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Review

Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020)

by
Sijia Chen
1,†,
Chongguo Jiang
1,†,
Nan Zheng
1,
Zhen Yang
1,2,3,* and
Lili Shi
1,*
1
State Key Laboratory of Chemical Oncogenomics and Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
2
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
3
Shenzhen Bay Laboratory, Shenzhen 518055, China
*
Authors to whom correspondence should be addressed.
†
Sijia Chen and Chongguo Jiang have contributed equally to this work.
Catalysts 2020, 10(10), 1199; https://doi.org/10.3390/catal10101199
Submission received: 23 September 2020 / Revised: 10 October 2020 / Accepted: 14 October 2020 / Published: 16 October 2020
(This article belongs to the Special Issue Metal Promoted Cyclocarbonylation Reactions in the Synthesis of Heterocycles)
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Abstract

:
Metal-mediated cyclizations are important transformations in a natural product total synthesis. The Pauson-Khand reaction, particularly powerful for establishing cyclopentenone-containing structures, is distinguished as one of the most attractive annulation processes routinely employed in synthesis campaigns. This review covers Co, Rh, and Pd catalyzed Pauson-Khand reaction and summarizes its strategic applications in total syntheses of structurally complex natural products in the last five years. Additionally, the hetero-Pauson-Khand reaction in the synthesis of heterocycles will also be discussed. Focusing on the panorama of organic synthesis, this review highlights the strategically developed Pauson-Khand reaction in fulfilling total synthetic tasks and its synthetic attractiveness is aimed to be illustrated.

Graphical Abstract

1. Introduction

The metal-mediated reaction plays an important role in constructing complex organic molecules [1,2,3]. The Pauson-Khand reaction (PKR), an effective set of annulation protocol defined in 1973 [4] for the construction of cyclopentenone-containing moieties, stands as a promising method to permit efficient cyclic frameworks. Its efficient and atom-economic elaboration to substituted cyclopentenones renders this process highly prized in the construction of architecturally complex natural products. Since reported more than 40 years ago [5,6,7,8,9,10,11,12], it has been developed with different metal catalytic systems, including Co [13,14,15,16,17], Rh [18,19,20,21,22,23,24,25], Ru [26,27,28,29,30], Ti [31,32,33,34], Ir [35,36,37], Ni [38], Mo [39,40], Fe [41]; and other metals could promote the PKR to build the heterocycle frameworks [42,43,44]. By identifying reactivity patterns for diverse PKR precursors in the prominent synthetic application, we aim to elevate this powerful reaction to a method of choice in the synthetic designation of complex biologically active entities.

1.1. Classic PK Reaction Catalyzed by Co

In 1973, I.U. Khand and P.L. Pauson found that the generation of enyne/Co2(CO)6 complex with olefin as substrates could lead to the formation of cyclopentenone. Moving forward, P.L. Pauson explored the substrate scope and limitations of this reaction [45]. Although the specific mechanism of PKR involving Co2(CO)8 is still uncertain, the mechanism proposed by Magnus [46,47,48] and Schore [49] is widely recognized based on the reaction results of regioselectivity and stereoselectivity (Scheme 1). The rate-determining step is alkene coordination with the cobalt and then insertion into cobalt–carbon bond to form the cobaltacycle, accounting for the regiochemical and stereochemical outcomes.
The regioselectivity of PKR is influenced by both steric and electronic effects (Scheme 2). For electrically neutral substrates, the insertion of olefins to enyne/Co2(CO)6 complex correlates with steric hindrance. The regioselectivity also has been demonstrated to be related to the electronegativity of alkynyl groups [50,51,52]. Under most circumstances, the electron-withdrawing group will be installed at the β position of cyclopentenone. It is noteworthy that the frontier molecular orbital (FMO) theory could be used to analyze the influence of olefins in PKR [53,54]. Moreover, subordinate interaction and the guiding group can affect the regioselectivity [55,56,57]. For allene-involved intramolecular PKR, a 5,7-bicyclic product is more inclined to be formed [58,59].
As for the diastereoselectivity of intramolecular PKR, both substrate conformation (especially the allyl chiral center) and electronic effect are relevant parameters (Scheme 3). Krafft reported their reaction with electron-deficient alkynes, and the PKR product could be obtained with a high dr value when norbornene was involved as an olefin substrate [51,60].
Most of the Co-catalyzed PKR conditions require a relatively high temperature and long reaction time. To accelerate the reaction rate, Smit and Caple’s group found that PKR could be promoted in a stepwise manner [61]. N-methylmorpholine oxide (NMO), acting as an additive, was reported to improve the reaction rate through oxidizing CO into CO2 on the enyne/Co2(CO)6 complex [62], forcing the cobalt to release a vacant orbital which can be coordinated with olefins [63]. Recently, the Dionicio Martinez-Solorio group demonstrated the value of 4-FBnSMe as a new, efficient, and recoverable/reusable thioether promoter in PKR by modulating the Lewis basicity of thioether to influence the rate of alkene insertion [64].
To circumvent the use of stoichiometric catalysts, some Lewis bases were discovered to achieve the catalytic version of PKR, such as phosphine ligand [65], tetramethyl thiourea [66], phosphane sulfide [14], and primary amines [67]. In 2005, the Milet and Gimbert groups converted to the density functional theory (DFT) and calculated the energy change of the PKR process with Lewis base [68]. The results indicate that the enyne/Co2(CO)6-alkene insertion is a reversible process, but the Lewis base coordination could reduce the energy and therefore make the olefin insertion process irreversible.

