Synthesis of enantiomerically pure tertiary 1,2-aminoalcohols by the highly diastereoselective reductive ring opening of oxazolidines

Article abstract of DOI:10.1016/j.tet.2007.08.053

A number of enantiomerically pure 1,2-aminoalcohols containing tertiary nitrogen atoms bearing chiral substituents have been prepared by highly diastereoselective reductive ring cleavage of oxazolidines derived from ketones and pseudoephedrine or ephedrin

Full text of DOI:10.1016/j.tet.2007.08.053

Tetrahedron 63 (2007) 10991–10999
Synthesis of enantiomerically pure tertiary 1,2-aminoalcohols
by the highly diastereoselective reductive ring opening
of oxazolidines
a
a
a
Philip C. Bulman Page,a, Benjamin R. Buckley, Mark R. J. Elsegood, Colin M. Hayman,
*
Harry Heaney,a, Gerasimos A. Rassias,a,b Salem A. Taliba and John Liddlea,b
*
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
bGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 24 May 2007; revised 27 July 2007; accepted 16 August 2007
Available online 22 August 2007
Abstract—A number of enantiomerically pure 1,2-aminoalcohols containing tertiary nitrogen atoms bearing chiral substituents have been
prepared by highly diastereoselective reductive ring cleavage of oxazolidines derived from ketones and pseudoephedrine or ephedrine.
The ring cleavage occurs with retention of configuration.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
They are also easily hydrolyzed as a result of the additional
stabilization of the incipient iminium ion in the ring-opened
tautomer. Our initial attempts to prepare oxazolidines from
mixtures of ketones and ephedrine or pseudoephedrine in di-
chloromethane solution at room temperature in the presence
In connection with a number of projects in asymmetric catal-
ysis, we required a range of non-racemic chiral 1,2-amino-
alcohols, preferably containing tertiary nitrogen atoms
bearing chiral substituents. We conjectured that such com-
pounds could in principle be accessed by the reductive
cleavage of oxazolidines prepared from ephedrine and
pseudoephedrine (Fig. 1); indeed, 1,2-aminoalcohols and
oxazolidines have both been widely used as ligand pre-
cursors and as chiral auxiliaries, and 1,2-aminoalcohols as
peptide isosteres and as chiral building blocks.1
˚
of 4 A molecular sievegave no oxazolidines after 2–3 days in
the absence of any other catalyst. Experiments involving
ketones such as acetophenone and 2-acetylfuran in reactions
with ephedrine were equally unsuccessful when carried out
using camphorsulfonic acid as catalyst in the presence of
˚
4 A molecular sieve, although a reaction between pseudo-
ephedrine and isopropyl methyl ketone did proceed in dichlo-
roethane at reflux in thepresence of camphorsulfonic acid and
˚
4 A molecular sieve with poor diastereoselectivity (2:1); we
have observed that pseudoephedrine is generally more
reactive than ephedrine in these cyclocondensation reactions.
The synthesis of oxazolidines derived from aminoalcohols
and aldehydes is well documented, but oxazolidines derived
from ketones have only been reported infrequently, presum-
ably as a result of the slow rate at which they are formed.2
2. Discussion
Me
R1
R2
Me
N
R1
R2
OH
R3
R4
Me
R1
R2
We anticipated that use of a Lewis acid catalyst might meet
with more success, and we have reported that scandium tri-
N
O
Me
Me NH OH
Me
R3 R4
˚
flate in the presence of carefully dried 4 A molecular sieve
does indeed mediate the desired reaction.3 Reactions of
ketones with (1S,2R)-(ꢀ)-ephedrine or (1S,2S)-(+)-pseudo-
ephedrine were initially carried out in dichloromethane
(DCM) at room temperature or reflux, and later in 1,2-di-
R1=Ph, R2= H ephedrine
R1=H, R2= Ph pseudoephedrine
Figure 1. 1,2-Aminoalcohols from reductive cleavage of oxazolidines.
1
chloroethane (DCE) at reflux, and were monitored by H
and 13C NMR spectroscopies; the 13C NMR chemical shift
at position 2 in the oxazolidine products is observed at dC
96–99 ppm and is diagnostic. Table 1 shows a number of
Keywords: Stereoselective; Oxazolidine; Aminoalcohol; Enantiomerically
pure; Reductive cleavage; Reduction.
* Corresponding authors. E-mail: p.c.b.page@lboro.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.053

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P. C. Bulman Page et al. / Tetrahedron 63 (2007) 10991–10999
Table 1. Formation of oxazolidines 3–14 from (1S,2R)-(ꢀ)-ephedrine or (1S,2S)-(+)-pseudoephedrine using Sc(OTf)3
Me
R1
R2
Me
R1
O
4 Å mol sieves
Sc(OTf)3,15 mol%
R2
+
N
O
R3 R4
Me
NH OH
Me
R4 R3
R1=Ph, R2= H ephedrine
R1=H, R2= Ph pseudoephedrine
Substrate
b-Aminoalcohol
Producta,b
Me Ph
Conditions
Yield (%) [d.r.]
CH2Cl2, rt, 5 d
DCE, D, 12 h
92 [2:1]
94 [2:1]
N
O
Me
Me
Me
Ephedrine
Me
4
O
Me
Ph
CH2Cl2, rt, 3 d
DCE, D, 12 h
87 [4.5:1]
88 [5.7:1]
N
O
Pseudoephedrine
Me
5
Me
Ph
N
Me
6
O
CH2Cl2, rt, 14 d
DCE, D, 7 d
81 [4:1]
Ephedrine
95 [ꢁ97:1]c
O
Me
Ph
N
O
CH2Cl2, rt, 7 d
DCE, D, 2 d
99 [ꢁ97.5:1]c
96 [ꢁ97.5:1]c
Me
Me
Pseudoephedrine
Me
3
Me
Ph
N
O
O
Pseudoephedrine
DCE, D, 2 d
93 [6:1]
Me
7
Me
Ph
N
O
Me
CH2Cl2, rt, 7 d
DCE, D, 3 d
61 [1.5:1]
72 [1.75:1]
Ephedrine
N
Me
O
N
8
Me
Ph
N
O
Me
CH2Cl2, rt, 9 d
DCE, D, 3 d
68 [7.6:1]
64 [8.5:1]
Pseudoephedrine
Me
N
9
CH2Cl2, rt, 14 d
DCE, D, 8 d
NR
NR
Ephedrine
—
O
Me
Ph
N
O
Me
CH2Cl2, rt, 1 month
DCE, D, 1 week
46 [7.5:1]
Pseudoephedrine
Me
55 [ꢁ97.5:1]c
10
(continued)

P. C. Bulman Page et al. / Tetrahedron 63 (2007) 10991–10999
10993
Table 1. (continued)
Substrate
b-Aminoalcohol
Producta,b
Me Ph
Conditions
Yield (%) [d.r.]
