[2+2+1] cyclization of allenes.

Volume 43 Number 9 7 May 2014 Pages 2879–3206

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Themed issue: Progress in allene chemistry ISSN 0306-0012

Guest editors: Benito Alcaide and Pedro Almendros REVIEW ARTICLE S. Kitagaki, F. Inagaki and C. Mukai [2+2+1] Cyclization of allenes

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REVIEW ARTICLE

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[2+2+1] Cyclization of allenes Cite this: Chem. Soc. Rev., 2014, 43, 2956

S. Kitagaki,† F. Inagaki and C. Mukai* The [2+2+1] cyclization of an alkyne, an alkene and carbon monoxide, i.e., the Pauson–Khand reaction, is one of the most powerful tools for constructing a five-membered ring. In place of the alkene or alkyne part, the use of an allene functionality has proven to make this reaction more valuable for organic

Received 28th October 2013

synthesis. This review focuses on the origin and progress of the allenic [2+2+1] cyclocarbonylation,

DOI: 10.1039/c3cs60382b

including the chirality transfer of the allene and its synthetic applications.

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1 Introduction Transition metal-mediated cyclization using an allene functionality has made significant advances in recent years because of allene’s unique structure and reactivity. Utilization of one of the two p-components of the allene in the [2+2+1] cyclization accompanied by incorporation of carbon monoxide, namely the Pauson– Khand-type reaction, is one of the examples, which successfully take advantage of the intriguing features of the allene. This review summarizes advances in the [2+2+1] carbonylative cycloaddition Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. E-mail: [email protected]; Fax: +81 76 234 4410; Tel: +81 76 234 4411 † Present address: Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan. E-mail: [email protected]; Fax: +81 52 834 8090; Tel: +81 52 839 2657.

Shinji Kitagaki received his PhD from Osaka University, Japan (Professor Yasuyuki Kita) in 1996. He was appointed as a Research Associate in the Faculty of Pharmaceutical Sciences, Hokkaido University (Professor Shunichi Hashimoto) in 1996. He joined Professor Chisato Mukai’s group in the Faculty of Pharmaceutical Sciences, Kanazawa University, in 2002. He spent half a year in 2007 as a visiting investigator at The S. Kitagaki Scripps Research Institute, USA (Professor Carlos F. Barbas III). He has been Full Professor in the Faculty of Pharmacy, Meijo University since 2012. His research interests include synthetic organic chemistry and asymmetric catalysis.

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using at least one allene functionality as the p-component.1 The examples using a heteroanalogue having the isoelectronic structure of an allene or a heteroatom-containing alkene or alkyne counterpart will also be discussed. In the early 1970’s, Pauson and Khand’s group reported the formal [2+2+1] cycloaddition of three components, i.e., an alkyne, an alkene, and carbon monoxide, to the two cobalt atoms in the cluster complex to produce cyclopentenone derivatives (Scheme 1).2 Since then, this Co2(CO)8-mediated cyclization reaction has attracted many organic chemists. In particular, through some improvements including the use of promoters or development of the catalytic version, this intramolecular reaction has emerged as one of the most valuable methods for the construction of bicyclo[3.3.0] and bicyclo[4.3.0] skeletons.3,4 The [2+2+1] cycloaddition reactions mediated or catalyzed by transition metals other than Co (Rh, Ir, Fe, Ru, Mo, Zr, Ti, etc.) have also been developed.

Fuyuhiko Inagaki received his PhD from Kanazawa University, Japan (Professor Chisato Mukai) in 2007. He joined the research centers of the Takeda Pharmaceutical Company Ltd. in 2007. He was appointed as Assistant Professor in the Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, in 2008. He spent one year in 2011 as a visiting investigator at F. Inagaki Stanford University, USA (Professor Paul A. Wender). He has been Associate Professor in the Graduate School of Medical Sciences, Kanazawa University, since 2012. His research interests are related to the development of novel cyclizations with multiple bonds.

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Scheme 1

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Pauson–Khand reaction.

Scheme 3

Fe-mediated intramolecular [2+2+1] cycloaddition.

Scheme 2 Pauson–Khand-type reaction (carbonylative [2+2+1] cycloaddition) of allenes.

On the other hand, if the reaction can overcome even the selectivity problem (which p-bond takes part in the reaction, proximal or distal?), the use of allene as a 2p component (Scheme 2) would become an attractive alternative due to the following reasons: (a) after cyclization, the remaining olefin in the cyclic product can be used for further transformations, (b) the intrinsic unique reactivity of the allene might make the [2+2+1] ring-closing process easier, and (c) the axial chirality of the allene must be transferred to the central chirality of the product. This review outlines activities of the allene in the carbonylative [2+2+1] cyclization based on the classification of every reaction partner with the allene, and finally focuses on its application to the synthesis of chiral nonracemic compounds and natural products.

2 Allene–yne carbonylative cycloaddition 2.1

Intramolecular cyclization

2.1.1 Fe-mediated reaction. The Fe-mediated intramolecular carbonylative [2+2+1] cycloaddition reaction using an allene as

Chisato Mukai joined Kanazawa University as a Research Associate after receiving his PhD from Osaka University in 1981. He spent two years (1986–1988) at Stanford University with Professor Paul Wender as part of his postdoctoral studies. He became Associate Professor in 1989 and Full Professor in 1998. He spent four months at Emory University in 2003. He received the Takaoka Citizen Cultural Award in 1999 C. Mukai and the Pharmaceutical Society of Japan Award for Divisional Scientific Promotions in 2002. His research interests are directed toward the development of efficient reactions based on transition metals and the stereoselective total syntheses of natural products.


a p-component was reported by Narasaka and Shibata in 1994. Alkylthioallene–alkynes 1 reacted with a stoichiometric amount of Fe(CO)4(NMe3) at room temperature under photoirradiation conditions to produce bicyclo[n.3.0]compounds (n = 3–5) by exclusive participation of the distal p-bond (Scheme 3).5,6 During the construction of a seven-membered ring from 1c, the Z3-allyl iron complex 3 was mainly formed along with the desired distal product 2c. The complex 3 was easily converted into 2c by heating, strongly indicating that 2c must have been formed via the Z3-allyl iron complex intermediate 3 during the cyclization process. The alkylthio group has the advantage of promoting this cyclization (cyclization yield for a certain SMe substrate: 49%; for SiMe2t-Bu: 30%; for Me: 22%; and for H: trace). This is the first example of the intramolecular carbonylative [2+2+1] cycloaddition reaction of an allene. 2.1.2 Co-mediated reaction. Cazes reported the Co-mediated cycloaddition using N-methylmorpholine N-oxide (NMO) as a promoter,7 whose conditions had already been found during their study of the intermolecular cycloaddition of allene–alkyne–CO (vide infra).8 The simplest unsubstituted allene–yne 4a gave no desired product because polymerization of the allene moiety might be faster than formation of the alkyne–cobalt complex. The more-sterically hindered allene–ynes 4b–f afforded the desired bicyclo compounds as a mixture of 5 and 6 in low to moderate yields. The regioselectivity depends on the substitution pattern of the allene moiety as shown in Scheme 4. Thus, use of 3,3-disubstituted allene–ynes predominantly afforded the distal products, whereas the reaction of the 1,3-disubsituted ones produced a mixture of proximal and distal products in nearly a 1 : 1 ratio. Livinghouse et al. reported the catalytic version of the Co-mediated cyclization of 1,1,3-trisubstituted allene–yne 4f, in which the preferential formation of the proximal product 6f over the distal one 5f was observed that is obviously in contrast to Cazes’ results (Scheme 5).9 In addition, the methylthio group on the alkyne terminus improved the chemoand regioselectivities. During an investigation of the synthesis of novel tricyclic b-lactams, Alcaide group found that the construction of the bicyclo[5.3.0] skeletons 12 as distal products from 3,3-disubstituted allene–ynes 10 was achieved with the aid of 2-azetidinone (Scheme 6).10 Conjugation of the diene moiety with the nitrogen

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Scheme 6 Preparation of tricyclic b-lactams based on Co-mediated [2+2+1] cycloaddition.

