisation from CH2Cl2/pet.
ether (40/60 8C).
1
d6): d 0.77–0.86 (m, 6H, CH(CH3)2), 1.82–1.84 (br m, 4H,
CH(CH3)2, pyr-H2C(4), pyr-H2C(3)), 2.09–2.22 (br m, 1H,
pyr-H2C(3)), 3.25–3.46 (m, 3H, pyr-H2C(5), CH2O), 3.57–
3.59 (br m, 1H, CHN), 4.22–4.30 (m, 1H, pyr-HC(2)),
4.47–4.53 (m, 1H, CH2O), 4.97–5.11 (m, 2H, CH2-
Ph(CBZ)), 7.29–7.37 (m, 5H, Ar-HC(CBZ)), [7.48 (d,
J¼9.2 Hz) and 7.52 (d, J¼9.2 Hz)] (1H, CONH, ratio
1.0:1.2); 13C NMR (75 MHz, DMSO-d6): d [18.4, 18.5]
(CH(CH3)2), 20.4 (CH(CH3)2), [23.7, 24.6] (pyr-H2C(4)),
[26.7, 28.8] (CH(CH3)2), [31.1, 32.4] (pyr-H2C(3)), [47.2,
47.8] (pyr-H2C(5)), 55.9 (CHN), [60.2, 60.8] (pyr-HC(2)),
62.0 (CH2O), 66.5 (CH2(CBZ)), [127.8, 128.5], [128.1,
128.2], [128.9, 129.1] (Ar-HC(CBZ)), 137.7 (ipso-
Ph(CBZ)), 154.6 (CvO(CBZ)), [172.3 172.6] (CONH);
IR (KBr): n 3455, 3303, 2970, 1673, 1655, 1551, 1441,
1353, 1178, 1129, 695, 624 cm21; MS-ESþ (CH3CN): m/z
335 (MþHþ, 100%). Anal. Calcd for C18H26N2O4: C,
64.63; H, 7.83; N, 8.41. Found: C, 64.35; H, 7.76; N, 8.35.
4.2.1. (2S)-2-(2-Hydroxy-ethylcarbamoyl)-pyrrolidine-
1-carboxylic acid benzyl ester (9a). Yield: 5.11 g, 87%.
White solid; mp: 106–108 8C; [a]D¼239.1 (c 0.45, EtOH);
1H NMR (300 MHz, DMSO-d6): d 1.80–1.92 (br m, 3H,
pyr-H2C(4), pyr-H2C(3)), 2.05–2.24 (br m, 1H, pyr-
H2C(3)), 3.10–3.24 (br m, 2H, CH2N), 3.43–3.51 (br m,

3410
H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
4.2.4. (2S)-2-(2-Hydroxy-(1S)-1-phenyl-ethylcarba-
moyl)-pyrrolidine-1-carboxylic acid benzyl ester (9d).
Yield: 4.21 g, 57%. White solid; mp: 151–154 8C;
[a]D¼þ29.8 (c 0.58, EtOH); H NMR (300 MHz, DMSO-
HC(CBZ)), [137.7, 137.8] (ipso-Ph(CBZ)), 154.6
(CvO(CBZ)), [172.6, 173.0] (CONH)); IR (KBr): n 3395,
3322, 2966, 1672, 1661, 1555, 1428, 1356, 1113 cm21; MS-
ESþ (CH3CN): m/z 349 (MþHþ, 100%). Anal. Calcd for
C19H28N2O4: C, 65.47; H, 8.10; N, 8.07. Found: C, 65.73; H,
8.00; N, 8.15.
1
d6): d 1.77–1.90 (m, 3H, pyr-H2C(4), pyr-H2C(3)), 2.09–
2.23 (m, 1H, pyr-H2C(3)), 3.39–3.50 (m, 2H, pyr-H2C(5)),
3.52–3.63 (m, 2H, CH2O), [4.30–4.33 (m) and 4.36 (dd,
J¼8.0, 2.3 Hz)] (1H, pyr-HC(2)), 4.82–4.88 (m, 2H, CHN,
CH2Ph(CBZ)), [5.03 (d, J¼12.9 Hz) and 5.09 (d,
J¼12.9 Hz)] (1H, CH2Ph(CBZ)), 7.17–7.38 (m, 10H, Ar-
HC(Ph), Ar-HC(CBZ)), [8.25 (d, J¼8.2 Hz), and 8.33 (d,
J¼8.2 Hz)] (1H, NH, ratio 1.0:1.3); 13C NMR (75 MHz,
DMSO-d6): d [23.8, 24.7] (pyr-H2C(4)), [30.9, 32.2] (pyr-
H2C(3)), [47.2, 47.9] (pyr-H2C(5)), 55.6 (CHN), [60.1,
60.6] (pyr-HC(2)), [65.3, 65.4] (CH2O), [66.4, 66.6] (CH2-
Ph(CBZ)), [127.3, 128.5], 127.6, 127.7, [128.1, 128.2],
128.6, [128.9, 129.1] (Ar-HC(Ph), Ar-HC(CBZ)), 137.7
(ipso-Ph(CBZ)), [141.7, 141.8] (ipso-Ph), [154.5, 154.8]
(CvO (CBZ)), [172.3, 172.6] (CONH); IR (KBr): n 3405,
3318, 2891, 1665, 1542, 1456, 1361, 1259, 1174, 1126,
1078, 771, 698 cm21; MS-ESþ (CH3CN): m/z 369 (MþHþ,
100%). Anal. Calcd for C21H24N2O4: C, 68.44; H, 6.56; N,
7.63. Found: C, 68.11; H, 6.49; N, 7.58.
4.2.7. (2R)-2-((1S)-1-Hydroxymethyl-2,2-dimethyl-pro-
pylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl
ester (9g). Yield: 5.57 g, 82%. White solid; mp: 100–
1
102 8C. [a]D¼þ47.4 (c 0.49, EtOH). H NMR (300 MHz,
DMSO-d6): d 0.85 (s, 9H, C(CH3)3), 1.83–1.87 (br m, 3H,
pyr-H2C(4), pyr-H2C(3)), 2.11–2.16 (br m, 1H, pyr-
H2C(3)), 3.39–3.59 (m, 4H, CH2O, pyr-H2C(5), OH),
3.62–3.66 (m, 1H, CHN), 4.21–4.35 (m, 2H, pyr-HC(2),
CH2O), 4.95–5.15 (m, 2H, CH2Ph(CBZ)), 7.22–7.37 (m,
5H, Ar-HC(CBZ)), 7.44 (d, J¼9.5 Hz, 1H, NH); 13C NMR
(75 MHz, DMSO-d6): d [23.7, 24.6] (pyr-H2C(4)), 27.6
(C(CH3)3), [31.0, 32.3] (pyr-H2C(3)), 34.7 (C(CH3)3),
[47.3, 47.8] (pyr-H2C(5)), [58.8. 58.9] (CHN), [60.4, 60.9]
(pyr-HC(2)), 61.5 (CH2O), 66.5 (CH2Ph(CBZ)), [128.0,
128.5], 128.2, [128.9, 129.1] (Ar-HC(CBZ)), 137.7 (ipso-
Ph(CBZ)), 154.8 (CvO(CBZ)), [172.3, 172.5] (CONH));
IR (KBr): n 3239, 3089, 2968, 1708, 1651, 1581, 1419,
1342, 1082, 697 cm21; MS-ESþ (CH3CN): m/z 349
(MþHþ, 100%). Anal. Calcd for C19H28N2O4: C, 65.47;
H, 8.10; N, 8.07. Found: C, 65.24; H, 7.98; N, 7.98.
4.2.5. (2S)-2-(2-Hydroxy-(1R)-1-phenyl-ethylcarba-
moyl)-pyrrolidine-1-carboxylic acid benzyl ester (9e).