O
N
O
Me
89 [ꢁ97.5:1]c
Me
Pseudoephedrine
DCE, D, 2 d
O2N
NO2
11
Me
Ph
O
N
O
Me
Pseudoephedrine
DCE, D, 2 d
94 [ꢁ97.5:1]c
Me
12
Me
Ph
89 [97.5:1]c,d
N
O
Me
Ephedrine
MeCN, D, 12 h
MeO2C
CO2Me
13
CO2Me
CO2Me
Me
Ph
Pseudoephedrine
MeCN, D, 12 h
93 [97.5:1]c,d
N
O
Me
MeO2C
CO2Me
14
a
Major diastereoisomer shown for clarity.
Major diastereoisomer determined by NOE analysis.
b
c
d
Only one diastereoisomer detected by 400 MHz 1H NMR spectroscopy.
Major diastereoisomer confirmed by X-ray crystallography and in agreement with NOE analysis.3
new examples together with our previously reported results
to provide a context. For example, when (1S,2S)-(+)-pseu-
doephedrine 1 was treated with isopropyl methyl ketone 2
(1.0 equiv), scandium triflate (10 mol %) and molecular
sieve, the oxazolidine 3 was formed in almost quantitative
yield, and only one diastereoisomer could be detected by
1H NMR spectroscopy (Scheme 1); the stereochemistry
was determined by NOE analysis.
that reactions carried out in 1,2-dichloroethane at reflux
are generally more stereoselective than those carried out in
dichloromethane.
We have also previously shown that the reductive cleavage
of a number of different oxazolidines can be carried out us-
ing chlorotrimethylsilane in the presence of sodium cyano-
borohydride.4 This method, however, failed in our hands
when 2,2-dialkyl oxazolidines derived from ketones were
used as substrates. A number of alternative potential reduc-
ing agents were considered, including polymethyl hydro-
siloxane5 and chlorodibutyltin hydride–HMPA complex.6
We also noted that reductive cleavage of the C–N bond in
cyclic amidines has been reported using DIBAL.7 Further,
oxazolines have been reductively cleaved to yield carbinols
by treatment with diborane in tetrahydrofuran8 and by treat-
ment with chloromethyl methyl ether followed by reaction
with DIBAL.9 In addition, 2-aryl-4,4-dimethyl-2-oxazolines
and trans-(4S,5S)-2-aryl-(4-methoxymethyl)-5-phenyl-2-
oxazolines give the corresponding aminoalcohols when
treated with DIBAL.10 A few examples of the reductive
ring cleavage of oxazolidines by DIBAL have previously
been reported.2e,f We therefore focused our attention on
the use of DIBAL. Although, presumably due to reduced
reactivity, DIBAL in tetrahydrofuran did not effect the re-
ductive cleavage of (2S,4S,5S)-2-isopropyl-5-phenyl-2,3,4-
trimethyloxazolidine 3, we were pleased to observe that
the corresponding 2-aminoethanol derivative 15 was pro-
duced with very high diastereoselectivity and in high yield
Ph
Sc(OTf)3 (15 Mol%)
4 Å Mol Sieves
O
Ph
+
O
N
CH2Cl2 , r.t. 2 weeks or
C2H4Cl2, reflux 2 d
NH OH
99 % yield >97.5:1 d.r.
1
2
3
Scheme 1.
The reactions were very clean, only oxazolidine products
1
being visible in the H and 13C NMR spectra at 400 MHz;
products were isolated after stirring the reaction mixtures
with anhydrous sodium hydrogen carbonate in order to re-
move adventitious protic acid and the Lewis acid. Attempts
to purify the products further by chromatography or recrys-
tallization resulted in decomposition. One experiment was
carried out using (1S,2S)-(+)-pseudoephedrine and butanone
using indium(III) chloride but, although the yield of the
products was similar (84%), the ratio of diastereoisomers
was poor (1.2:1). Of particular interest is the observation

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P. C. Bulman Page et al. / Tetrahedron 63 (2007) 10991–10999
Ph
Ph
Ph
I) HCl (4.0 M in dioxane),
H
DIBAL,
EtOAc, 5 min
BPh4
N
O
N
OH
N
OH
Hexanes,
0 °C, 48 h,
92% yield
II) NaBPh4, MeCN, 5 min
53%
3
15
16
Scheme 2.
Table 2. Ring opening of oxazolidines using DIBAL
when the oxazolidine was treated with 1.5–2 equiv of
DIBAL in hexanes (Scheme 2). Treatment of 15 with HCl
followed by addition of sodium tetraphenylborate afforded
the corresponding ammonium salt 16, X-ray crystallo-
graphic analysis of which showed product 15 to have the
absolute configuration N-methyl-N-((2R)-2-(3-methylbutyl))-
(1S,2S)-1-phenyl-2-aminopropanol (Fig. 2), confirming
retention of configuration in the ring cleavage process.
R1
R1
Me
Me
Me N
R4
R2
DIBAL,
R2
Hexanes,
N
O
OH
H
0 °C-r.t.,
16 h.
Me
R4 R3
R3
Oxazolidine
d.r.
Producta
d.r.
Yield
(%)
Me
N
Ph
Me
N
Ph
Me
Me
OH
O
H
2:1
1.5:1
88
91
Me
4
17b
Me
N
Ph
Me
N
Ph
OH
O
H
4.5:1
4:1
Me
b
5
18
Me
N
Ph
Me
N
Ph
Figure 2. X-ray crystal structure of the cation in 16.
Me
Me
OH
O
H
Me
ꢁ97.5:1
ꢁ97.5:1
ꢁ97.5:1c 92
Following this, a range of oxazolidines were similarly treated,
providing the corresponding aminoalcohols 17–24 with high
diastereoselectivities and yields (Table 2). Reaction of 9
resulted only in decomposition of the starting material. In all
cases but one (22), the diastereoisomeric ratios of the oxazo-
lidine starting materials were mirrored by the diastereo-
isomeric ratios of the derived aminoalcohols, suggesting a
ring-opening process involving a high degree of stereoconser-
vation. The absolute configuration of 20 was also determined
by X-ray crystallography (Fig. 3). Interestingly, we were able
to isolate oxazolidine 23 from reduction of diester 14 when
using 4 equiv of DIBAL in hexanes. In order to achieve the
products 22 and 24 of reductive cleavage of 13 and 14, respec-
tively, 6 equiv of DIBAL in hexanes were required.
d
3
15
Me
N
Ph
Me
N
Ph
OH
O
H
Me
ꢁ97.5:1c 87
b
19
12
Me
N
Me
N
Ph
Ph
Me
OH
O
H
Me
ꢁ97.5:1
ꢁ97.5:1c 91
NO2
NO2
This level of retention of stereochemistry in a ring-opening
reaction that formally proceeds through an acyclic iminium
ion is remarkable and strongly suggests intramolecular
hydride delivery through an intermediate position as shown
in 25, wherein the C–O bond is lengthened and weakened,
but in which the oxazolidine ring remains intact.