Scheme 4

Co-mediated [2+2+1] cycloaddition.

Scheme 7

Scheme 5

Co-catalyzed [2+2+1] cycloaddition.

lone pair is believed to promote the isomerization of the initially formed 11 to the final products 12. 2.1.3 Mo-mediated reaction. Brummond and co-workers found that using the conditions which Jeong et al. reported for the PKR of enyne substrates,11 a stoichiometric amount of Mo(CO)6 and DMSO at 100 1C, afforded bicyclo compounds from allene–ynes via a carbonylative [2+2+1] cycloaddition.12–14 The regioselectivity depends on the substitution pattern of the allene moiety; the use of mono-, 1,3-di-, and 1,1,3-tri-substituted allenes (13, 17, and 19) led to the predominant conversion to a-alkylidenecyclopentenones as proximal products whereas the 3,3-disubstituted allenes (15) cyclized with a distal p-bond (Scheme 7). The stereoselectivity (E/Z ratio) in the reaction of

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Mo-mediated [2+2+1] cycloaddition.

the 1,3-disubstituted allene–ynes 17 is enhanced by increasing the steric bulk of the substituent R on the allenic terminus. The Mo-mediated reaction of allenamides 21 as 3,3-disubstituted allenes to produce the distal products 22 has been reported by Hsung et al. (Scheme 8).15 Allene–yne 23a with a silicon-containing tether afforded the silabicyclo[3.3.0]octenone 24a, which could be converted into

Scheme 8

Mo-mediated [2+2+1] cycloaddition of allenamides.


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Scheme 11 Mo-catalyzed [2+2+1] cycloaddition.

Scheme 9

Silicon-tethered [2+2+1] cycloaddition and cleavage of the tether.

the monocyclic cyclopentenone 25 via the 1,2-reduction, vinylsilane cleavage, and Tamao–Kumada oxidation (Scheme 9).16 This protocol can be used as an alternative to the intermolecular allenic [2+2+1] cycloaddition. During the cyclization of the amino acid derived allene–ynes, an interesting substituent effect on the diastereoselectivity was observed by Brummond’s group.17 Thus, the products, derived from the allene–yne 26a with an aromatic side chain, showed diastereoselectivities opposite to those of 26b with an aliphatic side chain, presumably due to complexation of the metal to the aromatic ring in the side chain (Scheme 10). Oh et al. demonstrated that allene–ynes 30 could be converted into bicyclo[3.3.0]octadienones 31 in the presence of a catalytic amount of Mo(CO)6 under 1 atm of CO (Scheme 11).18 In this case, no a-alkylidenecyclopentenones derived from the reaction with a proximal p-bond of the allene were obtained because of its strained structure. 2.1.4 Rh-catalyzed reaction. Narasaka and co-workers first reported the reaction with allene–yne 32 as an example of the Rh-catalyzed carbonylative [2+2+1] cycloaddition (Scheme 12).19 The treatment of 32 with 5 mol% of [RhCl(CO)2]2 at room temperature under 1 atm of CO afforded the bicyclo[4.3.0]nonadienone

Scheme 10

Reversal in diastereoselectivity of [2+2+1] cycloaddition.


Scheme 12

The first example of Rh-catalyzed [2+2+1] cycloaddition.

33 in which the distal p-bond of the allene exclusively took part in the ring-closing process. Brummond and Mukai et al. independently studied the Rh-catalyzed carbonylative [2+2+1] cycloaddition of allene–ynes in detail and demonstrated that the reaction consistently occurred with the distal p-bond of the allene. Brummond and co-workers focused upon the contrast between the Rh-catalyzed reaction and Mo-mediated one. In fact, the mono-, 1,3-di-, and 1,1,3-tri-substituted allenes (23b, 36, and 39) cyclized under the influence of a catalytic amount of [RhCl(CO)2]2 produced bicyclo[4.3.0] compounds whereas they afforded the bicyclo[3.3.0] skeletons in the presence of a stoichiometric amount of Mo(CO)6 (Scheme 13).20 The Rh-catalyzed reaction of the 3,3-disubstituted allene 41 gave the distal product 42 similar to the Mo-mediated conversion of 15 to 16 (Scheme 7). The intramolecular [2+2+1] cycloaddition reaction of an allene with an ynone, a rarely used functionality in the Pauson–Khand reaction, was catalyzed by the Rh and Mo complexes, leading to the formation of b- and a-alkylidenecyclopentenones, respectively (Scheme 14).21 The fact that Rh preferentially reacted with the distal p-bond of the allene and Mo reacted with the proximal one has successfully been explained by calculations using the B3LYP functional as implemented in Gaussian 03. Upon the oxidative addition to the allene–yne, Rh has a distorted square planar geometry leading to the energetically preferred complexation with the distal p-bond to form metallocycles C (Fig. 1).22 The free energy of the transition state for the oxidative addition of Rh to the distal p-bond is 5.5 kcal mol1 lower than that to the proximal one. In contrast, a distorted trigonal bipyramidal structure constructed by Mo prefers the reaction with the proximal bond to produce the intermediate C 0 . The energy difference between proximal and distal bonds is 4.8 kcal mol1. Mukai and co-workers investigated the potential for the construction of more than seven-membered rings, which could hardly be obtained by the general [2+2+1] cycloaddition methods due to the entropic and enthalpic factors.23 In fact, the application of the Co2(CO)8-mediated intramolecular Pauson–Khand reaction

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Fig. 1

Proposed mechanism of carbonylative [2+2+1] cycloaddition of allene.

Scheme 13 Rh-catalyzed and Mo-mediated carbonylative [2+2+1] cycloaddition.

Scheme 15 reaction.

Scheme 14

Rh-catalyzed and Mo-mediated reaction of allene–ynones.

of the ene–ynes to the synthesis of the bicyclo[5.3.0] ring system has not yet been realized, except for the preparation of the azabicyclo[5.3.0]decenones 4724 and medium-sized oxacyclic compounds 4925 from ene–ynes with an aromatic ring as a template (Scheme 15).23 The Fe- and Co-mediated carbonylative [2+2+1] cycloaddition of allene–ynes having no templates produced bicyclo[5.3.0]decadienones but in low yields (Schemes 3 and 4). Mukai developed a high-yielding reliable procedure for preparing

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Construction of a medium-sized ring by Pauson–Khand

bicyclo[5.3.0] compounds by the Rh-catalyzed reaction on the basis of Narasaka’s19 or Jeong’s procedure26 (Scheme 16).20,27,28 Thus, the treatment of 3,3-disubstituted allene–ynes 50 with 2.5 or 5 mol% of [RhCl(CO)2]2 or [RhCl(CO)dppp]2 in refluxing toluene under 1 atm of CO afforded the desired cycloaddition products 51 in moderate to high yields. The other possible isomer, the proximal product 52, could never be detected in the reaction mixture. This Rh-catalyzed carbonylative [2+2+1] cycloaddition requires neither a geminal dialkyl effect nor a template effect. The ester functionality and hydroxy and siloxy groups can be tolerated, and azabicyclo- as well as oxabicyclo frameworks can be constructed. In the reaction of allene–ynes bearing substituents at the allenic terminus, in some cases, the carbonylative [2+2+1] cycloaddition


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Scheme 18

Proposed mechanism for formation of triene derivative.

