[5+ 2] Cycloaddition Reactions in Organic and Natural Product Synthesis

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[5 + 2] Cycloaddition Reactions in Organic and Natural Product Synthesis Kai E. O. Ylijoki* and Jeffrey M. Stryker

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Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada Corresponding Author Notes Biographies Acknowledgments References

1. INTRODUCTION Within the realm of organic synthesis, cycloaddition methodology has played a role of ever-increasing importance. This focus is driven by the nature of the cycloaddition process, during which multiple carbon−carbon bonds can be formed in a single step, often with a high degree of regioselectivity and stereoselectivity. Many organic and metal-mediated cycloaddition pathways have been developed for the synthesis of both small and medium sized carbocycles, with much attention being paid to the formation of four-, five-, and six-membered rings (i.e., [2 + 2] , [3 + 2] , and [4 + 2] cycloaddition reactions). In comparison, the synthesis of seven-membered rings has received much less attention.1 However, the almost continuous identification of bioactive natural products that contain a seven-membered carbocycle in the core structure has driven recent interest. Some examples of these compounds are ingenol,2 a molecule interesting for both its bioactivity and its “inside/outside”3 ring-fusion geometry, the guanacastepene family, illustrated by guanacastepene A,4 and the tropolonoids5 such as manicol, among others (Figure 1). Although a range of cycloaddition schemes leading to seven-membered ring products have been developed,6 this review is limited to consideration of the [5 + 2] reaction manifold as applied to carbocycle synthesis, covering research in both pericyclic organic synthesis and transition metal-mediated chemistry. Although other reviews have appeared on this subject, they focus on small subsets of the literature.7,8 Here, we endeavor to provide a thorough and near comprehensive examination of the field within a historical context.

CONTENTS 1. Introduction 2. Perezone-Type [5 + 2] Cycloaddition Reactions 2.1. Perezone to Pipitzol Transformation 2.2. Intermolecular [5 + 2] Cycloaddition Variants 2.3. [5 + 2] Cycloaddition Reactions via Oxidation of Phenols 2.4. Additional Natural Product Syntheses 3. Oxidopyrylium Ylid [5 + 2] Cycloaddition 3.1. Oxidopyrylium Ylids Generated via Group Transfer. Kojic Acid-Type [5 + 2] Cycloadditions 3.2. Oxidopyrylium Ylids Generated via Group Elimination 3.3. Natural Product Syntheses 4. Vinylcyclopropane Cycloaddition Reactions 4.1. Rhodium-Catalyzed Vinylcyclopropane Cycloaddition Reactions 4.1.1. Intramolecular Cycloaddition Reactions 4.1.2. Intermolecular Cycloaddition Reactions 4.1.3. Natural Product Syntheses 4.1.4. Mechanistic Studies 4.2. Ruthenium-Catalyzed Vinylcyclopropane Cycloaddition Reactions 4.3. Nickel- and Iron-Catalyzed Vinylcyclopropane Cycloaddition Reactions 5. Rh-Catalyzed [5 + 2] Cycloaddition via Trapping of Rautenstrauch Intermediates 6. Fischer Carbene-Mediated [5 + 2] Cycloaddition Reactions 7. Allylsilane [5 + 2] Cycloaddition Reactions 8. Metal-Mediated η3-Pentadienyl [5 + 2] Cycloaddition Reactions 9. Metal-Mediated η5-Pentadienyl [5 + 2] Cycloaddition Reactions 10. Conclusion Author Information © 2012 American Chemical Society

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2. PEREZONE-TYPE [5 + 2] CYCLOADDITION REACTIONS

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2.1. Perezone to Pipitzol Transformation

Although they did not understand the nature of the process, Anschütz and Leather9 observed in 1885 the transformation of perezone to pipitzol, the first example of [5 + 2] cycloaddition chemistry. They reported a reaction between the silver salt of the natural product perezone (1) and ethyl bromide; this reaction produced a crystalline material, isomeric with

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Received: February 29, 2012 Published: November 15, 2012 2244

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change from a concerted to a stepwise mechanism involving intermediate 5, as demonstrated by deuterium-labeling experiments. Alternatively, when using AlCl3·SEt2 as the Lewis acid promoter, the selectivity was reversed, favoring β-pipitzol in a 3:1 ratio.16 This change in selectivity has been applied in a formal total synthesis of β-pipitzol. A related example of an intramolecular [5 + 2] cycloaddition reaction occurs upon treatment of aethiopinone (6) with acids.17 When orthoquinone 6 was treated with either sulfuric acid or BF3·OEt2, cyclization product 7 was isolated in low yields (14 and 58%, respectively). The authors proposed that the product arises from an acid catalyzed [5 + 2] cycloaddition, followed by extrusion of carbon monoxide (Scheme 2). Scheme 2. [5 + 2] Cycloaddition of Aethiopinone

Figure 1. Some natural products containing seven-membered rings.

perezone. Years later, Sanders10 and then Remfry11 revisited this reaction, and both found this same transformation could be achieved by heating perezone to temperatures in excess of 200 °C. Although Sanders rejected the standard formulation of perezone (C15H20O3) in favor of another, Remfry verified the original. Remfry also found that the product of this thermolysis, which he dubbed pipitzol, was a crystalline material melting at 141 °C, isomeric with perezone, thereby confirming the results of Anschütz and Leather. It was not until 1965 that Joseph-Nathan and co-workers determined the structure of pipitzol.12 He repeated the thermal reaction of perezone and found that a 1:1 mixture of diastereomeric products resulted, which he named α- (3) and β-pipitzol (4) (Scheme 1). Early mechanistic proposals were

2.2. Intermolecular [5 + 2] Cycloaddition Variants

Shortly after Joseph-Nathan’s seminal work on the intramolecular [5 + 2] cycloaddition reaction, Mamont reported the first intermolecular variants, where the acid-promoted reactions of quinones 8−10 with olefins were examined (Scheme 3).18 Scheme 3. Intermolecular Perezone-Type Cycloaddition

Scheme 1. Perezone to Pipitzol Transformation

Upon reaction with styrene, the products were tricyclic compounds arising from a [5 + 2] cycloaddition process, proposed to occur in a stepwise fashion. The nature of the substituents (R1, R2) and the olefin greatly influence the course of the reaction. For instance, when the quinone is benzannulated, or when using 1,1-diphenylethene as the cycloaddition partner, the reaction does not proceed to [5 + 2] products (eq 1), presumably a consequence of steric constraints. Büchi and co-workers further developed the intermolecular [5 + 2] cycloaddition of quinone-type systems.19 To overcome difficulties associated with reduced reactivity in the intermolecular reactions, the more electrophilic quinone ketals (11) were used. Even then, however, the product yields remained very low, typically below 50%, and the reactions resulted in mixtures of products. Despite these shortcomings, this process

complicated by an incorrect characterization of perezone. Shortly after this initial work, structural revisions were reported,13 and a much simpler [5 + 2] cycloaddition of the pendant olefin with pentadienyl cation intermediate 2 was proposed, the latter arising from intramolecular proton transfer. The cycloaddition was later demonstrated to proceed in a concerted fashion.14 Joseph-Nathan and co-workers extensively studied the stereocontrol of this transformation. He found that the cycloaddition reaction occurs at 0 °C in the presence of Lewis acid (BF3·OEt2), a much lower temperature than required for the thermal conversion. Further, this reaction proceeds in a diastereoselective fashion, yielding a 9:1 ratio of products favoring α-pipitzol 3.15 This selectivity arises via a 2245


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by the ratio of TiCl4/Ti(OiPr)4 used in preparation. The formation of [5 + 2] cycloadducts is favored by higher amounts of TiCl4. Recently, Grieco and co-workers reported that the yields of intermolecular reactions are significantly improved by using trimethylsilyl triflate as the catalyst in the very polar solvent 3.0 M lithium perchlorate/ethyl acetate.22 This medium likely stabilizes the ionic 16, allowing more selective formation of the [5 + 2] adduct. Although not directly related to the perezone-type cycloaddition processes, the report of an intermolecular [5 + 2] cycloaddition reaction between cycloheptadienyl chloride 17 and 2-methyl-1-methoxy-1-propene warrants discussion here.23 When 17 and a vinyl ether are combined in the presence of ZnCl2·OEt2, five distinct products are obtained (Scheme 6).

was used in the total syntheses of the neolignans (±)-guianin (13), (±)-burchellin (14), and (±)-futoenone (15), among others (Scheme 4). Each of these products was believed to arise Scheme 4. Natural Product Syntheses via Perezone-Type Cycloaddition

Scheme 6. [5 + 2] Cycloaddition via Halide Abstraction

Four of these (20−23) proved to be isomers of [5 + 2] cycloadducts, obtained in 37% combined yield. In the proposed mechanism, initial halide abstraction generates the cycloheptadienyl cation 18, which is trapped by the enol ether. Although this reaction can occur in either a stepwise or concerted fashion, the formation of 19 suggests that at least part of the reaction proceeds in a stepwise manner.

