Metal-catalyzed enyne cycloisomerization in natural product total synthesis

Ying Hu a, Miao Bai a, Ying Yang a and Qianghui Zhou *ab
aCollege of Chemistry and Molecular Sciences, Wuhan University, 430072, Wuhan, P.R. China. E-mail: qhzhou@whu.edu.cn
bThe Institute for Advanced Studies, Wuhan University, 430072, Wuhan, P.R. China

Received 7th August 2017 , Accepted 16th September 2017

First published on 18th September 2017


Since the seminal work of B. M. Trost et al. in 1985, metal catalyzed enyne cycloisomerization has become a fast growing and fascinating field. Due to its diversified chemistry and ability to increase molecular complexity in an efficient, atom economical, step economic and redox economic way, enyne cycloisomerization has become a powerful and attractive strategy for the construction of cyclic compounds, and thus has great potential for applications in total synthesis of natural products and pharmaceuticals. In this review, a brief summary of the state-of-the-art mechanism studies, the classification of structures accessed through enyne cycloisomerizations, and recent completed total synthesis of representative natural products showcasing creative and ingenious incorporation of enyne cycloisomerization as a strategic manoeuver are included, with the aim of providing a complement to the existing reviews to inspire future developments.


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Ying Hu

Ying Hu grew up in Anhui Province, China. He received his B.Sc. degree in Chemistry from Anhui University of Science & Technology in 2012. After earning his M.Sc. degree from Xiamen University under the guidance of Prof. Eric Meggers and Prof. Lei Gong in 2015, he joined Prof. Qianghui Zhou's group at Wuhan University as a research assistant. One year later, he became Prof. Zhou's Ph.D. student. His research focuses on total synthesis of furanosteroid natural products.

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Miao Bai

Miao Bai was born in Taiyuan, Shanxi, China. He obtained his B.Sc. degree in Pharmaceutical Engineering from Ningxia University in 2016. In the fall of 2016, he began graduate study at Wuhan University under the direction of Prof. Qianghui Zhou. His research focuses on total synthesis of bioactive natural products.

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Ying Yang

Ying Yang was born in Jiangxi Province, China. He just got the B.Sc. degree in Chemistry from Wuhan University in 2017. In the fall of this year, he will start his graduate research under the guidance of Prof. Qianghui Zhou in Wuhan University. His research interest is total synthesis of bioactive natural products and novel synthetic methodology development.

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Qianghui Zhou

Qianghui Zhou grew up in Hunan Province, China, and received his B.S. from Peking University in 2005. He pursued graduate study under the guidance of Professor Dawei Ma at Shanghai Institute of Organic Chemistry and earned his Ph.D. degree in 2010. He then took a postdoctoral position in the laboratory of Professor Phil S. Baran at the Scripps Research Institute. In June 2015, he began his independent career in the College of Chemistry and Molecular Sciences of Wuhan University. His lab currently focuses on developing new strategies and methodologies for the synthesis of complex natural products and other biologically important molecules.


1. Introduction

According to the stringent requirements of green chemistry1 and sustainable development of human society, economy,2 practicality (reliability),3 efficiency,4 and diversity5 have become the essential elements in organic synthesis of the 21st century, particularly in natural product total synthesis. Matching these standards requires organic chemists to practice with excellent selectivity (chemo-,6 regio-, and stereo-selectivity) and economy (atom-,2a–c step-,2d,e and redox-economy2f) etc. A successful total synthesis should provide the target molecule and structural related derivatives efficiently and in practical amounts, which highly depends on the strategies or methodologies used.3,4

Among the recent methodological advances, metal-catalyzed 1,n-enyne cycloisomerizations undoubtedly occupy a commanding position and have revolutionized the synthetic field in an unprecedented manner.7 Since the seminal work of B. M. Trost et al. in 1985,8 metal-catalyzed 1,n-enyne cycloisomerizations have made the transition from emerging methodologies to fully established synthetic techniques that are used routinely in research laboratories around the world.7,9 The metal-catalyzed 1,n-enyne cycloisomerization is among the most important strategies for the synthesis of functionalized cyclic structures, e.g. cyclized 1,3- or 1,4-dienes, in an inherently atom economical way.2a–c The significance of this process stems from the rapid increase in structural complexity starting with relatively simple acyclic precursors containing ene and yne fragments. A range of metal complexes and salts are capable of catalyzing enyne cycloisomerizations to deliver a diverse array of cyclic products under mild conditions, with excellent chemoselectivity and high synthetic efficiency even on a large scale. Thus, they meet many of the stringent criteria imposed upon contemporary organic synthesis.1 Due to possessing the above promising characteristics, metal-catalyzed 1,n-enyne cycloisomerizations have become one of the most successful systems for synthetic applications.7 Excellent reviews and book chapters which have compiled different aspects of the advances in enyne cycloisomerizations have been published.7,9

With the aim of providing a complement to the existing reviews and book chapters to inspire future developments of this field, this designated review will cover a brief summary of the state-of-the-art mechanism studies, the classification of structures accessed through enyne cycloisomerizations, and recent completed total synthesis of representative natural products showcasing creative and ingenious incorporation of enyne cycloisomerization as a strategic manoeuver.

2. Metal-catalyzed enyne cycloisomerizations-basic mechanistic aspects

Since the seminal work of B. M. Trost et al.,8 a huge step forward in metal-catalyzed enyne cycloisomerization has been made.9 Various 1,n-enynes have been demonstrated to undergo cycloisomerization in the presence of several metal complexes and salts through different reaction pathways to give functionalized carbo- or heterocycles, creating a large structure diversity and complexity.

Considering the mechanistic rationale of the metal-catalyzed cycloisomerization of 1,n-enynes, different pathways can be considered depending on the enyne substrate selected, the choice of the catalyst, and the reaction conditions. Generally, the complexation of the metal to an alkene or alkyne motif allows the activation of either both moieties or only one of them. Depending on the interaction modes of the 1,n-enyne substrate and the catalyst, five typical mechanisms are proposed.7d,9c,j,10

As depicted in Scheme 1, the simultaneous complexation of both the triple and double bonds led preferentially to the metallacycle intermediate Ia through an oxidative coupling event (the oxidation state of the metal center increased two numerically), which is called “oxidative cyclometalation mechanism” (pathway I). On the other hand, when a metal hydride was applied as the catalyst, the reaction proceeds through a hydrometalation of the alkyne moiety first, thus leading to a vinylmetal intermediate Ib, which is reactive enough to allow the carbometalation of the neighboring olefin. This is called “vinyl metal mechanism” (pathway II). The third pathway called “π-allyl–metal complex mechanism” features a π-allyl complex (intermediate Ic, pathway III), which is favored if an appropriate substitution at the allylic position is present, could further react with the triple bond. There is normally no skeletal rearrangement of enynes in pathway I–III.


