Metal Complex Catalysis in the Synthesis of Spirocarbocycles Vladimir A. D’yakonov,*,† Ol’ga A. Trapeznikova,† Armin de Meijere,‡ and Usein M. Dzhemilev† †

Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Russia Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany Synthetic and natural spirocarbocycles attract the attention of organic chemists due to their unique structural features and numerous possible reactions in which they undergo carbon− carbon bond cleavage. For example, natural compounds such as fredericamycine (1),2 acorenone B (2),3 β-vetivone (3),4 ACAT inhibitor (4),5 and isocomene (5)6 isolated from plants contain spirocarbon atoms; synthetic spirans include unique compounds such as []fenestrane (6),7 triangulanes (7),8 and [6.5]coronane (8) (Figure 1).9 The peculiar properties of certain targeted spirocarbocycles such as high reactivities of some or fairly high thermal stabilities CONTENTS of others have challenged many organic chemists to develop the appropriate preparative approaches to specific compounds. 1. Introduction A There are quite a few published reviews, papers, and patents, 2. Catalyzed Addition of Diazo Compounds Leading some of which are outdated, that mainly present methods for to Spirans A the synthesis based on multistep synthetic strategies and exotic 3. Alkene Metathesis with Grubbs Catalysts in the and/or expensive reagents.10 Meanwhile, the development of Synthesis of Spirans G metal complex catalysis has also markedly streamlined the 4. The Pauson−Khand Reaction in the Synthesis of synthetic routes to spirans and thus made them more easily Spirocarbocycles H accessible. Especially during the last 10−15 years, considerable 5. Catalyzed Cycloadditions in the Synthesis of progress has been made, and a series of original methods as well Spirans J as effective reagents for the preparation of various spirocarbo6. Intramolecular Cyclization of Alkenes Catalyzed cycles have been reported. Therefore, we want to present a by Transition Metal (Zr, Ti, Ru, Au, Rh, Pd, Ni, Fe) critical account and general survey of the published literature Complexes Q on the synthesis of spirans employing metal complex catalysis. 7. The Heck Reaction in the Synthesis of Spirans Y ‡

8. Cyclocarbonylation Catalyzed by Palladium Complexes in the Synthesis of Spirocarbocycles 9. The Nazarov Reaction in the Synthesis of Spirans 10. The Kulinkovich Reaction in the Synthesis of Hydroxy-Substituted Spirocarbocycles 11. Cyclization of Enynes Catalyzed by Palladium Complexes as an Approach to Spiranes (Zipper Reactions) 12. Synthesis of “Expanded” Rotanes through the Cu-Catalyzed Oxidative Coupling of Alkynes 13. Catalyzed Cycloalumination in the Synthesis of Spirocarbocycles 14. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments References


2. CATALYZED ADDITION OF DIAZO COMPOUNDS LEADING TO SPIRANS One of the classical approaches to spiro[2.n]alkanes is based on the cyclopropanation of methylenecycloalkanes using either the Simmons−Smith reagent or the [2π+1π] cycloaddition of diazo compounds or other cyclopropanating reagents. This section gives a detailed account of the catalytic cyclopropanation of methylenecycloalkanes employing diazo compounds. Cyclopropanation of methylenecyclobutane (9) with a solution of diazomethane 10 in diethyl ether in the presence of Pd(acac)2 as a catalyst gave spiro[2.3]hexane (11) in 48% yield (Scheme 1).11 Palladium(II) acetate has been shown to catalyze the cyclopropanation of β-pinene 12 with diazomethane 10 furnishing the spirocyclopropane derivative 13 in 63% yield.12a The same hydrocarbon had previously been prepared by Simmons−Smith-type cyclopropanation of 12 with diiodo- and dibromomethane, respectively.12b,c In the presence of copper(II) triflate, pinene 12 reacts with diazomethane to give 13 in virtually quantitative yield (Scheme 2).12d



1. INTRODUCTION Spirans contain at least two rings, which share one carbon atom called the spirocarbon atom.1 © XXXX American Chemical Society

Received: May 30, 2013

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Figure 1. Synthetic and naturally occurring spirocarbocycles.2−9

Scheme 1. Palladium-Catalyzed Cyclopropanation of Methylenecyclobutane11

Scheme 4. Palladium-Catalyzed Cyclopropanation for the Synthesis of Various Triangulanes8d,14a,f

Scheme 2. Copper(II)-Catalyzed Cyclopropanation of βPinene12d

Scheme 3. Copper(I)-Catalyzed Cyclopropanation of Dimethylenecyclobutene with Diazomethane13a

Scheme 5. Cyclopropanation of an Alkylidenecyclopropane in the Presence of Pd(OAc)215

Hopf et al. have demonstrated that dimethylenecyclobutene (14) reacts with diazomethane 10 in the presence of copper(I) chloride to give mono- (15) and dispirocyclopropanecyclobutene (16) along with dispirocyclopropanebicyclo[2.1.0]pentane (17), the latter resulting from exhaustive cyclopropanation of 14 (Scheme 3).13a The hydrocarbon 16 had previously been prepared along a completely different route.13b The palladium acetate-catalyzed cyclopropanation of the double bond in methylenecycloalkanes 18, 20, and 22 with diazomethane has been used as the final step in the syntheses of several so-called triangulanes such as 19, 21, and 23 (Scheme 4).8,14 Similarly to the terminally unsubstituted double bond in methylenecyclopropanes, alkylidenecyclopropanes such as 24 also react with diazomethane 10, giving rise to the

corresponding alkyl-substituted spiro[2.2]pentanes like 25 in yields of 90% or more (Scheme 5).15 In 1993, de Meijere et al. reported the first enantiomerically pure unbranched [4]triangulane, (M)-(−)-trispiro[]nonane (32),8g which was obtained in six steps from racemic bicyclopropylidenecarboxylic acid rac-26 in an overall yield of 6% (Scheme 6).8h The optical resolution of rac-26 using dehydroabietylamine as resolving agent furnished (S)-(+)-26 and (R)-(−)-26. The ethyl ester (R)-27 of the latter was cyclopropanated to give ethyl (1R,3R)- and (1R,3S)-[3]triangulane-1-carboxylates (1R,3R)-28 and (1R,3S)-28. Carboxylate (1R,3S)-28 was converted into (M)-(−)-32 with 99% ee B | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 6. First Synthesis of the Enantiomerically Pure Unbranched [4]Triangulane8g

Scheme 7. Synthesis of Enantiomerically Pure Unbranched [5]Triangulanes8j

Scheme 8. Synthesis of a Branched Triangulane8e,18

to increase the number of cyclopropane rings, these compounds were also used as precursors to the enantiomerically pure [5]triangulanes (P)-35 and (M)-35 (Scheme 7). Thus, the addition of ethoxycarbonylcarbene, generated by decomposition of ethyl diazoacetate in the presence of dirhodium tetraoctanoate, onto (R)-31 and (S)-31 furnished the enantiomerically pure esters (1S,3R,4R)-(+)-33 and (1R,3S,4S)-(−)-33 in 19% and 27% isolated yields, respectively, which were isolated by simply distilling off the other three diastereomers in each case over a concentric-tube column. The enantiomerically pure esters 33 were transformed to the enantiomerically pure [5]triangulanes (P)-35 and (M)-35 in four routine steps. Cyclopropanation of the latter under the conditions mentioned above furnished the enantiomerically pure (M)-(−)- and (P)-(+)-[5]triangulane (M)-(−)-35 and (P)-(+)-35 in 55% and 52% yields, after gas chromatographic separation in the last step (Scheme 7), corresponding to a 5% and 9% overall yield from the methylene[3]triangulanes (R)-31 and (S)-31, respectively, with >94% ee for both.8j In continuing development of this strategy for the efficient synthesis of enantiomerically pure unbranched [n]triangulanes having different lengths, de Meijere et al. have achieved impressive results. They synthesized a whole family of such oligospirans, containing 4−15 spiroannelated cyclopropane units.8g,j,17 Ethoxycarbonyltriangulanes have been widely used in the preparations of higher members in the triangulane family. de Meijere et al. note that sterically congested tetraspirocyclopropanated bicyclopropylidenes such as 36, when treated with ethyl diazoacetate in the presence of [Rh(OAc)2]2, can yield byproducts such as 38 by ring expansion (Scheme 8).8e,18 The preparation of optically active spiro[2.2]pentanes 40, 43, and 46 by exhaustive cyclopropanation of 1,2-dienes 39, 42,

Scheme 9. Copper-Catalyzed Cyclopropanation of 1,2Dienes19

by reduction to the alcohol exo-(1R,3S)-29 for the conversion to the bromide exo-(1R,3S)-30 followed by dehydrobromination to (S)-1-methylene[3]triangulane (S)-31 and the Pdcatalyzed cyclopropanation with diazomethane in the final step. The cycloadditions of various carbenes onto bicyclopropylidene and its derivatives to give various dispiro[]heptane derivatives are well covered in several surveys.16 Due to the appropriate position of the methylene group in methylene[3]triangulanes (R)-31 and (S)-31, which allows one C | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 10. Catalytic Cyclopropanation in the Synthesis of Cycloalkane-Annelated Triangulanes20

Scheme 11. CuCl-Catalyzed Cyclopropanation in the Synthesis of Unbranched Triangulanes21b

Scheme 13. Synthesis of Mono- and Oligoalkoxycarbonyl Triangulanes23f

and 45 with diazomethane in diethyl ether catalyzed by chiral copper(II) complexes deserves particular attention. This was first demonstrated by Noyori et al. (Scheme 9).19 Employing the cyclic allene 48 or alkylidenecyclopropanes 51, 53, and 54 in the reaction with diazomethane 10 under palladium catalysis, various cycloalkane-annelated spiropentanes and dispiro[]heptanes 50, 52, 55, and 56 could be prepared (Scheme 10).20 In the case of CuCl-catalyzed cyclopropanation of bicyclopropylidene (57) and dicyclopropylidenemethane (59), dispiro[]heptane ([3]triangulane) 19 and trispiro[]nonane ([4]triangulane) 32 have been prepared in 80% and 30% yields, respectively (Scheme 11).21 CuCl-catalyzed cyclopropanation with diazomethane has been used22 to prepare functionally substituted spiropentanes. For example, cyclopropanation of the trans- and cis-isomeric ethylidenecyclopropanecarboxylates 60 and 63 with an excess of diazomethane 10 in the presence of CuCl provides two diastereomeric ethoxycarbonylspiropentanes, 61 and 62, as well as 64 and 65. The spatial arrangement of substituents in the starting materials 60 and 63 apparently influences both the

efficiency of the methylene addition (60% vs 90% yield) and the diastereomeric ratio (1:1 vs 7:1) (Scheme 12). Mono- and oligoalkoxycarbonyltriangulanes were prepared by metal-catalyzed cycloaddition of alkyl diazoacetates onto methylenecyclopropane derivatives or diazomethane to alkoxycarbonyl-substituted methylenecyclopropanes.23 Examples for both types of transformations are shown for Feist’s ester 67 (Scheme 13). Palladium-catalyzed selective single- and 2-fold cycloadditions of cyclic diazo compounds like diazocyclopentane, generated in situ by oxidation of the corresponding hydrazones like 70 (n = 1), to C60 fullerene 69 give spiroannelated fullerene derivatives of types 71−74. Bi- and oligocyclic diazo compounds 76, 77, 79 provide derivatives of pinane, adamantane, and steroids 75, 78, 80, and 81, respectively, with a spiroannelated C60 fullerene moiety (Schemes 14 and 15).24,25 Fox et al. recently reported the Rh2(OPiv)4-catalyzed cyclopropanation of 4-chlorostyrene 83 with the α-diazocyclohexanone 82 providing the spiro[2.5]heptanone 84 in 63% yield and with a diastereoselectivity of 93:7 (Scheme 16).26 Racemic 1-aminospiropentanecarboxylic acid (R/S-88) was prepared by Rh-catalyzed addition of dimethyl diazomalonate to methylenecyclopropane (85) and subsequent Curtius degradation of the half ester 87 (overall yield 14%) (Scheme 17).27

Scheme 12. Cyclopropanation of Ethylidenecyclopropanecarboxylates22

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Scheme 14. Palladium-Catalyzed Cycloadditions of Cyclic Diazo Compounds to C60 Fullerene24

Scheme 15. Palladium-Catalyzed Cycloadditions of Oligocyclic Diazo Compounds to C60 Fullerene25