from the cationic intermediate 12 formed upon [5 + 2] cycloaddition, either by nucleophilic trapping (as in the case of 13) or by further rearrangement (14 and 15). Angle and Turnbull have studied similar isomerizations in the course of neolignan synthesis.20 In a very elegant series of studies, Engler and co-workers addressed the problem of product mixtures in these intermolecular reactions.21 By using a TiCl4/Ti(OiPr)4 catalyst combination and selected substituents, it was possible to tune the reaction conditions to give only the bicyclic [5 + 2] cycloadducts in good yields. This result was rationalized by invoking cationic intermediate 16 arising from an initial [5 + 2] cycloaddition reaction (Scheme 5). This intermediate functions as a branching point on the reaction pathway. Substituents R2 that are easily displaced (e.g., R2 = H) accelerate the rate of the reaction, leading to the [5 + 2] adduct (i.e., B ≫ A). The structure of the titanium catalyst is not understood but is likely to be TiCln(OiPr)4−n, with the exact ratio of ligands determined

2.3. [5 + 2] Cycloaddition Reactions via Oxidation of Phenols

Yamamura and co-workers have extensively studied the use of electrochemically generated intermediates in organic synthesis,24 including pentadienyl cations 25 for both intra- and intermolecular [5 + 2] cycloaddition reactions.25 When 3,4dimethoxy-6-methylphenol (24) was oxidized electrochemically in the presence of 3,4-methylenedioxystyrene, a 3:1 mixture of endo and exo cycloadducts 26 was obtained in an overall yield of 64% (Scheme 7). This work has been extended to Scheme 7. Electrochemical [5 + 2] Cycloaddition

Scheme 5. Lewis Acid-Mediated [5 + 2] Cycloaddition intramolecular cases, including a rare use of disubstituted Zolefins (27) in [5 + 2] cycloaddition reactions, demonstrating that the olefin stereochemistry is fully translated to the product 28 (eq 2). Even highly substituted phenols can be used, leading to densely functionalized seven-membered ring products. For example, pentasubstituted phenols of type 29 readily form bridged tricyclic products 30, albeit in low yields (eq 3). This reaction has been exploited for the total synthesis of a variety of natural products26 including neolignans 13, 14, and 15, (±)-helminthosporal, (±)-8,14-cedranoxide, (±)-silphenene, (±)-pentalenene, a member of the 2-epi-cedrene 2246


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oxidation, thereby aiding the cycloaddition. Alternatively, cycloaddition may proceed unaided to form an oxyallyl intermediate. In either case, the final step entails only trapping of the cation with water, followed by tautomerization. 2.4. Additional Natural Product Syntheses

Outside of the examples described above, the perezone-type cycloaddition has not found widespread application in the synthesis of natural compounds. Büchi and co-workers, in addition to the neolignan syntheses previously noted, described the preparation of (±)-gymnomitrol29 and an entry into the tropolone core 37.30 The key step in the synthesis of gymnomitrol is a [5 + 2] cycloaddition between ketal 33 and 1,2-dimethylcyclopentene to yield a mixture of diastereomeric cycloadducts (Scheme 9). This was immediately reduced, with

isoprenologues, and a racemic synthesis of a highly oxygenated Acourtia isocedrene (Figure 2). Although the potential of this

Scheme 9. Synthesis of Gymnomitrol

Figure 2. Natural products synthesized by Yamamura.

reaction is evident, the low product yield and often poor diastereoselectivity severely hamper the practical utility. Recently, Green and Pettus have harnessed this reaction manifold to rapidly prepare α-cedrene, α-pipitzol, and seccedrenol from curcurphenol (31) in a biosynthetically inspired dearomatization/[5 + 2] cycloaddition sequence (Scheme 8).27

the desired diastereomer 34 isolated in a 10% overall yield. They reasoned that the poor yield of the cycloaddition was due to the extra strain introduced by the cyclopentene ring. The tropolone synthesis made use of a cycloaddition reaction similar to that used in the neolignan syntheses (Scheme 10). Thus, 2,4,6-trinitrobenzenesulfonic acid promoted condensation of ketal 35 with isosafrole produced 36 in good yield (61%), with complete diastereocontrol.

Scheme 8. [5 + 2] Cycloaddition via Oxidation

Scheme 10. Synthesis of Tropolones

In another example, shinjulactone C (41) was synthesized via a [5 + 2] cycloaddition as a key step late in the synthesis.31 Although ailanthone (38) can be converted directly to shinjulactone in one step by treatment with pyridine at reflux, the yield is only 8%. To investigate the mechanism and optimize the synthesis, a stepwise transformation was developed. Over five steps, 38 can be converted into the key intermediate 39. This diketone yielded the acetylated shinjulactone C on heating in pyridine, presumably via pentadienyl cation 40 (Scheme 11). Deprotection provided 41 in 20% overall yield, providing a rational alternative but with little improvement.

The reaction terminates via selective incorporation of acetate, effectively generating four stereocenters in one step. In contrast to the work of Yamamura, the reaction proceeds with excellent diasteroeselectivity. From the same single [5 + 2] cycloaddition diastereomer 32, very short and efficient syntheses of the natural products were achieved. In a related reaction, Tsuji and co-workers have demonstrated intramolecular [5 + 2] cycloadditions in cyclophane benzoquinone systems prepared via chemical oxidation of diphenols (eq 4).28 The mechanism of this transformation could involve protonation of the quinone generated via 2247


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into inter- and intramolecular subclasses. The fundamental research work will be discussed separately, with applications to synthesis grouped together. In the interest of brevity, oxidopyrylium generation through valence tautomerization33,34 and pathways involving metal carbenes7c,35 will not be discussed here: in the opinion of the authors, these reactions are better interpreted as [3 + 2] cycloaddition processes. Similarly, although excellent work has been done in the field of oxidopyridinium [5 + 2] cycloaddition chemistry, to retain a manageable scope, this material will not be discussed here.36

Scheme 11. Synthesis of Shinjulactone C

3.1. Oxidopyrylium Ylids Generated via Group Transfer. Kojic Acid-Type [5 + 2] Cycloadditions

Long after the first report of the perezone to pipitzol transformation, but before Joseph-Nathan’s elucidation of the process, Woods published on the reaction of the natural product kojic acid (44) with acrylonitrile37 and β-bromopropionic acid,38 isolating a product proposed to be 2-(2hydroxymethyl-5-hydroxy-4-pyrone-6)-propionic acid. Hurd and Trofimenko, who were unable to replicate the results, isolated only kojic acid and called this result into question.39 They later obtained reaction products;40 however, these materials analyzed as C15H14O9, proving to be more than the result of a simple cyanoethylation (eq 5). Further investigations

Finally, Kim and Rychnovsky and Harrowven and co-workers have each published a total synthesis of (−)-elisapterosin B (43)32 using [5 + 2] cycloaddition in the final step (Scheme 12). In each report, the key intermediate 42 is synthesized via a Scheme 12. Synthesis of (−)-Elisapterosin B

using α-deoxykojic acid led to product proposals requiring a complex mechanistic rationale.41 Eighteen years later, the structure of the kojic acid/acrylonitrile reaction product (45) was correctly determined,42 leading to the proposal of a [5 + 2] cycloaddition mechanism. Early work in the cycloaddition chemistry of kojic acid led to a mechanistic proposal invoking transfer of the acidic phenolic proton to the carbonyl, generating a zwitterionic intermediate 46 (Scheme 14). Both

different strategy not detailed here. Upon treatment of 42 with BF3·OEt2 , an intramolecular cycloaddition occurs with complete diastereoselectivity, giving acceptable to good yields of the natural product (41 or 71%).