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Scheme 1 The mechanisms involving no skeletal rearrangement of enyne.

The left two mechanisms are based on a metal carbene complex (mostly ruthenium, tungsten or molybdenum species) (pathway IV) and alkynophilic metal complex (gold, platinum, silver, copper species, etc.) (pathway V), respectively, involving a skeletal rearrangement of 1,n-enyne. As depicted in Scheme 2, the fourth pathway is actually an intramolecular enyne metathesis, and the metal carbene species IIa or IIb is the key intermediate to form the exo-type product 1 or endo-type product 2 correspondingly. The fifth pathway is catalyzed by alkynophilic metal complexes, and metal carbene species IIc or IId is the key intermediate to form the exo-type product 1 or endo-type product 2 correspondingly.


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Scheme 2 The mechanisms involving the skeletal rearrangement of enyne.

A brief discussion of the established mechanisms of metal-catalyzed cycloisomerizations of 1,n-enynes will be presented in the following part of this review by organizing the text on the basis of the intermediate Ia–Ic and IIa–IId involved in the cyclization and then further subdivided according to their reactivity. In each case, an illustration of representative reactions will be given.

2.1 Oxidative cyclometalation mechanism

The cyclometalation mechanism was first suggested by Prof. Trost and co-workers for palladium(II) pro-catalyst systems.8 The lack of activity of Pd(0) complexes in the reaction suggested that the active catalyst is at the Pd(II) oxidation state and thus the oxidative cyclometalation step would result in a Pd(IV) cyclometallic intermediate. Thus, a Pd(II)–Pd(IV)–Pd(II) based oxidative cyclometalation mechanism was assumed to be operative.9i

As depicted in Scheme 3, the catalytic cycle starts with a concomitant complexation of both unsaturation motifs of 1,n-enyne to the metal to afford III, which then leads to the metalacyclopentene 3 through a formal oxidative process in terms of the oxidation state of the metal center. Following the formation of this intermediate, there are various pathways to proceed depending on the features of the examined substrate and the reaction conditions. The predominant process, that happens to be the fastest one, is β-hydride elimination (paths a and b), that leads, after reductive elimination, to the corresponding 1,3- or 1,4-diene 4 or 5, depending on which hydride (Ha or Hb) is more favorable to eliminate. Both steric and electronic effects of the substituents at the allylic site as well as the substitution pattern of the tether linking the alkyne and the olefin direct the regioselectivity of the β-elimination to form either 1,3- or 1,4-diene cycloadducts.11 Other alternative pathways from the intermediate are mainly the direct reductive elimination (to form the strained anti-Bredt12 cyclobutene product 6) (path c) or electrophilic quenching of the C–M bonds of the metalacyclic intermediate 7 (path d). Usually, when coordinatively saturated metals (such as titanium, cobalt and zirconium) are involved in the metalacyclic intermediate, path d can occur in the presence of electrophiles, leading to cyclic mono or double functionalized products.9c

 
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Scheme 3 The oxidative cyclometalation mechanism.

The oxidative cyclometalation pathway is demonstrated to be very general and can operate with almost every transition metal9i such as Pd,8 Ru,13 Rh,14 Ir,15 Co,16 Ti,17etc. For instance, Murai disclosed that the iridium complex [IrCl(CO)3]n catalyzed the cycloisomerization of 1,6-enyne 8, providing the corresponding 1,3-diene 9 in good yield15 [eqn (1)].

2.2 Vinyl metal mechanism

In cases where a metal hydride is engaged in the catalytic cycle of a cycloisomerization reaction, the vinyl metal pathway predominates. As depicted in Scheme 4, the mechanistic procedure is constituted by the following steps: the generation of a metallo-hydride species (the real catalyst); a hydrometalation of the alkyne provides the vinyl metal intermediate IV that is able to carbometalate the alkene; the resulting alkylpalladium intermediate 10 can react in the following three directions: a β-H elimination furnishes the 1,3- or 1,4-diene 11 or 12 and regenerates the palladium(II) hydride (paths a and b) or coupling reactions to yield 13 (path c) or further cyclizations lead to functionalized cycloadducts 14 (path d). The identical regioselectivity issue appears during the β-H elimination step as the previous oxidative cyclometalation pathway. The chemoselectivity of this process is quite remarkable; free alcohols, silyl ethers, esters, amines, and acetals are compatible.18a It has to be noted that in this pathway the oxidation state of the metal remains unchanged during the whole process of cyclization.
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Scheme 4 The hydrometallation of alkyne initiated mechanism.

The above mechanism and the factors governing the regio-, chemo-, and stereoselectivity have been fully investigated by the Trost group.18a As for the generation of the active catalyst: the “MH” species, the palladium hydride species are typically generated in situ, when Pd(0) is used in the presence of an acid18,19 or when a hydrosilane is utilized.20 Apart from palladium, several other metals, like nickel,21,22 and rhodium complexes,23 have been demonstrated for their ability to give hydrometalation reactions. For instance, Carboni and co-workers24 described the cycloisomerization of boronated 1,6-enynes such as 15 in the presence of a system consisting of a Pd(0) source, tris(orthotolyl)phosphane, and acetic acid, which provided 16 in excellent yield [eqn (2)].

2.3 π-Allyl metal complex mechanism

The cyclizations of enynes involving a π-allylic metal complex are quite rare. As depicted in Scheme 5, the cyclization is usually initiated by activation of the allylic C–H bond to form the π-allyl metal hydride species 17. For the next step of carbometalation of alkyne, since both ends of the π-allyl metal motif could react, there is a selectivity issue to produce the (hydrido)vinyl metal species 18 or 19 with a different sized ring. Reductive elimination followed by a decomplexation from 20 gives the corresponding 1,4-diene product and regenerates the catalyst.
 
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Scheme 5 The allylic C–H activation initiated mechanism.