The above-described reactions mainly catalyzed by Cu and Rh complexes were used to construct three-, four-, five-, and six-membered spirocarbocycles in total syntheses of numerous natural compounds. For example, under the action of CuSO4 as a catalyst, the diazo ketone 89 was converted to the intermediate 90, which was transformed to (±)-modhephene 91 in a number of consecutive reactions (Scheme 18).29 The Rh-catalyzed intramolecular decomposition of the diazo ester 92 leads to the spirocyclopentane-annelated cyclobutanone 93 in 55% yield (Scheme 19).30 Later, it was found that the nature of the ligand in the Rh catalyst considerably affects the selectivity in favor of formation of spirocyclopentane-annelated cyclobutanone or a 1,2-cyclo-

Scheme 16. Rhodium-Catalyzed Cyclopropanation of 4Chlorostyrene with α-Diazocyclohexanone26

In recent years, numerous examples for the use of diazocarbonyl compounds for the selective formation of carbon−carbon bonds by carbene insertion into a carbon− hydrogen bond have been reported. This line of research is becoming important for organic synthesis.28 E | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 17. Rhodium-Catalyzed Cyclopropanation with Dimethyl Diazomalonate in the Synthesis of 1Aminospiropentanecarboxylic Acid27

Scheme 18. Total Synthesis of (±)-Modhephene29

Catalyzed reactions of diazo ketones for the construction of spiroannelated cyclopentanes have also been successfully used in the key steps of the syntheses of gibberelline A12 102, (±)-isocomenic acid 106, (±)-epiisocomenic acid 107, (±)-retigeranic acid 108, epiisocomene 112, pentalenene 116, and pentalenic acid 117 (Scheme 22).33−39 The same approach was used to prepare a series of []and []fenestrane derivatives. For example, the diazo ketone 118 upon treatment with dirhodium tetraacetate as a catalyst in dichloromethane instantaneously decomposes to afford the tetracyclic ketoacetal 119 in high yield. Note that the formation of the five-membered ring in these reactions is stereospecific (Scheme 23).40−42 In addition to the above-described transformations of diazo ketones, another known reaction is catalytic decomposition of diazocarbonyl compounds containing a heteroatom in the allylic position to the C−H bond into which the carbene is inserted. The ylides thus formed and their subsequent [2,3]sigmatropic rearrangement constitute a significant tool in organic synthesis to approach intricate molecular cages, and, for example, spiroalkane natural products (Scheme 24).43 A similar approach to spirocarbocycles was utilized in the stereoselective synthesis of the sesquiterpene (+)-acorenone A 125 (Scheme 25). The intramolecular analogue of the cyclopropanation of aromatic compounds known as the Buchner reaction can also be counted as a method for the preparation of spiro compounds. In most cases, however, cyclopropanation products like 127 exist in dynamic equilibrium with the corresponding cycloheptatrienes like 128, which are the more stable valence tautomers (Scheme 26).44−46 A study of the diastereoselectivity of the intramolecular cyclization of chiral α-diazo ketones of type 129 demonstrated that, in each case, the trans-diastereomer 130 is formed predominantly, and its relative amount tends to increase with an increase in the size of the β-substituent (Scheme 27).44−46 Davies et al. have shown that vinyldiazoacetates 133 react with cyclic enol ethers 132, 135a−c under catalysis of the binuclear gold complex (R)-DTBM-Segphos(AuCl)2 activated

Scheme 19. Rhodium-Catalyzed Intramolecular Decomposition of a Diazo Ester30

Scheme 20. Rhodium-Catalyzed Decomposition of an αDiazo-β-ketoester31

pentane-annelated cyclopentanone. Indeed, the catalytic decomposition of α-diazo-β-ketoester 94 induced by rhodium(II) acetamidate favors the formation of the spiroannelated cyclobutanone 96 in a ratio 14:86, whereas the use of rhodium(II) triphenylacetate in this reaction predominantly gives the 1,2-annelated cyclopentanone 95 in 75% yield with a selectivity of 96:4 (Scheme 20).31 Hashimoto et al. succeeded in performing a 2-fold cyclization of the bis(α-diazo-β-ketoester) 97 by means of a Rh(II)complex-based catalyst to produce the spirobiindanone derivative 99, which, without purification, was transformed by demethoxycarbonylation to give 1,1′-spirobi[Indane-3,3′dione] (99) in 78% yield (Scheme 21).32 Scheme 21. Synthesis of 1,1′-Spirobi[indane-3,3′-dione]32

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Scheme 22. Catalytic Intramolecular Cyclization in the Synthesis of Natural Cyclopentanoids33−39

dialkenyl (mainly allyl) groups or an alkenyl group and an adjacent cyclopentene ring. This is exemplified in Scheme 29, which shows some cases of cyclization of gem-diallyl substrates, resulting in the corresponding spirocarbocycles in 92−98% yields under mild conditions. The synthesis of the benzospiro[4.5]decadienone 140, which is the precursor of an important therapeutic agent used as an ACAT-inhibitor, served as an example to demonstrate that second-generation Grubbs catalysts are able to provide only the desired ketone 140, while upon use of first-generation catalysts, the formed ketone 140 is accompanied by a considerable amount of the isomerized product 141.48−56 Recent years have brought forward a large number of publications dealing with the synthesis of natural compounds or intermediate building blocks using an approach based on the ring-closing metathesis of gem-diallyl derivatives.57−60 Harrity et al. have shown61 that 2-fold ring-closing metathesis of the tetraene 148 affords spiro[5.5]nona-1,6-diene (149) in almost quantitative yield under mild conditions (Scheme 30). The same group reported the 2-fold addition of allylmagnesium chloride to the previously obtained diketone 150 and the subsequent 2-fold ring-closing metathesis of the resulting diastereomeric diols 151a,b to the tricyclic spirane-type diols 152a,b (Scheme 31).62 In contrast, the spiro[4.4]non-7-ene-1,4-diols 153 and 156 with one vinyl and one allyl or longer alkenyl chain in the 1and 4-positions under carbeneruthenium catalysis underwent

Scheme 23. Synthesis of Fenestrane Derivatives by Catalytic Decomposition of Diazo Ketones41

by silver hexafluoroantimonate to yield spiroannelated [3π+2π]-cycloadducts 134, 136a−c with a high degree of enantioselectivity (Scheme 28).47 The reaction is initiated by nucleophilic attack of the vinyl ethers at the vinylogous position of the vinylcarbenegold intermediate.

3. ALKENE METATHESIS WITH GRUBBS CATALYSTS IN THE SYNTHESIS OF SPIRANS The ring-closing metathesis of alkenes is among the most successful and effective methods for introducing a spiroannelated cyclopentene or cyclohexene moiety, which are the most abundant ring sizes in complex biologically active natural compounds. Moreover, these reactions became much more facile and versatile with the advent of the second-generation Grubbs catalysts, which have higher stability against moisture and oxygen (Figure 2). In general, the preparation of spirocarbocycles by alkene metathesis is performed using substrates containing gem-

Scheme 24. Catalytic Decomposition of Heteroatomic Diazocarbonyl Compounds43

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Scheme 25. Stereoselective Synthesis of (+)-Acorenone A43

Scheme 26. The Intramolecular Buchner Reaction44

isocomene 174 (R = Me). In the presence of dicobaltoctacarbonyl in benzene, the enyne 171 is reproducibly converted to the tricyclic enone 172 (R = H) in about 35% yield (Scheme 36). Subsequently, this same group used an analogous approach to perform a highly stereoselective synthesis of the sesquiterpene pentalenene in high yield.69 In 1996, Moyano and Pericas et al. have demonstrated for the first time that a structurally complex angular triquinane, (+)-15-norpentalenene 177, can be obtained in a short, convergent, and enantioselective manner by a process involving an intramolecular Pauson−Khand reaction in which the stereochemical control is exclusively effected by a peripheral, eliminable chiral alkoxy group (Scheme 37). The absolute configuration of (+)-15-norpentalenene is the same as that in natural (+)-pentalenene.70 In 2007, an enantioselective synthesis of (−)-pentalenene 180 was reported by Fox et al.71a Catalytic enantioselective cyclopropanation with (R,R)-Rh2(OAc)(DPTI)3 was used to set the correct absolute configuration on the cyclopropene ring in the precursor enyne 178, and an intramolecular Pauson− Khand reaction of the alkynyl-substituted cyclopropene 178 was used to establish the quaternary center of the resulting tricyclic compound 179, which was converted in several further steps into the target molecule 180 (Scheme 38).71 Serratosa et al.72 observed an unexpected double bond migration in bicyclo[3.3.0]oct-2-ene (181) preceding the intermolecular cocyclization with the dicobalthexacarbonyl complex 182; the resulting product 183 was employed in an original approach to other hard-to-access spirocarbocyclic triquinanes of type 183 (Scheme 39). Intramolecular cocyclizations involving acetylenehexacarbonyldicobalt complexes proved rather fruitful in the synthesis of a number of natural terpenes. Thus, the key intermediate in a synthesis of α- and β-cedrene, cedrone 186, was obtained in high yield by such an intramolecular cyclization of the enyne complex 184 to the corresponding cyclopentenone derivative 185, which was converted to α- and β-cedrene 187 and 188 in a sequence of further transformations (Scheme 40).73 An analogous approach was employed74 toward the key intermediate 190 in a total synthesis of the diterpene crinimpelline A by heating the hexacarbonyldicobaltacetylene complex 189 for several hours, to give the angularly fused tetracyclic diketone 190 in 73% yield (Scheme 41). The dicobaltoctacarbonyl-mediated intramolecular Pauson− Khand reaction of the enynes 191 with a bicyclopropylidene

ring-rearrangement metathesis (RRM)63a through relaying cyclohexene and cycloheptene moieties to give the angularly fused tricyclic compounds 154, 155, and 157 (Scheme 32).63b In 2008, Stoltz et al. accomplished the total synthesis of (+)-laurencenone B 160 and (+)-elatol 161 using a ring-closing metathesis of the 6-(2-chloroallyl)-6-(2-methylbuten-4-yl)cyclohexenone derivative 158 as a key step (Scheme 33).64 A domino of two consecutive Michael additions was used to construct the skeleton 162 of the bicyclo[2.2.2]octane derivative 163, which, by a subsequent ring-closing metathesis, gave the spirocyclohexenone-annelated bicyclo[2.2.2]octane 165 as precursor to paclitaxel mimetics (Scheme 34).65 These examples demonstrate that ring-closing intramolecular metatheses of various gem-diallyl- or gem-dialkenylcycloalkane and -bicycloalkane derivatives induced by Grubbs catalysts can be successfully employed for one-pot syntheses of valuable, both natural and synthetic spiroannelated carbocycles and carbobicycles with intricate structures.