Yield: 4.21 g, 57%. White solid; mp: 133–136 8C;
[a]D¼2108.7 (c 0.55, EtOH); 1H NMR (300 MHz,
DMSO-d6): d 1.77–1.80 (br m, 3H, pyr-H2C(4), pyr-
H2C(3)), 2.09–2.18 (br m, 1H, pyr-H2C(3)), 3.40–3.47 (m,
2H, pyr-H2C(5)), 3.51–3.59 (m, 2H, CH2O, OH), 4.28–
4.34 (br m, 1H, pyr-HC(2)), 4.81–4.88 (m, 2H, CHN,
CH2O), 4.99–5.10 (m, 2H, CH2Ph(CBZ)), 7.21–7.40 (m,
10H, Ar-HC(CBZ), Ar-HC(Ph)), 8.25–8.31 (m, 1H, NH);
13C NMR (75 MHz, DMSO-d6): d [23.7, 24.5] (pyr-
H2C(4)), [30.8, 31.9] (pyr-H2C(3)), [47.3, 47.8] (pyr-
H2C(5)), 55.5 (CHN), [60.2, 60.7] (pyr-HC(2)), [65.1,
65.4] (CH2O), 66.6 (CH2Ph(CBZ)), 127.4, 127.5, [127.8,
128.5], [128.15, 128.25], 128.7, [129.0, 129.1] (Ar-HC(Ph),
Ar-HC(CBZ)), [137.6, 137.8] (ipso-Ph(CBZ)), 142.0 (ipso-
Ph), [154.7, 154.8] (CvO(CBZ)), [172.1, 172.3] (CONH);
IR (KBr): n 3473, 3265, 3066, 1705, 1654, 1559, 1421,
1355, 1169, 1089, 699 cm21; MS-ESþ (CH3CN): m/z 369
(MþHþ, 100%). Anal. Calcd for C21H24N2O4: C, 68.44; H,
6.56; N, 7.63. Found: C, 68.00; H, 6.52; N, 7.59.
4.2.8. (2S)-2-((2-Hydroxy-(1S)-1-methyl-ethylcarba-
moyl)-pyrrolidine-1-carboxylic acid benzyl ester (9h).
Yield: 3.69 g, 60%. White solid; mp: 116–118 8C.
[a]D¼236.7 (c 0.46, EtOH); 1H NMR (300 MHz,
DMSO-d6): d [0.99 (d, J¼6.6 Hz) and 1.08 (d, J¼6.6 Hz)]
(3H, CH3, ratio 1.5:1.0), 1.84–1.96 (br m, 3H, pyr-H2C(4),
pyr-H2C(3)), 2.09–2.22 (br m, 1H, pyr-H2C(3)), 3.22–3.27
(m, 1H, CH2O), 3.34–3.54 (m, 3H, pyr-H2C(5), OH), 3.75–
3.84 (m, 1H, CHN), [4.20 (d, J¼6.0 Hz) and 4.24 (dd,
J¼8.4, 2.9 Hz)] (1H, pyr-HC(2)), 4.66–4.73 (m, 1H,
CH2O), [5.02 (d, J¼12.9 Hz), 5.09 (d. J¼12.9 Hz), 5.12
(d, J¼12.8 Hz), 5.15 (d, J¼12.8 Hz)] (2H, CH2Ph(CBZ)),
7.32–7.43 (m, 5H, Ar-HC(CBZ)), [7.68 (d, J¼8.1 Hz) and
7.73 (d, J¼8.1 Hz)] (1H, NH); 13C NMR (75 MHz, DMSO-
d6): d [17.7, 17.8) (pyr-H2C(4)), [23.8, 24.6] (CH3), [31.0,
32.1] (pyr-H2C(3)), [47.1, 47.2] (pyr-H2C(5)), 47.8 (CHN),
[60.1, 60.6] (pyr-HC(2)), 65.1 (CH2O), 66.4 (CH2Ph(CBZ)),
[127.7, 128.5], [128.1, 128.2], [128.9, 129.1] (Ar-HC(CBZ)),
137.7 (ipso-Ph(CBZ)), 154.6 (CvO(CBZ)), [172.0, 172.3]
(CONH); IR (KBr): n 3427, 3307, 2958, 2890, 1698, 1548,
1432, 1362, 769, 736 cm21; MS-ESþ (CH3CN): m/z 307
(MþHþ, 100%). Anal. Calcd for C16H22N2O4: C, 62.70; H,
7.23; N, 9.18. Found: C, 62.52; H, 7.20; N, 8.93.
4.2.6. (2S)-2-((1S)-1-Hydroxymethyl-2,2-dimethyl-pro-
pylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl
ester (9f). Yield: 5.50 g, 81%. White solid; mp: 136–
1
138 8C; [a]D¼242.0 (c 0.49, EtOH); H NMR (300 MHz,
DMSO-d6): d [0.77 (s) and 0.85 (s)] (9H, C(CH3)3, ratio
1.2:1.0), 1.76–1.93 (br m, 3H, pyr-H2C(4), pyr-H2C(3)),
2.04–2.19 (br m, 1H, pyr-H2C(3)), 3.24–3.33 (br m, 1H,
CH2O), 3.38–3.46 (br m, 2H, pyr-H2C(5)), 3.54–3.58 (br
m, 2H, CHN, OH), 4.25–4.38 (br m, 2H, pyr-HC(2),
CH2O), [4.90 (app d, J¼13.1 Hz, 1H) and 5.04 (d,
J¼12.6 Hz), 5.10 (d, J¼12.6 Hz)] (2H, CH2Ph (CBZ)),
7.27–7.38 (m, 5H, Ar-HC(CBZ)), 7.44–7.49 (m, 1H, NH);
13C NMR (75 MHz, DMSO-d6): d [23.6, 24.6] (pyr-
H2C(4)), [27.5, 27.6] (C(CH3)3), [30.7, 32.2] (pyr-H2C(3)),
[34.2, 34.4] (C(CH3)3), [47.2, 47.9] (pyr-H2C(5)), 59.3
(CHN), [60.1, 60.6] (pyr-HC(2)), 61.3 (CH2O), 66.4 (CH2-
Ph(CBZ)), [127.9, 128.4], 128.2, [128.9, 129.1] (Ar-
4.2.9. (2S)-2-((1S)-1-Benzyl-2-hydroxy-ethylcarbamoyl)-
pyrrolidine-1-carboxylic acid benzyl ester (9i). Yield:
6.68 g, 87%. White solid; mp: 138–140 8C; [a]D¼268.7 (c
0.52, EtOH); 1H NMR (300 MHz, DMSO-d6): d 1.65–1.72
(m, 3H, pyr-H2C(4), pyr-H2C(3)), 1.95–2.09 (m, 1H,
pyr-H2C(3)), 2.60–2.72 (m, 1H, CH2Ph), 2.77–2.88 (m,
1H, CH2Ph), 3.23–3.38 (m, 2H, pyr-H2C(5)), 3.40–3.47
(m, 1H, CH2O), 3.90–3.94 (m, 1H, CHN), 4.15–4.18 (m,
1H, CH2O), 4.71–4.78 (m, 1H, pyr-HC(2)), [4.95 (d,
J¼13.0 Hz), 5.01 (d, J¼13.0 Hz) and 5.07–5.15 (m)]
(2H, CH2Ph(CBZ), ratio 1.9:1.0), 7.12–7.40 (m, 10H,

H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
3411
Ar-HC(Bn), Ar-HC(CBZ)), [7.65 (d, J¼8.2 Hz) and 7.73 (d,
J¼8.4 Hz)] (1H, NH, ratio 1.0:1.2); 13C NMR (75 MHz,
DMSO-d6): d [23.5, 24.4] (pyr-H2C(4)), [30.6, 31.9]
(pyr-H2C(3)), 37.0 (CH2Ph), [47.2, 47.8] (pyr-H2C(5)),
52.9 (CHN), [60.4, 60.8] (pyr-HC(2)), 63.1 (CH2O), [66.3,
66.6] (CH2Ph(CBZ)), 126.5, 127.7, 128.2 (Ar-HC(Bn),
Ar-HC(CBZ)), 128.5 (ipso-Ph(Bn), [128.7, 128.9], 129.1,
[129.7, 129.9] (Ar-HC(Bn), Ar-HC(CBZ)), [137.8, 139.9]
(ipso-Ph(CBZ)), [154.6, 154.9] (CvO(CBZ)), [172.1,
172.4] (CONH); IR (KBr): n 3367, 3321, 2875, 1679,
1643, 1541, 1430, 1364, 741, 698, 624 cm21; MS-ESþ
(CH3CN): m/z 383 (MþHþ, 100%). Anal. Calcd for
C22H26N2O4: C, 69.07; H, 6.85; N, 7.35. Found: C, 68.88;
H, 6.74; N, 7.28.
