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Syntheses and Applications of Functionalized Bicyclo[3.2.1]octanes: Thirteen Years of Progress Marc Presset, Yoann Coquerel,* and Jean Rodriguez* Aix Marseille Université, CNRS, iSm2 UMR 7313, 13397 Marseille, France 6. Bicylo[3.2.1] Ring System from Polycyclic Precursors 6.1. Rearrangement of Bicyclo[2.2.2]octane Derivatives 6.2. Rearrangements of Fused Bicyclo[n.m.0] Derivatives 6.3. Ring-Expansion-Based Methods 6.4. Ring-Contraction-Based Methods 6.5. Rearrangement of Tricyclic Compounds 7. Enantioselective Approaches 7.1. From Acyclic Precursors 7.2. From Five-Membered Rings 7.3. From Six-Membered Rings 8. Bicyclo[3.2.1]octanes as Synthetic Intermediates 8.1. Fragmentation to Seven-Membered Rings 8.2. Fragmentation to Six-Membered Rings 8.3. Fragmentation to Five-Membered Rings 8.4. Rearrangement to Other Bicyclooctane Systems 8.5. Ring-Contraction/Expansion to Other Bicyclic Systems 9. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Bicylo[3.2.1] Ring System from Acyclic Precursors 2.1. Carbonyl-Type Condensations and Related Cyclizations 2.2. Transition Metal-Mediated Cyclizations 2.3. Carbocation-Based Cyclizations 2.4. Radical-Based Cyclizations 2.5. Cycloadditions, Electrocyclizations, and Cycloisomerizations 3. Bicylo[3.2.1] Ring System from Five-Membered Rings 3.1. Carbonyl-Type Condensations and Related Cyclizations 3.2. Alkylation-Based and Related Cyclizations 3.3. Michael Addition-Based Cyclizations 3.4. Carbocation-Based Cyclizations 3.5. Radical-Based Cyclizations 3.6. Transition Metal-Mediated Cyclizations 3.7. Cycloadditions, Electrocyclizations, and Cycloisomerizations 4. Bicylo[3.2.1] Ring System from Six-Membered Rings 4.1. Carbonyl-Type Condensations and Related Cyclizations 4.2. Alkylation-Based Cyclizations 4.3. Michael-Based Cyclizations 4.4. Carbenoid-Based Cyclizations 4.5. Carbocation-Based Cyclizations 4.6. Radical-Based Cyclizations 4.7. Transition Metal-Mediated Cyclizations 4.8. Cycloadditions, Electrocyclizations, and Cycloisomerizations 5. Bicylo[3.2.1] Ring System from Seven-Membered Rings 5.1. Carbonyl-Type Condensations and Related Cyclizations 5.2. Alkylation-Based Cyclizations 5.3. Michael Addition-Based Cyclizations 5.4. Carbocation-Based Cyclizations 5.5. Radical-Based Cyclizations 5.6. Transition Metal-Mediated Cyclizations © XXXX American Chemical Society

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1. INTRODUCTION Although the first construction of a functionalized bicyclo[3.2.1] skeleton was proposed by Kompa and Hirn in 1903 using an intramolecular Piria reaction,1 the first comprehensive review on this particularly attractive nucleus appeared in Chemical Reviews only in 1999.2 Other reviews on bridged systems have appeared more recently.3 Because of the significance of this scaffold both from theoretical and synthetic points of view, tremendous progress has been achieved in this field during the past 13 years. The continual renewal of interest in the chemistry of this framework is mainly due to its ubiquity in numerous families of biologically active natural products (Figure 1) coupled with its versatile reactivity, making it a very useful building block with a valuable impact in modern organic synthesis. Hence, the stereoselective formation of this nucleus is still receiving broad attention from many groups all over the world as shown by the development of new, more efficient

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dx.doi.org/10.1021/cr200364p | Chem. Rev. XXXX, XXX, XXX−XXX

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Figure 1. Representative natural products incorporating a bicyclo[3.2.1]octane moiety.

synthetic methodologies that have proved particularly welladapted in some elegant total syntheses of complex natural products. On the other hand, directed selective fragmentations or specific skeletal rearrangements of this strained nucleus4 well-illustrate the synthetic potential of functionalized bicyclo[3.2.1]octanes in the construction of elaborated molecular structures otherwise difficult to obtain. The objective of the present contribution is to cover comprehensively the abundant literature from early 1999 up to December 2011, giving a special emphasis on the

development of new synthetic approaches for their preparation and their reactivity, complemented by some important applications to the total synthesis of natural products. The article has been organized according to the nature of the precursor of the bicyclo[3.2.1]octane moiety, i.e., acyclic, five-, six-, and seven-membered rings, or polycyclic precursors. Within these different sections, the methodologies are presented based on the nature of the ring-closure elemental step even when domino processes are involved (i.e., Michael− aldol is found in the section on aldol). The review is limited to B


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Scheme 1. Domino [4 + 2]-Wittig

Scheme 2. Domino Michael−Aldolization

2.1. Carbonyl-Type Condensations and Related Cyclizations

carbocycles, and some nongeneral unique reactions have not been included. When the bicyclo[3.2.1]octane moiety is not the main structural element of a more complex polycyclic ring system, the work has not been included. Some natural products or classes of natural products containing the bicyclo[3.2.1]octane ring system have been the topic of recent reviews, and in each case, the synthesis of the bicyclo[3.2.1]octane moiety has been clearly highlighted and compared therein. This includes quadranes,5 class II and III Galbulimima alkaloids,6 platensimycin,7 gelsemine,8 and sordarin and sordaricin.9 Thus, all the previously covered work concerning the elaboration of the bicyclo[3.2.1]octane ring system in these families of natural products has not been included in the present review, and the interested reader is invited to consult appropriate reviews. However, the most recent work uncovered in previous reviews has been included. In the following, molecules that have been prepared in racemic form are depicted with straight stereochemical information, while molecules prepared in their optically active form have been drawn using wedged stereochemical representation. Several NMR methods have been established for the attribution of the relative stereochemistry in functionalized bicyclo[3.2.1]octane derivatives.10

In 2006, McDougal and Schaus have discovered a phosphinemediated dimerization reaction of 1,4-dien-3-ones that provides access to bicyclo[3.2.1]octenones.11 When a series of dienones of type 1 were treated with diethylphenyl phosphine in the presence of pyridine, the dimeric products 4 were obtained in moderate to good yields (Scheme 1). The reaction sequence is initiated by a regioselective addition of the phosphine to the less-hindered enone to form the zwitterionic species 2, which then undergoes a formal endo-[4 + 2]-cycloaddition with another molecule of 1 to give the corresponding betaine in equilibrium with the phosphorus ylide 3. A final intramolecular Wittig olefination affords the functionalized bridged bicyclooctenones. A more traditional, but efficient, Michael−aldolization step was reported more recently by Liau and Shair to assemble the bicyclo[3.2.1]octane ring system in the total synthesis of (+)-fastigiatine.12 Exposure of the enamino ester 5 to aqueous hydrochloric acid led to the tetracyclic product 7 as a single diastereomer in high yield following a formal [3 + 3]cycloaddition (Scheme 2). The reaction is believed to occur via initial hydrolysis of the ketal moiety in 5 with generation of the corresponding ketone 6, which then underwent a diastereoselective intramolecular conjugate addition and a transannular aldol reaction.

2. BICYLO[3.2.1] RING SYSTEM FROM ACYCLIC PRECURSORS Although particularly attractive, direct annulation reactions to the bicyclo[3.2.1]octane framework from acyclic precursors still constitute an important synthetic challenge. However, some interesting ionic, metal-catalyzed, or radical approaches have been recently proposed from various research groups and are presented here.

2.2. Transition Metal-Mediated Cyclizations

Besides the approach for the cage core of platensimycin by the group of Lee,7 there has been only one other carbenoid-based approach to the bicyclo[3.2.1]octane ring system from acyclic compounds reported. Bhunia and Liu proposed a gold(I)catalyzed cycloisomerization of the 3-alkenyl allene substrates 8 C


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Scheme 3. Cycloisomerization of Vinyl Allenes

Scheme 4. Rearrangement of Cyclopropyl Carbinols

Scheme 5. Rearrangement of Dichlorocyclopropane (TIPS = Triisopropylsilyl)

to provide the bicyclo[3.2.1]oct-6-en-2-ones 11 (Scheme 3).13 Remarkably, these reactions proceed through intramolecular hydride transfer from the acetal to the gold carbenoid (9 → 10), followed by addition of the resulting allyl gold species to the oxocarbenium ion (10 → 11).

Seven years later, a related cyclopropyl rearragement was proposed by the group of West from 2-siloxy-2-alkenyl-1,1dichlorocyclopropanes 14.15 On treatment with AgBF4 in refluxing CH3CN, 14 furnished the Nazarov oxyallyl cation intermediates, which could be trapped in an intramolecular fashion by the tethered nucleophilic arene to give the tricyclic benzobicyclo[3.2.1]octene products 15 in a single chemical operation in 57−81% yield (Scheme 5). Closely related to this cationic approach, Liu and co-workers described a domino gold-catalyzed deoxygenative Nazarov-type carbocyclization/nucleophilic addition with 2,4-dienals and allylsilanes for the stereoselective synthesis of various polycyclic structures.16 Thus, the reaction of the dienals 16 in the

2.3. Carbocation-Based Cyclizations

Ila, Junjappa, and co-workers have reported the synthesis of the bicyclo[3.2.1]octadienes 13 by a Lewis acid rearrangement of the cyclopropyl carbinols 12 (Scheme 4).14 On treatment with stannyl chloride, 12 underwent a cationic cascade beginning with the ring-opening of the cyclopropane and a thiomethylassisted cyclopentannulation followed by four other rearrangement steps to stereoselectively give the product 13. D


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Scheme 6. Nazarov-Type Cyclization

Scheme 7. Intramolecular Diyl Trapping

Scheme 8. Fragmentation of Methylene Cyclopropanes

presence of allyl silane nucleophiles gave the bicyclo[3.2.1]octadienes 17 (Scheme 6). The reaction sequence is initiated by a Nazarov cyclization to give the cationic intermediate 18. This reactive intermediate then undergoes addition of the allylsilane from the less-hindered face and another goldcatalyzed ionization with loss of TMSOAuL to give intermediate 19. Finally, 19 cyclizes to furnish the tertiary carbocation 20, a direct precursor of the product.

The latter was then converted into a previously described intermediate in the total synthesis of aphidicolin. In complement, Kilburn’s group has introduced methylene cyclopropanes as powerful building blocks for the generation of complex polycyclic structures including the bicyclo[3.2.1] skeleton.2 More recently, the same group described a direct diastereoselective route to simple functionalized bicyclo[3.2.1]octanes involving a samarium diiodide-mediated cascade cyclization of methylene cyclopropyl hydroxyketones.18 The monoelectronic reduction of the methylenecyclopropyl ketone 23 with SmI2 provided the corresponding ketyl radical anion, which underwent a cyclization/fragmentation/cyclization cascade to give the product 24 (Scheme 8). The role of the chelating hydroxyl group in the substrate was found to be crucial for the success of this reaction. On the other hand, the reduction of suitably halogenated olefins followed by intramolecular trapping of the in situ formed radical intermediate also constitutes an important cyclization methodology, which has found many interesting applications for the elaboration of bridged systems. Haney and Curran have proposed an interesting example during their synthetic studies toward the sesquiterpene gymnomitrene.19

2.4. Radical-Based Cyclizations

Some interesting halogen-free reductive radical cyclizations of functionalized unsaturated substrates have been developed to efficiently form cyclic systems. Among these, in the early 1980s, Little and co-workers proposed the intramolecular diyl trapping cycloaddition for the rapid elaboration of polycyclic systems from the thermal or photochemical decomposition of 4methylenepyrazolines. More recently, the same group applied this strategy for the assembly of the bicyclo[3.2.1]octane framework of aphidicolin.17 The thermal decomposition of the azadiene 21 produced the corresponding diyl, which underwent a 6-endo-trig-cyclization followed by a nondiastereoselective σbond formation to give the tricyclic product 22 (Scheme 7). E


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Scheme 9. Round-Trip Radical Cascade (AIBN = Azobisisobutyronitrile)

They have described a “round trip” radical cascade of the iodo compound 25. This transformation is a succession of 5-exo-, 6endo-, and 5-exo-cyclizations in which the last radical step occurs at the same carbon atom as the initial radical generation. Thus, exposure of the acyclic precursor 25 to a fluorous tin hydride and a radical initiator promoted its conversion to the tricyclic compounds 26a,b in an elegant domino process (Scheme 9). Similarly, Yang et al. have described a Lewis acid-promoted atom-transfer cascade radical cyclization for the formation of various bi- and tricyclic molecules including some bicyclo[3.2.1]octanes, as illustrated with the conversion of 27 into 28 (Scheme 10).20 On examples targeting other ring systems, the reaction was turned enantioselective with chiral Lewis acids.

tives by Mitasev and Porco in a number of cyclization modes including two examples of full construction of the bicyclo[3.2.1]octane framework as illustrated by the conversion of 31 into 32 (Scheme 12).22 Also of interest is the work from the groups of Velu and Li, in studies on biomimetic dimerization reactions of resveratrol derivatives, to give, among other products, ampelopsin F analogues by means of one-electron oxidants as illustrated in Scheme 13.23 The issue of these reactions is highly dependent on the nature of the oxidant, the solvent, and the oxygenated pattern of the starting material, often producing relatively low yields of bicyclo[3.2.1]octane derivatives. Finally, Šindler-Kulyk and co-workers have reported the photochemical cyclization of the o-vinyl heterostilbenes 33 to give the benzobicyclo[3.2.1]octadienes 34 albeit in modest yields (Scheme 14).24 The reaction proceeds by initial intramolecular cycloaddition to give an indane biradical, which then undergoes a cyclohexene ring-closure followed by a rearomatization step. Also, Lee and co-workers reported a related isolated example of an unexpected intramolecular [3 + 2]-cycloaddition reaction of a trimethylenemethane diyl with an olefin.25

Scheme 10. Radical Atom-Transfer Cascade

2.5. Cycloadditions, Electrocyclizations, and Cycloisomerizations

Some elegant intramolecular Diels−Alder cycloadditions allowing a complete assembly of the bicyclo[3.2.1]octane ring system have been reported in the course of total syntheses of sordarin and its analogues.9 In their total synthesis of 9isocyanoneopupukeanane, Ho and Jana used another intramolecular Diels−Alder reaction for the full construction of the bicyclo[3.2.1]octane ring system of the natural product.26 The pyrolysis of the diacetate substrate 35 provided directly the symmetrical tricyclic olefin 37, indicating the generation of the intermediate triene species 36 (Scheme 15). Further functionalization of the double bond in 37 afforded the natural product. Peese and Gin used a similar tactic with more complex substrates to generate the bicyclo[3.2.1]octane subunit of the

Alternatively, a related halogen-free substrate was used by Snider and Duvall in a manganese(III)-mediated oxidative radical cyclization terminated by trapping of the final radical with sodium azide.21 Among other cyclizations, they reported the full construction of the diastereomeric bicyclo[3.2.1]octanes 30 from the acyclic precursor 29, albeit as minor components of the reaction product mixture (Scheme 11; see section 3.5 for an example of a related reaction with a fivemembered ring precursor). This manganese(III)-mediated oxidative cyclization was applied more recently to dearomatized phloroglucinol derivaScheme 11. Oxidative Radical Cyclization and Functionalization

F


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Scheme 12. Oxidative Radical Cyclization

Scheme 13. Oxidative Radical Dimerization

Scheme 14. Photochemical-Induced Radical Cyclization

Scheme 15. Ho and Jana’s Intramolecular Diels−Alder Approach

diterpene alkaloid natural product nominine.27 The exposure of the β,γ-unsaturated ketone 38 to pyrrolidine in methanol afforded the intramolecular Diels−Alder adduct 40 in good yield (Scheme 16). Although not explicitly detected, the reactive dienamine isomer 39 probably formed in minor equilibrating amount, which drove the reaction to completion. A related strategy involving an intramolecular aza-Diels−Alder was also reported.28 An intermolecular combination of Nazarov electrocyclization/6π-[4 + 3]-cycloaddition sequence was proposed by West and co-workers to give bridged cyclooctenes incorporating the bicyclo[3.2.1]octane core.29 This reaction proceeds via initial Lewis acid-catalyzed generation of the Nazarov oxyallyl intermediate from the dienones 41, which then reacts as a

dienophile and can be trapped with various cyclic and acyclic dienes. When the trapping is realized with cyclopentadiene, the bicyclo[3.2.1]octane derivatives 42 are obtained in good yields (Scheme 17). Murakami and co-workers have described some rhodiumcatalyzed cyclization reactions of allenynes with arylboronic acids.30 Among the reported examples, the reaction of allenyne 43 with phenylboronic acid afforded the bicyclo[3.2.1]octanone 44 (Scheme 18). The reaction is likely to be initiated by transmetalation of the boronic acid to form a phenyl rhodium species that undergoes 1,2-regioselective addition to the alkyne moiety. The resulting alkenyl rhodium further reacts by intramolecular carborhodation onto the allene in a 6-exo mode to provide yet another alkenyl rhodium species that G


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Scheme 16. Peese and Gin’s Intramolecular Diels−Alder Approach

Scheme 17. Domino Nazarov−[4 + 3]

Scheme 18. Domino Carbometallation−Cyclization of Allenyne


undergoes intramolecular acylation by addition to the ester group to complete the formation of the bicyclic ring system.

