Catalytic Asymmetric Synthesis of Butenolides and Butyrolactones

Abstract

γ-Butenolides, γ-butyrolactones, and derivatives, especially in enantiomerically pure form, constitute the structural core of numerous natural products which display an impressive range of biological activities which are important for the development of novel physiological and therapeutic agents. Furthermore, optically active γ-butenolides and γ-butyrolactones serve also as a prominent class of chiral building blocks for the synthesis of diverse biological active compounds and complex molecules. Taking into account the varying biological activity profiles and wide-ranging structural diversity of the optically active γ-butenolide or γ-butyrolactone structure, the development of asymmetric synthetic strategies for assembling such challenging scaffolds has attracted major attention from synthetic chemists in the past decade. This review offers an overview of the different enantioselective synthesis of γ-butenolides and γ-butyrolactones which employ catalytic amounts of metal complexes or organocatalysts, with emphasis focused on the mechanistic issues that account for the observed stereocontrol of the representative reactions, as well as practical applications and synthetic potentials.

Figure 1

Naturally occurring products which contain chiral γ-butenolide or γ-butyrolactone core.

Figure 2

Basic structures of γ-butenolide and γ-butyrolactone.

Scheme 1. Illustrative Transformations of γ-Butenolides and γ-Butyrolactones

Scheme 2. Catalytic Asymmetric Synthetic Approaches to γ-Butenolides and γ-Butyrolactone Derivatives

Scheme 3. Catalytic Enantioselective Aldol Reactions for the Construction of γ-Butenolides and γ-Butyrolactone Derivatives

Scheme 4. Vinylogous Aldol Reaction of 2-(Trimethylsilyloxy)furan (TMSOF) Catalyzed by Chiral Titanium–BINOL Complex

Figure 3

Selected examples of chiral catalysts for the asymmetric vinylogous aldol reaction of TMSOF with aldehydes.

Scheme 5. Use of Protected Chiral γ-Hydroxy Butenolide 5 in the Total Synthesis of (−)-Rasfonin

Scheme 6. Application of Chiral γ-Hydroxy Butenolide 9 for the Total Synthesis of (−)-Azaspiracid-1

TMS = trimethylsilyl, PMB = p-methoxybenzyl.

Scheme 7. Copper(II)-Catalyzed Mukaiyama Aldol Reaction of 2-(Trimethylsilyloxy)furan (TMSOF) to Methyl Pyruvate 11a

Scheme 8. Copper-Catalyzed VMAR between TMSOF and Electrophiles 11

Scheme 9. VMAR of α-Keto Phosphonates 13 with TMSOF

Scheme 10. Vinylogous Aldol Reaction of Unactivated γ-Butenolides 15 to Aldehydes Catalyzed by Chiral Guanidine Base Catalyst C11

Scheme 11. Vinylogous Aldol Reaction of γ-Butenolides to Aldehydes Catalyzed by Chiral Amine–Thiourea Catalyst C12

Scheme 12. Vinylogous Aldol Reaction between γ-Butenolide 15d and Aromatic Aldehydes

Scheme 13. Enantioselective Direct Vinylogous Aldol Reaction of 2(5H)-Furanone Derivatives with Various Aldehydes Using an Ion-Pairing Organocatalytic System

Scheme 14. Switch in Regioselectivity with Aqueous Solvents in the Mukaiyama Aldol Reaction of TMSOF 1 and Aldehydes

Scheme 15. Aldol Reaction of Silylketene Acetal Derived from γ-Butyrolactone and (Benzyloxy)acetaldehyde 22

Scheme 16. Direct Aldol Reaction of α-Sulfanyl Lactones and Aldehydes

DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene, TBDPS = tert-butyldiphenylsilyl.