Scheme 14. Intramolecular [5 + 2] Cycloaddition

3. OXIDOPYRYLIUM YLID [5 + 2] CYCLOADDITION Kojic acid-type cycloaddition reactions yield products similar to those obtained via the perezone-type pathways, with the only difference being a bridging oxygen atom rather than a bridging carbonyl. Mechanistically, these reactions involve the formation of an oxidopyrylium ylid as the reactive intermediate, rather than a pentadienyl cation. As a consequence, this raises the question of whether these cycloadditions are better described in terms of a [5 + 2] pentadienyl cation cycloaddition or as a [3 + 2] 1,3-dipolar cycloaddition reaction (Scheme 13). With the widespread use of this class of reaction, this discussion will be cast in terms relating to [5 + 2] cycloaddition chemistry. The reactions can be further classified based on how the requisite oxidopyrylium ylid is generated: by group transfer or group elimination. Additionally, these classes can in turn be divided

alkenes and alkynes are reactive, and as Garst et al. have demonstrated, it is possible to form cycloadducts with both 3and 4-membered tethers; tethers of greater length are not reactive unless unfavorable entropic factors are minimized with substituents on the tether and an external acid catalyst is employed.43 Zwitterionic intermediates similar to 46 can be generated by other means; in fact, any group capable of equilibrium migration from one oxygen atom to the other promotes the cycloaddition reaction. Wender and McDonald investigated this possibility during model studies for the synthesis of phorbol (Scheme 15).44,45 During this investigation, compounds of the type 47 bearing various oxygen-protecting groups (R) were prepared and subjected to high-temperature reaction conditions. When R = alkyl, no reaction occurs. However, when a more easily transferred group was used, cycloaddition products

Scheme 13. Resonance Forms of the Oxidopyrylium Zwitterion

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of (±)-nemorensic acid, a unit of the natural product nemorensine. To expand the synthetic utility of this reaction, the potential of the alkene functionality in products such as 50 and 53 has been harnessed for a one-pot [5 + 2]/[4 + 2] tandem cycloaddition sequence, rapidly synthesizing highly functionalized tricyclic systems with excellent diastereoselectivity and yield (eq 6).49 Alkynes (55) were also reactive, producing unsaturated ring products 56, whose functionality was further exploited, unmasking the latent hydroxyl (57) (Scheme 18).

Scheme 15. Synthesis of a Phorbol Precursor

were obtained in good yields (71%, when R = TBDMS), with excellent stereoselectivity. Irradiation with UV light also promoted the cycloaddition, albeit in significantly reduced yield (15%). This product was elaborated to the tetracyclic intermediate 48, a precursor to phorbol and other natural products. Domingo and co-workers46 have performed density functional theory (DFT) mechanistic investigations of this process and determined that the energetically preferred mechanism does indeed proceed via a discrete intramolecular group transfer, followed by a rate-limiting concerted [5 + 2] cycloaddition step. The energy difference between the two diastereomeric cycloaddition transition states is ca. 10 kcal/mol due to constraints imposed by the tether, supporting the high diastereoselectivity observed in these reactions. Outside of the early results of Hurd and Trofimenko, intermolecular reactions of the kojic acid-type involving the group transfer mechanism have been rare; these reactions require electronically activated alkenes (vide infra). This dependence on tethering to promote cycloaddition of simple olefins arises from the need to minimize unfavorable activation entropy in the face of a large activation enthalpy.46 To address this limitation, Mascareñas and co-workers have used the intramolecular process to achieve formal intermolecular [5 + 2] cycloaddition reactions of unactivated alkenes via a temporary tethering strategy.47 The temporary tethers include both silicon (49) (Scheme 16; note the use of benzoyl as the migrating

Scheme 18. Tandem [5 + 2]/[4 + 2] Cycloaddition

Mascareñas and co-workers have also demonstrated that introduction of sulfur groups can be used to control both the diastereo- and enantioselectivity of these [5 + 2] reactions.50,51 Early work with sulfinyl or sulfoxide tethers offered lower reaction temperature but only modest diastereoselectivity. However, placing an enantiopure sulfinyl substituent at the terminal position of the alkene 58 provided remarkable diastereocontrol (ca. 30:1) and >90% yields (Scheme 19).

Scheme 16. Examples of Temporary Tethering

Scheme 19. Asymmetric [5 + 2] Cycloaddition via Chiral Auxiliaries

group) and sulfur (52) (Scheme 17), which upon cleavage provide very densely functionalized seven-membered ring products (51 and 54).48 Further bond cleavage leads to substituted tetrahydrofurans, a process applied to the synthesis

Upon Raney Ni cleavage of the auxiliary, [5 + 2] cycloadducts were obtained in good yield and >96% ee (59 and 60). To obtain the complementary regioisomer 62, the mismatched electronic arrangement required that the sulfinyl directing group be moved to the internal position of the alkene 61 (eq 7). Use of sulfoximine instead of sulfinyl groups (63) results in

Scheme 17. Synthesis of Nemorensic Acid

a switch of diastereoselectivity, with good diastereocontrol (up to 9:1) when R is COCF3, COPh, SO2CF3, and SO2pTol (eq 2249


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8). This new sulfoxide-based strategy, applied in tandem with the temporary tethering methodology, culminated in a total synthesis of (+)-nemorensic acid.

Scheme 21. Oxidopyrylium Generation with MeOTf

Good yields are obtained in all cases, however, with poor exo/ endo selectivity for all dipolarophiles other than norbornene. Scheme 22. Examples of Intermolecular [5 + 2] Cycloaddition

The stereocontrol of this method was rationalized, and later computationally verified, by assuming that the sulfoxide moiety adopts a conformation wherein the sulfur lone pair and the alkene are syn-coplanar (64) (Scheme 20). In accordance with Scheme 20. Rationalization of Diastereoselectivity

One example of using group transfer to achieve intermolecular cycloaddition with an electronically nonbiased twocarbon unit has been reported.53 When benzyne was generated in the presence of a kojic acid analogue (71 or 72) at 85 °C, cycloaddition occurs, incorporating 2 (eq 9) or 3 (eq 10) equiv of benzyne. These highly functionalized, polycyclic structures were isolated in 33−36% yield.

Curtin-Hammet kinetics, while the anti-coplanar conformation 65 is slightly lower in energy, the cycloaddition transition state 67 from the syn-coplanar conformation is 3.4 kcal/mol lower than 66 and 68, which lead to the opposite diastereomer, and ca. 5 kcal/mol lower than that from the anti-coplanar conformation (69). The arrangement of 67 minimizes dipole−dipole interactions with the pyrone ring at the transition state and disfavors approach from the face on which the bulky Ar group points into the ring. This same rationale holds for the selectivity reversed sulfoximine case, where the S−O bond is now syn-coplanar with the alkene moiety. The high temperature required to initiate these reactions can preclude the use of less thermally robust substrates. Although Mascareñas has shown that high-valent sulfur substituents lead to reaction at lower temperatures, another approach is to form the oxidopyrylium ylid in a discrete step, circumventing the group transfer. Wender developed such an approach, wherein MeOTf is used to generate the methoxy pyrylium salt at lower temperature, followed by generation of the ylid using a nonnucleophilic base, such as 2,2,6,6-tetramethylpiperidine, or a fluoride source, depending on the nature of the R group (Scheme 21).52 In this approach, the [5 + 2] cycloaddition reaction occurs smoothly at room temperature, yielding tricyclic products in >80% yield as a mixture of diastereomers. The highly activated intermediates of the type 70 have also been applied successfully to intermolecular cycloadditions using both electron-deficient and strained alkenes (Scheme 22).

3.2. Oxidopyrylium Ylids Generated via Group Elimination

Although group transfer to generate oxidopyrylium ylids was the earliest method developed, group elimination has found greater use in the synthetic organic community. Here, we will discuss the fundamental research performed in the area, leaving applications in total synthesis for a later section. In 1980, Hendrickson and Farina54 reported that the easily prepared cyclic unsaturated acetoxy ketone 7355,56 can function as an oxidopyrylium precursor, presumably via a heteroatomassisted elimination of the acetate followed by enolization. Intermolecular cycloaddition reactions were demonstrated, using electron-deficient olefins and alkynes.57,58 These reactions occur smoothly at 115−180 °C in yields ranging from 35 to 69% (Scheme 23). Attempts to reduce the reaction temperature by producing the ylid 74 in the presence of base led only to dimerization (75). This method introduced a facile new means of generating oxidopyrylium ylids, resulting in a plethora of reports since then. In contrast to group transfer, the group elimination method has found rather extensive use in intermolecular reactions. Shortly after the work of Hendrickson and Farina, Sammes and co-workers59 reported intermolecular oxidopyrylium cyclo2250


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simultaneously assisting oxidopyrylium formation and holding the substrate in the chiral catalyst environment. Interestingly, the 2-substituent (R1 in Scheme 25) has been shown to play a role in the stereocontrol of these reactions.61 In

Scheme 23. [5 + 2] Cycloaddition via Group Elimination

Scheme 25. Diastereocontrol in [5 + 2] Cycloaddition

addition reactions using the complementary electron-rich and strained olefins (e.g., ethyl vinyl ether and norbornadiene). A large excess of the olefin was required to trap the dipolar intermediate and prevent dimerization of the ylid; however, the reactions proceed with excellent diastereocontrol (Scheme 24). Scheme 24. [5 + 2] Cycloaddition via Group Elimination the reaction of dialkyl fumarates with compounds 78, larger R groups gave a higher degree of stereocontrol (up to 15.5:1 for R1 = CH2OTBS, R2 = tBu), presumably due to minimizing unfavorable steric interactions in the preferred transition state geometry 79. These intermediates were later used in studies directed toward the synthesis of phomoidride B (CP263,114).62 In a final example, it has been shown that cyclopropenone acetals undergo [5 + 2] cycloaddition reactions smoothly at room temperature to yield the exo diastereomer 80 exclusively (Scheme 26).63 Exposure of the initial cycloadduct 80 (which