1.2. PK Reaction Catalyzed by Rh and Pd

The first example of [RhCl(CO)2]2 catalyzed PKR was reported by Narasaka et al. in 1998 [18]. In their studies, the use of toluene as a reaction media reduced the loading of Rh catalysts and a good reaction reactivity was achieved with electron-deficient alkynes [69]. Moreover, under a low partial pressure of CO, it can effectively speed up the reaction and decrease the reaction temperature. Jeong et al. reported the first case of rhodium-catalyzed asymmetric PKR in the presence of 2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl(BINAP) and AgOTf [21]. Consiglio’s group used the molecular sieve to adsorb CO, greatly reducing the reaction temperature and accelerating the rate [70]. They accomplished the asymmetric PKR at 0 °C with a 99% ee value. In the course of Wender and his co-workers’ studies on the rhodium(I)-catalyzed intra- and intermolecular dienyl [2 + 2 + 1] PKR, they observed that when a diene was used in place of an alkene the reaction rate was significantly accelerated [71,72].
As the Rh-catalyzed PKR has several advantages, it has attracted the attention of many research groups to report their work in this area. Typical PKR requires the utilization of highly toxic CO gas. An important breakthrough was made by the Morimoto and Shibata groups, respectively by introducing metal carbonyl compounds as a masked CO source through transition metal decarbonylation to in situ generate CO in PKR [73]. Moreover, Chung’s group developed the use of a highly beneficial cinnamyl-alcohol as a CO source in the presence of the Rh catalyst to obtain corresponding hetero-Pauson-Khand (hPK) products in an inexpensive, safe, and environmentally friendly manner [74]. The catalytic dehydrogenation of cinnamyl alcohol could produce cinnamaldehyde, followed by Wilkinson decarbonylation and carbonylation constructed the desired cyclic product. Benzyl formate [75] has also been exploited as a non-gas CO surrogate. In 2019, they further demonstrated the utilization of the formic acid as a CO source in the formation of various bicyclic cyclopentenones. In their protocol, formic acid was employed as a bridging molecule for the conversion of CO2 to CO, which represented an indirect approach for the chemical valorization of CO2 in the construction of valuable heterocycles [76] (Scheme 4).
The theoretical analysis of Rh-catalyzed PKR diastereoselectivity was demonstrated by Baik’s group [25]. They revealed that two possible mechanistic scenarios and the optimum selectivity could be attributed to a five-coordinate organorhodium complex. The larger energy gap between the diastereomers and the Rh meta-cyclization trend to occur at the cis-position site dominated the diastereoselectivity. Based on the high efficiency, reliability and excellent diastereoselectivity of Rh-catalyzed PKR, its extraordinary impact on the synthetic campaign as a key step has been recognized [77].
Few metals could be applied in the catalytic PKR (Co, Ti, Rh, Ir, Ru) as most of them are air and moisture sensitive, and as such, it accounted for some limitations in synthetic applications. A series of thiourea and Pd-catalyzed reactions were developed by Yang’s group [78,79,80,81] (Scheme 5). PdCl2 coordinated to a thiourea ligand could catalyze an intramolecular PKR under mild conditions [81,82], and some interesting features were observed in this novel step. It could be catalyzed by PdCl2 alone with a low yield, whereas using thiourea, especially tetramethyl thiourea (TMTU), as a reaction additive could greatly increase the yield; the Lewis acids addition such as LiCl can increase both the reaction rate and yield. Based on this observed phenomenon, further DFT calculation and mechanism investigation were carried out [83]. According to the coordination mode of the transition state, the TMTU ligand and substrate are lying both on the same side of the Pd catalyst thus the trans-diastereomer in substituted cases outperformed its diastereoisomer. It is speculated that changes in thiourea ligands may affect the diastereoselectivity of PKR through steric effect and π-π interaction, etc.

1.3. Hetero-Pauson-Khand Reaction

The hetero-Pauson-Khand reaction has been harnessed as an effective tactic in the concise construction of functionalized polycyclic butenolides and α, β-unsaturated lactams (Scheme 6). In 1996, Crowe et al. reported the direct synthesis of bicyclic γ-butyrolactones via tandem reductive cyclization-carbonylation of tethered enals and enones [84,85]. In the same year, Buchwald et al. presented the heteroatom variant of the intramolecular PKR catalyzed by Cp2Ti(PMe3)2, in which the alkene could be replaced with a carbonyl for the diastereoselective synthesis of γ-butyrolactones or a fused butenolide, respectively [86,87]. Later on, chemists devoted themselves in the development of hetero-Pauson-Khand reaction, including Murai [28,88], Carretero [89], Saito [90], and Snapper [91]. However, the application of hPK in a natural product total synthetic work is relatively rare and therefore is underexplored in the synthetic version [92,93,94,95,96].