Scheme 17. Catalytic Asymmetric Vinylogous Mannich Reaction of Triisopropylsilyloxyl Furan and Aldimine

Scheme 18. Ag-Catalyzed Enantioselective Vinylogous Mannich Reaction of Silyloxyfurans

Scheme 19. Ag-Catalyzed Enantioselective Vinylogous Mannich Reaction of Methyl-Substituted Silyloxyfurans

Scheme 20. Ag-Catalyzed Enantioselective Vinylogous Mannich Reaction of 2-Silyloxyfurans

Scheme 21. Silver(I)-Catalyzed Asymmetric VM Reaction of Substituted α-Ketoimine Esters

Scheme 22. Other Phosphine Type Ligands in Silver(I)-Catalyzed Asymmetric VM Reaction of Aldimines

Scheme 23. Catalytic Asymmetric Vinylogous Mannich Reaction of N-(2-Thienyl)sulfonylimines with Silyloxyfuran

Scheme 24. Vinylogous Mannich Reaction of Phosphinoyl-imines with Silyloxyfurans

Scheme 25. Vinylogous Mannich-Type Reaction Catalyzed by an Iodine-Substituted Chiral Phosphoric Acid

Scheme 26. Direct Catalytic Asymmetric Mannich-Type Reaction of γ-Butenolide and Imines

Scheme 27. Direct Catalytic Asymmetric Mannich-Type Reaction of γ-Butenolides and N-Thiophosphinoyl Ketimines

Scheme 28. Catalytic Asymmetric Vinylogous Mannich-Type Reaction of γ-Butenolide 54

Scheme 29. Direct Asymmetric Vinylogous Mannich Reaction of 3,4-Dihalofuran-2(5H)-one 15a and 15b with Aldimines 55 Catalyzed by Quinine

Ts = 4-toluenesulfonyl.

Scheme 30. Vinylogous Mannich Reaction of Butyrolactone-Derived Silylketene Acetal

Scheme 31. Direct Asymmetric Vinylogous Mannich Reaction of β-Keto Lactone with Acyl Imines

Scheme 32. Enantioselective Mannich Reaction of β-Keto Lactone with N-Boc-Protected Aldimines

Scheme 33. Asymmetric Michael Addition of 2-(Trimethylsilyloxy)furan to Oxazolidinone Enoate

Figure 4

Chiral metal complexes used in the asymmetric vinylogous Mukaiyama–Michael reaction of 2-(trimethylsilyloxy)furans.

Scheme 34. Catalytic Enantioselective Mukaiyama–Michael Addition of 2-(Trimethylsilyloxy)furan with α′-Phenylsulfonyl Enone

TBDPS = tert-butyldiphenylsilyl.

Scheme 35. Catalytic Enantioselective Mukaiyama–Michael Addition of 2-Silyloxyfuran with Chalcones

TBS = tert-butyldimethylsilyl.

Scheme 36. Catalytic Enantioselective Addition of 2-(Trimethylsilyloxy)furan to (E)-Cinnamoyl-pyridine-N-oxide 74

Scheme 37. Enantioselective Mukaiyama–Michael Reaction of Silyl Enol Ethers 1 with 76

Scheme 38. Enantioselective Mukaiyama–Michael Reaction of Cyclic Dienol Silanes with α-Keto-β,γ-unsaturated-keto Phosphonates

Scheme 39. Catalytic Enantioselective Addition of 2-Silyloxyfurans to Cyclic Unsaturated Oxo Esters 83

Scheme 40. Catalytic Asymmetric Synthesis of Fused Butyrolactones 87

Scheme 41. Organocatalyzed Mukaiyama–Michael Addition of Silyloxy Furans with α,β-Unsaturated Aldehydes

DNBA = 2,4-dinitrobenzoic acid.

Scheme 42. Formal Synthesis of (+)-Compactin through Organocatalyzed Mukaiyama–Michael Addition

Scheme 43. Enantioselective Synthesis of C-5-epi ABCDE Core toward the Construction of Rubriflordilactone B

DNBA = 2,4-dinitrobenzoic acid.

Scheme 44. Catalytic Enantioselective Synthesis of the C17–C28 Fragment of Pectenotoxin-2

4-NBA = 4-nitrobenzoic acid.

