Short Total Synthesis of Aspartyl Protease Inhibitors L-685,434, L-682,679 and L-685,458

Abstract

Hydroxyethylene dipeptide isosteres L-685,434, L-682,679 and L-685,458 were synthesized in a few steps by a sequence involving an allyltrichlorostannane coupling with an α-aminoaldehyde followed by hydroboration of the corresponding 1,2-syn and 1,2-anti aminoalcohols to give the diols, lactonization under TPAP conditions, lactone opening and peptide coupling with the desired amine or dipeptide amide.

Key words

amino aldehydes - HIV - peptides - total synthesis - lactones

References

• 1a Vacca JP. Condra JH. Drug Discovery Today  1997,  2:  261 
• 1b Steele FR. Nature Med.  1996,  2:  257 
• 2 Wlodawer A. Vondrasek J. Annu. Rev. Biophys. Biomol. Struct.  1998,  27:  249 
• 3 Babine RE. Bender SL. Chem. Rev.  1997,  97:  1359 
• 4 Tomasselli AG. Heinrikson RL. Biochim. Biophys. Acta  2000,  189 
• 5 For comparative quantitative structure-activity relationship studies on anti-HIV drugs, see: Garg R. Gupta SP. Gao H. Babu MS. Debnath AK. Hansch C. Chem. Rev.  1999,  99:  3525 
• 6 Lyle TA. Wiscount CM. Guare JP. Thompson WJ. Anderson PS. Darke PL. Zugay JA. Emini EA. Schleif WA. Quintero JC. Dixion RAF. Sigal IS. Huff JR. J. Med. Chem.  1991,  34:  1228 
• 7 Panchagnula R. Thomas NS. Int. J. Pharm.  2000,  201:  131 
• For the synthesis of analogues of L-685,434, see:
• 8a Litera J. Budesinsky M. Urban J. Soucek M. Collect. Czech. Chem. Commun.  1998,  63:  231 
• 8b Litera J. Weber J. Krizova I. Pichova I. Konvaluka J. Fusek M. Soucek M. Collect. Czech. Chem. Commun.  1998,  63:  541 
• 8c Evans BE. Rittle KE. Homnick CF. Springer JP. Hirshfield J. Veber DF. J. Org. Chem.  1985,  50:  4615 
• 9a cis-Lactone 11 is also an important intermediate for the synthesis of potent HIV-1 protease inhibitors: Ghosh AK. McKee SP. Thompson WJ. Darke PL. Zugay JC. J. Org. Chem.  1993,  58:  1025 
• 9b Thompson WJ. Fitzgerald PMD. Holloway MK. Emini EA. Darke PL. McKeever BM. Schleif WA. Quintero JC. Zugay JA. Tucker TJ. Schwering JE. Homnick CF. Nunberg J. Springer JP. Huff JR. J. Med. Chem.  1992,  35:  1685 
• 10 For synthesis of analogues of L-682,679, see: deSolms SJ. Giuliani EA. Guare JP. Vacca JP. Sanders WM. Graham SL. Wiggins JM. Darke PL. Sigal IS. Zugay JA. Emini EA. Schleif WA. Quintero JC. Anderson PS. Huff JR. J. Med. Chem.  1991,  34:  2852 