Palladium25 and ruthenium26 complexes are mainly used as a catalyst for this pathway. For instance, in 1999, Prof. Trost and co-workers observed formation of the seven-membered ring product 22 from the cyclization of enyne 21 [eqn (3)]. It was postulated that the cycloheptene must be formed via a π-allyl ruthenium intermediate.26

2.4 Metathesis mechanism

The metathesis mechanism based enyne cycloisomerization is also called Ring-Closing Enyne Metathesis (RCEYM)27 or Intramolecular Enyne Metathesis.7a The most widely used catalysts (also called initiators) for enyne metathesis are the ruthenium carbene based catalyst precursors, which have been “borrowed” from the alkene-metathesis realm.28

The metathesis pathway is briefly outlined in Scheme 6 (the red and blue dots are incorporated for the clear explanation of skeletal rearrangement). The mode selectivity is classified into endo and exo, based on whether the alkyne carbons become incorporated into the newly formed ring (endo) or not (exo).27d The ruthenium carbene intermediate 24 generated from the starting enyne 23 can undergo ring closure, in an exo mode (for small to medium sized ring) to generate the metallacyclobutene intermediate 25, which subsequently yielded the 1,2-disubstituted product 26 as the exo-type product (single cleavage of the alkene motif). Meanwhile, a two-step process has been proposed to rationalize the formation of the endo-type product 28, involving an initial rapid intermolecular enyne cross-metathesis of the terminal alkyne unit with ethylene to generate a butadiene 27, which subsequently undergoes a conventional intramolecular alkene ring-closing-metathesis (RCM) reaction. Given the sensitivity of the ruthenium metathesis catalysts to steric effects, the less hindered terminal double bond of the butadiene moiety in 27 would engage selectively in the following RCM event to yield the formal endo enyne-metathesis product 28 (single cleavage of the alkene motif).


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Scheme 6 Models for ring-closing enyne metathesis.

RCEYM is a particularly powerful method for the construction of 1,3-diene motifs containing ring systems, both carbocyclic and heterocyclic. Except constructing small to medium sized rings, RCEYM also offers a useful method for the synthesis of macrocyclic ring systems under typical conditions involving high dilution of the enyne reactant. In smaller rings such as five- and six-membered rings, RCEYM is controlled by a geometric constraint that dictates the exo ring-closure mode. The macro-RCEYM usually follows endo mode. The obtained 1,3-diene products can be subjected to subsequent reactions, such as [4 + 2] cycloaddition29 or a second cross metathesis (CM) reaction,30 useful for the rapid assembly of molecular scaffolds.

Since the pioneering work presented by the Mori group:31 the first application of an intramolecular enyne metathesis reaction in a total synthesis the tricyclic alkaloid (−)-stemoamide (31) in 1996, RCEYM has been widely used in natural product synthesis, for example (±)-streptorubin B (32),32 roseophilin (33),33 (−)-longithorone A (34),29 (+)-anatoxin-a (35),34,35etc. (Scheme 7).


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Scheme 7 Synthetic applications of ring-closing enyne metathesis.

2.5 Alkynophilic metal-catalyzed mechanism

Recent developments of enyne cycloisomerization chemistry based on the activation of triple carbon–carbon bonds by alkynophilic metal centers, such as gold,7b,9f,h platinum,7b,9f silver,36 copper,37 and mercury38 complexes, salts etc., have provided a new entry to the selective synthesis of diversified cyclocompounds, including dienic compounds, cyclopropane derivatives and so on. Due to the efforts of Prof. Echavarren, Prof. Toste, Prof. Zhang and Prof. Fürstner et al., the chemistry flourished and the reaction mechanisms were well defined in the past fifteen years. A number of excellent review articles and book chapters regarding the reaction modes, mechanism studies and synthetic applications have appeared.7b,c,9f,h,k,m–o,39
 
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The versatility of this electrophilic alkyne activation triggered 1,6-enyne cycloisomerization is summarized in Scheme 8 (the red and blue dots are incorporated for the clear explanation of skeletal rearrangement). As can be seen, activation of the alkyne moiety of the enyne by the alkynophilic metal forms a metal alkyne π-complex 36 that is attacked by the pendant alkene in a 5-exo-dig or a 6-endo-dig fashion to produce the cyclopropyl metal–carbene intermediate 37 or 38 correspondingly.40 These two key metal carbenes are capable of reacting in both a ‘cationic’ and ‘carbenoid-like’ sense, and then evolve through different pathways.39 Intermediate 37 can resonate to a charge-delocalized intermediate 37′, which leads to new carbene intermediate 42via intermediate 40 through rearrangement path a, resulting in a formal insertion of the terminal alkene carbon into the alkyne carbons. The intermediate 42 undergoes a 1,2-hydride shift and protodemetalation to yield 1,3-diene 41′, a product of an overall double cleavage rearrangement (In this process, both the alkyne and the alkene units have been cleaved during this intramolecular transformation, so it is called “double cleavage”).41 The same intermediate 37′ can also be rearranged to intermediate 39 through path b and eventually leads to the formal enyne metathesis product diene 41 in a transformation where only the alkene unit has been cleaved (“single cleavage”).42 Fused cyclobutene product 43 also can be generated from intermediate 39 through direct demetalation. The highly strained anti-Bredt12 structure of 43 would promote the cyclobutene ring opening to diene 41 or isomerization to the relatively stable cyclobutene product 44. Commonly, cyclopropyl metal–carbene intermediate 38 preferably leads to bicyclo[4.1.0]hept-4-ene derivative 45 by a 1,2-hydride shift and protodemetalation process.43 The endo-type 1,3-diene product 47 can be generated from intermediate 46, which is formed through the rearrangement of intermediate 38′, the charge-delocalized resonance structure of 38. 38′ can also rearrange to intermediate 48, which is another precursor of intermediate 39. Similar pathways are followed by 1,5- or 1,7- and higher enynes in the presence of alkynophilic metals.


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Scheme 8 Mechanistic pathways for alkynophilic metal-catalyzed enyne cycloisomerization.

For instance, under the cation gold species catalyzed conditions, 1,6-enyne 49 bearing a terminal alkene and tethered with a nitrogen atom provides the six-membered ring diene 50 as the major product by endo-type single-cleavage rearrangement (eqn (4)).44

3. The classification of structures accessed through enyne cycloisomerizations

The metal-catalyzed 1,n-enyne cycloisomerization reaction has created a large diversity in the obtained cyclic structures. Most of the polycyclic derivatives may be key intermediates in the total synthesis of natural or biologically active products.7 The diversity of the metal-catalyzed 1,n-enyne cycloisomerization chemistry originates from the diversity of enyne substrates, metal catalysts, and reaction mechanisms.

The cycloisomerizable enyne substrates range from 1,3-enyne45 to 1,n-enyne (n can be as large as 27 to the best of our knowledge).46 Meanwhile, a large array of functional groups are tolerable or act as latent reaction centers in substrates 1,n-enyne.