Despite the previous negative results of Hendrickson and Farina, Sammes and co-workers reported that heating the reaction could be avoided by using a base, such as triethylamine, to generate the oxidopyrylium intermediate, a strategy rapidly adopted by others. Recently, a highly enantioselective (up to 95% ee) thioureacatalyzed intramolecular cycloaddition of both alkenes and allenes has been reported (eq 11).60 Although enantioselective

Scheme 26. Formal [5 + 3] Cycloaddition

was reduced to the alcohol for convenience) to acetic anhydride and a catalytic amount of TMSOTf cleaves the internal bond of the cyclopropene, generating an eight-membered ring moiety, ultimately resulting in a formal [5 + 3] cycloaddition process. 3.3. Natural Product Syntheses

The oxidopyrylium cycloaddition reaction has been extensively applied to the total syntheses of natural products and natural product cores. In early examples, Sammes and co-workers demonstrated the versatility of this chemistry through the synthesis of several natural products:64 (±)-β-bulnesene, (±)-cryptofauronol, (±)-fauronyl acetate, and (±)-valeranone (Schemes 27 and 28). In each case the intramolecular group elimination methodology was adopted, followed by skeletal rearrangements in several cases. Wender and co-workers,65 in addition to the work described above, have used this methodology in landmark asymmetric total syntheses of phorbol and (+)-resiniferatoxin (Schemes 29, 30). In both cases, the key cycloaddition step occurred with complete diastereoselectivity, controlled by the stereogenic centers of the tether. General approaches66 to the cores of the

oxidopyrylium cycloaddition reactions have been achieved previously through the use of chiral auxiliaries, this new catalytic approach marks an important milestone achievement in this field. A cooperative catalyst effect has been observed wherein the combination of both chiral (76) and achiral (77) thiourea catalysts lead to optimal results, although long reaction times (up to 96 h) are required. The authors propose that the achiral thiourea catalyst acts as a carboxylate-binding agent, while the amine functionality of 76 binds to the substrate, 2251


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Scheme 27. Synthesis of β-Bulnesene

strategies applicable to the BC-ring system of taxol 81 (Scheme 31),67,68 the stereoselective synthesis of the cyanthin ring Scheme 31. Synthesis of a Taxol Precursor

Scheme 28. Natural Product Syntheses

Scheme 32. Synthesis of the Cyanthin Ring Skeleton Scheme 29. Synthesis of Phorbol

skeleton (83) from furan 82 (Scheme 32), and a portion of the guanacastepene skeleton 85 from 84 (Scheme 33). The groups Scheme 33. Synthesis of a Guanacastepene A Precursor

Scheme 30. Synthesis of Resiniferatoxin

of both Trauner69 and Pattenden70 have reported biomimetic syntheses of (+)-intricarene, each using a [5 + 2] cycloaddition reaction of the bipinnatin J derivative 86 as the key step (eq 12). DFT calculations on this system suggest that the

macrocyclic structure lowers the energy of the cycloaddition step, resulting in a barrier of ∼20 kcal/mol.71 Pattenden and coworkers72 and Sohn73 have also leveraged [5 + 2] cycloaddition chemistry in their syntheses of (±)-anthecularin (Scheme 34) and arteminolide core precursors 87 and 88 (Scheme 35), respectively. Baldwin and co-workers have studied the synthesis of natural tropolone products via inter-74 and intramolecular75 kojic acidtype cycloaddition reactions. These reports include a synthesis of a deoxy-epolone B via intermolecular cycloaddition of an

tigliane, daphnane, and ingenane families, the C12-hydroxy daphnetoxins, and 1α-alkyldaphnanes have also been described. Other examples of intramolecular oxidopyrylium cycloaddition reactions in the synthesis of advanced intermediates and natural products have been reported. Magnus and coworkers have used this reaction for developing synthetic 2252


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Scheme 34. Synthesis of Anthecularin

Scheme 37. Syntheses of Cartorimine and Descurainin

Scheme 35. Synthesis of Arteminolide Precursors

Scheme 38. Synthesis of Polygalolide Precursors

acetate, as well as a formal asymmetric total synthesis of (−)-englerin A.77 These syntheses relied upon a regio- and diastereoselective intermolecular [5 + 2] cycloaddition reaction to prepare the bicyclic molecular core in low yield (46%) (Scheme 39). The formal asymmetric synthesis was achieved Scheme 39. Synthesis of Englerins

oxidopyrylium ylid and α-acetoxyacryonitrile (Scheme 36). The cycloaddition yielded a 2:5 mixture of stereoisomers, which was of little consequence because both were elaborated to the final product. Scheme 36. Synthesis of Deoxy-epolone B

through the use of a chiral sulfonamide acrylate derivative in the key [5 + 2] cycloaddition step, resulting in a separable 2:1 mixture of diastereomers favoring the desired absolute configuration 89. Synthetic applications from other research groups include an investigation into the synthesis of the FCCR toxin via a regioand diastereocontrolled [5 + 2] cycloaddition of indene78 to form 90 (Scheme 40), model studies for a potential dictyoxetane synthesis,79 and the synthesis of furanoethers 91 via [5 + 2] cycloaddition and subsequent C−C bond cleavage (Scheme 41).80

Recently, Snider and co-workers76 reported racemic syntheses of the natural products cartorimine and descurainin, along with formal biomimetic syntheses of racemic polygalolides A and B, all via intermolecular cycloaddition procedures (Schemes 37 and 38). The polygalolide syntheses in particular make use of an unconventional α-methylene lactone functionality in the cycloaddition reaction, giving a high degree (ca. 90%) of stereocontrol. Very recently, Nicolaou, Chen, and co-workers have reported racemic total syntheses of englerin A, englerin B, and englerin B

4. VINYLCYCLOPROPANE CYCLOADDITION REACTIONS The Diels−Alder reaction is the most important discovery in pericyclic cycloaddition chemistry, providing a powerful means to prepare six-membered carbocycles in a [4 + 2] fashion. Efforts to extend this to a [5 + 2] homologue in a strictly 2253


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maleimide, DMAD, and TCNE, and many yields remain unreported.

Scheme 40. Synthesis of an FCRR Toxin Precursor

4.1. Rhodium-Catalyzed Vinylcyclopropane Cycloaddition Reactions

4.1.1. Intramolecular Cycloaddition Reactions. It was not until Wender reported the intramolecular rhodiumcatalyzed cycloaddition of vinylcyclopropanes 96 with alkynes that the [5 + 2] homologue to the Diels−Alder reaction was developed into a useful synthetic method (eq 13). Initial work

Scheme 41. Synthesis of Furanoethers

demonstrated that the steric and electronic effects of the alkyne substituents, as well as the nature of the tether, do not greatly control or alter the reactivity.85 However, some π-bond isomerization was observed with additional substitution on the alkene (98). These undesired transformations are eliminated by switching from Wilkinson’s catalyst to [Rh(CO)2Cl]2. In most cases, the reaction proceeds in excellent yield, hampered only by the volatility of some products (97, X = O; R1, R2, R3 = H). A notable limitation of the [Rh(CO)2Cl]2-catalyzed system is the intolerance of terminal alkynes, due to preferential insertion into the alkynyl C−H bond. Martin and co-workers have developed a domino-type extension of this reaction,86 using [Rh(CO)2Cl]2 to catalyze an allylic alkylation followed by a [5 + 2] cycloaddition in one pot (Scheme 44). The reaction proceeds with excellent regio- and diasterocontrol, with yields ranging from 83 to 92%

organic sense have met with limited success. The first published example was in 1959:81 vinylcyclopropane (VCP) and maleic anhydride were reported to produce a seven-membered carbocycle in 40% yield. Unfortunately, the results were irreproducible in the hands of others.82 Vinylcyclopropanes do however undergo formal [5 + 2] cycloaddition with the highly activated olefin tetracyanoethylene (TCNE).83 In these systems, TCNE first undergoes a [2 + 2] cycloaddition with the vinylcyclopropane (92), followed by rearrangement to the formal [5 + 2] product 93 (Scheme 42). Unfortunately, the final product yield was not Scheme 42. VCP [5 + 2] Cycloaddition

Scheme 44. Tandem Allylation/[5 + 2] Cycloaddition

reported and the reaction appears to be limited to TCNE; other electron-poor π-systems such as dimethyl acetylenedicarboxylate (DMAD) do not lead to [5 + 2] products. Starting materials incorporating alternate ring sizes and dicyclopropylvinyl functionality were also explored. Substrates wherein the vinylcyclopropane moiety is embedded in a strained heterobicyclic framework (94) also react, with more success.84 The reaction tolerates heteroatoms including oxygen, sulfur, and nitrogen, and the mechanism may proceed in a fashion similar to oxidopyrylium cycloaddition, through the involvement of a zwitterionic intermediate 95 (Scheme 43). In these cases, however, the reaction is limited to highly activated two-carbon electrophiles such as maleic anhydride, N-phenyl-