1.4. Summary

Cobalt, rhodium, and palladium were involved in PK reactions represented in different advantageous patterns, among which the outstanding superiorities are as follows: a. Cobalt-catalyzed PKRs can overcome the high tension and construct an all-carbon quaternary chiral center [7,97,98,99]; b. rhodium-catalyzed PKRs normally exhibit excellent diastereoselectivity and are attractive in building a variety of ring structures; c. palladium-catalyzed PKRs could lead to the opposite stereoselectivity compared with others and are more operable due to the stability of Palladium species. Co/Rh-catalyzed PKRs are already widely applied in natural products total syntheses, in contrast, restriction existed in Pd-catalyzed PKRs and most of the work is still under methodological study.
The stereoselective formation of quaternary chiral centers is challenging in the construction of the cyclic system. PKR is an effective method for generating 5,5-bicyclic ring systems and has already been studied comprehensively. In 1984, Schore’s group reported the first case of PKR to construct a 5,5,5-tricyclic skeleton containing an all-carbon quaternary chiral center [100]. Numerous research groups reported their studies and applications in natural products total syntheses. Joseph M. Fox et al. applied a thiourea-facilitated PKR in establishing the quaternary center and built a 5,5,3-tricyclic framework, and then completed the enantioselective total synthesis of (−)-pentalenene [101]. In the past few years, many chemists have made their efforts to broaden the application of the intramolecular PKR in natural products total syntheses, with some reviews already published [5,6,7,8,9,10,11,12]. In this mini-review, a perspective on the development of strategic Pauson-Khand reaction within natural products total syntheses portfolio over the past five years is presented by the categories of the constructed bicyclic ring systems (5,5/5,6/5,7- and macrocycles), with the aim to provide an updated overview of its tremendous power and versatility.

2. Recent Pauson-Khand Reaction Applications in Natural Products Total Syntheses

PKR proved to be a powerful strategy in natural products syntheses, particularly in those containing fused five-membered rings. The tethered length plays an important role in the efficiency and viability of all intramoleculars.
Pauson-Khand-like reactions [102], and the substrates with tethers that result in the formation of a five-membered ring are most effective in a great variety of intramolecular reactions [103]. Collections of 5,5/5,6/5,7-bicyclic ring systems or even macrocycles could be accessed depending on substrate identity as shown in this review.

