Two decades of recent advances of Ugi reactions: synthetic and pharmaceutical applications

Abstract

Multicomponent reactions (MCRs) are powerful synthetic tools in which more than two starting materials couple with each other to form multi-functionalized compounds in a one-pot process, the so-called "tandem", "domino" or "cascade" reaction, or utilizing an additional step without changing the solvent, the so-called a sequential-addition procedure, to limit the number of synthetic steps, while increasing the complexity and the molecular diversity, which are highly step-economical reactions. The Ugi reaction, one of the most common multicomponent reactions, has recently fascinated chemists with the high diversity brought by its four- or three-component-based isonitrile. The Ugi reaction has been introduced in organic synthesis as a novel, efficient and useful tool for the preparation of libraries of multifunctional peptides, natural products, and heterocyclic compounds with stereochemistry control. In this review, we highlight the recent advances of the Ugi reaction in the last two decades from 2000-2019, mainly in the synthesis of linear or cyclic peptides, heterocyclic compounds with versatile ring sizes, and natural products, as well as the enantioselective Ugi reactions. Meanwhile, the applications of these compounds in pharmaceutical trials are also discussed.

Fig. 1. Structure of Crixivan I, furanomycin II and demethyldysidenin III.

Scheme 1. Synthesis of α-aminoacyl amides via (U-4CR).

Scheme 2. Synthesis of a synthetic opioid analgesic norsufentanil derivative 2.

Scheme 3. Synthesis of carfentanil 4.

Scheme 4. Synthesis of (±)-viridic acid 10 using anthranilate-derived isonitriles 8a and b.

Scheme 5. Synthesis of phosphonic pseudo-peptides via Ugi reaction.

Scheme 6. Synthesis of bis-peptides containing benzamides 22a and b or hydroxamate 23a and bvia Ugi reaction.

Scheme 7. Synthesis of bis-amides 24 and 25via Ugi reaction.

Scheme 8. Synthesis of C-capped dipeptides BU-005 27.

Scheme 9. Synthesis of Ugi nucleosides using 5-formyl-2′-deoxyuridine 29.

Scheme 10. Synthesis of (UPOC) methyl ester 38via Ugi reaction.

Scheme 11. Synthesis of gem-di-fluorinated pseudo-peptides via Ugi reaction.

Scheme 12. Synthesis of tertiary glycosyl amides 45via Ugi reaction.

Scheme 13. Synthesis of cyclic peptide via Ugi reaction.

Scheme 14. Two-step synthesis of biaryl ether-containing macrocycles.

Scheme 15. Sulfur-switch Ugi reaction for the synthesis of disulfide-bridged peptides 61.

Scheme 16. Synthesis of triazole-linked cyclic glycopeptidomimetics via Ugi reaction.

Scheme 17. Macrocyclization of pentapeptides assisted by a traceless turn-inducing core derived from the Ugi reaction.

Scheme 18. General synthesis of ditopic bifunctional chelating agents 78a and bvia U-4CR.

Scheme 19. Synthesis of a heteroditopic Y–Gd complex by U-4CR.

Scheme 20. Total synthesis of a despirocyclic boneratamide A analogue 86 and exigurin 89via the Ugi reaction.

Fig. 2. Structure of pacidamycin D 90 and its analogue 3′-hydroxypacidamycin D 91.

Scheme 21. Total synthesis of 3′-hydroxypacidamycin D 91.

Scheme 22. Synthetic route for julocrotine 105.

Fig. 3. Structures of some biologically active dihydroxypyrrolidines.

Scheme 23. Synthesis of 1,2-disubstituted-cis-3,4-dihydroxypyrrolidine derivatives 114a and b.

Scheme 24. Synthesis of N-acyloxazolidinones.

Scheme 25. Synthesis of N-acylpyrroles 122.

Scheme 26. Synthesis of N-acyl-2-vinylpyrrolidines derivatives 126.

Scheme 27. Synthesis of tetramic acid derivatives 131a and bvia Ugi–Dieckmann reactions.

Scheme 28. Synthesis of 2,4,5-trisubstituted oxazoles via Ugi/Robinson–Gabriel reactions.

Scheme 29. Synthesis of aryloxazolone derivatives utilizing trichloroacetic acid via Ugi reaction.

Scheme 30. Two-pot synthesis of benzene/imidazole systems.

Scheme 31. Synthesis of fused benzimidazole–isoquinolinones 150via Ugi reaction.

Scheme 32. Synthesis of fused benzimidazole–quinoxalinones 154a–cvia UDC reaction.

Scheme 33. Synthesis of fused BIDs polycyclic 160a–fvia UDC reaction.