The aldol condensation and related reactions are among the most robust and venerable methods for C−C bonds formation, and as such, in the time frame covered by this review, many strategies toward the stereoselective construction of the bicyclo[3.2.1] ring system have still relied on aldolization and related transformations. In an approach to triquinane natural products, Mehta and Pallavi have reported the synthesis of the tricyclo[4.3.2.01,5]undecane compound 46 (thus containing the bicyclo[3.2.1] ring system) by a base-promoted regioselective aldolization of the diketone 45 with creation of a neopentylic tertiary alcohol

3. BICYLO[3.2.1] RING SYSTEM FROM FIVE-MEMBERED RINGS Since the pioneering work from Julia’s group,31 the development of new synthetic methodologies involving selective cyclizations of a functionalized five-membered ring precursor have received particularly important attention. Traditional stoichiometric or catalytic C−C bond formations have been applied to some elegant syntheses, and more innovative processes could be developed to extend the molecular diversity and push over the knowledge in this field. H


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Scheme 19. Intramolecular Aldolization

Scheme 20. Domino Isomerization−Aldolization (DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene)

Scheme 21. Meyers’ Approach to Zizaene (RCM = Ring-Closing Metathesis)

Scheme 22. Organocatalyzed Regioselective Aldolization (DMF = Dimethylformamide)

I


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Scheme 23. Thorpe−Ziegler Annulation toward Maritimol

Scheme 24. Organolithium-Promoted Cyclizations of N-Aziridinylimines (Azi = 2-Phenyl Aziridine)

(Scheme 19).32 Under acid-catalyzed conditions, 45 gave the desired triquinane skeleton via a regioisomeric aldol reaction. Another example of unexpected regioselectivity in aldolization was reported by Krafft et al. in a study directed at the synthesis of triquinanes.33 Treatment of aldehyde 47 with 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) gave rise to the tricyclo[4.3.2.01,5]undecane compound 48 via a surprising isomerization/aldol sequence (Scheme 20). As an application of their approach to optically active spirobicyclic systems, Meyers and co-workers reported a formal total synthesis of zizaene based on an aldolization reaction as the key step for the formation of the bicyclo[3.2.1] ring system (Scheme 21).34 The optically active spirobicyclo[4.4]nonane substrate 49a was prepared via a stereoselective double alkylation of optically active lactams with olefinic halides as previously reported by the authors, followed by a ring-closing metathesis, removal of the remote chiral auxiliary, and functional group manipulation. With 49a in hand, the key intramolecular aldolization proceeded only under acid catalysis (TsOH, toluene, reflux) but the target aldol product could only

be obtained together with a large proportion of unreacted starting material. Alternatively, the corresponding diethyl acetal 49b underwent a smooth acid-catalyzed aldolization/crotonization sequence to afford the expected tricyclic enone 50 in good yield. Further functional group manipulation afforded a previously described intermediate in Coates’ total synthesis of zizaene. In an attempt to use the tetrazole derivative of (1R,2S)cispentacin 52a as an organocatalyst to promote the Hajos− Parrish−Eder−Sauer−Wiechert reaction with the triketone 51, Davies et al. obtained the bicyclic compound 53 in 67% yield as a racemic mixture. The bicyclic product 53 was actually obtained from an aldol condensation, but with an unexpected regioselectivity (Scheme 22).35 They conclude that, in regards to previous work, the incorporation of a tetrazole moiety within organocatalysts as a carboxylic acid replacement should not be regarded as a “panacea strategy”. However, the (1S,2S) diastereomeric tetrazole derivative 52b organocatalyst did afford the expected bicyclo[4.3.0]undecane ring system 54 following the anticipated aldolization-based cyclization. After J


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Scheme 25. NHC-Catalyzed Domino Michael−Aldolization

Scheme 26. TMSOTf-Catalyzed Domino Michael−Aldolization (DMP = Dess−Martin Periodinane; KHMDS = Potassium Bis(trimethylsilyl)amide; mCPBA = meta-Chloroperoxybenzoic Acid)

aziridinylimine to generate, after rearrangement and loss of nitrogen gas and styrene, the intermediate allylic anion 59. This intermediate then reacts by a regio- and diastereoselective intramolecular nucleophilic addition to another N-aziridinylimine present in the molecule to form, after loss of nitrogen and styrene, the anionic bicyclo[3.2.1]octane derivative 60, which, in turn, undergoes another similar cyclization and a final elimination step to give the tricyclic compound 61. The same strategy has also been applied to the synthesis of cedrane sesquiterpenes (see section 4.1). As previously demonstrated by us and others, the domino Michael−aldolization sequence from activated cyclopentanone derivatives allows a rapid and stereoselective access to bicyclo[3.2.1]octan-8-ones.41 The scope of promoters and catalysts available for this reaction has been recently expanded. In their study on N-heterocyclic carbene (NHC)-catalyzed Michael additions, Boddaert, Coquerel, and Rodriguez discovered that N,N-diaryl-1,3-imidazol(in)-2-ylidenes are excellent organocatalysts not only for the Michael addition but also for the aldol condensation.42 More specifically, they reported that IPr (63, [1,3-bis(2,6-diisopropylphenyl)imidazol2-ylidene]) could efficiently catalyze the archetypal Michael− aldol cascade for the preparation of 2-hydroxy-bicyclo[3.2.1]octan-8-ones 64a−c from the corresponding cyclopentanones 62a−c and acrolein, and that the diastereoselectivity of the reaction was strongly dependent on the nature of the R substituent in the activating group (Scheme 25). Of importance, it was demonstrated that, contrary to similar base-catalyzed reactions, these NHC-catalyzed domino Michael−aldol reactions are not reversible under the conditions studied (or are reversible at a very slow rate). A dendrimeric

acid-catalyzed dehydration, the desired enone product 55 was obtained in good yield but with a low enantiomeric excess (Scheme 22).36 Following these results, Mahrwald and coworkers observed the same unexpected regioselective aldolization promoted by a catalytic amount (0.2 mol %, no solvent, 48 h, 55 °C) of their chiral tetranuclear complex Ti4(μBINOLato)6(μ3-OH)4, giving the bridged bicyclic compound 53 in 44% yield with high regio- and diastereoselectivies, but also without detectable enantioselectivity.37 Apart from 1,5-dicarbonyl precursors, 1,5-dinitriles in some cases constitute an interesting alternative to form the final C−C bond via a Thorpe−Ziegler annulation. For example, in their total synthesis of the stemodane diterpene (+)-maritimol, Deslongchamps and co-workers38 used Piers’ approach to the same natural product in the racemic series. 39 Under thermodynamic basic conditions, the dinitrile 56 was converted into an enaminonitrile intermediate, the hydrolysis of which furnished the previously described tetracyclic dione 57 containing the desired bicyclo[3.2.1]octane ring system (Scheme 23). The latter was then converted to (+)-maritimol in four further steps. The aldolization has also been quite often involved as an endgame elemental step in domino reaction starting from more or less sophisticated precusors. In 1999, Kim et al. proposed a novel anionic cyclization reaction of N-aziridinylimines and explored the synthetic usefulness of the method for the formation of carbocycles, including the elegant synthesis of the tricyclic compound 61 exhibiting the quadrane natural products skeleton by a domino anionic reaction (Scheme 24).40 Upon treatment with vinyllithium, the substrate 58 underwent regioselective nucleophilic addition at the less-hindered NK


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Scheme 27. Stereodivergent Approach to Terpene-Like Molecules (μW = Microwave Irradiation)

Scheme 28. Domino Michael−Elimination−Aldolization

hydroxy diketone 66 was not studied because both stereocenters were destroyed in the subsequent steps to 67. More recently, Boddaert, Coquerel, and Rodriguez reported a protection-free stereodivergent approach for the expeditious synthesis of 3-oxa- and 3-aza-tricyclo[7.2.1.01,6]dodecane compounds related to several classes of terpene natural products based on a synergistic combination of consecutive and domino reactions. For example, the tricyclic compound 71 and its diastereomer 73 could be selectively obtained in good yield and excellent diastereoselectivity from the 2-diazo-1,3diketone 68, the homoallylic amine 69, and acrolein (Scheme 27).46 The sequence was initiated by a microwave-assisted Wolff rearrangement of 68 and trapping of the resultant α-oxoketene with the secondary amine to give the corresponding β-

catalyst containing 16 highly basic bicyclic azidophosphine moieties has also been reported by Verkade and co-workers to catalyze the same 62a → 64a (R = OMe) Michael−aldolization domino reaction (79% yield, diastereoselectivity not studied).43 Also, Kaneda and co-workers evaluated the efficiency of their reusable calcium vanadate apatite (VAp) catalyst Ca10(VO4)6(OH)2 in water with a closely related reaction in the ethyl ester series (R = OEt, 84% yield, diastereoselectivity not studied).44 Similarly, in the course of their studies toward the total synthesis of hyperforin and perforatumone, Nicolaou et al. described a related domino Michael−aldol sequence from the diketone 65 and methacrolein catalyzed by TMSOTf (Scheme 26).45 The diastereoselectivity of the reaction leading to L


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Scheme 29. Pyrrolidine-Catalyzed Domino Michael−Aldolization

Scheme 30. Domino Michael−Aldolization with Allenyl Ketone

solution of 74 and Dieckmann ester 75 afforded the bridged compound 76 as the main product in moderate yields in addition to various amounts of the corresponding Z isomer following a Michael−elimination−regioselective aldolization domino reaction. The stereoselectivity of the aldolization step has not been studied. When the same reaction mixture is heated to reflux, the regioselectivity of the aldolization step of the cascade is inverted, and the domino process is terminated by an irreversible crotonization reaction to give the dienone 77 as the major product. It was demonstrated that the kinetic product 76 could be converted into the thermodynamic product 77 under the conditions of the reaction. Unactivated cyclopentanones have also been used in domino Michael−aldolization sequences with activated acrylic derivatives. For example, the trifluoromethyl ketone 78 has been reported by Liu and co-workers to react with cyclopentanone in the presence of a catalytic amount of pyrrolidine (enamine catalysis) to afford the bridged bicyclic adduct 79 in good yield and excellent stereoselectivity (Scheme 29).49 For related enantioselective organocatalytic cascades, see section 7.2. Of course, enamines derived from cyclopentanone can be used directly as pronucleophiles. Using this strategy, Lepore and co-workers reported the stereoselective preparation of the bicyclic compound 82 from N-(cyclopenten-1-yl)morpholine 80 and allenyl methyl ketone 81 as bis-electrophile (Scheme 30).50 The E stereochemistry of 82 is likely to be established in the initial Michael−Stork addition on the less-hindered face of the allene, whereas the endo preference of the ring-closure step has been attributed to a thermodynamically favored formation

ketoamide bearing a pendant olefin, which was directly engaged in a ruthenium-catalyzed cross-metathesis reaction with acrolein in the same reaction mixture (consecutive reaction) to give the intermediate compound 70. After simple replacement of the solvent of the crude reaction mixture of 70, the expected intramolecular Michael−aldol domino reaction was promoted by addition of DBU to afford the targeted tricyclic compound 71 (59% from 68) as the only detectable diastereomer, the relative stereochemistry of which was unambiguously proven by X-ray techniques. It is remarkable that compound 71, which exhibits the 3-azatricyclo[7.2.1.01,6]dodecane framework with four controlled stereogenic centers, was obtained by a one-pot combination of a consecutive reaction and a domino reaction.47 Alternatively, when the crude reaction mixture of 70 was treated with silica gel directly after the olefin metathesis step, an acid-catalyzed intramolecular Michael addition occurred and the crude spiro δ-lactam product 72 was obtained showing an inverted relative configuration at C6 when compared to 71. The treatment of this material with DBU in methanol promoted the desired intramolecular aldolization to afford stereoselectively the tricyclic product 73 (diastereomeric ratio (dr) = 7:1), thus paving the way to a concise and stereodivergent approach to natural-product-like 3-aza-tricyclo[7.2.1.01,6]dodecane compounds. Kim et al. used Baylis−Hillman adducts as bis-electrophiles in their kinetically controlled approach to 3alkylidenebicyclo[3.2.1]octan-8-ones (Scheme 28).48 Upon treatment with K2CO3 at room temperature, an ethanolic M


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Scheme 31. Domino Michael−Aldolization with Unsaturated Fischer Carbenes

Scheme 32. Iron Pentacarbonyl-Catalyzed Domino Isomerization−Aldolization

85 after β-elimination, reductive metal elimination, and hydrolysis of the iminium ion. Alternatively, starting with unsaturated hydroxy aldehydes, Grée, Branchadell, and co-workers reported the preparation of the 4-hydroxy-bicyclo[3.2.1]octan-2-one 91 by an appealing domino isomerization−intramolecular aldolization sequence (Scheme 32).52 Interestingly, the 1,3-cis-difunctionalized cyclopentane 89 or its bicyclic lactol 90a, when treated with 5 mol% of Fe(CO)5, smoothly evolved to the expected bridged hydroxy ketone 91 as the only observed diastereomer, together with 17% of uncyclized saturated keto aldehyde intermediate. The observed diastereoselectivity was found in agreement with density functional theory (DFT) computational studies, which indicated that the Z-exo transition state is slightly favored. Alternatively, the direct C−O versus C−C rearrangement of the silyl ether 90b via a consecutive isomerization/Mukaiyama aldol sequence was also found to efficiently lead to 91 in 64% yield. Further chemical manipulations of 91 (e.g., dehydration followed by conjugated additions) were also reported.

of the endo bicyclic zwitterionic intermediate relative to its exo isomer due to a better charge stabilization. Barluenga et al. also used enamines derived from cyclopentanone in their annulation reaction but, remarkably, with Fischer alkenyl carbene complex bis-electrophiles.51 Stirring a solution of the chiral enamine 83 and tungsten carbene complexes 84 followed by trifluoroacetic acid (TFA) quenching and hydrolysis provided the optically active bicyclic products 85 in high yields and enantiomeric excesses (Scheme 31). Similar reactions can also be performed with the corresponding chromium Fischer carbene complexes and enamines derived from cyclohexanone for the synthesis of bicylo[3.3.1]nonane derivatives. From a mechanistic point of view, the reaction is believed to proceed via the Michael adduct 86, which does not undergo cyclopropanation as otherwise observed but rather undergoes a simple ring-closure to give the isolable zwitterionic intermediate 87. Upon treatment with TFA, the metalate complex 87 would undergo elimination of methanol to give the nonheteroatom-stabilized carbene 88, which would convert to N


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Scheme 33. Domino Michael−Aldolization with Pyrrole Acetates

Scheme 34. Domino Michael−Michael−Henry (DABCO = 1,4-Diazabicyclo[2.2.2]octane)

Scheme 35. α,α′-Dialkylation Approach

Finally, the first organocatalyzed three-component diastereoselective approach to highly functionalized bicyclo[3.2.1]octanols was proposed recently by He and co-workers involving the Michael−Michael−Henry cascade reaction presented in Scheme 34.54 In the presence of a catalytic amount of 1,4diazabicyclo[2.2.2]octane (DABCO), a nitromethane solution of cyclopentenone and methylenemalonitrile derivative 94 afforded the bicyclo[3.2.1]octanol 95 as a single diastereomer in good yield. Although the exact mechanism for this threecomponent annulation remains unclear, the reaction most likely proceeds by initial Michael addition of nitromethane to the methylenemalonitrile substrate 94, and the resulting stabilized anion in turn serves as nucleophile for a second Michael addition to cyclopentenone. After proton transfer, an intramolecular Henry reaction affords the bicyclic product 95.

More elaborated nucleophilic partners have been introduced recently by Dixon and co-workers during their work on the construction of perhydro indol-2-ones using a Michael−aldol strategy. The direct synthesis of the complex tricyclic compound 93 has been achieved in a one-pot process from the pyrrole acetate 92 as bis-nucleophile toward cyclopentenone (Scheme 33).53 The starting material 92 was prepared in four steps and 20% overall yield from 2methylsuccinic anhydride. Deacetylation of the pyrrole acetate 92 with a catalytic amount of methoxide anion revealed a conjugated dienolate, which, in the presence of cyclopentenone, underwent a regioselective Michael addition at C5 of the pyrrole. Under the basic conditions of the reaction, a proton transfer generated yet another conjugated dienolate, which evolved via an intramolecular aldol-type reaction to the product 93 as the only detected diastereomer. The origin of the high diastereoselectivity in the initial Michael addition remains to be determined.

3.2. Alkylation-Based and Related Cyclizations

Although the simple formation of C−C bonds using alkylation with halides or derivatives is a well-established procedure, only a few developments in the field of the construction of O


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Scheme 36. C-Alkylation of Phenol

Scheme 37. Regioselective Alkylation (LiHMDS = Lithium Bis(trimethylsilyl)amide)

Scheme 38. Domino Isomerization−Michael

In the course of synthetic studies toward the enantiomer of the natural product 2-isocyanoallopupukeanane, Banwell and co-workers reported the regioselective formation of the tricyclic compound 102 by intramolecular alkylation of the lithium enolate derived from 101 (Scheme 37).57 Unfortunately, the product 102 is the wrong regioisomer for the application of the method to the synthesis of the target compound.

bicyclo[3.2.1]octanes have been proposed in the past 13 years. Rodriguez and co-workers reported that α,α′-diactivated ketones can undergo a completely chemo- and regioselective C−C domino cycloalkylation with 1,3-allylic-dihalides (e.g., 97) or cis-configured 1,4-allylic (or benzylic) dihalides; transconfigured dihalides lead exclusively to the C−O cycloalkylation products.55 For example, the cyclopentanone derivative 96 reacted with the 1,3-bishalides 97a−c to give the 3-alkyl- (or aryl)-idene bicyclo[3.2.1]octan-8-ones 98a,b in good yields (Scheme 35). The method has found more applications for the preparation of bicyclo[4.2.1]octan-9-one derivatives due to better availability of cis-1,4-dihalides. In their total synthesis of pseudoclovene B, Mukherjee and co-workers constructed the key bicyclo[3.2.1]octane ring system of the natural product by cyclization of the bromophenol 99 obtained in seven steps from m-cresol (Scheme 36).56 Thus, treatment of 99 with potassium tbutoxide afforded regioselectively the dienone 100 exhibiting the tricyclic skeleton of the natural product. From 100, pseudoclovene B was obtained after regioselective conjugate addition with dimethyl cuprate, diastereoselective hydrogenation, and a Shapiro reaction.

