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F. Andersson, E. Hedenstro¨m / Tetrahedron: Asymmetry 15 (2004) 2539–2545
128.89 (2C), 139.69, 177.87; MS (EI) m/z (relative inten-
sity): 276 (MH+, 100%), 258 (51), 126 (63), 91 (10), 70
(14).
1H NMR (250MHz; CDCl3; Me4Si; Two rotamers,
ꢁ3:2): d 0.87 (1.8H, s), 0.96 (1.2H, s), 1.00 (1.2H, s),
1.06 (1.8H, s), 1.11 (1.8H, d, J = 6.5Hz), 1.24 (1.2H,
d, J = 6.5Hz), 1.29–1.83 (2.6H, m), 1.92–2.07 (1.4H,
m), 2.61–3.06 (3H, m), 3.07 (1.8H, s), 3.11 (1.2H, s),
3.22–3.38 (1.4H, m), 3.55–3.64 (0.6H, m), 3.77 (0.4H,
ddd, J = 5.6, 9.1, 12.2Hz), 4.34 (0.6H, dd, J = 2.1,
8.8Hz), 7.14–7.29 (5H, m); 13C NMR (62.9MHz;
CDCl3; Me4Si; Asterisk denotes minor rotamer peaks):
d 16.87, 18.20*, 19.34*, 21.59*, 21.95, 22.28*, 23.22,
24.69, 25.08, 26.30*, 39.95*, 40.16, 40.73, 42.20*,
46.03*, 47.75, 49.06*, 49.27, 62.67, 65.09*, 77.96*,
78.23, 126.06 (2C)*, 126.06 (2C), 128.20 (2C)*, 128.20
(2C), 128.76*, 129.05, 140.06, 140.27*, 175.45, 176.62*;
MS (EI) m/z (relative intensity): 290 (MH+, 73%), 274
(5), 258 (28), 217 (33), 126 (43), 91 (51), 73 (39), 70 (100).
(S,S)-3 (minor isomer): 100% chemical purity and
>99.5:0.5 dr; bp 190–193ꢁC/0.8mbar (lit.,5 185–190ꢁC/
20
0.1mmHg); ½aꢂ ¼ þ29:9 (c 1.39, MeOH) {lit.,5
D
19
D
1
½aꢂ ¼ þ30:8 (c 1.145, MeOH)}; H NMR (250MHz;
CDCl3; Me4Si): d 0.71 (3H, s), 1.12 (3H, s), 1.18 (3H,
d, J = 6.5Hz), 1.47–1.74 (2H, m), 1.77–1.90 (1H, m),
1.97–2.08 (1H, m), 2.69 (1H, dd, J = 5.2, 12.4Hz),
2.87–3.17 (3H, m), 3.62–3.71 (1H, m), 4.09 (1H, t,
J = 7.6Hz), 5.24 (1H, br s), 7.13–7.31 (5H, m); 13C
NMR (62.9MHz; CDCl3; Me4Si): d 17.11, 22.80,
24.39, 27.83, 28.59, 40.57, 40.92, 48.80, 68.17, 73.38,
126.22, 128.35 (2C), 129.00 (2C), 139.60, 177.52; MS
(EI) m/z (relative intensity): 276 (MH+, 76%), 258 (45),
126 (100), 91 (25), 70 (37).
(S,R)-5 (minor isomer): >96% chemical purity and
20
>99.5:0.5 dr; ½aꢂ ¼ ꢀ82:5 (c 1.45, CHCl3) {lit.,16
D
4.3.2. 1-[2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl]-2-meth-
ylhexan-1-one 4. (S,R)-4 (major isomer) and (S,S)-4
(minor isomer) were obtained as a diastereomeric
mixture. MS (EI) m/z (relative intensity) on a diastereo-
meric mixture: 242 (MH+, 100%), 225 (5), 182 (1), 127
(10), 126 (5), 70 (8), 59 (2). 1H NMR (250MHz; CDCl3;
Me4Si) spectral data was similar to those reported for
(S,R)-4 and (S,S)-4.5
[a]D = ꢀ97 (c 1.071, CHCl3)}; 1H NMR (250MHz;
CDCl3; Me4Si): d 1.10 (3H, s), 1.14 (3H, s), 1.20 (3H,
d, J = 6.5Hz), 1.28–1.40 (1H, m), 1.49–1.63 (1H, m),
1.76–2.00 (2H, m), 2.61 (1H, dd, J = 5.2, 12.0Hz),
2.85–3.04 (2H, m), 3.15 (3H, s), 3.17–3.32 (2H, m),
4.35 (1H, dd, J = 2.3, 8.7Hz), 7.14–7.29 (5H, m); 13C
NMR (62.9MHz; CDCl3; Me4Si): d 18.58, 22.07,
22.86, 24.48, 24.83, 40.00, 40.37, 47.48, 49.26, 62.59,
78.48, 126.08, 128.28 (2C), 128.98 (2C), 140.31, 175.83;
MS (EI) m/z (relative intensity): 290 (MH+, 23%), 274
(4), 258 (11), 217 (68), 126 (34), 91 (56), 73 (40), 70 (100).