Scheme 45. Diastereo- and Enantioselective Cascade Organocatalysis To Promote the Synthesis of Butenolide Containing Three Adjacent Stereocenters

Scheme 46. Total Synthesis of (−)-Aromadendranediol through Cycle-Specific Organocascade Catalysis

Scheme 47. Typical Chiral Amine Organocatalysts Applied in the Direct Asymmetric Vinylogous Michael Addition of γ-Butenolides

Scheme 48. Catalytic Asymmetric Addition of β,γ-Butenolides to α,β-Unsaturated Ketones Containing an Oxazolidinone Moiety

Scheme 49. Catalytic Asymmetric Vinylogous Michael Addition of β,γ-Butenolides in the Presence of Quinine Catalyst

Scheme 50. Direct Vinylogous Michael Addition of β,γ-Unsaturated Butenolide to Chalcone

Scheme 51. Catalyst-Controlled Enantioselective Diastereodivergent Vinylogous Michael Reaction

Scheme 52. Catalytic Asymmetric Vinylogous Conjugated Addition of Butenolides to α,β-Unsaturated Thioamides

Scheme 53. Asymmetric Vinylogous Michael Addition of γ-Substituted β,γ-Unsaturated Butenolides to Maleimides

Scheme 54. Asymmetric Vinylogous Michael Addition of γ-Substituted β,γ-Unsaturated Butenolides to Cyclopentene-1,3-dione Substrates

Scheme 55. Enantioselective Direct Vinylogous Addition of γ-Substituted β,γ-Unsaturated Butenolides to Allenoates

2,6-DTBP = 2,6-di-tert-butylphenol.

Scheme 56. Organocatalytic Asymmetric Vinylogous Michael Addition of Furanones to Enals

Scheme 57. Vinylogous Michael Reaction of Enals with 2(5H)-Furanone Employing Chiral Prolinol-Derived Organocatalyst

Scheme 58. Direct Asymmetric Michael Addition of 2(5H)-Furanone to Nitroalkenes

Scheme 59. Direct Asymmetric Michael Addition of α-Substituted Furanone 125 to Nitroalkene Catalyzed by Guanidine C11

Scheme 60. Guanidine-Catalyzed Asymmetric Michael Addition of α-Substituted Deconjugated Butenolide to Nitroalkene

Scheme 61. Asymmetric Substitution of MBH Acetates with 2-Trimethylsilyloxy Furan

Scheme 62. Direct Substitution of MBH Acetates with β,γ-Unsaturated Butenolides

Scheme 63. Lewis Base Catalyzed Assembly of MBH Carbonates 137 with γ-Methyl-Substituted β,γ-Unsaturated Butenolide

Scheme 64. Cu(I)-Catalyzed Asymmetric Tandem Michael Addition–Elimination Reaction

Scheme 65. Enantioselective Acylation of Butyrolactone Derived Silyl Ketene Acetals Using a Chiral DMAP Analogue

Scheme 66. Enantioselective Acylation through a Thiourea-Bond Acylpyridinium Enolate Ion Pair

Scheme 67. Catalytic Asymmetric Synthesis of γ-Butenolides through the Acylation of Furanyl Enol Carbonates

Scheme 68. Palladium-Catalyzed Kinetic Resolution of 1,3-Disubstituted Unsymmetrical Allylic Acetates with Silyloxy Furans

dba = dibenzylideneacetone.

Scheme 69. Iridium-Catalyzed Asymmetric Allylic Substitution Reaction between Silyloxyfurans

Scheme 70. Palladium-Catalyzed Asymmetric Allylic Alkylation of Cyclic Dienol Carbonates

Scheme 71. Nickel–BINAP Catalyzed Asymmetric α-Arylation of α-Substituted γ-Butyrolactones

Scheme 72. Palladium Catalyzed Asymmetric α-Arylation of Substituted γ-Butyrolactones

Scheme 73. Enantioselective Phase-Transfer Catalytic α-Alkylation of α-Acyl-γ-butyrolactones

Scheme 74. Enantioselective Phase Transfer Catalytic α-Benzylation and α-Allylation of α-tert-Butoxycarbonyl-lactone

Scheme 75. Enantioselective Cu-Catalyzed Conjugate Additions of Dialkylzinc Reagents to Unsaturated Furanones

Figure 5

Concept for palladium catalyzed dynamic kinetic asymmetric transformation (DYKAT) of γ-acyloxybutenolides. (Adapted from ref (195). Copyright 1999 American Chemical Society.)