d
20
11
Me
Me
N
Ph
Ph
OH
Me
N
O
H
Me
ꢁ97.5:1
ꢁ97.5:1
ꢁ97.5:1c 78
b
L
Al
21
10
Me
N
O
Me
L
R2
Me
Ph
H
Ph
OH
R1
25
N
O
Me
HO
N
O
H
3:1e 75
Me
MeO
OMe
OH
We have noted, however, that in our process, 1.5–2 equiv of
DIBAL are normally required in order to ensure high yields
and high selectivities (e.g., Scheme 3). This may suggest that
O
b
22
13
(continued)

P. C. Bulman Page et al. / Tetrahedron 63 (2007) 10991–10999
10995
Table 2. (continued)
some interaction between two molecules of DIBAL occurs
during the reaction, and in this regard it may be significant
that DIBAL in THF, a strongly chelating solvent, is ineffec-
tive. Husson has noted that in the ring-opening addition of
alkynyl aluminium species to oxazolidines, 2 equiv of the
aluminium reagent are required (addition of 1 equiv afforded
not more than 50% yield of the ring-cleaved product).11
Oxazolidine
d.r.
Producta
d.r.
Yield
(%)
Me
N
Ph
Me
Ph
O
O
N
O
ꢁ97.5:1
ꢁ97.5:1c,f 63
Me
MeO
Me
HO
OMe
OH
O
b
Other mechanistic possibilities, such as those involving C–O
bond cleavage or intermolecular hydride delivery, would not
account for the observed stereocontrol. The reasons for the
poor stereocontrol in the ephedrine-derived examples re-
main unclear, but it perhaps results from an increased
propensity for oxazolidine ring cleavage in these cases, con-
ceivably resulting from steric interaction between the
oxazolidine ring substituents.
23
14
Me
Ph
Me
N
Ph
OH
N
O
O
Me
HO
ꢁ97.5:1
ꢁ97.5:1c,e 80
H
Me
MeO
OMe
OH
O
b
24
15
a
Major diastereoisomer shown for clarity.
Major diastereoisomer assigned by analogy with known structures 15 and
20 and correlation of NMR data.
b
Only one diastereoisomer detected by 400 MHz 1H NMR spectroscopy.
Major diastereoisomer confirmed by X-ray crystallography.
Six equivalents of DIBAL used.
c
d
e
f
3. Conclusion
DIBAL in hexanes has been shown to provide a very high de-
gree of retention of configuration in reductive ring opening
of 2,2-disubstituted oxazolidines derived from ketones and
pseudoephedrine, perhaps resulting from intramolecular
hydride delivery in an intermediate with a weakened but
not broken C–O bond. Reductive ring opening of 2,2-disub-
stituted oxazolidines derived from ketones and ephedrine is
less stereoselective.
Four equivalents of DIBAL used.
4. Experimental procedures
4.1. General experimental methods
All infrared spectra were obtained using a Perkin–Elmer
Paragon 1000 FTIR spectrophotometer; thin film spectra
1
were acquired using sodium chloride plates. All H and
13C NMR spectra were obtained at 250.13 and 62.86 MHz,
respectively, with a Bruker AC 250 MHz spectrometer, or
at 400.13 and 100.62 MHz, respectively, with a Bruker
DPX 400/Avance 400 MHz spectrometer, in deuteriochloro-
form solution unless otherwise stated, using TMS (tetra-
methylsilane) as the internal reference. Mass spectra were
recorded using a Jeol-SX102 instrument utilizing electron-
impact (EI) or fast atom bombardment (FAB) and by the
EPSRC National Mass Spectrometry Service Centre at the
University of Wales, Swansea, utilizing electrospray (ES).
Analysis by GC–MS utilized a Fisons GC 8000 series (AS
800), with a 15 mꢂ0.25 mm DB-5 column and an elec-
tron-impact low-resolution mass spectrometer. Melting
points were recorded using an Electrothermal-IA 9100 melt-
ing point instrument and are uncorrected. Optical rotation
values were measured with an Optical Activity-polAAar
2001 instrument operating at l¼589 nm, corresponding to
the sodium D line, at the temperatures indicated. Microanal-
yses were performed on a Perkin–Elmer 2400 CHN Elemen-
tal Analyzer. All chromatographic manipulations used silica
gel as the adsorbent. Reactions were monitored using thin
layer chromatography (TLC) on aluminium-backed plates
coated with Merck Kieselgel 60 F254 silica gel. TLC plates
were visualized by UV radiation at a wavelength of 254 nm,
or stained by exposure to an ethanolic solution of phospho-
molybdic acid (acidified with concentrated sulfuric acid),
Figure 3. X-ray crystal structure of 20.
Ph
Ph
Ph
+
N
O
N
O
N
OH
DIBAL 1.0 equiv.
DIBAL 1.5 equiv.
d.r. 4.5:1
d.r. 4.5:1
d.r. 5.5:1
21%
d.r. 2:1
79% Conv.
d.r. 4:1
–
100% Conv.
Ph
Ph
Ph
N
O
+
N
O
N
OH
DIBAL 1.0 equiv.
DIBAL 1.5 equiv.
d.r. >97.5:1
d.r. >97.5:1
d.r. >97.5:1
37%
d.r. 3:1
63% Conv.
d.r. >97.5:1
100% Conv.
–
Scheme 3.

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P. C. Bulman Page et al. / Tetrahedron 63 (2007) 10991–10999
followed by charring where appropriate. Reactions requiring
anhydrous conditions were carried out using flame-dried
glassware under a nitrogen atmosphere unless otherwise
stated. Reaction solvents were used as obtained commer-
cially unless otherwise stated. Light petroleum (bp 40–
60 ꢃC) was distilled from calcium chloride prior to use. Eth-
yl acetate was distilled over calcium sulfate or chloride. Di-
chloromethane was distilled over calcium hydride.
Dichloroethane was used as purchased.
4.44 (1H, d, J 8.8 Hz, minor), 7.20–7.40 (5H, m, major
and 5H, m, minor); dC (100 MHz; CDCl3) (major diastereo-
isomer) 7.7, 14.6, 20.5, 32.5, 32.7, 65.2, 85.7, 97.0, 126.8,
127.8, 128.3, 140.3; m/z (FAB) 219.1625; C14H21NO (M+)
requires: 219.1623.