CH(CH3)2), 1.86–1.95 (m, 1H, pyr-H2C(4)), 1.98–2.05
(m, 2H, pyr-H2C(4), pyr-H2C(3)), 2.12–2.28 (m, 1H, pyr-
H2C(3)), 3.42–3.64 (m, 2H, pyr-H2C(5)), 3.76–3.83 (m,
0.6H, CHN), 3.89 (app t, J¼7.9 Hz, 0.6H, CH2O), 3.95–
4.05 (m, 1.4H, CH2O(1H), CHN), 4.21 (app t, J¼7.9 Hz,
0.4H, CH2O), 4.54–4.60 (m, 1H, pyr-HC(2)), 5.04–5.23
(m, 2H, CH2Ph(CBZ)), 7.27–7.34 (m, 5H, Ar-HC(CBZ));
13C NMR (75 MHz, CDCl3): d [17.5, 17.7) (CH(CH3)2),
18.4 (CH(CH3)2), [23.5, 24.3] (pyr-H2C(4)), [30.6, 31.7]
(pyr-H2C(3)), 32.2 (CH(CH3)2),), [46.4, 47.0] (pyr-H2C(5)),
[54.7, 55.0] (pyr-HC(2)), [66.7, 66.8] (CH2Ph(CBZ)), 70.1
(CH2O), [71.6, 71.7] (CHN), 127.8, 128.3, 128.4 (Ar-
HC(CBZ)), 136.9 (ipso-ph(CBZ)), [152.3, 154.5]
(CvO(CBZ)), [166.9, 167.1] (CvN); IR (neat): n 2960,
2878, 1709, 1673, 1413, 1357, 1171, 1117, 982, 770,
697 cm21; MS (70 eV, EI): m/z(%) 316 (Mþ, 10), 225 (15),
199 (5), 164 (23), 140 (100), 127 (18). Anal. Calcd for
C18H24N2O3: C, 68.33; H, 7.65; N, 8.85. Found: C, 67.95;
H, 7.62; N, 8.76.
4.3. Synthesis of the oxazolines
The hydroxyamide (13.68 mmol) was dissolved in dry
CH2Cl2 (120 mL) in an oven-dried Schlenk tube under an
atmosphere of nitrogen and was cooled to 278 8C in a dry
ice/acetone bath. DAST (15.05 mmol) was added dropwise
via syringe and the resulting yellow solution was stirred at
278 8C for 1 h and then at room temperature overnight
(16 h). The reaction mixture was poured slowly onto sat. aq.
NaHCO3 (150 mL), the two layers were separated and the
organic layer was washed with water (2£50 mL). All the
aqueous layers were then combined and extracted with
CH2Cl2 (3£100 mL). The combined organic layers were
dried over anhyd. sodium sulfate and concentrated in vacuo
to give a brown oil. This crude oil was then purified by flash
column chromatography on silica gel (4£40 cm) using 10%
MeOH/AcOEt as the eluent.
4.3.3. (2S)-2-((4R)-4-Isopropyl-4,5-dihydro-oxazol-2-yl)-
pyrrolidine-1-carboxylic acid benzyl ester (10c). Yield:
3.77 g, 87%. Colourless oil; [a]D¼230.8 (c 0.37, EtOH);
1H NMR (300 MHz, CDCl3): d [0.78 (d, J¼6.7 Hz), 0.87
(app t, J¼7.2 Hz), 0.93 (d, J¼6.7 Hz)] (6H, CH(CH3)2),
1.51–1.62 (m, 0.5H, CH(CH3)2), 1.79–1.91 (m, 1.5H, pyr-
H2C(4)(1H), CH(CH3)2), 1.98–2.11 (m, 2H, pyr-H2C(4),
pyr-H2C(3)), 2.14–2.28 (m, 1H, pyr-H2C(3)), 3.42–3.65
(m, 2H, pyr-H2C(5)), [3.75–3.84 and 3.93–4.02] (m, 2H,
CHN, CH2O), 4.11–4.29 (m, 1H, CH2O), 4.56–4.59 (m,
1H, pyr-HC(2)), 5.06–5.21 (m, 2H, CH2Ph(CBZ)), 7.28–
7.34 (m, 5H, Ar-HC(CBZ)); 13C NMR (75 MHz, CDCl3): d
[17.8, 18.3] (CH(CH3)2), 19.1 (CH(CH3)2), [23.7, 24.4]
(pyr-H2C(4)), [30.8, 31.9] (pyr-H2C(3)), [32.5, 32.7]
(CH(CH3)2), [46.7, 47.2] (pyr-H2C(5)), [54.8, 55.2] (pyr-
HC(2)), [66.97, 67.08] (CH2Ph(CBZ)), [70.3, 70.6] (CH2O),
[72.1, 72.4] (CHN), [128.0, 128.1], [128.4, 128.6], 128.8
(Ar-HC(CBZ)), 137.1 (ipso-Ph), 154.8 (CvO(CBZ)),
[167.1, 167.5] (CvN); IR (neat): n 2958, 2881, 1708,
1673, 1414, 1356, 1186, 1118, 980, 696 cm21; MS (70 eV,
EI): m/z (%) 316 (Mþ, 14), 225 (16), 199 (5), 164 (25), 140
(100), 127 (19). Anal. Calcd for C18H24N2O3: C, 68.33; H,
7.65; N, 8.85. Found: C, 67.99; H, 7.52; N, 8.72.
4.3.1. (2S)-2-(4,5-Dihydro-oxazol-2-yl)-pyrrolidine-1-
carboxylic acid benzyl ester (10a). Yield: 3.22 g, 86%.
Colourless oil; [a]D¼268.4 (c 0.54, EtOH); 1H NMR
(300 MHz, CDCl3): d 1.89–1.97 (br m, 1H, pyr-H2C(4)),
2.01–2.09 (br m, 2H, pyr-H2C(4), pyr-H2C(3)), 2.12–2.23
(br m, 1H, pyr-H2C(3)), 3.45–3.65 (m, 2H, pyr-H2C(5)),
3.71 (app t, J¼9.5 Hz, 1H, CH2N/CH2O), 3.86 (app t,
J¼9.5 Hz, 1H, CH2N/CH2O), 4.02 (app q, J¼9.0 Hz, 0.5H,
CH2N/CH2O), 4.14 (app q, J¼9.0 Hz, 0.5H, CH2N/CH2O),
4.24–4.35 (m, 1H, CH2N/CH2O), 4.57 (br dd, J¼13.2,
7.8 Hz, 1H, pyr-HC(2)), [5.00 (d, J¼12.6 Hz), 5.08 (d,
J¼12.4 Hz), 5.21 (d, J¼12.4 Hz), 5.28 (d, J¼12.6 Hz)] (2H,
CH2Ph(CBZ)), 7.28–7.34 (m, 5H, Ar-HC(CBZ)); 13C NMR
(75 MHz, CDCl3): d [23.7, 24.4] (pyr-H2C(4)), [30.4, 31.6]
(pyr-H2C(3)), [46.6, 47.1] (pyr-H2C(5)), [54.5, 54.6]
(CH2N), [54.7, 55.1] (pyr-HC(2)), [66.9, 67.2] (CH2-
Ph(CBZ)), [68.0, 68.2] (CH2O), 127.96, 128.04, 128.1,
128.4, 128.57, 128.64, 128.8 (Ar-HC(CBZ)) [137.0, 137.2]
(ipso-Ph(CBZ)), [154.7, 155.0] (CvO(CBZ)), [168.3,
168.6] (CvN); IR (neat): n 2964, 2882, 1709, 1673,
1416, 1358, 1160, 1118 cm21; MS-ESþ (CH3CN): m/z 275
(MþHþ, 100%). Anal. Calcd for C15H18N2O3: C, 65.68; H,
6.61; N, 10.21. Found: C, 65.32; H, 6.54; N, 9.91.
