Natural Antifungal Alkaloids for Crop Protection: An Overview of the Latest Synthetic Approaches

Abstract

Alkaloids are nitrogen-containing compounds naturally occurring in plants, microorganisms, and marine organisms. Potent biological activities have been reported to date, ranging from neuroprotective to antioxidant and anticancer effects. Alkaloids have recently gained attention as potential antifungal agents for crop protection due to their broad spectrum of activity, eco-friendly nature, and ability to overcome some of the issues associated with synthetic fungicides, such as resistance development and environmental contamination. Several efforts have been made to obtain natural and nature-derived alkaloids endowed with significant activity against numerous pathogenic fungal strains. In this review, we collect synthetic strategies developed over the past decade to produce alkaloid fungicides for crop protection. Special emphasis is given to recent advancements in obtaining pure natural compounds and more potent analogs endowed with tailored and optimized properties.

Keywords: alkaloids; crop protection; fungicide; phytopathogenic fungi; total synthesis.

Figure 1

Chemical structures of the natural antifungal alkaloids whose synthesis is reported in this paper.

Figure 2

Structure of quinine and its natural analogs.

Scheme 1

C(sp³)–H activation of 3-aminoquinuclidine and synthesis of intermediate 3: (a) picolinic acid, CDI, DMF; (b) 4-iodoanisole, Pd(OAc)₂, Ag₂CO₃, DMF.

Scheme 2

Synthesis of building block 9. (a) RuCl₃, NaIO₄, H₂O, EtOAc, CH₃CN; (b) HATU, MeNHOMe·HCl, Et₃N, DMF; (c) DIBAL-H, DCM; (d) Ph₃PMeBr, LiHMDS, DMSO, THF; (e) Zn, HCl, Zn(OTf)₂, H₂O; (f) IBX, p-TsOH, CH₃CN.

Scheme 3

Conversion of (+)-9 to (−)-quinine. (a) LiHMDS, THF; (b) 6-methoxyquinoline-4-carbaldehyde; (c) Ti(O-iPr)₃Cl, MsNHNH₂; (d) LiAlH₄, MeOH, THF.

Scheme 4

Total synthesis of (−)-quinine starting from intermediate 11: (a) acetone cyanohydrin, PPh₃, DEAD, Et₂O; (b) OsO₄, NMO, acetone/H₂O, then Pb(OAc)₄, DCM; (c) NaBH₃CN, PMBNH₂, AcOH, MeOH; (d) triphosgene, Et₃N, DCM, then NaHCO₃, Boc₂O; (e) NaOH/MeOH, then EDC, HOBt, Et₃N, MeNH(OMe)•HCl, DCM; (f) 17, LDA, THF; (g) NaBH₄, MeOH; (h) OsO₄, NaIO₄, 2,6-lutidine, dioxane/H₂O; (i) DMP, DCM; (j) MeSO₂PT, KHMDS, THF; (k) LiAlH₄, THF; (l) TBSOTf, 2,6-lutidine, DCM, then MsCl, Et₃N, DCM; (m) DCM/TFA, then NaHCO₃, MeCN; (n) (COCl)₂, DMSO, Et₃N, DCM, then [Rh(COD)Cl]₂, dppp, diglyme; (o) NaH/DMSO, then O₂.

Scheme 5

Synthesis of key intermediate syn-29: (a) dimethyl malonate, 10 mol% c1, EtOH, then BnNH₂, NaBH(OAc)₃, DCM, 97% ee, 85%; (b) LiAlH₄, THF, >21:1 dr (isolated), 78%; (c) (COCl)₂, DMSO, DCM, then TEA, 9:1 dr (isolated), 82%; (d) pyrrolidine, AcOH, DCM; (e) NaBH₄, MeOH.

Scheme 6

Total synthesis of (–)-quinine starting from intermediate isolated stereoisomer syn-29: (a) TBSCl, imidazole, dry DMF; (b) TMSCH₂CH₂OH, triphosgene, K₂CO₃, toluene; (c) i. Pd/C, H₂, MeOH, ii. (COCl)₂, DMSO, DCM, then TEA; (d) 34, NaH, THF; (e) HCl/MeOH; (f) i. (COCl)₂, DMSO, DCM, then TEA; ii. Ph₃P⁺CH₃Br^–, KOt-Bu, THF; (g) ADmix-β, CH₃SO₂NH₂, t-BuOH, H₂O, >21:1 dr, 82%; (h) i. trimethylorthoacetate, PPTS, DCM; ii. TMSCl, DCM; iii. K₂CO₃, MeOH; (i) CsF, t-BuOH, DMF.