4.1.1.4. (L)-(2S,4S,5R)-2,3,4-Trimethyl-2-(1-methyl-
ethyl)-5-phenyloxazolidine (6). Prepared according to the
representative procedure from ephedrine (3.0 g, 18.8 mmol)
and 3-methyl-butanone (1.34 g, 27.3 mmol). Colourless oil
(3.43 g, 81%); [a]D25 ꢀ6.1 (c 1.04, CHCl3); nmax (neat)/
cmꢀ1 4299, 3736, 3261, 2929, 2362, 1460, 1375, 1336,
1198, 1146; dH (400 MHz; CDCl3) 0.61 (3H, d, J 6.4 Hz),
1.08 (3H, d, J 6.9 Hz), 1.09 (3H, d, J 6.9 Hz), 1.20 (3H, s),
1.85–1.92 (1H, m), 2.24 (3H, s), 3.07–3.14 (1H, m), 5.05
(1H, d, J 8.4 Hz), 7.25–7.45 (5H, m); dC (100 MHz;
CDCl3) 8.7, 14.6, 18.2, 32.5, 34.0, 60.1, 80.7, 97.0, 126.5,
127.5, 129.6, 140.6; m/z (FAB) 234.1858; C15H24NO
(MH+) requires: 234.1858.
4.1.1. Representative procedures for the formation of
oxazolidines from aminoalcohols and ketones.
4.1.1.1. (D)-(2S,4S,5S)-2-Isopropyl-2,3,4-trimethyl-5-
phenyloxazolidine (3). Pseudoephedrine (0.50 g, 3.0 mmol),
scandium triflate (0.22 g, 0.5 mmol) and 3-methylbutanone
(0.26 g, 3.0 mmol) were added to a suspension of flame-dried
˚
4 A molecular sieve (2.20 g) in dichloroethane (7.0 mL). The
mixture was heated under reflux for 48 h, allowed to cool to
room temperature, solid sodium hydrogen carbonate (1.0 g)
added and stirring continued for a further 2 h at room temper-
ature. The mixture was filtered, the filtrate washed with water
(2ꢂ5 mL) and the organic layer dried over anhydrous magne-
sium sulfate. Solvents were removed under reduced pressure
to afford a colourless oil (0.67 g, 96%); [a]2D5 +39.0 (c 1.00,
CHCl3); nmax (neat)/cmꢀ1 3130, 2924, 2761, 1459, 1373,
1326, 1189, 1135; dH (250 MHz; CDCl3) 0.95 (3H, d, J
2.8 Hz), 0.98 (3H, d, J 2.8 Hz), 1.01 (3H, d, J 6.0 Hz), 1.25
(3H, s), 1.70–1.86 (1H, m), 2.20 (3H, s) 2.41–2.50 (1H, m),
4.30 (1H, d, J 8.9 Hz), 7.22–7.40 (5H, m); dC (100 MHz;
CDCl3) 7.7, 14.4, 14.6, 18.6, 33.7, 36.4, 65.1, 85.4, 98.6,
126.2, 127.0, 127.7, 140.4; m/z (FAB) 234.1855; C15H24NO
(MH+) requires: 234.1858.
4.1.1.5. (2R,4S,5S)- and (2S,4S,5S)-2-Isobutyl-2,3,4-
trimethyl-5-phenyloxazolidine (7). Prepared according to
the representative procedure from pseudoephedrine (0.50 g,
3.0 mmol) and 4-methyl-2-pentanone (0.45 g, 4.5 mmol).
Colourless oil (0.69 g, 93%); nmax (neat)/cmꢀ1 3125, 2926,
2764, 1460, 1373, 1190, 1135; dH (400 MHz; CDCl3) (major
diastereoisomer) 0.95 (3H, d, J 6.7 Hz), 0.99 (3H, d,
J 6.7 Hz), 1.07 (3H, d, J 6.0 Hz), 1.27 (3H, s), 1.50 (1H,
dd, J 6.6, 14.6 Hz), 1.60 (1H, dd, J 6.6, 14.6 Hz), 1.91–
1.97 (1H, m), 2.23 (3H, s), 2.51–2.55 (1H, m), 4.39 (1H,
d, J 8.8 Hz), 7.26–7.37 (5H, m); dC (100 MHz; CDCl3)
(major diastereoisomer) 14.7, 21.1, 23.6, 24.3, 24.7, 32.5,
47.8, 64.7, 85.5, 97.3, 126.7, 127.8, 128.3, 140.5; m/z
(FAB) 248.2017; C16H26NO (MH+) requires: 248.2014.
4.1.1.2. (2R,4S,5R)- and (2S,4S,5R)-2,3,4-Trimethyl-2-
ethyl-5-phenyloxazolidine (4). Prepared according to
the representative procedure from ephedrine (3.0 g,
18.8 mmol) and 2-butanone (1.97 g, 27.3 mmol). Colourless
oil (3.74 g, 92%); nmax (neat)/cmꢀ1 3317, 2970, 2931, 1458,
1373, 1320, 1203, 1134, 1049; dH (400 MHz; CDCl3) (2:1
mixture of diastereoisomers) 0.63 (3H, d, J 6.4 Hz, major
and minor), 1.01 (3H, t, J 7.5 Hz, minor), 1.07 (3H, t, J
7.5 Hz, major), 1.17 (3H, s, major), 1.44 (3H, s, minor),
1.74–1.85 (2H, m, major and 2H, m, minor), 2.23 (3H, s,
major), 2.30 (3H, s, minor), 3.18 (1H, dq, J 6.4, 8.0 Hz,
major), 3.22 (1H, dq, J 6.4, 8.0 Hz, minor), 5.02 (1H, d, J
8.0 Hz, minor), 5.05 (1H, d, J 8.0 Hz, major), 7.22–7.34
(5H, m, major and 5H, m, minor); dC (100 MHz; CDCl3)
(major diastereoisomer) 8.4, 15.9, 32.1, 33.0, 33.7, 60.6,
80.3, 96.6, 125.9, 127.4, 127.8, 140.4; m/z (FAB)
220.1698; C14H22NO (MH+) requires: 220.1701.
4.1.1.6. (2R,4S,5R)- and (2S,4S,5R)-2-(2-Pyridyl)-
2,3,4-trimethyl-5-phenyloxazolidine (8). Prepared accord-
ing to the representative procedure from ephedrine (0.50 g,
3.0 mmol) and 2-acetylpyridine (0.55 g, 4.5 mmol). Colour-
less oil (0.58 g, 72%); nmax (neat)/cmꢀ1 3294, 3085, 1585,
1493, 1454, 1358, 1327, 1238, 1196, 1136; dH (250 MHz;
CDCl3) (major diastereoisomer) 0.98 (3H, d, J 4.9 Hz),
1.32 (3H, s), 2.63 (3H, s), 2.65–2.66 (1H, m), 5.22 (1H, d,
J 4.8 Hz), 7.25–7.91 (8H, m), 8.52–8.53 (1H, m); dC
(100 MHz; CDCl3) (major diastereoisomer) 24.9, 33.9,
60.2, 76.9, 82.1, 97.3, 121.2, 127.9, 128.1, 128.4, 136.2,
137.0, 140.7, 148.8, 163.0; m/z (FAB) 268.1573;
C17H20N2O (M+) requires: 268.1577.
