catalysts Review Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020) 1, 1, 1 1,2,3, 1, Sijia Chen y, Chongguo Jiang y, Nan Zheng , Zhen Yang * and Lili Shi * 1 State Key Laboratory of Chemical Oncogenomics and Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; [email protected] (S.C.); [email protected] (C.J.); [email protected] (N.Z.) 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 * Correspondence: [email protected] (Z.Y.); [email protected] (L.S.) Sijia Chen and Chongguo Jiang have contributed equally to this work. y Received: 23 September 2020; Accepted: 14 October 2020; Published: 16 October 2020 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. Keywords: metal-mediated reactions; Pauson-Khand reaction; cyclopentenones; natural products total syntheses 1. Introduction The metal-mediated reaction plays an important role in constructing complex organic molecules [1–3]. 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 [5–12], it has been developed with different metal catalytic systems, including Co [13–17], Rh [18–25], Ru [26–30], Ti [31–34], Ir [35–37], Ni [38], Mo [39,40], Fe [41]; and other metals could promote the PKR to build the heterocycle frameworks [42–44]. 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 Catalysts 2020, 10, 1199; doi:10.3390/catal10101199 www.mdpi.com/journal/catalysts Catalysts 2020, 10, x FOR PEER REVIEW 2 of 25 CatalystsIn 1973, 2020, 10I.U., x FORKhand PEER and REVIEW P.L. Pauson found that the generation of enyne/Co2(CO)6 complex2 of with 25 olefin as substrates could lead to the formation of cyclopentenone. Moving forward, P.L. Pauson exploredCatalystsIn2020 1973, the, 10 substrate ,I.U. 1199 Khand scope and andP.L. Pauslimitationson found of thatthis thereaction generation [45]. Although of enyne/Co the2(CO) specific6 complex mechanism with2 of 25 olefin as substrates could lead to the formation of cyclopentenone. Moving forward, P.L. Pauson of PKR involving Co2(CO)8 is still uncertain, the mechanism proposed by Magnus [46–48] and Schore [49]explored is widely the substrate recognized scope based and limitationson the reaction of this resultsreaction of [45]. regioselectivity Although the andspecific stereoselectivity mechanism explored the substrate scope and limitations of this reaction [45]. Although the specific mechanism of (Schemeof PKR involving1). The rate-determining Co2(CO)8 is still uncertain,step is alkene the mechanismcoordination proposed with the by cobalt Magnus and [46–48] then insertion and Schore into PKR[49] involvingis widely Co recognized2(CO)8 is still based uncertain, on the the reaction mechanism results proposed of regioselectivity by Magnus [and46– 48stereoselectivity] and Schore [49 ] cobalt–carbon bond to form the cobaltacycle, accounting for the regiochemical and stereochemical is(Scheme widely recognized1). The rate-determining based on the reactionstep is alkene results coor ofdination regioselectivity with the and cobalt stereoselectivity and then insertion (Scheme into1 ). outcomes. Thecobalt–carbon rate-determining bond to step form is alkene the cobaltacycle, coordination acco withunting the cobaltfor the and regiochemical then insertion and into stereochemical cobalt–carbon bondoutcomes. to form the cobaltacycle, accounting for the regiochemical and stereochemical outcomes.R2 O R2 R2 C R1 3 OC CO R R2 R1 R2 2 -CO 2 OC CoO Co CO R1 R R1 R Co(CO) Co(CO) R1 Co(CO) OC C CO 3 3 3 OC -2CO R3 Co CO 1 2 +CO CO C R R 1 -CO 1 alkene OC CoO Co CO R Co R Co CO (CO)3 Co(CO)3 (CO)2Co(CO)3 3 CO Co(CO)3 OC -2CO coordination R C - - +CO - o CO- 18 e complexC 18 eCocomplex 16 eCocomplex alkene 18 e complex O (CO) (CO) 3 2 coordination R3 CO - - - alkene- 18 e complex 18 e complex 16 e complex 18 e complex1 2 insertion R <R alkene+CO R1 <R2 R2 insertionR2 +CO (CO)3Co(CO)3 O 2 2 Co R1 R R1 R 1 3 R 2 Co(CO)3 Co(CO)3 2 R -Co (CO) (CO)R3Co(CO)3 +CO R O 2 6 Co R1 Co(CO)3 R1 1 Co(CO) Co(CO)Co(CO)3 3 R O2 3 3 R2 R -Co2(CO)6 R +COCO 1 3 Co(CO) 3 R 3 R 3 insertion R R O Co(CO)3 O CO R1 183 e- complex insertion 183 e- complex R3 R O R 18 e- complex 18 e- complex 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. The regioselectivity regioselectivity of of PKR PKR is isinfluenced influenced by byboth both steric steric and and electronic electronic effects eff ects(Scheme (Scheme 2). For2). electricallyFor electricallyThe regioselectivity neutral neutral substrates, substrates, of PKR the is theinsertion influenced insertion of byofolefins olefinsboth stericto to enyne/Co enyne and /electronicCo2(CO)2(CO)6 6complex effectscomplex (Scheme correlates correlates 2). Forwith with stericelectrically hindrance. hindrance. neutral The The substrates,regioselectivity regioselectivity the insertion also also has has beenof been olefins demonstrated demonstrated to enyne/Co to to be be2(CO) related related6 complex to to the the electronegativitycorrelates electronegativity with ofsteric alkynylalkynyl hindrance. groupsgroups [The50 [50–52].– 52regioselectivity]. Under Under most most also circumstances, hascircumstan been demonstrated theces, electron-withdrawing the electron-withdrawing to be related to groupthe electronegativity willgroup be installedwill be installedatof the alkynylβ position at the groups β position of cyclopentenone.[50–52]. of cyclopentenone. Under Itmost is noteworthy circumstan It is noteworthy thatces, thethe that frontierelectron-withdrawing the frontier molecular molecular orbital group (FMO)orbital will theory(FMO) be theorycouldinstalled becould used at the be to β used analyzeposition to theofanalyze cyclopentenone. influence the influence of olefins It is noteworthyof in PKRolefins [53 inthat,54 PKR]. the Moreover, frontier[53,54]. molecular subordinateMoreover, orbital subordinate interaction (FMO) interactionandtheory the guidingcould and be groupthe used guiding canto analyze affect group the the regioselectivity can influence affect ofthe [olefins55 regioselectivity–57]. in For PKR allene-involved [53,54]. [55–57]. Moreover, For intramolecular allene-involved subordinate PKR, intramolecularainteraction 5,7-bicyclic and product PKR, the a is guiding5,7-bicyclic more inclined group product tocan be isaffect formed more the inclined [58 regioselectivity,59]. to be formed [55–57]. [58,59]. For allene-involved intramolecular PKR, a 5,7-bicyclic product is more inclined to be formed [58,59]. SchemeScheme 2. 2. RegioselectivityRegioselectivity study study of of Pauson-Khand Pauson-Khand reaction. reaction. reaction. As for the diastereoselectivity of intramolecular PKR, both substrate conformation (especially the allyl chiral center) and electronic effect are relevant parameters (Scheme3). Kra fft 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]. Catalysts 2020, 10, x FOR PEER REVIEW 3 of 25 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 Catalystsreaction2020 with, 10, electron-deficient 1199 alkynes, and the PKR product could be obtained with a high dr value3 of 25 when norbornene was involved as an olefin substrate [51,60]. Scheme 3. Diastereoselectivity study of intramolecular Pauson-Khand reaction. Scheme 3. Diastereoselectivity study of intramolecular Pauson-Khand reaction. Most of the Co-catalyzed PKR conditions require a relatively high temperature