Gold-catalyzed synthesis of small-sized carbo- and heterocyclic compounds: A review

3.1 Gold-catalyzed diazo compound-mediated cyclopropanation

The strategy involving metal-catalyzed carbene transfer from diazo compounds is widely recognized as the most thoroughly investigated approach for the synthesis of acceptor or donor–acceptor cyclopropanes. Metal complexes, such as Au(i) catalysts, can facilitate the transition [19]. Over the past 15 years, several Au(i) complexes have been employed to facilitate carbene transfer processes towards diverse nucleophiles [20].

As of 2019, Pérez et al. revealed that ethylene 1, which is thought to be the basic alkene, can go through cyclopropanation when it meets ethyl diazoacetate (EDA) 2 and an NHC-Au(i) catalyst [21]. The reaction between 1 and 2 at room temperature is catalyzed by IPrAuCl in the presence of one equivalent of NaBArF₄, producing 3 with yields of around 70% (based on EDA) (Scheme 1). This is the first instance of ethylene being directly cyclopropanated using this technology, with notable conversions.

Scheme 1

Gold-catalyzed cyclopropanation of ethylene with EDA.

Using diazooxindoles 4 and α-CH₂F and CF₂H styrenes 5, Cao et al. created a very selective cyclopropanation [22] to obtain 3-spirocyclopropyl oxindoles 6 (Scheme 2) with vicinal all-carbon stereocenters. These are interesting compounds for medical research or could be used to make different kinds of fluorinated spirocyclopropanes [23]. They demonstrate that the formation of C-F⋯H-X interactions between fluorinated solvents and reactive intermediates may significantly aid the reaction.

Scheme 2

Gold(i)-mediated enantioselective cyclopropanation using diazooxindoles.

This study offers an unparalleled understanding of the role of fluorinated organic solvents in augmenting the reactivity of organic reactions while also presenting supplementary proof for the presence of C-F⋯H-X interactions.

Liu et al. explained the process of producing spirocyclopropyl oxindoles 9 using a gold(i) catalyst by reacting 1,2,4-substituted dienes 7 with diazooxindoles 8 (Scheme 3) [24]. The authors investigated a unique rearrangement of these spirocyclopropyl oxindoles 9, resulting in the formation of 3-(cyclopenta-1,3-dien-1-ylmethyl)oxindoles 11 as the product with the same gold catalyst. The reported products 11 of this rearrangement are generated through a thorough cleavage of the cyclopropane ring of spirocyclopropyl oxindoles 9 via a formal methyl C–H insertion at a C(3)–oxindole ring. Based on experimental results, the authors ruled out the possibility of a reversible gold-cyclopropanation pathway. In contrast, they proposed the formation of intricate pairs involving gold enolates and 1-methylen-2,3,4-cyclopentadienyl cations, leading to a 1,5-enolate shift.

Scheme 3

Gold(i)-mediated diastereoselective cyclopropanation using diazooxindoles and dienes.

The majority of the time, throughout the cyclopropanation process, small quantities of minor products such as 3-(4-phenylcyclopenta-2,4-dien-1-yl)indolin-2-one derivatives (<10%) were produced, posing challenges in purification using column chromatography.

Zhang et al. [25] reported on the synthesis of densely substituted cyclopropanes 14 (Scheme 4). The authors obtained good yields and great enantioselectivity and diastereoselectivity by using α-diazoarylacetate compounds 13 to help with the enantioselective cyclopropanation of enamides 12. The reaction exhibited high efficiency when applied to internal or terminal enamides, yielding the desired products in satisfactory quantities with remarkable levels of enantioselectivity (up to 98% ee) and diastereoselectivity, particularly when employing a chiral binol-derived phosphoramidite-gold(i) complex. The present methodology offers a clear and feasible approach for the synthesis of chiral cyclopropylamines possessing consecutive stereogenic centers, a structural feature of utmost importance in the fields of biological investigation and pharmaceutical advancement. The utilization of Carreira ligand 15 [26] in the process led to the synthesis of a broad spectrum of densely substituted donor–acceptor cyclopropanes, exhibiting significant degrees of diastereo- and enantioselectivity.

Scheme 4

Au-catalyzed enantioselective cyclopropanation of enamides using α-diazoarylacetate.

3.2 Gold-catalyzed cyclopropanation by cycloisomerization of unsaturated systems

3.2.1 Cyclopropanation through cycloisomerization of enynes

Gold complexes are a kind of carbophilic π acid that have been intentionally designed to have the capability to activate various C–C bonds [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]. This includes bonds present in alkynes, alkenes, and allenes. Extensive research has been conducted on the gold-catalyzed cycloisomerizations of enynes within the timeframe of the twenty-first century [44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66]. Au(i) can undergo interaction with an enyne, resulting in the formation of η ²-complexes involving either the double bond or the triple bond [67,68]. The η ²-alkyne gold complex has a smaller lowest unoccupied molecular orbital, which makes it more vulnerable to nucleophilic attack. Consequently, this results in a heightened affinity for alkynes over alkenes, a phenomenon commonly referred to as alkynophilicity [69].

3.2.1.1 Cyclopropanation via cycloisomerization of 1,6-enynes

Liu and co-workers reported the cyclization of aryl diazo ketones 17 and 1,6-enynes 16 by gold catalysis, which offers easy access to 3-cyclopropyl-2-en-1-one derivatives 18. The reaction was initiated through the creation of 5-exo-dig cyclopropyl gold carbenes from 1,6-enynes. As shown in Scheme 5 [70], aryl diazo ketones subsequently trapped these carbenes.

Scheme 5

Gold-catalyzed cycloisomerization of 1,6-enynes using diazo ketone.

Fensterbank (year) documented the process of cycloisomerization of O-tethered 1,6-enynes 19 using gold catalysis. This reaction resulted in the formation of a four-membered ring [71] inside the molecular structure. An important stage is to expand the Wagner–Meerwein rearrangement onto intermediate carbene center 20. Good yields of the corresponding cyclopropane-fused tricyclic systems with a dihydropyran moiety 21 were achieved (Scheme 6).