2.1. Construction of 5,5-Bicyclic Ring Systems

Ryanodol is a bioactive and complex poly-alcohol containing natural product which is a potent modulator of the calcium release channel [104,105]. In 2016, Reisman’s group reported a highly efficient way to rapidly build the carbon framework of ryanodol through intramolecular PKR which was promoted by the rigidity of the bicyclic conformation [106]. Starting from S-pulegone, the PK precursor 1 could be achieved after seven steps of transformation. In their promising reaction protocol, submitting 1 with 1 mol% [RhCl(CO)2]2 under an atmosphere of CO afforded enone 2 in an 85% yield as a single diastereomer. More impressively, the efficient protocol could be performed on the multi-gram scale and provided a 5.7 g of PK product (Scheme 7).
Tetramethyl thiourea (TMTU) has proven to be an efficient additive in the PKR based on Yang’s previous investigations [66]. In 2017, they developed a Co–TMTU catalyzed PKR and 6π electrocyclization tandem reactions to construct the highly strained core skeleton of presilphiperfolanols and related natural products [107,108]. Treatment of 3 with a catalytic amount of [Co2(CO)8] (0.2 equiv.) and TMTU (1.2 equiv.) in benzene resulted in the rapid construction of the tricyclic scaffold 5 with great regio- and stereochemical control in a 94% yield through one single operation. Most recently, they applied this PKR model to the synthesis of 4-desmethyl-rippertenol and 7-epi-rippertenol [109] (Scheme 8).
In the total synthesis of the potent antibiotic compounds (−)-crinipellin A and (−)-crinipellin B reported by Yang et al. [97], the fully functionalized tetraquinane core was achieved by a novel thiourea/palladium-catalyzed PKR. They implemented two PKRs in their synthetic strategy with the first being a conversion of 6 into 7 with a 40% yield and 98% ee after crystallization. As generally proved, the electron-deficient alkyne is not a perfect ligand for Co2(CO)8, gradual warming is essential for constructing the desired enyne/Co2(CO)6 complex. The other PKR allows the concise formation of the tetraquinane 10. Treatment of 8 in the presence of NaHCO3 as the base provided the desired tetraquinane core 10 in a 61% yield, with the undesired isomer suppressed to a 16% yield (Scheme 9).
In 2018, Yang’s group described a stereoselective construction of the CDEFGH ring system of lancifodilactone G acetate and a 28-step asymmetric total synthesis [110,111]. They performed an intramolecular PKR for the construction of the sterically congested F ring. In their model study, the authors observed that the butynoic ester was effective for the regio- and stereoselectivity in constructing the cyclopentenone ring system bearing two chiral centers. The developed well-orchestrated PKR facilitated the stereoselective synthesis of 14 from enyne 13 (Scheme 10).
Li et al. reported the first total synthetic work of hybridaphniphylline B featuring a late-stage intermolecular Diels–Alder reaction [112]. They implemented a PKR and C=C bond migration strategy to achieve the key intermediate 17. Through the investigation of Pauson-Khand conditions, it is determined that MeCN is an effective accelerator to transform the alkyne dicobalt complex into the desired product, which was depicted the same as Pauson’s work [113]. Under this condition, the two PKR products 16 and 16’ were constructed in a 73% yield with the ratio of ca. 2.4:1. Then, submitting the mixture to K2CO3/TFE realized the C=C bond migration and gave the more substituted enone 17 (Scheme 11).
Liang et al. described a concise total synthesis towards (−)-indoxamycins A and B, a novel class of polyketide natural products, which contain a highly congested cage-like carbon skeleton featuring six contiguous chiral centers [114]. The key step for rapidly constructing the framework bearing a quaternary carbon was an intramolecular PKR. Enyne 18 was converted into the 5,5,6-tricyclic compound 19 smoothly with a 74% yield, which could be further transformed into the target natural products (Scheme 12).
Guaianolide sesquiterpenes represent a particularly prolific class of terpene natural products, which have attracted biological and chemical communities for decades given their extensive documented therapeutic properties and fascinating chemical structures. Recently, the cobalt- mediated intramolecular PKR was applied in the total synthesis of sinodielide A and ent-absinthin by Mainone et al. [115]. Ester 20, converted from (−)-linalool via deprotonation and a subsequent reaction with the mixed anhydride of 2-butynoic acid, underwent a smooth PKR reaction using Co2(CO)8 and resulted in strained bicyclic lactone 21 (65% yield, 5:2 d.r.), which enabled concise and collective total syntheses of guaianolide sesquiterpenes (Scheme 13).
Yang et al. recently described the first asymmetric total synthesis of (−)-spirochensilide A featuring a tungsten-mediated cyclopropene-based PKR to install the quaternary chiral center [116]. Initially, they attempted various conditions to construct the cyclopentenone motif in 24 but all proved in vain presumably due to the low reactivity of enyne 23 and its steric rigidity. Recognizing the inherent of a chloride, they employed it as an σ electron-withdrawing group to promote polarization and reduce the activation barrier, with the idea in hand they prepared chloroenyne 25. However, reaction conditions screening only resulted in the undesired ring-closing compounds 26 and 27, respectively, which was generated by an Rh-catalyzed carbonylative C-H insertion and a double bond isomerization followed by a PKR. Then, they considered taking advantage of cyclopropene’s inherent strain and altered the pathway to construct enyne 28. After an investigation of many conditions, the W(CO)3(MeCN)3, Ni(COD)2/bipy, and Mo(CO)3(DMF)3-catalyzed PKR could lead to the formation of the desired 29a, which could be further transformed into (−)-spirochensilide A (Scheme 14).
Very recently, Yang and Snyder’s group both reported their total synthesis towards the challenging target (+)-waihoensene [98,99], which contains four contiguous quaternary carbon centers. In their strategies, they all involved a diastereoselective Conia-ene type reaction and an intramolecular PKR. The polycyclic skeleton of Waihoensene was achieved by the Co2(CO)8-mediated PKR under CO atmosphere (Scheme 15).
(−)-Conidiogenone B, (−)-conidiogenone, and (−)-conidiogenol feature a highly strained 6/5/5/5 tetracyclic core and 6-8 consecutive stereocenters. The concise total syntheses have been accomplished by Zhai et al. [117]. The key linear triquinane 38 was constructed as a single diastereomer in a 71% yield via a tandem Nicholas and amine-N-oxide-promoted PKR from 37 with the borane-methyl sulfide complex as the hydride source (Scheme 16).

