Figure 1
Structures of (-)-epibatidine and epiboxidine
Figure 2
Number of articles about epibatidine found at Web of Science® (*until July, 2014).
Figure 3
Recent synthetic approaches to form the azabicyclo ring during the synthesis of epibatidine
Scheme 1
(a) 85-90 °C; (b) n-BuLi, -78 °C, tetrahydrofuran (THF), PhSO2F, rt (43%, 2 steps); (c) meso-hydrobenzoin, NaH, THF, 0 °C → rt (85%); (d) 6% Na/Hg, NaH2PO4.H2O, 0 °C (95%); (e) TMSCl, NaI, CH3CN, rt; (f) Boc2O, Et3N, CH2Cl2, rt (95%, 2 steps); (g) Pd/C, H2, 55 psi, EtOH/EtOAc, rt (90%) (adapted from reference 8).
Scheme 2
(a) Boc-N3, Et3N, dioxane, rt (90%); (b) s-BuLi, TMSCl, TMEDA, -78 °C (90%); (c) s-BuLi, TMSCl, TMEDA, -50 → -30 °C (68%); (d) TFA, CH2Cl2, rt (quant.); (e) PhCH2Cl, K2CO3, CH3CN, rt (80%); (f) K2CO3, Pd(OAc)2, PPh3, CH3CN, reflux (85%); (g) AgF, CH2Cl2 (58%); (h) LiOH.H2O, THF:H2O, 35 °C; (i) SOCl2, MeOH, 0 °C → rt (90%, 2 steps) (adapted from reference 12).
Scheme 3
(a) SmI2, THF/MeOH, -78 °C (75%); (b) (R,R)-1,2-diphenylethylenediamine, 4Å molecular sieves, CH2Cl2, room temperature (rt) (42% for (+)-25 and 43% for (+)-26); (c) H3PO4/THF, 20 °C (95% for (+)-24and 96% for (-)-24); (d) 10% Pd/C, H2, MeOH, rt (> 99%) (adapted from reference 13).
Scheme 4
(a) AlCl3, CH2Cl2, -78 °C (88%); (b) Pd-C, H2, EtOAc, rt (99%); (c) LiAlH4, THF, rt (90%); (d) O3, CH2Cl2, -78 °C, Me2S, rt (93%); (e) Jones reagent, acetone, 0 °C; (f) toluene, reflux (54%, 2 steps) (adapted from reference 15).
Scheme 5
(a) LiCl, i-Pr2EtN, CH3CN, rt (81%); (b) Me2AlCl, CH2Cl2, -78 °C (79%); (c) Sm(OTf)3, MeOH, reflux (84%); (d) Boc2O, p-dimethylaminopyridine (DMAP), Et3N, CH2Cl2, rt (98%); (e) n-Bu4NF, THF/H2O, rt (81%); (f) dimethyl sulfoxide (DMSO), H2O, 130 °C (99%); (g) Me3SiOK, toluene, 70 °C (72%); (h) Pd(OAc)4, tert-butyl alcohol, 50 °C (70%); (i) NaBH4, MeOH, -40 °C, (89%, 92% enantiomeric excess (ee)); (j) MsCl, Et3N, CH2Cl2, rt (92%); (k) LiBr, THF, 50 °C (84%); (l) TFA, CH2Cl2, rt (91%); (m) CHCl3, reflux (95%) (adapted from reference 16).
Scheme 6
(a) NaBH4, THF:MeOH (3:1), 0 °C (99%); (b) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C (99%); (c) vinyl magnesium bromide, THF, 0 °C (96%); (d) PBr3, Et2O, 0 °C (98%); (e) NaSO4, CH2Cl2, 0 °C (99%); (f) Zn, THF, 0 °C (93%);. (g) 10% 62, CH2Cl2, 25 °C (94%); (h) Br2, Et4N+Br-, CH2Cl2, -78 °C (92%, dr 66:34); (i) diisobutylaluminium hydride (DIBAL-H), CH2Cl2, 0 °C (88%); (j) Pb(OAc)4, CH2Cl2:MeOH (2:1), 0 °C (65%); (k) CH3CN, 82 °C (85%); (l) Bu3SnH, azobisisobutyronitrile (AIBN), benzene, reflux (99%); (m) t-BuOK, t-BuOH, reflux (58%) (adapted from reference 17).