The first rhodium complex used for this transformation was Wilkinson’s catalyst [RhCl(PPh3)3]. Since then, however, other rhodium complexes have proven to be more effective under varying conditions. These catalysts include [Rh(CO)2Cl]2,87 [(C10H8)Rh(cod)]SbF6 99 (Figure 3),88 water-soluble [Rh(nbd)(o-(p-(NaO3SC6H4)2P)2C6H4)]SbF6 (the ligand 100 imparts the solubility),89 the highly active N-heterocyclic carbene complex 101,90 [Rh(DIPHOS)(CH2Cl2)2]SbF6,91 [Rh(cod)Cl]2,92 [Rh(dppb)Cl]2,93 and rhodium dinapthocyclooctatetraene complex 102.94 Although not always necessary, a halide-abstracting agent such as AgOTf in conjunction with the rhodium catalyst generally improves the product purity. To date, the most versatile catalysts reported are the cationic [(C10H8)Rh(cod)]SbF6 99 and rhodium dinapthocyclooctatetraene complex 102. Naphthalene complex 99 has been used in highly efficient intramolecular cycloadditions of both alkynes and alkenes (vide infra), demonstrating increased reactivity and scope. Unwanted side-reactions (formation of isomer 98) are

Scheme 43. Cyclic VCP [5 + 2] Cycloaddition

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Figure 3. Examples of [5 + 2] cycloaddition catalysts and ligands.

also avoided with this very active catalyst. Dinaphthocycloactatetraene complex 102 has been used in both intra- and intermolecular cycloadditions (vide infra), outperforming even the very active complex 99. The scope of this rhodium-catalyzed process is not limited to tethered alkynes. Shortly after the original report, the first examples of intramolecular cycloaddition with alkenes were published (eq 14),95 followed by allenes (eq 15).96 Both of

has shown that careful choice of the substrate and catalyst combination allows selective formation of any one of the possible stereoisomers (Scheme 45).99 Previous observations Scheme 45. Regio- and Diastereoselectivity in VCP [5 + 2] Cycloaddition

these systems displayed similar scope to the parent alkyne with regard to substituents. In addition, these systems provided an opportunity to determine the diastereoselectivity of the reaction. Interestingly, the process was found to be completely selective, yielding only the cis-fused isomer 103 from threeatom tethers (in a lone example of a four-atom tether, the transfused isomer 104 prevailed). Notably, the allene system also displayed complete selectivity for the internal olefin of the allenyl moiety, with the stereochemistry of the allene being relayed to the final product with complete retention (92% ee for 105, X = C(CO2Me)2, R2 = tBu, R3 = R4 = H). Although the transfer of stereochemistry from the allenyl moiety presented a potential substrate-controlled route to asymmetric synthesis, a catalyst-controlled method is considered more general and powerful. Early investigations suggested that the use of CHIRAPHOS and derivatives might provide asymmetric catalysis, with later results indicating that BINAP was a more effective chiral phosphine (eq 16).97 With this system, asymmetric cycloaddition reactions with alkenes resulted in enantiomeric excesses (ee’s) as high as 99%; similar reactions with alkyne substrates were not as successful, giving only moderate enantioselection. Hayashi and co-workers98 have addressed this shortcoming, reporting that chiral phosphoramidite ligands result in excellent enantiomeric excess (up to 99%) during intramolecular VCP/alkyne cycloaddition reactions (eq 17). Substitution on the cyclopropane ring raises the issue of regioselectivity in the cyclopropane ring-opening step. Wender

had shown that in trans-methyl-substituted cyclopropane cases, the seven-membered ring product formed via RhCl(PPh3)3 cycloaddition arose from cleavage of the less-substituted cyclopropane bond (107 versus 108) and that the initial cyclopropane configuration was translated to that of the product.100 This preference remains true for most electrondonating groups (106) and Wilkinson-type catalysts. When the substituent is an electron-withdrawing group, the preference for cleavage of the less-substituted bond is maintained, although some of the other regioisomer can be detected. This selectivity can be completely reversed by using [Rh(CO)2Cl]2 as the catalyst. In cis-substituted substrates 109, the preference for cleavage of the less-substituted bond is maintained (110 versus 111), but the selectivities are not as high. Although very versatile, early studies of the Rh-catalyzed VCP cycloaddition reaction suggested that extension to bicyclic systems beyond the [5.3.0] framework was difficult. This significant limitation has recently been addressed through the use of allenylcyclopropanes 112 in place of the standard VCP.101 Both [5.4.0] and [5.5.0] bicyclic ring systems 113 can be obtained under catalysis with either [Rh(CO)2Cl]2 or [RhCl(CO)dppp]2. The system is tolerant to a wide range of substituents, and both terminal and internal alkynes lead to 2255


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(116), which display a higher reaction rate, coupled with the use of the more reactive [Rh(CO)2Cl]2 catalyst. Under these conditions, good to excellent yields of [5 + 2] product 117 (hydrolyzed to the ketone in situ) were obtained over a range of electron-rich, electron-poor, and conjugated alkynes. In later work, vinylcyclopropanol derivative 118 was introduced, which proved to be both economical and easily prepared on large scale, while retaining the same high level of synthetic utility (eq 21).105 The intermolecular reaction also proceeds with sterically large groups in place of the heteroatom donors 119 (eq 22).106

cycloheptadiene products using [Rh(CO)2Cl]2 as the catalyst, something not readily achieved in earlier investigations (eq 18).

In related work, the selectivity of the cycloaddition reaction has been shown to depend on the regiochemical orientation of the vinylcyclopropane moiety (Scheme 46).102 If an internal Scheme 46. [5 + 2] versus [3 + 2] Cycloaddition

These groups reduce the energetic differences between the conformations of the vinylcyclopropane, allowing the reactive conformer 120 to be more readily populated, leading to more efficient C−C bond activation. The degree of steric bulk of the substituent is directly related to the efficiency of the reaction, with iPr and CH2OTBS giving the best yields. Another noteworthy example is that of allylic alcohol 119 (R1 = R4 = H, R2 = CH2OH), which undergoes [5 + 2] cycloaddition with methyl propiolate (R3 = CO2Me) in 23% yield. This suggests that the cycloaddition reaction can be achieved in the absence of both activating and sterically large groups when a potentially coordinating functional group is present to help bring the VCP into the coordination sphere of the metal. This possibility remains to be further explored. Although alkene substrates have yet to be used in intermolecular reactions, allenes that are substituted with an alkyne moiety (121) capable of coordinating to the metal can be effectively used in cycloaddition reactions (eq 23).107 The

vinylcyclopropane is used, only the cis-substituted substrate (114) leads to [5 + 2] products. The trans-system (115) reacts to produce a [3 + 2] cycloadduct. The authors propose that after C−C bond activation of 114, followed by alkene insertion, the configuration of the reactive intermediate is such that the C1 and C7 carbons are proximal, resulting in reductive elimination to form seven-membered ring compounds. Similarly, the configuration of 115 leads to preferential fivemembered ring formation due to a proximal C1/C5 relationship. 4.1.2. Intermolecular Cycloaddition Reactions. Binger, de Meijere, and co-workers103 reported the first intermolecular example of a rhodium-catalyzed [5 + 2] cycloaddition reaction (eq 19). This was, however, an isolated example, and Wender

and co-workers shortly thereafter reported the first extensive study of the bimolecular reaction of alkynes and siloxyvinylcyclopropanes (eq 20).104 The conditions for the intramolecular

yields are generally good to excellent, but the product is obtained as a mixture of isomers showing little regioselectivity. Other coordinating groups can be used, including alkenes and nitriles, again with excellent yields. Esters have proven to be ineffective. 4.1.3. Natural Product Syntheses. The rhodiumcatalyzed [5 + 2] cycloaddition has been used as a key step in the synthesis of a variety of natural products and natural product core structures. The first to be reported was Wender et al.’s synthesis of (+)-dictamnol (Scheme 47)108 followed shortly thereafter by a synthesis of (+)-aphanamol I (Scheme 48).109 Both of these syntheses made use of the intramolecular cycloaddition reaction of allenes, constructing the bicyclic cores in one substrate controlled step, albeit from densely functionalized precursors (122 and 123). Wender et al. have also

cycloaddition reaction mediated by Wilkinson’s catalyst were ineffective for the intermolecular cases. This difficulty was overcome by using heteroatom-substituted vinylcyclopropanes 2256


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improve on the rhodium conditions, but this led to product mixtures, necessitating the switch back to the Wender system. 4.1.4. Mechanistic Studies. The mechanism of the [Rh(CO)2Cl]2-catalyzed VCP [5 + 2] cycloaddition reaction has been thoroughly modeled via DFT calculations.113 These investigations show that the reaction likely proceeds via the mechanism shown in Scheme 52. The reaction begins with

