Comprehensive Review of Recent Advances in Chiral A-Ring Flavonoid Containing Compounds: Structure, Bioactivities, and Synthesis

Abstract

Flavonoids are a group of natural polyphenolic substances that are abundant in vegetables, fruits, grains, and tea. Chiral A-ring-containing flavonoids are an important group of natural flavonoid derivatives applicable in a wide range of biological activities such as, cytotoxic, anti-inflammatory, anti-microbial, antioxidant, and enzyme inhibition. The desirable development of chiral A-ring-containing flavonoids by isolation, semi-synthesis or total synthesis in a short duration proves their great value in medicinal chemistry research. In this review, the research progress of chiral A-ring-containing flavonoids, including isolation and extraction, structural identification, pharmacological activities, and synthetic methods, is comprehensively and systematically summarized. Furthermore, we provide suggestions for future research on the synthesis and biomedical applications of flavonoids.

Keywords: bioactivity; chiral A-ring-containing flavonoid; flavonoids; synthesis.

Figure 1

Basic skeleton of flavonoid compounds.

Figure 2

Chemical structure of cryptocaryone.

Figure 3

Chemical structure of infectocaryone, cryptocaryanone, bicaryanone, and chalcocaryanone.

Figure 4

Chemical structure of desmethylinfectocaryone.

Figure 5

Chemical structure of cryptochinone.

Figure 6

Chemical structure of cryptoflavanones.

Scheme 1

Transformation routes in plants.

Figure 7

Chemical structure of cryptogiones.

Figure 8

Chemical structure of cryptoconones.

Figure 9

Cytotoxicities of compounds 3, 5, 6, 7 and 16.

Scheme 2

Synthesis of the natural product (+)-cryptocaryone and its enantiomeric isomers. Conditions: (a) s-BuLi, TMEDA, THF, −78 °C, then BrCH₂CH(OEt)₂; (b) (R,R)-hydrobenzoin, p-TsOH, toluene, 50 °C, 75% for two steps; (c) NBS, CH₃CN, 63%; (d) thexylborane, then PDC, 53%; (e) CAN, CH₃CN-H₂O (2/1), 60 °C, 67%; (f) LiHMDS, PhCH=CHCOCl, THF, −78 °C; (g) 4 N HCl aq., 64%; (h) NIS, TBAI, DCM, 74%.

Scheme 3

Synthesis of the natural products (+)-cryptocaryone and (+)-infectocaryone. Conditions: (a) [Ir]/L catalyst, 85%; (b) NaOH, DMF, 155 °C, 82%; (c) AcOH, then DMP, 82%; (d) (+)-(Ipc)₂B(allyl), Et₂O, −100 °C; (e) Grubbs’I, DCM, 40 °C, 81%; (f) Dess-Martin oxidation; (g) DBU, 97%; (h) n-Bu₂BOTf, DIPEA, −78 °C; (i) cinnamaldehyde; (j) Dess-Martin oxidation, 64%; (k) TFA/DCM; (l) CH₂N₂, 91%; (m) NaOH, 90 °C; (n) NaHCO₃, KI, I₂, THF, H₂O; (o) Swern oxidation, 75%; (p) LiHMDS, THF, −100 °C; (q) cinnamoyl cyanide, 74%.

Scheme 4

Synthesis of natural product cryptocaryanone A. Condition: (a) cat. HgI₂, Et₂O, −78 °C to rt, 90%; (b) NaOH (0.5 M), TBAF, THF, 0 °C, 85%; (c) Ph₃P, PhCO₂H, DIAD, THF, 0 °C to rt; 82%; (d) TBSOTf, Et₃N, DCM, 0 °C to rt; (e) BF₃·OEt₂, DCM, −78 °C, 72% for 2 steps; (f) TFAA, DMSO, Et₃N, DCM, −78 °C, 87%; (g) TfOH, DCM, −30 °C, 91%; (h) K₂CO₃, MeOH, rt, 30%; (i) K₂CO₃, MeOH, rt, 61%; (j) TsOH, DCM, rt, 49%.

Scheme 5

Synthesis of (−)-infectocaryone and its enantiomeric isomers. Condition: (a) IBX, AcOEt, 80 °C; (b) toluene, 120 °C, 50% for 2 steps; (c) NaBH₄, MeOH, rt, 88%; (d) Ac₂O, DMAP, DCM, rt, 96%; (e) H₅IO₆, AcOEt, rt, 99%; (f) [Ph₃PCH₂Ph]·Br, n-BuLi, THF, 75%; (g) K₂CO₃, MeOH, H₂O, rt, 71%; (h) DMP, DCM, rt; (i) Pd(PPh₃)₄, THF, rt, 92% for two steps.

Scheme 6

Synthesis of (+)-cryptogione F and (+)-cryptocaryone. Condition: (a) Swern oxidation; (b) 2) 81, MeOH, 0 °C, 80% for two steps; (c) p-TsOH, MeOH, rt, 96%; (d) TBSCl, imidazole, DMF, rt, 97%; (e) O₂, CuCl, PdCl₂, DMF/H₂O, 84%; (f) Cy₂BCl, Et₃N, Et₂O, −78 °C, cinnamaldehyde, 85%; (g) DMP, DCM, rt, 70%; (h) DBU, DCM, 83%; (i) HF·Py, MeCN, 84%; (j) Burgess reagent, 71%.

Scheme 7

Synthesis of (+)-cryptocaryanone A, (+)-cryptochinone A, (+)-cryptochinone C and (+)-cryptocaryanone B. Condition: (a) DBU, DCM, −20 °C; (b) TFA, DCM, rt, 88% for 94, 89% for 95; (c) HF·Py, MeCN, 87% from 94; (d) MsCl, Et₃N, DCM, rt, 93%; (e) HF·Py, MeCN, 86% from 95; (f) MeI, Ag₂O, CaSO₄, rt, 92%; (g) MsCl, Et3N, DCM, rt, 90%.