Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine

Abstract

The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels-Alder cycloaddition between two unstable components, cyclopropene 10 and cyclopentadiene 11. A second Diels-Alder reaction features the first use of an azepinone dienophile (8), with high diastereofacial selectivity achieved via rational design of siloxydiene component 36 with a sterically demanding bromine substituent. Subsequent Mannich-type N-acyliminium and radical cyclizations provide complete hexacyclic skeleton 33 of the aconitine alkaloids. Key endgame transformations include the installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridghead enone intermediate 45 and one-carbon oxidative truncation of the C4 side chain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures.

Figure 1

Structures of selected C19- and C18-norditerpenoid alkaloids. Neofinaconitine and delphicrispuline have both been assigned the same structure (3), but have distinct chemical shifts reported for the C14 proton (neofinaconitine δ 3.68, delphicrispuline δ3.45 ppm, CDCl₃).

Figure 2

Retrosynthetic analysis of neofinaconitine (3) via late-stage formation of the C11–C17 and C7–C8 bonds and sequential Diels–Alder cycloadditions. Ar = 2-aminophenyl; R = TIPS, triisopropylsilyl.

Figure 3

Synthesis of fused tricyclic cyclopropane 9 via cyclopropene Diels–Alder cycloaddition. a) DIBAL, CH₂Cl₂, −78 °C to 20 °C; b) TIPSCl, imidazole, CH₂Cl₂, 72% over 2 steps; c) MeLi, THF, −78 °C; d) MeI, Ag₂O, CH₂Cl₂, 75%; e) 11, TBSOTf, Et₃N, 0 °C; f) NaOH, THF/H₂O; g) methyl diethylphosphonoacetate, KHMDS 0 °C to 23 °C, reflux; h) H₂, Pd/C, EtOAc; i) N,N-dimethylhydroxylamine hydrochloride, AlMe₃, THF, 39% over 6 steps from 13 (single isomer); j) vinylmagnesium bromide, 0 °C; k) TBSOTf, KHMDS, THF, −78 °C, 77% over 2 steps. DIBAL = diisobutylaluminum hydride; KHMDS = potassium bis(trimethylsilyl)amide; TBS = tert-butyldimethylsilyl; Tf = trifluoromethanesulfonyl; TIPS = triisopropylsilyl.

Figure 4

Synthesis of cyclopropane carboxaldehyde 24 via azepinone Diels–Alder cycloaddition. a) BnNH₂, 120 °C, 78%; b) SO₃·pyridine, Et₃N, CH₂Cl₂/DMSO, 93%; c) TsOH, toluene, 110 °C, 77%; d) Br₂, Et₃N, CH₂Cl₂, 0 °C, 86%; e) LiHMDS, ClCO₂Me, PhSeCl, −78 °C to 20 °C; f) H₂O₂, CH₂Cl₂, 0 °C, 99% over 2 steps; g) 10, Sc(OTf)₃, PhMe, 69%; h) TBAF, THF, 77%; i) IBX, CH₃CN, sonication, 87% combined yield from 23 and 7, 31% isolated yield of 24. LiHMDS = lithium bis(trimethylsilyl)amide; Ts = p-toluenesulfonyl.

Figure 5

Mannich-type N-acyliminium cyclization of 24 to form the key C11–C17 bond in 29. a) Tf₂NH, CH₂Cl₂, 0 °C, 71%.

Figure 6

Intramolecular radical conjugate addition of 32 to form the key C7–C8 bond in 33 and completion of the carbon skeleton of the C19-norditerpenoid alkaloids 35. a) TBSOTf, Et₃N, CH₂Cl₂, 86%; b) OsO₄, PhI(OAc)₂, 2,6-lutidine, THF/H₂O, 74%; c) Ce(NH₄)₂(NO₃)₆, CH₃CN/CH₂Cl₂/H₂O, 50 °C; d) MsCl, Et₃N, CH₂Cl₂, 50 °C, 57% over 2 steps; e) Bu₃SnH, AIBN, PhH, 80 °C, 86%; f) LiHMDS, PhSeCl, THF, −78 °C, 75%; g) H₂O₂, CH₂Cl₂, 0 °C, 90%; h) AcOH, THF, H₂O, 77%. AIBN = 2,2′-azobis(2-methylpropionitrile); Ms = methanesulfonyl.

Figure 7

Three-dimensional models of the original cyclopropane-containing siloxydiene 9 and bromine-containing siloxydiene 36 suggesting improved diastereofacial selectivity in Diels–Alder cycloaddition of 36. Dienes are shown in blue; bromine is shown as a green sphere; silyl groups are abbreviated as purple spheres for simplicity.

Figure 8

Diastereoselective Diels–Alder cycloaddition of bromide-containing siloxydiene 36. a) TBAF, THF, 99%; b) HBr/AcOH, C₆H₅F, 0 °C, 63%; c) vinylmagnesium bromide, THF, 0 °C; d) TBSOTf, KHMDS, THF, −78 °C, 80% over 2 steps; e) 8b, SnCl₄, 4 Å molecular sieves, CH₃CN, 87%; f) Tf₂NH, CH₂Cl₂, 46%; g) AgO₂CCF₃, CH₂Cl₂, 60%.

Figure 9

Completion of the total synthesis of neofinaconitine via C11–C17 Mannich-type N-acyliminium cyclization and C7–C8 radical cyclization; diagnostic ¹H-NMR peaks for neofinaconitine and delphicrispuline (CDCl₃). a) OsO₄, NMO, THF, H₂O, then Pb(OAc)₄, 65%; b) DBU, toluene, 87%; c) Tf₂NH, CH₂Cl₂, 75%; d) CAN, CH₃CN, H₂O, 60 °C; e) MsCl, Et₃N, CH₂Cl₂, 50 °C, 66% over 2 steps; f) Bu₃SnH, AIBN, PhH, 80 °C, 99%; g) TMSOTf, Et₃N, THF, 0 °C; h) PhSeCl, CH₂Cl₂, 0 °C 86% over 2 steps; i) NaIO₄, THF, H₂O, 59%; j) Pd/C, H₂, EtOAc; k) NaBH₄, MeOH, 0 °C, 89% over 2 steps; l) MeI, t-BuOK, THF, 0 °C, 34%; m) LiBH₄, THF; n) CrO₃, 0.5 N H₂SO₄, 40% over 2 steps; o) LiAlH₄, THF, 85 °C; p) o-NO₂BzCl, DMAP, Et₃N, C₆H₆, 80 °C; q) Zn, HCl, MeOH, H₂O, 13% over 3 steps.

Figure 10

Relay synthesis of neofinaconitine and 9-deoxylappaconitine from condelphine. a) NaOH, H₂O, EtOH. b) NaH, MeI, THF, 100 °C; c) KMnO₄, H₂O, CH₂Cl₂, 54% over 3 steps; d) BBr₃·SMe₂, CH₂Cl₂, −78 °C; e) CrO₃, 0.5 N H₂SO₄; f) 0.5 N H₂SO₄, 80 °C, 46% over 3 steps; g) LiAlH₄, THF, 80 °C; h) o-NO₂BzCl, DMAP, Et₃N, C₆H₆, 80 °C; i) Zn, HCl, MeOH, H₂O, 70% over 3 steps; j) Ac₂O, pyridine, 91%.