As for the catalyst, the first reports on the metal catalyzed cycloisomerisation of enynes involved palladium catalysis described by Trost.8 Following this initial discovery, a wide range of metal complexes and salts (mainly transition elements) have been demonstrated as effective catalysts for enyne cycloisomerizations, including ruthenium,13 rhodium,14 iridium,15 cobalt,16 iron,47 platinum,48 titanium,17 nickel,49 silver,36 gallium (main group),50 indium (main group),51etc., though their reactivity can be quite different.9i

As for the mechanisms, we have already known from the previous section that there are five pathways generally accepted to rationalize the enyne cycloisomerization process.

In this section we will briefly summarize the various structures accessed through metal-catalyzed enyne cycloisomerizations, to give the readers considering using this chemistry a rough guidance.

The very rich chemistry of enyne cycloisomerizations has made possible the preparation of a variety of carbo- or heterocycles, depending on both the nature of the enyne and the metal catalyst.9c,52–54 The substitution pattern of the starting enyne, as well as the nature of the catalyst, influences significantly the outcome of the cycloisomerization process.9c,i

Scheme 9 summarizes a range of observed reaction topologies for cycloisomerizations of 1,n-enynes. The diversity of cyclic structural motifs that can be efficiently accessed from a common enyne precursor is remarkable. 1,3-dienes 52 and the exo-type 1,4-dienes 53 (Alder-ene product) are typical products of enyne cycloisomerization, which can be obtained through pathway I or II.9bEndo-type 1,4-dienes 54 are formed through pathway III (π-allyl–metal mechanism).55 The skeletal rearrangement products cyclic 1,3-dienes 55 (single cleavage) and/or 56 (double cleavage) are usually formed via metathesis (pathway IV) or cyclopropyl metalcarbenes (pathway V) in the absence of nucleophiles.27a,56 Highly strained cyclobutenes 58 and its isomer 58′ are obtained through oxidative cyclometalation followed by reductive elimination (pathway I) or by other mechanisms.57 Product 1,3-dienes 57 of endocyclic skeletal rearrangement (single cleavage) are formed through pathway IV or V, and products 59–60 of intramolecular cyclopropanation have also been obtained through pathway V. In the presence of nucleophiles, adducts 61–64 can be obtained in stereospecific processes via pathway V.58 More complex transformations starting from more functionalized enynes are also possible, for example, incorporation of arene or alkene groups (R1) at the terminal alkyne position provides access to bicyclic and tricyclic products 65 as a result of a formal [4 + 2] cycloaddition.59


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Scheme 9 Observed reaction topologies in cycloisomerizations of 1,n-enynes.

The enyne cycloisomerization reaction can also be associated with various inter- or intramolecular processes implying cross coupling or electrophilic quenching of the metal intermediate,60 high order cycloadditions,61 or other cascade reactions,62 to access even more complex ring systems and structures.

4. Recent applications of enyne cycloisomerizations in natural product synthesis

As demonstrated in the previous parts, metal catalyzed enyne cycloisomerization is a fast growing and fascinating field. Due to its diversified chemistry and ability to increase molecular complexity in an efficient, atom economical, step economic and redox economic way, enyne cycloisomerization has become a powerful strategy for the construction of cyclic compounds, thus possessing great potential for applications in total synthesis of natural products and pharmaceuticals. In 2005, Prof. Nicolaou and co-workers presented an excellent review covering the applications of a special type of enyne cycloisomerization—intramolecular enyne metathesis in total synthesis.7a Recently, Prof. Zografos and co-workers summarized the applications of metal catalyzed enyne cycloisomerizations in sesquiterpenoids syntheses.7d Reviews regarding the applications of gold and platinum catalyzed enyne cycloisomerizations in total synthesis are well recorded.7b,c,9f,h,k,n,o,52

Providing a complement to the existing reviews, in the context of this part, a thorough summary of the important related applications in total synthesis of naturally occurring compounds since 2005 will be reported to showcase how the enyne cycloisomerization strategy becomes a powerful tool in the hands of organic chemists, illuminating a new paradigm in strategic synthetic planning.

4.1 (+)-Allocyathin B2

(+)-Allocyathin B2 is a metabolite isolated from the fruit bodies of Cyathus earlei Lloyd by the Ayer group in 1979. It belongs to the cyathins diterpene family exhibiting a broad spectrum of interesting biological activities.63

In 2005, the Trost group achieved the first enantioselective synthesis of (+)-allocyathin B2 highlighting a diastereoselective Ru-catalyzed 1,7-enyne cycloisomerization.64 Under their previously developed standard conditions,1e,13,26,55 the Ru-catalyzed cycloisomerization of enyne 66 proceeded with excellent stereocontrol, and only the desired 1,4-anti products 67a to 67c were provided as a mixture of E and Z olefinisomers. To their delight, the E/Z ratio could be improved drastically by simply changing the methyl ester to tert-butyl ester in the precursor without compromising the conversion and the diastereoselectivity, which could be attributed to attenuating the strain through increasing the size of the ester and thus promote the double bond isomerization. Ultimately, the desired product 67c could be obtained in 48% yield as a single diastereomer possessing the right stereochemistry, which was further transformed to (+)-allocyathin B2 in just 4 steps (Scheme 10).


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Scheme 10 Enantioselective synthesis of (+)-allocyathin B2 (Trost, 2005).

4.2 Pinnatoxin A

Pinnatoxin A, a marine toxin isolated from the shellfish Pinna muricata in 1995 by Uemura and co-workers, is the first and most prominent member of the marine iminium alkaloid family.65 Pinnatoxin A was reported to activate Ca2+ channels.65b

In 2008, Nakamura and co-workers reported their total synthesis of pinnatoxin A in 53 steps (the longest linear sequence) with a 0.21% overall yield.46 It is worth noting that one of the key transformations is Ru-catalyzed cycloisomerization of enyne 68 to construct the 27-membered macrocarbocyclic ring-one of pinnatoxin A's striking structural feature. The macrocyclization occurred with complete regioselectivity by application of the Trost procedure66 (10 mol% [CpRu(MeCN)3]PF6, acetone, 50 °C) to provide desired 1,4-diene product 69 in 79% yield, while no signs of dimerization and isomerization of the obtained (E)-alkene could be detected. Strikingly, only 15 min was required to perform this macrocycloisomerization with complete stereo-, chemo-, and regioselectivity (Scheme 11).


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Scheme 11 Total synthesis of pinnatoxin A (Nakamura and Hashimoto, 2008).