4. THE PAUSON−KHAND REACTION IN THE SYNTHESIS OF SPIROCARBOCYCLES The Pauson−Khand reaction,66 discovered in 1973, is currently widely used in organic synthesis as a convenient and fairly effective method for the construction of the cyclopentenone moiety. In addition, the intramolecular version of this reaction has also been used by some researchers to construct spiroannelated cyclopentenone moieties in the synthesis of a broad range of natural products, including certain alkaloids,67 and terpenes like isocomene, pentalenene, α- and β-cedrene, as well as crinipelline A. For example, by combining an intramolecular Pauson− Khand reaction of the enyne 168 with a subsequent radical cyclization, the angular azatriquinane 170 was obtained in a fairly high yield (Scheme 35).68 Earlier, Schore et al. employed the intramolecular Pauson− Khand reaction as a key step to construct the bisdesmethyl analogue 174 (R = H) of the naturally occurring sesquiterpene

Scheme 27. Diastereoselective Intramolecular Cyclization of Chiral α-Diazo Ketones46b

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Scheme 28. Gold(I)-Catalyzed Vinylogous [3π+2π] Cycloadditions of Enol Ethers and 1-(Methoxymethylene)cycloalkanes47

Scheme 30. Two-fold Ring-Closing Metathesis in the Synthesis of Spiro[5.5]nona-1,6-diene61

Figure 2. The first- and second-generation Grubbs catalysts.

analogues75b as well as 196a−c75c to give spirocyclopropanated bicyclo[3.3.0]octenones such as 195 as well as the enantiomerically enriched derivatives 197a−c in good yields (Scheme 43). Tetracarbonylnickel-mediated cocyclization of 1-bromomethylcycloalkenes 198 with alkynes has been shown to be a useful alternative to the Pauson−Khand reaction for the onepot synthesis of spirocyclopentenone-annelated cycloalkanecarboxylates 200 (Scheme 44). The latter were obtained in good yields and with total stereocontrol, when the homologues 198 were treated with 2-butyn-1-ol or methyl 2-butynoate and Ni(CO)4 in methanol at 40 °C.77a,b Such spiro compounds can be prepared in optically active form by employing the chiral acetylenic sulfoxide 202, which, for example, reacts with 1-

moiety leading to the tricyclic spirocyclopropanated cyclopentenone 192 in 30−45% yields, carried out by de Meijere et al., is a vivid demonstration of the unique reactivity of the strained, although tetrasubstituted, double bond in bicyclopropylidene (Scheme 42).75a,76 Co(I)-mediated intramolecular [2π+2π+2π] cocyclizations of (bicyclopropylidenyl)diynes also proceeded with retention of both cyclopropane rings and afforded Co-complexed tricyclo[,6]dodeca-1,6-dienes, with a spirocyclopropane moiety in moderate to good yields.76 An enhanced reactivity in Pauson−Khand reactions was also demonstrated for methylenecyclopropane moieties with the intramolecular cocyclization of the 1,6-enyne 19475a and

Scheme 29. Ring-Closing Metathesis of gem-Diallyl Derivatives48−56

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Scheme 31. Two-fold Ring-Closing Metathesis of cis- and trans-1,4-Diallylspiro[4.4]non-7-ene-1,4-diol62

out in the presence of phenylacetylene, furnishes the cyclobutane-annelated tricycle 209 in 87% yield without incorporation of the phenylacetylene (Scheme 46).79b The heterogeneous catalyst has the significant advantage of being removable by simple filtration and reusable. In 1992, Keese et al. reported a one-pot synthesis of the []fenestranedione 211 by tetracyclization of the branched open-chain enediyne 210 with incorporation of two molecules of CO from Co2(CO)8.80 Obviously, the sequence of events starts with a Pauson−Khand reaction involving one of the 1,6-enyne units in 210 providing 8trimethylsilyloxybicyclo[3.3.0]oct-1-en-3-one, which undergoes a second cocyclization with CO to afford the fenestrane product 211 (Scheme 47). All of these examples clearly demonstrate that the Pauson− Khand reaction is an efficient synthetic tool for the construction of cyclopentenones by intermolecular as well as intramolecular [2π+2π+1π] cocyclization of an alkyne, an alkene, and CO, mediated by carbonylcobalt complexes, and thus provides the possibility of targeted syntheses of spirocarbocycles of specified structures. Another versatile way of constructing five-membered carbocycles is the so-called cycloisomerization of 1,6-enynes under catalysis of palladium and ruthenium complexes as developed by Trost et al.81 An enantioselective rhodium-catalyzed version of this transformation has been employed by Nicolaou et al. to convert the cyclohexa-1,4-dienone 212 with its 1,6-enyne moiety into the spiro[4.5]decadienone 213 as the key intermediate in a total synthesis of the natural antibiotic (−)-platensimycin 214 (Scheme 48).82

Scheme 32. Formation of Angular Tricyclic Compounds by Ruthenium-Mediated Ring-Rearrangement Metathesis (RRM)63b

(bromomethyl)cyclooctene (201) to give only two epimers of the optically active cyclopentenone 203 in moderate yield, but with an excellent diastereoselectivity of 82:18.77c,d The intermolecular cocyclization of the alkynylhexacarbonyldicobalt complexes 204 with methylenecyclobutane (9) provides an equimolar mixture of the spiro[3.4]octenones 205 and 206 (Scheme 45).78 Lee et al. have shown that intra- as well as intermolecular Pauson−Khand reactions can be efficiently performed with cobalt on charcoal (Co/C) as a heterogeneous catalyst under 20−30 bar of CO. The cyclopentenones are isolated in yields mostly above 90%.79a Analogous cocyclization with CO under Co/C-catalysis has been developed by the same group for alkynes. Thus, the dipropargylmalonate 208 and analogous 1,6diynes upon heating at 130 °C in the presence of Co/C under 30 bar of CO underwent an interesting cascade reaction to give a 1:1 mixture of the two regioisomeric angularly fused tetracycles 207a and 207b in 72% yield.79b Upon extended (18 h) heating at 150 °C in tetrahydrofuran, 207a isomerizes to 207b, while the original reaction of 208 with CO, when carried

5. CATALYZED CYCLOADDITIONS IN THE SYNTHESIS OF SPIRANS Quite a few examples for the synthesis of spirocarbocycles by catalytic homodimerization, cooligomerization, and cycloaddition involving methylenecyclopropanes have been reported in the literature.83 The nature of the central atom of the catalyst

Scheme 33. Ring-Closing Metathesis in the Total Synthesis of (+)-Laurencenone B and (+)-Elatol64

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Scheme 34. Formation of Spirocyclohexenone-Annelated Bicyclo[2.2.2]octanes by Ring-Rearrangement Metathesis (RRM)65

Scheme 35. An Intramolecular Pauson−Khand Reaction in the Synthesis of an Angular Azatriquinane68

Scheme 36. An Intramolecular Pauson−Khand Reaction in the Synthesis of Bisnorisocomene69

Scheme 37. Enantioselective Synthesis of (+)-15-Norpentalenene70

Scheme 38. Enantioselective Synthesis of (−)-Pentalenene71a

spiro[2.9]dodecadienes 218a,b as cocyclization products with butadiene are formed in high yields (∼90%) (Scheme 49).85b,c A Ni(cod)2-catalyzed [2π+2π] cycloaddition of methylenecyclopropane (85) to norborna-2,5-diene (219) occurs under mild conditions at one of the double bonds to give endotricyclo[,5]non-7-ene-3-spirocyclopropane (220) in 86% yield (Scheme 50).86 Tetramethylmethylenecyclopropane (221) reacts with methyl acrylate (222) in the presence of Ni(cod)2 to give methyl tetramethylspiro[2.3]hexanecarboxylate (223) as the major product in 75% yield (Scheme 51).87 The formal [2π+2π] cycloaddition of cyclobutene (226) to bicyclopropylidene (57) catalyzed by Ni(0) yields 2,3-

Scheme 39. The Pauson−Khand Reaction in the Synthesis of Triquinanes72

was shown to considerably affect the course of these reactions. Indeed, methylenecyclopropane 85 [≡216 (R = H)] under palladium catalysis mainly undergoes homodimerization to give 5-methylenespiro[2.4]heptane 215, even in the presence of 1,3butadiene,84,85 but under nickel catalysis, regioisomeric K | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 40. Total Synthesis of α- and β-Cedrene73

Scheme 41. Synthesis of the Key Intermediate in a Total Synthesis of the Diterpene Crinimpelline A74

Scheme 44. Tetracarbonylnickel-Mediated Cocyclizations To Provide Spiroannelated Cyclopentenones77

Scheme 42. Bicyclopropylidene Involved in an Intramolecular Pauson−Khand Reaction75a,76

Scheme 43. Intramolecular Pauson−Khand Reactions of 1,6Enynes with Methylenecyclopropane Moieties75

Scheme 45. Methylenecyclobutane Employed in the Pauson−Khand Reaction78

dispirocyclopropanebicyclo[2.2.0]hexane (227) and 1,5-cyclooctadiene (224) in a 1:2 ratio. The latter apparently results from the ring-opening rearrangement of tricyclo[,5]octane, the cyclobutene dimer (Scheme 52).88a,b In contrast, under nickel(0) catalysis [Ni(cod)2, PPh3, toluene, room temperature], bicyclopropylidene (57) underwent cocyclization with two molecules of propargyl benzyl ether to yield the two isomeric dispiro[]deca-7,9-diene derivatives 229a and 229b (ratio 2:1), whereas several other terminal alkynes including propargyl methyl ether under the same conditions gave moderate to high yields of 7cyclopropylidenedispiro[]undec-10-ene derivatives 231 by cocyclization of one molecule of the alkyne with two molecules of 57, one of which reacted with ring-opening (Scheme 52).88c

A remarkably simple and efficient access to 13,14dicyclopropyltetraspiro[]tetradec-13-ene (233Cpr) has also been uncovered. Upon treatment of a 2:1 mixture of bicyclopropylidene (57) and dicyclopropylacetylene 232-Cpr in benzene solution with bis(cyclooctadiene)nickel in the presence of triphenylphosphine at 20 °C, 233-Cpr was obtained in 73% yield. In the context of other nickel(0)catalyzed cocyclizations of 57 with terminal alkynes (see above), the formation of 233-R (Scheme 52) must be interpreted to proceed via the tetraspirocyclopropanated nickelacyclopentane (234), but without a cyclopropylcarbinylmetal to homoallylmetal rearrangement as described above. Other 13,14-disubstituted tetraspirotetradecenes 233-R with R = Ph, CH2OMe were prepared from 57 and the corresponding symmetrically disubstituted acetylenes 232-R as well, albeit in lower yields (25% and 36%, respectively). In the crystal, 233Cpr adopts a twist-chair conformation.8b Under silver-salt catalysis, 227 rearranged at ambient temperature, apparently in a cascade of cyclopropylcarbinyl to cyclobutyl cation rearrangements, to yield the chiral cyclohexene-annelated spiro[3.3]heptane 235.88a,b Catalytic hydroL | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 46. Heterogeneous Catalysis of an Analogue of the Pauson−Khand Ractiona


E = CO2Et.79b

reactions depends both on the nature of the central atom of the catalyst and on the ligand environment (Scheme 57).93,94 The [2π+2π+2π] cyclocotrimerization of disubstituted acetylenes 232 with the gem-dipropargyl indanedione 257 catalyzed by cyclopentadienyldicarbonylcobalt gives rise to 2,2′spirobiindan-1,3-dione derivatives 258 in 22−26% yields (Scheme 58).95 A different methodology for the enantioselective construction of various chiral skeletons including spiro compounds relies on Rh(I)-catalyzed [2π+2π+2π] cycloadditions.96a In 2006, Shibata et al. described an enantioselective Rh-catalyzed [2π+2π+2π] cocyclization to yield spirocarbocycles such as 261, in which the quaternary carbon is the stereogenic center (Scheme 59).96b,c This example involves one intra- and one intermolecular cycloaddition of a diyne 259 and 2-methylenecyclopentanone (260), respectively, and proceeds via an achiral bicyclic metallacyclopentadiene intermediate 262 with a chiral ligand on rhodium. The subsequent insertion of the 1,1disubstituted alkene 260, followed by reductive elimination, apparently occurs with a high degree of facial selectivity to yield the enantiomerically enriched 261. Tanaka et al. developed an all-intramolecular 2-fold [2π+2π+2π] cocyclization of bis-diynyl-substituted malononitriles 264 (n = 1), which proceeded in the presence of 5−10 mol % [Rh(cod)2]BF4/Segphos or H8−BINAP to give the C2symmetric spirobipyridines 265 in 70−99% yield and with 47− 71% ee values.96d Spirobipyridines 263 with a spiro[5.5]undecane skeleton could be also obtained along this route from 264 (n = 2) in high yields (Scheme 60). The palladium-catalyzed cycloaddition of phenyldiazonium salts 266 to disubstituted acetylenes 232 follows an absolutely unusual route producing spiro[4.5]decatetraenones 267 in up to 90% yield (Scheme 61).97 On the basis of their own results and literature precedence, the authors proposed a mechanistic

Scheme 47. Sequential Two-fold Pauson−Khand Reaction of a Branched Open-Chain Enediyne To Yield a []Fenestranedione80

genation of 227 proceeded with addition across the central single bond in the bicyclo[2.2.0]hexane moiety and predominant concomitant opening of a proximal bond in each of the two adjacent spirocyclopropanes (Scheme 53).88d Binger et al.89 and de Meijere et al.75d found that bicyclopropylidene (57) undergoes a Pd(0)-catalyzed cocyclization with electron-deficient alkenes with opening of one cyclopropane ring, giving rise to 4-methylenespiro[2.4]heptanes 240−242, 244 (Scheme 54). Unlike Ni- and Pd-based metal complex catalysts, Rh complexes initiate a selective tetramerization of propadiene (245) to give 1,4,7-trimethylenespiro[4.4]nonane (246), the yield of which depends appreciably on the ligand environment of the catalyst central atom (Scheme 55).90,91 Cocyclization of 3,3-disubstituted cyclopropenes 247 with methylenecyclobutane (9) induced by Cu complexes mainly affords substituted spiro[2.3]hexanes 248 in 30−70% yields. Apart from cyclocodimers, homodimers are also formed (Scheme 56).92 Di-, tri-, and tetraspirocarbocycles can be prepared by catalytic cyclooligomerization of spiro[2.3]hex-1-ene (251) and spiro[2.4]hept-1-ene (254). The chemoselectivity of these