Scheme 16 Construction of bicyclo[5.3.0] skeleton by Rh-catalyzed carbonylative [2+2+1] cycloaddition of 3,3-disubstituted allene–ynes.

Scheme 19 Rh-catalyzed carbonylative [2+2+1] cycloaddition of allene– ynes bearing substituents at the allenic terminus. Scheme 17 Rh-catalyzed carbonylative [2+2+1] cycloaddition of 1,3,3trisubstituted allene–ynes.

competed with the formation of the seven-membered ring triene 55 (Scheme 17).29,30 For example, while azabicyclo[5.3.0] compound 54a is exclusively obtained from the corresponding 1,3,3-trisubstituted allene–yne 53a, its carbon analogue 54b is produced in poor yield under the conditions used in the reaction of 3,3-disubstituted allene–ynes 50. The one-carbon shortened six-membered ring triene derivatives had been produced by the [RhCl(CO)2]2-catalyzed cycloisomerization reaction in the absence of CO (N2 atmosphere).31,32 The undesired pathway via the b-hydride elimination as shown in Scheme 18 was effectively suppressed by increasing the CO pressure during the ring-closing reaction of the 1,3,3-trisubstituted allene–ynes. However, such conditions were shown to be insufficient for the construction of the bicyclo[5.3.0] skeletons from tetrasubstituted allene–ynes (data not shown). Mukai and co-workers have mainly utilized the 3-sulfonylsubstituted allene–ynes as substrates due to their ready availability as well as their ability to selectively react at the distal p-bond. However, they demonstrated that 1-sulfonylallene–ynes 58 also cyclized with the distal p-bond, confirming that the obtained


selectivity was achieved through only metal-based control elements (Scheme 19).33 Brummond et al. also reported that 1,3,3-trisubstituted allenol esters 60 gave a-acetoxycyclopentenone derivatives 61 by Rh-catalyzed cyclocarbonylation including the distal p-bond of the allene (Scheme 19).34 Moreover, they demonstrated that reaction of the tetrasubstituted allenes 62 afforded the corresponding cyclized products 63 accompanied by elimination of the acetoxy group. The Rh-catalyzed carbonylative [2+2+1] cycloaddition of allene– ynes could be applicable for constructing the bicyclo[6.3.0] frameworks by Mukai’s group. Even the simple linear allene–yne 64 (ZQH) underwent the carbonylative cycloaddition in the presence of [RhCl(CO)2]2 in refluxing xylene under 1 atm of CO to give bicyclo[6.3.0] compounds 65 in 23% yield (Scheme 20).35 Great success was achieved by using the benzene-containing tether (compounds 66) due to its template effect, although the position of the benzene ring is critical. 2.1.5 Miscellaneous reaction. Brummond et al. reported that the treatment of a 1,3-disubstituted allene–yne 70 with [IrCl(cod)]2 afforded the b-alkylidenecyclopentenone 71 in a yield higher than that of [RhCl(CO)2]2 (Scheme 21).20

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Scheme 22

IrCl(CO)(PPh3)2-catalyzed carbonylative [2+2+1] cycloaddition.

Scheme 23

Co2Rh2-catalyzed carbonylative [2+2+1] cycloaddition.

Scheme 24

Zr-mediated or Ti-catalyzed cyclocarbonylation of allene–ynes.

Scheme 20 Construction of bicyclo[6.3.0] skeleton by Rh-catalyzed carbonylative [2+2+1] cycloaddition.

Scheme 21 Ir-catalyzed carbonylative 1,3-disubstituted allene–yne.

[2+2+1]

cycloaddition

of

Shibata et al. reported the IrCl(CO)(PPh3)2-catalyzed carbonylative [2+2+1] cycloaddition in which allene–ynes bearing a dimethyl substituent at the allenic terminus efficiently transformed into the a-alkylidenecyclopentenones (Scheme 22).36 In contrast to Brummond’s results, the reaction of the monomethylsubstituted 76 gave a mixture of the cyclized products with a low selectivity. Application of cobalt–rhodium nanoparticles (Co2Rh2) to the carbonylative [2+2+1] cycloaddition of allene–ynes has been reported by Chung and co-workers (Scheme 23).37 The transformation of allene–ynes without substituents at the allenic terminus into bicyclo[4.3.0] and bicyclo[5.3.0] skeletons smoothly proceeded, although the use of ether tether led to some decrease in product yield and substituents at the C1 position caused trouble. The catalysts are easily recovered and reused at least six times without any loss of catalytic activity. A few examples of the Zr-mediated14 or Ti-catalyzed38 cyclocarbonylation of allene–ynes have also been reported (Scheme 24).

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2.1.6 Summary of intramolecular allene–yne carbonylative cycloaddition. Various metal complexes including Fe, Co, Mo, Rh, Ir, Zr and Ti have been used in the intramolecular [2+2+1] cycloaddition reactions. From the point of view of practical use, the potential for catalytic turnover and regio- and stereoselectivity as well as product yields are of vital importance to this metalmediated reaction. Rh, Ir and Ti complexes under 1 atm of CO can be used catalytically (Z5 mol%) for the [2+2+1] carbonylative cycloaddition. Use of Fe, Co, Mo and Zr usually leads to the stoichiometric reaction, but in some cases under a CO atmosphere, Co and Mo allow us to catalytically use them. The relationship between the regioselectivity and the metal/ substitution pattern of the allene is summarized in Table 1.


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Table 1 yne

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Distal and proximal selectivity in [2+2+1] cycloaddition of allene–

Metal

Monosubstituted

3,3Disubstituted

1,3Disubstituted

1,1,3Trisubstituted

Co Mo Rh Ir

— P D NR

D D D NR

D&P P D D (& P)

D&P P D P

D: distal; P: proximal; NR: data not reported.