4.3 Laulimalide

Laulimalide is a structurally unique 20-membered marine macrolide isolated from several sources of marine sponges.67a It was shown that laulimalide displays potent cytotoxicity toward numerous NCI cell lines,67b and microtubule stabilizing activity similar to that of paclitaxel and the epothilones.68

In 2009, Trost and co-workers reported an efficient and convergent synthesis of laulimalide.69 One of the key steps in their synthesis involved an intramolecular Ru-catalyzed enyne cycloisomerization reaction, akin to the previous Nakamura's practice.46 Exposure of enyne 70 to 5 mol% of [CpRu(MeCN)3]PF6 in acetone at 50 °C proceeded with exceptional efficiency to furnish the desired 1,4-diene containing 18-membered macrocycle 71 as a single regioisomer in 99% yield. An additional six steps were needed to achieve the total synthesis of laulimalide from 71. Meanwhile, they were delighted to find that a laulimalide analogue 72, synthesized from 71 in just three steps, displayed significant activity against Granta 519 and Jurkat cell lines with IC50 values of 200 and 182 nM, respectively (Scheme 12).


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Scheme 12 Synthesis of laulimalide and analogue (Trost, 2009).

The above elegant total synthesis of pinnatoxin A and laulimalide highlights the power and vitality of the Ru-catalyzed enyne cycloisomerization in the context of macrocyclizations via C–C bond formation.

4.4 Atisane-type diterpenes and atisine-type diterpenoid alkaloids

In 2016, Xu and co-workers reported an elegant collective synthesis of atisane-type diterpenes and atisine-type diterpenoid alkaloids.70 One of the key steps in their synthesis involves a crucial diastereoselective Ru-catalyzed 1,7-enyne cycloisomerization used to achieve the highly functionalized common 1,4-diene intermediate 74 possessing the pivotal tetracyclic atisane skeleton. With a slightly modified version of the Trost conditions,1e,13,26,55 cycloisomerization of 1,7-enyne 73 by employing 10 mol% [CpRu(MeCN)3]PF6 in the presence of 1.5 equivalents of DMF as the additive, followed by removal of the ketal protecting group in a one-pot step, proceeded efficiently to furnish 74 as a single diastereomer in excellent yield, which enabled the efficient collective total syntheses of several members of the structurally complex atisane-type diterpenes and related atisine-type diterpenoid alkaloids, namely (±)-spiramilactone B, (±)-spiraminol, (±)-spiramines C and D, and (±)-dihydroajaconine (Scheme 13).
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Scheme 13 Synthesis of atisane-type diterpenes and atisine-type diterpenoid alkaloids (Xu, 2016).

4.5 Platensimycin

Platensimycin, isolated from a strain of Streptomyces platensis by a Merck research team in 2006, is the flagship member of a new and growing class of antibiotics with promising antibacterial properties against drug-resistant bacteria through a novel mechanism of action, which presents a ray of hope for the development of a powerful new therapy.71

In 2006, Prof. Nicolaou and co-workers completed the first total synthesis of racemic platensimycin.72 One of the pivotal steps in the synthesis was the cycloisomerization of 1,6-enyne 75 under Trost's conditions:13,73 exposure of the substrate to the catalyst [CpRu(MeCN)3]PF6 in an acetone solution to form the spirocyclic framework 76 as an inconsequential 1[thin space (1/6-em)]:[thin space (1/6-em)]1 mixture of diastereoisomers in 92% total yield. The success of this ruthenium catalyzed enyne cycloisomerization reaction secured the first generation of synthetic route towards platensimycin (Scheme 14).


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Scheme 14 Racemic and asymmetric synthesis of platensimycin (Nicolaou, 2006 & 2007).

The next goal of the Nicolaou group was pursuing an enantioselective synthesis of platensimycin. Unfortunately, the planned enantioselective ruthenium catalyzed cycloisomerization of a similar substrate enyne 78 was not amenable to asymmetric modification. However, exposure of 78 to Zhang's rhodium(I)-catalyzed asymmetric enyne cycloisomerization conditions14,74 gave the desired spirocyclic product 79 in 91% yield and greater than 95% ee, which enabled a formal asymmetric synthesis of (−)-platensimycin in 2007.75 The ester group attached to the alkyne in enyne 78 is required to ensure a high yield and ee, which was later removed through Barton's free radical decarboxylation method (Scheme 14).

In 2009, to achieve a more practical synthesis of (−)-platensimycin and related analogs, Prof. Nicolaou and co-workers further improved the key rhodium catalyzed asymmetric enyne cycloisomerization by choosing enyne 80 with a terminal alkyne as the substrate. When 80 was subjected to Zhang's standard condition, only inferior yield (15%) and 95% ee was obtained. Luckily, when a slightly modification of the Zhang's protocol was conducted by applying the preformed catalyst ([Rh((S)-BINAP)]SbF6) (5 mol%), the desired spiro dienone aldehyde (−)-81 was afforded in 86% yield and >99% ee. This improvement facilitated the efficient total synthesis of platensimycin, a number of its naturally occurring congeners and designed analogues, e.g., platensimide A, homoplatensimide A, homoplatensimide A methyl ester, and platensimycins B1 and B3.77 The modified asymmetric rohdium catalyzed 1,6-enyne cycloisomerization reaction was also examined to exhibit a good generality and wide substrate scope76,77 (Scheme 15).


image file: c7qo00702g-s15.tif
Scheme 15 Synthesis of platensimycin family members and analogs (Nicolaou, 2009).

4.6 Lucentamycin A

Lucentamycin A is a naturally occurring tripeptide isolated from the fermentation broth of a marine-derived actinomycete Nocardiopsis lucentensis by Fenical in 2007.78 Lucentamycin A was found to have significant in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 0.20 μM. Owing to its high anti-proliferative activity against colon cancer cells, lucentamycin A has received great attention.

Due to the lack of solid spectrum evidence, the structure of lucentamycin A was only tentatively assigned, and the absolute configuration of the two contiguous C8 and C9 chiral centers in the central pyrrolidine rine was not fixed yet. To elucidate the correct structure and stereochemistry of lucentamycin A, Sim and co-workers selected a strategy developed by Krische and co-workers79 that employed Rh-catalyzed asymmetric reductive 1,6-enyne cycloisomerization to prepare all four possible stereoisomers corresponding to the two contiguous C8 and C9 stereocenters in the pyrrolidine core of putative lucentamycin A.80

Four optically active 1,6-enyne substrates: 82, 82′, 83 and 83′ (82 and 82′ were enantiomers and served as a ‘closed’ substrate; 83 and 83′ were also enantiomers, served as an ‘open’ substrate with hydroxyl group free) were exposed to the Rh-catalyzed reductive cyclization conditions in the presence of hydrogen, using chiral BINAP ligands. These processes afforded four key optically active intermediates, 84, 84′, 85 and 85′ with good yield and diastereoselectivity. It was concluded that the configuration of the newly generated chiral center in this process was defined by the chiral catalyst system over the chiral substrate, and the ‘closed’ substrate had better stereocontrol than the ‘open’ substrate as demonstrated by the difference from diastereoselectivity. Finally, 84, 84′, 85 and 85′ served as building blocks that led to the four possible isomers of the proposed structure of lucentamycin A. Unfortunately, the properties of these four synthesized substances did not match those of the natural one, suggesting that the putative structure of lucentamycin A needs to be revised (Scheme 16).


image file: c7qo00702g-s16.tif
Scheme 16 Stereoselective synthesis of four pyrrolidine isomers via Rh-catalyzed reductive cyclization.