3.3. Michael Addition-Based Cyclizations

Michael addition-based strategies have been used several times as a cornerstone for the construction of the bicyclo[3.2.1]octane ring system of the natural product platensimycin,7 but quite surprisingly, it has not yet been developed as a general method and only one interesting example from Jørgensen and co-workers appeared in the time frame covered by this review. It concerns the application of their organocatalytic enantioselective 1,6-conjugate addition of β-ketoesters to the construction of optically active bicyclo[3.2.1]octan-8-ones.58 Under phase-transfer conditions and in the presence of the cinchona alkaloid derivative catalyst 105, the β-ketoester 103 underwent 1,6-conjugate addition to the α,β,γ,δ-unsaturated ester 104 to afford the adduct 106 in excellent yield and good P


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Scheme 39. Application of Lansbury’s Approach

Scheme 40. Nicholas-Based Cyclizations of Cyclopentanols (CAN = Ceric Ammonium Nitrate; DCE = 1,2-Dichloroethane)

Scheme 41. Formal [4 + 3]-like Cycloaddition with Cyclopropanes

formic acid and further converted to the required stereodefined alkenes 110a,b. More interestingly, in a study on synthetic applications of the Nicholas reaction to the preparation of bridged compounds, Tyrrell et al. reported the cyclization of the enyne 111 to give the bicyclo[3.2.1]octane derivative 112 in a three-step, one-pot sequence (Scheme 40).61 Thus, the treatment of 111 with dicobalt octacarbonyl afforded the corresponding dicobalt hexacarbonyl complex. This crude material was then treated with TiBr4 to promote the formation of the cobalt-stabilized propargylic cation with a regioselective double-bond isomerization to afford the corresponding thermodynamically more stable disubstituted alkene. Then a rapid intramolecular cationic cyclization afforded the cyclized cationic product, which was trapped by a bromine anion. Finally, the crude bicyclic cobalt complex was then decomplexed under oxidative conditions with ceric ammonium nitrate (CAN) to afford 112. More recently, Jin, Himuro, and Yamamoto reported an acidcatalyzed cyclization of alkynyl cyclic tertiary alcohols via cationic acetylene intermediates to give essentially spiro- but

enantioselectivity (Scheme 38). In a separate experiment, the treatment of 106 with DBU promoted the isomerization of the double bond to restore the conjugated system, which then underwent an intramolecular Michael addition to give the corresponding bicyclic product 107 as a single diastereomer without erosion of the optical activity (no retro-1,6-conjugate addition occurred). The observed diastereoselectivity can be rationalized by the formation of the thermodynamically favored diastereomer 107 bearing the carboxymethyl substituent in the equatorial position. 3.4. Carbocation-Based Cyclizations

In this field, some important new developments have been realized starting from five-membered ring precursors since the pioneering work from Lansbury’s group in 1966.59 Very recently, Spencer et al. used this robust procedure to prepare the benzobicyclo[3.2.1]octenes 110a,b as model substrates to study carbocation−π interactions in these strained systems (Scheme 39).60 The desired ketone 109 was obtained in 64% yield from chlorovinyl indene 108 by simple treatment with Q


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Scheme 42. Brønsted Acid-Promoted Type II Carbonyl Ene Reaction

Scheme 43. Regiocontrolled Friedel−Crafts Alkylation

also bridged bicyclic compounds.62 For example, upon treatment with a catalytic amount of triflic acid, the cyclopentanol 113 was converted into the bicyclo[3.2.1]octane derivative 114 in good yield but with low diastereoselectivity. Both these carbocation-based reactions have been used also to construct the bicyclo[3.2.1]octane ring system from cyclohexane precursors (see section 4.5). A very recent contribution from Melnikov and collaborators introduced 2-(heteroaryl)cyclopropane-1,1-dicarboxylates as successful electrophiles toward cyclopentadiene that led to fused heteroaromatic bicyclo[3.2.1]octenes via a formal [4 + 3]-like cycloaddition.63 Like this, a series of bicyclic products 117 could be obtained by treatment of the corresponding cyclopropane substrates 115 with tin or ytterbium triflate in the presence of excess cyclopentadiene (Scheme 41). The reaction proceeds via initial nucleophilic addition of cyclopentadiene to the Lewis acid-activated cyclopropane to generate the zwitterionic cyclopentenyl intermediates 116, which then undergo cyclization with the nucleophilic heterocycle. Also of synthetic interest is the simple cationic type II carbonyl ene reaction as proposed by Srikrishna et al. as a key step for the preparation of the optically active bicyclo[3.2.1]octan-2-ol 119 from the cyclopentenyl enol ether 118 derived from α-pinene (Scheme 42).64 Finally, in their chemoselective approach to resveratrol-based natural products, Snyder et al. have converted the permethy-

lated analogue of ampelopsin D (120) into ampelopsin F by means of an elegantly regiocontrolled Friedel−Crafts alkylation promoted by bromine (Scheme 43).65a,b Initial halogenation of 120 provided the cationic quinone methide intermediate 121 that underwent the key Friedel−Crafts alkylation to give the ampelopsin F analogue 122 showing the bicyclo[3.2.1]octane ring system. A further radical-mediated dehalogenation followed by a deprotection step afforded the natural product. More recently, the same group reported a complementary strategy for the preparation of heimiol A, hopeahainol D, and constrained analogues.65c 3.5. Radical-Based Cyclizations

Radical-based strategies from 5-membered ring precursors have become very popular as key steps for the construction of the bicyclo[3.2.1]octane ring system of the natural product platensimycin, and only the work not covered in the previous reviews is highlighted here.7 Among these, Canesi and coworkers prepared Nicolaou’s intermediate aldehyde 123 as a mixture of regioisomers by a synthetic sequence including a domino Prins-pinacol rearrangement. 66 Nicolaou et al. previously demonstrated that both regioisomers of aldehyde 123 could be converted into the regioisomeric advanced tricyclic intermediates 124, both of which were useful for the total synthesis of platensimycin.67 Accordingly, the treatment of 123 with samarium iodide under the reported conditions R


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Scheme 44. Reductive Coupling of Enone (HFIP = Hexafluoro-2-propanol; HMPA = Hexamethylphosphoramide)

Scheme 45. Reductive Coupling of Allylic Acetate (DME = 1,2-Dimethoxyethane)

Scheme 46. Radical Xanthate Transfer Process

Scheme 47. Electrochemical Cyclizations

S


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Scheme 48. Oxidative Radical Cyclization and Functionalization

Scheme 49. Palladium-Catalyzed α,α′-Dialkylation

provided the reduced cyclized product 124 incorporating the key bicyclo[3.2.1] skeleton (Scheme 44). As an extension of their enantioselective catalytic Michael addition using La-linked-BINOL complex,68 Shibasaki and coworkers reported the challenging highly enantioselective Michael additions of α-substituted malonates and applied the method to the construction of optically active bicyclic compounds.69 The reactivity of the catalytic system was optimized by concentration effect and addition of HFIP (1,1,1,3,3,3-hexafluoro-2-propanol), which may facilitate the dissociation of the product from the La complex acting as a proton source. Thus, the reaction between cyclopentenone and the malonate derivative 125 under the optimized conditions provided the Michael adduct 126 in high yield and enantioselectivity (Scheme 45). The latter was then converted to the bicyclo[3.2.1]octane derivative 127 by a samarium iodide-mediated reductive cyclization, providing a two-step only efficient approach to this ring system in optically active form.

Pursuing their efforts to develop a unified strategy for the transmission of the chiral information using xanthates, Zard and co-workers have recently reported the regio- and stereoselective radical-mediated cyclization of 128 to afford the bicyclo[3.2.1]octane derivative 129 with a moderate diastereoselectivity (Scheme 46).70 Besides these reductive transformations, either electrochemical or chemical oxidative approaches have also found recent interesting applications starting from relatively simple substrates. In 2001, following their efforts to use intramolecular anodic olefin coupling reactions for building the bicyclo[3.2.1]octane ring system, Moeller and co-workers reported the preparation of compounds 131a,b and 133 from the precursors 130a,b and 132, respectively (Scheme 47).71 Thus, precursors 130a,b and 132 were oxidized at a reticulated vitreous carbon (RVC) anode using a platinum wire cathode in an undivided cell containing a lithium perchlorate solution in MeOH/ tetrahydrofuran (THF) and 2,6-lutidine as a proton scavenger. Although the cyclization of 130a was lacking stereoselectivity, the presence of a gem-diester group in 130b introduced a 1,3T


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Scheme 50. Heck-Type Cyclizations (DPPP = 1,3-Bis(diphenylphosphino)propane)

Scheme 51. Rhodium-Promoted Intramolecular Carbonylation

Scheme 52. Copper-Catalyzed Intramolecular Arene Cyclopropanation (hfacac = Hexafluoroacetylacetonate)

cloalkenes 138 to give the corresponding bridged exomethylene ketones 139.73b Following this new palladium-catalyzed method, Muratake’s group synthesized the benzobicyclo[3.2.1]octanone 141 by a palladium-catalyzed intramolecular α-arylation of the cyclopentanone 140 (Scheme 50).74 More recently, in a synthetic study toward designed nicotine receptor molecules, Coe and co-workers used an intramolecular Heck reaction from triflates 142 for the preparation of the pyridobicyclo[3.2.1]octenes 143a,b and other related compounds (Scheme 50).75 An asymmetric version of this reaction was also reported (see section 7.2). Other well-known organometallic catalysts have found interesting new developments in the synthesis of complex intermediates incorporating the bicyclo[3.2.1]octane core. Among them, Biju and Rao revealed a novel Wilkinson’s catalyst-mediated carbon−carbon bond-forming reaction and applied it to the synthesis of the tricyclo[4.2.1.13,9]nonane derivative 146 (containing the bicyclo[3.2.1] ring system) from the keto-aldehyde 144 (Scheme 51).76 The authors invoke the formation of the acyl rhodium hydride complex 145, which undergoes intramolecular hydride migration from the substrate

diaxial constraint in the six-membered transition state, which forced the enol ether substituent into the equatorial position. To differentiate chemically the two acetals produced in the reaction, a similar reaction was performed with substrate 132 bearing a dithioacetal moiety to give the desired product, 133, in similar yield. Alternatively, in their study on the termination of Mn(III)mediated oxidative cyclizations with azide anion, Snider and Duvall reported, among others, the synthesis of the azidecontaining diastereomeric bicyclo[3.2.1]octane products 134a,b in relatively low yields together with the corresponding reduction product 134c (Scheme 48).21 3.6. Transition Metal-Mediated Cyclizations

In this field, important developments have been made to propose relatively general catalytic approaches or more specific transformations involved in some total syntheses of natural products.72 For example, Buono and Tenaglia prepared a series of bicyclo[3.2.1]octandiones 137a,b via a palladium-catalyzed C,C-dialkylative cyclization of the 2-alkyl-1,3-diketones 135a,b with allylic diacetate or dicarbonate 136 (Scheme 49).73a A similar reaction was also performed with the 1-pyrrolidinocyU


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Scheme 53. Ring-Closing Metathesis Approach

Scheme 54. [4 + 3]-Cycloaddition Approach (TFE = 2,2,2-Trifluoroethanol)

3.7. Cycloadditions, Electrocyclizations, and Cycloisomerizations

to the rhodium atom and migration of the carbon−rhodium bond to generate the corresponding 1,3-diketone 146. An alternative mechanism involving a rhodium(I)-catalyzed reversible aldol condensation followed by dehydrogenation of the resulting alcohol could not be ruled out. Surprisingly, there has been only one carbenoid-based cyclization of a cyclopentanic precursor described for the synthesis of a bicyclo[3.2.1]octane moiety embedded in a more complex ring system. Reisman and co-workers have described a copper-catalyzed intramolecular arene cyclopropanation from the diazo compound 147 to give the advanced synthetic precursor 148 in the total synthesis of (+)-salvileucalin B (Scheme 52).77 Finally, a ring-closing metathesis-based strategy pioneered by Mehta and Kumaran78 was set up by Srikrishna et al. to construct the tricyclic ring system of the natural product tricycloillicinone in its optically active form.79 When treated with a catalytic amount of Grubbs’ catalyst, the bicyclic triene 149 derived from (S)-campholenaldehyde afforded the corresponding tricyclic olefin 150 in good yield (Scheme 53).

One of the popular strategies for the preparation of bicyclo[3.2.1]octane derivatives has relied on the 6π−7C-[4 + 3]-cycloadditions between cyclopentadienes and oxyallyl cations.80 In this field, Harmata and co-workers have studied the [4 + 3]-cycloaddition of cyclopentenyl oxyallylic cations derived from 2,2-dichloro- or 2,5-dibromocyclopentanone with dienes.81 These reactions easily afforded the tri- and tetracyclic products 151a−c in a one-pot procedure with synthetically valuable yields (Scheme 54). For the preparation of 151a, the required 2,2-dichlorocyclopentanone substrate was obtained in situ by regioselective chlorination of its 2-chloro analogue with LiHMDS and triflyl chloride. Upon reaction with cyclopentadiene in the presence of triethylamine, the [4 + 3]cycloadduct 151a could be obtained in 50% yield. The reaction of 2,5-dibromocyclopentanone under similar conditions provided the [4 + 3]-cycloadduct 151b in better yield. Yet another example of this reactivity allowed the preparation of the tetracyclic adducts 151c from the corresponding fused bicyclic 2,2-dichlorocyclopentanones.82 The latter compounds have V


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Scheme 55. Synthesis of Sodorifen (155a)

Scheme 56. Oxyallyl Cation Surrogates

Scheme 57. Domino [4 + 2]-Rearrangement with 2-Substituted Acroleins

permethylated volatile, naturally occurring compound isolated from Serratia odorifera exhibiting a unique carbon skeleton as reported recently by Francke and co-workers.86 Starting from commercially available pentamethylcyclopentadiene and 2,4dibromopentan-3-one using the sodium iodide/copper route described by Hoffmann,87 the [4 + 3]-adducts 154a,b could be obtained in good overall yield with moderate endo/exo selectivity (Scheme 55). Each cycloadduct was then olefinated with the Tebbe’s reagent [(C5H5)2TiCH2ClAl(CH3)2] to afford the natural product 155a and its unnatural diastereomer 155b, respectively. Alternatively, the 3-oxidopyridinium betaine 156,88 the oxyvinyliminium ions 157 generated by decomposition of αamino-α′-fluoro-ketones,89 and the chiral allene oxides 15890

found some applications for the synthesis of the spatane ring system (see section 8.5). In related work, Handy and Okello generated the oxyallyl cation intermediate from α-tosyloxyketones,83 and Montaña and Grima proposed to generate the same intermediate from α,α′-diiodoketones by reduction with the Zn/Cu couple.84 Also, Cha and co-workers developed a highly diastereoselective version of the reaction using cyclic oxyallyl cations bearing a β-alkoxy substituent such as 152, leading to 153.85 In this version of the reaction, the face differentiation of the oxyallylic cation is attributed either to intramolecular hydrogen bonding in the cation resulting in a rigidification of its structure or simply to dipole repulsion in the cation resulting in a preferred conformation of it. This [4 + 3]-cycloaddition reaction has found an application in the straightforward synthesis of sodorifen (155a), a W


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Scheme 58. [6 + 4]-Cycloaddition of Tropone Derivatives

Scheme 59. Gold-Catalyzed Cycloisomerization

tion of the silyl enol ether 164 to give the bicyclic product 166 with the phosphino gold(I) catalyst 165 (Scheme 59).98 The method was found to be applicable from 5- to 8-membered cyclic enol ethers.

were used as oxyallyl cation surrogates in related [4 + 3]cycloadditions with cyclopentadiene (Scheme 56). Following the pioneering work of Sasaki et al.,91 another [4 + 3]-cycloaddition-based route to bicyclo[3.2.1]octane derivatives has been further explored involving the Lewis acid-mediated reaction between acroleins and cyclopentadiene.92 The archetypal cycloadditions of 2-methylacrolein93 and 2-silyloxyacrolein94 with cyclopentadiene have now been investigated through DFT calculations.95 From this study, it was concluded that, in agreement with Davies's proposal,96 the formation of the formal [4 + 3]-cycloadduct 161a proceeded via an initial reversible polar Diels−Alder reaction (free activation barrier of ca. 20 kcal/mol) to give 159a, followed by a Lewis acid-assisted skeletal rearrangement to the zwitterionic ring-expanded intermediate 160a, which underwent a rapid intramolecular hydride shift to yield irreversibly the product 161a (Scheme 57). A two-step sequence consisting of an enantioselective [4 + 2]-cycloaddition step with a chiral Lewis acid followed by ring rearrangement promoted by AlCl3 allowed the preparation of 161a in enantioenriched form.91,94 A similar transformation with 2-triisopropylsilyloxy acrolein catalyzed by Sc(OTf)3 allowed the direct formation of α-hydroxy-bridged ketone 161b via the bicyclo[2.2.1]hexene 159b.92 According to our categorization of the approaches to bicyclo[3.2.1]octane derivatives, this section may have been better placed in section 6.3, but we have decided to place it here for better comparison with other [4 + 3]-cycloadditions. The higher-order [6 + 4]-cycloaddition between silyloxycyclopentadienes and tropone derivatives 162 is quite efficient and allows the synthesis of tricyclo[4.4.1.12,5]dodecane derivatives 163, thus incorporating a bicyclo[3.2.1]octane subunit (Scheme 58). This strategy was used by Gleason and co-workers in their approach to the important CP class of natural products.97 Finally, in a recent synthetic study on the preparation of bicyclo[m.3.1]alkanone under gold-catalysis conditions, Barriault and co-workers reported the 6-endo-dig cycloisomeriza-

4. BICYLO[3.2.1] RING SYSTEM FROM SIX-MEMBERED RINGS The cyclization of properly functionalized six-membered ring precursors to form the two-carbon bridge of the bicyclo[3.2.1] core is probably one of the most popular approaches, and many new developments have been proposed. This includes improvement of traditional transformations or discovery of innovative processes with high synthetic impact, both of which will be presented in the following section according to our general classification. 4.1. Carbonyl-Type Condensations and Related Cyclizations

Aldolization and related reactions have commonly been used to prepare the bicyclo[3.2.1] ring system from cyclohexane derivatives. For example, in 1999, Piers et al. reported the acid-catalyzed regioselective aldolization of the triketone 167 to give the complex tricyclic product 168 (thermodynamic product) incorporating the bicyclo[3.2.1]octane framework in very good yields (Scheme 60).99 Scheme 60. Intramolecular Aldolization of Ketones

X


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Scheme 61. Intramolecular Aldolization of Aldehydes

Scheme 62. Copper-Assisted Domino Michael−Aldol

preparation of the tetracyclic products 172 from 171,101 and more recently, Hagiwara et al. completed the total synthesis of (−)-drechslerine A involving the intramolecular aldolization of 173, derived from (S)-carvone, to give the advanced synthetic intermediate 174.102 Also, Hong and co-workers have described recently a NHC-catalyzed intramolecular domino Michael−

More recently, in their approach to kopsifoline alkaloids, Padwa and co-workers proposed to complete the construction of the CF domain of the hexacyclic core of the natural products via an intramolecular Mukaiyama aldol-type reaction of the silyl enol ether 169 to give the product 170 (Scheme 61).100 In analogous transformations, Marcos et al. reported the Y


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Scheme 63. Organolithium-Promoted Cyclizations of N-Aziridinylimines

Scheme 64. Intramolecular Alkylation of Six-Membered Ring Ketones (LDA = Lithium Diisopropylamide)

Scheme 65. Intramolecular Alkylation of Phenol (TBAF = Tetra-n-butylammonium Fluoride)

compound 182 exhibits the ring system of cedrane sesquiterpenes and was converted into cedrone by removal of the acetal group.

aldol sequence from the precursor 175 to give the tricyclic product 176 in good yield and diastereoselectivity.103 An elegant Michael−aldol domino sequence was imagined by Ryu et al. using cyclohexenone as a bis-electrophile in a copperassisted transformation for the preparation of bicyclo[3.2.1]octanes 180 (Scheme 62).104 On treatment with butyllithium, the sterically hindered β-stannylketone 177 was converted into the corresponding β-lithioenolate (a ketone α,β-dianion), which was then allowed to react with a copper salt to give the corresponding cuprate. The reaction of this cuprate with cyclohexenone provided the product 180. In a deuteriumlabeled experiment, the product d1-180 showed a highly diastereoselective deuterium incorporation as depicted in Scheme 62. The reaction most probably begins with a conjugate addition to give 178, which further reacts by an intramolecular aldol reaction to give the chelated intermediate 179, precursor of d1-180. Applying the chemistry of N-aziridinylimines highlighted previously (see section 3.1), Kim and Hwang reported the stereoselective synthesis of compound 182 from the sixmembered precursor 181 (Scheme 63).105 The tricyclic

4.2. Alkylation-Based Cyclizations

In 2000, during their total synthesis of nudenoic acid, Ho and Su obtained the tricyclo[7.2.1.01,6]dodecanone 184, a precursor of the natural product, by simple alkylation of the kinetic lithium enolate of tosylate 183 (Scheme 64).106 In related examples, Parker, Jr., et al. reported the preparation of compounds 186a,b by intramolecular alkylation of the fluorides 185a,b in the presence of lithium chloride, presumably via the corresponding chloride.107 Finally, two recent formal syntheses of (−)-platensimycin have been reported using similar alkylative dearomatization reactions for the construction of the tetracyclic core of the natural product. On the one hand, Eey and Lear treated the phenol 187 with TBAF (other bases gave poor conversions) to get 188,108 and on the other hand, Ito and co-workers treated the phenol 189 with tBuOK to get 190 (Scheme 65).109 Z


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Scheme 66. Acid-Catalyzed Michael Addition

Scheme 67. Michael Addition to Nitroso Compound (NaHMDS = Sodium Bis(trimethylsilyl)amide)

Scheme 68. Domino Michael−Michael Addition of 3-Nitropropionate Dianion (TMEDA = Tetramethylethylenediamine)

4.3. Michael-Based Cyclizations

compounds for the synthesis of bridged and fused bicyclic systems.111 For example, the malonate 193 was deprotonated with NaHMDS, and addition of TBAF led to the formation of the intermediate vinylnitroso anion 194, which underwent an intramolecular Michael addition to give the bicyclo[3.2.1]octane product 195 (Scheme 67). Under analogous conditions, the sulfone 196 gave stereoselectively the bicyclic product 197 as a single diastereomer.

