A RTEFACTOS

The interaction of the electron-deficient carbenoic carbon of the metal carbene intermediate with a pair of non-bonding electrons from a Lewis base (B:) generates a metal

complex associated ylide or a free ylide (Scheme 14). The ylide intermediate thus generated is usually highly reactive and undergoes further reactions to give stable products.

The common Lewis bases utilized to generate ylides include ethers, sulfides, amines, carbonyls and imines. Common reactions of the ylides include:

(1) [2,3]-sigmatropic rearrangement of allylic, propargylic and allenic ylides, (2) [1,2]-shift (Stevens rearrangement),

(3) 1,3-dipolar cycloaddition of the ylides generated from carbonyl compounds or imines,

(4) nucleophilic addition/elimination.

ML_n R² R¹

+ B: ML_n

R² R¹

B

B R² R¹

+ ML_n

Products Scheme 14. Ylide formation.

Until recently, the chemistry of oxonium ylides had received little attention compared to ammoniun and sulfonium ylides.1b,8,20d,41

Oxonium ylides are characterized by their instability and high reactivity; unlike the ammonium and sulfonium ylides, they have not been yet isolated and are difficult to characterize. Most of the evidence for their existence is circumstantial and is based on analysis of the products after the rearrangement of these putative intermediates. Over the past decade, oxonium ylides have found significant synthetic utility due to their easy generation by the reaction of metal carbenoids with ethers. The major reaction pathways for oxonium ylides are [2,3]-sigmatropic rearrangement, when an allyl group is present, and [1,2]-Stevens rearrangement. They may also undergo competing reactions such as β-eliminations and reactions with nucleophiles.

1.3.3.1. [1,2]-Stevens rearrangement of oxonium ylides

One of the earliest examples of the formation of an oxonium ylide was reported by Nozaki and co-workers (Scheme 15).^22b,42 The copper-catalysed reaction of ethyl diazoacetate 50 and phenyloxetane 49 delivered the tetrahydrofuran 52 in 87% yield. The isolation of the product 52 provided strong evidence for the formation of an oxonium ylide and its subsequent [1,2]-rearrangement. The oxonium ylide 51 is formed by the nucleophilic attack of a lone pair of the etheral oxygen of 49 on the metal carbenoid

generated from the diazocarbonyl compound 50. The oxonium ylide 51 then undergoes a [1,2]-shift, even though concerted [1,2]-shifts are forbidden processes according to the Woodward-Hoffmann rules.⁴³ Indeed, the [π2s + ω2s] process for a reaction involving 4n electrons is symmetry-forbidden, moreover the reaction is symmetry-allowed for [π2s + ω2a] or [π2a + ω2s] processes but geometrically impossible. Evidence has been obtained that oxonium ylides rearrange by a homolysis-recombination mechanism.⁴⁴ Homolytic cleavage of the oxonium ylide intermediate produces a singlet radical pair, which then recombines quickly within a solvent-cage to deliver the [1,2]-shift product 52.

O

Scheme 15. First example of [1,2]-shift of oxonium ylide and mechanism.

Since this early report, oxonium ylide generation followed by [1,2]-Stevens rearrangement has been found to be useful for the formation of new carbon-carbon bonds, and has been used extensively in organic synthesis. Johnson was the first to explore the intramolecular generation and rearrangement reaction of oxonium ylides and reported the synthesis of substituted carbocycles by a [1,2]-shift (Scheme 16).⁴⁵ He showed that the

Scheme 16. Synthesis of carbocycles via [1,2]-shift of oxonium ylide.

This approach was then used by West and co-workers to prepare a variety of substituted cyclic ethers (Scheme 17). They successfully utilized the tandem cyclic oxonium ylide generation/Stevens [1,2]-shift protocol to synthesise functionalised

tetrahydrofurans.⁴⁶ Catalytic decomposition of alkoxy-α-diazoketones 56 furnished the cyclic ethers 57 in good yield. They concluded that oxonium ylides generated from benzylic ethers generally undergo [1,2]-rearrangement with migration of the benzyl group rather than the ring contraction as described above.

O Scheme 17. Synthesis of cyclic ethers via [1,2]-shift of oxonium ylide.

