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In some cases the reactions of chelated
enolates with aromatic aldehydes proceed with low diastereoselectivicity, probably
because of the reversibility of the aldol process.
<A NAME="RG03009ST-18">18</A> No epimerization of the ester 7a was observed. According to Seebach et
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Beck AK.
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<A NAME="RG03009ST-19">19</A>
It should be mentioned, that NMR is
not a suitable method for determination of the isomeric ratios,
because in addition to the signals of the different isomers, in
general a double set of signals is observed caused by rotamers (hindered
rotation around the secondary amide bond).
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<A NAME="RG03009ST-21">21</A>
General Procedure
for Domino Michael-Aldol Additions-Cyclizations
In a Schlenk flask
HMDS (0.3 mL, 1.42 mmol) was dissolved in THF (2 mL). The solution
was cooled to -78 ˚C before n-BuLi
(1.6 M, 0.78 mL, 1.25 mmol) was added. The cooling bath was removed
and the solution was allowed to warm up for 15 min, before it was
cooled again to -78 ˚C. In a second Schlenk
flask ZnCl2 (80 mg, 0.57 mmol) was dried with a heat
gun in high vacuum, before it was dissolved in THF (3 mL). After
addition of TFA-Gly-Ot-Bu (115 mg, 0.5 mmol)
the solution was cooled to -78 ˚C, before
the fresh prepared LHMDS solution was added. Then, 15 min later, the
Michael acceptor (0.45 mmol) was added in THF (2 mL). After 2 h
the corresponding aldehyde (1-1.5 mmol) was added and the
reaction mixture was allowed to r.t. overnight. The solution was
diluted with Et2O before 1 N KHSO4 was added.
The layers were separated, the aqueous phase was washed twice with
CH2Cl2, and the combined organic layers were
dried (Na2SO4). After evaporation of the solvent
in vacuo the crude product was purified by flash chromatography
(SiO2, hexanes-EtOAc).
<A NAME="RG03009ST-22">22</A>
Spectroscopic
and Analytical Data of Selected Products 9
Compound 9a
Major rotamer, (2S,3S,4R,5R)-9a: ¹H NMR (500 MHz, CDCl3): δ = 0.91
(d, J = 6.6
Hz, 2 H), 1.00 (d, J = 6.5
Hz, 2 H), 1.45 (s, 9 H), 1.56 (m, 1 H), 1.94 (m, 1 H), 2.24 (m,
1 H), 2.54 (dd, J = 11.6,
2.6 Hz, 1 H), 3.01 (m, 1 H), 3.21 (ddd, J = 12.2,
9.9, 2.4 Hz, 1 H), 3.29 (br s, 1 H), 3.63 (m, 1 H), 3.75 (s, 3 H),
3.98 (dd, J = 9.8,
9.8 Hz, 1 H), 4.38 (d, J = 7.9 Hz,
1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.2,
19.8, 27.6, 27.7, 33.1, 40.2, 46.1 (J = 3.0
Hz), 47.5, 52.0, 62.9, 77.4, 83.0, 115.8 (J = 287.6
Hz), 157.3 (J = 37.4
Hz), 168.8, 172.2.
Minor rotamer (selected signals): ¹H
NMR (500 MHz, CDCl3): δ = 1.44
(s, 9 H), 1.78 (m, 1 H), 2.53 (dd, J = 11.5, 2.5
Hz, 1 H), 3.12 (m, 1 H), 3.77 (s, 3 H), 3.83 (dd, J = 11.9, 10.0
Hz, 1 H), 4.48 (dd, J = 7.4,
1.4 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 24.4,
32.0, 42.8, 47.9, 52.0, 61.8 (J = 2.7 Hz),
83.3, 168.9, 172.5.
Major rotamer, (2S,3S,4R,5S)-9a: ¹H
NMR (500 MHz, CDCl3): δ = 0.89
(d, J = 6.8
Hz, 2 H), 1.02 (d, J = 6.7
Hz, 2 H), 1.43 (m, 1 H) 1.44 (s, 9 H), 1.80 (m, 1 H), 2.04 (m, 1
H), 2.57 (dd, J = 7.8,
2.5 Hz, 1 H), 2.62 (br s, 1 H), 3.02 (m, 1 H), 3.56-3.65
(m, 2 H), 3.71 (s, 3 H), 3.98 (dd, J = 10.1,
9.4 Hz, 1 H), 4.61 (d, J = 7.8
Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.1,
19.7, 27.9, 28.0, 34.2, 39.6, 46.0 (J = 3.5 Hz),
47.7, 51.9, 62.8, 75.6, 83.1, 168.1, 174.4.