Scheme 47. Synthesis of (+)-Dictamnol

Scheme 48. Sythesis of (+)-Aphanamol I

Scheme 52. Proposed Mechanism for Rh-Catalyzed [5 + 2] Cycloaddition

published a synthesis of the tricyclic core of the cyanthane diterpenes 124 via intramolecular VCP/alkyne cycloaddition (Scheme 49).110 Scheme 49. Synthesis of (+)-Allocyathin B2

Ashfeld and Martin applied the rhodium-catalyzed cycloaddition to the synthesis of tremulenolide A and tremulenediol A (Scheme 50).111 The synthetic scheme uses the [5 + 2]

dissociation of the rhodium dimer, followed by coordination of the VCP. Carbonyl dissociation, followed by C−C bond activation, leads to an η1,η3-allyl complex 127, which then relaxes to a lower-energy square-pyramidal form 128. Alkyne coordination, insertion, reductive elimination, and dissociation then lead to the final product. The rate-limiting step in these VCP cycloadditions with alkynes and allenes is the migratory insertion of the two-carbon reactant; however, in the case of alkenes, the highest energy step is subsequent reductive elimination. In an elegant combined synthetic/theoretical study, the rhodium-catalyzed intermolecular VCP/alkyne cycloaddition reaction was examined to elucidate the nature and magnitude of the alkyne-insertion regioselectivity.114 Through this effort, it was shown that the cycloaddition occurs under both electronic and steric control, with steric effects predominating. The combined effect is such that large alkyne substituents will orient themselves to minimize steric repulsion during alkyne insertion, with electron-withdrawing groups modulating, and even reversing, the effect for small substituents (Scheme 53). Very recently, a computational study of the very active dinapthocyclooctatetraene complex 102 was reported.94b It has been shown that the high reactivity of this catalyst derives from the increased steric repulsion of the ligand at the product-complex resting state 129. Most interestingly, it has been shown that there is a strong distal-directing effect for aryl-substituted alkynes originating from π−π interactions with the ancillary ligand. This work provides a strong theoretical basis for selective formation of several cycloheptadiene substitution patterns.

Scheme 50. Syntheses of Tremulenediol A and Tremulenolide A

cycloaddition as a key step in the preparation of 125, which was easily transformed into 126 by regioselective oxidation of the diol. Finally, Trost has made use of the VCP cycloaddition in the synthesis of (−)-pseudolaric acid B (Scheme 51).112 Originally, the key cycloaddition step was attempted through Trost’s ruthenium-catalyzed method (vide infra), developed to Scheme 51. Synthesis of (−)-Pseudolaric Acid B

4.2. Ruthenium-Catalyzed Vinylcyclopropane Cycloaddition Reactions

The [CpRu(NCMe)3]PF6-catalyzed VCP cycloaddition is functionally identical to the rhodium-catalyzed version but has not been as heavily investigated (eq 24).115 First reported 2257


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Scheme 53. Regioselectivity in Rh-Catalyzed [5 + 2] Cycloaddition

Scheme 55. Proposed Mechanism for Ru-Catalyzed [5 + 2] Cycloaddition

Scheme 56. Synthesis of (+)-Frondosin A

in 2000, the reaction displays similar substrate tolerances to the rhodium version but has only been demonstrated in intramolecular cases and only for the cycloaddition of alkynes. As such, its complete scope remains to be explored. Side-products of type 131 and reactivity differences between E- and Z-olefins (Scheme 54) led the authors to propose a mechanism in which

Scheme 57. Synthesis of a Rameswaralide Precursor

Scheme 54. E- versus Z-Alkene Reactivity

oxidative cyclization to form a metallacyclopentene intermediate 132 precedes C−C bond activation, in contrast to the mechanism proposed for the rhodium-catalyzed reaction (Scheme 55). An interesting application of this variant is the construction of tricyclic systems of relevance to alkaloid syntheses (133) (eq 25).116 One total synthesis has been

heterocyclic carbene (NHC) complexes (eq 26).119 Selective seven-membered ring formation was achieved with bulky

reported: a route to (+)-frondosin A (Scheme 56).117 A preparation of the tricyclic core of rameswaralide (134) has also recently been disclosed (Scheme 57).118

alkyne substituents, with smaller substituents giving mixtures of seven-membered ring bicycles and monocyclic fivemembered ring ethers. Fürstner et al. have developed a promising iron-catalyzed VCP cycloaddition reaction,120 providing an economically attractive alternative to the rhodium- and ruthenium-catalyzed systems (eq 27). The unusual anionic complexes [CpFe(CH2CH2)2]Li·tmeda (tmeda = N,N,N′,N′-tetramethylethane1,2-diamine) and [CpFe(cod)]Li·(MeOCH2OMe) each cata-

4.3. Nickel- and Iron-Catalyzed Vinylcyclopropane Cycloaddition Reactions

Zuo and Louie have reported that VCP [5 + 2] cycloaddition reactions can be catalyzed by in situ-prepared nickel/N2258


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6. FISCHER CARBENE-MEDIATED [5 + 2] CYCLOADDITION REACTIONS Barluenga et al. have reported a conceptually different [5 + 2] cycloaddition reaction of lithium enolates and Fischer carbene complexes (Scheme 59).122 Both tungsten and chromium lyze the [5 + 2] cycloaddition reaction, with reasonable substrate tolerance and diastereoselectivity.

Scheme 59. Fischer Carbene-Mediated [5 + 2] Cycloaddition

5. Rh-CATALYZED [5 + 2] CYCLOADDITION VIA TRAPPING OF RAUTENSTRAUCH INTERMEDIATES Very recently, Tang and co-workers reported a fascinating Rhcatalyzed extension to the [5 + 2] cycloaddition literature.121 In this process, acyloxy enediynes 135 react to form bicyclo[5.3.0]decatrienes 136 in what the authors propose is a trapping of a metallacyclohexadiene cation 137 (i.e., a Rautenstrauch rearrangement intermediate), which itself may arise from a Rh-carbene intermediate 138 (Scheme 58). For Scheme 58. Proposed Mechanism for [5 + 2] Cycloaddition via Trapping of Rautenstrauch Intermediates complexes mediate the stoichiometric reaction, with superior yields obtained in the tungsten manifold. Interestingly, the reaction produced cycloheptadiene 140 with complete diastereocontrol and in reasonable to good yields. The authors propose a mechanism in which the lithium enolate first adds to the carbene complex 139 in a 1,2-fashion (141), followed by a 1,2-migration of the metal to induce cyclization (142). Decomplexation and quenching of the alkoxide complete the sequence.

7. ALLYLSILANE [5 + 2] CYCLOADDITION REACTIONS Recently, Tanino and co-workers reported a cobalt-mediated [5 + 2] cycloaddition procedure wherein an allylsilane dicobalt acetylene complex 143 undergoes a tandem nucleophilic addition/Sakurai reaction (Scheme 60).123,124 This reaction

substrates bearing internal alkynes, improved results are obtained with the addition of the electron-deficient ligand (CF3CH2O)3P. The reaction displays an excellent substrate scope in both intra- and intermolecular manifolds (eq 28),

Scheme 60. Allylsilane-Mediated [5 + 2] Cycloaddition

under reaction conditions similar to those used by Wender for VCP-cycloaddition reactions. The latter case represents only the second example of a catalytic intermolecular [5 + 2] cycloaddition reaction and proceeds with excellent regioselectivity (up to >20:1). The authors postulate that the regioselectivity is determined by preferential distal insertion of the alkyne into the Rh−C bond, which is consistent with the results of Wender discussed above. Higher selectivities with heteroatom-bearing alkynes may be due to a heteroatom/metal interaction.

produces mono- and bicyclic ring products 145 in 63−98% yield with high stereoselectivity, yielding the same product regardless of the stereochemistry of the initial silyl enol ether. Decomplexation with ceric ammonium nitrate in acetone/water liberates the final organic product as a maleic anhydride derivative 146. The authors propose an alkylation/Sakurai reaction mechanism where a hexacarbonyldicobalt propargyl cation is the key intermediate, which undergoes the Nicholas reaction.125 This reaction can therefore be conceptualized as a [5 + 2] cycloaddition of a cobalt-stabilized pentadienyl cation 144 and a π-system. A conceptually similar, nonmetal-mediated cyclization reaction of allylsilanes and silylenol ethers for the 2259


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preparation of seven-membered rings was previously described by Lee et al. in 1988.126 In the presence of TMSOTf or Lewis acids such as TiCl4 or AlCl3, allylsilane 148 undergoes an aldol condensation with the unmasked acetal 147, followed by a Sakurai reaction (Scheme 61). The cyclization product 149 is Scheme 61. Allylsilane-Mediated Cyclization