2.2. Construction of 5,6-Bicyclic Ring Systems

Clark et al. elucidated an efficient 12-step synthesis of the marine alkaloid (−)-nakadomarin A [118], which contains a unique hexacyclic structure featuring fused 5-, 6-, 8-, and 15- membered rings and exhibits cytotoxicity against murine lymphoma L1210 cells, antimicrobial and inhibitory activity against cyclin-dependent kinase 4. The fused bicyclic enone 40 was constructed in a good yield and with an excellent ee value using the asymmetric cobalt-catalyzed PKR, which was developed by Hiroi et al. earlier before (Scheme 17).
In the Hao et al. studies toward the 10 step-synthesis of a novel limonoid perforanoid A [119], they investigated Rh-catalyzed intramolecular PKR to build the cyclopentenone ring. Under their optimum conditions, treatment of 42 in toluene for 3 h at a reaction concentration of 8 mM with [Rh(CO)2Cl]2 (7 mol%) as the catalyst gave 43 in 85% as a single isomer (Scheme 18).
Zard, Takayama, and Mukai groups have explored the diastereoselective study of intramolecular PKR in the context of Lycopodium alkaloids syntheses [120,121,122]. Based on their previous study, Trauner et al. used a similar strategy to synthesize enone 46 with the desired stereoselectivity, which was proposed through a chair-like conformation of intermediate 45 ensuing the bicycle [4.3.0] nonenone [123] (Scheme 19).
Nakamura et al. have accomplished the stereoselective total synthesis of (+)-marrubiin involving a CyNH2-promoted PKR and subsequent oxidative cleavage of the resultant cyclopentenone ring [124,125]. According to their DFT studies, the irreversible olefin insertion step is critical to the stereochemistry of PKR. The steric interaction could be avoided through a trans-fused chair−boat-like TS and therefore the exclusive isomer 48 was afforded (Scheme 20).
Yu et al. have developed an Rh(I)-catalyzed [3 + 2 + 1] cycloaddition of 1-ene/yne−vinylcyclopropanes (VCPs) and CO, which was used to construct 5,6-bicyclic advanced intermediate 50 from yne-VCP (±)-49 [126]. The advanced intermediate 50 can be transformed into Gao’s intermediate for the formal synthesis of gracilamine [127]. This cycloaddition provided a solution to construct the bridgehead quaternary carbon center. The diastereoselectivity was realized by the repulsion between the OTBS (TBS = t-butyldimethylsilyl) group and the vinyl moiety (Scheme 21).
In the synthesis of calcitriol, the active form of vitamin D3, Mourino et al. utilized the NMO promoted PKR to form the 5,6-bicyclic core 52 in a diastereoselective way [128]. Intermediate 52 underwent Si-assisted allylic substitution and some other transformations to complete the synthesis of calcitriol (Scheme 22).
Khan et al. delineated the collective total synthesis of iridolactones [129]. The newly constructed iridoid framework 54 was accomplished by a diastereoselective intramolecular PKR [130]. With the key intermediate 55 in hand, they demonstrated a general and simple route to access structurally divergent iridolactones (Scheme 23).
A fawcettimine-type Lycopodium alkaloid (+)-sieboldine A contains an unprecedented fused tetracyclic skeleton and has been found to inhibit acetylcholinesterase with an IC50 value of 2.0 μM [131]. Mukai et al. have applied PKR to afford the bicyclo [4.3.0] nonenone derivative 57 with high stereoselectivity with an ee value of 93% in their total synthesis of (+)-sieboldine A [132] (Scheme 24).
Since the hPKR variant is much less reported, Zhai et al. applied an interesting hPKR in the formal synthesis of (±)-aplykurodinone-1 [133]. The tricyclic framework 59 has been constructed with a 60% yield through expeditiously one-pot intramolecular hPKR followed by the desilylation sequence. The hPKR is relatively rare to be found in natural product synthesis, and this application provided worthwhile insights for expanding the scope and boundaries (Scheme 25).
(−)-Sinoracutine, isolated from Stephania cepharantha in 2010 [134], proves to be a promising template for new neuroprotective reagents intervention as it was shown to increase cell viability against hydrogen peroxide-induced damage in PC12 cells [135]. Structurally, it features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to acyclopentenone. In the first total synthesis of (−)-sinoracutine [136], Trauner et al. utilized intramolecular PKR under the oxidative condition as a key transformation to construct the tricycle product 61 from an enyne precursor 60. The reaction was carried out in the presence of N-oxide dihydrate together with Co2(CO)8. The resulting tricyclic product 61 allows the concise total synthesis of (−)-sinoracutine with several steps of transformations, including a Mandai–Claisen reaction to install the quaternary stereocenter (Scheme 26).
Cyanthiwigin type diterpenes are biologically important marine natural products mostly isolated from marine sponges Epipolasis reiswigi and Mermekioderma styx. Particularly, cyanthiwigin C and F show medium cytotoxicity against A549 cell lines [137]. In 2019, Yang et al. reported the total synthesis of 5-epi-cyanthiwigin I [138]. The key [5–6–7] tricarbocyclic fused core structure was constructed via a well-orchestrated Co-mediated intramolecular PKR, which has two cis-configured all-carbon quaternary chiral centers and an isopropyl group. Enyne 62 could be transformed into the tricyclic product 63 as the sole isomer in a 70% yield in the presence of a stoichiometric amount of Co2(CO)8 combined with NMO as the additive (Scheme 27).
Lycopodium alkaloids are neuropharmacologically valuable scaffolds for central nervous system drug discovery. Takayama et al. reported an asymmetric total synthesis of lycopoclavamine A via a strategy involving a stereoselective PKR and a stereoselective conjugate addition to construct a quaternary carbon center at C12 [139]. The cobalt-mediated intramolecular PKR afforded a desired bicyclic enone 65 in a high yield as well as good diastereoselectivity (Scheme 28).
Complex sesterterpenoids astellatol and astellatene were isolated from Aspergillus stellatus in 1989 [140], which feature highly congested and unusual pentacyclic skeletons and contain a unique bicyclo[4.1.1]octane moiety consisting of ten stereocenters and a cyclobutane containing two quaternary centers. In the total syntheses of (+)-astellatol and (−)-astellatene reported by Xu et al. [141], an intramolecular PKR was exploited to construct the 6,5-bicyclic core embedded in the right-wing scaffold. The desired hydrindane skeleton 67 was generated from enyne 66 with a promising yield and diastereoselectivity at the C7 quaternary carbon center (Scheme 29).
Porée et al. reported an elegant synthesis of allosecurinine, utilizing the W(CO)6-promoted oxa-hetero-Pauson–Khand reaction (oxa-hPKR) in the late stage. Despite a low yield, the results constituted the first example of applying the W(CO)6 complex in hPKR, constructing tetracyclic securinega alkaloid featuring an α, β-unsaturated γ-lactone moiety [142] (Scheme 30).
The calyciphylline B-type alkaloids with a unique hexacyclic framework exhibited a variety of important pharmacological potentials. In the synthesis of daphlongamine H, Sarpong et al. used a late-stage cobalt-mediated PKR to accomplish the 6,5-bicyclic segment. The R configuration of C6 in the PKR enabled the desired 10-H α orientation in the PK product 70 [143] (Scheme 31).

