A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.


Introduction
γ-Butyrolactone, a five-membered heterocycle containing ester functionality, has been broadly studied in the drug discovery field since it is one of the privileged structures of biologically active small molecules. Several γ-butyrolactone-containing drugs have been FDA-approved and used in clinic for diverse purposes such as diuretics, anticancer agents, contraceptive drugs, treatment of heart disease, and anti-glaucoma agents. γ-Butyrolactone moiety is also found in a variety of biologically active experimental drugs [1][2][3][4] and synthetic intermediates [5][6][7][8][9][10]. Moreover, numerous natural products, showing diverse biological activities, have γ-butyrolactone moiety.
The most universal synthetic method for γ-butyrolactone is intramolecular esterification, which can be readily utilized with substrates bearing γ-hydroxybutanoic acid functionality. However, diverse synthetic methodologies have been developed based on the discovery of biologically active synthetic or natural lactone drugs. Consequently, there have been many efforts to develop efficient synthetic methods to construct γ-butyrolactone, and several focused reviews have been published [11][12][13][14]. For example, Taylor and colleagues summarized new synthetic approaches for α-methylene-γ-butyrolactones [12] and Marstral, Feringa and colleagues reviewed the catalytic asymmetric synthesis of γ-butyrolactone [13].
In this review, we first prepare a brief introduction of biologically active γ-butyrolactones including eight FDA-approved drugs (Table 1) and various natural and synthetic γbutyrolactones that have broad biological activities such as anticancer, anti-inflammatory, antibiotic, antifungal, antioxidant activities as well as immunosuppressive, neuroprotective, γ-butyrolactones that have broad biological activities such as anticancer, anti-inflammatory, antibiotic, antifungal, antioxidant activities as well as immunosuppressive, neuroprotective, and hypoglycemic activities (Table 2). Additionally, we summarize synthetic methodologies for the construction of γ-butyrolactone reported from 2010 to 2020, which are depicted in seven main sections based on the sites of bond formation ( Figure 1). Each section is further divided into subsections according to the type of reaction and contains a description focused on the reaction mechanism. Additionally, applications of the reaction to the synthesis of complex molecules are included to demonstrate the synthetic utility of the reactions. The synthetic methodology has been continuously improving over the past decade. Therefore, this review will provide an update of recent work in the development of synthetic methods for the construction of γ-butyrolactones.

Approved Drugs
Several γ-butyrolactone-containing drugs have been FDA-approved and used in clinics for diverse purposes (Table 1). Pilocarpine, isolated from Pilocarpus microphyllus, is used to treat xerostomia and reduce eye pressure. (Entry 1) [15]. Pilocarpine is also widely applied to pharmacological research as a control cholinergic agonist. γ-Butyrolactone moiety was employed in a steroid skeleton at the C-17 position to develop steroidal aldosterone antagonists (Entry 2 and 3). Spironolactone and eplerenone are common medications for cardiovascular diseases such as high blood pressure and heart failure [16,17]. Drospirenone, structurally similar with spironolactone, is used to prevent pregnancy as a progesterone agonist. (Entry 4) [18]. Podophyllotoxin, a natural DNA topoisomerase inhibitor from Podophyllum peltatum, is treated to kill genital warts (Entry 5) [19]. Two semisynthetic derivatives of podophyllotoxin, etoposide, and teniposide, were approved as anticancer agents used for lymphoma, leukemia, and various solid tumors (Entry 6 and 7) [20,21]. Vorapaxar, a derivative of himbacine, is a first-in-class protease-activated receptor-1 (PAR-1) antagonist (Entry 8) [22]. By inhibiting PAR-1, vorapaxar reduces thrombotic cardiovascular events and the risk of myocardial infarction. Now, several γ-butyrolactone-containing drug candidates have been investigated in clinical studies for the treatment of heart disease, rheumatoid arthritis, and infectious disease.

Anti-inflammation
Diverse butyrolactones have been studied to evaluate anti-inflammatory activities (Entry 1-9 in Table 2). Some of these butyrolactones modulate the NF-κB signaling pathway such as a santonine-derived butyrolactone that showed anti-inflammatory activity through the inhibition of the ubiquitin-conjugating enzyme, UbcH5c (Entry 1 in Table 2)

Approved Drugs
Several γ-butyrolactone-containing drugs have been FDA-approved and used in clinics for diverse purposes (Table 1). Pilocarpine, isolated from Pilocarpus microphyllus, is used to treat xerostomia and reduce eye pressure. (Entry 1) [15]. Pilocarpine is also widely applied to pharmacological research as a control cholinergic agonist. γ-Butyrolactone moiety was employed in a steroid skeleton at the C-17 position to develop steroidal aldosterone antagonists (Entry 2 and 3). Spironolactone and eplerenone are common medications for cardiovascular diseases such as high blood pressure and heart failure [16,17]. Drospirenone, structurally similar with spironolactone, is used to prevent pregnancy as a progesterone agonist. (Entry 4) [18]. Podophyllotoxin, a natural DNA topoisomerase inhibitor from Podophyllum peltatum, is treated to kill genital warts (Entry 5) [19]. Two semisynthetic derivatives of podophyllotoxin, etoposide, and teniposide, were approved as anticancer agents used for lymphoma, leukemia, and various solid tumors (Entry 6 and 7) [20,21]. Vorapaxar, a derivative of himbacine, is a first-in-class protease-activated receptor-1 (PAR-1) antagonist (Entry 8) [22]. By inhibiting PAR-1, vorapaxar reduces thrombotic cardiovascular events and the risk of myocardial infarction. Now, several γ-butyrolactone-containing drug candidates have been investigated in clinical studies for the treatment of heart disease, rheumatoid arthritis, and infectious disease.

Anticancer
The development of anticancer drugs is one of the long-term goals in the drug development field. Diverse natural and synthetic butyrolactones have been evaluated for their cytotoxic activities against various cancer cell lines. Protelichesterinic acid (Entry 10), a metabolite isolated from Antarctic lichens, showed cytotoxicity against HCT-116 cells with an IC 50 value of 34.3 µM [34]. P. K. Roy and colleagues isolated one of the cembrane-type butyrolactones (Entry 11) from the soft coral, Lobophytum, which displayed a strong cytotoxic activity against RAW 264.7 cells [35]. Sasaki and colleagues evaluated the AKT inhibitory activities of lactoquinomycin (Entry 12) [36,37], kalafungin (Entry 13) [36,38], and frenolicin B (Entry 14) [36,39], classified as pyranonaphthoquinone lactones, which were originally reported as antibiotics. These butyrolactones exhibited strong AKT inhibitory activities with IC 50 values of 0.149 µM~0.313 µM as well as cytotoxic activities with IC 50 values of 0.05 µM~0.07 µM in MDA468 cells. A cytotoxicity of synthetic butyrolactones has been reported as well. Lee and colleagues synthesized an adenine-linked butyrolactone (Entry 15) which exhibited a cytotoxicity with an ED 50 value of 0.3 µg/mL in L1210 cells [40]. Another example of synthetic butyrolactone, reported by Huth and colleagues, displayed strong HSP90 inhibitory activity (Ki = 1.9 µM) which could result in the development of anti-cancer agent (Entry 16) [41].

Immunosuppressive
Two synthetic γ-butyrolactones and two natural products were reported to show immunosuppressive activities. Yang and colleagues found that benzene-fused γ-butyrolactones (Entry 28) demonstrate highly efficacious immunosuppressive properties [57]. A sesquiterpene lactone, isolated from Artemisia argyi (Entry 29), also exhibited potent immunosuppressive activity, which was assessed via inhibitory effect on the proliferation of T lymphocytes [58]. A santonin derivative (Entry 30) reported by Chinthakindi and colleagues is another example of the immunosuppressant evaluated by T-and B-cell proliferation assay [59]. A natural γ-butyrolactone kinsenoside (Entry 31), originally isolated from Anoectochillus roxburghii, was reported as a potentially effective drug for treating patients with autoimmune hepatitis via targeting VEGFR2 to reduce the interaction between PI3K-AKT and JAK2-STAT pathways, which was confirmed in the vaccinated mouse model [60,61].

Neuroprotective
Recent studies found that natural and synthetic γ-butyrolactones can be useful in the treatment of neurodegenerative disorders. Zhu and colleagues showed phenolic γ-butyrolactones in Cinnamomum cassia (Entry 32) exhibit a neuroprotective effect against tunicamycin-induced cell death in human dopaminergic neuroblastoma SH-SY5Y cells [62]. Guo and colleagues conducted similar studies and found that japonipene C (Entry 33) is responsible for the neuroprotective effect of the extract of Petasites japonicas [63]. Bi and colleagues revealed that the γ-butyrolactone derivative 3-benzyl-5-((2nitrophenoxy)methyl)dihydrofuran-2(3H)-one (3BDO; Entry 34) protects against Aβ 25-35induced cytotoxicity in the PC12 cell. 3BDO was proposed to exhibit the protective effect by inhibiting ROS production and autophagy process [64]. In vivo assay was performed to evaluate memory rescuing activity as well as the Aβ lowering activity of 3BDO in mouse brain [65]. These findings show γ-butyrolactone can be utilized as potential therapeutic scaffold for the treatment of Parkinson's disease and Alzheimer's disease.

Antioxidant
The antioxidant activity of γ-butyrolactones has been verified using 1,1-diphenyl-2picrylhydrazyl (DPPH) assay and superoxide scavenging assay. Lee and colleagues studied the antioxidant activity of styraxlignolide E (Entry 35) in Styrax japonica [66]. Boustie and colleagues found that norstictic acid (Entry 36) isolated from Usnea articulate shows superoxide scavenging activity higher than the well-known antioxidant quercetin [67]. The result suggested that this activity is involved in the antioxidant defense of lichens.

Synthetic
[57] Immunosuppressive   The oxidative lactonization of alkenoic acid is one of the most popular transformations for the synthesis of lactone. A typical approach is usually initiated with the oxidation of olefin catalyzed by the highly toxic and expensive transition metal via the Prévost−Woodward reaction and Upjohn reaction conditions, and the subsequent intramolecular nucleophilic addition of carboxylic acid [70][71][72]. In contrast, recently reported methods for oxidative lactonization claimed metal-free and less toxic conditions, which utilized cheap and green organic catalysts and oxidants. These reactions have been developed with a view toward green chemistry.
In 2012, Gade and colleagues reported the triflic acid (TfOH)-catalyzed oxidative lactonization using peroxyacid as an oxidant (Figure 2) [73]. The cascade epoxidation of olefin 1 with peracetic acid and an intramolecular epoxide opening reaction provided γ-butyrolactone 2. TfOH was proposed as a catalyst in both the ring-opening reaction via epoxide activation and acetylation of the subsequent hydroxyl group of γbutyrolactone [74]. This method was applied to intramolecular lactonization as well as the intermolecular diacetylation of olefins. Considering the convenient process and the broad substrate scope, this might be an alternative approach to osmium tetroxide-catalyzed dihydroxylation of alkenes.