Mo and Rh complexes have excellent proximal and distal selectivities, respectively, so that they can be complementarily treated for the transformation of mono-, 1,3-di-, and 1,1,3trisubstituted allene–ynes. The 3,3-disubstituted allene–ynes behave in a different way and undergo the [2+2+1] cyclization at the distal p-bond of the allene under the influence of the Co, Mo, and Rh complexes. We don’t have enough data to discuss the E/Z selectivity and diastereoselectivity of [2+2+1] cyclization of allenes. Chirality transfer of the allene in Zr- or Mo-mediated and Rh-catalyzed reaction is discussed in Section 6. 2.2

Intermolecular cyclization

Intermolecular Pauson–Khand reaction of alkenes with alkynes generally gives low yields of cycloadducts except for strained olefins. In this context, Cazes’ group has systematically studied the Co-mediated intermolecular [2+2+1] cycloaddition of allenes in place of alkenes.8,39,40 They found that allene derivatives 84 reacted with the alkyne–Co2(CO)6 complexes 85 in the presence of the N-oxide promoter at low temperature to produce the b-alkylidenecyclopentenones 86 with high regioand E/Z-selectivities, although the thermal reaction gave a disappointing result as Pauson’s group41 reported (Scheme 25). Both the regioselectivity and the stereoselectivity depend on the bulkiness of the substituents on the alkyne and allene (R1–R3). The reaction of the unsymmetrical alkynes predominantly afforded cyclopentenones 86, which have a larger R2 group at the C2 position of the cyclopentenone. This can be rationalized using the Magnus mechanism, which is proposed for the Pauson–Khand reaction,42 after production of intermediate ps-eq I or ps-ax I by, respectively, pseudo-equatorial or pseudo-axial coordination of the double bond to the alkyne– Co2(CO)6 complex (with respect to the Co–Co bond) (Scheme 26). Cyclopentenones 88 or 89 were rarely obtained when the R2 and/or R3 were small groups like H or Me. The reaction of the 1,1-disubstituted allene 90 and 1,3-disubstituted allene 92 with 85a gave the cyclopentenones 91 and 93, respectively, in good yield. The trisubstituted allene 94, however, gave a 60 : 40 mixture of cyclized products 95 and 96 in lower yield, and the tetramethylallene produced no cyclized products. Aumann et al.43 first reported the intermolecular [2+2+1] cycloaddition of allene–alkyne–CO mediated by Fe2(CO)9, and Narasaka et al.6 improved this reaction using Fe(CO)4(NMe3) (Scheme 27). Recently, Williams and Baik’s group reported the ironmediated cycloaddition using 1,1-disubstituted allenylsilanes


Scheme 25

Co-mediated intermolecular [2+2+1] cycloaddition.

Scheme 26 Proposed mechanism of the Co-mediated intermolecular [2+2+1] cycloaddition.

98 as the substrates and NMO as an additive (Scheme 28).44 They showed that by isolation of a three-membered iron metallacycle intermediate 101 and by kinetic studies, this reaction occurs via an alternative mechanistic pathway which does not involve initial complexation of the alkyne component (Scheme 29).

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Scheme 27 Fe2(CO)9[2+2+1] cycloaddition.

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and

Fe(CO)4(NMe3)-mediated

intermolecular

Scheme 30 The first example of Rh-catalyzed [2+2+1] cycloaddition of allene–ene.

Scheme 28 Fe-mediated allenylsilanes.

Scheme 29 Proposed [2+2+1] cycloaddition.

intermolecular

mechanism

of

[2+2+1]

cycloaddition

Fe-mediated

of

allene probably due to the steric hindrance of the bulky dimethyl moieties at the allenic termini. Mukai et al. demonstrated that the modified conditions (5 atm of CO or addition of AgBF4 under a low CO pressure) of their allene–yne cycloaddition allowed the efficient conversion of the allene–enes 105 into the bicyclo[4.3.0] derivatives 106a,c–e as well as the bicyclo[5.3.0]dec-1(10)-en-9-one 106b by participation of the distal p bond of the allene (Scheme 31).46,47

intermolecular

3 Allene–ene carbonylative cycloaddition In 2004, during their investigation of the Rh-catalyzed cycloisomerization of allene–enes, Itoh and co-workers found that only allene–ene 102 (R = TMS) bearing a TMS group at the olefinic terminus was converted into the [2+2+1] cycloadducts 104a and 104b (Scheme 30).45 Thus, the treatment of 102 (R = TMS) with 2.5 mol% of [RhCl(CO)2]2 under 1 atm of CO afforded the bicyclo[3.3.0] derivative 104a and the desilylated product 104b, whereas, upon exposure to the same conditions, 102 (R = H) produced the seven-membered-ring product 103. The exclusive formation of the [2+2+1] cycloadducts is ascribed to the enhanced stabilization of the rhodacycle 102 0 by the TMS group. The reaction exclusively occurred with the proximal p-bond of

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Scheme 31

Rh-catalyzed intramolecular [2+2+1] cycloaddition of allene–ene.


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Scheme 32 Rh-catalyzed [2+2+1] cycloaddition of ene-vinylidenecyclopropanes.

While cyclization of the sulfonyl- or methoxycarbonylallene–enes was accompanied by the isomerization of the double bond after the formation of 105 0 , the reaction of the methylallene–ene gave the unisomerized product 106d. This reaction provides a new procedure for the construction of the trans-bicyclo[4.3.0] skeletons 106c (R3 a H) having an alkyl appendage at the ring juncture, which were hardly attained in satisfactory yields by the classical Pauson–Khand reaction of the corresponding enynes. This method was successfully applied to the construction of the more complex tricyclo[6.4.0.0[1,5]]dodecenone 106e. The Rh(I)-catalyzed [2+2+1] cycloaddition reaction of enevinylidenecyclopropanes 107 with carbon monoxide was reported by Li and co-workers (Scheme 32).48 This [RhCl(cod)]2-catalyzed reaction provided the corresponding bicyclo[4.3.0] derivatives 108 containing spiro-cyclopropane units in high yield. The reaction for the construction of the bicyclo[5.3.0] skeleton from a one-carbon homologated substrate was unsuccessful. Wender’s group found that the allene-1,3-diene 109 smoothly underwent the Rh-catalyzed [2+2+1] cycloaddition to

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produce bicyclo[3.3.0] derivatives 110.49,50 Treatment of 1,1,3trisubstituted or 1,3-disubstituted-allene-dienes 109a,b with the [RhCl(CO)2]2 catalyst under 1 atm of CO afforded the desired products 110a,b at ambient temperature (Scheme 33). Only in the case of monosubstituted-allene-diene 109c, the reaction required higher temperature (60 1C) and increased CO pressure (4 atm) to afford the desired product 110c with the concomitant [4+2] cycloadduct 111c. Thus, the reaction conditions of allene-dienes were generally milder than those of allene–enes (Mukai and Li’s work; 80–120 1C) due to the introduction of the conjugated double bond to the olefin part. They also reported that a similar ‘‘diene effect’’ was observed in the carbonylative [2+2+1] cycloaddition of the diene–yne and diene–ene.50

4 Bisallene carbonylative cycloaddition 4.1

Intermolecular cyclization

In 1985, Pasto et al. detected the carbonylative [2+2+1] cycloadducts 112 in the reaction of two molar equiv. of phenylallene (84a) and tris(triphenylphosphine)nickel(0) under bubbling CO conditions (Scheme 34).51,52 The efficient catalytic intermolecular [2+2+1] cycloaddition of two allene units and carbon monoxide was reported by Chung’s group.53 They found that the treatment of phenylallene (84a) with 5 mol% of Co2Rh2 nanoparticles in toluene (0.2 M) at 130 1C under CO pressure (2 atm) gave the desired cyclopentenones 112c (68%) and 112d (12%) (Scheme 35). Even in the presence of 1-phenylpropyne, the bisallene cycloaddition is superior to the allene–yne cycloaddition upon exposure to the conditions using Co–Rh nanoparticles. When 5 mol% of [RhCl(CO)2]2 was used for this reaction, the total chemical yields of 112 were rather low (112c: 32% and 112d: 25%). The reaction with other 1-substituted allenes 84 also provided the corresponding cyclopentenones 113 in moderate to high total yields. 4.2

Intramolecular cyclization

In addition to the intermolecular reaction, Chung et al. also reported the intramolecular [2+2+1] cyclization of bisallenes

Scheme 33

Rh-catalyzed [2+2+1] cycloaddition of allene–diene.