2.3. Construction of 5,7 Bicyclic Ring Systems

Thapsigargin (Tg1) and its analogs are biologically important candidates as potent inhibitors of the SERCA-pump protein, with the potential of application in a variety of medicinal areas [144,145]. Numerous attempts have been reported on the total synthesis of this bioactive molecule [146,147,148]. In 2019, Sorin et al. developed a linear route towards the core of Tg1, which features an allene-yne Rh(I)-catalyzed Pauson-Khand annulation (APKR) as key transformation [149]. The allene-yne precursor was generated from chiral propargylic alcohol 71, which underwent a Ti(II) mediated reductive coupling to form diol 72. The allene-yne product 73 was elaborated in several steps. The central feature was identified to be the Rh(I)-catalyzed Pauson-Khand annulation (APKR), resulting in the efficient synthesis of the Tg 1 framework bearing an enol ether moiety in a 71% yield (Scheme 32).
Bufospirostenin A, isolated in 2017 from the toad Bufo bufo gargarizans, is an unusual steroid with rearranged A/B rings, possessing a cardioactive effect and promoting blood circulation through causing a 43% inhibition of Na/K ATPase (NKA) at 25 μM [150]. Very recently, a unique intramolecular rhodium-catalyzed PKR of an alkoxyallene-yne substrate was applied to construct the key [5,6,7] A-B ring system in the first total synthesis of bufospirostenin A reported by Li et al. [151]. Generated from Hajos-Parish ketone, alkyne 74 underwent 1,2-addition to afford precursor 75, which further yielded tetracyclic product 76 catalyzed by [RhCl(CO2)]2 in the presence of a balloon pressure of CO in toluene with a high yield (85%). This work represented the first example of an intramolecular Pauson−Khand reaction of an alkoxyallene-yne in natural product synthesis (Scheme 33).

2.4. Construction of Macrocycles

The synthesis of macrocyclic natural products and related structures through a direct C-C bond formation is challenging. Widely applied methodologies include ring-closing metathesis (RCM), Nozaki-Hiyama-Kishi (NHK) reaction, and intramolecular Diels-Alder reactions. PKR has been used and confined in the synthesis of medium-sized rings (up to 11 atoms) [152,153], thus not yet been extended to macrocycles (Scheme 34).
Spring et al. reported their investigation of PKR for macrocyclization of a template substrate 79 [154]. After fluorous solid-phase extraction (F-SPE), optimized PKR conditions produced a mixture of structurally unusual macrocycles containing a cyclopentenone motif; these can be separated by HPLC, but they used the mixture in the modified phase (Scheme 35).

3. Summary and Outlook

The extraordinary impact of the Pauson-Khand reaction on synthetic methods is still recognized nowadays, and attempts are currently undertaken to further extend the use of various metal-assisted chemistry to environmentally friendly processes within the strongly invoked green chemistry paradigm. The PKR, especially when conducted in an intramolecular fashion, has been widely used as a convenient and powerful tool for the construction of cyclopentenone structural units in natural product synthesis. Though the classical PK cycloaddition has the shortcoming that requires high temperatures and a long reaction time, chemists have developed a range of promoters (TMTU/NMO/TMAO = trimethylamine N-oxide, etc.) to circumvent this situation. Moreover, PKR has the merit of well tolerance to a broad variety of functional groups, such as alcohols, ethers, thioethers, esters, nitriles, amines, amides, sulfonamides, etc. With the impressive developments in the catalytic version of the Pauson–Khand reaction, the application will be more facilitated. Additionally, 4,5-fused bicycles afforded by intermolecular PKR patterns are still called for intensive studies.