4.1.1.7. (2R,4S,5S)- and (2S,4S,5S)-2-(2-Pyridyl)-2,3,4-
trimethyl-5-phenyloxazolidine (9). Prepared according to
the representative procedure from pseudoephedrine
(0.50 g, 3.0 mmol) and 2-acetylpyridine (0.55 g, 4.5 mmol).
Colourless oil (0.51 g, 64%); nmax (neat)/cmꢀ1 4350,
3482, 3679, 1304, 1491, 1437, 1356, 1200, 1135, 1126;
dH (400 MHz; CDCl3) (major diastereoisomer) 1.13 (3H,
d, J 5.6 Hz), 1.80 (3H, s), 2.45 (3H, s), 2.73–2.67 (1H, m),
4.64 (1H, d, J 8.8 Hz), 7.19–7.45 (5H, m) 7.60–7.78
(3H, m), 8.50–8.63 (1H, m); dC (100 MHz; CDCl3) (major
diastereoisomer) 14.5, 19.3, 32.8, 65.9, 86.0, 96.8,
119.6, 122.4, 126.7, 127.9, 128.3, 136.6, 139.5, 148.1,
163.9; m/z (FAB) 269.1656; C17H21N2O (MH+) requires:
269.1654.
4.1.1.3. (2R,4S,5S)- and (2S,4S,5S)-2,3,4-Trimethyl-2-
ethyl-5-phenyloxazolidine (5). Prepared according to the
representative procedure from pseudoephedrine (3.0 g,
18.8 mmol) and 2-butanone (1.97 g, 27.3 mmol). Colourless
oil (3.6 g, 88%); nmax (neat)/cmꢀ1 3827, 3812, 2870, 2787,
1493, 1454, 1370, 1166; dH (400 MHz; CDCl3) (5.7:1 mix-
ture of diastereoisomers) 0.97 (3H, t, J 7.6 Hz, major), 1.05
(3H, d, J 6.0 Hz, major), 1.06 (3H, d, J 6.0 Hz, minor), 1.11
(3H, t, J 7.6 Hz, minor), 1.28 (3H, s, major), 1.36 (3H, s, mi-
nor), 1.50–1.75 (2H, m, major and 2H, m, minor), 2.24 (3H,
s, major), 2.32 (3H, s, minor), 2.51–2.58 (1H, m, major),
2.60–2.64 (1H, m, minor), 4.37 (1H, d, J 8.8 Hz, major),

P. C. Bulman Page et al. / Tetrahedron 63 (2007) 10991–10999
10997
4.1.1.8. (D)-(2S,4S,5S)-2,3,4-Trimethyl-2,5-diphenyl-
oxazolidine (10). Prepared according to the representative
procedure from pseudoephedrine (0.50 g, 3.0 mmol) and
acetophenone (0.60 g, 4.5 mmol). Colourless oil (0.44 g,
55%); [a]2D5 +67.0 (c 1.11, CHCl3); nmax (neat)/cmꢀ1 3488,
2309, 1483, 1437, 1360, 1352, 1278, 1230, 1187, 1121; dH
(400 MHz; CDCl3) 1.14 (3H, d, J 6.0 Hz), 1.72 (3H, s),
2.36 (3H, s), 2.70–2.80 (1H, m), 4.52 (1H, d, J 8.7 Hz),
7.30–7.67 (10H, m); dC (100 MHz; CDCl3) 14.7, 20.7,
33.1, 65.8, 85.2, 96.2, 125.9, 126.5, 127.4, 127.7, 127.9,
139.5, 139.5, 145.3; m/z (FAB) 268.1702; C18H22NO
(MH+) requires: 268.1701.
(14). Scandium triflate (0.22 g, 0.5 mmol) and but-2-yne-
dioic acid dimethyl ester (0.43 g, 3.0 mmol) were added to
a solution of pseudoephedrine (0.50 g, 3.0 mmol) in aceto-
nitrile (10 mL). The mixture was heated under reflux for
24 h, allowed to cool to room temperature, solid sodium
hydrogen carbonate (1.0 g) added and stirring continued
for a further 2 h at room temperature. The solution was fil-
tered, washed with water (2ꢂ5 mL) and the organic layer
dried over anhydrous magnesium sulfate. Solvents were
removed under reduced pressure to afford an orange oil;
crystallization from methanol afforded 14 as colourless
prisms (0.86 g, 93%); mp 74–76 ꢃC (lit.,12 76 ꢃC); [a]2D5
ꢀ10.1 (c 1.19, CHCl3); nmax (film)/cmꢀ1 3030, 2952,
1751, 1730, 1457, 1346, 1202, 1152, 1074, 752, 701; dH
(400 MHz; CDCl3) 1.03 (3H, d, J 6.0 Hz), 2.29 (3H, s)
2.86–2.90 (1H, m), 2.87 (1H, d, J 16.0 Hz), 3.19 (1H, d, J
16.0 Hz), 3.69 (3H, s), 3.84 (3H, s), 4.53 (1H, d, J 8.8 Hz)
7.26–7.60 (5H, m); dC (100 MHz; CDCl3) 14.1, 32.5, 41.3,
51.6, 51.7, 64.3, 87.1, 95.5, 127.6, 128.2, 128.6, 138.2,
170.1, 170.5; m/z (ESI) 308.1493; C16H22NO5 (MH+)
requires: 308.1498.
4.1.1.9. (D)-(2S,4S,5S)-2,3,4-Trimethyl-2-(4-nitrophen-
yl)-5-phenyloxazolidine (11). Prepared according to the
representative procedure from pseudoephedrine (0.50 g,
3.0 mmol) and 4-nitroacetophenone (0.74 g, 4.5 mmol). Col-
ourless oil (0.83 g, 89%); [a]2D5 +54.0 (c 1.10, CHCl3); nmax
(neat)/cmꢀ1 3061, 2970, 1604, 1523, 1445, 1355, 1043; dH
(400 MHz; CDCl3) 1.12 (3H, d, J 6.0 Hz), 2.41 (3H, s),
2.69 (3H, s), 2.70–2.81 (1H, m), 4.45 (1H, d, 8.8 Hz), 7.26–
7.39 (5H, m), 7.83 (2H, d, J 9.0 Hz), 8.20 (2H, d, J 9 Hz); dC
(100 MHz; CDCl3) 15.1, 22.7, 33.8, 66.5, 85.5, 97.9, 123.2,
127.2, 127.7, 128.2, 129.3, 138.9, 147.4, 153.2; m/z (FAB)
313.1554; C18H21N2O3 (MH+) requires: 313.1552.
