Total synthesis of TMC-95A and -B via a new reaction leading to Z-enamides. Some preliminary findings as to SAR

Abstract

A full account of the total syntheses of proteasome inhibitors TMC-95A and -B is provided. A key feature of the syntheses involved installation of a cis-propenylamide moiety by a thermal rearrangement of an alpha-silylallyl amide. The scope and mechanism of the enamide-forming reaction are discussed. Also provided are some preliminary results from SAR studies. It was found that simplified analogues can retain the full potency of proteasome inhibition.

Figure 1

Structures of TMC-95A-D.

Scheme 1

Synthetic Plan a a TIPS = triisopropylsilyl, Cbz = benzoxycarbonyl, Boc = tert-butoxycarbonyl, X = Br or I.

Scheme 2

Attempted Synthesis of 7-Bromooxindole 2aa a Conditions: (a) (1) DIBAL/toluene, −78 °C, 1 h; (2) methyl (triphenylphosphoranylidine)acetate, CH₂Cl₂, rt, 88% (two steps); (b) (1) LiOH, THF/MeOH/H₂O, (2) TBSCl, Et₃N/DMAP, (3) (COCl)₂, DMF (cat.); (c) 2,6-dibromoaniline, NaH, DMF/THF, 75 °C, 1.5 h, 44%; (d) [Pd(PPh₃)₄] or Pd(OAc)₂, 5–15%. DIBAL = diisobutylaluminum hydride, TBS = tert-butyldimethylsilyl, DMAP = 4-(dimethylamino)pyridine.

Scheme 3

Synthesis of 7-Iodooxindole 2ba a Conditions: (a) (1) TIPSCl, imidazole, 94%; DIBAL, –78 °C, 96%; (b) CCl₃CH(OH)₂, NH₂OH•HCl, Na₂SO₄, H₂O, 45 °C, 12 h, 66%; (c) H₂SO₄, 70 C, 15 min, 88–98%; (d) (1) NH₂NH₂•H₂O, 125 °C, 1 h, (2) HCl (6 N), 60 °C, 2 h, 81% (two steps); (e) 12, see Table 1.

Scheme 4

Synthesis of Aryl Borate 3aa a Conditions: (a) (1) MeOH/SOCl₂, (2) CbzCl, K₂CO₃, H₂O/acetone, 96% (two steps); (b) LiOH, Me₂SO₄, 86%; (c) I₂, Ag₂SO₄, MeOH, rt, 1.5 h, 93%; (d) bis(pinacolato)diboron, [PdCl₂(dppf)]•CH₂Cl₂, KOAc, DMSO, 80 °C, 13 h, 95%. dppf = bis(diphenylphosphanyl)ferrocene.

Scheme 5

Biaryl Linkage Formation by Suzuki Coupling a a Conditions: (a) 3a, [PdCl₂(dppf)]•CH₂Cl₂, KOAc, DME, 80 °C, 2 h, 72% (E/Z ~ 2/1); (b) I₂ (cat.), DME, 80 °C, 1 d, 87% (63% conv). DME = 1,2-dimethoxyethane.

Scheme 6

Synthesis of Diolsa a Conditions: (a) LiOH, THF/MeOH/H₂O; (b) hydroxysuccinimide, DDC, THF, 55% (two steps); (c) l-Asn•H₂O, Et₃N, THF/H₂O, rt, 4 h, 70%; (d) LiOH, THF/H₂O, 0 °C, 1.5 h; (e) H-Asn-O-t-Bu, EDC/HOAt, THF, rt, 2 h, 70% (two steps); (f) HF/Py, 84%; (g) for 23a: OsO₄/NMO, (DHQD)₂PHAL, t-BuOH/H₂O, rt, 1 h, 84% (S/R ~ 1/1.8); for 23b: (1) OsO₄/NMO, (DHQ)₂PHAL, t-BuOH/H₂O, rt, 4 h, (2) TIPSCl, imidazole/DMAP, 5 h, 81% (S/R ~ 1/1.8); (h) HF/Py; (i) DMP/PPTS, CH₂Cl₂. DCC = 1,3-dicyclohexylcarbodiimide, EDC = 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, HOAT = 1-hydroxy-7-azabenzotriazole, Asn = asparagine, NMO = 4-methylmorpholine N-oxide, (DHQD)₂PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine, (DHQ)₂PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine, DMP = 2,2-dimethoxypropane, PPTS = pyridinium p-toluenesulfonate.

