Asymmetric synthetic access to the hetisine alkaloids: total synthesis of (+)-nominine

Abstract

A dual cycloaddition strategy for the synthesis of the hetisine alkaloids has been developed, illustrated by a concise asymmetric total synthesis of (+)-nominine (7). The approach relies on an early-stage intramolecular 1,3-dipolar cycloaddition of a 4-oxido-isoquinolinium betaine dipole with an ene-nitrile dipolarophile. Subsequent late-stage pyrrolidine-induced dienamine isomerization/Diels-Alder cascade allows for rapid construction of the carbon--nitrogen polycyclic skeleton within this class of C(20)-diterpenoid alkaloids.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Scheme 1

First completed synthesis of a hetisine natural product reported by Muratake and Natsume.[34]

Scheme 2

Retrosynthetic analysis.

Scheme 3

Approach to bridged pyrrolidine core 23.

Scheme 4

a) (COCl)₂, DMSO, NEt₃, Et₂O, −78→0°C; b) BnNH₂, solvent evaporation, 23°C; c) add 27, ZnCl₂, CH₂Cl₂, 0→23°C, 61% overall.

Scheme 5

Synthesis of azabicyclo[3.2.1]octane cycloadducts 30–33.

Scheme 6

a) i) Al(CN)Et₂, PhH, 23°C; ii) TBAT, then Tf₂O, 81%; b) DIBAL-H, 0°C, toluene, NaBH₄/MeOH quench, 88%; c) i) TMSCHO, Et₂O, 0°C; ii) solvent evaporation, 0°C; iii) 27, ZnCl₂, CH₂Cl₂, 0→23°C, 55%, 1.2:1 dr; d) methyl (E)-3-tributylstannylacrylate, [Pd(PPh₃)₄], LiCl, THF, reflux, 87%; e) MeOTf, CH₂Cl₂, 23°C; DMAD, TBAT, 57%, 1:1 dr; f) MeOTf, CDCl₃, 23°C, >95%.

Scheme 7

3-Oxidopyridinium betaine cycloaddition.

Scheme 8

a) DIBAL-H, 0°C, PhMe, 92%; b) furfurylamine·HCl, NaBH₄, MeOH, 3 Å MS, 23°C, 99%; c) KCN, [18]crown-6, [Pd(PPh₃)₄], PhH, 75°C, 75%; d) Br₂, 1:1 AcOH/water, 0°C, 65%; e) [0.15 m] toluene, 170°C, 5 d, 73%.

Scheme 9

a) PhSH, P₂O₅, CH₂Cl₂, 23°C, 84%; b) DIBAL-H, toluene, 0°C, 82%; c) m-CPBA, CH₂Cl₂, 0°C, 91%; d) furfurylamine·HCl, NaBH₃CN, 3 Å MS, NEt₃, MeOH, 23°C, 91%; e) Br₂, MeOH, H₂O, 0°C, 77%; f) [0.05 m], PhMe, reflux, 70 %.

Scheme 10

a) Br₂, MeCN, 80°C, 92%; b) iPr₂MgCl, CuCN, THF, 0°C, then BOMCl, 81%; c) DIBAL-H, toluene, 0°C, 74%; d) m-CPBA, CH₂Cl₂, 0°C, 62%; e) furfurylamine·HCl, NaBH₄, 3 Å MS, NEt₃, MeOH, 23°C, 78%; f) Br₂, MeOH, H₂O, 0°C, 41%; g) [0.01 m], PhMe, 120°C, 67%.

Scheme 11

Scheme 12

a) iPr₂NMgBr; TMSCl, NEt₃, HMPA, Et₂O, 23°C, 77%; b) TrClO₄, 2-methoxy-1,3-dioxolane, CH₂Cl₂, −78°C, 81%; c) iBuONO₂, tBuOK, 23°C, 91 %; d) CeCl₃·7H₂O, NaBH₄, EtOH, 23°C, 69%; e) TFA/H₂O 4:1, 23°C, 78%; f) i) furfurylamine·HCl, NEt₃, 4 Å MS, MeOH; ii) NaBH(OAc)₃, CH₂Cl₂, 23°C, 34%; g) Br₂, 1:1 AcOH/H₂O, 0°C, 64%; h) [0.01 m], PhMe, 170°C (MW wave), 14% (plus 81 % rec. 81).

Scheme 13

Scheme 14

a) tBuLi, Et₂O, −23°C; ClCH₂C(O)N(OMe)Me, 52%; b) NaN₃, acetone, 23°C, 95%; c) AcCl, MeOH, 99%, 3:2 dr.

Scheme 15

a) 93, PBu₃, CH₂Cl₂, 23°C; add 79; add NaBH(OAc)₃, 74% (3:3:2:2 dr); b) 1:10 TFA/CH₂Cl₂, 0°C, 98%; c) [0.008 m], PhMe, 90°C (MW wave), 30 min, → 98/100/96 with 4:2:3 isomeric ratio.

Scheme 16

a) Zn(CN)₂, [Pd(PPh₃)₄], DMF, 60°C, 85%; b) 93, PBu₃, CH₂Cl₂, 23°C; add 101; add NaBH(OAc)₃, 79% (3:3:2:2 dr); c) 1:10 TFA/CH₂Cl₂, 0°C, 93%; d) [1.5 m], 180°C, THF, 97%, 104/105 1:3.6 at equilibrium.

Scheme 17

a) NaBH₄, EtOH, 23°C; b) SOCl₂, CH₂Cl₂, reflux; c) Bu₃SnH, AIBN, PhH, reflux, 68% (3 steps); d) DIBAL-H, PhMe, 0°C, 85%; e) Ph₃P=CH₂, THF, 23°C, 96%; f) Na⁰, Me₂CHOH, THF, NH₃, −78°C; HCl_(aq), 97%; g) 9:1 MeOH/pyrrolidine, 60°C, 78%; h) Ph₃P=CH₂, THF, 70°C, 77%; i) SeO₂, tBuOOH, CH₂Cl₂, 23°C, 66%, 7:1 dr.

Scheme 18

Scheme 19

a) CrO₃, Ac₂O, AcOH, CH₂Cl₂, 23°C, 56%; b) 114, (CuOTf)₂·PhH, ZnMe₂, tBuOMe, 0°C; add 117, −30°C; add Tf₂O, 0°C, 88%, 92:08 er; c) DIBAL-H, pentane, −105°C, 92%; d) Zn(CN)₂, [Pd-(PPh₃)₄], DMF, 60°C, 82%; e) 93, PBu₃, CH₂Cl₂, 23°C; add (+)-101; add NaBH(OAc)₃, 82% (3:2 dr); f) 1:10 TFA/CH₂Cl₂, 0°C, 98%; g) [0.32 m], 180°C, THF, 97%, (+)-104/105 1:3.6 at equilibrium; recrystallized from iPrOH, 104 92:8 → > 99:01 er.