Scheme 76. Highly Enantioselective Allylic Substitution of γ-Acyloxybutenolide with Phenol Nucleophiles

Scheme 77. Chiral Ruthenium Complexes for the Asymmetric Hydrogenation of Butenolides

Scheme 78. Copper-Catalyzed Asymmetric 1,4-Reduction of β-Substituted γ-Butenolides

Scheme 79. Catalytic Asymmetric Synthesis of Eupomatilone-3

Scheme 80. Copper-Catalyzed Conjugate Reduction Synthesis of γ-Aryl-Containing β-Substituted Butenolides

Scheme 81. Cationic Oxazaborolidine Catalyzed Asymmetric Diels–Alder Reaction of Butenolide

Figure 6

Chiral metal complexes for the enantioselective halolactonization to afford the corresponding γ-butyrolactones.

Scheme 82. Asymmetric Synthesis of Fused γ-Butyrolactones through Iodolactonization of Malonate with I₂

Scheme 83. Catalytic Asymmetric Chlorolactonization of Alkenoic Acids

Scheme 84. Tertiary Aminourea-Catalyzed Enantioselective Iodolactonization

Figure 7

Chiral amino-thiocarbamate catalysts for the enantioselective bromolactonization of 4-pentenoic acid derivatives.

Scheme 85. Enantioselective Bromolactonization of 1,1-Disubstituted Olefinic Acids and cis-1,2-Disubstituted Olefinic Acids

Scheme 86. Enantioselective Synthesis of (R)-(+)-Boivinianin A

AIBN = 2,2′-azoisobutyronitrile.

Figure 8

BINOL-derived bifunctional catalysts to promote enantioselective bromolactonizations.

Scheme 87. Enantioselective Bromolactonizations of Substituted Unsaturated Carboxylic Acids

TBCO = 2,4,4,6-tetrabromocyclohexa-2,5-dienone.

Scheme 88. Catalytic Asymmetric Synthesis of Bicyclic Bromolactones with Three Contiguous Stereocenters

TBDPS = tert-butyldiphenylsilyl.

Scheme 89. Selenium-Catalyzed Enantioselective Oxidative Cyclization of β,γ-Unsaturated Carboxylic Acids

Scheme 90. Enantioselective Synthesis of γ-Butyrolactones via Copper-Catalyzed Radical Oxyfunctionalization of Alkenes

MTBE = methyl tert-butyl ether.

Figure 9

Concept for catalytic asymmetric BV oxidation.

Scheme 91. Synthesis of Bicyclic Butyrolactones by Catalytic Asymmetric BV Oxidation

Scheme 92. Chiral Catalysts Employed in the Asymmetric BV Oxidation of 3-Substituted Cyclobutanone

Figure 10

cis-β-Zr(salen) complex chelated by the Criegee adduct intermediate.

Scheme 93. Organocatalyzed Asymmetric Baeyer–Villiger Oxidation of Cyclobutanones

Scheme 94. Catalytic Enantioselective Hydrogenation of γ-Keto Esters

Scheme 95. Dynamic Kinetic Resolution of α-Keto Esters via Asymmetric Transfer Hydrogenation

Scheme 96. Transformations of Densely Functionalized Chiral γ-Butyrolactones

Scheme 97. Synthesis of γ-Butyrolactones via Enantioselective Ketone Hydroacylation

Scheme 98. Concept for the Catalytic Asymmetric Synthesis of Cyclic and Bicyclic Lactones through Metal Carbene Transformations

Scheme 99. Concept for the Catalytic Asymmetric Synthesis of Butyrolactones through Conjugated Umpolung Reaction

Scheme 100. Stereoselective Synthesis of γ-Butyrolactones via Organocatalytic Annulations of Enals and Keto Esters

DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene.

Scheme 101. Chiral Imidazolium-Derived N-Heterocyclic Carbene Catalysts Applied in the Stereoselective Synthesis of Cyclopentane-Fused Lactones

DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene.

Scheme 102. Enantioselective Synthesis of cis-γ-Butyrolactones Promoted by Chiral Titanium Lewis Acid C79 in the Presence of Achiral NHC Catalyst C80

Scheme 103. Enantioselective Synthesis of Spiro γ-Butyrolactones in the Presence of Chiral NHC Catalyst

Scheme 104. Stereoselective Synthesis of Spirooxindole Lactones Using N-Heterocyclic Carbene/Lewis Acid as Cooperative Catalyst System

Scheme 105. Synthesis of Optically Active γ-Butyrolactones via Enantioselective Palladium(II)-Catalyzed Cyclization

Scheme 106. Proposed Mechanism in the Enantioselective Palladium(II)-Catalyzed Cyclization of of Enyne Esters (Adapted from ref (334). Copyright 2001 American Chemical Society.)