4.3.4. (2S)-2-((4S)-4-Phenyl-4,5-dihydro-oxazol-2-yl)-
pyrrolidine-1-carboxylic acid benzyl ester (10d). Yield:
1
3.88 g, 81%. Yellow oil; [a]D¼285.1 (c 0.26, EtOH); H
NMR (300 MHz, CDCl3): d 1.92–2.05 (br m, 1H, pyr-
H2C(4)), 2.08–2.19 (br m, 2H, pyr-H2C(4), pyr-H2C(3)),
2.23–2.35 (br m, 1H, pyr-H2C(3)), 3.45–3.62 (br m, 1H,
pyr-H2C(5)), 3.64–3.70 (m, 1H, pyr-H2C(5)), [4.02 (app t,
J¼8.0 Hz,) and 4.12 (app t, J¼8.0 Hz)] (1H, CH2O/CHN,
ratio 1.0:1.0), 4.40 (app t, J¼9.1 Hz, 0.5H, CH2O/CHN),
4.60–4.68 (m, 1.5H, pyr-HC(2), CH2O/CHN(0.5H)), 5.05
(app t, J¼9.1 Hz, 0.5H, CH2O/CHN), 5.11–5.24 (m, 2.5H,
CH2Ph(CBZ), CH2O/CHN (0.5H))), 7.12–7.27 (m, 1H, Ar-
HC(Ph)), 7.30–7.39 (m, 9H, Ar-HC(Ph), Ar-HC(CBZ));
13C NMR (75 MHz, CDCl3): d [23.6, 24.4] (pyr-H2C(4)),
[30.6, 31.7] (pyr-H2C(3)), [46.5, 47.0] (pyr-H2C(5)), [54.7,
55.0] (pyr-HC(2)), [66.9, 67.0] (CH2Ph(CBZ)), [69.4, 69.6]
(CHN), [75.2, 75.5] (CH2O), 126.5, 126.7, 127.4, 127.6,
127.85, 127.93, 128.5, 128.7 (Ar-HC(Ph), Ar-HC(CBZ)),
136.9 (ipso-Ph(CBZ)), 142.5 (ipso-Ph), 154.8 (CvO(CBZ)),
4.3.2. (2S)-2-((4S)-4-Isopropyl-4,5-dihydro-oxazol-2-yl)-
pyrrolidine-1-carboxylic acid benzyl ester (10b). Yield:
3.98 g, 92%. Colourless oil; [a]D¼2113.6 (c 0.39, EtOH);
1H NMR (300 MHz, CDCl3): d [0.80 (d, J¼6.8 Hz), 0.86 (d,
J¼6.8 Hz), 0.87 (d, J¼6.8 Hz), 9.06 (d, J¼6.8 Hz)] (6H,
CH(CH3)2), [1.62–1.73 and 1.76–1.83] (m, 1H,

3412
H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
168.7 (CvN); IR (neat): n 3031, 2957, 2893, 1703, 1668,
1416, 1358, 1170, 985, 761, 703 cm21; MS (70 eV, EI): m/z
(%) 350 (Mþ, 11), 259 (9), 215 (15), 198 (14), 174 (100),
161 (28), 132 (8), 104 (84). Anal. Calcd for C21H22N2O3:
C, 71.98; H, 6.33; N, 7.99. Found: C, 71.80; H, 6.34; N,
7.98.
4.60 (br d, J¼8.1 Hz, 1H, pyr-HC(2)), 5.06–5.19 (m, 2H,
CH2Ph(CBZ)), 7.27–7.34 (m, 5H, Ar-HC(CBZ)); 13C NMR
(75 MHz, CDCl3): d [23.7, 24.4] (pyr-H2C(4)), [26.0, 27.0]
(C(CH3)3) [30.8, 32.0] (pyr-H2C(3)), [33.7, 34.0]
(C(CH3)3), [46.6, 47.2] (pyr-H2C(5)), [54.8. 55.2] (pyr-
HC(2)), [63.1, 67.0] (CH2Ph(CBZ)), 69.2 (CH2O), 75.9
(CHN), 127.9, 128.0, 128.4, 128.6, 128.8 (Ar-HC(CBZ)),
137.1 (ipso-Ph), 154.9 (CvO(CBZ)), 167.4 (CvN)); IR
(neat): n 2956, 2879, 1709, 1675, 1414, 1358, 1194, 1116,
979, 789, 698 cm21; MS-ESþ (CH3CN): m/z 331 (MþHþ,
100%). Anal. Calcd for C19H26N2O3: C, 69.06; H, 7.93; N,
8.48. Found: C, 68.78; H, 7.99; N, 8.34.
4.3.5. (2S)-2-((4R)-4-Phenyl-4,5-dihydro-oxazol-2-yl)-
pyrrolidine-1-carboxylic acid benzyl ester (10e). Yield:
1
4.51 g, 94%. Yellow oil; [a]D¼216.9 (c 0.46, EtOH); H
NMR (300 MHz, CDCl3): d 1.91–2.01 (br m, 1H, pyr-
H2C(4)), 2.06–2.14 (br m, 2H, pyr-H2C(4), pyr-H2C(3)),
2.21–2.34 (br m, 1H, pyr-H2C(3)), 3.48–3.58 (br m, 1H,
pyr-H2C(5)), 3.60–3.69 (br m, 1H, pyr-H2C(5)), [3.94 (app
t, J¼8.3 Hz) and 4.08 (app t, J¼7.9 Hz)] (1H, CH2O/CHN,
ratio 1.0:1.0), 4.54 (app t, J¼8.8 Hz, 0.5H, CH2O/CHN),
4.63–4.69 (m, 1.5H, pyr-HC(2), CH2O/CHN(0.5H)), 5.05–
5.24 (m, 3H, CH2Ph(CBZ), CH2O/CHN), 7.11–7.13 (br m,
1H, Ar-HC(Ph)), 7.24–7.36 (m, 9H, Ar-HC(Ph), Ar-
HC(CBZ)); 13C NMR (75 MHz, CDCl3): d [23.6, 24.4]
(pyr-H2C(4)), [30.6, 31.9] (pyr-H2C(3)), [46.5, 47.1] (pyr-
H2C(5)), [54.6, 55.0] (pyr-HC(2)), [66.9, 67.0] (CH2-
Ph(CBZ)), [69.6, 69.7] (CHN), [75.1, 75.5] (CH2O),
126.6, 126.7, 127.4, 127.6, 127.8, 127.9, 128.5, 128.7 (Ar-
HC(Ph), Ar-HC(CBZ)), 136.9 (ipso-Ph(CBZ)), [142.1,
142.5] (ipso-Ph), 154.6 (CvO(CBZ)), [168.6, 168.9]
(CvN); IR (neat): n 3029, 2956, 2892, 1704, 1667, 1454,
1416, 1358, 1170, 1116, 984, 770, 699 cm21; MS (70 eV,
EI): m/z (%) 350 (Mþ, 16), 259 (13), 215 (15), 198 (58), 174
(100), 161 (29), 132 (9), 104 (76). Anal. Calcd for
C21H22N2O3: C, 71.98; H, 6.33; N, 7.99. Found: C, 71.72;
H, 6.44; N, 7.81.