Scheme 7

Macrolactamization of (S)-24a a Conditions: (a) TFA/CH₂Cl₂ (4:1), rt, 2 h; (b) EDC, HOAT, DIEA, CH₂Cl₂/DMF (4/1, 4 mM), 20 h, 55% (two steps). DIEA = N,N-diisopropylethylamine.

Scheme 8

Synthesis of Macrolactam 6ba a Conditions: (a) LDA (2.0 equiv), THF, −78 °C, 1.5 h; then Et₃N, MsCl, CH₂Cl₂, −70 to −50 °C, 1.5 h, 81% (E/Z = 1.3/1); (b) I₂ (cat.), benzene, 80 °C, 26 h; DMP/PPTS, toluene, 65 °C, 5 h; 85% (60% conv); (c) MeOH/SO₂Cl₂; (d) CbzCl/K₂CO₃; (e) BnBr, Cs₂CO₃, acetone, reflux, 88% (three steps); (f) Ag₂SO₄/I₂, MeOH, rt, 1 h, 99%; (g) pinacolatodiborane, [PdCl₂(dppf)]CH₂Cl₂, K₂CO₃, DME, 80 °C, 10 h, 91%; (h) (E)-2c, [PdCl₂(dppf)]CH₂Cl₂, K₂CO₃, DME, 80 °C, 2 h, 75%; (i) (1) LiOH, THF/H₂O, 0 °C, 1.5 h, (2) H-Asn-O-t-Bu, EDC/HOAT, THF, rt, 2 h, 85% (two steps); (j) OsO₄/NMO, (DHQD)₂PHAL, t-BuOH/H₂O, rt, 12 h, 88% (dr = 5:1); (k) (1) PPTS/MeOH, reflux, 2 h; (l) TIPSCl, imidazole/DMAP, CH₂Cl₂, rt, 5 h, 88% (two steps); (m) (1) TFA/CH₂Cl₂ (4:1), rt, 2 h, (2) EDC/HOAT/DIEA, CH₂Cl₂/DMF (2 mM), rt, 24 h, 36%. DMP = 2,2-dimethoxypropane, PPTS = pyridinium p-toluenesulfonate, dppf = bis-(diphenylphosphanyl)ferrocene.

Scheme 9

Proposed Strategy for cis-Enamide Formation

Scheme 10

Synthesis of α-Silyl Allylamine

Scheme 11

Completion of the Synthesis of TMC-95A/Ba a Conditions: (a) (1) Pd/C, H₂, EtOH, rt, 19 h, (2) (±)-3-methyl-2-oxopentanoic acid (5), EDC/HOAT, CH₂Cl₂/DMF, rt, 2 h, 85% (two steps); (b) (1) HF/Py, (2) TESOTf, 2,6-lutidine, CH₂Cl₂, 0 °C to rt, 15 h, (3) NaHCO₃, (4) citric acid, EtOAc/H₂O, 73% (four steps); (c) (1) Jones reagent, acetone, 0 °C, 2 h, (2) 39, EDC/HOAT, CH₂Cl₂/DMF, rt, 13 h, 45% (two steps); (d) (1) o-xylene, 140 °C, 3 d, (2) HF/py, THF/py, then Me₃SiOMe, 49% (two steps).

Scheme 12

Synthesis of Analogues a a Conditions: (a) Pd/C, H₂, EtOH, rt, 19 h; (b) 44, EDC/HOAT, CH₂Cl₂/DMF, rt, 2 h, 57% (two steps); (c) (1) HF/Py, (2) TESOTf, 2,6-lutidine, CH₂Cl₂, 0 °C to rt, 15 h, (3) NaHCO₃, (4) citric acid, EtOAc/H₂O, 56% (four steps); (d) (1) Jones reagent, acetone, 0 °C, 2 h, (2) allylamine or n-propylamine, EDC/HOAT, CH₂Cl₂/DMF, rt, 13 h; (e) HF/py, THF/py; then Me₃SiOMe, 39% for 47, 32% for 48 (three steps).