Scheme 48. An Enantioselective Rhodium-Catalyzed 1,6-Enyne Cycloisomerization To Construct a Spiroannelated Cyclopentane in the Total Synthesis of (−)-Platensimycin82

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Scheme 49. Catalytic Homodimerization and a Cocyclization with 1,3-Butadiene of Methylenecyclopropanes to Spirocyclopropane-Annelated Carbocycles84,85

Scheme 50. Nickel-Catalyzed [2π+2π] Cycloaddition of Methylenecyclopropane to Norborna-2,5-diene86

Scheme 53. Some Catalytic Transformations of Dispiro[cyclopropane-1,2′-bicyclo[2.2.0]hexane-3′,1″cyclopropane]88b,d

Scheme 51. Catalytic [2π+2π] Cycloaddition of a Methylenecyclopropane to Methyl Acrylate Yielding Methyl Tetramethylspiro[2.3]hexanecarboxylate87

Scheme 54. Palladium-Catalyzed Cocyclization of ElectronDeficient Alkenes with Bicyclopropylidene75d,89 Scheme 52. Nickel(0)-Catalyzed Cocyclizations of Cyclobutene and Alkynes with Bicyclopropylidene88

Scheme 55. Catalytic Tetramerization of Propadiene To Yield 1,4,7-Trimethylenespiro[4.4]nonane90

scenario starting with the oxidative addition of the diazonium cation A to Pd0 to give the Pd-σ-aryl complex B (Scheme 61). A cis-selective sequential 2-fold carbopalladation resulting in D then follows, and the latter undergoes an intramolecular carbopalladation with ipso-attack on the aromatic ring to yield

the π-allylpalladium intermediate E, which, by deprotonation, yields the products 267. N | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 56. Copper-Catalyzed Cocyclization of 3,3Disubstituted Cyclopropenes with Methylenecyclobutane92

Scheme 58. Cobalt-Catalyzed [2π+2π+2π] Cyclocotrimerization of Acetylenes95a

An interesting intramolecular cascade cyclization of 1,6-dien11-ynes 268 occurs under the action of 4% [RuCl2(CO)3]2 as a catalyst and furnishes tetracyclic spirans of type 269 in 62−84% yields (Scheme 62).98 Such skeletons would be difficult to obtain along any other route. Murai et al. postulated that this reaction involves the initial formation of the ruthenacyclopentene 272, which undergoes a retro-vinylcyclopropane-cyclopentene rearrangement instead of β-hydride shift, thus giving the ruthenium carbenoid 273. A subsequent intramolecular cyclopropanation, presumably through the ruthenacyclobutane 271, furnishes the observed spirocarbocycle 269 (Scheme 63). By analogy, a number of cycloheptyl- or cyclooctylsubstituted 1,5-enynes 274 and 1,4-enallenes 276 undergo an Au(I)-catalyzed cycloisomerization/C−H insertion reaction (Scheme 64).99 Along with [4π+3π+2π] cocyclizations, Ogoshi and Saito et al. also observed [4π+2π+2π] and [2π+2π+2π] cocyclizations of methylenecyclopropane and ethyl cyclopropylideneacetate, respectively, with dienynes of type 278 under nickel(0) catalysis to provide the spirocyclopropanated bicyclo[6.3.0]undecadiene 279 and bicyclo[4.3.0]nonene 281, respectively, in moderate to good yields (Scheme 65).100 The construction of the interesting pentacyclic spirans 283 and 285 has been achieved by cobalt-catalyzed intramolecular [2π+2π+2π] and [2π+2π+4π] cycloadditions of the alkynyland alkadienyl-tethered norbornadiene derivatives 282 and 284, respectively (Scheme 66), according to reports by Lautens et al.101 In the authors’ opinion, Co(acac)2 can also be used as the catalyst, but Co(acac)3 ensures higher yields. A similar concept of transition metal-promoted higher-order cycloaddition reactions has been designed by Rigby et al.102 With the thermal as well as photochemical intramolecular versions of [6π+2π] and [6π+4π] cycloadditions that tricarbonylchromium complexes of cycloheptatrienes 286 and 288 with alkenyl and alkadienyl tethers undergo, tricyclic

spirans 287 and 290, respectively, are formed in up to 90% yield (Scheme 67).102b Analogous formal intramolecular [6π+2π] cycloadditions were observed for 1-pent-4-ynyl-tethered cycloheptatrienes 291 under PtCl2 catalysis at ambient temperature to afford bicyclo[4.2.1]nona-2,4,7-trienes 292 (n = 1) with 1,8-annelated five-membered rings that constitute tricyclic spirans as well (Scheme 68).103 A single example of a 1-hex-5-ynyl-tethered cycloheptatriene 291 (n = 2) was tested successfully to give the corresponding cyclohexane-annelated tricycle 292 (n = 2, R1 = R2 = CO2Me), but only at elevated temperature and under an atmosphere of CO. According to a development of Hayashi et al., spiro[2.4]heptane derivatives of type 295 can be prepared by a Pdcatalyzed cocyclization of substituted γ-methylene-δ-valerolactones of type 293 with electron-deficient alkenes like methyl acrylate (222, EWG = CO2Me). Depending on the point of the intramolecular nucleophilic attack on the π-allylpalladium intermediate 294, be it C-2 or C-1, the reaction yields either the spiran 295 or the formal [4π+2π] cycloaddition product 296 (Scheme 69). With triisopropyl phosphite as an added ligand, the spiro[2.4]heptanedicarboxylate 295 (EWG = CO2Me, Ar = Ph) is obtained in 86% yield, and the methylenecyclohexanedicarboxylate is formed as a minor byproduct (5%). With other phosphorus ligands, the yield of the latter can be up to 29%. Ethyl acrylate, t-butyl acrylate, and acrylonitrile instead of methyl acrylate as well as a variety of other aryl-substituted γ-methylenevalerolactones of type 293 have been employed in this reaction to give the correspondingly substituted spiro[2.4]heptane derivatives of type 295 in 77−97% yields.104 The spiro[4.5]decanedione 299 was synthesized in 23% overall yield by successive transformations of the cyclic enone 297 including an intramolecular photochemical [2π+2π] cycloaddition and an oxidative cleavage with in situ generated RuO4 of the resulting tricyclic cyclobutene derivative 298 (Scheme 70).105

Scheme 57. Catalytic Cyclooligomerization of Spiro[2.3]hex-1-ene and Spiro[2.4]hept-1-ene94

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Scheme 59. An Enantioselective Rhodium-Catalyzed [2π+2π+2π] Cocyclization96b

Scheme 60. Rhodium-Catalyzed Two-fold [2π+2π+2π] Cocyclizations of Bisdiynyl-Substituted Malononitriles96d

Scheme 61. Palladium-Catalyzed [2π+2π+1π] Cocyclization of Disubstituted Acetylenes with Phenyldiazonium Salts97

Scheme 63. Proposed Mechamism for Ru-Catalyzed Tetracyclization of 1,6-Diene-11-ynes98

Scheme 62. An Intramolecular Tetracyclization of 1,6-Dien11-ynes Catalyzed by [RuCl2(CO)3]298

in the presence of TiCl4 to produce the benzospiro[4.5]decanone 302 in 86% yield (Scheme 71).106 Several 2alkylidenecyclopentanones, under the same conditions, gave the correspondingly substituted spiro[4.4]nonanones. Presumably, the one-pot synthesis of the pentacyclic spiran 306 having five stereogenic centers involves the intermediate formation of the dispiro[]tridecanone 304 resulting from a 2-fold cycloaddition of the allylsilane 301 to the 2,5dialkylidenecyclopentanone 303 and subsequent Wagner− Meerwein rearrangement followed by an intramolecular Friedel−Crafts acylation (Scheme 72).107 Hayashi and Shintani et al. showed that the benzospiro[5.5]undecanones 309 (n = 1) are formed in high yields (up to 74%) from 3-(2-alkynylethyl)-2-cyclohexenones 307 (n = 1)

The Lewis acid-promoted [2π+3π] cycloaddition of allylsilanes to 2-alkylidenecycloalkanones is an effective method for the construction of spiran systems. For example, the αmethylenetetralone 300 reacts with allyltriisopropylsilane (301) P | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 64. Gold(I)-Catalyzed Cycloisomerization of 1,5Enynes and 1,4-Enallenes99

Scheme 67. Intramolecular [6π+2π] and [6π+4π] Cycloadditions of 7-Alkenyl- and 7-Alkadienyl-Tethered 1,3,5-Cycloheptatrienetricarbonylchromium Complexes102

transformation toward the construction of spirocarbocycles, because along with the formation of new C−C bonds, it is possible to introduce various functional groups into the molecules across the reactive Mg−C bonds. Waymouth et al.,109,110 who studied in detail the cyclization of 1,6- and 1,7-dienes, performed Cp2ZrCl2-catalyzed cyclomagnesiations of the bisallylfluorene 310 with BuMgCl or Bu2Mg to give spiro[4.4]nonanes 311 in up to 95% yield (Scheme 74). The presumed mechanism for the catalytic cyclomagnesiation involves an intermediate formation of a zirconacyclopentane 320, which is transmetalated with the Grignard reagent 312 under the reaction conditions to give the dimagnesium compound 313 with regeneration of the catalytically active species 318. In a competing reaction, the monomagnesium intermediate 316 can undergo β-hydride transfer to directly form the butene adduct 318 and the monomagnesium derivative 317. Waymouth et al. specially note an effect of the nature of the ether solvent on the reaction chemoselectivity. Indeed, the dimagnesium compound 313 is formed faster than the monomagnesium derivative 317 in diethyl ether, while in tetrahydrofuran, the β-hydride transfer to form 317 and the butene complex directly wins (Scheme 75).121 While this research was further extended, it was found that the nature of the initial diene has a considerable effect on the reaction chemoselectivity. For example, the presence of a methoxymethyl group at the terminus of one of the allyl groups as in the 9,9-diallylfluorene 322 does not prevent the system from undergoing carbocyclization under the conditions developed previously, but, instead of the expected methoxymethyl derivative of type 311, it gives the corresponding 1ethenyl-2-methylcycloalkene 323 (Scheme 76). Treatment of the reaction mixture with D3O+ does not lead to any deuterium-containing products, which indicates that the intermediates do not contain any Mg−C bonds.111,112 This outcome was rationalized assuming that the initially formed zirconacyclopentane 324 undergoes β-alkoxide elimination113−115 to give the corresponding alkoxyzirconocene intermediate 326. A subsequent Zr to Mg transmetalation with BuMgCl 312 and final β-hydride transfer furnishes the product 323 with simultaneous regeneration of the catalytically active butenezirconocene intermediate 318 (Scheme 77). Further developments of this type of catalytic carbocyclization of 1,6-dienes with organomagnesium reagents led to interesting asymmetric versions. Indeed, Mori et al. accomplished an intramolecular cyclization of various 1,6-dienes using n-BuMgCl in the presence of the chiral (S)-(EBTHI)Zr(BINOL) catalyst. In this way, carbocyclization of the 1,6-diene

Scheme 65. Ni-Catalyzed [4π+2π+2π] and [2π+2π+2π] Cocyclizations of Methylenecyclopropane and Cyclopropylideneacetate, Respectively, with Dienynes100

Scheme 66. Intramolecular [2π+2π+2π] and [2π+2π+4π] Cycloadditions of Alkynyl- and Alkadienyl-Tethered Norbornadienes Catalyzed by Co(acac)3101

and tetraphenylborate 308 (X = H) under Rh(I) catalysis (Scheme 73).108 The same transformation has been carried out with the analogous cyclopentenone derivative 307 (n = 0, R = Ph) and a series of tetraarylborates 308 (X = H, 4-Me, 4-Cl, 4F, 3-OMe, 3-Cl) to provide the corresponding benzospiro[4.5]decanones 309 (n = 0) in 62−77% yield.