Scheme 34 bisallene.

Ni-mediated

intermolecular

[2+2+1]

cycloaddition

of

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Scheme 35 bisallenes.

Co2Rh2-catalyzed intermolecular [2+2+1] cycloaddition of

Scheme 36 bisallenes.

Co2Rh2-catalyzed intramolecular [2+2+1] cycloaddition of

using Co–Rh nanoparticles as a catalyst.53 Under conditions (5 mol% Co2Rh2, toluene (0.1 M), 100 1C, 2 atm of CO) similar to the intermolecular version, the 1,5-bisallenes 114 were converted into bicyclo[5.3.0] derivatives 116 in 45 to 74% yields (Scheme 36). The formation of 116 can be rationalized in terms of the intermediacy of the initially formed 115, which would be formed through the reaction between the distal double bonds of the two allenyl groups, and its subsequent isomerization to the a,b-unsaturated ketones. The reaction of a substrate having a 1,1,3-trisubstituted allene provided a cycloisomerized product instead of the desired [2+2+1] cycloadduct. In 2009, Mukai and co-workers found that the [RhCl(CO)dppp]2-catalyzed intramolecular [2+2+1] cycloaddition of the bis(phenylsulfonylallene) derivatives gave not only the bicyclo[5.3.0]decadienones 118, but also the larger-sized bicyclo[6.3.0]undecadienone skeletons 122 in satisfactory to high yields (Scheme 37).54,55 In some cases, small amounts of the [2+2] cycloadducts 119 or 123 were observed as byproducts. The reaction of the mono- or non-sulfonylated bisallene 117b or 117c gave lower yields or no trace of the corresponding [2+2+1] cycloadducts. These results imply that the introduction of two sulfonyl groups allows an extremely smooth intramolecular [2+2+1] cycloaddition. The bicyclo[7.3.0]dodecadienone 125 could be formed in a rather low yield.55

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Scheme 37

Rh-catalyzed intramolecular [2+2+1] cycloaddition of bisallenes.

5 Hetero-[2+2+1] cyclization In 1996, Crowe et al.56 and Buchwald’s group57 independently reported the Cp2Ti(PMe3)2-mediated or catalyzed hetero [2+2+1] cycloaddition of d-unsaturated ketones and aldehydes with carbon monoxide for the formation of fused bicyclic g-butyrolactones (Scheme 38). Since then, in addition to the carbon–oxygen double bond (ketone and aldehyde), various types of hetero p-systems, such as an imine, nitrile, and heterocumulene, have then been involved in the hetero [2+2+1] cycloaddition to form the corresponding heterocycles. This chapter describes the transition metal-mediated or catalyzed hetero [2+2+1]


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Scheme 38

[2+2+1] Cycloaddition of CQX bonds.

Chem Soc Rev

Scheme 41 Proposed mechanism for formation of a-methylene-gbutyrolactone.

Scheme 42 ketones.

Scheme 39

Hetero [2+2+1] cycloaddition of allene or heterocumulene.

cycloaddition of (1) allene-carbon–heteroatom (C–X) multiple bonds and (2) heterocumulene–ynes (Scheme 39). 5.1

Allene-C–X multiple bonds

Murai and Chatani first reported that the Ru3(CO)12 smoothly catalyzed the hetero [2+2+1] cycloadditions of substituted d-alkynyl aldehydes with carbon monoxide to form fused a,b-unsaturated g-butyrolactones.58 Based on this result, Kang et al. found that the Ru3(CO)12-catalyzed hetero [2+2+1] cycloaddition reactions of allenyl aldehydes and ketones 127 with carbon monoxide efficiently afforded the cis ring-fused a-methylene-gbutyrolactone products 128 (Scheme 40).59 They considered that the mechanistic pathway in this catalytic process involved the intermediacy of metallacyclopentene 131 followed by insertion of CO to form the carbonylated metallacycle 132 and subsequent reductive elimination (Scheme 41). The allenylimine 129 was

Scheme 40 and imine.

Hetero [2+2+1] cycloaddition of allenyl aldehydes, ketones,


Mo-mediated [2+2+1] cycloaddition of allenyl aldehydes and

also applicable for the formation of the a-methylene-gbutyrolactam 130 using this methodology. In 2004, Yu and co-workers demonstrated that the conversion of allenyl aldehydes and ketones 127 into a-methylene-gbutyrolactones 128 was also mediated by a stoichiometric amount of Mo(CO)6 with DMSO (Scheme 42).60 More recently, the [RhCl(CO)dppp]2-catalyzed intramolecular carbonylative [2+2+1] cycloaddition of allene-nitrile derivatives 133 under the mild conditions leading to the formation of benzo[ f ]oxyindole derivatives 134 was developed by Mukai et al. (Scheme 43).61 Based on their working hypothesis, the reaction would be initiated by isomerization of the nitrile group to the phenylketenimine 135 following by the typical [2+2+1] cycloaddition process. Actually, experiments with allene-nitriles 136 or 137, which could not proceed via the proton-tautomerization of the nitrile functionality, did not afford the desired [2+2+1] cycloadducts. Furthermore, application of this aza-Pauson–Khand-type reaction was extended to aliphatic substrates 138 for producing the azabicyclo[m.3.0] derivatives 139 (m = 3–5). 5.2

Heterocumulene–yne

In 1970, Ohshiro et al. reported that the reaction of 2 equivalents of phenyl isocyanate (140), 1 equivalent of diphenylacetylene (141) and 1 equivalent of Fe(CO)5 at 175 1C produced 1,3,4-triphenylmaleimide (142) and 1,3,4-triphenyl-5-phenyliminopyrrolin-2-one (143) in 42% and 15% yields, respectively (Scheme 44).62 The pyrroline 143 was also obtained in 45% yield in the equimolecular reaction using diphenylcarbodiimide (144), diphenylacetylene (141) and Fe(CO)5 at 185 1C. Based on their proposed mechanisms, the ‘‘doubly s-bonded’’ acetylene complex 145 was initially formed and easily added to PhNCX (140, 144) across the NQC bond to form the complex 146 followed by the CO insertion to form the pyrrolines 142 and 143 (Scheme 45). The production of pyrroline 143 from the former reaction is ascribed to the in situ generation of diphenylcarbodiimide (144) from phenyl isocyanate (140) by catalysis using Fe(CO)5.

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Scheme 45 Proposed mechanism of Fe-mediated intermolecular hetero [2+2+1] cycloaddition.

Scheme 46

Scheme 43

Rh-catalyzed [2+2+1] cycloaddition of allene-nitriles.