• 11 Evans J. Chem. Brit.  2001,  April:  47 
• 12 Pesti JA. Chorvat RJ. Huhn GF. Chem. Innovation  2000,  October:  29 
• 13 de Clerq E. Pure Appl. Chem.  2001,  73:  55 
• 14 Ghosh AK. Shin D. Mathivanan P. Chem. Commun.  1999,  1025 
• 15 Li YM. Xu M. Lai MT. Huang Q. Castro JL. DiMuzio-Mower J. Harrison T. Lellis C. Nadin A. Neduvelil JG. Register RB. Sardana MK. Shearman MS. Smith AL. Shi XP. Yin KC. Shafer JA. Gardell SJ. Nature (London)  2000,  405:  689 
• 16 Li YM. Lai MT. Xu M. Huang Q. DiMuzio-Mower J. Sardana MK. Shi XP. Yin KC. Shafer JA. Gardell SJ. Proc. Natl. Acad. Sci. U.S.A.  2000,  97:  6138 
• 17 Shearman MS. Beher D. Clarke EE. Lewis HD. Harrison T. Hunt P. Nadin A. Smith AL. Stevenson G. Castro JL. Biochemistry  2000,  39:  8698 
• 18 Nadin A. López JMS. Neduvelil JG. Thomas SR. Tetrahedron  2001,  57:  1861 
• 19 Dias LC. Giacomini R. J. Braz. Chem. Soc.  1998,  9:  357 
• 20 Dias LC. Giacomini R. Tetrahedron Lett.  1998,  39:  5343 
• 21 Dias LC. Meira PRR. Ferreira E. Org. Lett.  1999,  1:  1335 
• 22 Dias LC. Meira PRR. Synlett  2000,  37 
• 23 Dias LC. Ferreira E. Tetrahedron Lett.  2001,  42:  7159 
• 24a Fehrentz JA. Castro B. Synthesis  1983,  676 
• 24b Saari WS. Fisher TE. Synthesis  1990,  453 
• For optical stability studies of N-protected α-amino aldehydes, see:
• 25a Jurczak J. Golebiowski A. Chem. Rev.  1989,  89:  149 
• 25b Myers AG. Zhong BY. Movassaghi M. Kung DW. Lanman BA. Kwon S. Tetrahedron Lett.  2000,  41:  1359 
• 26 Benedetti F. Miertus S. Norbedo S. Tossi A. Zlatoidzky P. J. Org. Chem.  1997,  62:  9348 
• 27a D’Aniello F. Mann A. Mattii D. Taddei M. J. Org. Chem.  1994,  59:  3762 
• 27b Ciapetti P. Falorni M. Taddei M. Tetrahedron  1996,  52:  7379 
• 28 Ley SV. Norman J. Griffith WP. Marsden SP. Synthesis  1994,  639 
• For other synthesis of these lactones, see:
• 29a Ghosh AK. Fidanze S. J. Org. Chem.  1998,  63:  6146 
• 29b Pégorier L. Larchevêque M. Tetrahedron Lett.  1995,  36:  2753 ; see also ref. 9a
• 30a Dess DB. Martin JC. J. Am. Chem. Soc.  1991,  113:  7277 
• 30b Ireland RE. Liu L. J. Org. Chem.  1993,  58:  2899 
• 31 Hoffman RV. Maslouch N. Cervantes-Lee F. J. Org. Chem.  2002,  67:  1045 