Author Contributions

Conceptualization, S.C. and C.J.; data collection S.C. and C.J.; writing—original draft preparation, S.C. and C.J.; writing—review and editing, S.C., C.J., N.Z., Z.Y. and L.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Key Research and Development Program of China (grant no. 2018YFC0310905); National Science Foundation of China (grant nos. 21632002 and 21801123); and Shenzhen Basic Research Program (grant nos. 2019SHIBS0004, JCYJ20170818090044432, and JCYJ20180302180215524).

Acknowledgments

Research activities in related areas in Yang’s lab are financially supported by the National Key Research and Development Program of China (grant no. 2018YFC0310905); National Science Foundation of China (grant nos. 21632002 and 21801123); and Shenzhen Basic Research Program (grant nos. 2019SHIBS0004, JCYJ20170818090044432, and JCYJ20180302180215524).

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 10 01199 sch001 550
Scheme 1. Generally accepted mechanism of Pauson-Khand reaction with Co2(CO)8.
Scheme 1. Generally accepted mechanism of Pauson-Khand reaction with Co2(CO)8.
Catalysts 10 01199 sch001
Catalysts 10 01199 sch002 550
Scheme 2. Regioselectivity study of Pauson-Khand reaction.
Scheme 2. Regioselectivity study of Pauson-Khand reaction.
Catalysts 10 01199 sch002
Catalysts 10 01199 sch003 550
Scheme 3. Diastereoselectivity study of intramolecular Pauson-Khand reaction.
Scheme 3. Diastereoselectivity study of intramolecular Pauson-Khand reaction.
Catalysts 10 01199 sch003
Catalysts 10 01199 sch004 550
Scheme 4. Non-gas CO surrogates in the Pauson-Khand reaction for heterocycle’s formation.
Scheme 4. Non-gas CO surrogates in the Pauson-Khand reaction for heterocycle’s formation.
Catalysts 10 01199 sch004
Catalysts 10 01199 sch005 550
Scheme 5. Tetramethyl thiourea (TMTU) and Pd-catalyzed Pauson-Khand reaction.
Scheme 5. Tetramethyl thiourea (TMTU) and Pd-catalyzed Pauson-Khand reaction.
Catalysts 10 01199 sch005
Catalysts 10 01199 sch006 550
Scheme 6. Hetero-Pauson-Khand reaction in natural products total syntheses.
Scheme 6. Hetero-Pauson-Khand reaction in natural products total syntheses.
Catalysts 10 01199 sch006
Catalysts 10 01199 sch007 550
Scheme 7. Reisman’s total synthesis of (+)-ryanodol.
Scheme 7. Reisman’s total synthesis of (+)-ryanodol.
Catalysts 10 01199 sch007
Catalysts 10 01199 sch008 550
Scheme 8. Yang’s concise synthesis of presilphiperfolane core.
Scheme 8. Yang’s concise synthesis of presilphiperfolane core.
Catalysts 10 01199 sch008
Catalysts 10 01199 sch009 550
Scheme 9. Yang’s total synthesis of crinipellins.
Scheme 9. Yang’s total synthesis of crinipellins.
Catalysts 10 01199 sch009
Catalysts 10 01199 sch010 550
Scheme 10. Yang’s asymmetric total synthesis of lancifodilactone G acetate.
Scheme 10. Yang’s asymmetric total synthesis of lancifodilactone G acetate.
Catalysts 10 01199 sch010
Catalysts 10 01199 sch011 550
Scheme 11. Li’s total synthesis of hybridaphniphylline B.
Scheme 11. Li’s total synthesis of hybridaphniphylline B.
Catalysts 10 01199 sch011
Catalysts 10 01199 sch012 550
Scheme 12. Liang’s total synthesis of (−)-indoxamycins A and B.
Scheme 12. Liang’s total synthesis of (−)-indoxamycins A and B.
Catalysts 10 01199 sch012
Catalysts 10 01199 sch013 550
Scheme 13. Maimone’s allylative approaches to the synthesis of complex guaianolide sesquiterpenes.
Scheme 13. Maimone’s allylative approaches to the synthesis of complex guaianolide sesquiterpenes.
Catalysts 10 01199 sch013
Catalysts 10 01199 sch014 550
Scheme 14. Yang’s asymmetric total synthesis of (−)-spirochensilide A.
Scheme 14. Yang’s asymmetric total synthesis of (−)-spirochensilide A.
Catalysts 10 01199 sch014
Catalysts 10 01199 sch015 550
Scheme 15. Yang’s and Snyder’s total synthesis of (+)-waihoensene.
Scheme 15. Yang’s and Snyder’s total synthesis of (+)-waihoensene.
Catalysts 10 01199 sch015
Catalysts 10 01199 sch016 550
Scheme 16. Zhai’s total synthesis of (−)-conidiogenone B.
Scheme 16. Zhai’s total synthesis of (−)-conidiogenone B.
Catalysts 10 01199 sch016
Catalysts 10 01199 sch017 550
Scheme 17. Clark’s total synthesis of (−)-nakadomarin A.