The total synthesis of (−)-platensimycin has attracted a lot of attention,7 and a recent formal synthesis was proposed by Hirai and Nakada. The key precursor 192 containing the tricyclic carbon skeleton of the core of the natural product was efficiently obtained by an intramolecular acid-catalyzed Michael addition of enone 191 in very high yield (Scheme 66).110 Weinreb and co-workers reported some interesting intramolecular Michael reactions of in situ-generated vinylnitroso AA


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Scheme 69. Oxidative Coupling of Bisanthraquinones

Scheme 70. Domino Arene Cyclopropanation−Fragmentation (TFA = Trifluoroacetic Acid)

excess of triethylamine, 201 could undergo a double Michael addition to give 202. A further oxidation step with MnO2 provided compound 203 exhibiting the skyrane ring system. Remarkably, the overall cascade of reactions 200 → 201 → 202 → 203 could be performed as a beautiful domino reaction in quantitative yield solely promoted by a prolonged treatment of 200 with freshly prepared MnO2, which contains mild basic species. The application of this chemistry has led to the asymmetric total syntheses of 2,2′-epi-cytoskyrin A, rugulosin, and a simplified analogue of rugulin.

The double-conjugate addition is also particularly powerful from a synthetic point of view and was involved in a recent formal synthesis of gelsemine by Grecian and Aubé.112 The strategy is based on the formation of the lithium dianion of ethyl 3-nitropropionate, which adds smoothly to p-benzoquinone monodimethyl acetal to afford the diastereomeric mixture of bicyclo[3.2.1]octanones 198 (Scheme 68). This mixture of diastereomers was converted efficiently to the unsaturated ester 199, which was transformed into a previously described intermediate in Fukuyama’s total synthesis of gelsemine.8 Concomitantly with Snider and Gao,113 Nicolaou et al. described in a series of papers their approach to a class of natural products often referred to as bisanthraquinones.114 Depending on their molecular architecture, these molecules can exhibit up to four interlinked bicyclo[3.2.1]octane moieties, as found, for example, in rugulin (see Figure 1) and in compound 203 (Scheme 69). The strained cagelike core highlighted in red in compound 203 has been coined “skyrane” by the authors. They discovered that the dimeric quinone 200 could be oxidized to the corresponding bisanthraquinone 201 by treatment with MnO2 and also that, in the presence of an

4.4. Carbenoid-Based Cyclizations

Mander’s intramolecular ipso-alkylation of aryl moieties via αdiazonium intermediates115 has found applications in some total syntheses of the natural product platensimycin,7 as illustrated again recently by the groups of Mulzer and Pfaltz, who prepared the previously described tricyclic compound 205 by acidic treatment of the highly enantioenriched αdiazoketone precursor 204 obtained by enantioselective iridium-catalyzed hydrogenation of the corresponding unsaturated methyl ester (Scheme 70).116 AB


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Scheme 71. Cyclopropanation−Fragmentation Sequence

Scheme 72. Rhodium Carbenoid C−H Insertion

Scheme 73. Rhodium Carbenoid C−H Insertion (acam = Acetamidate)

Srikrishna and Gharpure described the cyclopropanation reaction of the α-diazoketone 206 derived from (−)-carvone to give the tetracyclic product 207, the reductive fragmentation of which afforded the precursor of (−)-4-thiocyanatoneopupukeanane 208, a natural product with a isotwistane (tricyclo[4.3.1.03,7]decane) ring system (Scheme 71).117 In a related series of papers, the same group reported on the application of the rhodium carbenoid C−H intramolecular insertion reaction of α-diazoketones toward cyclopentane derivatives for the total synthesis of the pupukeanane class of sesquiterpenoids.118 Representative of this approach for the formation of a bicyclo[3.2.1] nucleus is the regioselective conversion of the α-diazoketone 209 derived from (−)-carvone to the tricyclic diketone 210 by treatment with rhodium trifluoroacetate, which was then converted into (−)-2pupukeanone (Scheme 72). Wood and co-workers studied a similar approach to the isotwistane skeleton (i.e., a tricyclo[4.3.1.03,7]decane as in 210) based on a rhodium carbenoid C− H insertion reaction in their approach to the CP molecules (phomoidrides A and B).119

In the course of a synthetic study toward other terpenoids, Magnus et al. reported the synthesis of the bicyclo[3.2.1]octan6-one 212 by a rhodium-catalyzed C−H insertion reaction from the bicyclic α-diazoketone 211 (Scheme 73).120 In an analogous manner, in their total synthesis of (+)-codeine (the non-natural enantiomer of codeine), White et al. also used a rhodium carbenoid insertion reaction for the regioselective preparation of the advanced intermediate 214 from the diazo compound 213 catalyzed by dirhodium(II) tetrakisacetamide.121 4.5. Carbocation-Based Cyclizations

The above-mentioned carbocation-based methodologies from the groups of Tyrrell61 and Jin/Yamamoto62 (Scheme 40, section 3.4) were also successfully employed from sixmembered ring precursors. The Nicholas reaction-based cyclization of Tyrrell afforded the bicyclic product 216 from the propargylic alcohol 215, whereas the triflic acid-catalyzed cyclization of the alkynyl tertiary alcohol 217 furnished 218 stereoselectively under the conditions of Jin and Yamamoto (Scheme 74). AC


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Scheme 74. Nicholas Reaction-Based Cyclizations of Cyclohexanols (DCE = 1,2-Dichloroethane)

Scheme 75. Type II Prins Cyclization

Scheme 76. Allylsilane-Mediated Cyclization

illustrated in Scheme 77, the α-thioketone 224 underwent a Pummerer reaction to provide regioselectively the bicyclo[2.2.2]octanone 225. In sharp contrast, the transformation of the corresponding allylsilane 226 provided selectively the bicyclo[3.2.1]octanone 227 in good yield. However, the allyl silane moiety was not needed for the regioselective conversion of the conformationally constraint substrate 228 into 229 under related conditions.124 The acid-catalyzed rearrangement of hydrobenzofuranoid neolignans into bicyclo[3.2.1]octanoid neolignans discovered by Gottlieb and co-workers (C- versus O-alkylation), has been exploited by Pan and co-workers for the total syntheses of the naturally occurring bicyclo[3.2.1]octanoid neolignans kadsurenins C and L. The strategy relies on the steroselective reduction of the 8-oxo-bicyclo[3.2.1]octanone 231 obtained by the acid-catalyzed rearrangement of 230 (Scheme 78).125 Closely related syntheses of the natrural bicyclo[3.2.1]octanoid neolignans cinerins A−C were reported more recently by Coy, Cuca, and Sefkow.126 Finally, in their biomimetic total synthesis of the neolignan helisorin, Snyder and Kontes have performed the final cyclization step of the precursor 232 by an intramolecular Friedel−Crafts reaction followed by removal of the protecting

The first example of a type II Prins reaction for the ringclosing of the two-carbon bridge in a bicyclo[3.2.1]octane was proposed in 2003 by Burton and co-workers during the synthesis of some progesterone analogues. Treatment of the unsaturated aldehyde 219 with an excess of TiCl4 promoted the cationic cyclization with concomitant trapping of the carbocation intermediate to give the chlorinated bridged product 220 in moderate yield (Scheme 75).122 Allylsilanes constitute particularly powerful nucleophiles in many electrophilic additions to carbonyl compounds and have been exploited in a series of papers by Pulido and co-workers for stereoselective carbocyclizations.123 Depending on the ability of a hydrogen atom β to the carbonyl group to be removed in an ene-type process, two reactivity patterns were observed: ene-type reactions without loss of the silyl group or allylsilane-mediated cyclization as illustrated in Scheme 76. Thus, upon treatment with EtAlCl2, ketoallylsilane 221 was converted into the corresponding bridgehead alcohol 223, probably involving the β-silyl-stabilized carbocation 222. Alternatively, allylsilanes have been used by Magnus et al. to control the regioselectivity of the Pummerer reaction in a synthetic study on complex diterpenoids such as irroratin including a bicyclo[3.2.1]octanone.120 For example, as AD


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Scheme 77. Pummerer-Based Cyclizations (NCS = N-Chlorosuccinimide)

Scheme 78. Acid-Catalyzed Rearrangement of Hydrobenzofuranoid Neolignans

p-CF3-benzylether groups to afford the natural product (Scheme 79).127

enyne 233 by a selective 5-exo-dig cyclization process (Scheme 80).129 The compound 234 was then transformed into an advanced known intermediate in the total synthesis gibberellin A12. Laxmisha and Rao reported a related tin hydride-mediated 5-exo-dig cyclization.130 In the course of a synthetic study toward polyquinane terpenoids, Biju and Rao reported the 5exo-trig allyl radical cyclization of the bromo enone 235 (already containing a bicyclo[3.2.1]octane ring system) with trin-butyltin hydride under the standard reaction conditions to afford the tricyclic product 236 containing two distinct interlinked bicyclo[3.2.1]octane moieties.131


Radical cyclizations of cyclohexane derivatives is a frequently encountered strategy to synthesize bicyclo[3.2.1]octane derivatives, as exemplified in several total syntheses of platensimycin7 and a recent synthetic approach of pierisformaside C.128 In a study on radical cyclizations of cyclic enynes, Toyota, Yokota, and Ihara reported the regiocontrolled formation of the bicyclo[3.2.1]octane derivative 234 from AE


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Scheme 79. Friedel−Crafts-Type Alkylation (TfBn = 4-Trifluoromethylbenzyl, brsm = Based on Recovered Staring Material)

Scheme 80. Tin Hydride-Mediated Radical Cyclizations

phomoidride A (CP-263,114), Takemoto and co-workers used a similar radical-based cyclization for the preparation of a related isotwistane derivative intermediate, the selective fragmentation of which afforded the ring system of the natural product (see section 8.1).133 Following their efforts to perform reactions of organotin hydrides with a catalytic amount of tin, Terstiege and Maleczka reported in 1999 that the combination of catalytic nBu3SnCl, polymethylhydrosiloxane (PMHS), and aqueous potassium fluoride was performing well in model tin hydride-mediated reactions and could be recycled as exemplified by the stereoselective cyclization of the bromo enone 239 to the simple bicyclo[3.2.1]octanone 240 (Scheme 82).134 In their total synthesis of (+)-acanthodoral, Zhang and Koreeda employed a nonreductive regioselective acyl radical cyclization reaction for the synthesis of the advanced intermediate 242 with a bicyclo[3.2.1]octane framework from the seleno ester 241 (Scheme 83).135 The natural product was

Contemporaneously, Singh et al. proposed a closely related strategy in a stereoselective route to the isotwistane ring system.132 Thus, the reaction of 237 with nBu3SnH in the presence of AIBN in refluxing benzene furnished mainly the tricyclic compound 238, which exhibits the tricyclo[4.3.1.03,7]decane (isotwistane) framework of pupukeanane sesquiterpenes (Scheme 81). In their approach to the natural product Scheme 81. Radical Route to the Isotwistane Ring System

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distinct tricyclic intermediates with the isotwistane skeleton using different SmI2-mediated reductive cyclizations.142 Early in the synthesis, they have prepared intermediate 254 by reaction of the keto allyl chloride 253 with SmI2 and HMPA, and at a more advanced stage, they have obtained intermediate 256 from the keto tosylate 255 under similar conditions (Scheme 86). In subsequent reports, the same group related the cyclization of precursor 257 using a samarium-mediated pinacol coupling reaction to afford 258.143 A few years later, some unexpected reactivities of the SmI2promoted radical reactions were exploited for the selective formation of elaborated bicyclo[3.2.1]octane skeletons. Like this, Kilburn and co-workers discovered that the treatment of cyclic enones with SmI2 in THF/MeOH led to dimeric tricyclic products in a single step.144 For example, the reaction with cyclohexenone provided the product 259 by initial reduction and conjugate addition followed by protonation and aldol condensation (Scheme 87). Other cyclization patterns were observed depending on the enone substrate. Alternatively, Matsuda and co-workers reported a complete reversal of diastereoselectivity in SmI2-mediated reductive cyclizations of the hydroxy- and acetoxy-unsaturated ketones 260a,b, leading selectively to 261a,b in comparable yields (Scheme 88).145 These results were explained by assuming a different chelation control model in each case. More recently, in their recent total synthesis of the galbulimima alkaloid GB-13, Ma and co-workers achieved the construction of the pentacyclic skeleton of the natural product by a samarium-mediated cyclization leading to bicyclo[3.2.1]octane core.146 The expected reductive coupling of the advanced intermediate enone 262 could be performed with SmI2 in refluxing THF in the absence of any additives (HMPA, MeOH, and tBuOH were deleterious to the reaction) to give the corresponding pentacyclic hydroxy ketone 263, a synthetic precursor of the natural product (Scheme 89). In 2008, Chen and co-workers reported the interesting single example of radical cyclization involving in situ-formed lowvalent titanium reagent (TiCl4/Zn). They proposed an elegant enantioselective two-step synthesis of highly functionalized bicyclo[3.2.1]octane 265 from enantiomerically enriched dicyano decalone 264 obtained by an organocatalytic Michael−Michael domino reaction catalyzed by a primary amine catalyst derived from cinchona alkaloid (Scheme 90).147 The final cyclization proceeded smoothly at room temperature in 45% yield. Oxidative radical cyclizations have been much less used than their reductive counterparts for the preparation of the bicyclo[3.2.1]octane system from six-membered rings. Among these, Rawal and co-workers reported the total syntheses of some elisabethane diterpenes including the stereocontrolled synthesis of elisapterosin B via a biomimetic oxidative

Scheme 82. Radical Cyclization with a Catalytic Amount of Tin (PMHS = Polymethylhydrosiloxane)

then obtained from 242 in a few steps including a ringcontraction reaction (see section 8.5). Photochemically induced radical cyclizations have also been studied for the preparation of bicyclo[3.2.1]octane-containing molecules. For example, Nair et al. reported that, upon simple exposure to sunlight, the dibromo tricyclic compound 243 rearranged into the tetracyclic product 244 (Scheme 84).136 The reaction can be explained by initial photolytic cleavage of the allylic C−Br bond followed by radical reorganization and a final bromine radical capture. In another example, Wessig used a stereoselective photochemical cyclization of phenyl ketones 245 to prepare the chimerical amino acids containing the bicyclo[3.2.1]octane skeleton 247 via the diradical 246 (Scheme 84).137 The stereoselectivity of the reaction has been explained by the different stabilities of the triplet biradical conformers. More recently, Danishefsky and co-workers reported optimized reaction conditions for the photochemical rearrangement of illicinone A into tricycloillicinone.138 Radical cascade approaches to polycyclic compounds are widely used in modern organic chemistry directed to the selective construction of complex scaffolds or to the total synthesis of natural products.139 Of course, this elegant strategy has also found some interesting applications in the elaboration of functionalized bicyclo[3.2.1]octane frameworks from sixmembered cyclic precursors. For example, in 2001, Zhang and Pugh reported the preparation of the bridged spirolactones 250a,b via a double-radical cyclization of allyl-substituted enol ester radicals (Scheme 85).140 Indeed, upon reaction with (TMS)3SiH in the presence of AIBN, the brominated substrates 248a,b were converted to the corresponding enol ester radicals evolving via an intramolecular Michael addition leading to the spirolactone-containing stabilized radicals 249a,b, which, in turn, underwent 5-exo-trig cyclizations onto the alkene to give the bridged products 250a,b. In a related radical cascade reaction, Zhang et al. reported the synthesis of 252a,b from the iodo dienones 251a,b under similar conditions.141 In their approach to the bicyclo[4.3.1]decane ring system of the CP molecule natural product CP-263,114 (see section 8.1), Yoshimitsu, Yanagiya, and Nagaoka have synthesized two Scheme 83. Intramolecular Radical Acylation

AG


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Scheme 84. Photochemical Radical Cyclizations

Scheme 85. Silyl Hydride-Promoted Radical Cyclizations

AH


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Scheme 86. SmI2-Promoted Reductive Coupling of Carbonyls

Scheme 87. SmI2-Promoted Dimerization of Cyclohexenone

cyclization of an elisabethin precursor.148 The tricyclic compound 266, which actually corresponds to O-methyl-2epi-ent-elisabethin A, was successfully converted into the tetracyclic natural product elisapterosin B by simple treatment with cerium(IV) ammoniun nitrate (CAN) followed by treatment with base (Scheme 91). The reaction proceeds by the regioselective addition of the initially formed, stabilized radical 267 to the alkene to generate the tertiary alkyl radical 268, which is then oxidized by a second equivalent of CAN to the corresponding cation 269, a precursor of the product. More recently, in their biomimetic approach to the polyprenylated polycyclic acylphloroglucinol (PPAP) ialibinones A and B, Simpkins and Weller149 and the group of George150 reported simultaneously the use of an oxidative freeradical cascade cyclization of the acylphloroglucinol precursor 270 to prepare the natural products (Scheme 92). Thus, upon treatment with either manganese(III) acetate (Simpkins and

Scheme 88. Reversal of Diastereoselectivity in SmI2Mediated Reductive Cyclizations

Scheme 89. SmI2-Mediated Reductive Coupling toward (−)-GB-13

AI


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Scheme 90. Radical Cyclization with Low-Valent Titanium Reagent

Scheme 91. Oxidative Cyclization for the Synthesis of Elisapterosin B (CAN = Cerium(IV) Ammonium Nitrate)

Scheme 92. Oxidative Cyclization for the Synthesis of Ialibinones A and B

groups obtained the mixture of the two diastereomeric natural products in similar proportions, but the reaction conditions developed by George et al. were found to be more efficient (a CAN-mediated oxidative cyclization was also tested).