Scheme 6

Cycloisomerization of O-tethered 1,6-enynes via gold catalysis.

In 2020, Michelet et al. presented a robust method for the rapid synthesis of 3/6-membered moderately volatile enol ethers 23 with distinct olfactive characteristics. In this method, oxygen-tethered enynes 22 were cycloisomerized with the help of gold, as shown in Scheme 7 [72]. The fact that the reaction is feasible and can use a 0.04 mol% catalyst loading on a 25 g scale in mild conditions is proof of its viability. The olfactory characteristics of a library of synthetic bicyclic compounds were investigated. Depending on the substituents, these compounds’ odor characteristics can vary greatly. Some of them have aromas that are like some well-known synthetic perfumes, such as rhubafuran, hexalon, and hyacinth body. Various research groups have utilized diverse ligands in their investigations, exploring the gold-catalyzed cycloisomerization of enynes and producing analogous cyclopropane-fused six-membered heterocyclic products [73 74 75 76].

Scheme 7

Gold-catalyzed bicyclic scent synthesis via cycloisomerization of oxygen-tethered enynes.

According to Calleja et al. (Scheme 8) [77], 1,6-enyne 24 undergoes a cyclization/1,5-OR migration/cyclopropanation reaction under gold catalysis to produce a tricyclic molecule 25. Given that racemization does not occur in the cascade reaction, it is not possible for propargyl carbocations to form. To synthesize (+)-schisanwilsonene A with better enantiomeric purity, this has been used to prepare important intermediates. Based on density functional theory (DFT) calculations, the 1,5-OR migration seems to move stepwise through a cyclic intermediate 26 after the first cyclization, even though the cleavage occurs through a low barrier.

Scheme 8

Sequential cyclization, migration, and cyclopropanation in dienynes.

Karunakar et al. have recently devised a method for accessing the tetrahydrobenzo[h]cyclopropa[c]-chromenes 28 through the cycloisomerization of 1,6-ene-diynes 27 catalyzed by gold (Scheme 9) [78]. Regioselective yields of ≤92% tetrahydrobenzochromenes fused with cyclopropane were achieved. Three new C–C bonds were successively produced in one pot during this atom-economic biological transition. The reaction progresses through cycloisomerization of enyne with gold, producing the gold carbene intermediate 27′/1,2-hydride shift/deauration/6-endo-dig cyclization.

Scheme 9

Au-catalyzed tandem cycloisomerization and 6-endo-dig cyclization of ene-diynes.

3.2.1.2 Cyclopropanation via cycloisomerization of 1,5-enynes

The enantioconvergent direct 1,5-enyne 29 cycloisomerization and kinetic resolution [79] are part of a new Au(iii)-catalyzed process shown in Scheme 10. The reaction also creates 1,5-enynes 31 that are optically more abundant and highly enantioenriched bicyclo[3.1.0]-hexenes 30 at all conversion levels without causing any racemization or symmetrization. Primarily, this finding provides proof for the exceptional capability of Au(iii) complexes in enantioselective catalysis. It is also the first time that a very selective enantioselective conversion has been made possible by a carefully studied cationic Au(iii) catalyst.

Scheme 10

Enantioconvergent cycloisomerization and kinetic resolution of 1,5-enynes catalyzed by Au(iii).

Davies synthesized tetracyclic compounds 33 by a C–H insertion or cyclization cascade of N-homoallyl ynamides 32, catalyzed by Au(picolinate)Cl₂. The generation of N-homoallyl ynamides 32 resulted in considerable diastereoselectivity in most cases (Scheme 11) [80].

Scheme 11

The C–H insertion/cyclization cascade of N-allyl ynamides catalyzed by gold.

The reaction is likely to occur along the gold keteniminium 34 pathways, which involves [1,5] hydride transfer to create benzylic cation 35. A 4π electrocyclic ring closure (4π ERC) process can result in the formation of the gold complex 36, and cyclopropanation can complete the cascade reaction.

Wei et al. have developed a cycloisomerization reaction using Au(i) catalysts to convert easily accessible 1,5-enynes 37 with a cyclopropane ring into biscyclopropane 38. This reaction has demonstrated moderate to good yields, as reported in Scheme 12 [81]. Through the manipulation of temperature and the choice of gold(i) catalyst, it is possible to selectively synthesize three different products that possess an ortho substituent. The required products are made by changing the key intermediate, tricyclic cyclobutene. This is done by first applying a standard enyne cycloisomerization reaction to the 1,5-enyne substrate.

Scheme 12

Au(i)-mediated cycloisomerization of cyclopropyl 1,5-enynes.

3.2.2 Cyclopropanation through cycloisomerization of allenynes

The production of 1-naphthylcyclopropane-fused benzoheterocycle derivatives 41 was observed by Ohno’s group via the reaction of benzoheterocycles 40 with benzene-tethered 5-allenynes 39, as depicted in Scheme 13a and b [82]. In this transition, benzofuran 40 engages in an attack on the vinyl cation 42 that was formed earlier. The attack takes place at either the 2-position or 3-position of benzofuran 40. When the ring closes, aromatization and protodeauration occur, and the heterocycle is in the axial position that is least affected by steric hindrance. This yields either (E)-43 or (Z)-43. This process ultimately leads to the production of the regioselective product 41a.

Scheme 13

(a) Gold(i)-catalyzed 5-allenynes cycloisomerization to 1-naphthylcyclopropane systems and (b) possible reaction mechanism.

3.2.3 Cycloisomerization of diynes via migration of 1,2- and 1,3-acyloxy groups

The tandem cycloisomerization, or 1,2-OAc shift, of trienynes 44, which incorporates a propargylic ester, was reported by the Gagosz group. This reaction was catalyzed by Au(i). Because of this, divinyl cyclopropanes 45 were made, and these then went through a thermal Cope rearrangement that created a complex polycyclic structure 46 (Scheme 14) [83].

Scheme 14

Tandem Au(i) catalyst cycloisomerization/cope rearrangement.

