Synthesis of Tamiflu and its Phosphonate Congeners Possessing Potent Anti-Influenza Activity

Transcription

1 Synthesis of Tamiflu and its Phosphonate Congeners Possessing Potent Anti-Influenza Activity Shie, J. et al. J. Am. Chem. Soc. 2007, 129, Intramolecular eck eactions of Unactivated Alkyl alides Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129,

2 Current Influenza Therapy Two major classes of drugs exist to treat influenza infections M2 ion channel blockers rimantadine and amantadine N N 3 3 Cl Cl amantadine rimantadine Neuraminidase inhibitors oseltamivir and zanamivir mimic transition state of enzymatic cleavage of sialic acid N 3 C 2 t 2 P 4 N 3 C 2 t 2 P 4 N N C N 2 N N N 2 C oseltamivir (Tamiflu) zanamivir (elenza)

3 Biological ationale AcN N 2 P seltamivir (Tamiflu) binds in the active site of the enzyme neuraminidase (NA) through -bonding interactions with three Arg residues (118, 292 and 371) Tamiflu cannot inhibit mutant avian flu (5N1) 274Y neuraminidase Phosphonate group is used as bioisostere for the carboxylate group, as phosphonate-guanidinium ion pair has stronger electrostatic interactions than carboxylate-guanidinium ion pair eplacement of amine with guanidine also increases interactions with enzyme Molecular docking experiments show that the phosphonate derivative of Tamiflu binds strongly to the active site of NA (8 pairs of -bonding interactions compared to 6 in Tamiflu) Accepted synthetic methods for Tamiflu cannot be extended to include synthesis of phosphonate derivative

4 Synthesis of Phosphate Congeners 1) 3 CCCl, pyridine 0 C, 8 h; 8 9% 2 ) PDC, Ac 2, ref lux, 1.5 h; then N 2 -C l, pyridine, 60 C, 24 h; 82% 3) LiAl 4, TF, 0 C; then reflux 1.5 h; 88% 2 N 1) Ac 2, pyridine 25 C, 3h; then Cl/1,4-dioxane (4M), Bn, toluene 0-25 C, 24 h; 85% 2) 2,2'-dimethoxyp ropane, tolu ene, p-ts (cat.), 80 C, 4 h; 90% AcN Bn N 3 1) (Ph) 2 PN 3, DIAD, PPh 3 TF, 25 C, 48 h 2) C l, t, reflux, 1 h AcN 1) 2, Pd/C, t, 25 C, 24 h; then Na, TF, 25 C, 1 h N at, t, 25 C, 5 h t t P AcN 1) Tf 2, pyridine, C 2 Cl 2, -15 C, 2 h; the n t 2 C C 2 P(t) 2 or 2 C[ P(t) 2 ] 2, Na, 1 5-crow n-5, DM F, 25 C, 24 h Bn 9 9 a = C 2t, 83% 9 b = P(t) 2, 74% 8 8 a = C 2 t, 83% 8 b = P(t) 2, 80% 7 7a = C 2 t, 80% 7b = P(t) 2, 7 3% 1) Tf 2, pyridine, C 2 Cl 2, -15 to -10 C, 2 h; then KN 2, 18-crown-6, DMF, 40 C, 24 h N a = C 2 t, 70 % 10b = P(t) 2, 71%

5 Synthesis of Phosphate Congeners, cont. N 3 1 0a = C 2 t, 70% 1 0b = P(t ) 2, 71% = 10 1) C l 3 CC (=N )C t 2, CF 3 S 3, C 2 C l 2, 2 5 C, 24 h 1 2a = C 2 t, 78% 1 2b = P(t ) 2, 58% 1) 2, Lindlar catalyst, t, 25 C, 16 h N 2) N,N'-bis(t - BocN butoxycarbonyl) thiourea, N 3 N Boc gcl 2, t 3 N, DMF, C, h a = C 2 t, 78% 1) TMSBr, C Cl 3, 25 C, 24 h; then N 4 C 3, lyophilization 2) K, TF/ 2, 0-25 C, 1 h; then TFA, C 2 C l 2, 0 C, 1 h 1 1b = P(t ) 2, 82% 1) 2, Lindlar catalyst, t, 25 C, 16 h 2 ) 3 P 4, t, 40 C, 1 h N 3 2 P 4 1) 2, Lindlar catalyst, t, 25 C, 16 h 2) K, TF/ 2, 0-25 C, 1 h TM SBr, CC l 3, 25 C, 24 h; then N 4 C 3, lyophilization Ac N 1 = C 2 t, 9 1% (Tamiflu) 3b = P(t)2, 85% N 2 A 2 A = C 2, 88% 3 A = P(N 4 ) 2, 8 5% ( Tam iphosphor) N N N 2 13a = C 2, 88% 13b = P(N4 ) 2, 72%