Weller) or phenyliodine diacetate (George et al.), 270 underwent oxidation to the α-keto radical 271 that then underwent two successive 5-exo-trig cyclizations to give the tertiary radical 272, followed by oxidation to the corresponding cation and loss of a proton to give the final products. The two AJ


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Scheme 93. Palladium-Catalyzed C−C versus C−O Cycloisomerizations (dppe =1,2-Bis(diphenylphosphino)ethane)

Scheme 94. Palladium-Catalyzed Cycloalkenylations

then cyclized by nucleophilic addition of the carbon atom of the enolate onto the π-allyl palladium complex to give 274 and 276 in good yields, respectively (Scheme 93). The reaction is nicely regioselective as the formation of seven-membered rings was not observed, and the sometimes low diastereoselectivity can be explained by π−σ−π isomerization of the π-allyl palladium complex. This reaction is related to the C−C versus C−O dialkylation reaction of Rodriguez and co-workers presented in section 3.2. A sulfoximine analogue of sulfones 275 did not undergo the same C−O to C−C rearrangement under similar reaction conditions [Pd(dppe)2, dimethyl sulfoxide (DMSO), 70 °C, 6 h].154 Contemporaneously, in a work on the total synthesis of the rearranged kaurane diterpene methyl atis-16-en-19-oate, Toyota, Ihara and co-workers reported an efficient palladium(II)-catalyzed cycloalkenylation reaction for the construction of functionalized bicyclo[3.2.1]octane compounds.155 The optimized conditions of the catalytic version of the reaction were Pd(OAc)2 in DMSO under an oxygen atmosphere as

Alkyl or stannyl cobaloximes were found to catalyze intramolecular alkyl Heck-type coupling reactions of alkyl iodides to alkenes upon irradiation with visible light in the presence of a tertiary amine base, which was applied to the preparation of one example of simple bicyclo[3.2.1]octane derivative.151 4.7. Transition Metal-Mediated Cyclizations

In this area, palladium-catalyzed intramolecular coupling reactions clearly lead the way, and some elegant approaches to bicyclo[3.2.1]octane derivatives essentially based on cycloisomerization or intramolecular Heck coupling have been reported in recent years. In 2000 the group of Langer152 and more recently Rodriguez and co-workers153 reported the stereoselective synthesis and palladium-catalyzed rearrangement of bicyclic 2-alkylidene-5-vinyl-tetrahydrofurans for the preparation of bicyclo[3.2.1]octan-8-ones. Under the Tsuji− Trost reaction conditions, the substrates 273 and 275 underwent initial ring-opening of the furan to form the corresponding π-allyl palladium(0) complex enolates, which AK


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Scheme 95. Heck-Type Cyclizations (PMP = 1,2,2,6,6-Pentamethylpiperidine)

Scheme 96. Palladium-Catalyzed Formal [3 + 2]-Cycloaddition (dba = Dibenzylideneacetone; dppf =1,1′Bis(diphenylphosphino)ferrocene)

Scheme 97. Diels−Alder-Initiated Dimerization of [5]Dendralene

determined for the representative conversion of the silyl enol ether 277 into the bicyclic product 278 (Scheme 94). Cascade reactions leading to the cedrane sesquiterpene skeleton were also proven possible albeit in reduced yield, for example, from the bis(allyl) silyl enol ether 279 to give the tricyclic product 280.156 The same group157 and others158 further exploited this reaction in additional total syntheses of kaurane-type and related terpenoid natural products. Finally, an intramolecular Heck reaction of the vinyl iodide substrate 281b was introduced by Piers and co-workers in 2004 for the preparation of the bicyclo[3.2.1]octane moiety of the kaurane natural product 13-methoxy-15-oxozoapatlin (Scheme 95).159 In early experiments, the Heck reaction was attempted on substrate 281a, but all these reactions have led to complex mixtures of unidentified products, presumably due to the existence of a stabilized five-membered oxa-palladacycle that

shuts down the catalytic cycle. With the corresponding protected vinyl iodide 281b, standard Heck reaction conditions also failed to give the desired product 282. Finally, it was found that the subjection of 281b to a Heck reaction with 1,2,2,6,6pentamethylpiperidine (PMP) in the absence of phosphine ligand provided the desired product 282 in good yield, and the latter was converted into the natural product in a few steps. More recently, Yoshimitsu et al. described a closely related transformation in their total synthesis of (±)-platencin based on a previous intramolecular α-arylation of cyclopentanone (e.g., 140 → 141 in Scheme 50).160 Under standard palladiumcatalyzed reaction conditions, the vinyl bromide 283 easily cyclized to give the bicyclo[3.2.1]octenone 284, a precursor of platencin following skeletal rearrangement (see section 8.4). Yoshida et al. have described the palladium-catalyzed reaction of propargylic acetates 285 with 2-oxocyclohex-3AL


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Similarly, Orac and Bergmeier used the Lewis acid-promoted [3 + 2]-cycloaddition of allylsilanes with α,β-unsaturated carbonyl compounds 296 to prepare a class of 8-silylbicyclo[3.2.1]octanes 294 from silylcyclohexenes 295 (Scheme 100).165 In a recent article, Schomaker, Toste, and Bergman reported the reactions of cobalt dinitrosyl/alkene adducts 297 with cyclohexenone (or the corresponding t-butylsulfinyl imine) in the presence of scandium triflate and LiHMDS to afford the corresponding tetracyclic [3 + 2]-annulation products 298 as exemplified in Scheme 101.166 Lithium aluminum hydride reduction or retrocycloaddition in the presence of norbornadiene of these products allowed removal of the metallic moiety to yield the functionalized 6,7-diamino-bicyclo[3.2.1]octane product 299 or the bicyclo[3.2.1]oct-6-ene product 300, respectively. The synthesis of bicyclo[3.2.1]octanoid scaffolds derived from 6π-[5 + 2]-cycloaddition of quinone monoacetals and styrene derivatives was first reported by Büchi and co-workers during their work on biomimetic syntheses of neolignans.2 A microfluidic reaction platform has been developed and applied recently for the multidimensional reaction screening of this reaction.167 In 1999, Horne, Yakushijin, and Büchi reported additionally the reaction of the ortho-quinone monoacetals 301 with (E)- or (Z)-302, which on exposure to stannic chloride reacted by a [5 + 2]-cycloaddition to form minor amounts of bicyclo[3.2.1]octane derivatives 303 and 304, respectively, together with O-cyclization products (Scheme 102).168 Following this work, Kim and Rychnovsky used a Lewis acidpromoted intramolecular [5 + 2]-cyclization of the bicyclic precursor 305 exhibiting a serrulatane diterpene skeleton to complete their biomimetic synthesis of elisapterosin B (Scheme 103).169 Presumably, this [5 + 2]-cycloaddition proceeded preferentially from a conformation of 305 with an axial diene side-chain, leading to a 1.7:1 mixture of the natural product and its C7 epimer 306. In the same article, the authors also described the synthesis of the closely related natural product colombiasin A from 305. Two years later, Harrowven et al. employed a similar final [5 + 2]-cycloaddition in their total synthesis of elisapterosin B.170 In a subsequent report, Jacobsen and co-workers reported that colombiasin A could actually be transformed into elisapterosin B by treatment with BF3·OEt2, possibly occurring by a retro [4 + 2]-cycloaddition followed by a [5 + 2]-cycloaddition.171 Finally, Davies et al. used the same end-game strategy in their approach to the same natural products.172 In a recent modified version of this reaction, Green and Pettus have performed oxidative dearomatization-induced intramolecular [5 + 2]-cycloaddition reactions of ortho-(pent4-enyl)-phenols 307 (Scheme 104).173 On treatment with lead tetraacetate, compounds 307 underwent an oxidative dearomatization to give the corresponding phenoxonium intermediates 308, which evolved to the [5 + 2] cationic cycloadducts. The

enecarboxylates 286 for the synthesis of the functionalized bicyclo[3.2.1]octenones 287 in a highly stereoselective manner (Scheme 96).161 The reaction proceeds via initial formation of a π-propargylpalladium complex, followed by a regioselective C− C cyclization. The C−C cyclization was preferred to the previously observed C−O cyclization mode due to the introduction of a conjugated enone in the bis-nucleophile substrate 286. 4.8. Cycloadditions, Electrocyclizations, and Cycloisomerizations

In the course of their exploratory chemistry of [5]dendralene 288, Sherburn and co-workers reported a spectacular cyclodimerization reaction leading to the tetracyclic [5.6.6.6]fenestrane hydrocarbon 290 containing the bicyclo[3.2.1]octane moiety (Scheme 97).162 Under controlled conditions, Diels−Alder dimerization of 288 led to 289 as a minor component of the reaction mixture. Upon heating in refluxing chlorobenzene, 289 underwent a remarkable domino 6πelectrocyclization/intramolecular Diels−Alder sequence to form the product 290 in good yield. Chen and co-workers used a challenging bioinspired intramolecular Diels−Alder reaction to construct the tricyclo[3.2.1.02,7]octane domain of salvileucalin B.163 Under microwave-assisted conditions and in the presence of HMDS, the spiro compound 291 was converted efficiently into the desired tetracyclic product 292 exhibiting the core of the natural product (Scheme 98). Scheme 98. Intramolecular Diels−Alder Reaction En Route to Salvileucalin B (HMDS = Hexamethyldisilazane)

In a series of papers, Miller et al. reported on several applications of the 8-chloro-bicyclo[3.2.1]oct-6-enes 293 prepared from 6-chlorocyclohexenes and alkynes by their zinc(II)-promoted cationic formal [3 + 2]-cycloaddition.164 From compounds 293 they synthesized a collection of diversely substituted (essentially at C8) simple bicyclo[3.2.1]octane derivatives. The general [3 + 2]-cycloaddition reaction is illustrated in Scheme 99. Remarkably, several of the relatively lightly functionalized and substituted, easily accessible, synthetic bicyclo[3.2.1]octane derivatives prepared from 293 have exhibited some interesting biological activities in models as cytotoxic, antiviral, and anticonvulsant agents. Scheme 99. Cationic Formal [3 + 2]-Cycloaddition

AM


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Scheme 100. [3 + 2]-Cycloaddition of Allylsilanes

Scheme 101. Reactions of Cobalt Dinitrosyl/Alkene Adducts with Cyclohexenone (LAH = Lithium Aluminium Hydride)

Scheme 102. [5 + 2]-Cycloadditions of ortho-Quinone Monoketals

and co-workers.174 In their approach to the tricyclo[5.3.1.01,5]undecane ring system of cedrane sesquiterpenes, the authors envisioned the simultaneous construction of the two fivemembered rings by a Pauson−Khand reaction from the enyne complex 310. In practice, the diastereomeric mixture of the dicobalt hexacarbonyl complex 310 was treated with known promoters of the Pauson−Khand reaction, including two different amine N-oxides or a soluble or polymer-supported alkyl methyl sulfide, to afford in all cases the desired [2 + 2 +

reaction is then terminated by the diastereoselective addition of an acetate ligand of Pb(OAc)4 to give the products 309. The cycloadducts were obtained in low to moderate yields and could be easily transformed into the natural sesquiterpenes αcedrene, α-pipitzol, and sec-cedrenol. Notwithstanding its efficiency and reliability as a cyclopentannulation method, the Pauson−Khand reaction (PKR) has not been applied to the synthesis of bicyclo[3.2.1]octane derivatives before 2001 with the preparation of cedrone by Kerr AN


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Scheme 103. [5 + 2]-Cyclizations toward Elisapterosin B

Scheme 104. Oxidative [5 + 2]-Cycloaddition

Scheme 105. Pauson−Khand Approaches to Sesquiterpenes (PKR = Pauson−Khand Reaction)

study on the total synthesis of (−)-tricycloillicinone, Furuya and Terashima reported the synthesis of the [2 + 2 + 1]cycloadduct 313 from the enyne 312.176 The [2 + 2 + 2] homo-Diels−Alder cycloaddition of norbornadiene derivatives with acetylenic dienophiles produces deltacyclene compounds (e.g., 315) incorporating the bicyclo[3.2.1]octane subunit. Tenaglia and co-workers further examined this reaction with the ruthenium catalyst [(nbd)-

1]-cycloaddition product 311 in good to excellent yield (Scheme 105). The reaction is stereospecific, and the undesired major isomer (Z)-310 gave the precursor of 8-epi-cedrone. Later, the stereoselective synthesis of (E)-310 was improved [(Z)/(E) = 1:2.4] and the undesired diastereomer of 311 (αMe-C8) could be efficiently epimerized under basic conditions to the desired product 311 with a β-configured methyl at C8.175 The latter was converted to cedrone in a few steps. In a related AO


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Scheme 106. Homo-Diels−Alder Cycloaddition of Norbornadiene Derivatives (nbd = norbornadiene)

Scheme 107. Gold-Catalyzed Cycloisomerizations

Scheme 108. Domino Transannular Diels−Alder/Intramolecular Aldolization

RuCl2(PPh3)2] either in its inter- or intramolecular version and found it very efficient as illustrated in Scheme 106 for the cyclization of the tethered norbornadienes 314.177 HomoDiels−Alder [2 + 2 + 2]-cycloadditions are also possible with other bridged 1,4-dienes, for example, with bicyclo[2.2.2]octa-

2,5-dienes, to give the corresponding tetracyclic cycloadducts containing two interlinked bicyclo[3.2.1]octane subunits.178 Finally, the well-established affinity of gold catalysts for alkynes has been successfully applied in 2004 by Toste and coworkers for the efficient preparation of bicyclo[3.2.1]octane AP


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Scheme 109. Sequential Ring-Expansion−Intramolecular Aldolization

Scheme 110. Intramolecular Claisen Approaches


derivatives. They have proposed some intramolecular gold(I)catalyzed 5-exo-dig and 5-endo-dig cyclizations of the terminal and internal alkyne tethered β-ketoesters 316 and 318 (Coniaene reaction), respectively, leading to the expected bridged compounds 317 and 319 under mild reaction conditions and with almost quantitative yields (Scheme 107).179 Alternatively, Yang and co-workers reported a nickel-catalyzed version of the transformation 316 → 317.180 In a related study, Kirsch’s group reported the combination of gold catalysis with aminocatalysis to give unexpectedly the tricyclic product 321 as a single diastereomer resulting from a formal intramolecular [3 + 2]cycloaddition of 320 instead of the awaited Conia-ene reaction product.181

In 2000, Deslongchamps and co-workers exploited an intramolecular aldol reaction in their approach to the diterpene aphidicolin. The strategy involves the in situ formation of the required functionalized seven-membered ring by an intramolecular Diels−Alder reaction from the macrocyclic trienones 322a,b. The reaction conducted in the presence of triethylamine at relatively elevated temperature directly afforded the bridged products 323a,b having the tetracyclic ring system of the natural product by an efficient and elegant domino transannular Diels−Alder/intramolecular aldol sequence (Scheme 108).182 A related approach was proposed 2 years later by Karimi et al. starting from the Wieland−Miescher ketone derivative 324. The ring-expansion reaction of the cyclohexanone moiety in 324 furnished the corresponding seven-membered bicyclic keto acetal as a mixture of regioisomers. Upon hydrolysis of the acetal group, the resulting diketones 325 underwent thermodynamically controlled acid-catalyzed intramolecular aldol cyclizations to give the tricyclic products 326 in moderate yields (Scheme 109).183 In their approach to gelsemine, Simpkins and co-workers prepared the oxabicyclo[3.2.1]octane compound 327 with its conversion to the fused ring system 328 by a domino elimination/conjugate addition sequence (Scheme 110).184 Upon treatment with TMSOTf and base, 327 underwent the

5. BICYLO[3.2.1] RING SYSTEM FROM SEVEN-MEMBERED RINGS This approach consisting of closing the one-carbon bridge of the bicyclo[3.2.1] skeleton appears relatively straightforward, but surprisingly, it has not been broadly developed, probably due to difficulties in the preparation of the seven-membered ring precursors. Nevertheless based on traditional C−C bondforming reactions some important contributions have been published recently. AQ


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Scheme 111. Intramolecular Dienolate Alkylation

membered ring. They have found that the treatment of 337 with sodium methoxide in methanol promoted the desired cascade, leading to the product 338. The reaction proceeds by initial retro-Dieckmann-type ring-opening of 337 followed by an elimination to set up the α,β-unsaturated ester functionality, and the resulting intermediate then undergoes the expected intramolecular Michael addition. Finally, in a recent biomimetic total synthesis of the natural products hopeahainol A and hopeanol derived from resveratrol, Nicolaou, Chen, and co-workers disclosed an elegant and efficient transformation of the former natural product into the latter in good yield by sodium methoxide-promoted γ-lactone opening followed by an intramolecular vinylogous Michael addition (Scheme 114).189

expected transformation to give 328, but the major product of the reaction was the tricyclic mixed O-silyl acetal 329 bearing the bicyclo[3.2.1]octane motif formed by an intramolecular Claisen condensation from 328. Dixon and co-workers recently exploited this type of cyclization, pioneered by Sedgeworth and Proctor in 1985,185 for the synthesis of bicyclo[3.2.1]alkenediones 331 from the enone 330 (Scheme 110).186 5.2. Alkylation-Based Cyclizations

In a recent formal synthesis of platensimycin targeting the previously described intermediate 334,7 Oblak and Wright have prepared the tetracyclic core of the natural product 333 by a γalkylation of the endocyclic enone 332 promoted by an alkoxide base (Scheme 111).187 A diastereoselective hydrogenation of enone 333 catalyzed by a chiral rhodium complex furnished the desired product 334.