4.7 Alcyopterosin A

In 2016, Prof. Dudley and co-workers reported a six-step synthesis of alcyopterosin A,81 a bioactive illudalane sesquiterpene isolated from soft coral species.82 The pivotal step in this synthesis involved a Rh-catalyzed cycloisomerization of dienyne 86 (a formal intramolecular [4 + 2] addition) and oxidative aromatization cascade to afford alcyopterosin A. Precursor 86, prepared from commercial reagent dimedone in 5 steps, was subjected to the conditions of 2,5-norbornadiene-rhodium(I) chloride dimer in trifluoroethanol at 50 °C for 8 h, followed air bubbled through the solution for 2 h, to complete the process and produce the target molecule alcyopterosin A in 83% yield. The mechanism of this transformation could be rationalized to be a Cyclometalation-Reductive Elimination-Oxidative Aromatization cascade83 (Scheme 17).
image file: c7qo00702g-s17.tif
Scheme 17 Synthesis of Alcyopterosin A (Dudley, 2016).

4.8 Nakadomarin A

In 2007, Dake and co-workers developed a novel platinum(II)-catalyzed cyclization method to generate quaternary carbon centers using enamides, enesulfonamides, or enecarbamates as nucleophiles, thus generated intermediary azacarbenium ions could isomerize to a new enamine (8990) or be trapped by an internal nucleophile in a Friedel–Crafts/Pictet–Spengler-type process (9192, 93).48 This methodology provided an effective entry to alkaloid ring systems. As demonstrated by the same group in 2008, an efficient total synthesis of (+)-fawcettidine was developed based on this chemistry84 (Scheme 18).
image file: c7qo00702g-s18.tif
Scheme 18 Platinum(II)-catalyzed cycloisomerization to construct alkaloid ring systems.

In 2008, inspired by Prof. Dake's work, Prof. Zhai and co-workers accomplished the construction of the tetracyclic core structure (ABCD rings) of the complex bioactive marine alkaloid (+)-nakadomarin A with high efficiency.85 (Scheme 19) Treatment of highly functionalized enecarbamate 94 with PtCl2 (18 mol%) in toluene at reflux effected the desired tandem reaction sequence in an apparently regiospecific (6-endo versus 5-exo) and stereospecific manner since spiro-fused tetracyclic heterocycle 97 was obtained exclusively. The starting material 94 seemed to be susceptible to decomposition at the reaction temperature. Therefore, a syringe pump was used for addition of the substrate to secure a better yield. In contrast, under Dake's standard conditions (i.e., reaction with PtCl2 in toluene in a sealed tube heated at 110 °C) the reaction produced 97 in only 38% yield. The cascade sequence presumably consisted of the following steps:85 (1) nucleophilic attack of enecarbamate on the PtCl2-activated alkyne to generate intermediate 95, (2) interception of the azacarbenium ion in 95 by the proximate nucleophilic furan moiety to form intermediate 96, and (3) rearomatization of the dihydro-furanyl cation in 96 to furan and release of a proton leading to the desired product 97 and regeneration of the platinum catalyst. Finally, it's striking to find that no racemization was observed at the labile C14 chiral center.


image file: c7qo00702g-s19.tif
Scheme 19 Construction the core structure of nakadomarin A (Zhai, 2008).

Based on the above successful model study, the Zhai group was able to complete the total synthesis of (−)-nakadomarin A in 2011 with high practicality and efficiency.86 By adopting their modified procedure,85 treatment of highly functionalized precursor 99 (prepared from known compound 98 in three steps) with PtCl2 (20 mol%) in toluene at 80 °C triggered the anticipated cascade sequence in a regiospecific and stereospecific fashion to afford the key intermediate 100 in 81% yield. With compound 100 in hand and additional fifteen step manipulations, they finally accessed the natural (−)-nakadomarin A (Scheme 20).


image file: c7qo00702g-s20.tif
Scheme 20 Synthesis of (−)-nakadomarin A (Zhai, 2011).

4.9 Cortistatin A

In 2008, Prof. Sarpong and co-workers reported a synthesis of the pentacyclic core of the famous anticancer marine steroidal alkaloid cortistatin A,87 utilizing a PtCl2-catalyzed enyne cycloisomerization to form the seven-membered B ring.88 Treatment of the indene compound 101 with catalytic PtCl2 effected an enyne cycloisomerization (enyne metathesis, single cleavage) that provided the benzocycloheptadiene 102 in 61% yield. Six steps of further manipulations from 102 provided the highly functionalized pentacycle intermediate 105, which possessed the basic skeleton and five out of eight chiral centers of cortistatin A (Scheme 21).
image file: c7qo00702g-s21.tif
Scheme 21 Sarpong's first-generation synthesis of the pentacyclic core of cortistatin A.

Based on this preliminary study, they devised an improved route to 105 (Scheme 22), which began with the benzyl-protected indanone 106.89 The robustness of the benzyl protecting group relative to the previously employed PMB enabled a higher yield in the key PtCl2-catalyzed enyne cycloisomerization reaction to obtain benzocycloheptadiene107, which led to an nearly doubled overall yield of 105 in six steps compared to that of the first effort. With significant quantities of 105 available, eight more manipulations were required to afford the Nicolaou/Hirama intermediate 108, so a formal synthesis of (±)-cortistatin A was achieved.90


image file: c7qo00702g-s22.tif
Scheme 22 Sarpong's formal synthesis of (±)-cortistatin A.

4.10 Icetexane diterpenoid

In 2002, Prof. Chatani and co-workers51 demonstrated for the first time that main group III A salt GaCl3 could be used as a catalyst for the skeletal rearrangement of 1,6-enynes (1,6-enyne metathesis), just similar to the Au and Pt catalysts. Treatment of enyne 109 with 10 mol% GaCl3 in toluene at 0 °C afforded 1,3-diene 110 in 77% yield via a formal metathesis (single cleavage). The mildness of these reaction conditions was very impressive. The authors proposed a mechanistic rationale based on the intermediacy of cyclobutenes (Scheme 23). An initial electrophilic addition of GaCl3 to the triple bond of substrate 109 leads to the formation of vinylgallate 111. Nucleophilic attack of the alkene function and subsequent ring closing of intermediate 112 delivers cyclobutane 113. Elimination of GaCl3 then gives cyclobutene 114. Conrotatory opening of this strained four-membered ring releases 1-vinylcyclopentene 110 as the final stable product.
image file: c7qo00702g-s23.tif
Scheme 23 GaCl3 catalyzed 1,6-enyne metathesis and proposed mechanism (Chatani, 2002).