Oxidative Lactonization of Pentenoic Acid
The oxidative lactonization of alkenoic acid is one of the most popular transf mations for the synthesis of lactone. A typical approach is usually initiated with the o dation of olefin catalyzed by the highly toxic and expensive transition metal via the P vost−Woodward reaction and Upjohn reaction conditions, and the subsequent intram lecular nucleophilic addition of carboxylic acid [70][71][72]. In contrast, recently repor methods for oxidative lactonization claimed metal-free and less toxic conditions, wh utilized cheap and green organic catalysts and oxidants. These reactions have been dev oped with a view toward green chemistry.
In 2012, Gade and colleagues reported the triflic acid (TfOH)-catalyzed oxidative tonization using peroxyacid as an oxidant (Figure 2) [73]. The cascade epoxidation of o fin 1 with peracetic acid and an intramolecular epoxide opening reaction provided γtyrolactone 2. TfOH was proposed as a catalyst in both the ring-opening reaction via ep ide activation and acetylation of the subsequent hydroxyl group of γ-butyrolactone [ This method was applied to intramolecular lactonization as well as the intermolecu diacetylation of olefins. Considering the convenient process and the broad substr scope, this might be an alternative approach to osmium tetroxide-catalyzed dihydroxy tion of alkenes. Kang and colleagues also developed the TfOH-catalyzed oxidative lactonization alkenoic acid 3 ( Figure 3) [75]. Instead of peroxyacetic acid, sodium periodate was used an oxidant. This method showed a high tolerance for a broad range of α,β-substitu pentenoic acid, providing the corresponding γ-butyrolactones 4 and bicyclic lactone sc folds.  Kang and colleagues also developed the TfOH-catalyzed oxidative lactonization of alkenoic acid 3 ( Figure 3) [75]. Instead of peroxyacetic acid, sodium periodate was used as an oxidant. This method showed a high tolerance for a broad range of α,βsubstituted pentenoic acid, providing the corresponding γ-butyrolactones 4 and bicyclic lactone scaffolds.

Oxidative Lactonization of Pentenoic Acid
The oxidative lactonization of alkenoic acid is one of the most popular transformations for the synthesis of lactone. A typical approach is usually initiated with the oxidation of olefin catalyzed by the highly toxic and expensive transition metal via the Prévost−Woodward reaction and Upjohn reaction conditions, and the subsequent intramolecular nucleophilic addition of carboxylic acid [70][71][72]. In contrast, recently reported methods for oxidative lactonization claimed metal-free and less toxic conditions, which utilized cheap and green organic catalysts and oxidants. These reactions have been developed with a view toward green chemistry.
In 2012, Gade and colleagues reported the triflic acid (TfOH)-catalyzed oxidative lactonization using peroxyacid as an oxidant (Figure 2) [73]. The cascade epoxidation of olefin 1 with peracetic acid and an intramolecular epoxide opening reaction provided γ-butyrolactone 2. TfOH was proposed as a catalyst in both the ring-opening reaction via epoxide activation and acetylation of the subsequent hydroxyl group of γ-butyrolactone [74]. This method was applied to intramolecular lactonization as well as the intermolecular diacetylation of olefins. Considering the convenient process and the broad substrate scope, this might be an alternative approach to osmium tetroxide-catalyzed dihydroxylation of alkenes. Kang and colleagues also developed the TfOH-catalyzed oxidative lactonization of alkenoic acid 3 ( Figure 3) [75]. Instead of peroxyacetic acid, sodium periodate was used as an oxidant. This method showed a high tolerance for a broad range of α,β-substituted pentenoic acid, providing the corresponding γ-butyrolactones 4 and bicyclic lactone scaffolds.  Furthermore, Kokotos and colleagues developed an oxidative lactonization catalyzed by an organocatalyst, which relied on the use of hydrogen peroxide as the oxidant with 2,2,2-trifluoroacetophenone 5 as the organocatalyst (Figure 4) [76]. Mild reaction conditions led to an environmentally and industrially friendly process. Furthermore, Kokotos and colleagues developed an oxidative lactonization catalyzed by an organocatalyst, which relied on the use of hydrogen peroxide as the oxidant with 2,2,2-trifluoroacetophenone 5 as the organocatalyst (Figure 4) [76]. Mild reaction conditions led to an environmentally and industrially friendly process. The oxidative ring contraction strategy from 3,4-dihydropyran-2-ones 6 developed by Legault and colleagues using hypervalent iodine has been shown to provide 3,4-transγ-butyrolactones 7 ( Figure 5) [77]. The authors suggested that the hyperiodine reagent selectively reacts with trans-face to β-substituents of 6. This face selectivity generates iodinated intermediate 8 and the subsequent attack of a water molecule at the carbonyl position affords intermediate 9. γ-butyrolactone 7 was diastereoselectively obtained through intramolecular substitution by carboxylic acid. The development of an enantioselective protocol was evaluated using a specific chiral iodine reagent. As an analogous approach to oxidative lactonization, Dodd and colleagues reported aminolactonization with the use of in situ-generated nosyliminoiodane ( Figure 6) [78]. The Cu-catalyzed generation of nitrene from arylsulfonyliminoiodane 10 was reported to yield aziridines from alkene groups [79,80]. For example, the aziridine intermediate 11, generated after the metal-catalyzed reaction of t-butyl ester 12 with iminoiodane 10, was successfully transformed into a high yield of amino γ-butyrolactone 13. The usefulness of this aminolactonization was exemplified by further annulation of butyrolactone in novel complex heterocyclic systems (Figure 6, bottom). The oxidative ring contraction strategy from 3,4-dihydropyran-2-ones 6 developed by Legault and colleagues using hypervalent iodine has been shown to provide 3,4-transγ-butyrolactones 7 ( Figure 5) [77]. The authors suggested that the hyperiodine reagent selectively reacts with trans-face to β-substituents of 6. This face selectivity generates iodinated intermediate 8 and the subsequent attack of a water molecule at the carbonyl position affords intermediate 9. γ-butyrolactone 7 was diastereoselectively obtained through intramolecular substitution by carboxylic acid. The development of an enantioselective protocol was evaluated using a specific chiral iodine reagent. Furthermore, Kokotos and colleagues developed an oxidative lactonization catalyzed by an organocatalyst, which relied on the use of hydrogen peroxide as the oxidant with 2,2,2-trifluoroacetophenone 5 as the organocatalyst (Figure 4) [76]. Mild reaction conditions led to an environmentally and industrially friendly process. The oxidative ring contraction strategy from 3,4-dihydropyran-2-ones 6 developed by Legault and colleagues using hypervalent iodine has been shown to provide 3,4-transγ-butyrolactones 7 ( Figure 5) [77]. The authors suggested that the hyperiodine reagent selectively reacts with trans-face to β-substituents of 6. This face selectivity generates iodinated intermediate 8 and the subsequent attack of a water molecule at the carbonyl position affords intermediate 9. γ-butyrolactone 7 was diastereoselectively obtained through intramolecular substitution by carboxylic acid. The development of an enantioselective protocol was evaluated using a specific chiral iodine reagent. As an analogous approach to oxidative lactonization, Dodd and colleagues reported aminolactonization with the use of in situ-generated nosyliminoiodane ( Figure 6) [78]. The Cu-catalyzed generation of nitrene from arylsulfonyliminoiodane 10 was reported to yield aziridines from alkene groups [79,80]. For example, the aziridine intermediate 11, generated after the metal-catalyzed reaction of t-butyl ester 12 with iminoiodane 10, was successfully transformed into a high yield of amino γ-butyrolactone 13. The usefulness of this aminolactonization was exemplified by further annulation of butyrolactone in novel complex heterocyclic systems (Figure 6, bottom). As an analogous approach to oxidative lactonization, Dodd and colleagues reported aminolactonization with the use of in situ-generated nosyliminoiodane ( Figure 6) [78]. The Cu-catalyzed generation of nitrene from arylsulfonyliminoiodane 10 was reported to yield aziridines from alkene groups [79,80]. For example, the aziridine intermediate 11, generated after the metal-catalyzed reaction of t-butyl ester 12 with iminoiodane 10, was successfully transformed into a high yield of amino γ-butyrolactone 13. The usefulness of this aminolactonization was exemplified by further annulation of butyrolactone in novel complex heterocyclic systems (Figure 6, bottom).
In 2011, Togo and colleagues developed a sustainable electrophilic bromine sour via umpolung of alkali metal bromide [83]. Bromide (Br -) from potassium bromide, one the most abundant and stable bromide sources, is oxidized into bromonium ion (Br + ) by oxidation with Oxone. Encouraged by the success of intramolecular bromo-aminati with in situ-generated bromonium ion, the use of this umpolung system in the bromol tonization of 4-pentenoic acid 15 has been investigated, resulting in the production of butyrolactone moieties 16 (Figure 7) [84]. At this stage, the preference of the diequator conformation of the transition state over the diaxial form results in the diastereoselecti production of cis-isomer 16. The utility of this approach was demonstrated by the to synthesis of dubiusamin C 19 from bromo butyrolactone 18, which was obtained by t bromolactonization of pentenoic acid 17. Kumar and colleagues reported selenium-catalyzed bromolactonization by applyi isoselenazolone 20 as a catalyst (Figure 8) [85]. Organoselenium compounds react w
In 2011, Togo and colleagues developed a sustainable electrophilic bromine source via umpolung of alkali metal bromide [83]. Bromide (Br -) from potassium bromide, one of the most abundant and stable bromide sources, is oxidized into bromonium ion (Br + ) 14 by oxidation with Oxone. Encouraged by the success of intramolecular bromo-amination with in situ-generated bromonium ion, the use of this umpolung system in the bromolactonization of 4-pentenoic acid 15 has been investigated, resulting in the production of γ-butyrolactone moieties 16 (Figure 7) [84]. At this stage, the preference of the diequatorial conformation of the transition state over the diaxial form results in the diastereoselective production of cis-isomer 16. The utility of this approach was demonstrated by the total synthesis of dubiusamin C 19 from bromo butyrolactone 18, which was obtained by the bromolactonization of pentenoic acid 17.
In 2011, Togo and colleagues developed a sustainable electrophilic bromine source via umpolung of alkali metal bromide [83]. Bromide (Br -) from potassium bromide, one of the most abundant and stable bromide sources, is oxidized into bromonium ion (Br + ) 14 by oxidation with Oxone. Encouraged by the success of intramolecular bromo-amination with in situ-generated bromonium ion, the use of this umpolung system in the bromolactonization of 4-pentenoic acid 15 has been investigated, resulting in the production of γbutyrolactone moieties 16 (Figure 7) [84]. At this stage, the preference of the diequatorial conformation of the transition state over the diaxial form results in the diastereoselective production of cis-isomer 16. The utility of this approach was demonstrated by the total synthesis of dubiusamin C 19 from bromo butyrolactone 18, which was obtained by the bromolactonization of pentenoic acid 17. Kumar and colleagues reported selenium-catalyzed bromolactonization by applying isoselenazolone 20 as a catalyst (Figure 8) [85]. Organoselenium compounds react with Kumar and colleagues reported selenium-catalyzed bromolactonization by applying isoselenazolone 20 as a catalyst (Figure 8) [85]. Organoselenium compounds react with bromine to generate reactive bromoselenium intermediate 21, which has a greater reactivity than NBS and molecular bromine (Br 2 ) [86]. Several

Acid-Promoted Cyclopropane Opening
The electrocyclic ring-opening reaction of cyclopropane has been demonstrated as a powerful tool for the construction of fused cyclic systems with sequential intramolecular trapping [87]. Several acid-catalyzed, domino cyclopropane opening/carboxylic acid trapping reactions have been investigated to construct fused-butyrolactone systems.
In 2017, Reddy and colleagues reported a Brønsted acid-catalyzed cascade reaction for the construction of a tricyclic structure 26 bearing a γ-butyrolactone core (Figure 9) [88]. This interesting reaction starts with p-toluenesulfonic acid (PTSA)-catalyzed aldol condensation of diketone 24 to afford bicyclic enone 25, which subsequently undergoes acid-catalyzed cyclopropane opening/intramolecular trapping by an ester moiety.