6. INTRAMOLECULAR CYCLIZATION OF ALKENES CATALYZED BY TRANSITION METAL (Zr, Ti, Ru, Au, Rh, Pd, Ni, Fe) COMPLEXES A few known examples of intramolecular cyclomagnesiations of nonconjugated dienes by means of Grignard reagents catalyzed by zirconocene dichloride attest to a high potential of this Q | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 68. Platinum-Catalyzed Intramolecular [6π+2π] Cycloadditions of 1-Alkynyl-Tethered Cycloheptatrienes103

Scheme 69. Palladium-Catalyzed Cocyclization of Substituted γ-Methylidene-δ-valerolactones with Electron-Deficient Alkenes like Methyl Acrylate To Yield Spiro[2.4]heptane-4,6-dicarboxylates104

Scheme 70. A Sequence of Intramolecular [2π+2π] Cycloaddition of a Cyclic Enone and Oxidative Cleavage of a Resulting Tricyclic Cyclobutene Derivative105

Scheme 73. Rhodium-Catalyzed Addition-Cyclization of Tetraarylborates to 3-(2-Alkynylethyl)-2-cyclohexanones108

Scheme 71. [2π+3π] Cycloaddition of Allyltriisopropylsilane to 2-Alkylidenecycloalkanones106

Scheme 74. Zirconocene-Catalyzed Cyclomagnesiation of 9,9-Diallylfluorene109

328 led to the syn-configurated spiro[4.5]decene derivative 329, apparently via the cis-configurated zirconatricycle 330, as the only product in 81% yield and with an enantiomeric exess of 94% (Scheme 78).116

5-Methylenenona-1,8-diene (331) upon treatment with Me3Al in the presence of bis(pentamethylcyclopentadienyl)dimethylzirconium and B(C6F5)3 undergoes an interesting domino-cyclocarboalumination to yield the spiro[4.4]nonylmethylaluminum derivative 332, which, upon oxidation,

Scheme 72. Plausible Mechanism of a Lewis Acid-Promoted Two-fold [2π+3π] Cycloaddition of an Allylsilane to a 2,5Dialkylidenocyclopentanone and Subsequent Rearrangement107

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Scheme 75. Proposed Mechanism for the ZirconoceneCatalyzed Cyclomagnesiations of 1,6-Heptadienes121

Scheme 79. Catalytic Intramolecular DominoCyclocarboalumination of 5-Methylenenona-1,8-diene117a

Scheme 80. An Intramolecular Carbomagnesiation in the Synthesis of a Spiro[4.5]decenone118

furnishes the spiro[4.4]nonylmethanol 333 as a mixture of two diastereomers in 83% yield (Scheme 79).117a Analogous domino reactions were observed by Negishi et al. upon treatment of the triene 331 and its bishomologue 6methyleneundeca-1,10-diene with diethylaluminum chloride in the presence of titanium tetraisopropoxide.117b A method for the preparation of the dimethylspiro[4.5]decenone 337 from 1-chlorocyclopent-1-en-3-one (334) and the dimagnesium reagent 335 in the presence of the copper complex CuBr·Me2S has also been described. Apparently, the reaction comprises two successive steps: initial copper-catalyzed cross-coupling to give the organomagnesium compound 336 and its subsequent intramolecular carbomagnesiation to furnish the desired ketone 337 in 65% yield (Scheme 80).118 Reaction of the titanocene-ethylene complex 338 with methylenecyclopropanes 216 leads to stable titanaspiro[2.4]heptanes 339. Thermal decomposition of 339 at 200 °C gave a mixture of products containing spiro[2.3]hexanes 340 (∼6%), while the reaction of 339 with CO produced an almost quantitative yield of 3-spirocyclopropanecyclopentanone 342 (Scheme 81).119 Suffert et al. developed some remarkable cascade reaction sequences to produce multifunctional []fenestradienes 345, which constitute complex spirocarbocycles.120 The precursor trienynes 344 were obtained from cyclohexenone in nine steps, including a sequential 4-exo-dicyclocarbopalladation/Stille coupling of the propargylic alcohol 343. In the presence of the catalyst P-2 Ni, formed in situ from Ni(OAc)2 and NaBH4 at room temperature (Scheme 82), the trienyne 344 undergoes a cascade of partial hydrogenation of the triple bond, then an 8π electrocyclization, followed by a 6π electrocyclization, leading to []fenestradienes 345 in a one-pot process.120b,c

Scheme 76. Intramolecular Cyclomagnesiation of a Methoxymethyl-Substituted 9,9- Diallylfluorene111

Scheme 77. Proposed Mechanism for the ZirconoceneCatalyzed Cyclomagnesiation of 1,6-Heptadienes Having an Allylic Alkoxy Group

Scheme 78. Enantioselective Carbocyclization of a 1,6-Diene in the Presence of a Chiral Zirconocene Catalyst116

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Scheme 81. Titanaspiro[2.4]heptane in the Synthesis of Spirocarbocycles119

Scheme 82. Synthesis of []Fenestradienes 345 Involving Palladium and Nickel Catalysis120b

Scheme 83. Pd-Catalyzed One-Pot Synthesis of Multifunctional []Fenestradienes 348120d

Scheme 84. Piers Annelation in the Synthesis of an Angular Triquinane121c

Scheme 86. Ruthenium-Catalyzed Intramolecular Cyclization of a 1,6-Diene123a

A few years later, the same group established an alternative approach to the multifunctional []fenestradiene derivatives 348 from the propargylic alcohol 346 (XH = OH) as well as propargylic amines 346 (XH = NHBoc, NHPh, NHBn) employing a new five-step cascade reaction (Scheme 83).120d Upon microwave irradiation at 90−100 °C of a mixture of 346,

347 in the presence of Pd(OAc)2, PPh3, CuI, and (iPr)2NH, a trienyne of type 344 is first formed by 4-exo-dig cyclocarbopalladation and Sonogashira coupling.120d The Pdcatalyzed addition of another equivalent of the enyne 347 to the triple bond of 344, formally an alkynylation, leads to a tetraene intermediate, which spontaneously undergoes an 8π electrocyclization and a subsequent 6π electrocyclization, leading to the []fenestradiene 348 as the major product.

Scheme 85. Radical Cyclization of gem-Diallylbetulonic Acid Derivatives in the Presence of Fe(III) Salts122

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corresponding spiro[4.5]decane derivatives 352 in up to 65% yield (Scheme 85).122 Examples of intramolecular cyclizations of various 1,6-dienes in the presence of ruthenium complexes to give exomethylenecyclopentanes have also been published. Thus, treatment of 2,2-diallylcyclopentane-1,3-dione (353) catalyzed by the [Ru(cod)Cl 2 ]2 −iPrOH system, which generates ruthenium hydrides, affords 7-methylene-8methylspiro[4.4]nona-1,4-dione (354) in a yield of 77% (Scheme 86).123a The putative mechanism of the latter reaction comprises the successive generation of a ruthenium hydride, hydrometalation, intramolecular carbometalation, and, finally, β-hydride transfer to afford the target exomethylenecyclopentane and regenerate the catalytically active [Ru]−H species (Scheme 87). Cyclopentane-1,3-diones and cyclohexane-1,3-diones with a 2-spiroannelated 3-ethenylcyclopentene moiety can be prepared by a palladium-mediated phosphine-dependent chemoselective sequential bisallylation of the respective cycloalkanedione with hexa-1,5-dien-3,4-diyldicarbonate, as developed by Tenaglia et al.123b During the last 5−10 years, numerous publications appeared concerning the use of gold complexes in the catalysis of various organic reactions. Relying on the ability of gold(I) species to be ligated by 1,2dienes, which is followed by intramolecular carbocyclization incorporating an alkynyl unit, the enantiomerically pure allenyne 359, upon treatment with Au(PPh3)OTf, led to the enantiomerically enriched spiro[4.5]decenones 360a,b (Scheme 88).124a,b This work considerably contributed to the mechanistic understanding of the cyclization reactions induced by gold(I) complexes. As the authors proposed, the observed loss of enantiomeric excess in the products 360a,b is likely caused by a gold-catalyzed epimerization of the allenyne 359 upon heating in 1,4-dioxane. On the basis of computational results, they conclude that the hydrative cyclization is likely mediated by π-allenegold intermediates. This new method is efficient to provide cyclized ketones incorporating a new quaternary carbon; the reaction is usefully complementary to Murakami’s platinum(II)-catalyzed hydrative cyclization of allenynes.124c An interesting gold(I)-catalyzed intramolecular coupling involving attack at a carbon−hydrogen bond has recently been reported by Barluenga et al.125a Upon microwave heating of terminally substituted 1-alkynylspiro[2.4]pentanes 361 (n = 1) or their homologues 361 (n = 2) in the presence of [(IPr)Au(NTf2)] in dichloroethane for 1 h, the 1,4-ethenylbridged spiro[2.n]alkanes 362 (n = 1, 2) were formed bearing various alkyl chains (R′ = nBu, iBu, and iPr) in moderate yields (Scheme 89). Structurally related skeletons, 4,6-bridged spiro[4.5]decenes and spiro[5.5]undecenes, were obtained by a unique gold(I)-

Scheme 87. Proposed Mechanism for the Cyclization of 1,6Dienes Catalyzed by an in Situ Formed Ruthenium Hydride Complex123a

Scheme 88. Gold-Catalyzed Enantioselective Synthesis of Spiro[4.5]decenyl Ketones124a

Scheme 89. Gold-Catalyzed Formation of 1,4-EthenylideneBridged 362 from 1-Alkynylspiro[2.n]alkanes 361125a

An attractive ring annelation procedure, in which one of the key steps is a palladium-catalyzed intramolecular cyclopentenolate alkenylation giving a cyclopentanone-fused methylenecyclopentane, was reported by Piers et al. in 1990.121a,b This procedure was implemented for the preparation of the angular triquinane derivative 350 as an intermediate in the synthesis of (±)-crinipellin B, an angular tetraquinane diterpenoid (Scheme 84).121c,d Radical-initiated cyclization of gem-diallylbetulonic acid derivatives 351 in the presence of Fe(III) salts provided the

Scheme 90. Gold-Catalyzed Intramolecular Cyclization of Enyne 363126

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Scheme 91. Gold(I)-Catalyzed Cyclization of a 1,6-Enyne in the Total Synthesis of Capnellene128b

Scheme 95. Intramolecular Domino-Cyclization of a pCarboxyalkenyl-Substituted Phenol131

Scheme 92. Cycloisomerization of Dienylallenes Catalyzed by Au(I) Complexes128b

Scheme 96. Palladium-Catalyzed Intramolecular Aerobic Oxidative Cyclization of a 3-Cyclohexenyl-Substituted Indole To Yield an Indole-Annelated Spiro[4.5]decadiene132

Scheme 93. Gold/Chiral Brønsted Acid-Catalyzed Formation of Substituted 2,3-Benzospiro[4.n]alka-1,6diones129

Scheme 97. A One-Pot Synthesis of a SpirocyclopentanoneAnnelated Adamantane Involving a Rhodium-Catalyzed Intramolecular Hydroacylation133

Scheme 94. Palladium-Catalyzed Cyclization of Cyclic 2Alkenyl Enol Ethers130

by 1,2-alkyl migration. An enantioselective variant of this reaction has been carried out with the bimetallic gold complexes of (R)-Xyl-SDP, which afforded the final product with 82% enantiomeric excess.126 Iwasawa et al. and Toste et al., who worked independently of each other,127 disclosed that platinum(II) and gold(I) can catalyze an intramolecular cyclization of vinylallenes occurring according to the so-called Nazarov metallacyclization pattern with the intermediate formation of metalcarbenoids. A subsequent intramolecular cyclopropanation or carbene insertion into a C−H bond can furnish spirocarbocycles, depending on the structure of the initial 1,6-enyne. Such a gold(I)-catalyzed cycloisomerization has been employed in the preparation of a number of oligocyclic spirans, for example, the key intermediate 366 in one of the known total syntheses of capnellene 367 (Scheme 91).124,128 The cyclization of optically active dienylallenes like 368, 370 was found to occur with a high degree of diastereoselectivity (Scheme 92).