4.1.1.13. (D)-N-Methyl-N-((2R)-2-(3-methylbutyl))-
(1S,2S)-1-phenyl-2-aminopropanol N-H ammonium
tetraphenylborate salt (16). (+)-N-Methyl-N-((2R)-2-(3-
methylbutyl))-(1S,2S)-1-phenyl-2-aminopropanol 15 (0.72 g,
3.0 mmol) was dissolved in ethanol (10 mL) and HCl in
dioxane (4.0 M, 0.77 mL) added dropwise. The mixture
was stirred for 30 min and sodium tetraphenylborate
(1.10 g, 3.2 mmol) added as a solution in acetonitrile
(2 mL). The solvents were removed under reduced pressure
to yield a colourless solid, which was suspended in ethanol,
removed by filtration and washed successively with water,
ethanol and diethyl ether, to give 16 as a colourless solid
(0.90 g, 54%).
4.1.1.10. (D)-(2S,4S,5S)-2-Cyclohexyl-2,3,4-trimethyl-
5-phenyloxazolidine (12). Prepared according to the repre-
sentative procedure from pseudoephedrine (0.50 g, 3.0 mmol)
and cyclohexyl methyl ketone (0.57 g, 4.5 mmol). Colour-
less oil (0.77 g, 94%); [a]2D5 +37.0 (c 1.00, CHCl3); nmax
(neat)/cmꢀ1 3133, 2922, 2758, 1461, 1371, 1194, 1130; dH
(400 MHz; CDCl3) 0.95 (3H, d, J 5.6 Hz), 1.09–1.24 (6H,
m), 1.50–1.85 (5H, m), 2.06 (3H, s), 2.16 (3H, s), 2.36–
2.45 (1H, m), 4.24 (1H, d, 8.8 Hz), 7.20–7.27 (5H, m); dC
(100 MHz; CDCl3) 14.5, 18.7, 25.7, 25.9, 27.9, 28.4, 33.4,
65.7, 85.8, 98.4, 126.9, 128.3, 128.6, 140.3; m/z (FAB)
274.2161; C18H28NO (MH+) requires: 274.2171.
4.1.2. Representative procedures for the ring opening of
oxazolidines with DIBAL.
4.1.2.1.
(D)-N-Methyl-N-((2R)-2-(3-methylbutyl))-
4.1.1.11. (L)-(2R,4S,5R)-2-(Methoxycarbonylmethyl)-
2-(methoxycarbonyl)-3,4-dimethyl-5-phenyloxazolidine
(13). Scandium triflate (0.22 g, 0.5 mmol) and but-2-yne-
dioic acid dimethyl ester (0.43 g, 3.0 mmol) were added to
a solution of ephedrine (0.50 g, 3.0 mmol) in acetonitrile
(10.0 mL). The mixture was heated under reflux for 24 h, al-
lowed to cool to room temperature, solid sodium hydrogen
carbonate (1.0 g) added and stirring continued for a further
2 h at room temperature. The solution was filtered, washed
with water (2ꢂ5 mL) and the organic layer dried over anhy-
drous magnesium sulfate. Solvents were removed under re-
duced pressure to afford 13 as an orange oil; crystallization
from methanol afforded colourless prisms (0.82 g, 89%). mp
71–73 ꢃC (lit.,12 72 ꢃC); [a]D25 ꢀ27.6 (c 1.16, CHCl3); nmax
(film)/cmꢀ1 3026, 2952, 1751, 1730, 1437, 1346, 1151,
1073; dH (250 MHz; CDCl3) 0.61 (3H, d, J 6.4 Hz), 2.28
(3H, s) 2.83 (1H, d, J 16.1 Hz), 3.17–3.24 (1H, m), 3.43
(1H, d, J 16.1 Hz), 3.69 (3H, s), 3.82 (3H, s), 5.39 (1H, d,
J 8.1 Hz) 7.20–7.45 (5H, m); dC (100 MHz; CDCl3) 15.3,
33.5, 41.0, 51.8, 51.9, 60.0, 83.3, 95.3, 127.7, 127.8,
127.9, 139.3, 169.8, 170.1.
(1S,2S)-1-phenyl-2-aminopropanol (15). (2S,4S,5S)-2-
Isopropyl-2,3,4-trimethyl-5-phenyloxazolidine 3 (1.00 g,
4.3 mmol) was dissolved in hexanes (30 mL) and the solu-
tion cooled using an ice bath. DIBAL in hexanes (6.4 mL,
6.4 mmol, 1.0 M, 1.5 equiv) was added dropwise over
10 min, the solution allowed to attain room temperature
and stirring continued for 48 h. Ethyl acetate (30 mL) was
added followed by a saturated solution of sodium potassium
tartrate (20 mL) and the mixture stirred for a further 30 min.
The layers were separated and the aqueous phase washed
with ethyl acetate (3ꢂ30 mL), the combined organic layers
dried (MgSO4) and the solvents removed under reduced
pressure to afford the crude product as a colourless oil. Col-
umn chromatography eluting with light petroleum/ethyl
acetate (20:1) afforded product 15 as a colourless oil
(0.92 g, 92%); [a]D25 +86.0 (c 1.10, CHCl3); nmax (CH2Cl2)/
cmꢀ1 3326, 3027, 2969, 2871, 2359, 1453, 1371, 1088,
1048, 1027, 765, 700; dH (400 MHz, CDCl3) 0.88 (3H, d,
J 6.4 Hz), 0.93 (3H, d, J 6.8 Hz), 1.05 (6H, d, J 6.4 Hz),
1.73–1.82 (1H, m), 2.16 (3H, s), 2.37–2.44 (1H, m), 2.66–
2.74 (1H, m), 4.18 (1H, d, J 9.2 Hz), 7.26–7.37 (5H, m);
dC (100 MHz, CDCl3) 11.3, 13.0, 19.7, 20.9, 32.0, 66.1,
66.5, 75.5, 127.5, 127.6, 128.2, 142.5; m/z (ESI) 236.2008;
C15H26NO (MH+) requires: 236.2014.