West and co-workers recently studied reactions of diazoketones in which competitive formation of two different oxonium ylides via the same metallocarbene precursor was possible (Scheme 18).⁴⁷ The metallocarbenoid could undergo intramolecular five or six-membered oxonium ylide formation. The study revealed that five-membered ylide formation is generally favoured. However, the properties of the migrating group in the subsequent rearrangement reaction may override the preferential formation of a five-membered ring. Indeed, when α-diazoketone 58 was treated with Cu(tfacac)2, pyranone 62 was formed predominantly since allylic [2,3]-sigmatropic rearrangement is more feasible than a [1,2]-shift. This result strongly suggests that the two possible ylides 59 and 60

Scheme 18. Catalyst and ring size effects on preselectivity of oxonium ylide rearrangements .

They noticed that the catalyst can dramatically influence the reaction selectivity.

When Rh2(OAc)4 and Rh2(tpa)4 were employed as catalysts, the reaction gave the five-membered ylide formation/[1,2]-benzyl shift product 61 predominantly. However, even a relatively minor change in the ligand of the copper catalyst (e.g. from Cu[tfacac]2 to Cu[hfacac]2) significantly altered the selectivity. The catalyst-dependent selectivity strongly suggests the involvement of a metal-associated ylide in the product-forming step.

The catalyst may thus alter the properties of ylide and affect the equilibrium between different species such as 59 and 60.

1.3.3.2. [2,3]-Sigmatropic rearrangement of allylic oxonium ylides

When an allylic ether is used for the ylide formation, the oxonium ylide that is generated may undergo [2,3]-sigmatropic rearrangement, which is one of the most versatile bond reorganisation processes in organic chemistry.

The intermolecular reaction has received considerable attention,⁴¹ but competitive cyclopropanation is frequently a major problem. The degree to which cyclopropanation occurs is highly dependent on the steric environment around the ether oxygen, the alkene substituents and the catalyst. However, there are many reports demonstrating that predominant ylide formation and subsequent [2,3]-sigmatropic rearrangement can occur.

R¹

Scheme 19. Intermolecular oxonium ylide formation and subsequent [2,3]-sigmatropic rearrangement.

For example, Doyle has explored the intermolecular generation of allylic oxonium ylides from simple allyl ethers (Scheme 19).⁴⁸ The generation of oxonium ylide 65 occurred almost exclusively, when diazoketone 63 and allylic methyl ether 64 were treated with rhodium(II) acetate. The alkene geometry was found to dictate the stereochemical course of the reaction, and the rearrangement of the putative oxonium ylide 65 is thought to proceed through an ‘envelope’ transition state in which steric interactions between the methyl substituent and the carbonyl group are minimised.

Intermolecular oxonium ylide formation and subsequent [2,3]-rearrangement reactions have found limited application in organic synthesis, compared to the more widely used intramolecular processes. Indeed, cyclic oxonium ylides are readily generated through intramolecular reaction of a metal carbene and a suitably positioned ethereal oxygen. This cyclic ylide formation/[2,3]-sigmatropic rearrangement reaction sequence has been employed by several groups for the synthesis of cyclic ethers and carbocycles. The first examples of intramolecular oxonium ylide and subsequent [2,3]-sigmatropic rearrangement were reported by Pirrung in 1986, where he described the construction of five-, six- and eight-membered oxygen heterocycles (Scheme 20).⁴⁹ Treatment of diazoketone 68 with rhodium(II) actetate produced furanone 69, whereas diazoketone 70 afforded eight-membered ring oxygen heterocycle 71. The ring expansion clearly illustrated the preference of the ylide to undergo symmetry allowed [2,3]-sigmatropic rearrangement over the symmetry forbidden [1,2]-process.

O

68

N2

O

Rh₂(OAc)₄

O

O 70%

91%

69

R R R = H

R = CO₂Me

O

70 N2

Rh₂(OAc)₄ 81%

67%

71

R R = H

R = CO₂Me O

O O R

Scheme 20. Pirrung’s synthesis of cyclic ethers via intramolecular oxonium ylide generation and [2,3]-sigmatropic rearrangement.

Simultaneously, Johnson and Roskamp also investigated this methodology and provided a set of additional examples (Scheme 21).⁴⁵ They found that diazoketone 72 was converted into the six-membered heterocycle 73, and the propargylic ether 74 underwent

the [2,3]-rearrangement to provide the allene 75. The latter example shows that the reaction is not only limited to allylic ethers.

O

Scheme 21. Johnson and Roskamp’s synthesis of cyclic ethers via [2,3]-sigmatropic rearrangement.

