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9 Peptide 1 is
soluble in polar solvents such as DMSO and DMF but to a lesser degree
in nonpolar solvents such as CH2Cl2 or hexanes.
10 For details on the synthesis of 1a see the Supporting Information. Analytical
data of peptide 1a: A cis/trans conformer ratio of 10:1 was observed
in the ¹H NMR and ¹³C NMR
spectra in CDCl3. Major isomer: ¹H
NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.0 Hz, 1 H, CONH), 7.89
(m, 1 H, CONH), 6.97 (m, 1 H, CONH), 4.52-4.74 (m, 3 H,
HαPro, HαPro, HαAsp),
3.38-3.72 (m, 4 H, HδPro), 3.10-3.28
(m, 2 H, NHCH2CH2), 2.66-2.88 (m,
2 H, HβAsp), 1.88-2.52 (m, 8 H, HβPro,
HγPro), 1.40-1.50 (m, 2 H, Et), 1.20-1.32
(m, 18 H, 9 × CH2), 0.87 (t, J = 6.4
Hz, 3 H, Me). Minor isomer: ¹H NMR (400 MHz,
CDCl3): δ = 8.38 (d, J = 8.0
Hz, 1 H, CONH), 7.64 (m, 1 H, CONH), 6.72 (m, 1 H, CONH), 4.92 (dd, J = 4.4, 8.8 Hz, 1 H, HαPro),
4.47 (d, J = 8.0 Hz, 1 H, HαAsp),
4.26 (m, 1 H, HαPro), 3.38-3.72 (m,
4 H, HδPro), 3.10-3.28 (m, 2 H, NHCH2CH2),
2.66-2.88 (m, 2 H, HβAsp), 1.88-2.52
(m, 8 H, HβPro, HγPro),
1.40-1.50 (m, 2 H, Et), 1.20-1.32 (m, 18 H, 9 × CH2),
0.87 (t, J = 6.4 Hz, Me). ¹³C
NMR (100 MHz, CDCl3): δ = 174.1, 172.1,
171.0, 168.1, 61.0, 59.2, 50.5, 47.9, 40.3, 32.3, 30.1, 29.8, 27.3, 25.5,
25.0, 23.1, 14.5. MS (ESI): m/z (%) = 495 (100) [M + H]+,
517 (15) [M + Na]+,
1013 (17) [2 M + Na]+.
11 For a recent review on organocatalytic
aldol reactions, see: Trost BM.
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12
General Procedure:
The catalyst 1a (3.5 mg, 0.007 mmol, 0.05
equiv) and 4-nitrobenzaldehyde (20.0 mg, 0.13 mmol, 1 equiv) were
placed in a glass vial and cyclohexanone (150 µL, 1.45
mmol, 11 equiv) along with the solvent (350 µL) was added.
The resulting clear solution was agitated until full conversion
for 3-48 h. It was then diluted with CH2Cl2 (3
mL) and quenched with a half saturated solution of NH4Cl (2
mL). The layers were separated, the aqueous phase was extracted
with CH2Cl2 (3 × 2 mL) and the combined
organic phases were washed with sat. NaCl (3 mL) and dried over MgSO4.
The filtrate was concentrated in vacuo and purified by flash chromatography
on silica gel (5.6 g, 25% EtOAc in cyclohexane) to afford
the aldol product as a colorless liquid that crystallized in long
needles upon standing.
For other examples of a rate accelerating
effect of water on organocatalytic aldol reactions, see:
13a
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14 For another example see ref. 4. Note
also here a peptidic catalyst is used.
15
¹H NMR spectra
of peptide 1a in DMSO-d
6 compared
to 10% D2O in DMSO-d
6 differ
significantly, both in the
cis/trans amide conformer ratios and the
chemical shifts (see Supporting Information).
16 For a review on peptides as asymmetric
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17 For a review, see: Rabanal F.
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