Ni-mediated intermolecular hetero [2+2+1] cycloaddition.

corresponding triphenylmaleimide 142 (Scheme 46).63 In this investigation, they isolated the azanickelacyclopentenone 147. The catalytic reaction for the preparation of maleimide derivatives from isocyanates and alkynes was then developed by Kondo and co-workers.64 They found that the treatment of 3 equivalents of isocyanates 148 and alkynes 149 with the Ru3(CO)12 catalyst produced the corresponding trisubstituted maleimide derivatives 150 in high yields (Scheme 47). Saito’s group initially reported the intramolecular hetero [2+2+1] cycloaddition of heterocumulene in 2003. The ynecarbodiimides 151 underwent the [2+2+1] cycloaddition in the presence of a stoichiometric amount of Mo(CO)6 and DMSO to afford the diazabicyclo[3.3.0] derivatives 152 in moderate to good yields (Scheme 48).65 In 2006, Mukai and co-workers reported the Co2(CO)8catalyzed hetero [2+2+1] cycloaddition of yne-carbodiimide derivatives 153 using tetramethylthiourea (TMTU) as an additive to produce the pyrrolo[2,3-b]indol-2-one ring systems 154 (Scheme 49).66,67 In all cases, a trace (or small) amount of the urea derivative 155, which must have been formed by hydrolysis of the starting material 153, was detected (or isolated). Saito et al. then reported the catalytic hetero [2+2+1] cycloaddition of the yne-carbodiimide derivatives 151 using the in situ prepared

Scheme 44 Fe-mediated intermolecular hetero [2+2+1] cycloaddition.

Hoberg and co-workers then reported the Ni-mediated intermolecular [2+2+1] cycloaddition of 140 and 141 to form the

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Scheme 47

Ru-catalyzed intermolecular hetero [2+2+1] cycloaddition.


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Scheme 48 Mo-mediated intramolecular hetero [2+2+1] cycloaddition.

Scheme 49

Co-catalyzed intramolecular hetero [2+2+1] cycloaddition.

catalyst from [RhCl(cod)]2 and dppp to afford the pyrrolo[2,3-b]pyrrolinones 152a and pyrrolo[2,3-b]indolones 152b (Scheme 50).68 In addition, a synthetic method for pyrrolo[2,3-b]quinolinones 157 based on the [RhCl(CO)2]2-catalyzed hetero [2+2+1] cycloaddition of yne-carbodiimides 156 was also reported by the same group.69 Saito’s group also reported the hetero [2+2+1] cycloaddition of yne-isothiocyanate, which represents the first example of a hetero [2+2+1] cycloaddition involving a thiocarbonyl functionality.70 2-Alkynylphenyl isothiocyanates 158 (R1 = t-Bu, TMS, and TBS) were converted into thieno[2,3-b]indol-2-one derivatives 159 using a stoichiometric amount of Co2(CO)8 or Mo(CO)6, or a catalytic amount of [RhCl(CO)dppp]2 under a CO atmosphere (Scheme 51). The reaction using Co2(CO)8 provided the 2,3-dihydrothieno[2,3-b]indol-2-one 160 via the reductive [2+2+1] cycloaddition.71 For the substrate 161 having a proton at the propargyl position, the Mo-mediated and Rh-catalyzed reaction provided the isomerized thieno[2,3-b]indol-2-one derivatives 162 as a mixture of E,Z-isomers. Both the cycloadduct 164 and isomerized product 165 were obtained from the yne-isothiocyanate 163 having an isopropyl group at the alkyne terminus. Thermally stable triarylketenimines were used for the intermolecular hetero [2+2+1] cycloaddition by Saito et al.72 The reaction of ketenimine 166, alkyne-dicobalthexacarbonyl complexes 167, and DMSO upon heating in toluene afforded the g-methyleneg-lactam derivatives 168 (Scheme 52).


Scheme 50

Rh-catalyzed intramolecular hetero [2+2+1] cycloaddition.

6 Enantioselective synthesis of bicyclic cyclopentenones 6.1

Transfer of chirality

It is expected that the axial chirality of the allene is efficiently transferred into the central chirality during an intramolecular [2+2+1] cyclization to produce an enantiomerically enriched bicyclo compound. For example, for the conversion of 1,3-disubstituted allene–ynes into the proximal products, it is predicted that the axial chirality of the allenic moiety could be transferred to the stereocenter by the ring fusion of the (E)-alkylidene product IV via the selective formation of the metallocycle III from the less hindered face of the allene (Scheme 53). The reaction of the more hindered face would produce (Z)-alkylidene product IV0 via the formation of III0 based on the transfer of the axial chirality. Brummond et al. showed that the Zr-mediated cyclization of allene–yne (R)-169 (95% ee) produced the proximal product (S)-170E in 39% yield and 85% ee without any production of 170Z (Scheme 54).73 In addition, the complementary experiments demonstrated that the loss in enantiomeric excesses might be due to the isomerization of the minor cyclization product (R)-170Z to (R)-170E during the acidic workup.

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Scheme 51 Intramolecular isothiocyanates.

Scheme 52

Review Article

hetero

[2+2+1]

cycloaddition

of

Chirality transfer of allene–ynes to proximal products.

Scheme 54

Chirality transfer of allene–yne in Zr-mediated reaction.

Scheme 55

Chirality transfer of allene–yne in Mo-mediated reaction.

yne-

Co-mediated intermolecular hetero [2+2+1] cycloaddition.

The Mo-mediated reaction was also investigated using an allene–yne bearing a dimethylphenylsilyl (DPS) group on the allenic terminus as a potentially removable stereocontrolling group.73 Treatment of the allene–yne (R)-172 (95% ee) with Mo(CO)6 and DMSO in toluene at 95 1C afforded an 8 : 1 mixture of (R)-173E (95% ee) and (S)-173Z (63% ee) (Scheme 55). The facile silica gel isomerization of the (E)-isomer to the

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Scheme 53

(Z)-isomer would explain the fact that the enantiomeric purity of the (Z)-isomer was significantly lost in contrast to the complete chirality transfer observed in the production of the (E)-isomer. The Rh-catalyzed transformation of 1,3,3-trisubstituted allene–ynes 174 and 176 into distal products 175 and 177, respectively, was found to be achieved with complete transfer of the axial chirality to the stereogenic carbon a to the carbonyl group (Scheme 56).74


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Scheme 56 Chirality transfer of 1,3,3-trisubstituted allene–ynes in Rhcatalyzed reaction.

On the other hand, the reaction of the 1,3-disubstituted allene–ynes 178 led to a decreased product ee (Scheme 57). The degree of chiral information from allenes to the products was dependent on the tether and alkyne substitution. This insufficient transfer of chirality must be attributed to the partial racemization of the allenes by the intramolecular attack of a nucleophilic X group on the activated proximal p-bond of the allene prior to product formation. Complete transfer of chirality in the reaction of the trisubstituted allene–yne is explained by selective complexation at the less substituted distal p-bond (Scheme 57, intermediate vi), which would not be subject to an internal nucleophilic addition, and complexation with the alkyne resulting in the formation of the desired bicyclo compound without any loss of enantiomeric excess. 6.2

Enantioselective catalysis

Only one example of the carbonylative [2+2+1] cycloaddition using a chiral catalyst has been reported by Shibata’s group.75 The combination between [IrCl(cod)2]PF6 and (S)-BINAP realizes the conversion of the allene–yne 73a into the proximal product 74a in 31% yield and 76% ee (Scheme 58).

7 Application to the synthesis of biologically or structurally interesting molecules 7.1

Scheme 57 Chirality transfer of 1,3-disubstituted allene–ynes and postulated mechanism for a decrease in enantiomeric excesses.