Scheme 7
(a) LiN(SiMe3)2, THF, -78 °C, vinyl 2-cyanoacetate, hexamethylphosphoramide, THF, rt (73%); (b) 10% (R,R)-74, toluene, 0 °C (90%, 75% ee); (c) KOH, EtOH, 0 °C (85%, 75% ee); (d) Pd(OAc)2, Ph3P, HCO2H, Et3N, THF, rt (99%); (e) L-selectride®, THF, -78 °C → 0 °C (71%); (f) NaOMe, t-BuOH, rt (71%); (g) NaBH3CN, CH3CO2H, MeOH, -20 °C (87%, 90% dr); (h) MsCl, Et3N, DMAP, CH2Cl2, 0 °C (91%); (i) CH3CO2H, Zn, THF, rt; (j) CHCl3, 60 °C (85%, 2 steps) (adapted from reference 18).
Scheme 8
(a) Pseudomonas putida UV4 (> 98% ee); (b) H2 (1,5 bar), 5% Rh-graphite catalyst, MeOH, rt (90%); (c) TBSCl, Py, rt (86%); (d) trichloroacetyl isocyanate, CH2Cl2, 0 °C, Na2CO3, Et2O:MeOH:H2O (4:4:1:), rt (90%); (e) Ph3P, Et3N, CBr4, CH2Cl2, -10 °C; (f) [3,3] sigmatropic rearrangement; (g) 1% MoCl2O2, CH2Cl2, t-BuOH, rt (76%, 3 steps); (h) 6-chloropyridin-3-ylboronic acid, 2% 85, PhMe:EtOH:H2O (1:1:1), Na2CO3, 100 °C (93%); (i) TBAF, THF (95%); (j) PtO2, H2 (1 bar), EtOH, rt (60%); (k) Et3N, MsCl, CH2Cl2, 0 °C (91%); (l) LiBr, THF, 60 °C (78%); (m) TFA, CH2Cl2, rt (94%); (n) CHCl3, 55 °C (95%) (adapted from reference 19).
Scheme 9
(a) KF.H2O, i-PrOH/THF, rt; (b) DMAP, Ac2O, CH2Cl2, rt (76%, 2 steps); (c) L-proline, 2,5-dimethoxybenzoic acid, DMSO, rt (81%, dr > 97%); (d) 91, NaBH4, THF, 0 °C (95%); (e) MsCl, Et3N, CH2Cl2, 0 °C (94%); (f) Zn, CH3CO2H/THF, rt; (g) CHCl3, reflux (78%, 2 steps) (adapted from reference 21).
Scheme 10
(a) 1,2-dicloroethane, 50 °C (98%); (b) 94(2×(S)-N-BocPhGly), t-BuOH, 75 °C (88%, 14:1 dr, 96% ee); (c) NaBH4, MeOH, 0 °C (87%, 10:1 dr) (adapted from reference 23).
Scheme 11
(a) Acrolein, Et3N, CH2Cl2, 0 °C; (b) ethylene glycol, p-TsOH·H2O, benzene, reflux (95%); (c) 109, [VO(acac)2], aq. H2O2, CHCl3, 0 °C (80%, > 98% ee); (d) NCS, K2CO3, CH2Cl2, 0 °C (86%, 95:5 dr); (e) NaHMDS, CD3OD, THF, -78 °C (85%, 86% dr); (f) (i) 6-chloro-3-pyridineboronic acid pinacol ester, (S)-anti-D-100, PhLi, THF, -78 °C → rt; (ii) (R)-anti-D-100, PhLi, THF, -78 °C → rt, then KOOH (49%, 97% ee, 79% dr); (g) MsCl, Et3N, CH2Cl2, 0 °C; (h) NaN3, DMF, 80 °C; (i) TsOH, MeOH, reflux (52%, 3 steps); (j) aq. TFA, CHCl3, rt; (k) Ph3PCH3I, n-BuLi, THF, -10 °C → reflux; (l) (CF3CO2)2O, Et3N, rt (12%, 3 steps); (m) 10% 110, CH2Cl2, reflux (85%) (adapted from reference 25).
