A Pictet-Spengler Cyclisation Methodology for the Construction of Nonproteinogenic Tetrahydroisoquinoline Quaternary Amino Acids

Abstract

A simple highly stereoselective route to tetrahydroisoquinoline quaternary amino acids from phenylalanine is described.

Key words

diastereoselective - amino acid - phenylalanine - tetra­hydroisoquinoline - oxidation - enantiomerically pure

References and Notes

• 1a Lohmar R. Steglich W. Chem. Ber.  1980,  113:  3706 
• 1b Stork G. Leong AYW. Touzin AM. J. Org. Chem.  1976,  41:  3491 
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• 2a Evans DA. Aldrichimica Acta  1982,  15:  23 
• 2b Gage JR. Evans DA. Org. Synth., Coll. Vol. VIII  1993,  339 ; Org. Synth. 1990, 68, 83
• 2d Evans DA. Vogel E. Nelson JV. J. Am. Chem. Soc.  1979,  101:  6120 
• 3 Pictet A. Spengler T. Ber. Dtsch. Chem. Ges.  1911,  44:  2030 
• 4 Seebach D. Boes M. Naef R. Schweizer WB. J. Am. Chem. Soc.  1983,  105:  5390 
• 5 Schöllkopf U. Hinrichs R. Lonsky R. Angew. Chem. Int. Ed.  1987,  26:  143 
• 6 Smith AB. Guzman MC. Sprengeler PA. Keenan TP. Holcomb RC. Wood JL. Carrol PJ. Hirschmann R. J. Am. Chem. Soc.  1994,  116:  9947 
• 8 Skiles JW. Suh JT. Williams BE. Menard PR. Barton JN. Love B. Jones H. Neiss ES. Schwab A. Mann WS. Khandwala A. Wolf PS. Weinryb I.
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7

Determined by ^¹H NMR spectroscopy at 400 MHz. Relative stereochemistry assigned by analogy with the work of Smith, established by single-crystal X-ray analysis.

10

( S )-3-Methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid 1 (R = Me, HCl Salt)
A mixture of α-methylated alloc-protected phenylalanine methyl ester 16 (2 g, 7.97 mmol) and aq formaldehyde (6 mL) in concd HCl (13.6 mL) was stirred at 100 ˚C under reflux for 24 h. The reaction mixture was allowed to reach r.t. and washed with EtOAc (3 × 50 mL). The aqueous layer was concentrated under reduced pressure to give a colourless foam (1.40 g, 77%). IR (film): ν_max = 3399, 2927, 2361, 1731, 1632, 1454, 1392, 1177, 1131, 1079, 750 cm^-¹. ^¹H NMR (400 MHz, MeOH): δ = 1.72 (br s, 3 H), 3.26 (d, J = 17.0 Hz, 1 H), 3.45 (d, J = 17.0 Hz, 1 H), 4.45 (d, J = 16.8 Hz, 1 H), 4.56 (d, J = 16.4 Hz, 1 H), 7.26-7.34 (m, 4 H). ^¹³C NMR (100 MHz, MeOH): δ = 21.4, 39.0, 43.1, 60.7, 127.6, 128.1, 128.7, 128.8, 129.6, 131.0, 173.2. ESI-MS: m/z calcd for C₁₁H₁₄NO₂ [M + H]: 192.1025; found: 192.1029. [α]_D ^²0 -17.9 (c 1.06, MeOH).

11

( S )-3-Ethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid 1 (R = Et, HCl Salt)
A mixture of alloc-protected phenylalanine carboxylic acid derivative 20 (2.0 g, 7.9 mmol) and aq formaldehyde (6 mL) in concd HCl (13.6 mL) was stirred at 100 ˚C under reflux for 24 h. The reaction mixture was allowed to reach r.t. and washed with EtOAc (3 × 50 mL). The aqueous layer was concentrated under reduced pressure to give a colourless foam (1.40 g, 80%). IR (film): ν_max = 3302, 2976, 2343, 1707, 1631, 1454, 1398, 1188, 1121, 1059, 758 cm^-¹. ^¹H NMR (400 MHz, MeOH): δ = 1.09 (t, J = 8.0 Hz, 3 H), 2.00-2.34 (m, 3 H), 3.21 (d, J = 17.0 Hz, 1 H), 3.44 (d, J = 17.0 Hz, 1 H), 4.42-4.49 (m, 2 H), 7.25-7.32 (m, 4 H). ^¹³C NMR (100 MHz, MeOH): δ = 10.6, 31.7, 37.6, 45.9, 67.5, 130.0, 130.7, 131.2, 131.4, 131.9, 132.9, 174.6. ESI-MS: m/z calcd for C₁₂H₁₆NO₂ [M + H]: 206.1181; found: 206.1185. [α]_D ^²0 -10.7 (c 1.08, MeOH).