By reacting styrene 47 with propargyl ester 48 as a model reaction, Reiersølmoen et al. reported employing Bis(pyridine)Au(iii) complexes as catalysts for the synthesis of vinyl cyclopropanes 49 (Scheme 15) [84]. They confirmed that the catalytic activity of Au(iii) is critically dependent on the electron density of the pyridine ligands. It appears that one pyridine must dissolve to produce the active species because ligands that have electron-withdrawing groups are noticeably more active. The use of ¹⁵N NMR (nuclear magnetic resonance) data confirmed the discovery. Furthermore, the application of DFT modeling elucidated that the energy associated with the pivotal transition state was contingent upon the electron density present on the nitrogen atom of the pyridine ligand. The same research group investigated the impact of various nitrogen ligands coordinated to gold salts in the cyclopropanation reaction involving styrene and propargyl ester [85,86].

Scheme 15

Au(i)-catalyzed enantioselective styrene cyclopropanation with propargylic esters.

Beginning with simple starting materials, ester-tethered terminal 1,6-diyne 50 and an alkene 51, the Hashmi group disclosed a unique synthesis method for producing cyclopropylnaphthalene derivatives 52 (Scheme 16a) [87]. A gold-catalyzed process involving the reaction of propargyl esters with a tethered alkynylphenyl group produced key intermediate naphthylcarbene complexes 53. Following the formation of the unusual carbene complex by a 1,2-carboxylate shift, an alkyne insertion produces a new naphthylcarbene complex. The next step is cyclopropanation with an alkene additive to capture this new complex. A smooth reaction inside the molecule of 1,6-diyne 54 attached to an alkene part also made the required cyclopropylnaphthalene derivatives 55 with a moderate yield (Scheme 16b). Notably, no competing enyne cyclization was seen, suggesting that the naphthyl carbenoid forms quickly. The research teams led by Oh [88] and Hashmi [89] delved into the significant role of gold carbenoids (formed by 1,2-carboxylate shift) in the cycloisomerization reaction of propargylic esters connected to alkyne motifs, aiming to produce naphthylene derivatives.

Scheme 16

(a) Intermolecular cyclopropanation of 1,6-diynes using gold catalysis and alkene. (b) Intramolecular cyclopropanation of 1,6-diynes pendant with alkenes.

In a study conducted by Rao, Chan, and colleagues, the authors detail the synthesis of tetracyclodecene and tetracycloundecene compounds 57. We made these chemicals by a series of steps that included an Au(i)-catalyzed tandem 1,3-acyloxy migration and double cyclopropanation of 1-ene-4,9-diyne and 1-ene-4,10-diyne esters 56 (Scheme 17) [90].

Scheme 17

Sequential tandem 1,3-migration and dual cyclopropanation in 1-ene-4,n-diyne esters.

3.3 Cyclopropanation by an oxygen-transfer agent via the oxidation of alkynes

Yeom and Shin showed that oxidative cyclopropanation of 1,6-enynes 58 with a propiolamide moiety attached could occur inside the molecule, creating cyclopropane carboxaldehydes 59 (shown in Scheme 18) [91]. In oxidative cyclopropanation, substrates containing terminal alkynes were initially utilized to produce cyclopropane carboxaldehydes, which possessed unique applications because of their aldehyde functionality. Diphenyl sulfoxide worked well as an oxidant for this kind of substrate, as opposed to pyridine-N-oxides, and this has been shown to have a broad universality about alkenes.

Scheme 18

Intramolecular cyclization for cyclopropane formation in 1,6-enynes.

The Zhang group reported a catalytic asymmetric oxidative cyclopropanation of 1,6-enynes 60 in 2014. Because of this reaction, densely functionalized bicyclo[3.1.0]hexanes 63 were made, which had a lot of enantioselectivity (Scheme 19 [92]). A highly effective gold(i) complex with cationic properties was successfully synthesized, utilizing ligand 62. To facilitate the reaction, 8-methylquinoline N-oxide 61 was selected as the external oxidizing agent.

Scheme 19

Asymmetric gold-catalyzed oxidative cyclopropanation of 1,6-enyne.

Ji et al. [93] developed a method for the enantioselective oxidative cyclization of 1,5-enynes 64, resulting in the formation of cyclopropane fused bicyclic derivatives 65 (Scheme 20). In order to achieve effective enantiocontrol, a hemilabile P,N-ligand [94,95] 66 containing a C2-symmetric piperidine ring was strategically developed. According to the existing literature, it has been suggested that piperidine offers a favorable chiral environment as a result of its capacity to coordinate with the metal center’s nitrogen atom and provide steric shielding. This helps mitigate the high reactivity of the highly electrophilic α-oxo gold carbene intermediate [96,97]. The approach performed by the Echavarren research team has been previously applied to produce enantioenriched 1,5-enyne 64, which was then utilized in the overall synthesis of (−)-nardoaristolone B 67 [98].

Scheme 20

Asymmetric Au-catalyzed oxidative cyclopropanation in 1,5-enynes.

Employing a conformationally rigid P,N-bidentate ligand 70, Zhang and colleagues reported a highly efficient three-step intramolecular cyclopropanation of alkyne tethered enals 68 to bicyclic or tricyclic functionalized cyclopropyl ketones 69 (Scheme 21) [99]. The reaction was completed with largely good yields. When considering step economy and operational safety, this reaction exhibits favorable comparisons to similar approaches that rely on the diazo approach.

Scheme 21

Gold-catalyzed synthesis of bi- and tricyclic cyclopropyl ketones through oxidative cyclizations.

The first-ever gold-catalyzed oxidative cyclopropanation of N-allyl ynamides 71 was reported by Li et al. The catalyst used in this process was [(IMes)AuCl]/AgBF4, and the oxidant employed was pyridine N-oxide 72. This reaction yielded diverse variants of 3-aza-bicyclo[3.1.0]hexan-2-one 73 (Scheme 22) [100]. Mechanistic studies were conducted to investigate the potential participation of the α-oxo gold carbene as an intermediary. The results of these tests indicated that the α-oxo gold carbene is not involved, hence suggesting that the alkene attacks the electrophilic β-oxypyridinium vinyl gold(i) species 74.