Liebeskind and co-workers have demonstrated the preparation of molybdenum allyl complexes in high enantiopurity and subsequent conversion to η3-pentadienyl compounds with little to no racemization.129 The η3-pentadienyl complexes 152 are similar to the oxidopyrylium species described previously and readily undergo [5 + 2] cycloaddition reactions with electrondeficient alkenes and alkynes in the presence of a Lewis acid (eq 30). Recently it was reported that, for cycloaddition of 6immediately converted to the enone, in overall yields of 68− 71%. Tanino and co-workers have further developed the cobaltmediated reaction system for the cycloaddition of allenes and demonstrated the utility of the novel decomplexation products through the total synthesis of furanether B (Scheme 62).127 The sterically controlled [5 + 2] cycloaddition step resulted in a 5.3:1 ratio of inseparable regioisomers. Scheme 62. Synthesis of Furanether B

substituted scaffolds (R2 ≠ H), the presence of both Lewis and Brønsted acids was necessary to promote the reaction.130 Both oxygen (152) and nitrogen (153) heterocycles have been employed (eq 31), delivering seven-membered ring products in good to excellent yields, with complete facial selectivity and high enantiopurity. The 6-substituted systems in particular lead to synthetically valuable products, with four contiguous stereocenters, one a quaternary carbon, installed in a one-pot process. The final organic product is liberated from the metal through one of several procedures, including proto-, iodo-, or oxidative demetalation, all with good yields and retention of stereochemistry. The potential of this reaction class has been demonstrated by the total synthesis of the simple alkaloid (−)-Bao Gong Teng A (Scheme 63).131 As of yet, however,

The work of Tanino's group represents an important extension of the [5 + 2] cycloaddition reaction of pentadienyl cations to acylic systems. Interestingly, only one such reaction has been reported for which metal mediation is avoided: although not an allylsilane cycloaddition reaction, we believe it warrants discussion here.128 In this system, compounds 150 dimerize through pentadienyl cation trapping by an alkene, with both reactive partners generated by BCl3-mediated abstraction/elimination, to yield cycloheptenes 151 in a [5 + 2] cycloaddition (eq 29). In the presence of Brønsted acid, the alkene dimerizes in a [4 + 2] fashion.

Scheme 63. Synthesis of Bao Gong Teng A

8. METAL-MEDIATED η3-PENTADIENYL [5 + 2] CYCLOADDITION REACTIONS The oxidopyrylium cycloadditions and, by extension, the oxidopyridinium analogues suffer from a lack of enantiocontrol and facial selectivity. One means of achieving enantiocontrol in these reactions is through the use of a chiral scaffold. 2260


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only 5- and 6-substituted η3-pyranyl and η3-pyridinyl systems have been thoroughly investigated, with the cycloaddition apparently limited to electron-deficient π-systems. The authors favor a mechanism wherein the electrondeficient alkene or alkyne is activated by the Lewis acid (or “super Brønsted acid” in the 6-substituted cases), followed by a stepwise sequence wherein the η3-pentadienyl undergoes nucleophilic addition to the activated species, generating a zwitterionic intermediate. Electrophilic ring closure completes the sequence. The products slowly racemize in the continued presence of Lewis acid, lending credence to the proposal that a persistent zwitterionic complex lies on the reaction coordinate. Tungsten η3-pentadienyl complexes 154 also undergo [5 + 2] cycloaddition, presumably via a similar stepwise mechanism (Scheme 64).132 As in the molybdenum analogue, electron-

Scheme 65. η5-Pentadienyl-Mediated [5 + 2] Cycloaddition

Scheme 64. η3-Pentadienyl-Mediated [5 + 2] Cycloaddition

Scheme 66. Proposed Zr-Pentadienyl-Mediated [5 + 2] Cycloaddition deficient olefins appear to be required; only the reaction with TCNE has been reported. The most notable difference between the molybdenum and tungsten systems is the open, as opposed to closed, nature of the tungsten pentadienyl substrate.

9. METAL-MEDIATED η5-PENTADIENYL [5 + 2] CYCLOADDITION REACTIONS The cycloaddition reactions of transition-metal η5-pentadienyl complexes discussed in this section, although fundamentally important, have not yet reached a level of development where the methodology can be applied to complex molecule synthesis. Ernst and co-workers were the first to demonstrate [5 + 2] cycloaddition reactivity using pentadienyl complexes adopting an η5-coordination mode.133 They observed that the titanium 2,4-dimethyl pentadienyl complex 155 incorporates 2 equiv of trimethylsilyl phenylacetylene to yield the bridged cycloheptadiene complex 156 stabilized by an agostic C−H bond; attempts to limit the incorporation of alkyne to 1 equiv were unsuccessful (eq 32). During the course of investigations into

similar reactivity in η5-manganese carbonyl complexes. Each determined that irradiation of complexes of the type 162 in the presence of alkyne leads to cycloaddition products, generally incorporating two alkyne units to make multicyclic systems of the type 163 in good to excellent yields (eq 33). Kreiter and co-

workers determined that the role of the light is to generate a vacant site on the metal by liberating 1 equiv of CO (Scheme 67). This was demonstrated via photolysis in tetrahydrofuran Scheme 67. Photochemical [5 + 2] Cycloaddition

C−C agostic interactions in unsaturated titanium complexes, Ernst and co-workers also reported [5 + 2] cycloaddition products formed from the reaction of titanium η5-cyclooctadienyl complex 157 with alkynes.134 These cycloaddition reactions also proceed by incorporation of two, three, or four alkyne units, depending on the nature of the phosphine ligand (Scheme 65), yielding complex multicyclic structures (158− 160). Ernst and co-workers also proposed that a [5 + 2] cycloaddition reaction is involved in the isomerization of zirconium alkyne complex 161; however, no characterization data was provided to support this conclusion (Scheme 66).135 Shortly after Ernst’s initial report, Kreiter and co-workers136 and Sheridan and co-workers137 independently demonstrated

(THF) in the absence of alkyne to produce the mono-THF complex 164. When complex 164 was exposed to alkyne in the absence of light, the expected cycloaddition products 165 were obtained. Attempts to limit the incorporation of alkyne to a single insertion led to significantly reduced yields. Improved yields (up to 40%) can be obtained by conducting the reaction under a CO atmosphere. Sheridan and co-workers harnessed the potential of the monocyclization product by incorporating two different alkyne units, demonstrating the intermediacy of the single-insertion product on the pathway to the final [5 + 2] , 2261


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Liebeskind’s molybdenum-mediated chemistry also shares this limitation. Despite harnessing the potential of the latent functional group in the resultant heteroatom bridge, this thermal chemistry cannot be applied to simple acyclic substrates, although the work of Tanino presents interesting opportunities for further development. In addition, the use of electronically biased or strained π-systems is necessary to achieve efficient intermolecular cycloaddition. Although elegant formally intermolecular processes have been developed via tethering protocols, these add potentially undesirable steps and extraneous functionality into a synthetic sequence. The vinylcyclopropane cycloaddition reaction became useful as a result of the pioneering work of the Wender group, demonstrating the potential of metal-mediated cycloaddition to extend [5 + 2] cycloaddition processes beyond cyclic systems. Although the tremendous value of this reaction is obvious, the efficiency of the catalytic process is purchased at the cost of multistep substrate synthesis and building strain into the starting materials, later released to provide a thermodynamic driving force. The recent reports of Tang have shown that [5 + 2] cycloaddition reactions can be performed catalytically with noncyclopropyl-based substrates and represent a very significant advance in the field. However, the potentially prohibitive cost associated with rhodium (and lower, but not insignificant, cost of ruthenium) make this procedure less attractive, particularly at large scale. Ultimately, the development of efficient base-metal catalysts will address both cost and toxicity issues, but this area of research is far from mature. Metal-mediated η5-pentadienyl cycloaddition processes avoid some of the drawbacks of the vinylcyclopropane system but are hampered by an absence of product selectivity, generally giving only higher-order cycloaddition products in synthetically useful yields. The cobalt-mediated methodology addresses this difficulty, yet is limited in scope by a lack of tolerance for pentadienyl substitution. Future research in the area of [5 + 2] cycloaddition must focus on developing inexpensive and structurally simple η5-pentadienyl systems that show the wide tolerance for substituents and cycloaddition partners demonstrated for the rhodium-catalyzed systems of Wender and Tang. When this has been developed, a truly general and powerful cycloaddition methodology for the preparation of sevenmembered rings will have been realized.

homo[5 + 2] cycloaddition products (Scheme 68). Sheridan and co-workers have also shown that chromium/tin bimetallic Scheme 68. [5 + 2]/Homo[5 + 2] Cycloaddition

complexes 166 mediate this reaction (eq 34),138 with the undesirable production of an equivalent of triaryltin hydride, generated via hyride abstraction from the cycloaddition product.