4.3.8. (2S)-2-((4S)-4-Methyl-4,5-dihydro-oxazol-2-yl)-
pyrrolidine-1-carboxylic acid benzyl ester (10h). Yield:
3.67 g, 93%. Colourless oil; [a]D¼2112.4 (c 1.09, EtOH);
1H NMR (300 MHz, CDCl3): d [1.12 (d, J¼6.2 Hz) and
1.23 (d, J¼6.4 Hz)] (3H, CH3, ratio 1.2:1), 1.87–1.93 (br m,
1H, pyr-H2C(4)), 1.96–2.10 (br m, 2H, pyr-H2C(4), pyr-
H2C(3)), 2.12–2.23 (br m, 1H, pyr-H2C(3)), 3.42–3.53 (m,
1H, pyr-H2C(5)), 3.55–3.65 (m, 1H, pyr-H2C(5)), [3.69
(app t, J¼6.6 Hz) and 3.82 (app t, J¼7.4 Hz)] (1H, CH2O,
ratio 1.2:1), 3.98–4.22 (m, 1.5H, CHN, CH2O), 4.33 (app t,
J¼8.3 Hz, 0.5H, CH2O), 4.50–4.58 (m, 1H, pyr-HC(2)),
5.02 (d, J¼12.6 Hz), 5.10 (d, J¼12.6 Hz), 5.18 (d,
J¼12.6 Hz), 5.25 (d, J¼12.6 Hz)] (2H, CH2Ph(CBZ)),
7.30–7.34 (m, 5H, Ar-HC(CBZ)); 13C NMR (75 MHz,
CDCl3): d [21.6, 21.7] (CH3), [23.7, 24.5] (pyr-H2C(4)),
[30.6, 31.6] (pyr-H2C(3)), [46.7, 47.2] (pyr-H2C(5)), [54.7
55.2] (pyr-HC(2)), 61.6 (CHN), [66.9, 67.1] (CH2Ph(CBZ)),
[74.5, 74.6] (CH2O), 127.9, 128.0, 128.1, 128.55, 128.60
(Ar-HC(CBZ)), 137.1 (ipso-Ph(CBZ)), [154.7, 154.9]
(CvO(CBZ)), [167.1, 167.3] (CvN); IR (neat): 2971,
2890, 1708, 1671, 1449, 1416, 1356, 1172, 1106, 977, 769,
701 cm21; MS-ESþ (CH3CN): m/z 289 (MþHþ, 100%).
Anal. Calcd for C16H20N2O3: C, 66.65; H, 6.99; N, 9.72.
Found: C, 66.41; H, 6.86; N, 9.73.
4.3.6. (2S)-2-((4S)-4-tert-Butyl-4,5-dihydro-oxazol-2-yl)-
pyrrolidine-1-carboxylic acid benzyl ester (10f). Yield:
3.98 g, 88%. Colourless oil; [a]D¼2120.3 (c 0.30, EtOH);
1H NMR (300 MHz, CDCl3): d [0.82 (s) and 0.87 (s)] (9H,
C(CH3)3, ratio 1.5:1), 1.85–1.94 (br m, 1H, pyr-H2C(4)),
1.96–2.04 (br m, 2H, pyr-H2C(4), pyr-H2C(3)), 2.10–2.26
(br m, 1H, Pyr-H2C(3)), 3.42–3.62 (m, 2H, pyr-H2C(5)),
3.70 (app t, J¼7.7 Hz, 0.5H, CH2O/CHN), 3.83–4.00 (m,
1.5H, CH2O/CHN), 4.07–4.20 (m, 1H, CH2O/CHN), 4.56–
4.60 (m, 1H, pyr-HC(2)), 5.04–5.23 (m, 2H, CH2Ph(CBZ)),
7.27–7.34 (m, 5H, Ar-HC(CBZ)); 13C NMR (75 MHz,
CDCl3): d [23.6, 24.3] (pyr-H2C(4)), 25.7 (C(CH3)3), [30.7,
31.8] (pyr-H2C(3)), 33.6 (C(CH3)3), [46.5, 47.0] (pyr-
H2C(5)), [54.7, 55.1] (pyr-HC(2)), 66.7 (CH2Ph(CBZ)),
[68.9, 69.1] (CH2O), 75.7 (CHN), 127.4, 127.9, 128.4 (Ar-
HC(CBZ)), 136.9 (ipso-Ph(CBZ)), 154.6 (CvO(CBZ)),
[166.8, 167.1] (CvN); IR (neat): n 2954, 2892, 1709, 1674,
1413, 1356, 1172, 1117, 982, 769 cm21; MS (70 eV, EI):
m/z (%) 330 (Mþ, 45), 273 (15), 229 (34), 195 (22), 154
(100), 141 (17), 114 (6). Anal. Calcd for C19H26N2O3: C,
69.06; H, 7.93; N, 8.48. Found: C, 68.69; H, 7.81; N, 8.26.
4.3.9. (2S)-2-((4S)-4-Benzyl-4,5-dihydro-oxazol-2-yl)-
pyrrolidine-1-carboxylic acid benzyl ester (10i). Yield:
4.89 g, 98%. Colourless oil; [a]D¼2101.7 (c 0.39, EtOH);
1H NMR (300 MHz, CDCl3): d 1.83–2.01 (m, 3H, pyr-
H2C(4), pyr-H2C(3)), 2.07–2.25 (m, 1H, pyr-H2C(3)), [2.46
(dd, J¼13.8, 8.5 Hz) and 2.65 (dd, J¼13.8, 8.5 Hz)] (1H,
CH2Ph, ratio 1.2:1.0), [2.96 (dd, J¼13.8, 4.8 Hz) and 3.08
(dd, J¼13.8, 4.8 Hz)] (1H, CH2Ph, ratio 1.2:1.0), 3.41–3.62
(m, 2H, pyr-H2C(5)), 3.81–3.96 (m, 1.5H, CH2O), 4.03
(app t, J¼7.9 Hz, 0.5H, CH2O), [4.19–4.29 (m) and 4.36–
4.46 (m)] (1H, CHN, ratio 1.2:1.0), 4.51–4.59 (m, 1H, pyr-
HC(2)), [5.02 (d, J¼12.6 Hz), 5.12 (d, J¼12.6 Hz), 5.19 (d,
J¼12.6 Hz) and 5.26 (d, J¼12.6 Hz)] (2H, CH2Ph(CBZ)),
7.10–7.34 (m, 10H, Ar-HC(Ph), Ar-HC(CBZ)); 13C NMR
(75 MHz, CDCl3): d [23.7, 24.5] (pyr-H2C(4)), [30.6, 31.6]
(pyr-H2C(3)), [41.6, 41.7] (CH2Ph), [46.7, 47.2] (pyr-
H2C(5)), [54.8, 55.2] (pyr-HC(2)), [67.0, 67.1] (CH2-
Ph(CBZ)), [67.2, 67.3] (CHN), [72.1, 72.2] (CH2O),
126.7, 128.1, 128.6, 128.7, 129.55, 129.64 (Ar-HC(Ph),
Ar-HC(CBZ)), 137.1 (ipso-Ph(CBZ)), [137.9, 138.1] (ipso-
Ph), 154.7 (CvO(CBZ)), 168.1 (CvN); IR (neat): n 2959,
2896, 1709, 1670, 1415, 1357, 1168, 1117, 980, 699,
624 cm21; MS-ESþ (CH3CN): m/z 365 (MþHþ, 100%).
Anal. Calcd for C22H24N2O3: C, 72.50; H, 6.64; N, 7.69.
Found: C, 72.40; H, 6.79; N, 7.52.