Scheme 22

Gold-catalyzed oxidative cyclopropanation of N-allylynamides.

Because of overoxidation, the oxidative cyclization of ynamides with aromatic substituents rich in electrons at the alkynes terminal was not tolerable. By utilizing various reaction circumstances, Davis and his team were able to solve this concern (Scheme 23) [101]. Diketone 76 was made when N-allylynamides 75 with a tosyl substituent connected to nitrogen went through oxidative cyclization in 1,2-DCE. The cyclopropanation product 77 in nitromethane, on the other hand, was made by oxidative cyclization of N-allylynamides 75, which had a mesyl substituent connected to nitrogen. An instance of Au(i)-catalyzed yne-ynamide with pendant alkene undergoing cascade reactions involving cyclization, oxidation, and intramolecular cyclopropanation was recently reported by the Hashmi group utilizing diphenyl sulfoxide [102].

Scheme 23

Oxidation of electron-rich ynamides by gold catalyst.

This study by Davies and his team showed how N-benzyl ynamides 78 react with oxygen in a Buchner-type way. This reaction creates [5.3.0] azabicycles 79′ (Scheme 24) [101]. The NMR technique effectively demonstrated the presence of a dynamic equilibrium between cyloheptatriene and norcaradiene. The synthesis of Polycycle 80 involved the utilization of a Diels–Alder reaction to capture the norcaradiene tautomer 79b, resulting in its formation. Conversely, the norcaradiene product 79a was obtained exclusively. It is easy to obtain benzyl propargyl ethers, which were used successfully by Ji and Zhang in their study to make a gold-catalyzed oxidative cyclization report of a similar nature [103].

Scheme 24

Intramolecular oxidative cyclopropanation of N-benzyl ynamides.

Zhang and others described a method to mix molecules called intermolecular cyclopropanation. They used 2-(tert-butyl)-6-chloro pyridine N-oxide as an outside oxidant to make α-oxo gold carbene from sulfonyl alkyne moiety 81 (Scheme 25) [104]. At first, carbene 84 is made when the carbon atom next to the alkyne group undergoes oxidation at the β position. A plausible chemical mechanism and this synthesis support the expected regioselectivity. Episulfone 85 would result from a Friedel–Crafts-style attack on the highly electrophilic carbene center, and it would fragment into α-oxo gold carbene 86 through SO₂ extrusion. It is important to highlight that the oxidation of an internal aryl alkyne is the exclusive approach to generating the resulting carbene as the lesser regioisomer.

Scheme 25

Gold-catalyzed intermolecular oxidative cyclopropanation.

The study focused on styrenes that were electronically unbiased, and a surplus of these styrenes, ten times greater than the required amount, was employed. Reactants with a significant electron density, such as 4-methoxystyrene or ethyl vinyl ether, were considered unfavorable. Instead of utilizing cyclopropane, the solvent α-methylstyrene resulted in the formation of a (3 + 2) cycloaddition product.

3.4 Oxidative cyclopropanation of alkynes with nitrogen-transfer agents

The first cyclopropanation that made cyclopropane-fused indanimines 90 (Scheme 26) was reported by Liu and colleagues [105]. They used α-imino gold carbene intermediates from earlier research on the oxidative cyclopropanation of 1,5-enynes 87 [106]. The application of iminopyridinium ylides, specifically compound 89, as nucleophilic nitrenoids is observed. The nitrenoids discussed here are nitrogen-based compounds that share similarities with pyridine N-oxides. Pyridine N-oxides are frequently used as oxidizing agents in the field of α-oxo gold carbenes.

Scheme 26

Gold-catalyzed intramolecular cyclopropanation of 1,5-enynes with iminopyridinium ylides.

The delivery of cyclopropane-fused indoloquinolines 92 was reported by Ohno et al. through the reaction of (azido)-ynamides 91 with tethered alkenes, as depicted in Scheme 27 [107]. The α-imino gold carbene 93 played a critical role in the transformation of the ynamide. This was done by the azide attack inside the molecules, which caused the loss of nitrogen and the cyclopropanation of the alkene that was present around.

Scheme 27

Intramolecular cyclopropanation of azidoynamides.

As part of their study, Hashmi et al. showed that adding external nitrene transfer reagents made α-imino gold carbenes more useful for intramolecular cyclopropanations of ynamides 94. By cutting N–S and attacking gold-activated ynamides across molecules, they made α-imino gold carbenes 97 using N-arylsulfilimines 95 (Scheme 28) [108]. The compound 3-azabicyclo[3.1.0] is of hexan-2-imines 96 and can be synthesized with high yields by employing various methods [109], including the utilization of a tethered alkene as one of the approaches. For the effective progression of the reaction, an electron-withdrawing group is attached to the arene of the sulfilimines, and a temperature of 80°C is necessary. Furthermore, it has been discovered that Au(iii) catalysts with Lewis acidity demonstrate superior efficiency in comparison to Au(i) catalysts.

Scheme 28

Intermolecular cyclopropanation of ynamides using sulfilimines.

After that, the Hashmi group showed that ynamides 94 could turn into 99 under milder conditions by using different nucleophilic nitrenoids, namely anthranils 98 (Scheme 29) [110].

Scheme 29

Anthranil-mediated intramolecular cyclopropanation of ynamides.

In this instance, the reaction might continue at room temperature with a catalytic quantity of NaAuCl₄ dihydrate. A related work with α-imino gold carbenes is worth mentioning, as it allowed the creation of bicyclic compounds fused with cyclopropane in certain situations [111].

3.5 Gold-mediated synthesis of cyclopropanes containing heteroatom

Additionally, heterocyclic 3-membered rings such as aziridines and epoxides were produced under gold(i) catalysis in several mechanistic contexts.

The group demonstrated that reacting 3-hydroxybenzofurans 101 with 2H-azirines 102 under gold catalysis generates aziridines 103 (Scheme 30) [112].

Scheme 30

Synthesis of aziridines from 2H-azirines via gold catalysis.