catalyzed dimerization of certain cycloalkyl-substituted yneamides.125b A gold-catalyzed intramolecular cyclization of the 1,6-enyne 363 with an aryl substituent on the alkyne terminus and an alkylidenecyclopropane at the other end, as reported by Toste et al., yields the benzoannelated tricyclic spiro[3.4]octane derivative 364 (up to 91%) in a sequence of rearrangement steps involving several cationic gold-containing intermediates (Scheme 90).126a The key steps of the postulated reaction pathway include a ring expansion of the cyclopropane moiety V | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 98. Total Syntheses of Acoradiene and (−)-Acorone Employing a Sequence of Claisen Rearrangement and RhCatalyzed Hydroacylation134

Scheme 99. Another Rhodium-Catalyzed Intramolecular Hydroacylation of a Pent-4-enal Furnishing an Indan-Annelated Spiro[4.5]decanone135

Scheme 100. A Nickel(0)-Catalyzed Intramolecular Cascade Tricyclization of 2-(6-Phenylhex-5-yn-1-ylidene)hexanedial136

The combination of gold(III) chloride or gold(I) complexes and a chiral Brønsted acid has been reported by Zhang et al. to function as a relay catalysis system for an efficient, highly enantioselective redox-pinacol-Mannich cascade.129 Chiral βamino-substituted 2,3-benzospiro[4.n]alka-1,6-diones 373 have thus been obtained from N-aryl-C-arylnitrones with an ortho(hydroxycycloalkyl)ethynyl unit in moderate to excellent yields with up to >99% ee (Scheme 93). The easily accessible 2-but-3-en-1-ylcyclohexenyl trimethylsilyl enol ether 374 is readily converted to a mixture of the regioisomeric spiro[4.5]decenones 375a,b under the action of Pd(OAc)2 as a catalyst (Scheme 94).130 Using the same catalyst, Stephenson et al.131 observed a domino-type 2-fold cyclization of the p-carboxyalkenylsubstituted phenol 376 to give the spiro[4.5]decadienoneannelated butyrolactone 377 in up to 43% yield (Scheme 95). Stoltz et al. developed a ligand-modulated cyclization of 2and 3-alkenyl- and cycloalkenyl-substituted indoles like 378 to yield 1,2- and spiro-annelated indoles including 379 through a Pd(OAc)2-catalyzed C−H bond functionalization using O2 as the sole oxidant and ethyl nicotinate as the ligand (Scheme 96).132 The cyclopentanone derivative 382 containing a spiroannelated adamantane moiety was obtained in ∼50% yield by a one-pot procedure involving a Claisen rearrangement of the allyl vinyl ether 381 derived from adamantanone 380 (Scheme 97) and subsequent rhodium complex-catalyzed intramolecular hydroacylation.133 This type of transformation was also used to prepare the spiro[4.5]decan-1-one 384 as a key intermediate in total syntheses of the sesquiterpenes acoradiene 385 and (−)-acorone 386 (Scheme 98).134

Scheme 101. A Lewis Acid-Catalyzed Ring Expansion of a 1Oxiranylcyclobutyl Trialkylsilyl Ether137

Scheme 102. ZnBr2-Catalyzed Ring Expansion of an Oxiranyl-Substituted Cyclobutanol138

Scheme 103. Pd(II)/Brønsted Acid-Catalyzed Semipinacol Rearrangement of an α-Indenyl-Substituted Cyclobutanol139

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Scheme 104. Samarium Diiodide-Initiated Intramolecular Cyclization of Aldehydes Tethered to Cycloalkenones140a

Scheme 105. Total Synthesis of (±)-Majusculone, a Spiro[5.5]undeca-1,7-diene-3,9-dione Natural Product140b

Scheme 106. Synthesis of Spiro[4.5]deca-6,9-dien-8-ones Employing a Palladium-Catalyzed Intramolecular ipso-Friedel−Crafts Allylic Alkylation141

Scheme 107. Palladium-Catalyzed Enantioselective Cyclization of 1-Silyloxy-1,6-enynes142

Scheme 108. Copper(I)-Catalyzed Borylative 4-exo-trigCyclization of Unactivated 5-Bromopent-1-enes To Yield (Spiro[3.n]alk-2-yl-methyl)boronates143

An interesting Ni(0)-induced cascade tricyclization involving nickel enolates was reported for the enyne with two aldehyde functionalities 390. Upon treatment with Ni(cod)2 in the presence of N,N,N,N-tetramethylethylenediamine, 390 furnished the cyclopentane-annelated spiro[4.4]nonenediol 393 as a single diastereomer in 49% yield. In the first step, the dialdehyde 390 undergoes a chemoselective oxidative cyclization across the enal group and the triple bond to give the metallacycle 391 which, by a diastereoselective intramolecular

The same method was employed to prepare the indanannelated spiro[4.5]decanone 389 in 93% yield as a precursor to a chiral semititanocene. In this case, the substrate for the intramolecular hydroacylation−alkylation, the pent-4-enal 388, was obtained from the indan-annelated cyclohexanone 387 by a one-pot sequence of acylation and ipso-allylation (Scheme 99).135 X | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 109. Effect of the Substitution Pattern of the Intermediate σ-Alkylpalladium Species on the Chemoselectivity of a Second Intramolecular Heck Reaction145b

Scheme 110. Palladium-Catalyzed Two-fold Cyclizations of Alkadienylaryl Iodides145b

of phenols (Scheme 106).141 The asymmetric version of this reaction in the presence of 5% of a Pd(dba)2 and (R,R)ANDEN-phenyl Trost ligand (6%) gives the 2ethenylspiro[4.5]deca-6,9-dien-8-one 408 in 80% yield with an ee of 89%.141a,b The α-naphthol derivative 409 with a tethered propargyl carbonate moiety undergoes an analogous reaction to furnish the benzoannelated spiro[4.5]decadienone 410 with an allene motif on the five-membered ring.141c,d In 2007 Toste et al. reported an efficient palladium-catalyzed enantioselective cyclization of 1-silyloxy-1,6-enynes. When the double bond of the latter is incorporated in a six-membered ring as in 411, the benzoannelated 1-methylenespiro[4.5]decanone 412 is obtained in very good yield (91%) and with a high enantiomeric excess (87%), when employing a palladium complex with a so-called binaphane ligand (Scheme 107).142 An interesting copper(I)-catalyzed borylative 4-exo-trigcyclization of pent-1-en-4-yl bromides, which is applicable to the synthesis of various spiro[3.n]alkanes, has recently been reported by Ito et al. (Scheme 108).143 Thus, the (spiro[3.4]oct-2-yl-methyl)boronate 414 (n = 1) and (spiro[3.5]non-2ylmethyl)boronate 414 (n = 2) in particular were obtained by this cyclization, in the presence of CuCl, of the secondary alkenyl bromides 413 in very high yields as singularly borylated products (90% and 92%, respectively). Under the same conditions, the dienyl dibromide 415 smoothly underwent a 2-fold borylative cyclization to furnish the spiro[3.3]heptane derivative 416 with methylboronate moieties in 88% yield.

aldol reaction gives rise to the nickel bis-alkoxide 392. Protonation of the latter upon aqueous workup furnishes the observed diol 393 (Scheme 100).136 A Lewis acid-catalyzed ring expansion of oxiranyl-substituted cyclobutanols and their silyl ethers has found extensive use in the stereoselective synthesis of chiral spiro[4.5]decanone derivatives and their 1-aza analogues. Thus, the 6hydroxyspiro[4.5]decan-1-one 395 was formed in high yield as a single diastereomer from the cyclobutyl silyl ether 394 with an attached epoxy functionality upon treatment with TiCl4 in dichloromethane (Scheme 101).137 When a catalytic amount of ZnBr2 is used as the Lewis acid, the 5-hydroxyspiro[4.4]nonan-1-one 397 can be obtained from the cyclobutanol 396 in equally high yield under milder conditions (Scheme 102).138 Higher homologues of 397 with six-, seven-, and eight-membered spirocycloalkanone moieties can be prepared the same way from the correspondingly substituted cycloalkanols in 60%, 55%, and 68% yields, respectively. Under Pd(II) catalysis (with 1,4-benzoquinone as the reoxidant), 1-indenylcyclobutanol 398 and 3-aryl-substituted analogues undergo a semipinacol rearrangement to yield spirocyclopentanone-annelated indenes of type 399. A Brønsted acid is required as a cocatalyst, and in the presence of a chiral, BINOL-derived phosphoric acid, the rearrangement proceeds with a high degree of enantioselectivity (Scheme 103).139 A preparatively useful reductive intramolecular cyclization of terminally cycloalkenone-substituted aldehydes 400 induced by SmI2 has been reported.140a This reaction followed by oxidation with pyridinium chlorochromate (PCC) provided spiroalkanediones 402 of various ring sizes in good yields under mild conditions (Scheme 104). This method has been employed by the same group as a key step in a concise total synthesis of (±)-majusculone 406, a spiro[5.5]undeca-1,7-diene-3,9-dione, from 2,6,6-trimethyl-2cyclohexen-1-one in seven steps (Scheme 105).140b Hamada et al. have developed a novel and efficient method for the synthesis of various spirocarbocycles based on a palladium-catalyzed ipso-Friedel−Crafts-type allylic alkylation

7. THE HECK REACTION IN THE SYNTHESIS OF SPIRANS The intramolecular Heck reaction has found extensive use in the synthesis of various carbo- and heterocycles including spirans.144,145 Generally, this reaction occurs via an initially formed σ-alkylpalladium(II) intermediate like 417, which carbopalladates an adjacent additional double bond to form the second ring, which can be spiro- as in 419 or 1,2-annelated as in 420 (Scheme 109).145b Overman et al. performed Pd(OAc)2-catalyzed 2-fold cyclizations of alkadienylaryl iodides 421 to benzomethylenespiro[4.4]nonanes 423 (n = 1) or Y | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 111. Cyclization of Methylenecycloheptenylalkylaryl Iodides for the Synthesis of Polycyclic Spirocarbocycles145b

Scheme 113. Palladium-Catalyzed Oxidative Cyclization of Cycloalkyl Aryl Ketones with Aryl Iodides147

benzomethylenespiro[4.5]decanes 423 (n = 2) (Scheme 110).145b The advantage of this transformation is its applicability for a broad range of substrates. For example, polycyclic compounds were prepared by cyclization of methylenecycloheptenylalkylaryl iodides 434, which demonstrated the unique potential of this method (Scheme 111). Katz et al. prepared spiro[cyclopent-2-ene-1,9′-fluorene] (441) by the reaction of 2,2′-diiodobiphenyl (439) with cyclopent-1-en-1-ylzinc chloride in the presence of (Ph3P)2Pd. After an initial Negishi coupling to form the intermediate 440, the subsequent 5-exo-trig-cyclization and β-hydride elimination is a typical intramolecular Heck reaction, which is catalyzed by an in situ formed palladium(0) species (Scheme 112).146 The same sequential coupling reaction has been performed with 2,2′-diiodo-1,1′-binaphthyl to furnish the bisbenzoannelated analogue of 441 in 66% yield. Phenanthrone derivatives 444 with spiroannelated five-, six-, and seven-membered carbocycles can be synthesized from corresponding cycloalkyl aryl ketones 442 and aryl iodides 443 under oxidative conditions using 10 mol % of Pd(OAc)2 and 1 equiv of Ag2O in TFA (Scheme 113).132c,147 This transformation involves a palladium-catalyzed dual C−H bond activation and enolate cyclization. The Heck reaction was successfully employed as the key step in the total synthesis of scopadulcic acid B 448, which is an active component used in the Paraguayan folk medicine, and the tetraquinone diterpenoid (±)-crinipellin B 452, which is contained in Crinipellis stipitaria (Agaricales) having an antibacterial activity (Scheme 114).148 The skeletons of 448 and 452 are bridged spiro[4.5]decane and spiro[4.4]nonane, respectively, frameworks. Yet another practical application of the Heck reaction toward the synthesis of natural products is involved in the palladiumcatalyzed domino-cyclization of 7-methyleneundeca-2,10-dienyl acetate 453 to the spiro[4.4]nonane derivative 455. The initial step is formation of the π-allylpalladium complex 454, which then undergoes two consecutive intramolecular carbopalladations to give a σ-alkylpalladium intermediate. The final step is a β-hydride elimination yielding the spiro[4.4]nonane 455, a key intermediate en route to gloiosiphone A 456, which is a known antimicrobial agent (Scheme 115).149