Utilizing Chatani's methodology, Sarpong and co-workers achieved a general approach to the tricyclic core of the icetexane diterpenoid natural products in 2006, which employed the challenging cycloisomerization of alkynyl indenes 115.91 Originally, they screened a variety of conditions known to catalyze cycloisomerization of enynes, including the Grubbs I and II catalysts, Rh(PPh3)3Cl, Rh(PPh3)3Cl/AgBF4, PtCl2, etc., without success. Inspired by Prof. Chatani's work, employing GaCl3 as the catalyst, they finally succeeded to access the key 1,3-cycloheptadiene intermediate 116 in excellent yield from enyne 115. Via such a unique synthetic strategy, they were able to finish the first total synthesis of the icetexane diterpenoid family member (±)-salviasperanol in three more steps from 116 with high efficiency. In 2007, they completed the total synthesis of three other members of the icetexane diterpenoid family, named (±)-5,6-dihydro-6α-hydroxysalviasperanol, (±)-brussonol, and (±)-abrotanone from salviasperanol dimethyl ether 118 in a few steps92 (Scheme 24).


image file: c7qo00702g-s24.tif
Scheme 24 Synthesis of icetexane diterpenoid natural products (Sarpong, 2006 & 2007).

In 2010, the Sarpong group applied the same strategy for the total synthesis of (±)-icetexone and (±)-epi-icetexone, another two members of icetexane diterpenoids family.93 With indenyl alkyne 119 as the substrate for the pivotal cycloisomerization, harsher conditions (higher temperature and longer reaction time, as compared to the previous (±)-salviasperanol synthesis) were required to secure product 120 in excellent yield, which paved a solid way for the efficient synthesis of (±)-icetexone and (±)-epi-icetexone. Interestingly, the use of PtCl2 or InCl3, which had been previously established as catalysts for enyne cycloisomerization,11 returned only the starting material (Scheme 25).


image file: c7qo00702g-s25.tif
Scheme 25 Synthesis of icetexane diterpenoid natural products (Sarpong, 2010).

In 2013, the same strategy was once again applied by the Sarpong group for the construction of the core structure of diterpenoid alkaloids: kobusine, nominine, etc.94 Cycloisomerization of indenyl alkyne 121 by using catalytic Ga(III) iodide under reaction conditions previously established gave benzannulated cycloheptadiene 122 in excellent yield, which could be further transformed to the advanced polycyclized intermediate 123, possessing the hetisine framework and the right stereochemistry (Scheme 26).


image file: c7qo00702g-s26.tif
Scheme 26 Construction of the hetisine framework (Sarpong, 2013).

4.11 Pradimicin A

In 2012, Hall and co-workers reported the synthetic study towards the core tricyclic ring system (CDE rings) of pradimicin A,95 a novel bioactive microbial metabolite.96 One of the key steps in their synthetic study involved a ruthenium or palladium-catalyzed enyne cycloisomerization. Under Grubbs II catalyzed conditions, 1,7-enyne 124 could transform to the product 1,3-diene 125 together with a small amount of skeleton rearranged side product. The reaction was also performed well with a catalytic amount of Pd(OAc)2 (10 mol%), PPh3 (20 mol%), and the acetic acid (20 mol%) at room temperature in toluene and resulted in a cleaner system. Since 1,3-diene 125 was unstable and prone to dimerize at elevated temperature through a [4 + 2] process, a one-pot sequential process involving palladium-catalyzed cycloisomerization, Diels–Alder reaction with dimethyl but-2-ynedioate, and DDQ mediated oxidative aromatization was designed, in which each reaction was performed directly on the crude material in the same reaction flask. Through intensive optimization, the synthesis of the model tricyclic intermediate 126 was realized in 45% yield over three steps, which laid a solid foundation for the total synthesis of pradimicin A (Scheme 27).
image file: c7qo00702g-s27.tif
Scheme 27 Synthetic study towards the core tricyclic ring system of pradimicin A (Hall, 2012).

4.12 Indole alkaloids: (−)-catharanthine, (±)-andranginine, and (±)-vincadifformine

In 2014, Prof. Oguri and co-workers developed a Cu(I)-catalyzed 6-endo cyclization of N-propargyl enaminocarbonyls (1,6-enyne cycloisomerization) to establish the 1,6-dihydropyridine (DHP) ring.97 As shown in Part a, Scheme 28, the reaction was initiated by coordination and activation of the alkyne group in substrate 127 with copper(I) to form the electrophilic π-complex 128. The subsequent nucleophilic attack of the pendant enamine affects 6-endo cyclization. The resulting ionic intermediate 129 undergoes a deprotonation and protodemetallation sequence to produce 1,6-DHP 130 with regeneration of the catalyst.
image file: c7qo00702g-s28.tif
Scheme 28 A biogenetically inspired synthetic process to furnish alkaloidal scaffolds (Oguri, 2014).

In the model study, investigation identified the optimum conditions, which used a cationic Cu(I) catalyst as an efficient alkyne activator. Upon treatment of model substrate 127 with a catalytic amount (10 mol%) of [Cu(dppf)(MeCN)]PF6 in dichloromethane, 6-endo cyclization proceeded smoothly within 60 min at room temperature to afford the desired 1,6-DHP 130 in 97% yield without affecting the non-protected indole or the resulting labile 1,6-DHP ring located in the vicinity, which demonstrated vividly the mildness of the reaction conditions.

Following the success of the model study, the multipotent 1,6-DHP-vinylindole 132a–c were flexibly synthesized from N-propargyl enaminocarbonyls 131a–c through the pivotal Cu(I)-catalyzed enyne cycloisomerization. By harnessing the versatile reactivity of 132a–c, three distinct modes of the bio-inspired [4 + 2] cyclizations were systematically implemented. The divergent process allowed concise and programmable access to three naturally occurring scaffolds (133, 134 and 135), which resulted in efficient total syntheses of (−)-catharanthine, (±)-andranginine and (±)-vincadifformine, respectively (Parts b and c, Scheme 28).