In their important work, Sahani and Liu provided a full explanation of the intermolecular (4 + 2) cycloaddition reaction involving benzisoxazoles 105 and electron-poor alkynes 104, specifically propiolates. The use of gold catalysis in this process led to the formation of tetrahydroquinolines 107, which possess an epoxide ring. This reaction is illustrated in Scheme 31 [113].

Scheme 31

Oxirane synthesis from benzisoxazoles under Au-catalysis.

Hashmi’s group used electron-rich alkynyl amines in a similar manner [114]. This led to the construction of a novel switchable approach that allowed for the synthesis of quinoline epoxides (containing an Au(iii) complex) or 6-acylindoles (containing an Au(i) complex) from the same two substrates by selecting the appropriate gold catalyst.

4.1 Formation of four-membered rings via cyclopropyl ring expansion

The Echavarren group has reported a diastereoselective Au(i)-catalyzed cascade transformation. In this process, a cyclopropyl group is changed into a cyclobutane through a series of chemical reactions that include ring expansion, enyne cyclization, and Prins cyclization. In particular, the change is made to cyclopropyl 1,6-enynes 109, which creates tricyclic compounds with a decahydrocyclobuta[a]pentalene skeleton 110. These compounds exhibit a syn/anti/syn relationship. Following this, the tricyclic compounds are changed into the natural product Repraesentin F 111 in six steps (Scheme 32) [127].

Scheme 32

Synthesis of cyclobutanes via Au-catalyzed expansion of cyclopropanes access to repraesentin-F.

The tricyclic core [128] belonging to the protoilludanes family was successfully obtained by a one-step process utilizing a closely comparable Au(i)-catalyzed allene-vinylcyclopropane cycloisomerization.

Shi et al. [81] documented the cycloisomerization of 1,5-enynes 112, which were tethered with a cyclopropyl group, using divergent gold(i) catalysis (Scheme 33). Cyclobutane-fused 1,4-cyclohexadienes 114 were synthesized in cases where the aryl group did not possess ortho-substitution, as depicted in Scheme 33a. The ortho-substitution of the aryl group facilitated the generation of a switchable protocol. Under controlled temperature conditions, three unique polycyclic scaffolds were synthesized using a suitable gold catalyst. The scaffolds encompass spiro compound 116, fused-cyclobutane-conjugated cyclohexadiene 115, and tricyclic cyclobutene 117. The synthesis was carried out according to Scheme 33b–d, respectively. Both labeling investigations and computational analysis were employed to demonstrate that the ortho-substituent effect played a crucial role in determining the transformation of the common biscyclopropane Au(i) carbene intermediate 113 into different products.

Scheme 33

Gold-catalyzed transformation of 1,5-enynes with cyclopropyl group into (a) cyclobutane-fused 1,4-cyclohexadiene; (b) 1,3-cyclohexadiene; (c) biscyclopropane; (d) tricyclic cyclobutene derivatives.

The Gagne group reported cyclic 1,5-dienes 118 undergoing Cope rearrangement and cyclopropane ring expansion under gold(i) catalysis to synthesize tricyclic compounds 119 (Scheme 34) [129].

Scheme 34

Cycloisomerization of cyclopropylidene-tethered frameworks.

The enantioselective cycloisomerization/ring expansion procedure for cyclopropylidene-containing 1,5-enynes 120 was found by the Gagne research team. This process led to the formation of enantioenriched bicycle [4.2.0] octanes 122 with an enantiomeric excess of up to 70% (Scheme 35, right) [130]. The same group of researchers later found that aldehydes could effectively capture Au(i)-stabilized allyl cation intermediates 121, which led to the formation of oxo-carbenium cations. The cations we talked about earlier went through Friedel–Crafts annulation, which created polycyclic structures 123 through a cascade reaction with high diastereoselectivity (shown in Scheme 35, left) [131].

Scheme 35

Au(i)-Catalyzed synthesis of cyclobutane fused systems.

Carreira has successfully devised a process characterized by a high degree of diastereocontrol that enables the synthesis of cyclobutane derivatives 125 by the employment of Au(i)-catalyzed cyclo-isomerization of cyclic cyclopropylidene 1,5-enynes 124 in conjunction with a terminal alkyne. Harziane diterpenoid 126 (Scheme 36) was obtained through a series of 16 consecutive transformations, starting with the initial cyclobutane precursor [132].

Scheme 36

Cycloisomerization of cyclopropylidene1,5-enynes.

The Shi group made a big discovery about how ortho-substituents affect the phenyl group (R1) in the reaction between (propargyloxy)arenemethylenecyclopropanes 127 and an Au(i) catalyst that attracts electrons, specifically [(p-CF₃C₆H₄)₃PAuCl. This reaction exhibited chemodivergent results, as seen in Scheme 37 [133]. There have been observations in chemical reactions that when bulky substituents like t-Bu and t-Am are used, the methylene cyclopropane group moves instead of expanding. This leads to the creation of bicyclic products 129, as depicted in Scheme 37 on the left. Methoxy (MeO), halogens, or methyl (Me) groups are thought to be non-bulky and can help the ring become bigger and the propargyl group moves around. Au(i) facilitates the catalytic process, which results in the synthesis of 2,3-dihydrobenzofuran cyclobutane fused allene derivatives 131. The reaction is visually represented in Scheme 37, situated on the right-hand side.

Scheme 37

Regiodivergent cycloisomerization of cyclopropylidene 1,7-enynes catalyzed by Au(i).

In addition, Shi effectively developed a regiodivergent catalytic cyclization/ring opening sequence (Scheme 38) utilizing alkynylamide-tethered alkylidenecyclopropanes 132 [134]. In this case, the gold(i) catalysts utilized resulted in the formation of two unique types of fused 4-membered rings, namely cyclobutenes 134 and cyclobutanes 135. The cationic Au(i) catalyst’s ligand and counteranion were discovered to be significant factors in the distribution of the product. Cyclobutenes 134 were the only compounds produced when [(Ph₃P)AuCl] was employed in conjunction with AgOTf (Scheme 38, left). Cyclobutanes 135 was the lone product, however, because of using JohnPhos as a ligand with the BArF₄ counteranion (Scheme 38, right). It is possible for a Friedel–Crafts annulation to create spiropolycyclic cyclobutanes 135 from the Au(i)-stabilized carbocation 133 after the ring has grown. When intermediate 133 is deprotonated, cyclobutene 134 is obtained as an alternative.