6 Biological Testing N neuraminidase inhibition, IC 50 (nm) Compound Wt (WSN) Mut (WSN) Wt (anoi) Mut (anoi) 2 ( = N 2, = C 2 ) ( = N 2, = P(N 4 ) 2 ) a ( = guanidine, = C 2 ) b ( = guanidine, = P(N 4 ) 2 ) Phosphonate congeners 3 (Tamiphosphor) and 13b are more effective than the carboxylate compounds 2 and 13a nly 13b shows activity against the mutant neuraminidase enzymes Phosphonate 3 is more active than oseltamivir in NA inhibition by 19-fold and in antiflu assays by 7-fold eplacing amino group in 3 by guanidino group in 13b enhances NA inhibition and antiflu activity

7 The eck eaction base base- X Cis!-elimination -Pd-X Pd(0) -X Pd-X xidative Addition Z -Pd(II)-X!-hydride limination Insertion -Pd(II)-X Coordination Z Z as a wide variety of uses in coupling olefins with aryl/vinyl sulfonates and halides, but there has been limited success with unactivated alkyl halides Competing β-hydride elimination can occur with alkyl halides Alkyl halides often need to be activated to obtain reactivity

8 Previous Alkyl alide eck Couplings Bridgehead halide is unlikely to undergo β-elimination Br + Pd/C, K 2 C 3 DMF 120 C, 24 h 0-41% No available β-hydrogens on activated substrates Bräse, S.; Waegell, B.; de ijere, A. Synthesis 1998, t N t C l + Pd(PPh 3 ) 2 Cl 2, ipr 2 Nt C 3 C N, 110 C 65% t N t + t N A t B atio A:B 65:35 Glorius, F. Tetrahedron Lett. 2003, 44, Ph Cl + Ph Pd(Ac) 2, nbu 3 N 130 C, 10 h 70% Wang, L.; Pan, Y.; Jiang, X.; u,. Tetrahedron Lett. 2000, 41,

9 Synthetic Plan base base- X rate of β-elimination > rate of insertion -Pd-X Pd(0) -X Pd-X B Z -Pd(II)-X A -Pd(II)-X Z Z rate β-elimination < rate of insertion In order to get the correct reactivity profile, intermediate A should be more prone to insertion than elimination pposite reactivity should be seen with intermediate B

10 General thod Br 5% Pd 2 (-dba) 3 20% SIs BF 4 20% Kt-Bu 1.1 equiv base C 3 CN or NMP,! p-anisyl p-anisyl s N N s -dba BF 4 SIs BF 4 Intramolecular alkyl eck reactions fit the desired profile Intermediate A undergoes intramolecular insertion more rapidly than β-hydride elimination Intermediate B undergoes β-hydride elimination more rapidly than intermolecular insertion Catalyst was optimized with various carbenes and ligands to garner the desired reactivity

11 Substrate Scope Br 5% Pd 2 (-dba) 3 20% SIs BF 4 20% Kt-Bu 1.1 equiv Cs 2 C 3 C 3 CN or NMP, 65 C t 2 C n-ct t 2 C 85% 73% 71% F 3 C 73% 82% 79% 78% 8 3%

12 eactions with Alkyl Chlorides Cl 5% Pd 2 (-dba) 3 20% SIs BF 4 20% Kt-Bu 1.1 equiv K 3 P 4 NMP, 100 C t 2 C t 2 C n-ct 80% 66% 72% This methodology also works on the corresponding chlorides Yields are slightly lower for chloride substrates igher temperatures are needed for these reactions