Mo-mediated cyclization of allene–ynes

In 1999, Brummond et al. reported the first application of the allenic [2+2+1] cycloaddition to the synthesis of a biologically active compound.76,77 The methyl ketone 180, derived from 1,1-diacetylcyclopropane and siloxypropyne, was converted into


Scheme 58 complex.

Enantioselective [2+2+1] cycloaddition catalyzed by the Ir

propargyl acetate 181, followed by reduction with [CuH(PPh3)]6 to produce the allene 182 after removal of the TMS group (Scheme 59). Treatment of the allene–yne 182 with Mo(CO)6 and DMSO in toluene at 110 1C in a stoichiometric manner afforded the cyclized product 183, which was transformed into ()-hydroxymethylacylfulvene (HMAF), an illudine analogue, in four steps. Taking advantage of the Sharpless AD, they also synthesized the enantiomerically pure cyclization precursor (R,R)-180, which enables the enantioselective synthesis of HMAF. Dicyclopenta[a,e]pentalene derivatives, highly strained [14] annulenes, have fascinated both physical and theoretical organic chemists. Cook and co-workers reported the synthesis of diisopropylsilyl-substituted dicyclopenta[a,e]pentalenes 192

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Scheme 60

Scheme 59 Synthesis of ()-HMAF via the Mo-mediated [2+2+1] cycloaddition.

using the Mo-mediated bisallene–bisalkyne [2+2+1] cyclization (Scheme 60).78,79 Bisallene 189 was obtained by Red Al reduction of bis(propargyl chloride) 188, which was prepared from the diketone 187. After protection of the diol, the resulting acetals 190 were heated with a large excess of Mo(CO)6 in toluene at 53–55 1C to afford the desired tetracyclic dione compounds 191 in 65–70% yields through a tandem cyclization process. The diones 191 were successfully converted into dicyclopenta[a,e]pentalenes 192, which were shown to have a planar structure and undergo significant electronic delocalization. The carbonylative [2+2+1] cycloaddition of allene–yne bearing a removable silicon tether was used for the first total synthesis of ()-15-deoxy-D12,14-prostaglandin J2.80 The allene part 193 was constructed by the Sonogashira coupling of 4-pentynol with (E)-1-bromo-1-heptene, followed by treatment with n-BuLi and TMEDA (Scheme 61). The allene–yne 194, derived from 193 via a three-step conversion, was treated with Mo(CO)6 and DMSO in toluene at 100 1C to give a 1 : 2 mixture of 195E and 195Z in 38% yield. The undesired 195Z can be isomerized to the desired 195E using boron trifluoride and propanedithiol. Completion of the

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Synthesis of dicyclopenta[a,e]pentalenes.

total synthesis was done via the oxidative ring opening of the silacyclopentane moiety. Liu et al. reported the construction of the cyclopenta[a]indene skeleton using the Mo-mediated cyclocarbonylation of allene–ynes.81 The skeleton is found in pallidol and geafricanin F, naturally occurring polyphenols found in several plant families which have diverse bioactivities. Although 1-ethynyl-2-propadienylbenzene (197) is known to readily undergo the Myers–Saito or Schmittel cyclization via the biradical 199 or 200 under ambient conditions, they found that a stoichiometric amount of Mo(CO)3(MeCN)3 effected the carbonylative [2+2+1] cycloaddition of 197 to produce cyclopenta[a]inden-2-ones 198 in high yields (Scheme 62). They also tried the catalytic version of that transformation in the presence of 5 mol% of [RhCl(CO)2]2 at 90 1C to furnish 198 in 62% yield along with the Myers–Saito cyclization product (2-methylnaphthalene, 8% yield). 7.2

Rh-catalyzed cyclization of allene–ynes

On the other hand, Mukai and co-workers reported that the Rh-catalyzed cycloaddition of sulfonylallene–yne 203 more effectively afforded the corresponding tricyclic compound 204 without any production of 2-methylnaphthalene (Scheme 63).82 Furthermore, the consecutive [2,3]-sigmatropic rearrangement of propargyl sulfinate 202 and the [2+2+1] cyclization of the resulting sulfonylallene 203 proceeded under Rh-catalyzed conditions in one-pot.35 Thus the resulting 204 was transformed into the optically active 207, the core carbon framework of cyanosporasides A and B. The presence of the sulfonyl group contributes


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Scheme 61

Scheme 62

Chem Soc Rev

Synthesis of 15-deoxy-D12,14-prostaglandin J2.

Scheme 63

Synthesis of the core framework of cyanosporasides A and B.

Scheme 64

Synthesis of the tricyclic core of guanacastepene A.

Mo-mediated synthesis of 1H-cyclopenta[a]inden-2-ones.

to the regioselective epoxidation and the efficient SN2-type ringopening of the epoxy group by the alcohol reagent. Brummond’s group studied the synthesis of linearly and angularly fused [6-7-5] tricyclic systems by taking advantage of the Rh-catalyzed [2+2+1] cycloaddition of the allene–yne connected to the cyclohexane ring. Their first targeted carbon skeleton was the linearly fused tricyclic core of guanacastepene A (Scheme 64).83 The silylallene–yne substrate 210 was prepared from propargyl mesylate and (Me2PhSi)2Cu(CN)Li2, and treated with 10 mol% of [RhCl(CO)2]2 in toluene at 80 1C under 1 atm of CO to give the highly functionalized tricyclic compound 211 in 65% yield. The linearly fused [6-7-5] system 213 and the angularly fused tricyclic compounds 215 and 217, found in the core structure of grayanotoxin, rippertene, and resiniferatoxin, respectively, were also prepared by the Rh-catalyzed cyclocarbonylation


reaction of the corresponding allene–ynes 212, 214, and 216 (Scheme 65).21,84 Mukai’s group accomplished the first total synthesis of (+)-achalensolide.85 The known epoxide 218, derived from D-isoascorbic acid, was converted into propargyl alcohol 219,

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Scheme 65

Review Article

Scheme 66

Synthesis of (+)-achalensolide.

Scheme 67

Synthesis of (+)-indicanone.

Synthesis of linearly and angularly fused [6-7-5] ring systems.

which was then mesylated and treated with organocuprate to give allene–yne 220 (Scheme 66). The key cyclization was attained in high yield by [Rh(CO)(dppp)2]Cl, prepared in situ from 10 mol% [RhCl(cod)]2 and 50 mol% dppp under a CO atmosphere, instead of the previously established conditions ([RhCl(CO)2]2 or [RhCl(CO)dppp]2). After the construction of the cis-fused g-lactone moiety, chemical elaboration of the obtained bicyclo[5.3.0]decadienone 221 including the Pd-catalyzed hydrogenation resulted in the completion of the total synthesis of (+)-achalensolide. Mukai et al. reported the first total synthesis of another natural product possessing the bicyclo[5.3.0]decane skeleton, (+)-indicanone.86 The synthesis began with the (+)-limonene ring opening reaction, and the allene functionality was formed by the Pd-catalyzed migration of the propargyl carbonate (Scheme 67). The [RhCl(CO)dppp]2-catalyzed cyclocarbonylation of the allene– yne 228 produced (+)-indicanone in an excellent yield after deprotection. Ardisson’s group reported the asymmetric synthesis of the highly functionalized bicyclo[5.3.0]decane system similar to the thapsigargin framework using the Rh-catalyzed carbonylative [2+2+1] cycloaddition.87 The allene–yne 232 was prepared by

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mesylation and subsequent SN2’ reaction with methyl cyanocuprate of the propargyl alcohol 231, derived from the known chiral epoxide 229, and treated with the in situ prepared [Rh(CO)(dppp)2]Cl or [RhCl(CO)2]2 in toluene under 1 atm of CO to afford the desired cycloadduct 233 in good yield (Scheme 68). Brummond et al. demonstrated that the allene–ynes containing the a-methylene g-lactone moiety could be transformed into the 6,12-guaianolide ring systems by the Rh-catalyzed carbonylative [2+2+1] cycloaddition.88,89 The allene–yne-g-lactone substrates 238 were prepared using the allylboration/lactonization sequence and were cyclized in the presence of 10 mol% [RhCl(CO)2]2 in toluene at 90 1C, constructing the tricyclic core structure of cumambrin (Scheme 69). The monosubstituted allene–ynes 239 also underwent


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Scheme 68

Chem Soc Rev

Synthesis of the thapsigargin framework.