5.4. Carbocation-Based Cyclizations

In the course of a synthetic study toward analogues of Ambrox, a molecule used in perfumery, Snowden and Linder reported a series of acid-mediated cyclizations of bicyclic homoallylic and allenic alcohols.190 For example, the homoallylic alcohol 339 and the allenic alcohol 341 could be respectively transformed into the tetracyclic compounds 340 and 342 containing the bicyclo[3.2.1]octane unit by exposure to chlorosulfuric acid (Scheme 115).

5.3. Michael Addition-Based Cyclizations

In the course of a study on the preparation and synthetic applications of dihydrotropone compounds, Koo and coworkers reported the synthesis of the tricyclic product 336 showing two intricated bicyclo[3.2.1]octane units (Scheme 112).188 The reaction proceeds via an intramolecular Michael addition of a seven-membered ring dienolate.


Scheme 112. Intramolecular Dienolate Michael Addition

Recently, Procter and co-workers have reported the selective reduction of cyclic 1,3-diesters to the corresponding 3hydroxyacids by using SmI2/H2O.191 The radical formed by monoelectronic reduction of one ester carbonyl group has been exploited in intramolecular additions to alkenes as exemplified in Scheme 116. For example, the reduction of the diester 343 with SmI2/H2O gave stereoselectively the bicyclo[3.2.1]octanol 344. 5.6. Transition Metal-Mediated Cyclizations

The tricyclic acetal 329 described by Simpkins and coworkers in their approach to gelsemine (see Scheme 110) was deprotected with aqueous HCl to afford the corresponding alcohol 337 (Scheme 113).184 The synthetic plan of these authors was to construct the bicyclo[3.2.1]octane core of the natural product by an intramolecular Michael addition of the βamido nitrile moiety in 337 onto an enone in the seven-

Following the route they established earlier, Overman and coworkers realized an intramolecular cascade Heck reaction from methylenecycloheptene iodides to generate the BCD ring system of (−)-scopadulcic acid.192a For example, the reaction of the vinyl iodide 345 under the Heck reaction conditions with silver carbonate afforded cleanly the tricyclic product 346

Scheme 113. Intramolecular Michael Addition toward Gelsemine

AR


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Scheme 114. Biomimetic Synthesis of Hopeanol

Scheme 115. Acid-Mediated Cyclization of Bicyclic Unsaturated Alcohols

6. BICYLO[3.2.1] RING SYSTEM FROM POLYCYCLIC PRECURSORS

Scheme 116. Reductive Cyclization of Meldrum’s Acid Derivative

6.1. Rearrangement of Bicyclo[2.2.2]octane Derivatives

The well-established cationic rearrangement of 1methoxybicyclo[2.2.2]octenes obtained by a Diels−Alder cycloaddition has proven to be a reliable and efficient strategy to prepare stereodefined functionalized bicyclo[3.2.1]octan-2ones and has received significant attention. The efficient acidcatalyzed pinacol rearrangement of 347 into 348 reported by Uyehara and co-workers in their approach to the pupukeanane series of natural products is representative of this strategy (Scheme 118).193 Similar rearrangements were also used in a domino combination with an ene reaction by the groups of Kim194 and Rao.131,195 Still in the pupukeanane series of natural products, Srikrishna and co-workers proposed the related rearrangement of the hydroxy bicyclo[2.2.2]octanone 349 to give the enone 350 (Scheme 118),118f,g and a very similar rearrangement was described recently by Bettolo and co-

(Scheme 117). A similar strategy was also used to prepare the closely related ring system of stemodane and stemarane diterpenes.192b

Scheme 117. Intramolecular Cascade Heck Reactions Toward (−)-Scopadulcic Acid A

AS


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Scheme 118. Acid-Catalyzed Rearrangement toward Pupukeanane Natural Products

Scheme 119. Domino aza-Prins Cyclization/Wagner−Meerwein Rearrangement

Scheme 120. Domino Ene Cyclization/Ring Rearrangement

that upon treatment with Et2AlCl cyclohexenones 354 can undergo cyclization to form the transient zwitterionic bicyclo[2.2.2]octane intermediates 355, which evolve by 1,2hydride shift to the isomeric zwitterions amenable to the key rearrangement, leading to 356 in fair to good yields (Scheme 120). In related studies, Menzek reported the rearrangement of benzhomobarrelene derivatives to provide efficiently some benzobicyclo[3.2.1]octene compounds.200 Radical-based methods have also been used for the rearrangement of bicyclo[2.2.2]octane derivatives into the corresponding bicyclo[3.2.1]octanes. Among these, Liao and co-workers reported that, upon reduction with Raney nickel or tin hydride, the Diels−Alder adducts 357 produced carboncentered radicals, which underwent various rearrangements to the bicyclo[3.2.1]octenes 358 and/or 359, depending on the substitution pattern and the reagent used (Scheme 121).201

workers for the preparation of the C/D ring system of stemarane diterpenes.196 Finally, Bondarenko et al. used an analogous rearrangement for the preparation of 5α,9α-bridged steroids.197 In their studies toward the total synthesis of (±)-gelsemine, the group of Overman reported a domino aza-Prins cyclization/ Wagner−Meerwein rearrangement for the synthesis of the tricyclic compound 353.198 The reaction of the carbamate ester 351 with para-formaldehyde in trifluoroacetic acid most probably started with an aza-Prins cyclization to generate the carbocation intermediate 352, which underwent a Wagner− Meerwein rearrangement and trapping of the resulting carbocation with trifluoroacetic acid (Scheme 119). At the same time, Goeke et al. reported a domino ene cyclization/ring rearrangement for the preparation of fragrant substituted bicyclo[3.2.1]octenones.199 They have discovered AT


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Scheme 121. Reductive Radical Rearrangement

Scheme 122. Oxametathesis of Paternò−Büchi Photoadducts

Scheme 123. Rearrangements of Fused Bicyclo[4.2.0] Derivatives

rearrangement of the allylic alcohol 362 to prepare intermediate 363, which was not pursued (Scheme 123).121 Alternatively, Blanchard and Burnell have proposed a synthetic approach to bridged diketones based on a Lewis acid-promoted cyclization reaction of 1,2-bis(trimethylsilyloxy) cyclobutene derivatives.204 Upon treatment with BF3·OEt2, the acetal tethered cyclobutene 364 underwent a first cyclization to give the bicyclo[4.2.0]octane intermediate 365, which was then treated with TFA to promote its rearrangement into the product 366 (Scheme 123). Fitjer and co-workers observed some related rearrangements in a study on a synthetic approach to (±)-cerapicol,205 and Oshima and co-workers reported some

Photoinduced electron-transfer reactions of bicyclo[2.2.2]octene derivatives have also allowed related rearrangements.202 The oxametathesis reaction of Paternò−Büchi [2 + 2]photoadducts 360 described by Valiulin and Kutateladze also provides an interesting synthetic route to various aldehydesubstituted polycyclic structures.203 For example, the reactions of 360 with a trace amount of HCl or BF3·OEt2 provided cleanly the rearranged bicyclo[3.2.1]octenes 361 in good to excellent yields (Scheme 122). 6.2. Rearrangements of Fused Bicyclo[n.m.0] Derivatives

In their synthesis of codeine, White et al. finally used a rhodium carbenoid-mediated cyclopentannulation reaction (see section 4.4), but they also studied another approach involving the AU


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Scheme 124. Rearrangement of Fused Bicyclo[3.2.0] Derivatives (LA = Lewis Acid)

Scheme 125. Rearrangement of Fused Bicyclo[3.1.0] Derivatives

Scheme 126. Radical Rearrangement of Fused Bicyclo[3.3.0] Derivatives

to give the spiranic bicyclo[3.2.1]octadiene product 370 in high yield (Scheme 125). Finally, following their successful total synthesis of the quadrane sesquiterpene suberosenone,5,210 Lee et al. generalized their free radical cyclization/rearrangement sequence for the construction of tricyclo[4.3.n.01,5]alkane cores.211 Upon treatment with tin hydride and a radical initiator, the enediyne (or dienyne) precursor of the free radical cascade reaction 371 underwent a first cyclization to produce a bicyclo[3.3.0]octane radical intermediate, which rearranged to a bicyclo[3.2.1]octane radical, the precursor of the tricyclic compound 372 following a silica gel-mediated C−Sn bond cleavage (Scheme 126).

interesting observations on the Lewis acid-catalyzed rearrangement of cyclobutene-fused diphenylhomoquinones.206 In a study targeting the bicyclo[5.3.1]undecane AB ring system of taxane diterpenes, Kakiuchi and co-workers used a ring-expansion/rearrangement of a bicyclo[3.2.0]heptane enone−allene photoadduct to prepare a bicyclo[3.2.1]octane intermediate.207 Like this, the reaction of ketone 367 with excess TiCl4 produced the desired rearranged bridged ketone 368 in good yield via a seven-membered ring zwitterionic intermediate (Scheme 124). Cope rearrangements of 6-vinylbicyclo[3.1.0]hex-2-enes, which may be regarded here as divinylcyclopropanes, have also provided some beautiful entries to bicyclo[3.2.1]octane derivatives, notably in some total syntheses of gelsemine.208 Kesavan, Panek, and Porco, Jr., have reported three examples of a closely related Cope rearrangement with optically active alkylidene indanes.209 Following their enantioselective crotylation/Heck cyclization sequence, they prepared the cisdivinylcyclopropane precursor 369 in a few steps, which on heating at 100 °C underwent the desired Cope rearrangement

6.3. Ring-Expansion-Based Methods

The ring-expansion strategy of bicyclo[2.2.1]heptane derivatives has provided several new routes to bicyclo[3.2.1]octane compounds. In 2002, Maier and co-workers studied the Wagner−Meerwein type rearrangement of reduced benzoquinone cyclopentadiene cycloadducts to prepare bicyclo[3.2.1]octane derivatives.212 The treatment of the diols 373 with a strong acid triggered a skeletal rearrangement, which is believed to occur via the formation of the allylic carbocation 374, which AV


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Scheme 127. Wagner−Meerwein-Type Rearrangement of Bicyclo[2.2.1]heptanes

and stereoselectively the alkyl- or arylated bicyclo[3.2.1]octane derivatives (e.g., 381a,b). A plausible mechanism for these reactions would involve the deprotonation of the tertiary alcohol by the organometallic reagent followed by a ringexpansion step to give the intermediates 380a,b, as depicted in Scheme 129. The latter would then undergo a stereoselective nucleophilic addition with a second equivalent of the organometallic reagent to give the products 381a,b after hydrolysis. Similar acid-catalyzed nonalkylative rearrangements of 379a,b have been described more recently.217 In 2000, during synthetic studies in the zizaane group of sesquiterpenes, Mukherjee and co-workers obtained the tricyclo[6.2.1.01,5]undecane carbon skeleton of these natural products (e.g., in zizaene) by a ring rearrangement of a tricyclo[6.2.1.01,6]undecane (e.g., 382).218 This pinacol-type rearrangement can be regarded as a ring expansion of the bicyclo[2.2.1]heptane moiety with a concomitant ring-contraction of the cyclohexane ring. Thus, the base-induced rearrangement of mesylate 382 furnished smoothly in good yield the trans-fused ketone 383 as the sole product, which was then converted into zizaene by a Wittig olefination (Scheme 130). Eight years later, Cha and co-workers documented a related semipinacol rearrangement approach to bicyclo[3.2.1]octanones from functionalized norbornane derivatives utilizing the 1,2-alkyl shift of epoxy alcohols pioneered by Tsuchihashi and Suzuki.219 They found that tin(IV) chloride was able to induce a 1,2-alkyl migration in the epoxy alcohols 384a and 387a to give the ring-enlarged products 385 and 388 together with various amounts of the corresponding halohydrines 386a,b (Scheme 131). The regio- and stereochemical outcomes of these reactions reflect the inversion of configuration at the epoxide functionalities (stereospecific reactions) and were rationalized by stereoelectronic factors (antiperiplanar requirement). The same reactions from the corresponding trimethyl-

would then evolve to the product 375 by addition of methanol (Scheme 127). Other acid-catalyzed unusual rearrangements leading to bicyclo[3.2.1]octanoids have been reported. For example, Zwanenburg and co-workers have described a unique rearrangement of a tricyclo[5.2.1.02,6]decenone under flash vacuum thermolysis in the presence of solid acid catalysts,213 and Collado and co-workers have reported some novel rearrangements of panasinsane sesquiterpenes derivatives under acidic conditions.214 An interesting, albeit isolated, example concerns the domino retro-ene/Conia-ene sequence introduced in 2004 by Rüedi et al. for the regio- and stereoselective ring expansion of fenchol derivatives.215 For example, on pyrolysis by dynamic gas-phase thermo-isomerization, the fenchol derivative 376 underwent an initial retro-ene reaction to form the enol-ene intermediate 377, which then underwent a Conia-ene rearrangement with a onecarbon ring expansion to give the bicyclo[3.2.1]octanone product 378, and the sequence proceeded without loss of optical purity (Scheme 128). Scheme 128. Domino Retro-ene/Conia-ene Approach

In another study with closely related compounds, Yang et al. revealed a Grignard reagent-promoted ring-expansion/alkylation sequence leading to bicyclo[3.2.1]octandiols.216 The reaction of fenchone and camphor-derived formyl bicyclo[2.2.1]heptane carbinols (e.g., 379a and 379b, respectively) with Grignard or organolithium reagents afforded regio-

Scheme 129. Grignard or Organolithium Reagent-Mediated Domino Ring Expansion−Addition

AW


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Scheme 130. Pinacol Ring-Expansion toward (±)-Zizaene

Scheme 131. Semi-pinacol Rearrangement of Norbornyl Epoxy Alcohols

Scheme 132. Domino Rhodium-Catalyzed Hydroformylation/Fischer Indole Synthesis (PTSA = p-Toluenesulfonic Acid)

Scheme 133. Regioselective Carbene-Mediated Ring-Expansion

Demjanov ring-expansion reaction of the bicyclo[2.2.1]heptan2-one intermediate 390 into the corresponding functionalized bicyclo[3.2.1]octan-2-one 391 with ethyl diazoacetate in the presence of BF3·OEt2 (Scheme 133). We may also mention here the observation by Wagner and co-workers of an unusual platinum-catalyzed cycloisomerization of 2,3-bis(ethynyl)-3hydroxycamphorsultam to give a ring-expanded bicyclo[3.2.1]octane derivative.223 Ultimately, in the organometallic series, Barluenga et al. have reported the thermal ring-expansion of bicyclo[2.2.1]heptane Fischer carbene complexes of tungsten to give some bicyclo[3.2.1]octenones.224 An interesting access to the enantiomerically pure AB ring system of taxanes from the chiral pool was proposed by Blechert and co-workers based on iron pentacarbonyl-catalyzed CO insertion into (−)-β-pinene.225 The optically pure bicyclo[3.2.1]octenones 392a,b obtained in 77% yield were used as the starting material for the construction of the bicyclic

silyl ethers 384b and 387b were best mediated by titanium(IV) chloride and provided a more selective entry to the bicyclo[3.2.1]octanones 385 and 388. Eilbracht and co-workers described that norbornene itself has been involved in a domino rhodium-catalyzed hydroformylation/Fischer indole synthesis for the preparation of fused substituted indoles.220 Using phenyl hydrazine under CO atmosphere, the transient hydrazone evolved selectively to the ring-expanded bicyclo[3.2.1] indole derivative 389 in good yield (Scheme 132). Carbenes and related species have also proven useful as reactive intermediates in ring-expansion reactions of bicyclo[2.2.1]heptane compounds, although not always synthetically valuable for the construction of bicyclo[3.2.1]octanes.221 In the course of a total synthesis of cedrane sesquiterpenes, the group of Ihara found an interesting example.222 They have reported a regioselective Tiffeneau− AX


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Scheme 134. Ring-Expansion of a Bicyclo[3.1.1]heptane Derivative

Scheme 135. Rhodium-Catalyzed Intramolecular Olefin Insertion (dppp =1,3-bis(diphenylphosphino)propane; BHT = 2,6-di(tbutyl)-4-methylphenol)

Scheme 136. Ring-Contraction of Bicyclo[3.3.1]nonane Derivatives (MOM = Methoxymethyl)

rhodium−carbon bond then affords the bicyclic acylrhodium intermediate 397, which gives rise to the product 398 after reductive elimination (Scheme 135).

core of the natural product (Scheme 134). Another related ring-expansion of a bicyclo[3.1.1]heptane derivative was reported by Miyashita and co-workers, albeit for a different purpose, with the one-carbon ring-expansion of the bridged ketone 393 with diazomethane to afford cleanly the corresponding bicyclo[3.2.1]octanone 394 (Scheme 134).226 Finally, Murakami et al. have disclosed an unusual rhodiumcatalyzed intramolecular olefin insertion into a carbon−carbon bond, which has allowed the preparation of benzobicyclo[3.2.1]octanones 398 from the key 3-(o-styryl)cyclobutanones 395 (three examples).227 As demonstrated by a 13 C-labeled experiment, the reaction proceeds by initial regioselective rhodium(I) insertion in the cyclobutanone to give intermediate 396 with the vinyl group coordinating to rhodium. Migratory insertion of the vinyl group into the

6.4. Ring-Contraction-Based Methods

Only a small number of methods relying on a ring-contraction of a bicyclo[3.3.1]nonane derivative are available. Among these, Takeuchi and co-workers described in detail the solvolysis of the 2-oxobicyclo[3.3.1]non-1-yl triflate (399) to give the onecarbon ring-contracted product 400 (Scheme 136).228 Also, Mander and co-workers have established a Wolff rearrangement-based ring-contraction strategy in their total synthesis of the Galbulimima alkaloid G.B. 13,6 which was also used in the early steps of their approach to himandrine as illustrated in Scheme 136 with the conversion of the α-diazo ketone 401 into AY


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Scheme 137. Radical-Mediated Fragmentation of Tricyclo[3.3.0.02,8]octane Derivatives

Scheme 138. Hydrogenation-Mediated Fragmentation of Tricyclo[3.3.0.02,8]octane Derivatives

Scheme 139. Regioselective Oxidative Fragmentation of Tricyclo[3.3.0.02,8]octane Derivatives (NIS = N-Iodosuccinimide)

the methyl ester 402, showing a benzobicyclo[3.2.1]octane framework.229

In the course of a formal total synthesis of the triquinane sesquiterpene coriolin, Singh et al. reported a similar photochemical 1,2-acyl shift in precursor 409 to give the tetracyclic intermediate 410, which was then submitted to a regioselective reductive cleavage by hydrogenation to afford quantitatively the bicyclo[3.2.1]octanoid 411 (Scheme 138).232 Interestingly, when the reductive cleavage of 410 was performed with tributyltin hydride, the absence of electron-withdrawing group at the bridgehead led to another regioselectivity in the fragmentation to give the triquinane framework. In a recent study, Liao and co-workers reported similar fragmentation reactions of an analogue of 410 either with tributyltin hydride under radical condition or by a Lewis acid-assisted nucleophilic addition (TMSOTf, nBu4NI) for the regioselective ringopening of the cyclopropane to give a bicyclo[3.2.1]octanone related to 411.233 However, under the latter conditions, the fragmentation of tricyclo[3.3.0.02,8]octane derivatives bearing an electron-withdrawing group at the bridgehead led this time to the triquinane framework. Tricyclo[3.3.0.02,8]octane derivatives can also be obtained by tethered meta-arene−alkene cycloadditions. This strategy has been studied by Penkett and co-workers in their approach to