Scheme 38

Cycloisomerizations of ynamide-cyclopropylidene 1,7-enyne.

Li and Yu used cyclopropylidene 1,6-enynes 136 as a starting point for the synthesis of azepine-fused cyclobutanes 137. As shown in Scheme 39 [135], a series of steps involving Au(i)-catalyzed cyclization, C–C cleavage, and Wagner–Meerwein rearrangement were necessary to achieve the result. The authors found that in this instance, the influence of both the counterion and the solvent enhanced enantioinduction. It was shown that AgSbF₆, toluene, and [(R)-4-MeO-3,5-(t-Bu)₂-MeOBIPHEP)(AuCl)₂] can improve the enantioselectivity of cyclobutane products 137 by as much as 99% ee. Noting the creation of spirocyclic molecule 137′ during the reaction is very important because it shows great chemoselectivity, especially when aryl groups lacking electrons are connected to the cyclopropylidene moiety.

Scheme 39

Enantioselective gold(i)-catalyzed cycloisomerization of cyclopropylidene 1,6-enynes.

Shi et al. reported a novel method of generating gold(i) carbenes based on vinylidenecyclopropanes’ ambiphilic properties. A vinylidene cyclopropane, like 138, is activated by gold(i) to produce cyclopropyl gold(i) intermediate 139, which then expands the ring to form Au(i) carbene 140 (Scheme 40) [136].

Scheme 40

Cycloisomerization of vinylidenecyclopropanes coupled with O-allyl and benzyl moieties.

When this method was used, the pendant alkene part of vinylidenecyclopropane-enes of type 138′ underwent cyclopropanation by temporary Au(i) carbenes 140′. Therefore, 3-, 4-, and 8-membered fused rings 141 (Scheme 40, left) were constructed in a single step [136]. Vinylidenecyclopropane-enes were the only ones that worked as substrates because they only bound to aromatic rings without ortho substitution. The researchers came up with new methods to achieve this. The Au(i) carbene that was made in the reaction mixture was very important in a process called intramolecular C(sp³)-H insertion. This resulted in the successful synthesis of the required fused cyclobutane products, denoted as 142. This was achieved by strategically modifying the pendant chain of vinylidene cyclopropanes, as depicted in Scheme 40 (right) [137].

4.2 Gold(i)-catalyzed 1,3-acyloxy migration in propargylic carboxylates

The challenge associated with the 1,3-acyloxy migration of 1,3-diarylpropargyl carboxylates under the influence of a gold(i) catalyst has been ascribed to the formation of uncharacterized amalgamations. In the context of the intermolecular synthesis of cyclobutanes 144b catalyzed by Au(i), as described by Shi et al., they developed a silver-free process that demonstrates both chemo- and regioselectivity. This methodology was employed to investigate the characteristics of the various products, as depicted in Scheme 41 [138]. Here, the intermolecular [2 + 2] cycloaddition between the in situ-produced allenes 143′ is catalyzed by gold(i). Only 1,4-enyne 144a was produced when silver was present (Scheme 41). On the other hand, depending on the catalyst selected and the carboxylate moiety’s substitution pattern, cyclobutane isomer 144b may be produced as the main product in a silver-free environment.

Scheme 41

Au(i)-mediated intermolecular 1,3-acyloxy shift followed by [2 + 2] cycloaddition.

Fiksdahl recently reported an isolated case of this reactivity in the context of [2 + 2 + 2] cyclotrimerizations catalyzed by Au(i) [139].

In the context of a computational modeling investigation on the structural properties of acyclic diaminocarbene ligands, an accompanying enantioselective reaction was performed. The goal of this reaction was to change indolyl substrates 145, which have a propargyl ester part, into complex tetracyclic scaffolds 146 (shown in Scheme 42) [140].

Scheme 42

Enantioselective Au(i)-catalyzed tandem rearrangement and cyclization of indolyl propargylic esters with acyclic diaminocarbene complexes.

It is easier to tell the difference between enantiomers when gold catalyst 147 is used with bigger alkyl groups on the alkyne moiety. In contrast, complex 148 demonstrates an inverse impact. In general, it can be observed that complex 147 exhibits superior enantioselectivity and yields compared to those of complex 148.

4.3 Gold(i)-catalyzed [2 + 2]-cycloaddition between allenes and alkenes

The efficacy of 3-(Propa-1,2-dien-1-yl)oxazolidin-2-one 149 as a suitable two-carbon partner in a full regio- and stereocontrolled intramolecular [2 + 2] cycloaddition with alkenes 150 has been established by López et al. As shown in Scheme 43, the presence of gold acts as a catalyst to facilitate this reaction. The formation of trans isomer 152 is independent of the alkene 150′s structure. The proposed mechanism entails a sequential cationic pathway characterized by the formation of cationic intermediates. The regioselectivity of the reaction is determined by the nucleophilic attack of the alkene on a second cationic intermediate 151. This attack favors the creation of a more stable benzylic or iminium cation [141]. An important discovery was made by Chen et al. about the catalytic properties of the chiral bis-1,2,3-triazol-5-ylidene diAu(i) complex 153 in a recent study. This complex has amazing catalytic properties that the researchers used to show how it can help make cyclobutanes selectively using a [2 + 2] cycloaddition process [142]. This ligand can be used with a wider range of substrates, such as different allenamide and alkene chemical counterparts.

Scheme 43

Gold-catalyzed allenamide-alkene [2 + 2] cycloaddition.

