F. Andersson, E. Hedenstro¨m / Tetrahedron: Asymmetry 17 (2006) 1952–1957
1957
Extraction of the aqueous phase with Et2O (4 · 10 ml) was
followed by drying over MgSO4 of the combined organic
extracts. Concentration by evaporation of the solvent affor-
ded the crude alkylation products. Conversions and diaste-
reomeric ratios were determined by GC as below.
(72), 195 (7), 174 (7), 119 (60), 118 (100), 91 (62), 77 (4),
59 (12). Anal. Calcd for C21H25NO2: C, 78.0; H, 7.8; N,
4.3. Found: C, 77.8; H, 7.8; N, 4.4.
Acknowledgements
GC retention times (EC-5 capillary column; isothermal
200 ꢁC): tR(S,R)-6 20.06 min and tR(S,S)-6 21.12 min,
(VF-23ms capillary column; 200 ꢁC, 5 min, then pro-
grammed 2 ꢁC/min up to 220 ꢁC, 15 min): tR(S,R)-7
21.18 min and tR(S,S)-7 21.77 min and (EC-1 capillary col-
umn; 100 ꢁC, 2 min, then programmed 10 ꢁC/min up to
250 ꢁC, 5 min): tR(SR)-8 and (S,S)-8 13.75 min.
We are grateful for financial support from EU (Objective 1
the Region of South Forest Countries) and La¨nsstyrelsen i
Va¨sternorrlands la¨n.
References
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Acta Chem. Scand. 1999, 53, 620–630.
4.8. Determination of the configuration at the newly created
stereogenic centre of amides 6, 7 and 8
2. For some examples see: (a) Evans, D. A.; Dow, R. L.; Shih,
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The diastereomeric amide mixtures
6 [(S,R):(S,S) =
84.4:15.6] and 8 [(S,R):(S,S) = unknown] were hydrolysed
to the corresponding enantiomerically enriched 2-benzyl-
propanoic acid and 2-methylhexanoic acid, respectively,
following the procedure of Lin et al.11
The negative sign of the specific rotation of the obtained
2-benzylpropanoic acid {(R)-2-benzylpropanoic acid lit.11
20
½aꢁD ¼ ꢀ22:1 (neat)} verified (S,R)-6 as the major diaste-
reomer produced in the alkylation reaction. The acid was
1
reduced to the corresponding 2-benzylpropanol. The H
NMR spectrum of this alcohol is in agreement with litera-
ture data14 and the enantiomeric ratio (R:S) was analysed
by GC of the corresponding trifluoroacetate (b-dex 225
capillary column; 70 ꢁC, 1 min, then programmed 0.5 ꢁC/
min up to 110 ꢁC): tR(S) 66.50 min and tR(R) 67.05 min.
The enantiomerically enriched 2-methylhexanoic acid ob-
tained from amide mixture 8 was analysed on a b-dex
225 GC column and compared with non-racemic samples
of (R)- and (S)-2-methylhexanoic acids.7b This verified
(S,R)-8 as the major diastereomer produced in the alkyl-
ation reaction (b-dex 225 capillary column; 80 ꢁC,
10 min, then programmed 0.2 ꢁC/min up to 90 ꢁC): tR(S)
43.98 min and tR(R) 44.87 min.
8. (a) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21,
4233–4236; (b) Ho¨gberg, H.-E. Alkylation of amide enolates.
In Houben-Weil Methods of Organic Chemistry; Helmchen,
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Thieme: Stuttgart, 1995; Vol. E21, pp 791–915; (c) Evans, D.
A. Stereodifferentiating addition reactions, Part B. In Asym-
metric Synthesis; Morrison, J. D., Ed.; Academic Press: New
York, 1984; Vol. 3, pp 1–110.
After etherification of the hydroxyamide mixture 6 of
known diastereomeric composition (84.4:15.6) with MeI,
following the procedure described above, the major diaste-
reomer of the corresponding amide mixture 7 was verified
as (S,R)-7 according to GC analysis on a VF-23ms column
as above.
4.9. (R)-2-Benzyl-1-((S)-2-(2-hydroxypropan-2-yl)indolin-
1-yl)propan-1-one (S,R)-6
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Norin, T. Acta Chem. Scand. 1984, B38, 795–801.
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45, 2417–2429.
14. Mezzetti, A.; Keith, C.; Kazlauskas, R. J. Tetrahedron:
Asymmetry 2003, 14, 3917–3924.
(S,R)-6 (major isomer): 98.5% chemical purity and
20
dr = 99.7:0.3; ½aꢁD ¼ ꢀ170:2 (c 0.60, MeOH); 1H NMR
(500 MHz; DMSO-d6; Me4Si, 363 K): d 0.87 (3H, s), 0.98
(3H, s), 1.10 (3H, d, J = 6.7 Hz), 2.62 (1H, dd, J = 13.5,
8.0 Hz), 2.86 (1H, d, J = 16.4 Hz), 3.01 (1H, dd, J = 13.5,
6.1 Hz), 3.05–3.10 (1H, m), 3.53 (1H, sextett, J = 7.0 Hz),
4.33 (1H, s), 4.43 (1H, d, J = 9.0 Hz), 6.95 (1H, t,
J = 7.4 Hz), 7.10–7.21 (7H, m), 7.61 (1H, br s); MS (EI)
m/z (relative intensity): 324 (MH+, 13%), 306 (8), 265