Acid-Promoted Cyclopropane Opening
The electrocyclic ring-opening reaction of cyclopropane has been demonstrated as a powerful tool for the construction of fused cyclic systems with sequential intramolecular trapping [87]. Several acid-catalyzed, domino cyclopropane opening/carboxylic acid trapping reactions have been investigated to construct fused-butyrolactone systems.
In 2017, Reddy and colleagues reported a Brønsted acid-catalyzed cascade reaction for the construction of a tricyclic structure 26 bearing a γ-butyrolactone core (Figure 9) [88]. This interesting reaction starts with p-toluenesulfonic acid (PTSA)-catalyzed aldol condensation of diketone 24 to afford bicyclic enone 25, which subsequently undergoes acidcatalyzed cyclopropane opening/intramolecular trapping by an ester moiety.

Acid-Promoted Cyclopropane Opening
The electrocyclic ring-opening reaction of cyclopropane has been demonstrated as a powerful tool for the construction of fused cyclic systems with sequential intramolecular trapping [87]. Several acid-catalyzed, domino cyclopropane opening/carboxylic acid trapping reactions have been investigated to construct fused-butyrolactone systems.
In 2017, Reddy and colleagues reported a Brønsted acid-catalyzed cascade reaction for the construction of a tricyclic structure 26 bearing a γ-butyrolactone core (Figure 9) [88]. This interesting reaction starts with p-toluenesulfonic acid (PTSA)-catalyzed aldol condensation of diketone 24 to afford bicyclic enone 25, which subsequently undergoes acid-catalyzed cyclopropane opening/intramolecular trapping by an ester moiety.

Au-Catalyzed Oxaallylation
Gold-catalyzed allylic functionalization has been the object of diverse cyclization reactions and has been found to be efficient for the preparation of γ-butyrolactone [90][91][92]. Chen and colleagues examined the Au-catalyzed lactonization of allylic acetate 29 to construct a butyrolactone system ( Figure 11) [93]. The proposed mechanism involved the generation of an allylic cation intermediate 30 from allylic acetate 29 in the presence of the Au catalyst. The subsequent nucleophilic attack by the ester moiety resulted in the formation of bicyclic γ-butyrolactone 31. Figure 11. Gold-catalyzed intramolecular allylic alkylation of allylic acetate.
Bandini and colleagues reported the direct activation of free allylic alcohol 32 by applying a gold catalyst with N-heterocyclic carbene ( Figure 12) [94]. An allylic cation intermediate is generated upon coordination of the NHC-gold complexes to a free allylic alcohol 32. The resulting poly-substituted γ-butyrolactone 33 was obtained via nucleophilic attack by ester and subsequent dealkylation. More recently, Aponick and colleagues developed a gold-catalyzed oxa-allylation of a free allyl alcohol 34 with an intramolecular free carboxylic acid to prepare γ-butyrolactone 35 (Figure 13) [95]. In contrast to Brønsted acids generating a 7-membered lactone

Au-Catalyzed Oxaallylation
Gold-catalyzed allylic functionalization has been the object of diverse cyclization reactions and has been found to be efficient for the preparation of γ-butyrolactone [90][91][92]. Chen and colleagues examined the Au-catalyzed lactonization of allylic acetate 29 to construct a butyrolactone system ( Figure 11) [93].

Au-Catalyzed Oxaallylation
Gold-catalyzed allylic functionalization has been the object of diverse cyclization reactions and has been found to be efficient for the preparation of γ-butyrolactone [90][91][92]. Chen and colleagues examined the Au-catalyzed lactonization of allylic acetate 29 to construct a butyrolactone system ( Figure 11) [93]. The proposed mechanism involved the generation of an allylic cation intermediate 30 from allylic acetate 29 in the presence of the Au catalyst. The subsequent nucleophilic attack by the ester moiety resulted in the formation of bicyclic γ-butyrolactone 31. Figure 11. Gold-catalyzed intramolecular allylic alkylation of allylic acetate.
Bandini and colleagues reported the direct activation of free allylic alcohol 32 by applying a gold catalyst with N-heterocyclic carbene ( Figure 12) [94]. An allylic cation intermediate is generated upon coordination of the NHC-gold complexes to a free allylic alcohol 32. The resulting poly-substituted γ-butyrolactone 33 was obtained via nucleophilic attack by ester and subsequent dealkylation. More recently, Aponick and colleagues developed a gold-catalyzed oxa-allylation of a free allyl alcohol 34 with an intramolecular free carboxylic acid to prepare γ-butyrolactone 35 (Figure 13) [95]. In contrast to Brønsted acids generating a 7-membered lactone Bandini and colleagues reported the direct activation of free allylic alcohol 32 by applying a gold catalyst with N-heterocyclic carbene ( Figure 12) [94]. An allylic cation intermediate is generated upon coordination of the NHC-gold complexes to a free allylic alcohol 32. The resulting poly-substituted γ-butyrolactone 33 was obtained via nucleophilic attack by ester and subsequent dealkylation.

Au-Catalyzed Oxaallylation
Gold-catalyzed allylic functionalization has been the object of diverse cyclization r actions and has been found to be efficient for the preparation of γ-butyrolactone [90][91][92] Chen and colleagues examined the Au-catalyzed lactonization of allylic acetate 29 to co struct a butyrolactone system ( Figure 11) [93]. The proposed mechanism involved the ge eration of an allylic cation intermediate 30 from allylic acetate 29 in the presence of the A catalyst. The subsequent nucleophilic attack by the ester moiety resulted in the formatio of bicyclic γ-butyrolactone 31. Bandini and colleagues reported the direct activation of free allylic alcohol 32 by a plying a gold catalyst with N-heterocyclic carbene ( Figure 12) [94]. An allylic cation inte mediate is generated upon coordination of the NHC-gold complexes to a free allylic alc hol 32. The resulting poly-substituted γ-butyrolactone 33 was obtained via nucleophi attack by ester and subsequent dealkylation. More recently, Aponick and colleagues developed a gold-catalyzed oxa-allylation a free allyl alcohol 34 with an intramolecular free carboxylic acid to prepare γ-butyrola tone 35 (Figure 13) [95]. In contrast to Brønsted acids generating a 7-membered lacto More recently, Aponick and colleagues developed a gold-catalyzed oxa-allylation of a free allyl alcohol 34 with an intramolecular free carboxylic acid to prepare γ-butyrolactone 35 ( Figure 13) [95]. In contrast to Brønsted acids generating a 7-membered lactone skeleton 36 via direct acid-catalyzed esterification, γ-butyrolactone 35 was obtained using a transition-metal catalyst via an S N 2 -type oxa-allylation mechanism.
Allenylglycine 37 was also used as a precursor for the construction of γ-butyrolactone 38. Ohfune and colleagues applied the Au-catalyzed intramolecular lactonization into the allene system 37, which is a useful substrate for gold catalysis (Figure 14) [96]. Interestingly, γ-butyrolactone 38 was obtained regio-and diastereoselectively via 5-endodig cyclization in the presence of bulky TBS at the allenic terminal carbon.

Photoredox-Catalyzed Lactonization
Photoredox catalysis through single-electron transfer (SET) has attracted significant attention in the community of organic chemistry. Not surprisingly, the application of photoredox catalysis to the ring formation reaction, including γ-butyrolactone synthesis, has been intensively explored. As shown in Table 3, several synthetic approaches have been reported to provide 5,5-disubstituted γ-butyrolactone. Photoredox-catalyzed γ-butyrolactone synthesis generally starts with radical generation through the reduction of radical precursors 39 (e.g., diazonium salt, N-hydroxylphthalimide ester, etc.) by the oxidative quenching of the excited state of the photocatalyst (PC *). The in situ-generated radical 40 adds to the alkene of 41 to produce intermediate 42, which is transformed to carbocation 43 through single-electron transfer (SET) with an oxidized photocatalyst (PC + ). Nucleophilic attack of the carboxylic acid results in the γ-butyrolactone 44 ( Figure 15). Aryl diazonium salts (Entry 1) [97], Umemoto's reagent (Entry 2) [98], N-hydroxylphthalimide ester (Entry 3) [99], and α-bromo ester [100] were used in these reactions. Allenylglycine 37 was also used as a precursor for the construction of γ-butyrolactone 38. Ohfune and colleagues applied the Au-catalyzed intramolecular lactonization into the allene system 37, which is a useful substrate for gold catalysis (Figure 14) [96]. Interestingly, γ-butyrolactone 38 was obtained regio-and diastereoselectively via 5-endo-dig cyclization in the presence of bulky TBS at the allenic terminal carbon.  Allenylglycine 37 was also used as a precursor for the construction of γ-butyrolactone 38. Ohfune and colleagues applied the Au-catalyzed intramolecular lactonization into the allene system 37, which is a useful substrate for gold catalysis (Figure 14) [96]. Interestingly, γ-butyrolactone 38 was obtained regio-and diastereoselectively via 5-endodig cyclization in the presence of bulky TBS at the allenic terminal carbon.

Photoredox-Catalyzed Lactonization
Photoredox catalysis through single-electron transfer (SET) has attracted significant attention in the community of organic chemistry. Not surprisingly, the application of photoredox catalysis to the ring formation reaction, including γ-butyrolactone synthesis, has been intensively explored. As shown in Table 3, several synthetic approaches have been reported to provide 5,5-disubstituted γ-butyrolactone. Photoredox-catalyzed γ-butyrolactone synthesis generally starts with radical generation through the reduction of radical precursors 39 (e.g., diazonium salt, N-hydroxylphthalimide ester, etc.) by the oxidative quenching of the excited state of the photocatalyst (PC *). The in situ-generated radical 40 adds to the alkene of 41 to produce intermediate 42, which is transformed to carbocation 43 through single-electron transfer (SET) with an oxidized photocatalyst (PC + ). Nucleophilic attack of the carboxylic acid results in the γ-butyrolactone 44 ( Figure 15). Aryl diazonium salts (Entry 1) [97], Umemoto's reagent (Entry 2) [98], N-hydroxylphthalimide ester (Entry 3) [99], and α-bromo ester [100] were used in these reactions.

