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.

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

References and Notes

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<A NAME="RY02810ST-9">9</A>

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.

<A NAME="RY02810ST-10">10</A>

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]⁺.

<A NAME="RY02810ST-11">11</A> For a recent review on organocatalytic aldol reactions, see: Trost BM. Brindle CS. Chem. Soc. Rev.  2010,  39:  1600 

<A NAME="RY02810ST-12">12</A>

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:

<A NAME="RY02810ST-13A">13a</A> Nyberg AI. Usano A. Pihko PM. Synlett  2004,  1891 

<A NAME="RY02810ST-13B">13b</A> Torii H. Nakadai M. Ishihara K. Saito S. Yamamoto H. Angew. Chem. Int. Ed.  2004,  43:  1983 

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<A NAME="RY02810ST-13D">13d</A> Hayashi Y. Angew. Chem. Int. Ed.  2006,  45:  8103 

<A NAME="RY02810ST-13E">13e</A> Hayashi Y. Sumiya T. Takahashi J. Gotoh H. Urushima T. Shoji M. Angew. Chem. Int. Ed.  2006,  45:  958 

<A NAME="RY02810ST-13F">13f</A> Gryko D. Saletra WJ. Org. Biomol. Chem.  2007,  5:  2148 

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<A NAME="RY02810ST-14">14</A>

For another example see ref. 4. Note also here a peptidic catalyst is used.

<A NAME="RY02810ST-15">15</A>

^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).

<A NAME="RY02810ST-16">16</A> For a review on peptides as asymmetric organocatalysts, see: Colby Davie EA. Mennen SM. Xu Y. Miller SJ. Chem. Rev.  2007,  107:  5759 

<A NAME="RY02810ST-17">17</A> For a review, see: Rabanal F. Ludevid MD. Pons M. Giralt E. Biopolymers  1993,  33:  1019 

<A NAME="RY02810ST-18A">18a</A> Kümin M. Sonntag L.-S. Wennemers H. J. Am. Chem. Soc.  2007,  129:  466 

<A NAME="RY02810ST-18B">18b</A> Kuemin M. Schweizer S. Ochsenfeld C. Wennemers H. J. Am. Chem. Soc.  2009,  131:  15474 

<A NAME="RY02810ST-18C">18c</A> Kuemin M. Engel J. Wennemers H. J. Pept. Sci.  2010,  16:  596