4.4. Alkylation reactions of amide 2b. General procedure
Methylether amide 2b (125mg, 0.63mmol) dissolved in
THF (0.6mL) was added to freshly prepared LDA or
LiHMDS in THF [prepared from a THF (0.4mL) solu-
tion of diisopropylamine (0.11mL, 0.82mmol) or
HMDS (0.17mL, 0.82mmol) and 1.55M n-butyllithium
in hexanes (0.51mL, 0.79mmol) at 0ꢁC] or to commer-
cial 1.0M NaHMDS in THF (0.79mL, 0.79mmol) at
0ꢁC. After 0.3h the reaction solution was cooled to
the indicated temperature (see Table 2) and the electro-
phile [benzyl bromide (0.19mL, 1.58mmol) or n-butyl
iodide (0.18mL, 1.58mmol)] dissolved in THF
(0.6mL) was added or alternatively an additive (Table
2, LiCl was added to the LDA solution) was added be-
fore addition of the electrophile. After the indicated
reaction time and temperature (Table 2), the reaction
was quenched with dilute hydrochloric acid. Extraction
of the aqueous phase with CH2Cl2 was followed by dry-
ing over MgSO4 of the pooled organic phases with con-
centration by evaporation afforded the crude alkylation
products 5 or 6. Final conversion and diastereomeric
ratio was determined by GC. GC retention times
(EC-1 capillary column: 180ꢁC, 2min, then pro-
grammed 2ꢁC/min up to 210ꢁC), tR[(S,R)-5] 13.85min
and tR[(S,S)-5] 14.49min.
4.4.2.
1-[2-(2-Methoxypropan-2-yl)pyrrolidin-1-yl]-2-
methylhexan-1-one 6. (S,S)-6 (major isomer) and
(S,R)-6 (minor isomer) were obtained as a diastereomeric
mixture.
MS (EI) m/z (relative intensity): 256 (MH+, 100%), 240
(5), 183 (15), 127 (68), 73 (33), 70 (93).
4.4.3. Determination of the diastereomeric ratio and
assignment of the configuration at the newly created
stereogenic centre in the alkylated amide 6 (entries 21–28
in Table 2). The diastereomeric mixture of amide 6 was
dissolved in aqueous 3M HCl/1,4-dioxan (15mL/mmol
amide, 1/1) and heated to 90–95ꢁC. After complete con-
version of amide 6, the reaction mixture was cooled to
room temperature and extracted with Et2O. The pooled
organic phases were dried over MgSO4 and concen-
trated by evaporation to yield nonracemic 2-methylhex-
anoic acid. The specific rotation of this acid5 dissolved in
Et2O was measured with the positive sign indicating an
excess of (S)-2-methylhexanoic acid, that is (S,S)-6 is the
major isomer in the alkylation reaction. The diastereo-
meric ratio of the starting amide 6 was then calculated
as the determined enantiomeric ratio of (S)-2-methyl-
hexanol [obtained from LiAlH4-reduction of the (S)-
acid] by GC analysis and ranged from 76% de to 94%
de.
4.4.1. 2-Benzyl-1-[2-(2-methoxypropan-2-yl)pyrrolidin-1-
yl]propan-1-one 5. (S,S)-5 and (S,R)-5 was obtained
from the diastereomeric mixture as single isomers by
LC.
GC retention times (b-dex 225 capillary column: 65ꢁC,
1min, then programmed 0.5ꢁC/min up to 70ꢁC),
20min, tR[(R)-2-methylhexanol] 25.10min and tR[(S)-2-
methylhexanol] 25.96min.
(S,S)-5 (major isomer): 100% chemical purity and
20
D
>99.5:0.5 dr; bp 160–164ꢁC/0.7mbar; ½aꢂ ¼ þ39:5 (c
1.44, CHCl3) {lit.,16 [a]D = + 42.5 (c 1.051, CHCl3)};