Photoredox-Catalyzed Lactonization
Photoredox catalysis through single-electron transfer (SET) has attracted significant attention in the community of organic chemistry. Not surprisingly, the application of photoredox catalysis to the ring formation reaction, including γ-butyrolactone synthesis, has been intensively explored. As shown in Table 3, several synthetic approaches have been reported to provide 5,5-disubstituted γ-butyrolactone. Photoredox-catalyzed γ-butyrolactone synthesis generally starts with radical generation through the reduction of radical precursors 39 (e.g., diazonium salt, N-hydroxylphthalimide ester, etc.) by the oxidative quenching of the excited state of the photocatalyst (PC *). The in situ-generated radical 40 adds to the alkene of 41 to produce intermediate 42, which is transformed to carbocation 43 through single-electron transfer (SET) with an oxidized photocatalyst (PC + ). Nucleophilic attack of the carboxylic acid results in the γ-butyrolactone 44 ( Figure 15). Aryl diazonium salts (Entry 1) [97], Umemoto's reagent (Entry 2) [98], Nhydroxylphthalimide ester (Entry 3) [99], and α-bromo ester [100] were used in these reactions.

Synthesis of γ-Butyrolactone via C4-C5 and C2-O1 Bonds Formation
Connecting the C4-C5 bond in [3 + 2] annulation-type γ-butyrolactone formation is one of the most promising routes. Retrosynthetically, the disconnection of the C4-C5 and C2-O1 bonds gives a 3 and a 2 synthons; thus, this mismatched relationship should be overcome through a certain umpolung reaction.

Transition-Metal Catalyzed C-C Bond Coupling
Krische et al. applied their transfer hydrogenative C-C bond coupling chemistry to the γ-butyrolactone syntheses. In 2012, they reported that the iridium-catalyzed carbonyl 2-(alkoxycarbonyl)allylation between various primary alcohols 45 and acrylic ester 46 afforded γ-substituted α-exo-methylene-γ-butyrolactone 47 with high enantioselectivity (Figure 16) [101]. As shown in the mechanism, this transformation involves an a 3 -d 3 umpolung process regarding the β-position of the acrylate counterpart 46, which normally acts as an electrophile during C-C bond-forming reactions [102].

Synthesis of γ-Butyrolactone via C4-C5 and C2-O1 Bonds Formation
Connecting the C4-C5 bond in [3 + 2] annulation-type γ-butyrolactone formation is one of the most promising routes. Retrosynthetically, the disconnection of the C4-C5 and C2-O1 bonds gives a 3 and a 2 synthons; thus, this mismatched relationship should be overcome through a certain umpolung reaction.

Transition-Metal Catalyzed C-C Bond Coupling
Krische et al. applied their transfer hydrogenative C-C bond coupling chemistry to the γ-butyrolactone syntheses. In 2012, they reported that the iridium-catalyzed carbonyl 2-(alkoxycarbonyl)allylation between various primary alcohols 45 and acrylic ester 46 afforded γ-substituted α-exo-methylene-γ-butyrolactone 47 with high enantioselectivity (Figure 16) [101]. As shown in the mechanism, this transformation involves an a 3 -d 3 umpolung process regarding the β-position of the acrylate counterpart 46, which normally acts as an electrophile during C-C bond-forming reactions [102].

Synthesis of γ-Butyrolactone via C4-C5 and C2-O1 Bonds Formation
Connecting the C4-C5 bond in [3 + 2] annulation-type γ-butyrolactone formation is one of the most promising routes. Retrosynthetically, the disconnection of the C4-C5 and C2-O1 bonds gives a 3 and a 2 synthons; thus, this mismatched relationship should be overcome through a certain umpolung reaction.

Transition-Metal Catalyzed C-C Bond Coupling
Krische et al. applied their transfer hydrogenative C-C bond coupling chemistry to the γ-butyrolactone syntheses. In 2012, they reported that the iridium-catalyzed carbonyl 2-(alkoxycarbonyl)allylation between various primary alcohols 45 and acrylic ester 46 afforded γ-substituted α-exo-methylene-γ-butyrolactone 47 with high enantioselectivity (Figure 16) [101]. As shown in the mechanism, this transformation involves an a 3 -d 3 umpolung process regarding the β-position of the acrylate counterpart 46, which normally acts as an electrophile during C-C bond-forming reactions [102].  In the C-C bond constructing catalytic transfer hydrogenation, a secondary alcohol was not a suitable partner of acrylates because of the low susceptibility to the nucleophilic attack [103] of the π-allyl complex derived from the acrylates. Just a year after their first report, Krische and colleagues also revealed that ruthenium(0)-catalyzed hydrohydroxyalkylation of acrylates with vicinal diols or their oxidized congeners could provide a series of γ-butyrolactones, including spiro-γ-butyrolactones (Figure 17a), polysubstituted 2,3 -spirooxindole-γ-butyrolactones (Figure 17b), and α-exo-methylene-γ-butyrolactones (Figure 17c) [104]. As illustrated in Figure 17d, 1,2-diol 48 and its highly oxidized congeners 49 and 50 were transformed into the same outcome 51, indicating that this transformation proceeds in a redox level-independent manner. In the C-C bond constructing catalytic transfer hydrogenation, a secondary alcoh was not a suitable partner of acrylates because of the low susceptibility to the nucleoph attack [103] of the π-allyl complex derived from the acrylates. Just a year after their fi report, Krische and colleagues also revealed that ruthenium(0)-catalyzed hydrohydrox alkylation of acrylates with vicinal diols or their oxidized congeners could provide a ser of γ-butyrolactones, including spiro-γ-butyrolactones (Figure 17a), polysubstituted 2 spirooxindole-γ-butyrolactones (Figure 17b), and α-exo-methylene-γ-butyrolactones (F ure 17c) [104]. As illustrated in Figure 17d, 1,2-diol 48 and its highly oxidized congen 49 and 50 were transformed into the same outcome 51, indicating that this transformati proceeds in a redox level-independent manner. The asymmetric synthesis of α-exo-methylene γ-butyrolactones was developed Zhang and colleagues in 2015 ( Figure 18) [105]. This methodology utilized an enantio lective chromium-catalyzed carbonyl 2-(alkoxycarbonyl)allylation of a wide range of dehydes. To achieve superior enantioselectivity, the C2 symmetric bisoxazoline liga was essential. Rigidification of Guiry's tridentate ligand [106] provided a new ligand which resulted in excellent enantiomeric excess of up to 99%. Similar to the previous me ods [101,104], the inherent positive character of the acrylate β-position was inverted the cobalt-assisted generation of allyl-chromium species 53. To demonstrate the synthe utility, the total synthesis of an antitumor and antimicrobial natural product, (+)-me ylenolactocin 54, was successfully conducted with a 53% overall yield over three steps a 92% ee. (Figure 18, bottom). The asymmetric synthesis of α-exo-methylene γ-butyrolactones was developed by Zhang and colleagues in 2015 ( Figure 18) [105]. This methodology utilized an enantioselective chromium-catalyzed carbonyl 2-(alkoxycarbonyl)allylation of a wide range of aldehydes. To achieve superior enantioselectivity, the C2 symmetric bisoxazoline ligand was essential. Rigidification of Guiry's tridentate ligand [106] provided a new ligand 52, which resulted in excellent enantiomeric excess of up to 99%. Similar to the previous methods [101,104], the inherent positive character of the acrylate β-position was inverted via the cobalt-assisted generation of allyl-chromium species 53. To demonstrate the synthetic utility, the total synthesis of an antitumor and antimicrobial natural product, (+)-methylenolactocin 54, was successfully conducted with a 53% overall yield over three steps and 92% ee. (Figure 18, bottom). Spirooxindoles [107] and α-exo-methylene-γ-butyrolactones [12,108], biologically relevant structural motifs, have received attention from medicinal chemists. In this regard, the fusion of two scaffolds would be a promising strategy for securing biologically active scaffolds. In 2013, the first asymmetric synthesis of 2,3′-spirooxindole-α-exo-methylene γbutyrolactone 57 via the indium(III)-catalyzed allylation of isatins 55 and β-amido allylstannanes 56 was reported ( Figure 19) [107,109]. The amide NH proton of allylstannanes was essential for enhancing enantioselectivity as well as complete conversion by engaging in six-coordinated indium complex 58 with tridentate ligand 59, thereby inducing 56 to approach from Re-face [109]. The resulting acyclic 2-oxindoles 60 was cyclized under acidic conditions to afford the desired lactone 57 with complete stereochemistry retention.

NHC-Catalyzed C-C Bond Coupling
A chiral N-heterocyclic carbene (NHC) has played an important role in making a homoenolate nucleophile from enals through the a 3 -d 3 umpolung reaction [110]; thus, it has been widely used in the optically active γ-butyrolactone synthesis via [3 + 2] annulation. Over the last decade, this strategy has been employed to construct a 2,3 spirooxindole-γbutyrolactone system.
In 2011, Ye and colleagues discovered the first enantioselective NHC-catalyzed synthesis of spirooxindole-γ-lactone with isatin and an enal as substrates (Figure 20a) [111]. A chiral NHC 61 derived from L-pyroglutamic acid displayed the best result, affording the desired spirolactone up to 99% ee. A proximal hydroxy group in 61 was crucial to obtain the lactone with an excellent yield and enantioselectivity because the hydrogen bonding between the carbonyl group of isatin and the catalyst hydroxy group may guide the direction of the isatin approach and enhance its reactivity.