6.5. Rearrangement of Tricyclic Compounds

In this section, we have assembled the strategies involving the preparation and the fragmentation of tricyclooctane compounds, where the bicyclo[3.2.1]octane framework is revealed by simplification of the tricyclic ring system. One important and popular approach of this strategy is the fragmentation of tricyclo[3.3.0.02,8]octane derivatives. For example, Lahiri and co-workers have reported the preparation of the tricyclic compound 404 by a photochemical oxa-di-π-methane rearrangement in the Diels−Alder adduct 403.230 The photochemical electron transfer-induced reduction of the cyclopropane ring in 404 proceeded with excellent regioselectivity to give the bicyclo[3.2.1]octanone 405 in good yield (Scheme 137). The same product 405 was also obtained, although in lower yield, by reduction of 404 with tributyltin hydride. The group of Liao reported similar results from ketoacetals 406 for the preparation and radical-mediated reduction of a series of tricyclic compounds 407, leading to masked 1,2-bicyclic ketones 408 (Scheme 137).231 AZ


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Scheme 140. Acid-Catalyzed Fragmentation of Tricyclo[3.3.0.02,8]octane Derivatives

Scheme 141. Heck-Mediated Fragmentation of Tricyclo[3.3.0.02,8]octene

Scheme 142. Dichlorocarbene-Mediated Ring-Expansion

Scheme 143. FeCl3-Mediated Fragmentation of a Tricyclo[3.2.1.02,4]octane Derivative

mediated by treatment with hydrochloric acid and the double bond in the product was hydrogenated to give the optically active bicyclo[3.2.1]octan-8-one 418 (Scheme 140). Wang and Chen reported more recently another diastereoselective intramolecular meta-photocycloaddition in their approach to the 5,6,7-tricyclic ring system of lancifodilactone F.236 Importantly, Penkett et al. also described some palladiumcatalyzed fragmentation reactions of anisole-derived tricyclo[3.3.0.02,8]octene meta-photocycloadducts.237 Under Heck arylation conditions, the anisole−allyl alcohol meta-photocycloadduct 419 was converted into the arylated products 420a,b with moderate yield and selectivity (Scheme 141). When 419 was treated under the same conditions but in the absence of aryliodide and in the presence of a co-oxidant such as copper(II), the intramolecular addition product 420c was obtained.237c

gelsemine skeleton using the silicon-tethered substrate 3(phenoxydimethylsilyl)prop-1-ene (412), the meta-photocycloaddition of which afforded 413.234 They found electrophileassisted cleavage reaction conditions for the two possible regioselective fragmentations of 413 that lead to a bicyclo[3.2.1]octane framework: upon treatment with Niodosuccinimide (NIS), 413 was selectively converted into product 414, while the reaction promoted by m-CPBA afforded the desired product 415 via the corresponding epoxide (Scheme 139). The origin of the unusual selectivity leading to 414 remains unclear. The use of chiral tethers in meta-photocycloadditions has also been studied, as exemplified by the 2,4-pentanedioltethered compounds 416 reported by Sugimura and coworkers.235 After the diastereoselective meta-photocycloaddition yielding product 417, its regioselective fragmentation was BA


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Scheme 144. Platinum-Catalyzed Domino [2 + 1]/[3 + 2]-Cycloadditions

Scheme 145. Solid-Phase Regioselective Fragmentation of Tricyclo[3.2.1.02,7]octane Derivatives

Scheme 146. Regioselective Fragmentation of Tricyclo[3.2.1.02,7]octane Derivatives

propargyl ethers or esters.240 The reaction between norbornadiene and propargyl derivatives 427 catalyzed by the welldefined platinum-based catalyst 428 in the presence of acetic acid in toluene at 55 °C afforded after 72 h the product 430 in 71% yield (Scheme 144). The reaction has been demonstrated to involve first a platinum-catalyzed [2 + 1]-cycloaddition to give the reactive tricyclic methylene cyclopropane intermediate 429, which is the substrate of a subsequent formal [3 + 2]cycloaddition yielding the product 430. Another fragmentation approach has relied on the regioselective cleavage of tricyclo[3.2.1.02,7]octane derivatives. The important work of Spitzner and co-workers illustrated in Scheme 145 on its solid-supported version is representative of this strategy toward bicyclo[3.2.1]octanones.241 The lithium dienolate obtained from 431 reacted with the α-halo-α,βunsaturated ester 432 following a domino Michael addition/ alkylation sequence to afford the tricyclo[3.2.1.02,7]octanone 433, which could then be fragmented either into the bicyclo[3.2.1]octandione 434 or the bicyclo[3.2.1]octenone

To some extent, the C2−C4 fragmentation reactions of tricyclo[3.2.1.02,4]octane derivatives have also been used to prepare some bicyclo[3.2.1]octanoids. For example, Ho et al. reported that the transient dichlorocyclopropane 422 obtained from the cyclopentadiene−methyl acrylate Diels−Alder adduct 421, fragmentated under the reaction conditions to form the tricylic lactone 423, was the starting point of the total synthesis of (±)-2-isocyanoallopupukeanane (Scheme 142).238 Alternatively, based on their important previous work, Ogasawara and co-workers have implemented their two-step cyclopropanation/oxidative fragmentation sequence of norcamphor enol ethers leading to bicyclo[3.2.1]octenones. Scheme 143 illustrates this general approach by the conversion of ketone 424 into enone 426 via the fragmentation of hydroxycyclopropane intermediate 425, which after derivatization and resolution was used in the total synthesis of optically active natural products (see section 8.2).239 Very recently, Buono and co-workers described a platinumcatalyzed domino [2 + 1]/[3 + 2]-cycloaddition sequence leading to the tricyclic products 430 from norbornadiene and BB


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Scheme 147. Domino Ene Cyclization−Ene Cyclization (MS = Molecular Sieves)

Scheme 148. Domino Michael−Aldolization with Cyclic Imines

mediate that contains an olefin and an aldehyde in a 1,3-syn orientation. This intermediate is poised to undergo a second intramolecular ene reaction, resulting in the observed bicyclic product.

435. This approach was used in a total synthesis of the marine sesquiterpene 2-isocyanopupukeanane.242 Abad, Cuñat, and co-workers, during their studies on the synthesis of polycyclic diterpenoids, have also used a tricyclo[3.2.1.02,7]- to bicyclo[3.2.1]octane route, notably in the enantiomerically pure series from carvone, using acidic conditions or monoelectronic reduction in the fragmentation step.243 This approach is illustrated in Scheme 146 by the conversion of 436 into 437 and 438, respectively.

7.2. From Five-Membered Rings

In connection with their work on the total synthesis of galbulimima alkaloids,6 Movassaghi and Chen reported in 2007 a formal [3 + 3]-cycloaddition leading to the target ring system from cyclopentenone (Scheme 148).245 Unfortunately, this reaction gave only poor to moderate enantioselectivities under organocatalytic conditions in the asymmetric series. The overall transformation can actually be regarded as a Michael−aldol cascade, between cyclic enamines and cyclic enones leading to tricyclic imino alcohols. For example, the reaction between imine 442 and cyclopentenone in the presence of catalytic Lproline was reported to give the tricyclic product 444 via the 1,4-conjugate addition intermediate 443. The nature of the solvent was critical for the success of the reaction. In 10:1 trifluoroethanol/water, the reaction was effective but proceeded with poor enantioselectivity (ca. 5−10% ee), whereas in chloroform, only the conjugate addition product 443 was obtained and its cyclization was promoted by treatment with base in a separate experiment to afford the product 444 in still modest but improved enantioselectivity. Tang and co-workers have described a related organocatalytic enantioselective Michael−aldol cascade, so-called formal [3 + 3]-cycloaddition, promoted by proline derivatives (enamine catalysis).246 The reaction was essentially studied for the preparation of optically active bicyclo[3.3.1]nonan-9-ones, but

7. ENANTIOSELECTIVE APPROACHES The synthesis of optically active bicyclo[3.2.1]octanes from achiral precursors by means of catalytic methods is still in its infancy and constitutes a fascinating and open area of research with a promise of important synthetic developments. In this section, we wish to highlight the few recent contributions reported to date mainly based on organometallic and organic catalyzes. 7.1. From Acyclic Precursors

Jacobsen and co-workers pioneered this strategy in 2008.244 The group has reported a quite spectacular enantioselective carbonyl-ene cyclization reaction catalyzed by the chromium(III) complex 440, used for the preparation of bicyclo[3.2.1]octane derivatives with excellent enantioselectivity. Upon treatment with catalyst 440, the prenylated 1,3-dialdehydes 439 underwent a domino ene cyclization−ene cyclization to yield the bicyclo[3.2.1]octanes 441 as a single diastereomer in moderate yields (Scheme 147). The first ene cyclization generates enantioselectively a transient cyclopentane interBC


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Scheme 149. Domino Michael−Aldolization with α,β-Unsaturated Pyruvate

Scheme 150. Domino Michael−Elimination−Michael with (E)-2-Nitroallylic Acetates

one example of bicyclo[3.2.1]octan-8-one was also reported. Under optimized conditions, the reaction of cyclopentanone with the activated enone 445 was promoted by the bifunctional Wang’s catalyst to provide the Michael−aldolization product 446 in high yield and moderate enantioselectivity (Scheme 149). Afterward, the same group reported another enantioselective organocatalytic approach to bridged compounds from cyclic ketones, this time employing a domino Michael−elimination− Michael sequence with (E)-2-nitroallylic acetates as biselectrophiles.247 Like this, in the presence of a pyrrolidine− thiourea bifunctional catalyst, the reaction of cyclopentanone with the nitroolefin 447 afforded the bicyclo[3.2.1]octan-8-one 449 in excellent yield and enantioselectivity (Scheme 150). The reaction most probably occurred by initial Michael addition− elimination to form the transient enamine 448, which then cyclized following a second Michael addition to give the product after hydrolysis. The nature of the bifunctional catalyst was found to be crucial for the high reactivity, diastereoselectivity, and enantioselectivity, which was demonstrated by theoretical calculations and experimental data. The only organometallic catalytic asymmetric approach to the bicyclo[3.2.1]octane ring system from a five-membered ring precursor was reported by Coe and co-workers during their synthesis of a nicotinic receptor probe.248 They have proposed an efficient enantioselective palladium-catalyzed Heck cyclization reaction of the bromide 450 (Scheme 151). Under controlled conditions using (R,R)-BINAP as ligand, the benzobicyclo[3.2.1]octane product 451 could be obtained in good yield with 93% enantiomeric excess on the gram scale, and the reaction was scaled up on an 18-kg scale (with a loss of enantioselectivity attributed to an ineffective purging of the process reactor).

Scheme 151. Intramolecular Heck Reaction (BINAP = 2,2′Bis(diphenylphosphino)-1,1′-binaphthyl)

7.3. From Six-Membered Rings

The first important contribution is due to Engler et al. back in 1999.249 They have reported an enantioselective version of the 6π-[5 + 2]-cycloaddition of 1,4-benzoquinones with styrene derivatives using effective chiral titanium−TADDOLate complex catalysts and obtained the bicyclo[3.2.1]octanediones 452 and 453 in good yields and acceptable levels of enantioselectivity (Scheme 152). One year after, Takasu, Ihara, and co-workers introduced the utilization of a stoichiometric chiral amine to promote a Michael-based desymmetrization reaction via an enantioselective deprotonation.250a Upon treatment with a chiral amine− silyl triflate complex, the achiral unsaturated ketoester 454 was converted into the optically active tricyclo[4.2.1.03,8]nonane product 455 following a Michael−aldol cascade in fair to good yields but modest enantioselectivity (Scheme 153). If the enantioselective deprotonation−enolate trapping reaction is performed in a separate experiment, the Michael−aldol BD


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Scheme 152. [5 + 2]-Cycloaddition of 1,4-Benzoquinones

Scheme 153. Michael-Based Desymmetrization Reaction

Scheme 154. Organocatalytic Aldol-Based Desymmetrization

reacts with α,β-unsaturated aldehydes to give the bicyclo[3.2.1]octane-6-carbaldehyde products 459 in high yields and selectivities in a one-pot process (Scheme 155). It should be noted that cyclohexan-1,2-dione is used here as both a pronucleophile and an electrophile. Later on, the same group reported a conceptually similar enantioselective organocatalytic Michael−Henry cascade with cyclohexan-1,2-dione and nitrostyrene derivatives,253 and a very similar report from Zhao and co-workers appeared contemporaneously.254 Both groups used cinchona alkaloid−thiourea bifunctional catalysts and obtained very comparable results. For example, the reaction with nitrostyrene provided the 6-nitro-bicyclo[3.2.1]octan-8-ones 460 in good yield but modest diastereoselectivity due to a basecatalyzed isomerization of the product under the reaction conditions, with α-NO2−460 being the thermodynamic product (Scheme 155). However, both diastereomers exhibited excellent enantiomeric excesses. Finally, in a closely related study, Zhong and co-workers have reported another enantioselective organocatalytic Michael−Henry cascade promoted by cinchona alkaloid−thiourea bifunctional catalysts, this

products (e.g., 455) can be obtained in two steps with better yields and enantiomeric excesses.250b Shortly after the report of this spectacular transformation, Iwabuchi’s group described a related organocatalytic desymmetrization reaction leading to a simple hydroxyl bicyclo[3.2.1]octanone.251 The intramolecular aldol reaction of ketoaldehyde 456 could be catalyzed by the aspartic acid derivative 457 to afford chemo- and diastereoselectively the endo product 458 in moderate yield and poor enantioselectivity (Scheme 154). This desymmetrization approach was actually found to be much more efficient for the preparation of bicyclo[3.3.1]octanes. After these pioneering results, the organocatalyzed domino approach has met with a very recent and growing interest. In 2009, Rueping et al. reported an important breakthrough in this area.252 They have used a simple and elegant strategy involving an enantioselective organocatalytic Michael−aldol cascade for the fairly general synthesis of polyfunctionalized bicyclo[3.2.1]octanes. Upon treatment with a catalytic amount of trimethylsilyl diphenylprolinol ether, cyclohexan-1,2-dione BE


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Scheme 155. Michael-Initiated Organocatalytic Domino Cyclizations

Scheme 156. Oxidative Alkoxy Radical β-Fragmentation

BF


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Scheme 157. Oxidative Fragmentation of 1,2-Diols (DMAP = 4-Dimethylaminopyridine)

Scheme 158. MARDi Cascade

an oxidative cleavage of the triol 468 using sodium periodate, which provided the seven-membered ring 469 without loss of optical purity (Scheme 157).252 Alternatively, an original and general oxidative fragmentation reaction of the 8-oxobicyclo[3.2.1]octenone 67 and its analogues was proposed by Nicolaou et al. based on a diastereoselective dihydroxylation− intramolecular retro-Dieckmann domino sequence to afford the cycloheptane 470 containing a bridged lactone (Scheme 157).45 Finally, Buono and Tenaglia have also reported some Baeyer−Villiger-mediated oxidative fragmentation reactions of the 8-oxo-bicyclo[3.2.1]octanes 139.73b The retro-Dieckmann-type fragmentation of 8-oxobicyclo[3.2.1]octane derivatives pioneered by Stork and Landesman in 1956259 has been frequently used for the preparation of seven-membered rings. Some of the recent examples include the fragmentation of substrates 85a−c with formic acid,51b 98a,b55 and 137a,b73a with methanol, and a series of quinone−styrene [5 + 2]-cycloadducts with primary amines.167 Coquerel, Rodriguez, and co-workers have developed a three-component approach to seven-membered rings from activated cyclopentanones, acrylic derivatives, and methanol, based on a domino Michael−aldolization−retroDieckmann (MARDi) cascade.260 In the course of the reaction, the intermediate bicyclo[3.2.1]octanol 471 is formed following a reversible Michael−aldol cascade, and its in situ retroDieckmann fragmentation gives the cycloheptane product in generally high yields and diastereoselectivity in a single simple chemical operation (Scheme 158). This methodology allows the regio- and stereocontrolled access to a variety of

time using functionalized diketone 461 as both a pronucleophile and an electrophile, leading to the bicyclic products 462 in high yield and excellent diastereo- and enantioselectivities.255

8. BICYCLO[3.2.1]OCTANES AS SYNTHETIC INTERMEDIATES In this section, the use of bicyclo[3.2.1]octane intermediates for the preparation of other ring systems will be highlighted. Functional group interconversions on bicyclo[3.2.1]octanes derivatives are not included. 8.1. Fragmentation to Seven-Membered Rings

The temporary-bridge approach has become a classic for the preparation of medium-sized rings,256 and bicyclo[3.2.1]octane derivatives have been thoroughly employed for the synthesis of polyfunctionalized cycloheptanes, which are also found in the core structure of many natural products and biologically active molecules. For example, Ramesh and Hassner have described the preparation and then the fragmentation of the tricyclic hemiacetals 463 using Suarez’s oxidative alkoxy radical βfragmentation to give the seven-membered rings 464a−d in good overall yield, albeit with low regio- and diastereoselectivity (Scheme 156).257 Under similar conditions, a diastereomeric mixture of the 8-hydroxybicyclo[3.2.1]octane 465 was converted into the corresponding cycloheptane 466; the latter underwent an elimination to provide the cycloheptene 467 (Scheme 156).258 As an early application of their enantioselective approach to 1-hydroxy-8-oxo-bicyclo[3.2.1]octanes, Rueping et al. proposed BG