Scheme 7

Synthesis of quininone and quinotoxine starting from quinine. (a) t-BuOK, benzophenone, toluene; (b) H₂O/AcOH.

Figure 3

Chemical structure of luotonin A.

Scheme 8

Synthesis of luotonin A. (a) MgSO₄, Na₂SO₄, THF; (b) 1,2,4-trichlorobenzene, μW; (c) KOH, MeOH/H₂O; (d) i. (COCl)₂, DCM, DMSO; ii. NaBH₄, THF; (e) PPh₃, DIAD, THF.

Scheme 9

Synthesis of luotonin A by copper-catalyzed photoinduced radical domino cyclization reaction. (a) BrCN, Na₂CO₃, THF, then (b) BzCl, NaH, THF; (c) [(DPEphos)(bcp)Cu]PF₆, Cy₂NiBu, K₂CO₃, light (420 nm), MeCN.

Figure 4

Chemical structure of sanguinarine.

Scheme 10

Synthesis of sanguinarine chloride salt. (a) MeLi, CeCl₃, THF, then (b) PPTS, DCM; (c) K₂OsO₂(OH)₄, NMO, THF/H₂O then (d) NaIO₄·SiO₂, Et₂O; (e) MeNH₂, EtOH, then (f) NaBH₄, MeOH, quant; (g) ZnCl₂, DCE; (h) phenanthroline, t-BuOK, benzene; (i) DDQ, NaOH, benzene then HCl.

Figure 5

Chemical structures of natural cryptolepine, neocryptolepine, and isocryptolepine.

Scheme 11

Synthesis of cryptolepine iodine salt. (a) n-BuLi, THF, then 56; (b) PPh₃, MoO₂Cl₂(dmf)₂, toluene; (c) aq. NaOH, MeOH; (d) CH₃I, sulfolane.

Scheme 12

Synthesis of cryptolepine, starting from protected pyrrole 60. (a) NBS, H₂O, acetone, then (b) Et₃N; (c) N-methyl aniline, Et₃N, EtOAc, then (d) BF₃, EtOAc; (e) POCl₃, DMF; (f) Me₂NH·HCl, DMF, then (g) aq. Na₂CO₃.

Scheme 13

Synthesis of cryptolepine, starting from anthranilic acid 64: (a) bromoacetyl bromide, 1,4-dioxane/DMF 1:1; (b) aniline, DMF; (c) PPA; (d) POCl₃; (e) H₂, Pd/C, AcOH, NaOAc, 60 psi; (f) MeI, DMF.

Scheme 14

Synthesis of neocryptolepine. (a) Ac₂O, Et₃N, reflux; (b) EtOH, H₂SO₄, 24 h; (c) Fe/HCl, AcOH:EtOH:H₂O; (d) Me₂SO₄, DMF, μW, or Me₂SO₄, MeCN.

Scheme 15

Optimized synthesis of neocryptolepine. (a) Et₃N, CHCl₃; (b) Fe/HCl, AcOH; (c) MeI, THF.

Scheme 16

Synthesis of neocryptolepine, starting from cyano substrate 78. (a) K₂CO₃, MeOH; (b) benzyl amine, Pd₂(dba)₃, xantphos, t-BuONa, toluene; (c) anhydrous AlCl₃, benzene; (d) MeI, aq. KOH, THF [37].

Scheme 17

Synthesis of neocryptolepine, starting from substituted indole 82. (a) iPrOH, MeI; (b) KOH, H₂O₂; (c) indole, p-TSOH, EtOH.

Scheme 18

Synthesis of isocryptolepine, starting from 4-amino quinoline 85. (a) Br₂, AcOH; (b) Pd(PPh₃)₄, K₂CO₃, toluene:EtOH:H₂O 3:2:1; (c) t-BuOK, DMSO; (d) MeI, toluene.

Figure 6

Chemical structure of natural β-carbolines.

Scheme 19

Classical synthesis of harmine via Pictet–Spengler reaction: (a) 0.1 N HCl, acetaldehyde; (b) 5% Pd/C, dry toluene.