An intramolecular Heck-type coupling of the 2-bromo-1,6heptadiene 457 catalyzed by the phosphine−rhodium complex Rh(PPh3)3Cl provided the dibenzodimethylenespiro[4.4]nonane derivative 458 in a yield of 80% (Scheme 116).150 The interesting helical fluorene-annelated dibenzospiro[5.5]undecane 460 was formed in 68% yield by a palladiumcatalyzed 2-fold intramolecular arylation of 9,9-di(2bromobenzyl)fluorene (459) (Scheme 117). The reaction occurs even faster, when the bromobenzyl moieties in 459 carry an electron-withdrawing group. 4-Methoxybenzyl derivatives of type 459 proved to be the least reactive in this transformation.151 An analogous intramolecular enol arylation of 2-[2-(2bromophenyl)ethyl]cyclopentanone (461, n = m = 1) catalyzed by bis(triphenylphosphine)palladium dichloride in the presence of cesium carbonate in THF at 100 °C under argon produced the benzospiro[4.4]nonanone 462 (n = m = 1) in 71% yield (Scheme 118).152 Higher homologues of 461 (n = 2, m = 1; n = m = 2) correspondingly gave the benzospiro[4.5]decanone 461 (n = 2, m = 1) and benzospiro[5.5]undecanone 461 (n = m = 2) in 57% and 35% yields, respectively. According to Buchwald et al., 4-(2-bromophenylalkyl)phenols of type 463, under palladium catalysis, undergo ipso arylation to yield up to 91% of spiroannelated cyclohexadienones 464 (Scheme 119).153 The Heck coupling of haloarenes with bicyclopropylidene (57) afforded 1-arylallylidenecyclopropanes 466, which can be trapped in situ in a Diels−Alder reaction with an appropriate dienophile to give 8-arylspiro[2.5]oct-4-enes 468 (Scheme 120).154a,b In the presence of trisfurylphosphine instead of triphenylphosphine, the 1-arylallylidenecyclopropanes undergo readditions of the hydridopalladium halide to yield πallylpalladium intermediates, which are efficiently trapped with various nitrogen and carbon nucleophiles to yield functionally substituted methylenecyclopropane derivatives 471 (Scheme 120).154c Employing the former three-component domino reaction, a new large family of substituted spiro[2.5]oct-4-ene derivatives has been synthesized from bicyclopropylidene (57), various aryl halides, and dienophiles mostly in high yields (49−100%) (Scheme 120).154d This three-component domino reaction has also been extended to monosubstituted bicyclopropylidenes.154e The

Scheme 112. A Heck Reaction Involved in the Synthesis of Spiro[cyclopent-2-ene-1,9′-fluorene]146

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Scheme 114. Heck Reactions Employed in the Total Syntheses of Scopadulcic Acid B and (±)-Crinipellin B148

Scheme 115. A Palladium-Catalyzed Domino-Cyclization in the Total Synthesis of Gloiosiphone A149

Scheme 119. Palladium-Catalyzed Arylative Dearomatization of 4-(2-Bromophenylalkyl)-Substituted Phenols153

Scheme 116. A Rhodium-Catalyzed Intramolecular HeckType Coupling150

Scheme 120. Two Reaction Modes of Bicyclopropylidene under Conditions of the Heck Reaction and a Domino Heck−Diels−Alder Reaction154

Scheme 117. Palladium-Catalyzed Two-fold Intramolecular Arylation Leading to an Interesting Chiral FluoreneAnnelated Dibenzospiro[5.5]undecane151

second reaction mode of bicyclopropylidene with an intermediate π-allylpalladium species in the presence of trisfurylphosphine and a secondary amine was further developed into a one-pot, four-component two-step queuing cascade with iodoethenes 473 and secondary amines 472 to provide 8-(10aminoethyl)-substituted spiro[2.5]oct-7-ene derivatives 474 (Scheme 121).155a The same one-pot, two-step queuing cascade can be carried out with cyclic dienophiles such as Narylmaleinamides and N-phenyltriazolinedione to furnish highly substituted spiro[2.5]oct-4-enes and spirocyclopropanated heterobicycles. Finally, further cascade reactions involving Heck-type coupling of bicyclopropylidene (57) with 2bromo-1,6-enynes afforded cross-conjugated tetraenes, which,

Scheme 118. Intramolecular Arylation of 2-[2-(2Bromophenyl)alkyl]cycloalkanones Catalyzed by (Ph3P)2PdCl2152

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The synthesis of chiral spirotricyclic hydrindenone 478 in a yield of >90% with 45% ee from the oxocyclohexenyl triflate 477 with an alkadienyl side chain was one of the first successful examples of an asymmetric Heck reaction performed by Overman et al. in 1989 (Scheme 122).156 A steroid-like skeleton with a C2-bridged spiro[2.4]hept-4ene moiety annelated to the B-ring was obtained by Knochel et al.157a The underlying concept was based on the assumption that the intramolecular 6-endo-trig-cyclization of the vinyl iodide 479 (Scheme 123) under Heck conditions would yield the Torgov diene, a known intermediate in the synthesis of estrone. This assumption was not borne out; instead, a 5-exotrig-cyclization took place, followed by a 3-exo-trig-cyclization and β-hydride elimination to furnish the pentacyclic compound 480 in 57% isolated yield after removal of the TBS group with TBAF (Scheme 123).157

Scheme 121. Four-Component Two-Step Cascade Reactions of Bicyclopropylidene and Palladium-Catalyzed CrossCoupling Cascade Reactions155

8. CYCLOCARBONYLATION CATALYZED BY PALLADIUM COMPLEXES IN THE SYNTHESIS OF SPIROCARBOCYCLES In a study of the cyclocarbonylation (cyclic acylpalladation) of o-iodoaryl alkenyl ketones under carbon monoxide, Negishi et al. showed that, when the reaction is catalyzed by Pd complexes in the presence of phosphine ligands, spirocarbocycles 483 are formed by a preferred 5-exo-trig-acylpalladation of the remote double bond. It is of interest that in the absence of additional ligands, for example, when the Pd(dba)2 complex is used, a completely selective acylpalladation with 6-endo-trig-cyclization furnishes tricyclic quinones 481 in high yields (Scheme 124).158 Under palladium catalysis, an intramolecular carbocyclization of the 8-homoallyl-substituted bicyclo[3.3.0]oct-1-ene derivative 484 with a 1,6-diene unit under a CO atmosphere is followed by a cyclocarbonylation leading to []fenestranes 485 and 486 in a total yield of 65% (Scheme 125).159

Scheme 122. Asymmetric Heck Reaction in the Synthesis of Spirotricyclic Hydrindenones156

Scheme 123. Heck Reaction in the Synthesis of a Spirocyclic Steroid-Like Skeleton157a

9. THE NAZAROV REACTION IN THE SYNTHESIS OF SPIRANS Spiroannelated cyclopentenones can be constructed by a Nazarov cyclization of cycloalkylidenealkyl vinyl ketones. For example, treatment of the α-(trimethylsilylmethyl)divinyl ketone 487 with a weak Lewis acid such as FeCl3 leads to a 7:1 mixture of the two diastereomeric 1-methylenespiro[4.5]decan-2-ones 488a and 488b in 61% yield (Scheme 126).160 Under the same conditions, the dienal 489 in dichloromethane undergoes cyclization to furnish 2-methylspiro[4.5]dec-2-en-1-one (491) in 78% yield. This transformation is presumed to involve the intermediate formation of the spirocyclohexane-annelated cyclopentenyl cation 490, which is stabilized by the β-positioned trimethylsilyl group (Scheme 127).161

at elevated temperatures, underwent 6π-electrocyclization to give spiro[cyclopropane-1,4′-bicyclo[4.3.0]nona-1(6),2-dienes] 476 (Scheme 121).155b,c The recently developed asymmetric version of the Heck reaction is an effective method for the enantioselective construction of quaternary carbon centers and of bi- and polycyclic skeletons, applicable in the syntheses of biologically active compounds.

Scheme 124. Effect of Phosphine Ligands on the Chemoselectivity of Cyclocarbonylation of o-Iodoaryl Alkenyl Derivatives158

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Scheme 125. Palladium-Catalyzed Sequential Cyclization-Cyclocarbonylation Yielding all-cis-[]Fenestranes159

Scheme 126. Iron(III)-Catalyzed Cyclization of a α(Trimethylsilylmethyl)divinyl Ketone160

Scheme 129. The Kulinkovich Reaction Employed in a Synthesis of a Cyclopropanol-Annelated Spiro[4.5]decane164

Scheme 127. Cyclization of 4-Cyclohexylidenebutenals Catalyzed by FeCl3161

The reaction of methyl cyclopent-1-enecarboxylate and cyclohex-1-enecarboxylate (496, n = 1, 2) with ethylmagnesium bromide in the presence of titanium tetraisopropoxide yields 1cyclopentenylcyclopropanol and 1-cyclohexenylcyclopropanol 497 (n = 1, 2), which, after silylation with trimethylsilyl triflate and treatment of the resulting trimethylsilyl ethers 498 (n = 1, 2) with 3-bromopropanal dimethylacetal in the presence of titanium tetrachloride, in a Mukaiyama-type aldol reaction provide the spiro[3.5]nonan-1-ones 499 (n = 1, 2). The latter were further transformed into the cyclopentane- and cyclohexane-annelated cyclooctanones 500 (n = 1, 2) (Scheme 130).165 The transformation of ethyl [n]triangulanecarboxylates with ethylmagnesium bromide in the presence of Ti(iPrO)4 to give (1′-hydroxycyclopropyl)triangulane derivatives 502a−c, 504 in excellent yields (Scheme 131) deserves special mentioning.8b,166 The latter have served as precursors to a whole family of branched higher [n]triangulanes. 3-Methoxycyclohex-2-en-1-one (505) and its derivatives can be considered as vinylogous esters, and, as such, their transformations into cyclopropanes have conceptually been envisaged by Cha et al. Indeed, when treated with nbutylmagnesium bromide in the presence of titanium(IV) isopropoxide in toluene, they undergo a reductive cyclopropanation of the carbonyl group to furnish, after mildly acidic hydrolytic workup, 1-ethylspiro[2.5]octan-5-one as a 2:1 mixture of diastereomers in 77% yield (Scheme 132).167,168 Other Grignard reagents provided the corresponding 2substituted spiro[2.5]octan-5-ones in comparable yields. In the same paper, the authors describe the titaniummediated transformation of 6-(but-3-en-1-yl)-3-methoxycyclohexenone 507 in diethyl ether under otherwise identical conditions, proceeding with incorporation of the alkenyl appendage to furnish, after addition of BF3·OEt2 prior to aqueous workup, the five-membered ring 1,8-bridged 5methoxyspiro[2.5]oct-4-ene in 75−80% yield (Scheme 133).167

Scheme 128. Spirocycle Synthesis by a Sequence of NazarovCyclization and Wagner−Meerwein Rearrangement162d

An efficient, chemoselective method for the preparation of highly functionalized spirocyclopentane-annelated cyclopentenones based on a stereospecific, copper(II)-mediated Nazarov cyclization/Wagner−Meerwein rearrangement sequence has been developed.162 For example, treatment of the divinyl ketone 492 with (MeCN)5Cu-(SbF6)2 (10 mol %) and NaBAr4 (90 mol %) at room temperature for 10 min leads to formation of the spiro[4.4]non-2-en-1-one 493 in 90% yield (Scheme 128).162d

10. THE KULINKOVICH REACTION IN THE SYNTHESIS OF HYDROXY-SUBSTITUTED SPIROCARBOCYCLES The Kulinkovich reaction constitutes a simple and convenient tool to construct the hydroxycyclopropane moiety. It is applicable toward the synthesis of a broad range of organic skeletons including spirans.163 Thus, the 1-but-3-en-1′-yl-substituted methyl cyclohexanecarboxylate 494 is transformed upon treatment with iPrMgBr in the presence of Ti(OiPr)4 according to an intramolecular Kulinkovich reaction pattern to give the cyclopropanolannelated spiro[4.5]decane derivative 495 (Scheme 129).164

11. CYCLIZATION OF ENYNES CATALYZED BY PALLADIUM COMPLEXES AS AN APPROACH TO SPIRANES (ZIPPER REACTIONS) Particular emphasis should be placed on the one-step synthesis of mono-, di-, and polyspirocyclic compounds by palladiumcatalyzed cycloisomerization (zipper reactions) of enynes, dienynes, and polyenynes as reported by Trost et al.169,170 AC | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 130. A Sequence of Kulinkovich Reaction, Silylation, and Mukaiyama-Type Aldol Reaction To Yield Spiro[3.n]alkanones165