Scheme 70

Synthesis of (+)-ingenol.

the Rh-catalyzed carbonylative [2+2+1] cycloaddition of allene– yne 243 on a gram-scale (Scheme 70). The diol protection of the substrate and the use of a degassed and anhydrous solvent under high dilution (0.005 M) conditions were required for the clear conversion. Installation of a methyl group and dihydroxy groups were stereoselectively achieved, and via a skeletal rearrangement and some oxidation and deprotection process, (+)-ingenol was synthesized in only 14 steps. The Rh-catalyzed [2+2+1] cycloaddition of allene–ynes can be applied to Curran’s fluorous mixture synthesis.91,92 A library of small, drug-like heterocycles 250 (16 compounds) was prepared from a mixture of four a-amino acid derivatives tagged with different fluorous benzyl carbamates (FCBz) of varying fluorine contents via an ester–enolate Claisen rearrangement to give a mixture of allenic amino esters, propargylation with four different propargyl bromides, and [2+2+1] cycloaddition (Scheme 71). Although the final detagging conditions led to the epimerization of the cyclopentenones, no effort was required in reoptimizing the already established reactions for a library synthesis. 7.3 Cyclization of allene–enes, bis-allenes, and heterocumulene Scheme 69

Synthesis of 6,12-guaianolide ring systems.

this Rh-catalyzed reaction to afford the 6,12-guaianolide ring systems 240. These results show that this cycloaddition tolerates the reactive a-methylene g-lactone moiety. Recently, Baran et al. reported the short-step synthesis of (+)-ingenol from (+)-carene.90 This excellent synthesis includes


Mukai et al. achieved the asymmetric total syntheses of two tricyclic sesquiterpenes 257 and 258, isolated from Jatropha neopauciflora, by the Rh-catalyzed [2+2+1] cycloaddition of an allene–ene developed by themselves (Scheme 72).93 Cyclization of methoxycarbonylallene–ene 253, prepared from a D-tartaric acid derivative 251, did not occur under the typical conditions (5 mol% [RhCl(CO)2]2, 5 atm CO, toluene, 120 1C) but smoothly and stereoselectively proceeded in the presence of 5 mol% of

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Scheme 73 Scheme 71

Construction of 6-8-5 tricyclic ring system.

Fluorous mixture synthesis of heterocycles.

the in situ prepared [RhCO(dppp)2]Cl in refluxing toluene under 1 atm CO to produce the bicyclo[4.3.0]nonenone derivative 254. Some stereoselective transformations including the dibromocyclopropanation led to the first total syntheses of the dihydroxyand diacetoxycycloax-4(15)-ene 257 and 258.

Scheme 72 Syntheses neopauciflora.

of

sesquiterpenes

isolated

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from

The Rh-catalyzed carbonylative [2+2+1] cycloaddition of bisallenes was applied to the construction of tricyclic ring systems including the bicyclo[6.3.0]undecane skeleton by Mukai’s group.94 They focused on the preparation of the 6-8-5 ring system, the core structure analogue of the ophiobolin and fusicoccin

Jatropha Scheme 74

Synthesis of hexahydropyrrolo[2,3-b]indole alkaloids.


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families, from the inexpensive dimedone (Scheme 73). Installation of the bis-allene functionality was attained by the double [2.3]-sigmatropic rearrangement of the propargylic ester. Treatment of the bis-allene derivative 261 possessing phosphinyl and sulfonyl groups on each allene moiety with 20 mol% of [RhCl(CO)dppp]2 in refluxing toluene under a CO/Ar atmosphere (0.05/0.95 atm) afforded the corresponding 6-8-5 tricyclic compound 262 in 65% yield. Mukai et al. applied the alkyne-carbodiimide [2+2+1] cycloaddition to the synthesis of the hexahydropyrrolo[2,3-b]indole alkaloids.66,67 A benzene-bridged substrate 265 was obtained from iodoaniline 263 by the Sonogashira coupling, reaction with triphosgene, and dehydration sequence (Scheme 74). Upon treatment with 30 mol% Co2(CO)8 and 30 mol% TMTU in toluene at 70 1C, 265 efficiently underwent a ring-closing reaction to produce pyrrolo[2,3-b]indol-2-one 266 in 72% yield. The synthesis of ()-flustramide B and formal synthesis of ()-flustramine E were accomplished via a successive 1,4-addition, prenylation at the C3a position, and reduction of the formed imine moiety to provide 267. Using this method, they also synthesized ()-debromoflustramides B and E, ()-debromoflustramines B and E, and ()-physostigmine.

8 Conclusions Allenes have been found to show unique reactivities even for the carbonylative [2+2+1] cycloaddition reaction. In sharp contrast to an isolated double bond, an allene, an accumulated diene, for example, serves as a powerful p-component in the intramolecular carbonylative cyclization with the alkyne part and enables us to efficiently construct the bicyclo[5.3.0] and bicyclo[6.3.0] skeletons. Allene–enes and bis-allenes also undergo intramolecular cyclization to produce a medium-sized ring as well as a normal one. Regioselectivity regarding the double bond of the allene can be predicted based on the metal and/or the substitution pattern of the allene. With the increasing examples for application to natural product syntheses, it is now recognized that this cyclization is a highly reliable method for constructing a- or b-alkylidenecyclopentenones. Hereafter, regardless of the inter- and intramolecular cyclizations, both more efficient utilization of the remaining functionalities on the cyclized products and development of the asymmetric cyclization using a chiral catalyst are highly desirable. The use of unprecedented transition metal catalysts and/or cumulene-p-component combination might further expand the possibilities for constructing the cyclic systems.

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Palladium-catalyzed cyclization reactions of allenes in the presence of unsaturated carbon-carbon bonds.

diels-alder cyclization of enyne-allenes: effect of topology.

Enantioselective semireduction of allenes.

A new gold-catalysed azidation of allenes.

Phosphine catalysis of allenes with electrophiles.

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Highly regio- and stereoselective nitro-oxoamination of mono-substituted allenes.

[4+2] and [4+3] catalytic cycloadditions of allenes.

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The conversion of allenes to strained three-membered heterocycles.

Nazarov-like cyclization reactions.

Expression of miR-221 in colon cancer correlates with prognosis.

Palladium-catalyzed C-H activation and intermolecular annulation with allenes.

Carcinoma of the supraglottic larynx. A review of 221 cases.

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