Scheme 17. Clark’s total synthesis of (−)-nakadomarin A.
Catalysts 10 01199 sch017
Catalysts 10 01199 sch018 550
Scheme 18. Hao’s asymmetric total synthesis of perforanoid A.
Scheme 18. Hao’s asymmetric total synthesis of perforanoid A.
Catalysts 10 01199 sch018
Catalysts 10 01199 sch019 550
Scheme 19. Trauner’s expedient synthesis of (+)-lycopalhine A.
Scheme 19. Trauner’s expedient synthesis of (+)-lycopalhine A.
Catalysts 10 01199 sch019
Catalysts 10 01199 sch020 550
Scheme 20. Nakamura’s total synthesis of (+)-marrubiin and (−)-marrulibacetal.
Scheme 20. Nakamura’s total synthesis of (+)-marrubiin and (−)-marrulibacetal.
Catalysts 10 01199 sch020
Catalysts 10 01199 sch021 550
Scheme 21. Yu’s formal synthesis of gracilamine.
Scheme 21. Yu’s formal synthesis of gracilamine.
Catalysts 10 01199 sch021
Catalysts 10 01199 sch022 550
Scheme 22. Mourino’s total synthesis of calcitriol.
Scheme 22. Mourino’s total synthesis of calcitriol.
Catalysts 10 01199 sch022
Catalysts 10 01199 sch023 550
Scheme 23. Khan’s total synthesis of several iridolactones.
Scheme 23. Khan’s total synthesis of several iridolactones.
Catalysts 10 01199 sch023
Catalysts 10 01199 sch024 550
Scheme 24. Mukai’s enantioselective total synthesis of (+)-sieboldine A.
Scheme 24. Mukai’s enantioselective total synthesis of (+)-sieboldine A.
Catalysts 10 01199 sch024
Catalysts 10 01199 sch025 550
Scheme 25. Zhai’s formal synthesis of (±)-aplykurodinone-1.
Scheme 25. Zhai’s formal synthesis of (±)-aplykurodinone-1.
Catalysts 10 01199 sch025
Catalysts 10 01199 sch026 550
Scheme 26. Trauner’s enantioselective synthesis and racemization of (−)-sinoracutine.
Scheme 26. Trauner’s enantioselective synthesis and racemization of (−)-sinoracutine.
Catalysts 10 01199 sch026
Catalysts 10 01199 sch027 550
Scheme 27. Yang’s stereoselective total synthesis of (±)-5-epi-cyanthiwigin I.
Scheme 27. Yang’s stereoselective total synthesis of (±)-5-epi-cyanthiwigin I.
Catalysts 10 01199 sch027
Catalysts 10 01199 sch028 550
Scheme 28. Takayama’s asymmetric total synthesis of lycopoclavamine-A.
Scheme 28. Takayama’s asymmetric total synthesis of lycopoclavamine-A.
Catalysts 10 01199 sch028
Catalysts 10 01199 sch029 550
Scheme 29. Xu’s asymmetric total synthesis of (+)-astellatol.
Scheme 29. Xu’s asymmetric total synthesis of (+)-astellatol.
Catalysts 10 01199 sch029
Catalysts 10 01199 sch030 550
Scheme 30. Porée’s enantioselective synthesis of (−)-allosecurinine.
Scheme 30. Porée’s enantioselective synthesis of (−)-allosecurinine.
Catalysts 10 01199 sch030
Catalysts 10 01199 sch031 550
Scheme 31. Sarpong’s total synthesis of (−)-daphlongamine H.
Scheme 31. Sarpong’s total synthesis of (−)-daphlongamine H.
Catalysts 10 01199 sch031
Catalysts 10 01199 sch032 550
Scheme 32. Sorin’s synthesis of a thapsigargin core.
Scheme 32. Sorin’s synthesis of a thapsigargin core.
Catalysts 10 01199 sch032
Catalysts 10 01199 sch033 550
Scheme 33. Li’s asymmetric total synthesis of bufospirostenin A.
Scheme 33. Li’s asymmetric total synthesis of bufospirostenin A.
Catalysts 10 01199 sch033
Catalysts 10 01199 sch034 550
Scheme 34. Synthetic strategy for medium-sized rings.
Scheme 34. Synthetic strategy for medium-sized rings.
Catalysts 10 01199 sch034
Catalysts 10 01199 sch035 550
Scheme 35. Spring’s synthetic strategy for structurally diverse and complex macrocycles.
Scheme 35. Spring’s synthetic strategy for structurally diverse and complex macrocycles.
Catalysts 10 01199 sch035
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Chen, S.; Jiang, C.; Zheng, N.; Yang, Z.; Shi, L. Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020). Catalysts 2020, 10, 1199. https://doi.org/10.3390/catal10101199

AMA Style

Chen S, Jiang C, Zheng N, Yang Z, Shi L. Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020). Catalysts. 2020; 10(10):1199. https://doi.org/10.3390/catal10101199

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Chen, Sijia, Chongguo Jiang, Nan Zheng, Zhen Yang, and Lili Shi. 2020. "Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020)" Catalysts 10, no. 10: 1199. https://doi.org/10.3390/catal10101199

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