4.1.1.12. (L)-(2R,4S,5S)-2-(Methoxycarbonylmethyl)-
2-(methoxycarbonyl)-3,4-dimethyl-5-phenyloxazolidine

10998
P. C. Bulman Page et al. / Tetrahedron 63 (2007) 10991–10999
4.1.2.2. N-Methyl-N-((2R)-2-butyl)-(1R,2S)-1-phenyl-
2-aminopropanol (17)Denantiomer. Prepared according
to the representative procedure from (2R,4S,5R)- and
(2S,4S,5S)-2,3,4-trimethyl-2-(4-nitrophenyl)-5-phenyloxazo-
lidine 11 (1.0 g, 3.2 mmol). Recrystallized from hexane,
pale yellow crystals (0.91 g, 91%); mp 144–147 ꢃC; [a]D25
+47.5 (c 0.52, CHCl3); C18H22N2O3: calcd C 68.77, H
7.05, N 8.91; found C 68.85, H 6.98, N 8.79; nmax (film)/
cmꢀ1 3350, 3060, 2971, 2359, 1604, 1520, 1455, 1345,
1042, 856, 756, 701; dH (400 MHz; CDCl3) 0.68 (3H, d, J
6.6 Hz), 1.48 (3H, d, J 8.0 Hz), 2.36 (3H, s), 2.53–2.60
(1H, m), 3.83 (1H, q, J 6.6 Hz), 4.23 (1H, d, J 9.6 Hz),
4.90 (1H, br s), 7.09–7.26 (5H, m), 7.51 (2H, d, J 8.9 Hz),
8.24 (2H, d, J 8.9 Hz); dC (100 MHz; CDCl3) 7.8, 21.4,
31.2, 61.7, 61.9, 74.7, 124.0, 127.2, 127.8, 128.2, 141.7,
147.2, 152.1; m/z (ESI) 315.1702; C18H23N2O3 (MH+)
requires: 315.1709.
(2S,4S,5R)-2-ethyl-2,3,4-trimethyl-5-phenyloxazolidine
4
(2.00 g, 8.2 mmol). Colourless oil (1.77 g, 88%); nmax
(film)/cmꢀ1 3314, 3028, 2963, 2872, 2348, 1604, 1493,
1453, 1372, 1026, 994, 746, 700; dH (400 MHz; CDCl3)
(2:1 mixture of diastereoisomers) 0.71 (3H, d, J 6.8 Hz, mi-
nor), 0.76 (3H, d, J 6.8 Hz, major), 0.82–0.89 (3H, m, major
and 6H, m, minor), 0.95 (3H, d, J 6.8 Hz, major), 1.23–1.33
(2H, m, major), 1.44–1.51 (2H, m, minor), 2.02 (3H, s, ma-
jor), 2.18 (3H, s, minor), 2.72–2.78 (1H, m, major and 2H,
m, minor), 2.86–2.89 (1H, m, major), 4.70 (1H, d, J
4.4 Hz, major), 4.83 (1H, d, J 3.5 Hz, minor), 7.13–7.25
(5H, m, major and 5H, m, minor); dC (100 MHz; CDCl3)
(major diastereoisomer) 11.6, 12.0, 14.6, 26.7, 30.2, 58.4,
61.5, 72.7, 126.1, 126.7, 127.9, 142.0 (minor diastereoiso-
mer) 11.5, 11.7, 14.1, 27.3, 32.2, 56.3, 61.8, 72.1, 125.9,
126.7, 128.0, 142.1; m/z (FAB) 222.1861; C14H24NO
(MH+) requires: 222.1858.
4.1.2.6.
(D)-N-Methyl-N-((1R)-1-(1-phenylethyl))-
(1S,2S)-1-phenyl-2-aminopropanol (21). Prepared according
to the representative procedure from (+)-(2S,4S,5S)-2,3,4-
trimethyl-2,5-diphenyloxazolidine 10 (1.50 g, 5.6 mmol).
Colourless oil (1.18 g, 78%); [a]2D5 +92.5 (c 0.80, CHCl3);
nmax (film)/cmꢀ1 3346, 3060, 3027, 2971, 2359, 1602, 1493,
1453, 1372, 1214, 1044, 920, 761, 700; dH (400 MHz;
CDCl3) 0.64 (3H, d, J 6.7 Hz), 1.46 (3H, d, J 6.6 Hz), 2.33
(3H, s), 2.68–2.72 (1H, m), 3.71 (1H, q, J 6.7 Hz), 4.17 (1H,
d, J 9.4 Hz), 7.09–7.35 (10H, m); dC (100 MHz; CDCl3) 7.9,
21.3, 31.4, 60.7, 62.5, 74.7, 127.3, 127.47, 127.52, 128.1,
128.6, 142.5, 148.0; m/z (ESI) 270.1848; C18H24NO (MH+)
requires: 270.1858.
4.1.2.3. N-Methyl-N-((2R)-2-butyl)-(1S,2S)-1-phenyl-
2-aminopropanol (18)Denantiomer. Prepared according
to the representative procedure from (2R,4S,5S)- and
(2S,4S,5S)-2-ethyl-2,3,4-trimethyl-5-phenyloxazolidine
5
(2.00 g, 9.1 mmol). Colourless oil (1.84 g, 91%); nmax
(film)/cmꢀ1 3314, 3028, 2966, 1604, 1493, 1453, 1371,
1218, 1048, 923, 762, 700; dH (400 MHz; CDCl3) (4:1 mix-
ture of diastereoisomers) 0.83 (3H, d, J 6.6 Hz, minor), 0.87
(3H, d, J 6.6 Hz, major), 0.91–0.93 (3H, m, minor), 0.93
(3H, t, J 7.6 Hz, major), 1.05 (3H, d, J 6.3 Hz, minor),
1.06 (3H, d, J 6.5 Hz, major), 1.29–1.36 (1H, m, major),
1.37–1.52 (1H, m, minor), 1.58–1.68 (1H, m, major and
1H, m, minor), 2.18 (3H, s, major), 2.29 (3H, s, minor),
2.69–2.73 (2H, m, major and 2H, m, minor), 4.12 (1H, d, J
9.2 Hz, minor), 4.14 (1H, d, J 9.6 Hz, major), 7.26–7.37
(5H, m, major and 5H, m, minor); dC (100 MHz; CDCl3)
(major diastereoisomer) 11.5, 11.6, 16.5, 27.7, 27.8, 61.6,
64.2, 75.0, 127.4, 127.6, 128.2, 142.6; (minor diastereoiso-
mer) 11.3, 11.4, 16.5, 27.8, 32.0, 59.9, 61.0, 74.6, 127.4,
127.6, 128.2, 142.7; m/z (FAB) 222.1861; C14H24NO
(MH+) requires: 222.1858.
4.1.2.7. N-Methyl-N-((2R)-2-(1,4-dihydroxybutyl))-
(1R,2S)-1-phenyl-2-aminopropanol (22)Denantiomer.