4.3.7. (2R)-2-((4S)-4-tert-Butyl-4,5-dihydro-oxazol-2-yl)-
pyrrolidine-1-carboxylic acid benzyl ester (10g). Yield:
3.39 g, 75%. Colourless oil; [a]D¼þ36.8 (c 0.13, EtOH);
1H NMR (300 MHz, CDCl3): d [0.80(s) and 0.89 (s)] (9H,
C(CH3)3, ratio 1.1:1), 1.87–1.93 (br m, 1H, pyr-H2C(4)),
1.96–2.23 (br m, 3H, pyr-H2C(4), pyr-H2C(3)), 3.45–3.64
(m, 2H, pyr-H2C(5)), [3.74–3.89 (m, 1.2H), 3.97 (app t,
J¼8.1 Hz, 0.5H), 4.04–4.22 (m, 1.2H)] (3H, CHN, CH2O),

H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
3413
4.4. Deprotection of the CBZ-oxazolines
(dd, J¼9.4, 8.2 Hz, 1H, CH2O); 13C NMR (75 MHz,
CDCl3): d 18.1 (CH(CH3)2), 18.9 (CH(CH3)2), 25.8 (pyr-
H2C(4)), 30.6 (pyr-H2C(3)), 32.6 (CH(CH3)2), 47.2 (pyr-
H2C(5)), 55.6 (pyr-HC(2)), 70.5 (CH2O), 71.8 (CHN),
169.4 (CvN); IR (neat): n 3340, 2962, 2873, 1667, 1465,
1367, 1204, 1190, 1098, 988, 946, 789 cm21; MS-ESþ
(CH3CN): m/z (183 (MþHþ, 80%); HRMS (ESþ) calcd. for
C10H19N2O [MþH]þ: 183.1497, found: 183.1490.
An oven-dried Schlenk tube was charged with 10% Pd/C
(0.810 g) and to this was added cyclohexene (14.2 mL,
140 mmol). A solution of the protected oxazoline
(10.13 mmol) in 10 mL of dry MeOH was added via
syringe and the resulting black suspension was heated at
reflux under a nitrogen atmosphere until TLC (10% MeOH
in AcOEt) showed complete reaction (1–15 h). After
cooling to room temperature, the reaction mixture was
filtered through a pad of celite, washed thoroughly with
MeOH and the filtrate was concentrated in vacuo to give
product. The crude product was then purified by flash
column chromatography on silica gel (3x30 cm) using 20%
pet. ether(40–60 8C)/MeOH or 20% MeOH/AcOEt as the
eluent.
4.4.4. (4S)-4-Phenyl-2-pyrrolidin-(2S)-2-yl-4,5-dihydro-
oxazole (6d). Yield: 1.01 g, 46%. Yellow oil;
[a]D¼þ37.6 (c 0.25, EtOH); 1H NMR (300 MHz,
CDCl3): d 1.72 (br s, 1H, NH), 1.78–1.90 (m, 2H, pyr-
H2C(4)), 1.92–2.04 (m, 1H, pyr-H2C(3)), 2.09–2.19 (m,
1H, pyr-H2C(3)), 2.91–2.99 (m, 1H, pyr-H2C(5)), 3.10–
3.19 (m, 1H, pyr-H2C(5)), 3.93–4.00 (m, 1H, pyr-HC(2)),
[4.137 (app t, J¼8.2 Hz) and 4.144 (app t, J¼8.2 Hz)] (1H,
CH2O/CHN), [4.65 (dd, J¼8.3, 1.3 Hz) and 4.68 (dd, J¼8.3,
1.3 Hz)] (1H, CH2O/CHN), 5.18 (app t, J¼8.3 Hz, 1H,
CH2O/CHN), 7.21–7.38 (m, 5H, Ar-HC(Ph)); 13C NMR
(75 MHz, CDCl3): 25.9 (pyr-H2C(4)), [30.6, 30.8] (pyr-
H2C(3)), 47.2 (pyr-H2C(5)), 55.6 (pyr-HC(2)), [69.46,
69.52] (CHN), 75.5 (CH2O), [126.77, 126.80], 127.8,
[128.96, 128.98] (Ar-HC(Ph)) [142.40, 142.48] (ipso-Ph),
[171.01, 171.07] (CvN); IR (neat): n 3324, 2959, 2874,
1661, 699 cm21; MS (70 eV, EI): m/z (%) 216 (Mþ, 4), 174
(28), 161(4), 120 (76), 104 (100); HRMS (ESþ) calcd. for
C13H17N2O [MþH]þ: 217.1341, found: 217.1347.
4.4.1. 2-Pyrrolidin-(2S)-2-yl-4,5-dihydro-oxazole (6a).
Yield: 0.70 g, 49%. Yellow oil; [a]D¼25.2 (c 1.8,
1
MeOH); H NMR (300 MHz, CDCl3): d¼1.72–1.95 (m,
3H, pyr-H2C(4), pyr-H2C(3)), 2.00–2.13 (m, 1H, pyr-
H2C(3)), 2.43 (br s, 1H, NH), 2.88–2.95 (m, 1H, pyr-
H2C(5)), 3.05–3.13 (m, 1H, pyr-H2C(5)), 3.80–3.87 (m,
3H, CH2O/CH2N, pyr-HC(2)), 4.29 (app t, J¼9.3 Hz, 2H,
CH2N/CH2O); 13C NMR (75 MHz, CDCl3): d 25.6 (pyr-
H2C(4)), 30.1 (pyr-H2C(3)), 46.9 (pyr-H2C(5)), 54.1
(CH2N), 55.3 (pyr-HC(2)), 67.9 (CH2O), 170.4 (CvN);
IR (neat): n 3317, 2938, 1649, 1569, 1406, 1350,
1072 cm21; MS-ESþ (MeOH): m/z 141 (MþHþ, 100%);
HRMS (ESþ) calcd. for C7H12N2O [MþH]þ: 141.1028,
found: 141.1023.
4.4.5. (4R)-4-Phenyl-2-pyrrolidin-(2S)-2-yl-4,5-dihydro-
oxazole (6e). Yield: 0.88 g, 40%. Yellow oil; [a]D¼þ132.9
1
(c 0.24, EtOH); H NMR (300 MHz, CDCl3): d 1.64 (br s,
4.4.2. (4S)-4-Isopropyl-2-pyrrolidin-(2S)-2-yl-4,5-di-
hydro-oxazole (6b). Yield: 1.64 g, 89%. Yellow oil;
[a]D¼291.0 (c 0.48, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.87 (app d, J¼6.7 Hz, 3H, CH(CH3)2), [0.94
(d, J¼6.9 Hz) and 0.95 (d, J¼6.7 Hz)] (3H, CH(CH3)3),
1.69–1.93 (m, 4H, pyr-H2C(4), pyr-H2C(3), CH(CH3)2),
2.03–2.13 (m, 1H, pyr-H2C(3)), 2.22 (br s, 1H, NH), 2.87–
2.95(m, 1H, pyr-H2C(5)), 3.08–3.14 (m, 1H, pyr-H2C(5)),
3.82–3.94 (m, 2H, CHN, pyr-HC(2)), [3.99 (app t,
J¼7.8 Hz,) and 4.00 (app t, J¼7.8 Hz)] (1H, CH2O), 4.26
(dd, J¼9.5, 8.2 Hz, 1H, CH2O); 13C NMR (75 MHz,
CDCl3): d [18.0, 18.1] (CH(CH3)2), 18.8 (CH(CH3)2),
[25.6, 25.8] (pyr-H2C(4)), 30.5 (pyr-H2C(3)), [32.5, 32.6]
(CH(CH3)2), [47.07, 47.10] (pyr-H2C(5)), [55.46, 55.50]
(pyr-HC(2)), [70.4, 70.5] (CH2O), [71.7, 71.9] (CHN),
[169.2, 169.3] (CvN); IR (neat): n 3344, 2962, 2873, 1667,
1479, 1363, 1203, 1105, 985, 946 cm21; MS (70 eV, EI):
m/z (%) 182 (Mþ, 35), 153 (15), 140 (100), 127 (62), 111
(41), 84 (30), 70 (81); HRMS (ESþ) calcd. for C10H19N2O
[MþH]þ: 183.1497, found: 183.1488.