Recently, Stryker and co-workers reported a cobalt-mediated η5-pentadienyl/alkyne cycloaddition reaction that proceeds in excellent yield, providing monocyclic products selectively (Scheme 69).139 A very interesting feature of this reaction is Scheme 69. Cobalt η5-Pentadienyl-Mediated [5 + 2] Cycloaddition

that, while the common η5-coordinated cycloheptadienyl complexes 169 can be obtained, an unprecedented η2,η3cycloheptadienyl isomer 168 can be obtained selectively under kinetic control. The reaction is limited to 1-substituted pentadienyl complexes and both unsubstituted and moderately electron-rich alkynes. With nonsymmetric alkynes, poor regiocontrol is observed, with 2:1 selectivity being the best obtained in the absence of sterically large groups. DFT investigations suggest that the substituent dependence of the cycloaddition is related to a significant destabilization of the pentadienyl ground state due to steric repulsion between the ancillary ligand and the C1-substituent.140 These computational investigations also support the mechanistic proposal of ratelimiting η5 → η3 pentadienyl isomerization with concomitant alkyne coordination. Alkyne insertion, olefin recoordination, and subsequent migratory insertion complete the cycloaddition sequence.

10. CONCLUSION Although a great deal of [5 + 2] cycloaddition chemistry has been developed, each reactivity motif remains at least to some extent limited by inherent drawbacks. The early work in the areas of perezone-type and kojic acid-type cycloaddition chemistry is limited by the necessity of using a cyclic system to fix the geometry of the pentadienyl cation in the former, or allow the formation of the oxidopyrylium ylid in the latter.

AUTHOR INFORMATION Corresponding Author

*Dr. Kai E. O. Ylijoki e-mail: [email protected]. Notes

The authors declare no competing financial interest. 2262


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Biographies

REFERENCES (1) Reviews: (a) Battiste, M. A.; Pelphrey, P. M.; Wright, D. L. Chem.Eur. J. 2006, 12, 3438. (b) Butenschön, H. Angew. Chem., Int. Ed. 2008, 47, 5287. (2) For a review on synthetic efforts, see: Kuwajima, I.; Tanino, K. Chem. Rev. 2005, 105, 4661. (3) For a review of inside/outside stereochemistry, see: Alder, R. W.; East, S. P. Chem. Rev. 1996, 96, 2097. (4) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am. Chem. Soc. 2000, 122, 2116. (5) For a review on tropolonoids, see: Bentley, R. Nat. Prod. Rep. 2008, 25, 118. (6) Reviews: (a) Harmata, M. Chem. Commun. 2010, 46, 8886. (b) Harmata, M. Chem. Commun. 2010, 46, 8904. (c) Lohse, A. G.; Hsung, R. P. Chem.Eur. J. 2011, 17, 3812. (7) (a) Sammes, P. G. Gazz. Chim. Ital. 1986, 119, 109. (b) Mascareñas, J. L. Adv. Cycloaddition 1999, 6, 1. (c) Singh, V.; Krishna, U. M.; Vikrant; Trivedi, G. K. Tetrahedron 2008, 64, 3405. (d) Wender, P. A.; Love, J. A. Adv. Cycloaddition 1999, 5, 1. (e) Wender, P. A.; Gamber, G. G.; Williams, T. J. Modern RhodiumCatalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: New York, 2005. (f) Pellisier, H. Adv. Synth. Cat. 2011, 353, 189. (8) In the field of cycloaddition chemistry, confusion over nomenclature may exist. For the purpose of this review, [5 + 2] cycloaddition refers to the number of carbon atoms in each of the reactive components. This is not to be confused with common descriptors of pericyclic reactions where the number of p-electrons is used. For example, a Diels−Alder reaction is both a [4 + 2] and [4p + 2p] cycloaddition reaction, whereas the perezone-type cycloaddition can be described as a [5 + 2] or a [4p + 2p] cycloaddition. Electronbased descriptors are best applied to pericyclic reactions only. (9) Anschütz, R.; Leather, W. Chem. Ber. 1885, 18, 715. (10) Sanders, J. M. Proc. Chem. Soc. 1906, 22, 134. (11) Remfry, F. G. P. J. Chem. Soc. 1913, 103, 1076. (12) (a) Walls, F.; Padilla, J.; Joseph-Nathan, P.; Giral, F.; Romo, J. Tetrahedron Lett. 1965, 21, 1577. (b) Walls, F.; Padilla, J.; JosephNathan, P.; Giral, F. Tetrahedron 1966, 22, 2387. (13) (a) Archer, D. A.; Thomson, R. H. Chem. Commun. 1965, 354. (b) Wagner, E. R.; Moss, R. D.; Brooker, R. M.; Heeschen, J. P.; Potts, W. J.; Dilling, M. L. Tetrahedron Lett. 1965, 47, 4233. (c) Bates, R. B.; Paknikar, S. K.; Thalacker, V. P. Chem. Ind. 1965, 1793. (14) Joseph-Nathan, P.; Mendoza, V.; García, E. Tetrahedron 1977, 33, 1573. (15) (a) Sánchez, I. H.; Yáñez, R.; Enríquez, R.; Joseph-Nathan, P. J. Org. Chem. 1981, 46, 2818. (b) Joseph-Nathan, P.; Garibay, M. E.; Santillan, R. L. J. Org. Chem. 1987, 52, 759. (16) (a) Sánchez, I. H.; Basurto, F.; Joseph-Nathan, P. J. Nat. Prod. 1984, 47, 382. (b) Sánchez, I. H.; Larraza, M. I.; Basurto, F.; Yáñez, R.; Avila, S.; Tovar, R.; Joseph-Nathan, P. Tetrahedron 1985, 41, 2355. (17) Cuadrado, M. J. S.; de la Torre, M. C.; Lin, L.-Z.; Cordell, G. A.; Rodríguez, B.; Perales, A. J. Org. Chem. 1992, 57, 4722. (18) (a) Mamont, P. Bull. Soc. Chim. Fr. 1970, 1557. (b) Mamont, P. Bull. Soc. Chim. Fr. 1970, 1564. (c) Mamont, P. Bull. Soc. Chim. Fr. 1970, 1568. (19) (a) Büchi, G.; Mak, C.-P. J. Am. Chem. Soc. 1977, 99, 8073. (b) Büchi, G.; Chu, P.-S. J. Org. Chem. 1978, 43, 3717. For related work, see: (a) Mortlock, S. V.; Seckington, J. K.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1988, 2305. (b) Goodell, J. R.; McNullen, J. P.; Zaborenko, N.; Maloney, J. R.; Ho, C.-X.; Jensen, K. F.; Porco, J. A., Jr.; Beeler, A. B. J. Org. Chem. 2009, 74, 6169. (c) Treece, J. L.; Goodell, J. R.; Velde, D. V.; Porco, J. A., Jr.; Aubé, J. J. Org. Chem. 2010, 75, 2028. (20) Angle, S. R.; Turnbull, K. D. J. Org. Chem. 1993, 58, 5360. (21) (a) Engler, T. A.; Combrink, K. D.; Takusagawa, F. J. Chem. Soc., Chem. Commun. 1989, 1573. (b) Engler, T. A.; Letavic, M. A.; Combrink, K. D.; Takusagawa, F. J. Org. Chem. 1990, 55, 5810. (c) Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K. O., Jr.; Ray, J. E. J. Org. Chem. 1994, 59, 6567.

Kai E. O. Ylijoki was born in the small northern Ontario town of Geraldton in 1978. He earned his H.B.Sc. and M.Sc. degrees in chemistry at Lakehead University in Thunder Bay, ON, under the supervision of Prof. Christine Gottardo. Afterwards, he joined the laboratories of Prof. Jeffrey M. Stryker at the University of Alberta, where he received his Ph.D. in chemistry in 2010. His graduate research was focused on the cobalt-mediated η5-pentadienyl/alkyne [5 + 2] cycloaddition reaction and its application to the synthesis of bicyclic systems. From 2010 to 2012, he worked with Prof. E. Peter Kündig at the University of Geneva (Switzerland), as a Postdoctoral Fellow in the field of catalytic and stoichiometric organometallic synthesis.

Jeffrey M. Stryker was born in Bloomington, IN, in 1956 and obtained his A.B. degree in chemistry from Harvard University, where he worked, at least a little, in the laboratories of Prof. Paul Wender. He subsequently joined the laboratory of Prof. Gilbert Stork at Columbia University, obtaining his doctorate in 1983. He thereafter served an NIH postdoctoral fellowship in the laboratories of Prof. Robert G. Bergman at University of California, Berkeley, after which he moved to a faculty position at Indiana University and, in 1992, to his present position at the University of Alberta, where he is Professor of Chemistry and Principal Investigator in the Imperial Oil/Alberta Centre for Oil Sands Innovation. His research interests remain in synthesis and, in particular, molecular design, most recently of highactivity coordination catalysts for applications to, basically, everything.

ACKNOWLEDGMENTS Financial support from the Natural Sciences and Engineering Research Council of Canada, the province of Alberta (Q.E. II− Doctoral Scholarship to K.E.O.Y.), and the University of Alberta is gratefully acknowledged. 2263


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