Stereoselective Synthesis of the Key Intermediates of the HIV Protease Inhibitor Fosamprenavir and Its Diastereomer

In memory of Professor RNDr. Antonín Holý, DrSc., dr.h.c.

Abstract

Highly stereoselective Henry reaction has been used in the synthesis of the fosamprenavir precursor (2S,3R)-N-tert-butyl­oxycarbonyl-2-amino-3-hydroxy-1-phenyl-4-nitrobutane and its 2S,3S diasteromer from N-tert-butyloxycarbonyl-(S)-phenylalaninal and nitromethane. The complex of (2S,5R)- or (2R,5S)-5-isopropyl-5-methyl-2-(pyridine-2-yl)imidazolidine-4-one with copper(II) acetate has been used as the catalyst which provided the product with 2S,3R absolute configuration (dr = 90:10, overall yield 89%) or 2S,3S (dr = 99:1, overall yield 94%), respectively.

Key words

aldol reaction - diastereoselectivity - HIV - homogenous catalysis - ligands

• References and Notes

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• 19 One of the ligands L1 or L2 (0.055 mmol) and Cu(OAc)₂ (9.1 mg, 0.05 mmol) were stirred for 1 h in a mixture of EtOH (1.5 mL) and MeNO₂ (0.54 mL, 10 mmol) at r.t. to generate the catalyst. The solution was cooled to 18 °C, and then the aldehyde (1 mmol) was added. The mixture was stirred for the 96 h, the solvents were removed under reduced pressure, and the product was purified by short flash chromatography using EtOAc as an eluent.
• 20 The diastereomeric ratio of 4c/5c was determined by HPLC with a Chiralcel AD-H column [hexane–isopropyl alcohol (90:10), 0.8 mL/min, 254 nm]: t _R (5c) = 12.1 min; t _R (4c) = 23.1 min.
• 21 Compound 5c: yield 291 mg (94%); mp 168–170 °C. ¹H NMR (400 MHz, DMSO-d₆ , 75 °C): δ = 7.28–7.15 (m, 5 H, ArH), 6.47 (br s, 1 H, NH), 5.51 (d, J = 6.9 Hz, 1 H, OH), 4.67 (dd, J = 12.5, 3.0 Hz, 1 H, CH₂), 4.39 (dd, J = 12.5, 9.2 Hz, 1 H, CH₂), 4.19–4.10 (m, 1 H, CH_OH), 3.69–3.61 (m, 1 H, CH_NH), 3.02 (dd, J = 13.5, 3.8 Hz, 1 H, CH₂), 2.62 (dd, J = 13.5, 10.1 Hz, 1 H, CH₂), 1.28 (s, 9 H, t-Bu). ¹³C NMR (100 Mz, DMSO-d ₆): δ = 155.4, 139.0, 129.2, 128.1, 125.9, 80.0, 77.9, 71.2, 54.7, 36.0, 28.2.
• 22 Compound 4c: yield 280 mg (89%); mp 133–134 °C. ¹H NMR (400 MHz, DMSO-d ₆, 75 °C): δ = 7.28–7.17 (m, 5 H, ArH), 6.31 (br s, 1 H, NH), 5.42 (d, J = 6.6 Hz, 1 H, OH), 4.67 (dd, J = 12.5, 2.0 Hz, 1 H, CH₂), 4.37–4.32 (m, 1 H, CH₂), 4.23–4.19 (m, 1 H, CH_OH), 3.79–3.77 (m, 1 H, CH_NH), 2.88 (dd, J = 13.7, 5.1 Hz, 1 H, CH₂), 2.66 (dd, J = 13.6, 9.4 Hz, 1 H, CH₂), 1.31 (s, 9 H, t-Bu). ¹³C NMR (100 Mz, DMSO-d ₆): δ = 155.4, 139.0, 129.2, 128.2, 126.1, 79.5, 78.0, 69.8, 54.4, 35.7, 28.2.