1H, NH), 1.79–1.90 (m, 2H, pyr-H2C(4)), 1.93–2.04 (m,
1H, pyr-H2C(3)), 2.09–2.21 (m, 1H, pyr-H2C(3)), 2.91–
2.99 (m, 1H, pyr-H2C(5)), 3.10–3.19 (m, 1H, pyr-H2C(5)),
3.93–4.00 (m, 1H, pyr-HC(2)), [4.137 (app t, J¼8.2 Hz)
and 4.144 (app t, J¼8.2 Hz)] (1H, CH2O/CHN), [4.65 (dd,
J¼8.5, 1.5 Hz) and 4.68 (dd, J¼8.5, 1.6 Hz)] (1H, CH2O/
CHN), 5.18 (app t, J¼8.5 Hz, 1H, CH2O/CHN), 7.21–7.37
(m, 5H, Ar-HC(Ph)); 13C NMR (75 MHz, CDCl3): d 25.9
(pyr-H2C(4)), [30.6, 30.7] (pyr-H2C(3)), 47.2 (pyr-H2C(5)),
55.6 (pyr-HC(2)), [69.46, 69.52] (CHN), 75.5 (CH2O),
[126.76, 126.80], 127.8, [128.96, 128.97] (Ar-HC(Ph)),
[142.42, 142.49] (ipso-Ph), [171.02, 171.07] (CvN); IR
(neat): n 3321, 2969, 1661, 1174, 987, 700 cm21; MS
(70 eV, EI): m/z (%) 216 (Mþ, 11), 198 (21), 174 (45), 161
(50), 132 (6), 120 (96), 104 (100); HRMS (ESþ) calcd. for
C13H17N2O [MþH]þ: 217.1341, found: 217.1338.
4.4.6. (4S)-4-tert-Butyl-2-pyrrolidin-(2S)-2-yl-4,5-di-
hydro-oxazole (6f). Yield: 0.95 g, 48%. Yellow oil;
[a]D¼2150.2 (c 0.26, EtOH); 1H NMR (300 MHz,
CDCl3): d 0.88 (s, 9H, C(CH3)3), 1.69–1.92 (m, 3H, pyr-
H2C(4), pyr-H2C(3)), 2.01–2.12 (m, 1H, pyr-H2C(3), 2.27
(br s, 1H, NH), 2.86–2.93 (m, 1H, pyr-H2C(5)), 3.04–3.16
(m, 1H, pyr-H2C(5)), 3.80–3.87 (m, 2H, pyr-HC(2), CHN),
4.09 (app t, J¼8.6 Hz, 1H, CH2O), 4.20 (dd, J¼9.9, 8.6 Hz,
1H, CH2O); 13C NMR (75 MHz, CDCl3): d 25.9 (C(CH3)3),
26.0 (pyr-H2C(4), 30.7 (pyr-H2C(3)), 33.8 (C(CH3)3), 47.3
(pyr-H2C(5)), 55.7 (pyr-HC(2)), 69.3 (CH2O), 75.6 (CHN),
169.3 (CvN); IR (neat): n 3378, 2960, 2871, 1668,
1364 cm21; MS (70 eV, EI): m/z (%) 196 (Mþ, 18), 195
(22), 168 (25), 154 (100), 141 (100), 122 (23), 111 (96);
4.4.3. (4R)-4-Isopropyl-2-pyrrolidin-(2S)-2-yl-4,5-di-
hydro-oxazole (6c). Yield: 1.24 g, 67%. Yellow oil;
[a]D¼þ51.9 (c 0.16, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.87 (d, J¼6.7 Hz, 3H, CH(CH3)2), [0.94 (d,
J¼6.7 Hz) and 0.95 (d, J¼6.7 Hz)] (3H, CH(CH3)2), 1.71–
1.99 (m, 4H, pyr-H2C(4), Pyr-H2C(3), CH(CH3)2), 2.01–
2.13 (br m, 2H, NH, pyr-H2C(3)), 2.86–2.95 (m, 1H, pyr-
H2C(5)), 3.08–3.15 (m, 1H, pyr-H2C(5)), 3.82–3.88 (m,
1H, pyr-HC(2)), 3.88–3.95 (m, 1H, CHN), [3.99 (app t,
J¼7.8 Hz) and 4.00 (app t, J¼7.8 Hz)] (1H, CH2O), 4.26

3414
H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
HRMS (ESþ) calcd. for C11H21N2O [MþH]þ: 197.1654,
nitrogen atmosphere. Reaction tubes containing the metal
pre-catalyst (5.00 mmol metal) were placed in one reaction
block and to these were added ligand (as a solution in iPrOH
(approx. 300 mL) and dry iPrOH (approx. 2700 mL to bring
the total volume to 3000 mL). The resulting mixtures were
then heated at reflux for 30 min. After cooling to 25 8C,
catalyst solution (1500 mL, 2.50 mmol) from each of the
reaction vessels was transferred to the corresponding
reaction tube in the second reaction block to which
acetophenone (59 mL, 0.50 mmol) and dry iPrOH
(3428 mL) had previously been added. The reactions were
initiated by the addition of KOiPr (12.5 mL of a 1 M iPrOH
solution, 12.5 mmol) to each reaction tube. The reactions
were monitored by taking samples after 1 h and 10 h and
were analysed by GC using a CP-Chirasil-Dex CB column
(25 m, 0.25 mm (diam.), 25 mm). GC conditions: 100–
130 8C (1.3 8C min21) then 130–180 8C (30 8C min21).
Retention times: (R)-1-phenylethanol 12.34 min, (S)-1-
phenylethanol 13.14 min.
found: 197.1651.
4.4.7. (4S)-4-tert-Butyl-2-pyrrolidin-(2R)-2-yl-4,5-di-
hydro-oxazole (6g). Yield: 1.09 g, 55%. Yellow oil;
[a]D¼240.1 (c 0.44, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.88 (s, 9H, (C(CH3)3), 1.73–1.90 (m, 3H, pyr-
H2C(4), pyr-H2C(3)), 1.99–2.10 (m, 1H, pyr-H2C(3)), 2.38
(br s, 1H, NH), 2.87–2.94 (m, 1H, pyr-H2C(5)), 3.09–3.16
(m, 1H, pyr-H2C(5)), 3.80–3.86 (m, 2H, CHN, pyr-HC(2)),
4.09 (app t, J¼8.6 Hz, 1H, CH2O), 4.2 (dd, J¼9.8, 8.6 Hz,
1H, CH2O); 13C NMR (75 MHz, CDCl3): d 25.7 (pyr-
H2C(4)), 26.0 (C(CH3)3), 30.7 (pyr-H2C(3)), 33.9
(C(CH3)3), 47.2 (pyr-H2C(5)), 55.6 (pyr-HC(2)), 69.3
(CH2O), 75.5 (CHN), 169.3 (CvN); IR (neat): n 3312,
2959, 2908, 2860, 1669, 1478, 1364, 1207, 1176, 1105, 983,
943 cm21; MS-ESþ (CH3CN): m/z 197 (MþHþ, 88%);
HRMS (ESþ) calcd. for C11H21N2O [MþH]þ: 197.1654,
found: 197.1661.