Scheme 34. Synthesis of piperazine–benzimidazoles 164via Ugi reaction.

Scheme 35. Synthesis of piperazine–bis-benzimidazoles 169via Ugi reaction.

Scheme 36. Synthesis of oxindoles 172via Ugi/Buchwald–Hartwig reaction.

Scheme 37. Synthesis of oxoisoindoles 174via Ugi reaction.

Scheme 38. Synthesis of benzimidazoles derivatives 179via Ugi reaction/catalytic aza-Wittig cyclization.

Scheme 39. Synthesis of peptidic pyrazinones 184via Ugi reaction.

Scheme 40. Synthesis of pyrazin derivatives 188 and 189via Ugi reaction.

Fig. 4. Structure of epelsiban 190.

Scheme 41. Synthesis of epelsiban derivatives 197via Ugi reaction.

Scheme 42. Synthesis of 6-oxopyrazine-2-carboxamide derivatives 201via Ugi reaction.

Scheme 43. Synthesis of anti-schistosomal praziquantel drug via Ugi reaction.

Scheme 44. Synthesis of DKPs 210a–i with spin-labels attached.

Fig. 5. Structure of Valium 211 and Xanax 212.

Scheme 45. Synthesis of 1,4-benzodiazepines derivatives 217a and 218b using Boc-glycinal 214.

Scheme 46. Synthesis of 1,4-benzodiazepine-2-one derivatives 221a and b using N-Boc-amino acids 219.

Scheme 47. Synthesis of tetra-substituted pyridodiazepinedione 224–227.

Scheme 48. Synthesis of macrolactams 231 and 233.

Scheme 49. Synthesis of BDZs 237via UDC/S_NAr strategy.

Scheme 50. Synthesis of 1,4-benzodiazepine-2,5-diones 241 and ring-fused dihydroazaphenanthrenes 242via U-4CR.

Scheme 51. Synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-one 244 or 245.

Scheme 52. Microwave intensity controls the pathway selectivity of aza-Michael cyclization.

Scheme 53. Synthesis of BDZs 255 and ketopiperazines 257 in the solid phase via UDC.

Scheme 54. Synthesis of 1,4-benzodiazepin-2-one derivatives 261 using N-Boc amino acid 259via UDC.

Scheme 55. One-pot synthesis of 2,3-dihydro-1H-2-benzazepin-1-ones 265.

Scheme 56. Synthesis of benzo[d]pyrrolo[1,2-a]azepin-5(6H)-ones 269via Ugi–Heck reactions.

Scheme 57. Synthesis of amino-triazoloazepinone (Ata) 272via Ugi/Huisgen cycloaddition.

Scheme 58. Synthesis of coumarin-based α-acyl amino amides 277via Knoevenagel–Ugi strategy.

Scheme 59. Synthesis of benzoxazinones 281via U-4CR/Mitsunobu cyclization.

Scheme 60. Synthesis of 1,2,3-triazolo-quinolinone 285via Ugi “click”–Knoevenagel condensations.

Scheme 61. Synthesis of quinoxaline derivatives 289via Ugi reaction.

Scheme 62. Synthesis of 2-benzimidazolylquinoxalines derivatives 292 and 293via Ugi reaction.

Scheme 63. Synthesis of quinoxalin-2(1H)-ones 297via a U-4CR/catalytic aza-Wittig reaction.

Scheme 64. Synthesis of pseudo-peptides containing quinazolinone moiety 299via U-4CR.

Scheme 65. Synthesis of dihydroquinazolines 304 and 305via Ugi reaction.

Scheme 66. Synthesis of indolo[1,2-c]quinazolines 310via the sequential (U-4CR)–Staudinger–aza-Wittig–nucleophilic addition reaction.

Scheme 67. Synthesis of dihydroquinazoline–benzodiazepines 316 and 317.

Scheme 68. Synthesis of 1,2,3,4-tetrahydro-β-carboline 324 and 325a and bvia U-4CR/Pictet–Spengler reaction.

Scheme 69. Synthesis of azaspiro compounds 327–329via Ugi reaction.

Scheme 70. Ugi MCR reaction followed by the intramolecular Diels–Alder reaction of furan (IMDAF).

Scheme 71. Synthesis of chiral morpholin-2-one-3-carboxamide derivatives 4 and ketopiperazine-2-carboxamide.

Scheme 72. Synthesis of chiral isoindolinones 339.

Scheme 73. Enantioselective synthesis of (R)-lacosamide (347) via Ugi-3CR.

Scheme 74. CPA 349-catalyzed enantioselective reaction of aldehydes, amines, and α-isocyanoacetamides.

Fig. 6. Stereochemistry control of enantioselective four-component Ugi reaction.