Role of the Acid Group in the Pictet-Spengler Reaction of α-Amino Acids

Abstract

Pictet-Spengler reactions of different α-amino acids in very mild conditions have been studied. Excellent yields were obtained by simply heating the free acids in alcoholic solvents, both in the presence and absence of one equivalent of Et₃N. However, worse results were obtained for the corresponding methyl esters ­under the same conditions. These conditions are compatible with many functional groups.

Pictet-Spengler - mild conditions - histidine - dopa - phenylalanine - amino acids - free acid - microwave - alcoholic solvents

References and Notes

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The reaction has been done also with aldehydes containing functionalities such as acetals, esters, amides. These functionalities otherwise not stable to acidic catalyst have been proven to give good yields in these conditions.

15 Bison G, Schlupp J, Winterscheid J, and Thewalt K. inventors; US  4791210.  ; Chem. Abstr. 1987, 109, 73455

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General Procedure.
To a solution of the l-histidine or l-Dopa derivative (0.2 mmol) in 0.5 mL of the alcoholic solvent were added Et₃N (equiv indicated in the tables) and the aldehyde (0.24 mmol, 1.2 equiv). The mixture was stirred at 70 °C until completion. The mixture was evaporated to dryness to give the crude. For purifying the crude and eliminating the aldehyde in excess the mixture was taken up in DMF (1 mL) and sulfonylhydrazine resin (50 mg, 2.54 mmol/g) was added. The suspension was stirred for 4 h at 60 °C. The mixture was filtered and the resin washed with DMF (2 × 1 mL). The filtrate was evaporated to dryness to give the desired product.

Compound 7: ¹H NMR (400 MHz, CD₃OD): δ (mixture of diastereoisomers a + b) = 3 (m, H-7 a + b, 4 H), 3.7 (s, CO₂Me, a, 3 H), 3.76 (s, CO₂Me, b, 3 H), 3.85 (dd, H-6, a, 2 H), 3.90 (dd, H-6, b, 2 H), 5 (s, H-4, b, 1 H), 5.20 (s, H-4, a, 1 H), 7.40 (m, Ar) ppm. ESI-MS: m/z = 257.9 [MH⁺].
Compound 8: ¹H NMR (400 MHz, CD₃OD): δ (mixture of diastereoisomers in the form of triethylamonium salt) = 3.1 (m, H-7, a + b, 4 H), 3.66 (dd, H-6, a, 2 H), 3.76 (dd, H-6, b, 2 H), 5.20 (s, H-4, b, 1 H), 5.40 (s, H-4, a, 1 H), 7.50 (m, Ar) ppm. ESI-MS: m/z = 243.9 [MH⁺].
Compound 10: ¹H NMR (400 MHz, CD₃OD): δ (mixture of diastereoisomers) = 3.25 (m, H-3, a + b, 4 H), 3.80 (s, CO₂Me, a, 3 H), 3.90 (s, CO₂Me, b, 3 H), 4.28 (dd, H-2, a, 2 H), 4.62 (dd, H-2, b, 2 H), 5.60 (s, H-8, b, 1 H), 5.8 (s, H-8, a, 1 H), 6.0 (s, H-4, b, 1 H), 6.25 (s, H-4, a, 1 H), 6.68 (s, H-7, b, 1 H), 6.69 (s, H-8, a, 1 H), 7.5 (m, Ar) ppm. ESI-MS: m/z = 300.2 [MH⁺].
Compound 13: ¹H NMR (400 MHz, CD₃OD): δ (mixture of diastereoisomers in the form of triethylamonium salt): = 3.20 (m, H-3, a + b, 4 H), 3.80 (dd, H-2, a, 2 H), 3.90 (dd, H-2, b, 2 H), 5.40 (s, H-8, b, 1 H), 5.60 (s, H-8, a, 1 H), 6.00 (s, H-4, b, 1 H), 6.25 (s, H-4, a, 1 H), 6.68 (s, H-7, b, 1 H), 6.70 (s, H-8, a, 1 H), 7.40 (m, Ar) ppm. ESI-MS: m/z = 286.2 [MH⁺].

17 Guiso M. Marra C. Cavarischia C. Tetrahedron Lett.  2001,  42:  6531 

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Reaction with 3,4-dimethoxy-l-phenylalanine in which the hydroxy groups are methylated and the carboxylic acid is in its free form showed no reaction under these mild conditions. Methoxy groups are less activating than hydroxy groups on aryl systems. It seems that the intramolecular acidic catalysis only promoted reaction for activated systems.