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Synlett 2013; 24(10): 1280-1282
DOI: 10.1055/s-0033-1338803
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© Georg Thieme Verlag Stuttgart · New York

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

Illia Panov
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic   Fax: +420(466)037068   Email: milos.sedlak@upce.cz
,
Pavel Drabina
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic   Fax: +420(466)037068   Email: milos.sedlak@upce.cz
,
Jiří Hanusek
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic   Fax: +420(466)037068   Email: milos.sedlak@upce.cz
,
Miloš Sedlák*
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic   Fax: +420(466)037068   Email: milos.sedlak@upce.cz
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Further Information

Publication History

Received: 28 March 2013

Accepted after revision: 19 April 2013

Publication Date:
08 May 2013 (online)

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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
 

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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, CHOH), 3.69–3.61 (m, 1 H, CHNH), 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, CHOH), 3.79–3.77 (m, 1 H, CHNH), 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.