4.4.8. (4S)-4-Methyl-2-pyrrolidin-(2S)-2-yl-4,5-dihydro-
oxazole (6h). Yield: 0.86 g, 55%. Yellow oil; [a]D¼290.6
4.6. General procedure for transfer hydrogenation using
[Ir(cod)Cl]2
1
(c 0.32, CHCl3); H NMR (300 MHz, CDCl3): d [1.25 (d,
J¼6.6 Hz) and 1.25 (d, J¼6.6 Hz)] (3H, CH3), 1.74–1.93
(m, 3H, pyr-H2C(4), pyr-H2C(3)), 2.01–2.39 (m, 2H, NH,
pyr-H2C(3)), 2.87–2.95 (m, 1H, pyr-H2C(5)), 3.06–3.14
(m, 1H, pyr-H2C(5)), 3.78–3.85 (m, 2H, CH2O, pyr-
HC(2)), 4.12–4.19 (m, 1H, CHN), [4.371 (app t,
J¼9.2 Hz) and 4.374 (app t, J¼9.2 Hz)] (1H, CH2O); 13C
NMR (75 MHz, CDCl3): d [21.57, 21.61] (CH3), [25.80,
25.83] (pyr-H2C(4)), 30.4 (pyr-H2C(3)), 47.2 (pyr-H2C(5)),
55.5 (pyr-HC(2)), 61.4 (CHN), [74.59, 74.63] (CH2O),
[169.4, 169.5] (CvN); IR (neat): n 3318, 2971, 2889, 1664,
An oven-dried schlenk tube was charged with [Ir(cod)Cl]2
(1.7 mg, 2.53£1023mmol). To this was added a solution of
i
the ligand (1.01£1023mmol, 2.0 equiv./Ir) in dry PrOH
(0.5 mL) and dry iPrOH (4.5 mL). The resulting suspension
was heated at reflux under a nitrogen atmosphere for 30 min
to give a yellow solution. After cooling to room tempera-
ture, dry iPrOH (5 mL) and acetophenone (117 mL, 1 mmol)
were added and the reaction was started by the addition of
KOiPr (25 mL of a 1 M solution in iPrOH). The reaction was
allowed to stir at room temp. under an atmosphere of
nitrogen and was monitored at time intervals by quenching
aliquots of the reaction mixture with a 10% acetic
acid/iPrOH solution. The aliquots were filtered through a
pad of silica and the conversion and enantioselectivity of the
sample were determined by chiral GC analysis using a
Supelco b-Dex 120 chiral capillary column (30 m, 0.25 mm
(diam.), 0.25 mm). Retention times: 120 8C, (R)-1-phenyl-
ethanol 19.93 min, (S)-1-phenylethanol 21.15 min.
1450, 1363, 1287, 1203, 1178, 1106, 1068, 985, 949 cm21
;
MS-ESþ (CH3CN): m/z 155 (MþHþ, 100%); HRMS
(ESþ) calcd. for C8H15N2O [MþH]þ: 155.1184, found:
155.1188.
4.4.9. (4S)-4-Benzyl-2-pyrrolidin-(2S)-2-yl-4,5-dihydro-
oxazole (6i). Yield: 1.58 g, 68%. Yellow oil; [a]D¼237.4
1
(c 0.77, CHCl3); H NMR (300 MHz, CDCl3): 1.71–1.90
(m, 3H, pyr-H2C(4), pyr-H2C(3)), 2.00–2.11 (m, 1H, pyr-
H2C(3)), 2.17 (br s, 1H, NH), [2.64 (dd, J¼8.5, 4.4 Hz) and
2.69 (dd, J¼8.5, 4.4 Hz)] (1H, CH2Ph), 2.87–2.95 (m, 1H,
pyr-H2C(5)), 3.05–3.14 (m, 2H, CH2Ph, pyr-H2C(5)),
3.80–3.84 (m, 1H, pyr-HC(2)), 4.01 (app t, J¼7.5 Hz, 1H,
CH2O), 4.18–4.24 (m, 1H, CH2O), 4.32–4.44 (m, 1H,
CHN), 7.18–7.32 (m, 5H, Ar-HC(Ph)); 13C NMR (75 MHz,
CDCl3): d [25.8, 25.9] (pyr-H2C(4)), [30.3, 30.4] (pyr-
H2C(3)), [41.7, 41.9] (CH2Ph), 47.2 (pyr-H2C(5)), [55.4,
55.5] (pyr-HC(2)), [67.0, 67.2] (CHN), [72.3, 72.4] (CH2O),
126.7, [128.68, 128.72], [129.52, 129.59] (Ar-HC(Ph),
[137.9, 138.0] (ipso-Ph), 170.1 (CvN); IR (neat): n 3326,
2964, 2881, 1664, 1496, 1463, 1365, 1203, 1777, 1105, 985,
949, 754, 700 cm21; MS-ESþ (CH3CN): m/z 231 (MþHþ,
30%); HRMS (ESþ) calcd. for C14H19N2O [MþH]þ:
231.1497, found: 231.1489.
4.7. General procedure for transfer hydrogenation using
[Ru(p-cymene)Cl2]2
An oven-dried schlenk tube was charged with [Ru(p-
cymene)Cl2]2 (7.7 mg, 1.25£1022 mmol). To this was
added a solution of the ligand (0.05 mmol, 2.0 equiv./Ru)
i
i
in dry PrOH (0.5 mL) and dry PrOH (2.0 mL). The
resulting suspension was heated at reflux under a nitrogen
atmosphere for 30 min to give an orange/brown solution.
After cooling to room temperature, dry iPrOH (2.5 mL) and
acetophenone (59 mL, 0.5 mmol) were added and the
reaction was started by the addition of KOiPr (125 mL of
a 1 M solution in iPrOH) which resulted in an instantaneous
red reaction mixture. The reaction was allowed to stir at
room temp. under an atmosphere of nitrogen and was
monitored at time intervals by quenching aliquots of the
reaction mixture with a 10% acetic acid/iPrOH solution. The
aliquots were filtered through a pad of silica and the
conversion and enantioselectivity of the sample were
determined by chiral GC analysis using a Supelco b-Dex
120 chiral capillary column (30 m, 0.25 mm (diam.),
4.5. General procedure for metal screening and
optimisation:
All reactions were carried out using Chemspeedw ASW
2000 apparatus equipped with two reaction blocks under a

H. A. McManus et al. / Tetrahedron 60 (2004) 3405–3416
3415
3116–3122. (c) Nordin, S. J. M.; Roth, P.; Tarnai, T.; Alonso,
0.25 mm). Retention times: 120 8C, (R)-1-phenylethanol
19.93 min, (S)-1-phenylethanol 21.15 min.
D. A.; Brandt, P.; Andersson, P. G. Chem. Eur. J. 2001, 7,
´
`
1431–1436. (d) Pasto, M.; Riera, A.; Pericas, M. A. Eur.
J. Org. Chem. 2002, 2337–2341. (e) Everaere, K.; Mortreux,
A.; Carpentier, J.-F. Adv. Synth. Catal. 2003, 345, 67–77.
(f) Takehara, J.; Hashiguchi, S.; Fujii, A.; Inoue, S.; Ikariya,
T.; Noyori, R. Chem. Commun. 1996, 233–234. (g) Petra,
D. G. I.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz,
K.; van Loon, A. M.; de Vries, J. G.; Schoemaker, H. E. Eur.
J. Inorg. Chem. 1999, 2335–2341. (h) Patti, A.; Pedotti, S.
Tetrahedron: Asymmetry 2003, 14, 597–602. (i) Petra, D. G.
I.; Reek, J. N. H.; Handgraaf, J.-W.; Meijer, E. J.; Dierkes, P.;
Kamer, P. C. J.; Brussee, J.; Schoemaker, H. E.; van Leeuwen,
P. W. N. M. Chem. Eur. J. 2000, 6, 2818–2828.
Acknowledgements
We thank Enterprise Ireland for the award of a Research
Scholarship (BR/99/239) and UCD for a Research Demon-
stratorship to H.McM. We also acknowledge Enterprise
Ireland International Collaboration Grant (IC/2002/078) for
funding the research visit of H.McM. to Uppsala and the
Dublin-Uppsala collaboration. We also wish to thank Mr.
Stefan Modin (Uppsala) for his advice on the operation of
the Chemspeedw ASW 2000 equipment. This collaboration
was fostered under the COST D24 Chemistry Action.
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