Minor rotamer
(selected signals): ¹H NMR (500 MHz, CDCl3): δ = 1.45
(s, 9 H), 3.11 (m, 1 H), 3.72 (s, 3 H), 4.65 (dd, J = 7.4,1.4
Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 19.0,
19.7, 47.1, 61.6 (J = 2.8
Hz), 83.6, 168.0, 174.2. GC (isothermic, 170 ˚C): t
R [(±)-(2S,3S,4R,5S)-9a] = 39.96 min; t
R [(±)-(2S,3S,4R,5R)-9a] = 49.87
min. HMRS (CI):
m/z [M + H]+ calcd
for C18H29F3NO6: 412.1947;
found: 412.1991. Anal. Calcd for C18H28F3NO6 (411.42):
C, 52.55; H, 6.86; N, 3.40. Found: C, 52.37; H, 6.71; N, 3.42.
Compound 9b
Major rotatmer, (2S,3S,4R,5R)-9b: ¹H NMR (500 MHz, CDCl3): δ = 0.89
(s, 9 H, 15-H), 1.46 (s, 9 H, 7-H), 1.50 (br s, 1 H), 2.02 (m, 1
H), 2.29 (m, 1 H), 2.58 (dd, J = 11.2,
2.3 Hz, 1 H), 2.92 (m, 1 H), 3.32 (dd, J = 10.3,
2.1 Hz, 1 H), 3.64 (m, 1 H), 3.74 (s, 3 H), 3.97 (dd, J = 9.8, 9.8
Hz, 1 H), 4.34 (d, J = 7.6
Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 26.0, 27.7,
27.8, 35.8, 42.1, 44.8, 46.0 (J = 3.5
Hz), 52.1, 62.8, 79.1, 82.9, 115.8 (J = 287.6
Hz), 157.3 (J = 37.4
Hz), 168.6, 174.4.
Minor rotamer (selected signals): ¹H
NMR (500 MHz, CDCl3): δ = 0.89
(s, 9 H), 1.45 (s, 9 H), 1.87 (m, 1 H), 2.56 (dd, J = 11.3,
2.2 Hz, 1 H), 3.03 (m, 1 H), 3.35 (dd, J = 10.0, 2.0
Hz, 1 H), 3.75 (s, 3 H), 3.82 (dd, J = 11.5,
10.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 27.7,
35.8, 45.0, 45.4, 79.1, 83.3, 169.7, 174.2. GC (isothermic, 180 ˚C): t
R [(±)-(2S,3S,4R,5S)-9b] = 32.33
min; t
R [(±)-(2S,3S,4R,5R)-9b] = 35.17
min. Anal. Calcd for C19H30F3NO6 (425.44):
C, 53.64; H, 7.11; N, 3.29. Found: C, 53.76; H, 6.85; N, 3.41.
Compound 9e
Major rotamer, (2S,3S,4R,5R)-9e: ¹H NMR (500 MHz, CDCl3): δ = 0.96
(t, J = 7.4
Hz, 3 H), 1.43 (s, 9 H), 1.50 (m, 2 H), 1.87 (br s, 1 H), 1.94 (m,
1 H), 2.25 (m, 1 H), 2.54 (dd, J = 11.6,
2.7 Hz, 1 H), 3.00 (m, 1 H), 3.59-3.66 (m, 2 H), 3.74 (s,
3 H), 3.97 (dd, J = 9.7,
9.7 Hz, 1 H), 4.45 (d, J = 8.0 Hz,
1 H). ¹³C NMR (125 MHz, CDCl3): δ = 10.5,
27.7, 27.8, 29.1, 39.7, 46.2 (J = 3.4
Hz), 49.9, 51.9, 62.9, 72.9, 83.0, 116.1 (J = 287.4
Hz), 155.9 (J = 37.4
Hz), 168.8, 172.3.
Minor rotamer (selected signals): ¹H
NMR (500 MHz, CDCl3): δ = 1.42
(s, 9 H), 1.78 (m, 1 H), 2.33 (dd, J = 11.6, 2.7
Hz, 1 H), 3.11 (m, 1 H), 3.75 (s, 3 H), 3.82 (dd, J = 10.0, 10.0
Hz, 1 H), 4.50 (dd, J = 7.4,
1.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 42.7,
47.2, 61.8 (J = 2.7
Hz), 72.8, 83.4, 168.9, 172.2. The signals of the minor diastereomer
could not be separated from these of the major isomers.
GC
(155 ˚C, 60 min; 5˚/min; 180 ˚C,
3 min): t
R [(±)-(2S,3S,4R,5S)-9e] = 66.10
min; t
R [(±)-(2S,3S,4R,5R)-9e] = 75.16
min. Anal. Calcd for C17H26F3NO6 (397.39):
C, 51.38; H, 6.56; N, 3.52. Found: C, 50.98; H, 6.37; N, 3.56.
<A NAME="RG03009ST-23">23</A>
Unfortunately the aldol products obtained
with aromatic aldehydes could not be analyzed by GC; NMR has to
be used in this case. Therefore, we were not able to determine exact ratios,
but the NMR spectra indicated that the isomers were formed in comparable
amounts.