The asymmetric Au(i)-catalyzed cycloadditions of N-allenylsulfonamides 155 and 3-styrylindoles 154 were reported by Zhang and colleagues (Scheme 44) [143]. Here, it was discovered that the N-substituents’ electrical characteristics were responsible for switching the cycloaddition mode. The [4 + 2] cycloaddition reaction leading to the formation of tetrahydrocarbazole scaffolds 157 (Scheme 44, left) was facilitated by substituents with electron deficiency. Conversely, the [2 + 2] cycloaddition reaction resulting in the synthesis of 3-cyclobutylindole 156 (Scheme 44, right) was favored by substituents with electron-donating properties.

Scheme 44

Enantioselective [2 + 2] and [4 + 2] cycloaddition of 3-styrylindoles with allenamides.

Interestingly, it was discovered that employing the identical chiral phosphoramidite gold(i) catalyst allowed for diastereo- and highlyenantioselectivity in both routes. After that, a new method was created using a chiral Au(i) monophosphine catalyst to make the [2 + 2] cycloaddition process possible with N-allenyl oxazolidinone as the electrophilic reactant [144].

The Bandini group devised Scheme 45, an asymmetric technique for the dearomative [2 + 2] cycloaddition of 1,2-substituted indoles 160 and allenamides 161 [145,146]. To obtain very good chemo-, diastereo-, and enantioselectivity in the production of indolincyclobutanes 162, an electron-rich phosphine-based gold catalyst had to be used. In a previous paper, the same research group showed that indoles could selectively become C3-functionalized when they were exposed to an extremely electrophilic Au(i) catalyst, which is like the scaffolds used in this study [147].

Scheme 45

Enantioselective gold(i)-catalyzed [2 + 2] cycloaddition of indoles with allenes.

4.4 Gold(i)-catalyzed [2 + 2]-cycloadditions between alkynes and alkenes

Numerous studies have been conducted on the alkene–alkyne system to produce cyclobutanes, cyclobutenes, and cyclobutanones by intra- and intermolecular [2 + 2] cycloaddition [61]. With 1,6- [148–157], 1,7- [158–161], 1,8- [155,162,163], and 1,9-enynes [163] as substrates, many bicycles with four carbon rings have been formed. It was necessary to employ bulky phosphines, primarily biarylphosphines, as ligands for the majority of these unsaturated systems. Additionally, there have been documented instances of multiple situations involving the inclusion of macrocycles with ring sizes ranging from 9 to 15 members [164,165].

The access to cyclobutanones 166 is facilitated by the gold-catalyzed cycloisomerization of substituted 1,6-ene-ynamides 163, as described by Cossy [150,153] and Yeh (Scheme 46) [157]. This process involves the hydrolysis of the first formed cyclobutenes to obtain the desired cyclobutanones. The proposed mechanism for the formation of trimethylsilylanol involves the protonation of the double bond in the intermediate compound 164, which is a cyclobutene replaced with trimethylsilyl groups. This protonation event then triggers the removal of the trimethylsilyl group. The lack of rapid protosilylation in the presence of AuCl can be attributed to the behavior of trimethylsilyl-ynamides. The presence of H₂O leads to the transformation of component 165 into cyclobutanone 166.

Scheme 46

Cycloisomerization of trimethylsilyl-modified 1,6-ene-ynamide.

Furthermore, the formation of 6,6-diarylbicyclo[3.2.0]heptanes 169, which possess a quaternary core, is successfully accomplished by the utilization of a sequential gold-catalyzed cycloaddition/hydroarylation procedure involving 7-aryl-1,6-enynes 167. By using an arene 168 with a high electron density as the nucleophile, Scheme 47 [156] can perform the reaction. Many mono-, di-, and trisubstituted arenes have gone through this change, which creates diastereoisomer combinations in an endo/exo configuration. The ratios of these combinations vary from 1:7 to 25:1.

Scheme 47

Sequential gold-catalyzed [2 + 2] enynes’ cycloaddition and hydroarylation.

It is possible to selectively make substituted cyclobutenes by using Au(i) as an intermolecular catalyst in a [2 + 2] cycloaddition reaction with aromatic or aliphatic alkenes and terminal electron-rich alkynes. Kinetic measurements and DFT calculations support the mechanistic proposal. These results back up the idea that the rate-determining phase involves an associative ligand exchange between the gold-bound alkyne and the alkene. Additionally, the early intermediates are believed to be cyclopropyl Au(i) carbenes. The scope of the reaction includes reactions involving alkenes 171 and 1,3-butadiynes 172. When the highly substituted carbon of the alkene and the secondary carbon of the alkyne come into contact with each other, a chemoselective [2 + 2] cycloaddition reaction takes place. The only way this reaction can occur is through the terminal alkyne, which makes alkynyl cyclobutenes 172 (shown in Scheme 48) [166].

Scheme 48

Gold-catalyzed regioselective [2 + 2] 1,3-butadiyne cycloaddition with alkenes.

Similarly, alkenes 173 can combine with the equivalent 1,3-enynes 174 to produce 1-vinyl-3-substituted cyclobutenes 175 (Scheme 49) [167].

Scheme 49

Gold-catalyzed chemoselective alkene-diyne [2 + 2] cycloaddition.

Recently, it was reported that the [2 + 2] cycloaddition of unactivated monosubstituted alkenes 177 with chloroethynyls 176 has very good selectivity in certain regions. With 1,2-disubstituted unactivated alkenes, the reaction is essentially stereo-specific (Scheme 50) [168]. The fact that the 1-chlorocyclobutene derivatives 178 worked well as substrates in cross-coupling reactions shows that they are useful for making new things.

Scheme 50

Gold-catalyzed [2 + 2] cycloaddition of chloroalkynes with unactivated alkenes.

They used a gold catalyst with a Josiphos ligand and a [BAr₄F]⁻ counterion to show enantioselectivity for the first time. This catalyst was applied to di- and trisubstituted alkenes ranging from 180 to limit the formation of digold species, as seen in Scheme 51 [169]. The utilization of this technology in the enantioselective total synthesis of Rumphellaone A, a terpenoid known for its cytotoxicity against human tumor cells, is of particular significance as it involves a sequence of nine steps.