NHC-Catalyzed C-C Bond Coupling
A chiral N-heterocyclic carbene (NHC) has played an important role in making a ho moenolate nucleophile from enals through the a 3 -d 3 umpolung reaction [110]; thus, it ha been widely used in the optically active γ-butyrolactone synthesis via [3 + 2] annulation Over the last decade, this strategy has been employed to construct a 2,3′ spirooxindole-γ butyrolactone system.
In 2011, Ye and colleagues discovered the first enantioselective NHC-catalyzed syn thesis of spirooxindole-γ-lactone with isatin and an enal as substrates (Figure 20a) [111 A chiral NHC 61 derived from L-pyroglutamic acid displayed the best result, affordin the desired spirolactone up to 99% ee. A proximal hydroxy group in 61 was crucial t obtain the lactone with an excellent yield and enantioselectivity because the hydroge bonding between the carbonyl group of isatin and the catalyst hydroxy group may guid the direction of the isatin approach and enhance its reactivity.
A year later, a similar NHC-catalyzed transformation was carried out in the presenc of lithium chloride as an external activator. Scheidt and colleagues revealed that the add tion of two equivalents of LiCl to the reaction gave the beneficial effect of creating an or ganized transition state with 62, which offered excellent enantioselectivity, similar to th role of the internal hydroxy group of 61 in the previous method (Figure 20b) [112].
In 2015, it was independently disclosed by Chi (Figure 20c) [113] and Yao (Figure 20d [114] that aliphatic acids could participate in the NHC-catalyzed spiro-γ-lactone construc tion instead of the aldehyde substrates. The key to this modification was the in situ pre activation of carboxylic acid by various peptide coupling reagents, which enabled the for mation of a common NHC-coupled homoenolate intermediate. Finally, Xu and colleagues reported that the saturated aryl ester 64 was also able t engage in this type of NHC-catalyzed asymmetric annulation with catalytic amount of 1 hydroxybenzotriazole (HOBt) (Figure 20e) [115]. After the experimental studies, it wa revealed that HOBt had a dual role: activation of the ester for the next substitution by th chiral NHC, and the stabilization of the effective transition state via hydrogen bonding. A year later, a similar NHC-catalyzed transformation was carried out in the presence of lithium chloride as an external activator. Scheidt and colleagues revealed that the addition of two equivalents of LiCl to the reaction gave the beneficial effect of creating an organized transition state with 62, which offered excellent enantioselectivity, similar to the role of the internal hydroxy group of 61 in the previous method (Figure 20b) [112].
In 2015, it was independently disclosed by Chi (Figure 20c) [113] and Yao (Figure 20d) [114] that aliphatic acids could participate in the NHC-catalyzed spiro-γ-lactone construction instead of the aldehyde substrates. The key to this modification was the in situ pre-activation of carboxylic acid by various peptide coupling reagents, which enabled the formation of a common NHC-coupled homoenolate intermediate.
Finally, Xu and colleagues reported that the saturated aryl ester 64 was also able to engage in this type of NHC-catalyzed asymmetric annulation with catalytic amount of 1-hydroxybenzotriazole (HOBt) (Figure 20e) [115]. After the experimental studies, it was revealed that HOBt had a dual role: activation of the ester for the next substitution by the chiral NHC, and the stabilization of the effective transition state via hydrogen bonding.

Photoredox-Catalyzed C-C Bond Coupling
Photoredox catalysis achieves the cutting-edge evolution in the C-H bond activation chemistry; thus, it enables not only mild, economical, and environmentally friendly chemical reactions, but also the discovery of unprecedented reactivity of chemical bonds [117]. In 2015, MacMillan's seminal work demonstrated that the α-C-H bond of alcohols could by selectively activated in the presence of allylic, benzylic, α-C=O, and α-ether C-H bonds. In addition, the corresponding α-hydroxyl radical participated in the formation of the γ-lactones with methyl acrylate (Figure 22) [118]. The C-H bond-weakening, assisted by hydrogen bond, gave rise to the unique selectivity, which was supported by tetra-nbutylammonium phosphate as a catalytic H-bond acceptor. The versatility of this methodology was demonstrated by testing several structurally complex substrates 68-75 containing inherently activated C-H bonds (Figure 22, bottom).

Photoredox-Catalyzed C-C Bond Coupling
Photoredox catalysis achieves the cutting-edge evolution in the C-H bond activation chemistry; thus, it enables not only mild, economical, and environmentally friendly chemical reactions, but also the discovery of unprecedented reactivity of chemical bonds [117]. In 2015, MacMillan's seminal work demonstrated that the α-C-H bond of alcohols could by selectively activated in the presence of allylic, benzylic, α-C=O, and α-ether C-H bonds. In addition, the corresponding α-hydroxyl radical participated in the formation of the γlactones with methyl acrylate (Figure 22) [118]. The C-H bond-weakening, assisted by hydrogen bond, gave rise to the unique selectivity, which was supported by tetra-n-butylammonium phosphate as a catalytic H-bond acceptor. The versatility of this methodology was demonstrated by testing several structurally complex substrates 68-75 containing inherently activated C-H bonds (Figure 22, bottom). Recently, the greener variant of typical photoredox catalysis, the photo-organocatalytic synthesis of this lactone has been accomplished by Kokotos and colleagues. (Figure 23) [119]. By utilizing a readily available and cheap photoinitiator, phenylglyoxalic acid 76 as an alternative to transition metal catalysts, a variety of primary and secondary alcohol 77 and a maleic acid diester 78 merged into the corresponding γ-butyrolactones 79 in the presence of visible light from sunlight or simple household lamps. Through extensive mechanistic stud- Recently, the greener variant of typical photoredox catalysis, the photo-organocatalytic synthesis of this lactone has been accomplished by Kokotos and colleagues. (Figure 23) [119]. By utilizing a readily available and cheap photoinitiator, phenylglyoxalic acid 76 as an alternative to transition metal catalysts, a variety of primary and secondary alcohol 77 and a maleic acid diester 78 merged into the corresponding γ-butyrolactones 79 in the presence of visible light from sunlight or simple household lamps. Through extensive mechanistic studies, it was proposed that photoinduced exciplex 80 formation facilitates selective hydrogen atom abstraction from the secondary alcohol.

Miscellsious γ-Butyrolactone Formation
Electroreduction of carbonyl compounds can convert electrophilic carbonyl compounds into nucleophilic carbanion, which is further involved in the [3 + 2] coupling of γbutyrolactones. In this regard, electroreductive C-C coupling of α,β-unsaturated carbonyl compounds with ketones or aldehydes has been known to be useful for the synthesis of γ-butyrolactones. A previous electroreductive method [120] toward lactones in the presence of trimethylsilyl chloride (TMSCl) was improved by Kise and colleagues by means of a chiral auxiliary, leading to optically active 4,5,5-trisubstituted γ-butyrolactones 83 in high diastereoselectivity (Figure 24) [121]. The reaction is initiated with two-electron transfer to a more reducible diaryl ketone 82. The resulting carbanion 84 is diastereoselectively coupled with the Michael acceptor 81. DFT calculations for the bond-forming transition states explained the reason for its Si-face preference.

Miscellsious γ-Butyrolactone Formation
Electroreduction of carbonyl compounds can convert electrophilic carbonyl compounds into nucleophilic carbanion, which is further involved in the [3 + 2] coupling of γ-butyrolactones. In this regard, electroreductive C-C coupling of α,β-unsaturated carbonyl compounds with ketones or aldehydes has been known to be useful for the synthesis of γbutyrolactones. A previous electroreductive method [120] toward lactones in the presence of trimethylsilyl chloride (TMSCl) was improved by Kise and colleagues by means of a chiral auxiliary, leading to optically active 4,5,5-trisubstituted γ-butyrolactones 83 in high diastereoselectivity ( Figure 24) [121]. The reaction is initiated with two-electron transfer to a more reducible diaryl ketone 82. The resulting carbanion 84 is diastereoselectively coupled with the Michael acceptor 81. DFT calculations for the bond-forming transition states explained the reason for its Si-face preference. The synthesis of 3,3′-spirooxindole-γ-butyrolactones, another isomeric form of the spirooxindole-γ-lactone motif, has attracted less attention, but it is still valuable when it comes to the longstanding need to secure a structurally diverse chemical library in the drug discovery field. In 2017, Du and colleagues revealed that the peptide coupling reagent (PCR)-assisted β-functionalization of indoline-2-one aliphatic acids 85 could produce the desired spirofused γ-lactone 86 and 87 via [3 + 2] coupling with electrophilic carbonyl substrates; isatins 88 or trifluoromethyl ketones 89 ( Figure 25) [122]. After the intensive screening of the reaction conditions, it was found that the optimal PCR was HATU for isatin substrates and CDI for trifluoromethyl ketone substrates. In 2017, a one-pot multicomponent reaction was exploited to construct enantiomerically pure 4,5-disubstituted γ-butyrolactones 93 by Bhat and colleagues. (Figure 26) [123]. The synthesis of 3,3 -spirooxindole-γ-butyrolactones, another isomeric form of the spirooxindole-γ-lactone motif, has attracted less attention, but it is still valuable when it comes to the longstanding need to secure a structurally diverse chemical library in the drug discovery field. In 2017, Du and colleagues revealed that the peptide coupling reagent (PCR)-assisted β-functionalization of indoline-2-one aliphatic acids 85 could produce the desired spirofused γ-lactone 86 and 87 via [3 + 2] coupling with electrophilic carbonyl substrates; isatins 88 or trifluoromethyl ketones 89 ( Figure 25) [122]. After the intensive screening of the reaction conditions, it was found that the optimal PCR was HATU for isatin substrates and CDI for trifluoromethyl ketone substrates. The synthesis of 3,3′-spirooxindole-γ-butyrolactones, another isomeric form of the spirooxindole-γ-lactone motif, has attracted less attention, but it is still valuable when it comes to the longstanding need to secure a structurally diverse chemical library in the drug discovery field. In 2017, Du and colleagues revealed that the peptide coupling reagent (PCR)-assisted β-functionalization of indoline-2-one aliphatic acids 85 could produce the desired spirofused γ-lactone 86 and 87 via [3 + 2] coupling with electrophilic carbonyl substrates; isatins 88 or trifluoromethyl ketones 89 ( Figure 25) [122]. After the intensive screening of the reaction conditions, it was found that the optimal PCR was HATU for isatin substrates and CDI for trifluoromethyl ketone substrates. In 2017, a one-pot multicomponent reaction was exploited to construct enantiomerically pure 4,5-disubstituted γ-butyrolactones 93 by Bhat and colleagues. (Figure 26) [123]. In 2017, a one-pot multicomponent reaction was exploited to construct enantiomerically pure 4,5-disubstituted γ-butyrolactones 93 by Bhat and colleagues. (Figure 26) [123]. Their strategy was the organocatalyzed Knoevenagel condensation/Michael addition/ decarboxylative lactonization cascade utilizing cheap and readily accessible starting materials such as Meldrum's acid 90, aldehydes 91, hydroxyketones 92, and the chiral cinchona catalyst 94. Enamine (Z)-95, which has a chiral environment induced by 94, is subjected to asymmetric 1,4-addition with the Knoevenagel condensation adduct 96 to afford 97 bearing two contiguous stereogenic centers. This precisely designed three-component reaction was able to avoid possible side reactions such as aldol condensation products between 91 and 92.  Figure 26. Asymmetric synthesis of 4,5-disubstituted-γ-butyrolactones via organocatalyzed three-component coupling.

Synthesis of γ-butyrolactones via C3-C4 and C2-O1 bond formation
Connecting the C3-C4 bond in [3 + 2] annulation-type γ-butyrolactone formation has been less investigated than that of C4-C5 bond formation. Nevertheless, the development of this synthetic route is still significant, in that securing diverse synthetic tools has always been beneficial to organic chemists, particularly for complex natural product synthesis. Retrosynthetically, the disconnection of the C3-C4 and C2-O1 bonds gives d 3 and d 2 synthons; thus, this mismatched relationship should be overcome through a certain umpolung reaction.
A borrowing hydrogen methodology, also known as hydrogen autotransfer, is a subclass of a wide range of transfer hydrogenation chemistry similar to the aforementioned transfer hydrogenative C-C bond coupling [124,125]. Beller and colleagues reported that ruthenium (Ru) pincer catalyst 100 promoted γ-butyrolactone synthesis from 1,2-diols 98 and malonates 99 ( Figure 27) [126]. Catalyst 100 temporarily abstracts hydrogen from 1,2diols to give the corresponding α-hydroxyketone 101, which can act as an electrophile. This step belongs to a polarity inversion process at the C3 position of the resulting γ-lactones. Whereas the above-mentioned Ru-catalyzed spirolactonization consequentially delivers alcohol C-H functionalization type products (see Figure 17), this Ru-catalysis proceeds through a type of alcohol substitution, which offers monocyclic lactones.