L = ligand.

Scheme 107. Enantioselective Synthesis of (+)-Anthecotulide

Scheme 108. Synthesis of γ-Butyrolactones via Palladium-Catalyzed Enantioselective Cyclocarbonylation

Scheme 109. Proposed Mechanism for the Palladium Catalyzed Cyclocarbonylation (Adapted from ref (336). Copyright 1997 American Chemical Society.)

Scheme 110. Asymmetric hetero Pauson–Khand Reaction for the Synthesis of Optically Active Fused Bicyclic γ-Butyrolactones 209

Scheme 111. Organocatalytic Asymmetric Synthesis of 4-(Hydroxyalkyl)-γ-butyrolactones

Scheme 112. Synthesis of β,γ-Disubstituted-γ-butyrolactone via a Tandem Enantioselective Aldol Reaction/Cyclization

Scheme 113. Proposed Mechanism for the Tandem Enantioselective Aldol Reaction/Cyclization

Scheme 114. Asymmetric Synthesis of β,γ-Substituted Butyrolactones via Organocatalytic Formal Cycloaddition of Aryl Succinic Anhydrides with Aldehydes

Scheme 115. Synthesis of Chiral Isotetronic Acids 213 with Amphiphilic Imidazole/Pyrrolidine Catalysts Assembled in Oil-in-Water Emulsion Droplets

Scheme 116. Synthesis of Chiral Isotetronic Acids with Amphiphilic Imidazole/Pyrrolidine Catalysts Assembled in Oil-in-Water Emulsion Droplets

Scheme 117. Dearomatizing ortho-Spirocyclization of Naphthols Using Chiral Hypervalent Iodine Reagents

Scheme 118. Proposed Transition-State Model for the Formation of Spirolactone Products (Adapted from ref (354). Copyright 2013 American Chemical Society.)

Scheme 119. Synthesis of α-Alkylidene-γ-butyrolactones through Asymmetric Desymmetrization of the Prochiral Dienones

Scheme 120. Proposed Mechanism for the Formation of Spirolactone Products

Scheme 121. Synthesis of β-Substituted γ-Butyrolactones through Asymmetric Desymmetrization of Prochiral Diesters

Scheme 122. Asymmetric Synthesis of (R)-(+)-Boivinianin A and (S)-(−)-Boivinianin A

Scheme 123. Asymmetric Synthesis of trans-Fused Butyrolactones 224

Scheme 124. Synthesis of Substituted α-exo-Methylene γ-Butyrolactones through Catalytic Enantioselective Carbonyl 2-(Alkoxycarbonyl)allylation

Scheme 125. Catalytic Enantioselective Synthesis of γ-Butenolides 229 through Cu-AAA/RCM

Scheme 126. Bifunctional Aminothiourea Catalyzed Asymmetric Isomerization of ω-Hydroxy-α,β-Unsaturated Thioesters

Scheme 127. Dinuclear Zinc Catalyzed Enantioselective Formation of Spirocyclic δ-Lactones

Scheme 128. Highly Enantioselective Synthesis of Spirolactones through One-Pot Michael Addition and Cyclization

Scheme 129. Enantioselective Synthesis of Butyrolactones 235 via Gold-Catalyzed Domino Deracemization and Cyclopropanation

Scheme 130. Enantioselective Synthesis of γ-Substituted α,β-Unsaturated Butenolides via Olefin Isomerization

Scheme 131. Proposed Mechanism of Asymmetric Olefin Isomerization (Adapted from ref (372). Copyright 2011 American Chemical Society.)

Scheme 132. Rh-Catalyzed Highly Enantioselective Cycloaddition of Diynes with α-Methylene-γ-butyrolactone

Scheme 133. Kinetic Resolution of 2-Hydroxy-γ-butyrolactones by Asymmetric Esterification

Scheme 134. Synthesis of β,γ-Disubstituted γ-Butyrolactones by Copper-Catalyzed Asymmetric Cyclopropanation