32

New compounds and the additional isolatable intermediates gave satisfactory ¹H and ¹³C NMR, IR, HRMS and analytical data. Yields refer to chromatographically and spectroscopically homogeneous materials.

33

L-685,434(1): N -[(2 R )-Hydroxy-(1 S )-indanyl]-(5 S )-{[ tert -butoxycarbonyl]-amino-(4 S )-hydroxy-6-phenyl-(2 R )-benzyl}-hexanamide: IR (KBr) 3447, 3365, 3061, 3022, 2917, 2849, 1665, 1645, 1537, 1392, 1278, 1158, 1058, 899, 862, 733, 703, 649 cm^-1. ¹H NMR (500 MHz, DMSO): δ = 1.37 (s, 9 H), 1.80-1.96 (m, 2 H), 2.72-2.95 (m, 6 H), 3.02 (dd, J = 5.1, 16.8 Hz, 1 H), 3.45 (m, 1 H), 3.68 (m, 1 H), 3.81 (m, 1 H), 4.22 (t, J = 4.8 Hz, 1 H), 4.81 (d, J = 9.5 Hz, 1 H), 5.23 (dd, J = 6.1, 8.4 Hz, 1 H), 5.87 (d, J = 8.4 Hz, 1 H), 7.05 (brs, 1 H), 7.05-7.30 (m, 14 H). ¹³C NMR (125 MHz, DMSO): δ = 28.5, 37.5, 39.0, 39.1, 39.6, 47.1, 57.4, 57.6, 69.3, 73.1, 79.6, 124.1, 125.1, 126.4, 126.5, 127.0, 128.0, 128.4, 128.5, 129.0, 129.3, 138.4, 139.8, 140.1, 140.3, 156.2, 175.4. TLC: R_f = 0.21 (60% EtOAc:hexanes).
L-682,679(2): {(1 S )-benzyl-4 R -[1-((1 S )-carbamoyl-2-phenyl-ethylcarbamoyl)-(1 S )-3-methyl-butyl-carbamoyl]-(2 S )-hydroxy-5-phenyl-pentyl} Carbamic Acid tert -Butyl Ester: IR (KBr) 3377, 3341, 3190, 2955, 2924, 2872, 2853, 1667, 1649, 1621, 1531, 1451, 1365, 1273, 1250, 1172, 1080, 743, 698 cm^-1. ¹H NMR (500 MHz, DMSO): δ = 0.77 (d, J = 6.4 Hz, 3 H), 0.84 (d, J = 6.4 Hz,
3 H), 1.28 (s, 9 H), 1.20-1.35 (m, 2 H), 1.49 (m, 1 H), 1.60 (m, 2 H), 2.45 (dd, J = 8.2, 13.4 Hz, 1 H), 2.53 (dd, J = 9.5, 13.7 Hz, 1 H), 2.70 (dd, J = 5.0, 13.6 Hz, 1 H), 2.78-2.87 (m, 3 H), 3.00 (dd, J = 5.2, 3.7 Hz, 1 H), 3.51-3.57 (m, 1 H), 4.21 (q, J = 6.7 Hz, 1 H), 4.42 (q, J = 5.5 Hz, 1 H), 4.48 (d, J = 6.1 Hz, 1 H), 6.36 (d, J = 9.0 Hz, 1 H), 7.09 (brs, 1 H), 7.12-7.25 (m, 15 H), 7.34 (brs, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H). ¹³C NMR (125 MHz, DMSO): δ = 23.1, 24.2, 28.0, 28.4, 35.1, 36.3, 37.7, 38.9, 40.9, 43.7, 51.5, 53.5, 56.5, 69.4, 77.6, 125.9, 126.0, 126.4, 128.1, 128.2, 128.3, 129.1, 129.2, 129.4, 137.9, 139.8, 140.0, 155.5, 171.8, 172.8, 174.7. TLC: R_f = 0.18 (70% EtOAc:hexanes).
L-685,458(3): {(1 S )-benzyl-(4 R )-[1-((1 S )-carbamoyl-2-phenyl-ethylcarbamoyl)-(1 S )-3-methyl-butyl-carba-moyl]-(2 R )-hydroxy-5-phenyl-pentyl} Carbamic Acid tert -Butyl Ester: White solid. Mp 212-213 °C. [α]_D ²⁵ =
-26.8 (c 0.5, CHCl₃). IR (KBr): 3375, 3338, 3197, 2960, 2930, 2872, 2856, 1666, 1647, 16231, 1535, 1451, 13675, 1271, 1251, 1174, 1086, 743, 698 cm^-1. ¹H NMR (500 MHz, DMSO): δ = 0.74 (d, J = 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz,
3 H), 1.24 (s, 9 H), 1.25-1.40 (m, 2 H), 144-1.70 (m, 3 H), 2.40-3.00 (m, 7 H), 3.42 (m, 2 H), 4.16 (m, 1 H), 4.40 (m,
1 H), 4.70 (brs, 1 H), 6.48 (d, J = 9.0 Hz, 1 H), 7.05-7.27
(m, 17 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H). ¹³C NMR (125 MHz, DMSO): δ = 23.9, 25.4, 26.1, 30.4, 37.6, 38.0, 39.8, 39.9, 42.8, 46.6, 53.7, 55.8, 58.9, 73.5, 79.7, 127.9, 128.0, 128.6, 130.0, 130.2, 130.4, 131.1, 131.4, 140.0, 142.0, 142.3, 157.4, 174.0, 174.8, 175.2. TLC:
R_f = 0.21 (60% EtOAc:hexanes).