Synthesis of γ-Butyrolactones via C3-C4 and C2-O1 Bond Formation
Connecting the C3-C4 bond in [3 + 2] annulation-type γ-butyrolactone formation has been less investigated than that of C4-C5 bond formation. Nevertheless, the development of this synthetic route is still significant, in that securing diverse synthetic tools has always been beneficial to organic chemists, particularly for complex natural product synthesis. Retrosynthetically, the disconnection of the C3-C4 and C2-O1 bonds gives d 3 and d 2 synthons; thus, this mismatched relationship should be overcome through a certain umpolung reaction.
A borrowing hydrogen methodology, also known as hydrogen autotransfer, is a subclass of a wide range of transfer hydrogenation chemistry similar to the aforementioned transfer hydrogenative C-C bond coupling [124,125]. Beller and colleagues reported that ruthenium (Ru) pincer catalyst 100 promoted γ-butyrolactone synthesis from 1,2-diols 98 and malonates 99 ( Figure 27) [126]. Catalyst 100 temporarily abstracts hydrogen from 1,2diols to give the corresponding α-hydroxyketone 101, which can act as an electrophile. This step belongs to a polarity inversion process at the C3 position of the resulting γ-lactones. Whereas the above-mentioned Ru-catalyzed spirolactonization consequentially delivers alcohol C-H functionalization type products (see Figure 17), this Ru-catalysis proceeds through a type of alcohol substitution, which offers monocyclic lactones. An epoxide is a useful three-atom building block in the [3 + 2] annulation strategy because of its susceptibility to the attack of suitable carbon nucleophiles such as ester enolates. In 2017, ketene silyl acetal 102 was applied as the effective enolate equivalent to constructing the lactone via regioselective epoxide opening followed by lactonization ( Figure 28) [127]. Additionally, an ionic liquid system composed of a mixture of 1,3-dimethylimidazolium fluoride ([Dmim]F) and 1-butylimidazolium tetrafluoroborate ([Hbim]BF4) was utilized to achieve the desired transformation. The catalytic amount of [Dmim]F acted as a Si-O bond activator and [Hbim]BF4 served as the solvent providing acidic media. This ionic liquid mixture was able to be reused up to three times, which is valuable for the contribution toward green chemistry.

Synthesis of Butyrolactone via C3-C4 and C5-O1 Bonds Formation
There are a few examples of this synthetic approach through the formation of C3-C4 and C5-O1 bonds during 2010 to 2020. Mostly, the single-electron transfer pathway is involved in the C3-C4 and C5-O1 bond formation approaches. First, photoredox catalysis was applied with alkenes and suitable counterparts such as α,β-unsaturated acid [128], oxime acid [129], or haloacetic acid [130]. Second, a metal oxidant-mediated transformation of glycals to γ-butyrolactones was reported [131]. Third, the copper-catalyzed-cyclopropanol ring-opening cross-coupling reaction was utilized to synthesize γ-butyrolactones containing quaternary carbon centers [132]. An epoxide is a useful three-atom building block in the [3 + 2] annulation strategy because of its susceptibility to the attack of suitable carbon nucleophiles such as ester enolates. In 2017, ketene silyl acetal 102 was applied as the effective enolate equivalent to constructing the lactone via regioselective epoxide opening followed by lactonization ( Figure 28) [127]. Additionally, an ionic liquid system composed of a mixture of 1,3-dimethylimidazolium fluoride ([Dmim]F) and 1-butylimidazolium tetrafluoroborate ([Hbim]BF 4 ) was utilized to achieve the desired transformation. The catalytic amount of [Dmim]F acted as a Si-O bond activator and [Hbim]BF 4 served as the solvent providing acidic media. This ionic liquid mixture was able to be reused up to three times, which is valuable for the contribution toward green chemistry. An epoxide is a useful three-atom building block in the [3 + 2] annulation strategy because of its susceptibility to the attack of suitable carbon nucleophiles such as ester enolates. In 2017, ketene silyl acetal 102 was applied as the effective enolate equivalent to constructing the lactone via regioselective epoxide opening followed by lactonization ( Figure 28) [127]. Additionally, an ionic liquid system composed of a mixture of 1,3-dimethylimidazolium fluoride ([Dmim]F) and 1-butylimidazolium tetrafluoroborate ([Hbim]BF4) was utilized to achieve the desired transformation. The catalytic amount of [Dmim]F acted as a Si-O bond activator and [Hbim]BF4 served as the solvent providing acidic media. This ionic liquid mixture was able to be reused up to three times, which is valuable for the contribution toward green chemistry.

Polar Radical Crossover Cycloaddition (PRCC)
Polar radical crossover cycloaddition (PRCC) has been utilized in the construction of various saturated heterocycles, including tetrahydrofurans [133], γ-lactams, and pyrrolidines [134]. The co-catalyst of Fukuzumi acridinium single-electron photooxidant and a redox-active hydrogen atom donor is a key mediator of PRCC through photoredox catalysis. Nicewicz and colleagues extended the PRCC approach to the synthesis of γbutyrolactones [128]. First, the oxidizable alkenes 103 and α,β-unsaturated acids 105 as nucleophiles forged γ-butyrolactones 107 under photoredox catalysis. As depicted in Figure 29, an electrophilic alkene cation radical 104 is formed by the excited acridiniummediated single-electron oxidation followed by the generation of the radical intermediate 106 through the addition of carboxylic acid 105 to the alkene cation radical. 5-exo-trig radical cyclization and hydrogen atom transfer with thiophenol provided the desired γ-butyrolactones. Alternatively, α-amino-γ-butyrolactones 110 have also been synthesized by the PRCC method using oxidizable alkenes 108 and O-benzyloxime acids 109, which correspond to α,β-unsaturated acids 105 ( Figure 30) [129]. Polar radical crossover cycloaddition (PRCC) has been utilized in the construction of various saturated heterocycles, including tetrahydrofurans [133], γ-lactams, and pyrrolidines [134]. The co-catalyst of Fukuzumi acridinium single-electron photooxidant and a redox-active hydrogen atom donor is a key mediator of PRCC through photoredox catalysis. Nicewicz and colleagues extended the PRCC approach to the synthesis of γ-butyrolactones [128]. First, the oxidizable alkenes 103 and α,β-unsaturated acids 105 as nucleophiles forged γ-butyrolactones 107 under photoredox catalysis. As depicted in Figure 29, an electrophilic alkene cation radical 104 is formed by the excited acridinium-mediated single-electron oxidation followed by the generation of the radical intermediate 106 through the addition of carboxylic acid 105 to the alkene cation radical. 5-exo-trig radical cyclization and hydrogen atom transfer with thiophenol provided the desired γ-butyrolactones. Alternatively, α-amino-γ-butyrolactones 110 have also been synthesized by the PRCC method using oxidizable alkenes 108 and O-benzyloxime acids 109, which correspond to α,β-unsaturated acids 105 ( Figure 30) [129].

Atom-Transfer Radical Addition (ATRA)
Another example of γ-butyrolactone synthesis mediated by photoredox catalysis is atom-transfer radical addition (ATRA), which was reported by Kokotos and colleagues in 2018 [130]. ATRA has been utilized as a powerful method for one-step C-C and C-X bond formation between olefins and haloalkanes. Kokotos and colleagues applied photoredox catalysis in ATRA using Ru(bpy) 3 Cl 2 as a photoredox catalyst, which was employed in the conversion of alkenes 111 and α-iodoacetic acids 112 to γ-butyrolactones 113 under light irradiation. In this reaction, the excited photocatalyst is reduced by ascorbate, followed by reaction with α-iodoacetic acid 112 to generate the electrophilic radical 114, which reacts with the alkene leading to radical 115. Then, propagation proceeded with iodoacetic acid, resulting in the formation of 116. Finally, γ-butyrolactone 113 is formed by the deprotonated carboxylic acid under basic reaction conditions ( Figure 31).   Another example of γ-butyrolactone synthesis mediated by photoredox catalysis is atom-transfer radical addition (ATRA), which was reported by Kokotos and colleagues in 2018 [130]. ATRA has been utilized as a powerful method for one-step C-C and C-X bond formation between olefins and haloalkanes. Kokotos and colleagues applied photoredox catalysis in ATRA using Ru(bpy)3Cl2 as a photoredox catalyst, which was employed in the conversion of alkenes 111 and α-iodoacetic acids 112 to γ-butyrolactones 113 under light irradiation. In this reaction, the excited photocatalyst is reduced by ascorbate, followed by reaction with α-iodoacetic acid 112 to generate the electrophilic radical 114, which reacts with the alkene leading to radical 115. Then, propagation proceeded with iodoacetic acid, resulting in the formation of 116. Finally, γ-butyrolactone 113 is formed by the deprotonated carboxylic acid under basic reaction conditions ( Figure 31).

Mn(OAc) 3 -Mediated Radical Lactonization
Manganese (III) acetate has been utilized as a versatile single-electron transfer (SET) reagent. Mukherjee and colleagues reported Mn(OAc) 3 -mediated radical lactonization to synthesize carbohydrate-based γ-butyrolactones from glycals [131]. Under sonication, a variety of 1,2-glycals and 2,3-glycals were converted to γ-butyrolactones in a regioselective and stereoselective manner, which were governed by conformational preferences for glycal substrates (Figure 32). Cyclopropanols 117 are versatile substrates in various ring-opening and ring-expansion reactions because of the intrinsic stain of the three-membered ring. One of the representative reactions in this class is the cyclopropanol ring-opening cross-coupling reaction mediated by diverse transition metal catalysts or single-electron transferring oxidants, resulting in the formation of a variety of β-substituted ketones. Formation of α,β-unsaturated enone byproducts, which are normally caused by β-hydride elimination of the metallo-homoenolate 120, is one of the major issues in this reaction. Interestingly, Dai and colleagues developed a method to accelerate α,β-unsaturated carbonyl byproduct 121 by adding potassium iodide in the reaction mixture and reacting with 2-bromo-2,2-dialkyl acetate 118 to obtain γ-butyrolactones 119 bearing quaternary carbon centers, which are catalyzed by Cu(OTf)2 ( Figure 33) [132].

Copper-catalyzed cyclopropanol ring-opening cross-coupling reaction
Cyclopropanols 117 are versatile substrates in various ring-opening and ring-expa sion reactions because of the intrinsic stain of the three-membered ring. One of the repr sentative reactions in this class is the cyclopropanol ring-opening cross-coupling reactio mediated by diverse transition metal catalysts or single-electron transferring oxidants, r sulting in the formation of a variety of β-substituted ketones. Formation of α,β-unsatu rated enone byproducts, which are normally caused by β-hydride elimination of th metallo-homoenolate 120, is one of the major issues in this reaction. Interestingly, Dai an colleagues developed a method to accelerate α,β-unsaturated carbonyl byproduct 121 b adding potassium iodide in the reaction mixture and reacting with 2-bromo-2,2-dialk acetate 118 to obtain γ-butyrolactones 119 bearing quaternary carbon centers, which a catalyzed by Cu(OTf)2 ( Figure 33) [132].  Figure 33. Synthesis of γ-butyrolactones bearing quaternary carbon centers via copper-catalyzed cyclopropanol ring-opening cross-coupling reaction.