Scheme 12
(a) (i) K-Slectride®, THF, -78 °C; (ii) aq. 0.5 mol L-1 NaOH, THF, 0 °C; (b) tert-butyldimethylsilyl chloride (TBDMSCl), (i-Pr)2NEt, DMAP, CH2Cl2, 0 °C → rt (51%, 3 steps); (c) TFA, H2O, CH2Cl2, reflux (85%); (d) TBDMSCl, (i-Pr)2NEt, DMAP, CH2Cl2, 0 °C → rt (98%) (adapted from reference 29).
Scheme 13
(a) HCl, MeOH, 0 °C → reflux (> 99%); (b) BzCl, Et3N, CH2Cl, rt, DBU, MeOH, rt (94%); (c) 2-trimethylsiloxy-1,3-butadiene, ZnI2, CH2Cl2, reflux; (d) aq. HCl, THF, rt (94%, 2 steps); (e) 132, toluene, reflux; (f) aq. HCl, THF, rt, DBU, MeOH, 5 °C (55%, 2 steps); (g) H2, Pd/C, CH2Cl2, rt (95%); (h) L-selectride®, THF, -78 °C; (i) MsCl, N,N-diisopropylethylamine (DIPEA), CH2Cl2, rt (68%, 2 steps); (j) t-BuOK, THF, rt (81%); (k) LiOH. H2O, MeOH:H2O, rt (99%); (l) (i) (COCl)2, DMF, CH3CH2Cl2; (ii) N-hydroxypyridine-2-thione, Et3N, THF, 0 °C; (m) Bu3SnH, THF, light, rt (61%, 3 steps) (adapted from reference 31).
Scheme 14
(a) ICl3, HCl, H2O, 0 °C → rt (21%); (b) 2-chloro-5-bromopyridine, BuLi, Et2O, -78 °C → rt (ca. 70%); (c) Boc2O, DMAP, THF, reflux (> 99%); (d) (i) THF, -118 °C; (ii) DMF, -45 °C (41%, > 20:1 dr, 94% ee, 2 steps); (e) NaBH4, MeOH, -98 °C (83%, 10:1 dr); (f) MsCl, Et3N, CH2Cl2, rt; (g) TFA, CH2Cl2, rt; (h) CHCl3, reflux (90%, 3 steps) (adapted from reference 33).
Scheme 15
(a) DPPA, Et3N, toluene, reflux, t-BuOH, reflux (85%); (b) Br2, Et4NBr, CH2Cl2, -78 °C (50%); (c) NaH, DMF, rt (52%); (d) t-BuOK, THF, rt (78%) (adapted from reference 34).
Scheme 16
(a) KHF2, MeOH, H2O (71%); (b) Cs2CO3, 10% 150, THF/H2O, 80 °C (45%) (adapted from reference 36).
Scheme 17
(a) NBS, TsNClNa, CH3CN, rt (79%); (b) vinyl magnesium bromide, Et2O, -30 °C → rt (56%); (c) SnCl4, CH2Cl2, 0 °C → rt (32%); (d) Jones reagent, acetone, 0 °C → rt (92%); (e) (COCl)2, CH2Cl2, reflux, 2-mercaptopyridine-1-oxide, BrCCl3, 90 °C, sunlight (61%); (f) aq. HBr, phenol, reflux; (g) NaHCO3, Boc2O/THF, H2O (67%, 2 steps); (h) Ni(COD)2, bathophenanthroline, KO‘Bu, BuOH, rt, 6-chloropyridin-3-yl boronic acid, 60 °C (56%); (i) TFA, CH2Cl2 (89%) (adapted from reference 38).