Prepared according to the representative procedure from
(ꢀ)-(2R,4S,5R)-2-(methoxycarbonylmethyl)-2-(methoxy-
carbonyl)-3,4-dimethyl-5-phenyloxazolidine 13 (2.00 g,
8.2 mmol) and DIBAL in hexanes (6 equiv). Colourless oil
(1.56 g, 75%); [a]D ꢀ4.0 (c 0.89, CHCl3); nmax (film)/
cmꢀ1 3354, 3025, 2927, 1654, 1493, 1450, 1405, 1240,
1038, 758, 702; dH (400 MHz; CDCl3) (mixture of diastereo-
isomers) 1.03 (3H, d, J 6.9 Hz, minor), 1.11 (3H, d, J 6.9 Hz,
major), 1.40–1.50 (1H, m, major and 1H, m, minor), 1.60–
1.70 (1H, m, minor), 1.70–1.90 (1H, m, major), 2.23 (3H,
s, major), 2.30 (3H, s, minor), 2.81–3.15 (2H, m, major
and 2H, m, minor), 3.30–355 (2H, m, major and 2H, m, mi-
nor), 3.60–3.75 (2H, m, major and 2H, m, minor), 4.84 (1H,
d, J 5.0 Hz, major), 4.92 (1H, d, J 3.6 Hz, minor), 7.09–7.35
(5H, m, major and 5H, m, minor); dC (100 MHz; CDCl3)
(major diastereoisomer) 12.0, 30.2, 30.6, 60.9, 61.0, 62.0,
64.6, 74.7, 126.1, 127.4, 128.3, 1427; m/z (ESI) 254.1751;
C14H24NO3 (MH+) requires: 254.1756.
4.1.2.4. (D)-N-Methyl-N-((1R)-1-(1-cyclohexylethyl))-
(1S,2S)-1-phenyl-2-aminopropanol (19). Prepared accord-
ing to the representative procedure from (+)-(2S,4S,5S)-
cyclohexyl-2,3,4-trimethyl-5-phenyloxazolidine 12 (1.0 g,
3.7 mmol). Colourless oil (0.88 g, 87%); [a]2D5 +40.7 (c
1.13, CHCl3); nmax (film)/cmꢀ1 3337, 3060, 2923, 2851,
2360, 1604, 1450, 1372, 1341, 1198, 1087, 1047, 770,
700; dH (400 MHz; CDCl3) 0.89 (3H, d, J 6.6 Hz), 0.92–
1.09 (1H, m), 1.06 (3H, d, J 6.6 Hz), 1.10–1.30 (4H, m),
1.39–1.47 (1H, m), 1.65–1.70 (1H, m), 1.76–1.82 (3H, m),
1.98–2.02 (1H, m), 2.16 (3H, s), 2.47 (1H, quint, J
7.6 Hz), 2.68–2.72 (1H, m), 4.20 (1H, d, J 9.4 Hz), 7.26–
7.37 (5H, m); dC (100 MHz; CDCl3) 11.6, 13.1, 26.4, 26.9,
30.1, 30.8, 41.6, 65.9, 66.5, 75.5, 127.4, 127.6, 128.2,
142.4; m/z (ESI) 276.2323; C18H30NO (MH+) requires:
276.2327.
4.1.2.8. (D)-(2R,4S,5S)-2-(1-(2-Hydroxyethyl))-2-(2-
hydroxymethyl)-3,4-dimethyl-5-phenyloxazolidine (23).
Prepared according to the representative procedure from
(+)-(2R,4S,5S)-2-(methoxycarbonylmethyl)-2-(methoxy-
carbonyl)-3,4-dimethyl-5-phenyloxazolidine 14 (1.0 g,
3.26 mmol) and DIBAL in hexanes (4 equiv). Colourless
oil (0.82 g, 63%); [a]2D5 +46.1 (c 1.08, CHCl3); nmax (film)/
cmꢀ1 3388, 3060, 2963, 2870, 2348, 1604, 1494, 1454,
1377, 1258, 1058, 1022, 759, 701; dH (400 MHz; CDCl3)
1.11 (3H, d, J 6.0 Hz), 1.78 (1H, ddd, J 1.6, 3.6, 15.2 Hz),
1.96–2.06 (1H, m), 2.49 (3H, s), 2.99–3.05 (1H, m), 3.66
(1H, d, J 11.6 Hz), 3.73 (1H, dt, J 3.6, 11.4 Hz), 3.80 (1H,
d, J 11.4 Hz), 4.10–4.16 (1H, m), 4.67 (1H, d, J 8.8 Hz)
4.1.2.5. (D)-N-Methyl-N-((1R)-1-(1-(4-nitrophenyl)-
ethyl))-(1S,2S)-1-phenyl-2-aminopropanol (20). Prepared
according to the representative procedure from (+)-

P. C. Bulman Page et al. / Tetrahedron 63 (2007) 10991–10999
10999
Reider, P. J.; Dolling, U.-H. J. Org. Chem. 1998, 63, 3120; (f)
7.26–7.40 (5H, m); dC (100 MHz; CDCl3) 14.8, 31.7, 33.1,
58.9, 64.7, 65.3, 86.6, 98.1, 127.0, 128.6, 128.7, 138.5; m/z
(ESI) 252.1597; C14H22NO3 (MH+) requires: 252.1600.
ꢀ
€
ꢀ
Farfan, N.; Hopfl, H.; Santillan, R.; Ochoa, M. E.; Gutierrez,
A. Tetrahedron: Asymmetry 1999, 10, 799; (g) Rigby, J. H.;
Cavezza, A.; Heeg, M. J. Tetrahedron Lett. 1999, 40, 2473;
Lee, H.-S.; Kang, S. H. Synlett 2004, 1673.
4.1.2.9. ( )-N-Methyl-N-((2R)-2-(1,4-dihydroxybutyl))-
(1S,2S)-1-phenyl-2-aminopropanol (24). Prepared ac-
cording to the representative procedure from (+)-(2R,4S,
5S)-2-(methoxycarbonylmethyl)-2-(methoxycarbonyl)-3,4-
dimethyl-5-phenyloxazolidine 14 (0.50 g, 1.63 mmol).
Colourless oil (0.33 g, 80%); [a]2D5 +39.5 (c 1.10,
CHCl3); nmax (neat)/cmꢀ1 3355, 3020, 2931, 1654, 1491,
1239; dH (400 MHz; CDCl3) 0.86 (3H, d, J 6.7 Hz),
1.80–1.95 (1H, m), 2.33 (3H, s), 2.35–2.45 (1H, m),
2.55–3.10 (2H, m), 3.64–3.80 (4H, m), 4.25 (1H, d,
9.4 Hz), 7.26–7.40 (5H, m); dC (100 MHz; CDCl3) 11.7,
30.5, 32.2, 57.1, 63.2, 63.8, 64.3, 77.0, 127.1, 128.5,
128.7, 138.0; m/z (ESI) 254.1754; C14H24NO3 (MH+) re-
quires: 254.1756.
2. (a) Bergmann, E. D.; Zimkin, E.; Pinchas, S. Recl. Trav.
Chim. Pays-Bas 1952, 71, 237; (b) Aicher, T. D.; Balkan,
B.; Bell, P. A.; Brand, L. J.; Cheon, S. H.; Deems, R. O.;
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Acknowledgements
This investigation has enjoyed the support of the EPSRC and
GlaxoSmithKline. We acknowledge the support of the Royal
Society (P.C.B.P.: Industry Fellowship). We are indebted to
the EPSRC Mass Spectrometry Service Centre, University
of Wales, Swansea.
7. Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc. 1981, 103,
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References and notes
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