Synthesis of macrocyclic trypanosomal cysteine protease inhibitors

Abstract

The importance of cysteine proteases in parasites, compounded with the lack of redundancy compared to their mammalian hosts makes proteases attractive targets for the development of new therapeutic agents. The binding mode of K11002 to cruzain, the major cysteine protease of Trypanosoma cruzi was used in the design of conformationally constrained inhibitors. Vinyl sulfone-containing macrocycles were synthesized via olefin ring-closing metathesis and evaluated against cruzain and the closely related cysteine protease, rhodesain.

Figure 1

(a) K11002 and its 3-D structure when bound to cruzain; (b) Design rationale for conformationally constrained inhibitors 4 and 5.

Figure 2

Disconnective analysis of inhibitors 4 and 5.

Scheme 1

(a) (i) Boc₂O, NaHCO₃, H₂O, THF, 0 to 23 °C, 12 h; (ii) CH₃(CH₃O)NH•HCl, HOBT, NMM, EDC, CH₂Cl₂, 0 to 23 °C, 12 h, 84% (two steps); (b) TFA, CH₂Cl₂, quant.; (c) LDA, LiCl, THF, 0 °C, 29 h, 62% (de > 20:1); (d) (i) NaOH, H₂O, reflux, 3 h; (ii) Boc₂O, NaOH, H₂O, dioxane, 0 to 23 °C, 16 h, 82% (two steps); (e) CH₃(CH₃O)NH•HCl, HOBT, NMM, EDC, CHCl₃, 0 to 23 °C, 14 h, 88%; (f) TFA, CH₂Cl₂, 0 23 °C, 1 h, quant.

Scheme 2

(a) 16, toluene, 4 Å mol. sieves, −78 °C, 3 h, 70% (74 % ee); (b) (i) Tf₂O, pyridine, CH₂Cl₂, 0 to 23 °C, 30 min; (ii) 10, proton sponge, CHCl₃, −78 to 23 °C, 18 h, 70% (two steps); (c) CbzCl, n-BuLi, Et₂O, −78 to 23 °C, 72 h, 55%; (d) (i) NaOH, THF, MeOH, 0 °C; (ii) 8 or 9, EDC, HOBT, NMM, CH₂Cl₂, 0 to 23 °C, 14 h (two steps), 23 (77%), 24 (68%); (e) 25, 1,2-dichloroethane, 95 °C, 1 h; (f) H₂, 10% Pd/C, EtOAc, EtOH, 36 h, 26 (65% from 23), 27 (67% from 24); (g) (i) TFA, CH₂Cl₂, 6 h; (ii) benzylamine, EDC, HOBT, NMM, CH₂Cl₂, 0 to 23 °C, 14 h (two steps), 28 (89%), 29 (73%); (h) (i), LiAlH₄, THF, −10 °C 30 min; (ii) 30, NaH, THF, 0 to 23 °C; 4–8 h (two steps), 4 (58%), 5 (51%).