Scheme 20

Synthesis of harmine via Suzuki reaction: (a) bis(pinacolato)diboron, Pd(dppf)Cl₂, KOAc, dry 1,4-dioxane; (b) Pd(dppf)Cl₂, Cs₂CO₃, 1,4-dioxane/H₂O; (c) PPh₃, o-DCB.

Scheme 21

Synthesis of harmine via Negishi coupling: (a) i. LDA, THF; ii. ZnCl₂; iii. Pd XPhos G3, THF; (b) NaHMDS, THF.

Figure 7

Chemical structures of pityriacitrin and pityriacitrin B.

Scheme 22

Synthesis of pityriacitrin: (a) I₂, DMSO.

Scheme 23

Synthesis of carboline pityriacitrin B. (a) I₂, DMSO; (b) NaOH, MeOH, H₂O.

Figure 8

Chemical structure of meridianins A-G [51].

Scheme 24

(a) TsCl, NaOH, H₂O, n-Bu₄NHSO₄, toluene; (b) Ac₂O, AlCl₃, DCM; (c) DMF-DMA; (d) K₂CO₃, CH₃OCH₂CH₂OH.

Figure 9

Chemical structure of pyrrolnitrin.

Scheme 25

Synthesis of pyrrolnitrin. (a) HBPin, Et₃N; (b) Pd(OAc)₂:SPhos (1:2), K₃PO₄, n-BuOH:H₂O; (c) TBAF, THF.

Figure 10

Chemical structure of penipanoid A.

Scheme 26

Synthesis of penipanoid A, starting from 4-methoxy phenylacetic acid 111. (a) (COCl)₂; (b) formamide, Py, acetone; (c) 114, AcOH; (d) BBr₃, DCM.

Scheme 27

Synthesis of penipanoid A, starting from intermediate 113. (a) NH₂-NH₂, AcOH; (b) 117, CuI, Cs₂CO₃, L-proline, DMF; (c) BBr₃, DCM.

Scheme 28

Protection-free synthesis of penipanoid A: (a) formamidine hydrochloride, HATU, DIPEA, DMF; (b) 121, AcOH.

Figure 11

Chemical structure of kealiinine A–C.

Scheme 29

(a) EtMgBr/THF; (b) N-methyl formanilide, EtMgBr/THF; (c) 126, THF; (d) HCl, DCM; (e) i n-BuLi, THF; ii TsN₃; (f) Pd-C, H₂, MeOH/THF.

Figure 12

Chemical structure of naamines and naamidines.

Scheme 30

Synthesis of amino acids 135a–c. (a) BnBr, MeOH, K₂CO₃; (b) N-acetylglycine, AcONa, Ac₂O; (c) (i) aqueous NaOH; (ii) aqueous HCl; (d) Pd/C, H₂; (e) HCl conc.

Scheme 31

Synthetic approaches to naamines and naamidines. (a) Boc₂O, NEt₃, 1,4-dioxane, H₂O; (b) BnBr, K₂CO₃, MeOH; (c) MeI, NaH, THF; (d) N,O-dimethylhydroxylamine hydrochloride, DIPEA, HOBt, EDCI, DCM; (e) 139, THF, Et₂O; (f) HCl, H₂O; (g) NH₂CN, H₂O, EtOH; (h) H₂, Pd/C, MeOH, AcOH; (i) toluene.

Scheme 32

Synthesis of (±)-antofine. (a) NaH, THF; (b) H₂, Pd/C, EtOAc, then (c) NaN₃, TBAI, DMF; (d) DIBAL-H, DCM; (e) TFA, DCM, then (f) HCHO, HCl EtOH.

Figure 13

Chemical structure of (R)-antofine.

Scheme 33

Synthesis of enantiopure (R)-antofine. (a) CbzN=NCbz, D-Proline, CH₃CN, DCM, then (b) Ph₃P=CHCOOEt, 94% ee; (c) LiBH₄, THF; (d) MsCl, Et₃N, DMAP, DCM; (e) H₂, Raney Ni, MeOH; (f) HCHO, HCl, EtOH.

Figure 14

Structure of essramycin.

Scheme 34

Synthesis of essramycin: (a) n-butanol; (b) ethyl acetoacetate, glacial AcOH.

Figure 15

Chemical structure of phenazine-1-carboxylic acid (PCA).

Scheme 35

Synthesis of phenazine-1-carboxylic acid (PCA): (a) aniline, CuCl₂, copper powder, N-ethyl morpholine, 2,3-butanediol; (b) NaBH₄, EtONa, EtOH.