Synthesis of γ-Butyrolactones via C2-C3 and C2-O1 Bonds Formation
Carbon monoxide is used as a versatile C1 source in organic synthesis, thereby reacting with suitable unsaturated alcohols to afford various ring sizes of lactones [135]. There have been increasing reports of methodologies for producing γ-butyrolactones using carbonylations and hydroformylations over the past decades. However, due to the innate drawbacks of CO, including its high toxicity, gaseous nature, and strict regulations for transportation, bypassing the direct use of CO gas is another significant topic in carbonylation research [135].

Carbonylative Lactonization
Among various methodologies utilizing CO gas or other carbonyl sources, transitionmetal-catalyzed carbonylative lactonization is most commonly used for γ-lactone formation. Iron pentacarbonyl is a cheap, practical surrogate of the carbonyl donor, and it was first applied to convert (amino)polyhydroxylated terminal olefins 122 into the bicyclic lactones 123 by Gracza and colleagues ( Figure 34) [136]. In this system, a CO molecule is generated in situ by the assistance of copper(II) chloride and gentle heat, and subsequently participates in the palladium(II) catalysis cycle. Very recently, the same group showed that this protocol could be applicable to a continuous flow reaction in comparable yield with the batch reaction [137].

Synthesis of γ-Butyrolactones via C2-C3 and C2-O1 Bonds Formation
Carbon monoxide is used as a versatile C1 source in organic synthesis, thereby reacting with suitable unsaturated alcohols to afford various ring sizes of lactones [135]. There have been increasing reports of methodologies for producing γ-butyrolactones using carbonylations and hydroformylations over the past decades. However, due to the innate drawbacks of CO, including its high toxicity, gaseous nature, and strict regulations for transportation, bypassing the direct use of CO gas is another significant topic in carbonylation research [135].

Carbonylative Lactonization
Among various methodologies utilizing CO gas or other carbonyl sources, transitionmetal-catalyzed carbonylative lactonization is most commonly used for γ-lactone formation. Iron pentacarbonyl is a cheap, practical surrogate of the carbonyl donor, and it was first applied to convert (amino)polyhydroxylated terminal olefins 122 into the bicyclic lactones 123 by Gracza and colleagues ( Figure 34) [136]. In this system, a CO molecule is generated in situ by the assistance of copper(II) chloride and gentle heat, and subsequently participates in the palladium(II) catalysis cycle. Very recently, the same group showed that this protocol could be applicable to a continuous flow reaction in comparable yield with the batch reaction [137]. In 2014, Jiang and colleagues reported a unique one-pot-four-step cascade reaction in ionic liquid media by employing a palladium-catalyzed carboxylative annulation to construct highly functionalized γ-butyrolactones ( Figure 35) [138]. This transformation is initiated from the trans-chloropalladation of alkynoates 124, of which the regioselectivity is governed by electronic factors. Intermediate 127 undergoes carbopalladation with butenol 125, followed by CO insertion and reductive elimination, yielding C3 functionalized γ-lactones 126 bearing a tetrasubstituted olefin unit. The imidazolium type ionic liquids played an important role during the reaction as a ligand of the palladium catalyst and as a chloride source [139]. They further demonstrated the utility of vinyl chloride functionalities in the products by employing them to Suzuki-Miyaura coupling and Negishi coupling. In 2014, Jiang and colleagues reported a unique one-pot-four-step cascade reaction in ionic liquid media by employing a palladium-catalyzed carboxylative annulation to construct highly functionalized γ-butyrolactones ( Figure 35) [138]. This transformation is initiated from the trans-chloropalladation of alkynoates 124, of which the regioselectivity is governed by electronic factors. Intermediate 127 undergoes carbopalladation with butenol 125, followed by CO insertion and reductive elimination, yielding C3 functionalized γlactones 126 bearing a tetrasubstituted olefin unit. The imidazolium type ionic liquids played an important role during the reaction as a ligand of the palladium catalyst and as a chloride source [139]. They further demonstrated the utility of vinyl chloride functionalities in the products by employing them to Suzuki-Miyaura coupling and Negishi coupling. 37 Figure 35. Synthesis of C3-substituted γ-butyrolactones via palladium-catalyzed carbonylation cascade in the ionic liquid.
Organic disulfides, which have been considered as inefficient substrates for transition-metal-catalyzed carbonylative heteroatom addition, were successfully used as counterparts of thiolated α-alkylidene-γ-butyrolactone synthesis in the presence of dicobalt octacarbonyl or palladium complexes such as Pd(PPh3)4 and Pd(OAc)2 ( Figure 36) [140]. A variety of homopropagyl alcohols 128 and aryl disulfides produced the desired thiolated lactones 129 by both catalytic systems with high regio-and stereoselectivity (cis-isomer) Mechanistically, despite the difference in the order of metal-alkyne complexation, the presence of a hydroxy group plays a critical role in the regioselectivity of carbonyl insertion in both cases.  Organic disulfides, which have been considered as inefficient substrates for transitionmetal-catalyzed carbonylative heteroatom addition, were successfully used as counterparts of thiolated α-alkylidene-γ-butyrolactone synthesis in the presence of dicobalt octacarbonyl or palladium complexes such as Pd(PPh 3 ) 4 and Pd(OAc) 2 ( Figure 36) [140]. A variety of homopropagyl alcohols 128 and aryl disulfides produced the desired thiolated lactones 129 by both catalytic systems with high regio-and stereoselectivity (cis-isomer). Mechanistically, despite the difference in the order of metal-alkyne complexation, the presence of a hydroxy group plays a critical role in the regioselectivity of carbonyl insertion in both cases.  Figure 35. Synthesis of C3-substituted γ-butyrolactones via palladium-catalyzed carbonylation cascade in the ionic liquid.
Organic disulfides, which have been considered as inefficient substrates for transition-metal-catalyzed carbonylative heteroatom addition, were successfully used as counterparts of thiolated α-alkylidene-γ-butyrolactone synthesis in the presence of dicobalt octacarbonyl or palladium complexes such as Pd(PPh3)4 and Pd(OAc)2 ( Figure 36) [140]. A variety of homopropagyl alcohols 128 and aryl disulfides produced the desired thiolated lactones 129 by both catalytic systems with high regio-and stereoselectivity (cis-isomer). Mechanistically, despite the difference in the order of metal-alkyne complexation, the presence of a hydroxy group plays a critical role in the regioselectivity of carbonyl insertion in both cases.  C-C bonds in cyclopropanols can be easily activated by a transition-metal catalyzed ring-opening process generating metal-homoenolate species, which possess the potential of structural diversification by engaging in C sp3 -C sp2 and C sp3 -C sp3 cross-coupling with various counterparts [141]. Dai and colleagues combined this palladium-catalyzed C-C bond activation reaction with conventional carbonylation, and successfully constructed synthetically challenging oxaspirolactone structure 130 ( Figure 37) [142]. The usefulness of this strategy was demonstrated by total syntheses of α-levantanolide and α-levantenolide in two and four steps, respectively (Figure 37, bottom). C-C bonds in cyclopropanols can be easily activated by a transition-metal catalyzed ring-opening process generating metal-homoenolate species, which possess the potential of structural diversification by engaging in Csp3-Csp2 and Csp3-Csp3 cross-coupling with various counterparts [141]. Dai and colleagues combined this palladium-catalyzed C-C bond activation reaction with conventional carbonylation, and successfully constructed synthetically challenging oxaspirolactone structure 130 ( Figure 37) [142]. The usefulness of this strategy was demonstrated by total syntheses of α-levantanolide and α-levantenolide in two and four steps, respectively (Figure 37, bottom).

Hydroformylation-Oxidation
The hydroformylation of olefins is one of the extensively investigated classes of carbonylation, especially for industrial applications [143]. This reaction is also applicable to γ-butyrolactone syntheses by adding a formyl group to hydroxyalkenes and subsequent oxidation of the corresponding lactols. Although the carbonyl insertion step has been known to normally take place in the anti-Markovnikov direction, Breit and colleagues successfully converted 1,1-disubstituted homoallylic alcohols 131 into the desired γ-lactones 132 containing quaternary carbon at the α-position ( Figure 38) [144]. The key to this achievement was the use of a phosphinite as a removable catalyst-directing group. Diphenylphosphinites 133 was formed via transesterification with a catalytic amount of Ph2POMe and the resulting phosphinite group-guided approach of the rhodium hydride complex afforded a favorable six-membered cyclic hydrometallation transition state 134.

Hydroformylation-Oxidation
The hydroformylation of olefins is one of the extensively investigated classes of carbonylation, especially for industrial applications [143]. This reaction is also applicable to γ-butyrolactone syntheses by adding a formyl group to hydroxyalkenes and subsequent oxidation of the corresponding lactols. Although the carbonyl insertion step has been known to normally take place in the anti-Markovnikov direction, Breit and colleagues successfully converted 1,1-disubstituted homoallylic alcohols 131 into the desired γ-lactones 132 containing quaternary carbon at the α-position (Figure 38) [144]. The key to this achievement was the use of a phosphinite as a removable catalyst-directing group. Diphenylphosphinites 133 was formed via transesterification with a catalytic amount of Ph 2 POMe and the resulting phosphinite group-guided approach of the rhodium hydride complex afforded a favorable six-membered cyclic hydrometallation transition state 134. metal center [145]. Very recently, Zhang and colleagues addressed this challenge by modifying conventional chiral ligands to more sterically demanding variants ( Figure 39) [146]. Under the optimized conditions, the hydroformylation of allylic alcohol 135 occurred following the anti-Markovnikov rule in high ee values, producing the corresponding optically active lactol. The lactol was able to be transformed into not only the desired optically active lactone 136 via PCC oxidation, but also into the tetrahydrofuran derivative via reduction or allylation.