Scheme 131. The Kulinkovich Reaction Employed in the Synthesis of Branched Higher [n]Triangulanes8,166

Scheme 134. Palladium-Catalyzed Cycloisomerization of Enynes, Dienynes, and Higher Oligoenynes169,170

Scheme 132. Kulinkovich-Type Cyclopropanation of a Vinylogous Ester167

12. SYNTHESIS OF “EXPANDED” ROTANES THROUGH THE Cu-CATALYZED OXIDATIVE COUPLING OF ALKYNES Worth mentioning are the syntheses of the macrocyclic “expanded” analogues of [n]rotanes 521, 522, in which all carbon−carbon single bonds between two cyclopropane moieties in the [n]rotanes (for a review, see ref 8b) are replaced with butadiyne moieties,171 based on oxidative coupling with the CuCl/Cu(OAc)2/pyridine system of one, two, or more open-chain dehydrooligomers of 1,1-diethynylcyclopropane (519) as well as of 1,1-diethynyltetramethylcyclopropane (520) (Scheme 136).172,173 A similar approach was used in the synthesis of the spirocyclopropanated [n]pericyclyne 524, which was obtained by intramolecular acetylene−acetylene coupling of the acyclic unprotected pentayne 523 under oxidative conditions (Scheme 137).174 The “half-expanded” (with diacetylene moieties) [6]rotane 526 could be prepared under similar conditions by a “shotgun”

According to this reaction principle, which was first developed for various versions of 1,6-enynes including those like 510 to 1,2-dialkylidenecyclopentane derivatives like 511,169 polyenynes 512 were transformed in a single operational step into polyspirans 513 containing up to seven spiroannelated rings (Scheme 134). The high yields of these processes, in which up to eight new carbon−carbon bonds were formed, are particularly remarkable.170 The supposed reaction mechanism comprises three key steps: (1) initiation, (2) propagation, and (3) completion (Scheme 135).

Scheme 133. Titanium-Mediated Intramolecular Reductive Cyclopropanation of a Vinylogous Ester with a Butenyl Tether167

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Scheme 135. Mechanism of a Palladium-Catalyzed Zipper Reaction170

Scheme 136. Copper-Mediated Oxidative Coupling of OpenChain Dehydrooligomers of 1,1Diethynylcyclopropanes172,173

Scheme 137. Copper-Mediated Acetylene−Acetylene Coupling of an Acyclic Unprotected Pentayne174

Scheme 138. Intermolecular Copper-Mediated Oxidative Coupling of 1,1′-Diethynyl-1,1′-bi(cyclopropyl)175

macrocarbo- and heterocycles due to the presence in the molecule of C−C triple bonds and cyclopropane moieties. Thus, the treatment of “expanded” [n]rotanes 521 with Na2S·(H2O)9 under strongly basic conditions (KOH/DMSO) within 1 h was found to produce the macrocycles with alternating thiophene and spirocyclopropane fragments in good yields (Scheme 139).176

13. CATALYZED CYCLOALUMINATION IN THE SYNTHESIS OF SPIROCARBOCYCLES The catalytic cycloalumination and cyclomagnesiation of unsaturated compounds were discovered by U. M. Dzhemilev. Recent publications present data on the possibility of constructing spirocyclic compounds via the intermediate

approach, that is, by dehydrotrimerization of the diyne 525, albeit in a yield of only 2.1% (Scheme 138).175 The developed approaches to macrocyclic expanded rotanes open wide perspectives in the synthesis of promising AE | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 139. Treatment of “Expanded” [n]Rotanes 521 with Na2S·(H2O)9176

ing spirocyclopropanated cyclobutanes 529, tetrahydrothiophenes and tetrahydroselenophenes 530, as well as cyclopentanols 531 in high yields and with high selectivities (Scheme 140).178,179 Recently, D’yakonov et al. have shown that the abovedescribed reactions can serve as an effective tool to introduce the spiran substructures into complex oligocyclic non-natural and natural skeletons like that of norbornane (Scheme 141), a pinane (Scheme 142), and steroid derivatives (Scheme 143).178−182 Yet another synthetic approach to spirans starts with a catalytic cycloalumination of cycloalkynes like 557, 560.183−185 The resulting ring-annelated aluminacyclopentenes like 558, 561 undergo, without isolation, intramolecular carboalumination upon treatment with dimethyl sulfate (Scheme 144) or bromomethyl methyl ether (Scheme 145) to give, in one procedural step, macrocarbocycles with annelated spirocyclopropane moieties that are of interest for the synthesis of, for example, macrocyclic rotanes.

Scheme 140. Zirconocene-Catalyzed Cycloalumination of Strained Methylenecycloalkanes in Spirane Synthesis178,179

formation of aluminacarbocycles, which have now found wide use due to the development of catalytic cycloalumination of unsaturated compounds.177 This initiated the development of versatile synthetic methods for the preparation of spirocarboand heterocycles of various structures by Cp2ZrCl2-catalyzed cycloalumination of substituted methylidenecyclopropanes, alkylidenecyclopropanes, and methylenecyclobutanes by Et3Al with subsequent in situ transformation of the spirocyclic organoaluminum compounds thus formed to the correspond-

14. CONCLUSION The information presented in this Review indicates that quite a few publications in the world literature are devoted to the synthesis and properties of purely synthetic and naturally occurring spirocarbocycles of various structures. In most cases, the developed methods and approaches have limited scopes of applicability as the initial precursors and

Scheme 141. Palladium-Catalyzed Carbocyclization of Aluminacyclopentanes in the Synthesis of Spiro[3.3]heptanes178,180

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Scheme 142. Zirconocene-Catalyzed Cycloalumination of a Pinane Derivative181

Scheme 143. Zirconocene-Catalyzed Cycloalumination of Steroid Derivatives182

reagents used in the synthesis of spirans may be difficult to obtain, the selectivity of spiran formation may be low, and there are no universal accesses to spirocarbocycles that would enable their extensive use.

Meanwhile, the introduction of metal-complex catalysts into the organometallic chemistry of main group metals (Al, Mg, Zn, In, Ga, B) allowed the authors of this Review to develop in the last 15−20 years a new strategy of organic and organometallic AG | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 144. Zirconocene-Catalyzed Cycloalumination of Cycloalkynes for the Synthesis of Spirocyclopropanated Carbocycles184,185

Scheme 145. Intramolecular Carboalumination of Aluminacyclopent-2-enes with Bromomethyl Methyl Ether180,185


synthesis providing small, medium, and large rings of metallahetero- and -carbocycles and spirocarbo- and -metallacycles. For example, cycloalumination of methylenecycloalkanes and subsequent in situ demetalation of the resulting spiroaluminacarbocycles efficiently leads to various spirans. One more effective approach developed by the same authors comprises the cycloalumination of open-chain and cyclic alkynes, alkadiynes with AlEt3 in the presence of Cp2ZrCl2 as a catalyst giving rise to annelated aluminacyclopentenes, which are treated in situ with allyl chloride in the presence of Pd complexes or with dimethyl sulfate or bromomethyl methyl ether to afford spirocarbocycles in high yields. These investigations open a fundamentally new synthetic approach to spirans and the introduction of spirocyclopropane, spirocyclobutane, and spirocyclopentane moieties into organic frameworks. We hope, or rather we are sure, that the results considered in this Review would arouse much interest in researchers and would stimulate practical applications of this unusual class of organic compounds.

Corresponding Author

*Tel./fax: +7 347 2842750. E-mail: [email protected], [email protected] Notes

The authors declare no competing financial interest. Biographies

AH | Chem. Rev. XXXX, XXX, XXX−XXX

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include German Merit Foundation (Studienstiftung des Deutschen Volkes), “Dozentenstipendium” of the Fonds der Chemischen Industrie, member of the Norwegian Academy of Sciences, Alexander von Humboldt-Gay Lussac Prize, member of the Braunschweigische Wissenschaftliche Gesellschaft, Honorary Professor of St. Petersburg State University in Russia, Fellow of the Japan Society for the Promotion of Science, Paul Tarrant Distinguished Lecturer at the University of Florida, Lady Davis Distinguished Visiting Professor at the Technion in Haifa, Israel, the Merck-Eurolab Distinguished Lecturer of the French Chemical Society, Novartis Lecturer, ParkeDavies Lecturer, Adolf von Baeyer Medal of the German Chemical Society, and Honorary Doctorate (Dr. h. c.) of the Russian Academy of Sciences. He has been or still is an Editor or member of the editorial board of a number of scientific journals, periodicals, and books including Chemical Reviews, Synlett, and ChemistryA European Journal. His scientific achievements have been published in over 700 original publications, review articles, and book chapters. His reputation is in small ring as well as organometallic chemistry.

Vladimir A. D’yakonov was born in 1980 in Yakutia, Siberia, Russia, graduated from the Ufa State Petroleum Technical University in Ufa, Bashkortostan, Russia (2002) with an honors diploma, and obtained his Candidate, Ph.D. (2005) and Doctor of Science, Chemistry (2012) degrees from the Institute of Petrochemistry and Catalysis of Russian Academy of Sciences under the guidance of the Correspondent member of RAS, Prof. Usein M. Dzhemilev. His research interests include metal complex catalysis in organic and organometallic synthesis, the development of new catalytic synthetic methods based on transformations of strained molecules and metallacarbocycles, and the elaboration of simple “one-pot” operations for the preparation of various carbo-, hetero-, and macrocyclic compounds.

Ol’ga A. Trapeznikova was born in 1975 in Bashkortostan Republic, Russia. She graduated from Birsk Pedagogical Institute, the Faculty of Biology and Chemistry. Within the period from 2002 to 2007, she was an assistant of this Faculty. In 2007 she enrolled in a graduate school of the Institute of Petrochemistry and Catalysis RAS in the city Ufa, the Laboratory of Catalytic Synthesis, under the Leadership of Prof. Usein M. Dzhemilev. She received her Candidate (Ph.D.) from the Institute of Petrochemistry and Catalysis RAS in 2011. Her research interests include metal complex catalysis in organic and organometallic synthesis, and the chemistry of spiro compounds.

Usein M. Dzhemilev received his Candidate (Ph.D.) and Doctor of Science (Chemistry) degrees from the Institute of Chemistry, Bashkirian Branch of Academy of Sciences of the USSR (currently the Institute of Organic Chemistry of Ufa Scientific Centre of RAS). In 1982, he became a professor, and since 1980 he has held the position of the Deputy Director of the same Institute. Since 1992 he has become Director of the Institute of Petrochemistry and Catalysis of Bashkortostan Republic Academy of Sciences, which since 2004 has been associated with the Russian Academy of Sciences. As a visiting scientist he reported in Poland, Czechoslovakia, Bulgaria, Israel, China, and the U.S. In 1990 he was elected Corresponding Member of the Russian Academy of Sciences. He is a Laureate of State Prizes in the area of science and technology of the USSR (1990), the Russian Federation (2004), and the Butlerov Award for outstanding results achieved in Organic Chemistry (2009). His research interests include metal complex catalysis in organic and organometallic synthesis, chemistry and stereochemistry of the strained and cage compounds, organic chemistry of nontransition metals (Mg, Al, Zn, Ga, In), as well as chemistry of small, low-stability, and highly strained molecules. He is the author and coauthor of seven books, and about 1500 scientific articles and reviews. He also has more than 600 patents issued.

Armin de Meijere, born in 1939, received his doctoral degree (Dr. rer. nat.) in 1966 in Göttingen, and after postdoctoral training at Yale University from 1967−1969, obtained his Habilitation in 1971 in Göttingen. He was appointed full professor of Organic Chemistry in Hamburg, 1977−1989, and ever since has been in Göttingen. He was visiting professor at numerous places including the University of Wisconsin, Princeton University, the Universities of Aix-Marseille III, Paris-Sud, Orsay, Rennes, Toulouse, Bordeaux, Florence, the Ecole Normale Supérieure in Paris, the Universities of Florida at Gainesville and Colorado at Boulder, Indian Institute of Science in Bangalore, and University of Santiago de Compostela, Spain. His awards and honors

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Metal complex catalysis in the synthesis of spirocarbocycles.

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