Reversing the Enantioselectivity of a Peptidic Catalyst by Changing the Solvent

Abstract

The enantioselectivity of the peptidic catalyst H-Pro-Pro-Asp-NH(CH₂)₁₁CH₃ is reversed in different solvents. One enantiomer forms preferentially in pure DMSO or MeOH, whereas the other is preferentially formed in mixtures of water with DMSO or MeOH.

Key words

aldol reactions - organocatalysis - peptides - stereoselectivity - conformation - CD spectroscopy

References and Notes

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• 11 For a recent review on organocatalytic aldol reactions, see: Trost BM. Brindle CS. Chem. Soc. Rev.  2010,  39:  1600 
• For other examples of a rate accelerating effect of water on organocatalytic aldol reactions, see:
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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, H_αPro, H_αPro, H_αAsp), 3.38-3.72 (m, 4 H, H_δPro), 3.10-3.28 (m, 2 H, NHCH₂CH₂), 2.66-2.88 (m, 2 H, H_βAsp), 1.88-2.52 (m, 8 H, H_βPro, H_γPro), 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, H_αPro), 4.47 (d, J = 8.0 Hz, 1 H, H_αAsp), 4.26 (m, 1 H, H_αPro), 3.38-3.72 (m, 4 H, H_δPro), 3.10-3.28 (m, 2 H, NHCH₂CH₂), 2.66-2.88 (m, 2 H, H_βAsp), 1.88-2.52 (m, 8 H, H_βPro, H_γPro), 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]⁺.

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.

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).