Carboxylation-Lactonization
Carbon dioxide is the most abundant C1 source on earth; thus, harnessing this molecule would be appealing with respect to the development of economical and environmentally friendly synthetic methods. Nevertheless, due to the chemically inert nature of CO2 gas, carboxylation (CO2 activation) has been less widespread than carbonylation (CO activation). The nickel-catalyzed methyl-carboxylation of homopropagylic alcohols 137 met this demand, affording α-alkylidene-γ-butyrolactones 138 in a regio-and stereoselective manner (Figure 40) [147]. Ma and colleagues discovered that this catalytic system only required 1 mol % of Ni catalyst for CO2 activation and proceeded with broad functional group tolerance. The excellent regioselectivity may derive from the directing effect of the The enantioselective hydroformylation of 1,1-disubstituted olefins has proven to be unproductive, presumably due to the steric repulsion of an olefin coordination with a metal center [145]. Very recently, Zhang and colleagues addressed this challenge by modifying conventional chiral ligands to more sterically demanding variants ( Figure 39) [146]. Under the optimized conditions, the hydroformylation of allylic alcohol 135 occurred following the anti-Markovnikov rule in high ee values, producing the corresponding optically active lactol. The lactol was able to be transformed into not only the desired optically active lactone 136 via PCC oxidation, but also into the tetrahydrofuran derivative via reduction or allylation. The enantioselective hydroformylation of 1,1-disubstituted olefins has proven to be unproductive, presumably due to the steric repulsion of an olefin coordination with a metal center [145]. Very recently, Zhang and colleagues addressed this challenge by modifying conventional chiral ligands to more sterically demanding variants ( Figure 39) [146]. Under the optimized conditions, the hydroformylation of allylic alcohol 135 occurred following the anti-Markovnikov rule in high ee values, producing the corresponding optically active lactol. The lactol was able to be transformed into not only the desired optically active lactone 136 via PCC oxidation, but also into the tetrahydrofuran derivative via reduction or allylation.

Carboxylation-Lactonization
Carbon dioxide is the most abundant C1 source on earth; thus, harnessing this molecule would be appealing with respect to the development of economical and environmentally friendly synthetic methods. Nevertheless, due to the chemically inert nature of CO2 gas, carboxylation (CO2 activation) has been less widespread than carbonylation (CO activation). The nickel-catalyzed methyl-carboxylation of homopropagylic alcohols 137 met this demand, affording α-alkylidene-γ-butyrolactones 138 in a regio-and stereoselective manner (Figure 40) [147]. Ma and colleagues discovered that this catalytic system only required 1 mol % of Ni catalyst for CO2 activation and proceeded with broad functional group tolerance. The excellent regioselectivity may derive from the directing effect of the

Carboxylation-Lactonization
Carbon dioxide is the most abundant C1 source on earth; thus, harnessing this molecule would be appealing with respect to the development of economical and environmentally friendly synthetic methods. Nevertheless, due to the chemically inert nature of CO 2 gas, carboxylation (CO 2 activation) has been less widespread than carbonylation (CO activation). The nickel-catalyzed methyl-carboxylation of homopropagylic alcohols 137 met this demand, affording α-alkylidene-γ-butyrolactones 138 in a regio-and stereoselective manner (Figure 40) [147]. Ma and colleagues discovered that this catalytic system only required 1 mol % of Ni catalyst for CO 2 activation and proceeded with broad functional group tolerance. The excellent regioselectivity may derive from the directing effect of the adjacent hydroxy group. The potential of this methodology was illustrated through the first total synthesis of (±)-heteroplexisolide E 139 [148]. adjacent hydroxy group. The potential of this methodology was illustrated through the first total synthesis of (±)-heteroplexisolide E 139 [148]. Figure 40. Synthesis of α-alkyledene γ-butyrolactones via Ni(0)-catalyzed carboxylation and total synthesis of (±)-heteroplexisolide E.

C-H Insertion
Over the past several decades, Rh-catalyzed intramolecular C-H insertion has been intensively investigated and established as a powerful tool for the construction of structurally diverse cyclic compounds. Unsworth and colleagues reported a one-pot C-H insertion/olefination sequence to afford α-alkylidene-γ-butyrolactones ( Figure 41) [149]. Rhcatalyzed C-H insertion of diazo compound 140 gave α-phosphonated γ-lactone 141, which was subsequently converted to α-alkylidene-γ-lactone 142 via Horner-Wadsworth-Emmons-type olefination. A variety of γ-lactones were obtained in a one-pot procedure in useful yields. The versatility of this protocol was demonstrated by the successful synthesis of natural products, cedamycin A, B, and eudesmanolide [150,151].

Synthesis of γ-Butyrolactones via C3-C4 Bond Formation C-H Insertion
Over the past several decades, Rh-catalyzed intramolecular C-H insertion has been intensively investigated and established as a powerful tool for the construction of structurally diverse cyclic compounds. Unsworth and colleagues reported a one-pot C-H insertion/olefination sequence to afford α-alkylidene-γ-butyrolactones ( Figure 41) [149]. Rh-catalyzed C-H insertion of diazo compound 140 gave α-phosphonated γ-lactone 141, which was subsequently converted to α-alkylidene-γ-lactone 142 via Horner-Wadsworth-Emmons-type olefination. A variety of γ-lactones were obtained in a one-pot procedure in useful yields. The versatility of this protocol was demonstrated by the successful synthesis of natural products, cedamycin A, B, and eudesmanolide [150,151].

Synthesis of γ-Butyrolactones via Oxidative C2-O1 Bond Formation
A simple γ-butyrolactone is itself a broadly used material [152] as a solvent, extraction agent, and intermediate for polymers, pharmaceutics, herbicides, rubber production, etc. The oxidative lactonization of 1,4-butanediol under an efficient catalytic system has been a dominant industrial process because of its significant advantages [152]. This method does not produce any waste except for reusable hydrogen gas. Additionally, 1,4-butanediol can be obtained from renewable biomass such as glucose [153]. For these reasons, it is not surprising that many researchers have intensively modified this route to be more efficient and environmentally benign than conventional methods. The representative oxidative lactonization conditions recently developed for the synthesis of γ-butyrolactones from 1,4-butanediol are summarized in Table 4.

Synthesis of γ-Butyrolactones via Oxidative C2-O1 Bond Formation
A simple γ-butyrolactone is itself a broadly used material [152] as a solvent, extraction agent, and intermediate for polymers, pharmaceutics, herbicides, rubber production, etc. The oxidative lactonization of 1,4-butanediol under an efficient catalytic system has been a dominant industrial process because of its significant advantages [152]. This method does not produce any waste except for reusable hydrogen gas. Additionally, 1,4butanediol can be obtained from renewable biomass such as glucose [153]. For these reasons, it is not surprising that many researchers have intensively modified this route to be more efficient and environmentally benign than conventional methods. The representative oxidative lactonization conditions recently developed for the synthesis of γ-butyrolactones from 1,4-butanediol are summarized in Table 4.

Synthesis of γ-Butyrolactones via Oxidative C2-O1 Bond Formation
A simple γ-butyrolactone is itself a broadly used material [152] as a solvent, extraction agent, and intermediate for polymers, pharmaceutics, herbicides, rubber production, etc. The oxidative lactonization of 1,4-butanediol under an efficient catalytic system has been a dominant industrial process because of its significant advantages [152]. This method does not produce any waste except for reusable hydrogen gas. Additionally, 1,4butanediol can be obtained from renewable biomass such as glucose [153]. For these reasons, it is not surprising that many researchers have intensively modified this route to be more efficient and environmentally benign than conventional methods. The representative oxidative lactonization conditions recently developed for the synthesis of γ-butyrolactones from 1,4-butanediol are summarized in Table 4. .

Conclusions
γ-Butyrolactones have been broadly studied in drug discovery, resulting in the identification of diverse biologically active small molecules containing γ-butyrolactone. Moreover, significant efforts to develop efficient and concise synthetic strategies toward γ-butyrolactone moiety have been reported in recent years utilizing readily available starting materials and newly developed reactions. The construction of diverse biologically active natural products and synthetic pharmaceuticals bearing γ-butyrolactone are allowed with these novel strategies. This review includes a brief overview of biologically active γ-butyrolactones and a summary of the representative synthetic methodologies toward γ-butyrolactones developed between 2010 and 2020, which are classified in the seven sections based on the sites of bond formation (Table 5) and described their reaction mechanism and further application in the synthesis of biologically active molecules. This update will help to develop biologically active new γ-butyrolactones and to solve hurdles in the synthesis of γ-butyrolactone-bearing natural products and pharmaceuticals as well as to develop novel synthetic approaches toward γ-butyrolactones. Transition-metal catalyzed C-C bond coupling 18 NHC-catalyzed C-C bond coupling 20 Photoredox-catalyzed C-C bond coupling 23 Miscellsious γ-butyrolactone formation 24 .

Conclusions
γ-Butyrolactones have been broadly studied in drug discovery, resulting in the identification of diverse biologically active small molecules containing γ-butyrolactone. Moreover, significant efforts to develop efficient and concise synthetic strategies toward γbutyrolactone moiety have been reported in recent years utilizing readily available starting materials and newly developed reactions. The construction of diverse biologically active natural products and synthetic pharmaceuticals bearing γ-butyrolactone are allowed with these novel strategies. This review includes a brief overview of biologically active γ-butyrolactones and a summary of the representative synthetic methodologies toward γbutyrolactones developed between 2010 and 2020, which are classified in the seven sections based on the sites of bond formation (Table 5) and described their reaction mechanism and further application in the synthesis of biologically active molecules. This update will help to develop biologically active new γ-butyrolactones and to solve hurdles in the synthesis of γ-butyrolactone-bearing natural products and pharmaceuticals as well as to develop novel synthetic approaches toward γ-butyrolactones. Homogeneous solution phase reaction Fe complex 146 [171] 1 Simultaneous hydrogenation of acetophenone; 2 Simultaneous hydrogenation of furfural alcohol; 3 Simultaneous hydrogenation of nitrobenzene; 4 Simultaneous hydrogenation of ortho-chloronitrobenzene. 5  .

Conclusions
γ-Butyrolactones have been broadly studied in drug discovery, resulting in the identification of diverse biologically active small molecules containing γ-butyrolactone. Moreover, significant efforts to develop efficient and concise synthetic strategies toward γ-butyrolactone moiety have been reported in recent years utilizing readily available starting materials and newly developed reactions. The construction of diverse biologically active natural products and synthetic pharmaceuticals bearing γ-butyrolactone are allowed with these novel strategies. This review includes a brief overview of biologically active γ-butyrolactones and a summary of the representative synthetic methodologies toward γ-butyrolactones developed between 2010 and 2020, which are classified in the seven sections based on the sites of bond formation (Table 5) and described their reaction mechanism and further application in the synthesis of biologically active molecules. This update will help to develop biologically active new γ-butyrolactones and to solve hurdles in the synthesis of γ-butyrolactone-bearing natural products and pharmaceuticals as well as to develop novel synthetic approaches toward γ-butyrolactones. .

Conclusions
γ-Butyrolactones have been broadly studied in drug discovery, resulting in the identification of diverse biologically active small molecules containing γ-butyrolactone. Moreover, significant efforts to develop efficient and concise synthetic strategies toward γ-butyrolactone moiety have been reported in recent years utilizing readily available starting materials and newly developed reactions. The construction of diverse biologically active natural products and synthetic pharmaceuticals bearing γ-butyrolactone are allowed with these novel strategies. This review includes a brief overview of biologically active γ-butyrolactones and a summary of the representative synthetic methodologies toward γ-butyrolactones developed between 2010 and 2020, which are classified in the seven sections based on the sites of bond formation (Table 5) and described their reaction mechanism and further application in the synthesis of biologically active molecules. This update will help to develop biologically active new γ-butyrolactones and to solve hurdles in the synthesis of γ-butyrolactone-bearing natural products and pharmaceuticals as well as to develop novel synthetic approaches toward γ-butyrolactones.