The success of this biogenetically inspired synthesis and skeletal diversification of indole alkaloids relied heavily on the rapid construction of the 1,6-DHP ring under very mild Cu(I)-catalyzed enyne cycloisomerization conditions so as not to cause further intra- or intermolecular side reactions of the elaborate π-conjugated systems in 1,6-DHPs 132a–c.

4.13 Cannabinoid: (−)-cannabimovone

In 2016, Prof. Echavarren and co-workers accomplished the first total synthesis of (−)-cannabimovone, a unique cannabinoid from Cannabis sativa98 by means of a highly diastereoselective gold(I)-catalyzed cycloisomerization.99

Exposing precursor 1,5-enyne 136 to the cationic gold(I) complex [(JohnPhos)Au(MeCN)]SbF6 in DMSO, the desired 3-vinylcyclopent-1-ene 137 was obtained in excellent yield (88%). This reaction was able to perform up to a 2.1 gram scale. A similar result was observed when the reaction was performed in DMF (79%). Interestingly, the pivotal gold(I)-catalyzed cyclization was highly solvent dependent. Bicyclic compound 139 was isolated in 49% yield with CH2Cl2 as the solvent. A similar result was obtained using other solvents such as Et2O or toluene. Reaction in MeOH afforded methyl ether 140 (93%). Presumably, the initial gold carbene intermediate 138 of the gold(I)-catalyzed cyclization was the common precursor of products 137, 139, and 140. Solvent DMSO or DMF assisted proton elimination and protodeauration lead to the desired product 137. Notably, the whole process was highly diastereospecific, generating137 with the correct relative configuration at C3 (Scheme 29).


image file: c7qo00702g-s29.tif
Scheme 29 Synthesis of (−)-cannabimovone through Au(I)-catalyzed cycloisomerization (Echavarren, 2016).

This case was regarded as the first example of the cycloisomerization of simple 1,5-enynes into 3-vinylcyclopent-1-enes catalyzed by gold in the context of natural product synthesis.

4.14 Cycloisomerization/Cope cascade and gelsemium alkaloid: gelsenicine

In 2010, Prof. Chung and co-workers reported a facile method for the stereoselective construction of bicyclo-[3.2.2]-nonadienes from dienyne substrates using a PtCl2-catalyzed cycloisomerization and subsequent Cope rearrangement.100 As shown in Part a, Scheme 30, bicyclo-[4.1.0] heptenes 142 was easily obtained from the alkynophilic transition metal catalyzed cycloisomerization of dienyne 141. Under thermodynamic conditions, 142 would epimerize to form the more stable isomer 143, which was prone to undergo Cope rearrangement, and led to the formation of the bridged bicyclic compound 144. The optimized conditions for this cycloisomerization/Cope cascade were: 5–10 mol% PtCl2, toluene was used as the solvent for reactions conducted at 110 °C (xylene was used instead for reactions conducted above 110 °C).
image file: c7qo00702g-s30.tif
Scheme 30 An enyne cycloisomerization/Cope cascade; b. Synthesis of (±)-gelsenicine (Ferreira, 2016).

Following up on this path finding observation, Prof. Ferreira and co-workers decided to implement this cycloisomerization/Cope cascade strategy for the total synthesis of a bioactive gelsemium alkaloid-gelsenicine.101 As shown in Part b, Scheme 30, after carefully choosing the linear diene-diyne (E,E)-145 as the precursor, they did a few modifications to Chung's original conditions to realize the desired process. They found that (1) Au(I) catalysis was decidedly superior to Pt(II) catalysis in terms of yield, and (2) a stepwise process gave improved diastereoselectivity over the cascade option. This series of transformations established the core with outstanding efficiency, giving the key bicyclic intermediate 147 in 70% yield over two steps. Finally, they were able to achieve the first total synthesis of (±)-gelsenicine in just 13 steps (the longest linear sequence), representing the shortest total syntheses of a gelsemium alkaloid to date. The pivotal gold-catalyzed cycloisomerization/Cope rearrangement process definitively leverages the capacity of alkynophilic metal-catalyzed cyclization chemistry in a total synthetic context.

5. Conclusions and outlook

The metal catalyzed enyne cycloisomerisations advanced dramatically since the first examples appeared in 1985. Now, it has attracted considerable attention as a powerful methodology that allows the synthesis of highly complex molecules in a mild, selective and atom economical manner. Furthermore, a wide range of synthetically useful carbocyclic and heterocyclic scaffolds can be obtained from the same relatively simple acyclic starting materials, by changing the reaction conditions. These discoveries and innovations not only provide new synthetic methods, but also considerably change the traditional synthetic planning strategically.

From a synthetic chemist's point of view, we have provided in this review a brief summary of the state-of-the-art mechanism studies, the classification of structures accessed through enyne cycloisomerizations, and recent completed total synthesis of representative natural products showcasing creative and ingenious incorporation of enyne cycloisomerization as a strategic manoeuver, in order to inspire future developments of this fascinating field.

Despite considerable achievement and progress over the years, much work remains to be done to realize the full potential of metal catalyzed enyne cycloisomerizations: (1) the asymmetric metal catalysis of enyne cycloisomerization remains immature. Indeed, although substantial efforts have been made by Prof. Zhang, Prof. Toste and et al.,9m,102 it is still essential to develop strategic asymmetric protocols that are general and applicable to various structural types; (2) as an extension of this field, the association of enyne cycloisomerization reactions with various inter- or intramolcular processes is another gold mine, which enables a huge advance in the skeletal diversity of the synthesized molecules as demonstrated by the cases in this review.81,86,97,101 More efforts are needed to invest in this direction. (3) Besides the booming applications of gold, platinum, and ruthenium catalyzed enyne cycloisomerizations in complex total synthesis, cases employing other metal catalyzed enyne cycloisomerizations are quite limited.

Overall, it is envisaged that enyne cycloisomerizations will become increasingly important in organic synthesis in terms of the diversified platform they provide for the preparation of valuable natural products and their analogues. Both novel methodology developments and brilliant total synthesis applications of complex natural and unnatural products in the area can be expected in the near future.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to National “1000-Youth Talents Plan”, National Natural Science Foundation of China (Grant 21602161), the National Key Research and Development Program of China (Program No. 2016YFB0101200 (2016YFB0101203)), the Institute for Advanced Studies of Wuhan University (Grant 649/413000019), the Innovation Team Program of Wuhan University (Program No. 2042017kf0232), and the College of Chemistry and Molecular Sciences of Wuhan University for generous financial support. We would like to thank Dr Han-Qing Dong (Arvinas Inc., USA) for assistance with the preparation of the manuscript.

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Footnote

These authors contributed equally to this work.

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