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Scheme 159. Intramolecular MARDi Cascade

targeted bicyclic products 476a,b in good yield as a 7:1 mixture of diastereomers following acidic workup (Scheme 159). The formation of 476 is believed to result from a six-elemental-step process as detailed below. First, the domino Michael−aldol sequence from 472 afforded the tricyclic oxa analogues of 71 and 73 in a comparable manner as described in Scheme 27, which then gave the bicyclic cycloheptanols 473a,b following a domino retro-Dieckmann fragmentation with methanol. Under the basic reaction conditions, 473a,b are in dynamic equilibrium with their diastereomers 474a,b, both of which underwent a methanol-assisted trans-lactonization followed by an irreversible elimination reaction to afford the monocyclic carboxylates 475a,b. Upon treatment with hydrochloric acid, the water-soluble δ-hydroxy carboxylates 475a,b underwent lactonization to produce the bicyclic δ-lactones 476a,b, respectively. In the course of their studies on the total synthesis of (−)-CP-263,114, Yoshimitsu, Nagaoka, and co-workers reported the preparation of bicyclo[4.3.1]decanes, incorporating the seven-membered ring, by selective fragmentation of the

functionalized and substituted seven-membered rings. One attractive feature of this reaction is the easy and stereocontrolled modulation of the substitution array in the heptacyclic product as a function of the reaction substrates. The reaction allows the control of up to five newly created stereocenters and a complete chiral induction in the case of an optically active ketone precursor. The high level of diastereoselectivity observed has been attributed to total thermodynamic control of the reaction. This reaction is very general and has been transposed in the heterocyclic series for the preparation of azepanes, oxepanes, and thiepanes,261 and it has found some applications in the expeditious syntheses of the functionalized bicyclo[5.3.0]decane and bicyclo[5.4.0]undecane ring system found in some families of terpenoids.46,262 Very recently, Boddaert, Coquerel, and Rodriguez reported an intramolecular version of this reaction to prepare the bicyclic ring system of the 2,3-secoaromadendrane sesquiterpenes plagiochilide from the simple achiral precursor 472.46 Upon treatment with DBU in methanol, 472 afforded directly the BH


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Scheme 160. Fragmentation of Isotwistanes to Bicyclo[4.3.1]decanes

Scheme 161. ent-Kaurane Diterpenes Fragmentations (DEAD = Diethyl Azodicarboxylate)

8.2. Fragmentation to Six-Membered Rings

isotwistane skeleton. In their model studies, the substrate 477 obtained from 256 was fragmented into the desired ring system 478 by a Grob reaction (Scheme 160).142 Later, the same group reported the alkoxy radical-mediated oxidative fragmentation of the one-carbon bridge of the bicyclo[3.2.1] core in 479 (derived from 258) to afford the hydroxy iodo bicyclo[4.3.1]decane 480 (Scheme 160).143 The latter was then transformed into the natural product. During a synthetic study of the same natural product, Takemoto and co-workers accomplished the assembly of the functionalized target ring system 482 by using a reductive radical-mediated fragmentation of 481 with lithium naphthalenide.133 Mehta and Kumaran have also reported a related fragmentation on a simple model.78

This is a quite important approach that requires bridged precursors properly functionalized at the two-carbon bridge. Some naturally occurring ent-kaurane diterpenes have been modified by fragmentation of the bicyclo[3.2.1]octane subunit of their tetracyclic framework. For example, the group of Takeya263 reported the conversion of the excisanin analogue 483 into the α-methylene-γ-lactone 484 under Mitsunobu reaction conditions, and Xu and Wang described264 a related retro-aldol-based fragmentation of the natural product maoecrystal A to give the enal 485 (Scheme 161). More recently, related selective oxidative fragmentation of the lowBI


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Scheme 162. Fragmentations toward (+)-Vernolepin

Scheme 163. Unexpected Oxidative Fragmentations (m-CPBA = m-Chloroperbenzoic Acid; NBS = N-Bromosuccinimide)

Scheme 164. Oxidative Fragmentations of CC Bonds

catalyzed fragmentations related to 486 → 487 combined with carbocyclizations (Friedel−Crafts alkylation or Pictet−Spengler).267 In 1999, Blechert and co-workers observed some unusual fragmentation reactions of the bicyclo[3.2.1]octenones 392a and 392b.225 On treatment with m-CPBA, 392a did not undergo a Baeyer−Villiger oxidation but diastereoselectively furnished the corresponding endo-epoxide, which fragmented to the cyclohexenone 490 in the presence of a catalytic amount of sulfonic acid (Scheme 163). This unusual rearrangement is believed to be induced by polarization of both oxygen functionalities in the intermediate epoxide. The reaction of 392b with N-bromosuccinimide yielded the carboxylic acid 491 via a mechanism that remains to be clarified.

cost sweetener stevioside provided interesting tricyclic precursors of naturally occurring jolkinolides diterpenes.265 In more simple systems, Ogasawara and co-workers have exploited retro-aldol fragmentations of 2-oxo-bicyclo[3.2.1]octan-7-ol derivatives to obtain optically active functionalized six-membered rings. The strategy is illustrated in Scheme 162 with the acid-catalyzed fragmentation of the hydroxy ketone 486 for the preparation of the lactol 487, a potential intermediate in the total synthesis of the sesquiterpene lactone natural product (+)-vernolepin.266 Because of difficulties with introducing an enone functionality in 487, another route was examined based on the retro-Claisen fragmentation of the diketone 488 to the keto ester 489. The group has reported several elegant formal or total syntheses from more complex analogues of 486 using cascade reactions initiated by acidBJ


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Scheme 165. Fragmentation toward Bicyclo[5.3.1]undecanes

Scheme 166. Rearrangement toward Bicyclo[3.3.0]octanes (PMP = 4-Methoxyphenyl)

Scheme 167. Lead Tetraacetate-Promoted Cleavage

Scheme 168. Heteroatom-Assisted Beckmann Fragmentation

obtained from ketone 493 to give the expected 1,2,4trisubstituted cyclohexane (Scheme 164).268 Bicyclo[3.2.1]octane derivatives can be used as templates for the synthesis of larger ring systems incorporating a sixmembered ring. For example, several approaches to the bicyclo[5.3.1]undecane ring system, the AB ring system of taxane diterpenes, have relied on the selective fragmentation of tricyclo[5.3.1.02,6]undecane compounds. In this field, Kakiuchi and co-workers have performed an oxidative cleavage of the tetrasubstituted double bond in substrate 494 derived from 368 to give the bicyclic diketone 495 (Scheme 165).207 In their synthetic studies on taxoids, the groups of Chavan269 and Spitzner270 have reported closely related oxidative fragmentation reactions. Alternatively, in their approach to the same ring system, Toyota and Ihara have used a Grob fragmentation of

To a lesser extent, the cleavage of the two-carbon bridge in unsaturated bicyclo[3.2.1]octane derivatives has also been used to prepare functionalized six-membered rings. For example, Cha and co-workers realized an oxidative cleavage of the olefin bond in the [4 + 3]-cycloadduct 492 to form the corresponding functionalized aza-bicyclo[3.3.1]nonane product,88 and Mi and Maleczka, Jr., reported the ozonolysis of the methyl enol ether BK


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Scheme 169. Fragmentations toward Optically Active Cyclopentanes

Scheme 170. Domino Pinacol−Pinacol Reaction

bicyclo[3.2.1]octadienediones 501 as an interesting entry to bicyclo[3.3.0]octadienones 502.272 Contemporaneously, Biju and Rao explored some interesting synthetic routes for the elaboration of polyquinanes and proposed the preparation of the diquinane product 504 by a lead tetraacetate-promoted, selective ring cleavage of diol 503 obtained from 236 (Scheme 167).131 More recently, Yang et al. described an approach to 1,3-disubstituted cyclopentane derivatives 505 based on the similar oxidative cleavage of 1,2cis-diols 381a, derived from the chiral pool, in good yield.216b In a related tetracyclic complex system, Laxmisha and Rao reported an original heteroatom-assisted Beckmann fragmentation of the keto oxime 506 mediated by triflic anhydride to afford the tricyclo[4.3.3.01,6]dodecane compound 507 bearing two fused five-membered rings in good yield (Scheme 168).130 The group of Ogasawara has reported a series of interesting transformations for the preparation of optically active cyclopentanoids from enantiomerically enriched bicyclo[3.2.1]octanes.273 For example, on treatment with m-CPBA, 508 furnished regioselectively the lactone 509 together with a minor amount of the regioisomeric lactone (Scheme 169). The reduction of 509 with lithium aluminum hydride gave the diol 510, which was converted into cyclopentanoid monoterpenes. The intermediate bicyclic lactone can also undergo a ringopening reaction with nucleophilic amines to give the corresponding hydroxy amide cyclopentane derivative. The same group has also reported a related ozonolytic cleavage strategy toward functionalized cyclopentanes.274 In another

Scheme 171. Homoallyl−Homoallyl Radical Rearrangement

the hydroxy tosylate 496 to prepare the desired product 497, but the competitive formation of the oxetane 498 could not be avoided.156 8.3. Fragmentation to Five-Membered Rings

The fragmentation of the three-carbon bridge of bicyclo[3.2.1]octane derivatives constitutes a particularly attractive strategy to stereoselectively prepare polysubstituted five-membered rings. For example, back in 1999 Seki, Uyehara, and co-workers studied the anionic [1,3]-rearrangement of 2vinylbicyclo[3.2.1]oct-6-en-2-ols to prepare bicyclo[3.3.0]octane derivatives.193c,271 On treatment with KHMDS, the substrate 499, obtained by a pinacol rearrangement of the corresponding bicyclo[2.2.2]octane followed by addition of methyllithium, was converted into the hydroxydiquinane 500 in good yield (Scheme 166). Alternatively, Nair et al. reported a complementary simple photolytic rearrangement of Scheme 172. Wolff-Mediated Ring-Contraction

BL


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Scheme 173. Rearrangement toward Tricyclo[4.2.1.02,5]nonane

bicyclo[3.2.1]octanone moiety of compound 518, obtained in four steps from 242 as a key step in their total synthesis of (+)-acanthodoral.135 Irradiation of diazoketone 518 with UV light in dry MeOH at room temperature cleanly induced a stereoselective Wolff rearrangement to provide the ringcontracted bicyclo[3.1.1]heptane system 519 with the endomethoxycarbonyl group, which was then easily converted to the natural product (Scheme 172). The group of Harmata has thoroughly described the ringcontraction reaction of tricyclo[4.2.1.12,5]decane compounds into the corresponding tricyclo[4.2.1.02,5]nonane via a quasiFavorskii rearrangement.81a,82,277 The conversion of bromo ketone 151b into the corresponding ring-contracted ketone 520 depicted in Scheme 173 is representative of this reaction. In the presence of an organolithium compound, 151b underwent nucleophilic addition to the carbonyl group, and the resulting alcoholate rearranged to give ketone 520. The latter was then converted into the tricyclic compound 521 exhibiting the ring system of tricycloclavulone by a ringrearrangement metathesis. Noticeably, in the transformation 151b → 520, one of the two bicyclo[3.2.1]octane moieties in 151b was contracted into a bicyclo[2.2.1]heptane ring system, while the other was changed into a bicyclo[3.2.0]heptane system. Finally, Uyehara and co-workers have described another anionic [1,3]-rearrangement of a bicyclo[3.2.1]octane compound resulting formally in a one-carbon ring-expansion reaction.193b The reaction of the 8-methylenebicyclo[3.2.1]oct-6-en-2-ol compounds 522 with potassium hydride gave regio- and diastereoselectively the bicyclo[4.3.0]nonane derivative 523 containing a cyclopentadiene ring amenable to further transformations (Scheme 174).

Scheme 174. Anionic [1,3]-Rearrangement toward Bicyclo[4.3.0]nonane

closely related work, they reported the retro-Claisen fragmentation of the trione 511 with methanol, which afforded the cyclopentanone 512 (Scheme 169).275 This result is particularly interesting regarding the regioselectivity of the retro-Claisen reaction when compared to the closely related transformation 488 → 489 (see Scheme 162), with the nucleophilic addition of methanol occurring at the lesshindered keto group of the bicyclic ring system. 8.4. Rearrangement to Other Bicyclooctane Systems

In an approach to the synthesis of spirobicyclo[4.5]decane compounds, Biju and Rao have used an intermediate bicyclo[3.2.1]octane derivative (actually a tricyclo[6.2.1.01,5]undecane) for the net replacement of the bridgehead methoxy group by a methyl group in the bicyclo[2.2.2]octane compound 513 (actually a tricyclo[5.2.2.01,5]undecane).276 The sequence was initiated by a pinacol rearrangement of 513 into 514 in the forward direction; then an exo-selective 1,2-addition of methyl lithium to the enone generated the corresponding tertiary alcohol, which finally underwent another pinacol rearrangement in the backward direction to restore the original bicyclo[2.2.2]octane moiety and provided 515 (Scheme 170). In their approach to atisirane diterpene natural products, Toyota, Ihara, and co-workers used a homoallyl−homoallyl radical rearrangement for the construction of the bicyclo[2.2.2]octane moiety of the target molecules.155 For example, on treatment with nBu3SnH in the presence of AIBN, the diastereomeric thioimidazolides 516 were smoothly converted to the rearranged product 517 (Scheme 171). A tin-free rearrangement was also developed.157b Three recent syntheses of platencin have relied on similar homoallyl− homoallyl radical rearrangement to construct the bicyclo[2.2.2]octane core of the natural product from a bicyclo[3.2.1]octane derivative.7b,160

9. CONCLUSION The present comprehensive review describes the evolution of the state of the art in the synthesis and reactivity of functionalized bicyclo[3.2.1]octanes in modern synthetic organic chemistry during the past 13 years. The growing interest in this chemistry, all over the world, is mainly driven by both the ubiquity of this skeleton in many important natural compounds and by its specific reactivity involving the ring strain of the system. In this evolution, the need of more selective approaches to complete total syntheses of elaborated natural targets largely leads the way, resulting in the development of a large panel of very original methodologies together with the invention of new general transformations able to increase efficiently the functional diversity. Also of interest are the efforts made at controlling the diastereoselectivity and at elaborating optically active scaffolds. In these two directions, the development of ionic, radical, and metal-catalyzed reactions or cycloadditions and rearrangements has followed a regular progression with a special interest toward the utilization of the

8.5. Ring-Contraction/Expansion to Other Bicyclic Systems

In their total synthesis of (+)-codeine, White et al. have reported the regioselective Beckmann ring-expansion of the advanced bicyclo[3.2.1]octanone precursor 214 to provide the pentacyclic ring system of the target natural product incorporating the required aza-bicyclo[3.3.1]nonane core (Scheme 73).121 On the other hand, Zhang and Koreeda used a Wolff rearrangement mediated ring-contraction of the BM


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chiral pool and the implication of interesting and very elegant domino sequences. More recently, as in many areas of organic synthesis, organocatalysis has allowed efficient enantioselective approaches to optically enriched bicyclo[3.2.1]octanes from achiral precursors, paving the way for further innovative realizations.

organic chemistry (multiple bond-forming reactions and catalysis) and the total synthesis of natural products. In 2002 he was awarded the Fournier−French Chemical Society prize for his Ph.D. Thesis dissertation, and in 2009 he completed his Habilitation at AixMarseille Université.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected] (Y.C.), jean.rodriguez@ univ-amu.fr (J.R.). Notes

The authors declare no competing financial interest. Biographies

Jean Rodriguez was born in Cieza (Spain) in 1958, and in 1959 his family emigrated to France. After studying chemistry at Aix-Marseille Université (France), he completed his Ph.D. as a CNRS researcher with Prof. B. Waegell and Prof. P. Brun in 1987. He completed his Habilitation in 1992, also at Marseille, where he his currently Professor and Director of the UMR-CNRS-7313-iSm2. His research interests include the development of domino and multicomponent reactions and their application in stereoselective synthesis. In 1998 he was awarded the ACROS prize in Organic Chemistry, and in 2009 he was awarded the prize of the Division of Organic Chemistry from the French Chemical Society

Marc Presset was born in Thonon-les-bains (France) in 1981. After completing his Master in Chemistry in 2005 at the University of Avignon (France) under the supervision of Pr. Pucci, he joined the Ecole Normale Supérieure de Cachan, where he obtained the Agrégation de Sciences Physiques in 2007. He then moved to AixMarseille Université, where he obtained his Ph.D. under the supervision of the co-authors in 2010. He is currently postdoctoral associate at University of Pennsylvania in the group of Prof. Gary A. Molander. His research focuses on the development of new synthetic methods and their applications in total synthesis

ACKNOWLEDGMENTS M.P. thanks the ENS Cachan for a fellowship award. Financial support from the French Research Ministry, Aix-Marseille Université, and the CNRS (UMR 7313) is also gratefully acknowledged. REFERENCES (1) (a) Kompa, G.; Hirn, T. Chem. Ber. 1903, 36, 3610. (b) Kompa, G.; Hirn, T.; Rohrmann, W.; Beckmann, S. Justus Liebigs Ann. Chem. 1936, 521, 242. (2) Filippini, M.-H.; Rodriguez, J. Chem. Rev. 1999, 99, 27. (3) Bridged compounds: (a) Zhao, W. Chem. Rev. 2010, 110, 1706. (b) Ruiz, M.; López-Alvarado, P.; Giorgi, G.; Menéndez, J. C. Chem. Soc. Rev. 2011, 40, 3445. (4) Liebman, J. F.; Greenberg, A. Chem. Rev. 1976, 61, 8456. (5) Presset, M.; Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem. 2010, 2247. (6) Rinner, U.; Lentsch, C.; Aichinger, C. Synthesis 2010, 3763. (7) (a) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2548. (b) Palanichamy, K.; Kaliappan, K. P. Chem.Asian J. 2010, 5, 668. (c) Lu, X.; You, Q. Curr. Med. Chem. 2010, 17, 1139. (8) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36. (9) Liang, H.; Ciufolini, M. Org. Prep. Proced. Int. 2010, 42, 111. (10) (a) Filippini, M.-H.; Faure, R.; Rodriguez, J. J. Org. Chem. 1995, 60, 6872. (b) Patrusheva, O. V.; Verbitskii, G. A.; Vysotskii, V. I. Tetrahedron 2004, 60, 1761. (11) McDougal, N. T.; Schaus, S. E. Angew. Chem., Int. Ed. 2006, 45, 3117. (12) Liau, B. B.; Shair, M. D. J. Am. Chem. Soc. 2010, 132, 9594. (13) Bhunia, S.; Liu, R.-S. J. Am. Chem. Soc. 2008, 130, 16488. (14) Kumar, U. K. S.; Patra, P. K.; Ila, H.; Junjappa, H.; Bharadwaj, P. K. J. Chem. Soc., Perkin Trans. 1 2000, 1547. (15) Grant, T. N.; West, F. G. Org. Lett. 2007, 9, 3789.

Yoann Coquerel was born in Rouen (France) in 1975. After studying chemistry at the University Joseph Fourier in Grenoble (France), where he completed his Ph.D. in 2001 under the supervision of Prof. Jean-Pierre Deprés, he moved to Florida State University in Tallahassee (U.S.A.) to join the group of Prof. Robert A. Holton as a postdoctoral associate. Since 2003, he works as a CNRS researcher with Prof. Jean Rodriguez at Aix-Marseille Université (France). His research interests include the development of eco-compatible synthetic BN


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