Scheme 51

Enantioselective [2 + 2] cycloaddition between trisubstituted alkenes and terminal alkynes.

Sparr et al. conducted an experimental investigation on the novel atropisomeric teraryl monophosphine ligand, Joyaphos, employing the same methodology as described in the study of Castrogiovanni et al. [170]. The study’s results show that using (Sa)-Ph₂JoyaphosAuCl and Cy₂JoyaphosAuCl with AgSbF6 can help the reaction occur, even though the yields aren’t very high and the enantioselectivity isn’t very good.

In a recent study, Echavarren et al. conducted research on the enantioselective synthesis of hushinone, a norsesquiterpenoid present in the essential oils obtained from Betula pubescens buds. The synthesis involved a series of 16 steps, resulting in a yield of around 1.1%. Additionally, they also successfully synthesized Rumphellaone A in 12 steps, achieving an approximate yield of 8% [165]. To synthesize the cyclobutene part 183, the 1,10-enyne 182 needs to be diastereoselectively [2 + 2] macrocyclized with the help of Au(i) catalysis (Scheme 52).

Scheme 52

Crucial step strategy for the total syntheses of hushinone and rumellaone A.

Xu et al. have developed a convergent approach utilizing pinacol rearrangement and Au(i)-catalyzed [2 + 2] enyne 184 cycloaddition. This method enables the formation of the central bridging tricyclic BCD ring system found in norditerpenoid alkaloids, specifically Racemulsonine (Scheme 53) [160].

Scheme 53

Synthesis of the bridged tricyclic BCD ring system core.

4.5 Gold(i)-mediated alkyne [2 + 2]-cycloadditions

With gold catalysis, 1,n-diynes have not been utilized nearly as frequently as 1,n-enynes. Every scenario given involves the formal [2 + 2] cycloaddition-mediated evolution of an allene molecule from its initial production.

Gold can be used as a catalyst to convert 1,7-diyn-3,6-bis(propargyl) carbonates 187 into functionalized naphtho[b]cyclobutenes 188 with great stereoselectivity. The double 3,3-rearrangement that forms bis(allenyl)carbonate 189 in the cascade sequence. The naphthyl derivative 190, which is produced via a 6π-electrocyclic reaction and can be thought of as a highly stabilized biradical 191, is then followed by cyclobutenyl dicarbonate 192 when it spontaneously cyclizes (Scheme 54) [171]. At last, 188 is obtained through a decarbonylative cyclization (pathway A). On the other hand, approach B suggests that the allenic group attacks the gold-activated allene with a nucleophilic attack inside the molecule, which creates oxocarbenium.

Scheme 54

Gold-catalyzed diyne [2 + 2] cycloaddition for naphtho[b]cyclobutene formation.

Alternatively, the intramolecular gold-catalyzed cycloisomerization of stable alkylidene tethered diynes 194 can be utilized to facilitate the production of cyclobutene-fused azepines 195. A viable mechanism, shown in Scheme 55, has been developed based on the findings obtained from the 1H NMR investigation. A single pair of electrons on the nitrogen atom facilitates a 6-endo-dig attack, which is how the reaction starts. This attack results in the nucleophilic addition of an alkene to an activated alkyne.

Scheme 55

[2 + 2] Gold-catalyzed Diyne cycloaddition to cyclobutene-fused azepines.

An allylic cation, 197, is produced by cleavage of the C–N bond, 196, and then demetallation to form the allene, 198. Finally, the activation of the vicinal alkyne [172] causes a [2 + 2] cycloaddition with the former allene.

Chan et al. investigated the cycloisomerization of 1,6-diyne esters 199 through 1,3-migration[2 + 2]-cycloaddition. This reaction resulted in the selective formation of bicyclo[3.2.0]hepta-1,5-dienes 200 (Scheme 56) [173].

Scheme 56

Synthesis of alkylidencyclobutenes by [2 + 2] Diynes cycloaddition.

4.6 Heteroatom-incorporating 4-membered ring synthesis

The approach to creating 4-membered rings, including O and N atoms, was devised by Zhang. This was achieved by utilizing the intramolecular insertion capacity of α-oxo gold carbenes into N–H and O–H bonds. The carbenes discussed in this study are generated from alkynes via a gold(i)-catalyzed intermolecular oxidation process [174].

A viable approach for the synthesis of oxetan-3-ones [175], 202, and 204 was devised by utilizing propargylic alcohols 201 [176] that are easily available. The synthesis was conducted under ambient air conditions, employing pyridine N-oxides as oxidizing agents and catalytic quantities of Au(i) complexes, as illustrated in Scheme 57 [177]. To mitigate potential side reactions arising from the generation of propargylic cations in an acidic environment, it was necessary to include an electron-withdrawing group at the alkyne terminus of tertiary propargylic alcohol substrates 203.

Scheme 57

Gold(i)-catalyzed formation of oxetan-3-ones via oxidative synthesis.

The disclosed technique (Scheme 58) was employed to successfully synthesize a drug discovery library of 419 spirocyclic oxetane-piperidine scaffolds. These scaffolds are considered significant motifs in the field of medicinal chemistry [178–180].

Scheme 58

Efficient gold(i)-catalyzed production of oxetane–piperidine system at scale.

Zhang et al. utilized a similar methodology in order to synthesize 208 from N-tert-butylsulfonyl propargylamines [181]. The requirement for acidic additives when working with secondary propargyl amine substrates was eliminated by utilizing a large Buchwald ligand and an electron-deficient, obstructed pyridine N-oxide, hence improving compatibility with functional groups.

Based on the previous research conducted by Ye et al. [181], a tripartite approach was developed to efficiently synthesize azetidin-3-ones 208 using readily available propargylic alcohols 207 (as shown in Scheme 59) [182]. A convenient and practical method for the synthesis of diverse azetidin-3-ones involves the oxidative cyclization of N-tosyl propargylamines with gold as the catalyst. Several other sulfonyl-protecting groups were found to be suitable for use in this process.

Scheme 59

Au(i)-catalyzed formation of azetidin-3-ones via oxidative synthesis.