Catalytic oxonium ylide formation and [2,3]-sigmatropic rearrangement has been applied to the total synthesis of the anti-fungal agent (+)-griseofulvin.⁵⁰ Treatment of the enantiomerically pure diazoketone 76 with rhodium(II) pivalate in benzene under reflux afforded the rearrangement product 77 as a single diastereoisomer in good yield with high enantiomeric purity following ‘transfer of chirality’. The stereochemistry of this process can be understood in terms of a transition state model that resembles an oxabicyclo[3.3.0]octane ring system with the key, stereochemistry-defining methyl group located on the convex face. A further six steps, including a Dieckmann cyclization to construct the spirocyclic core, were necessary to convert the benzofuranone intermediate 77 into the target natural product.

O

Scheme 22. Total synthesis of (+)-griseofulvin via [2,3]-rearrangement of oxonium ylide.

West and co-workers have developed an iterative approach to polycyclic ethers based on the [2,3]-sigmatropic rearrangement of cyclic oxonium ylides (Scheme 23).⁵¹ The polycyclic etheral structure occurs in marine ladder polyether toxins, such as brevetoxin B.

In the West’s approach, the diazoketone 78 was treated with Cu(tfacac)2 to give the [2,3]-rearrangement products 79 and 80 with high diastereoselectivity and good yields, along with a small amount of the C-H insertion product 81. This study proved once again that copper catalysts favour ylide formation, while rhodium catalysts promote carbenoid C-H insertion. After epimerization, the mixture of diastereoisomers 79 and 80 was converted into diazoketone 82, which was then subjected to the same Cu(tfacac)2-catalysed ylide formation/[2,3]-sigmatropic rearrangement. Tris(tetrahydropyran) 83 was isolated in an excellent yield as the only detectable isomer.

78

Scheme 23. Iterative approach to polycyclic ethers based on stereoselective oxonium ylide [2,3]-shifts.

1.3.3.3. The [1,4]-shift reaction

When oxonium ylide formation occurs, products derived from either [2,3]-sigmatropic rearrangement or [1,2]-migration are usually observed and products formed by [1,4]-migration are very unusual. Pirrung and co-workers were the first to notice an example of [1,4]-migration in a rhodium(II)-mediated reaction,⁵⁰ whereas West⁵² and Clark⁵³ described the isolation of [1,4]-migration products in low yield when oxonium ylides were derived from copper(II) carbenoids. Indeed, diazoketone 84 underwent predominant C-H insertion when treated with Rh2(OAc)4, and only a small amount of [1,2]-shift product 85 was obtained (Scheme 24). However, the use of Cu(hfacac)2 gave the [1,2]- and [1,4]-migration products 85 and 86 along with a small amount of the C-H insertion product 87. West and co-workers proposed a mechanism for the formation of the

[1,2]- and [1,4]-migrated products. They firstly assumed that the [1,4]-migration product 86 is derived from the same ylide and radical pair intermediates that lead to the [1,2]-shift product 85, but with recombination at oxygen instead of carbon (path a). However, because radical homodimers were not isolated, they suggested that an alternative, metal-assisted mechanism is operating in this case (path b).

O Scheme 24. Copper-catalysed [1,4]-migration mechanism.

The formation of [1,4]-migration products has been observed to be the dominant pathway in the rhodium(II) catalysed decomposition of α-diazo β-keto esters in certain cases.⁵⁴ Since Rh(II)- and Cu(II)-catalysed reactions of diazo compounds give different product distributions, Dhavale and co-workers proposed an independent mechanism for the rhodium carbenoid-mediated [1,4]-rearrangement (Scheme 25).^54a They suggested that the oxonium ylide 93 can not be a possible intermediate for the formation of [1,4]-migration because of the large distance between the migration origin and the terminus. To explain the outcome of the reaction, they proposed an intermediate 94 resulting from migration of the -CH2Ar group from oxygen to Rh, and they considered 94 as the true intermediate in the formation of both [1,2]- and [1,4]-migration products 90 and 89 respectively. The selectivity of the [1,2] versus [1,4]-migration depends on the electronic nature of the migrating group. For electron-rich substituents only [1,4]-migration products were isolated, but in the case of electron-poor substituents, both products were obtained.

O

Scheme 25. Rhodium-catalysed [1,4]-migration mecahnism.

1.3.3.4. Miscellaneous reactions of oxonium ylides

Besides undergoing [2,3]-sigmatropic rearrangement, [1,2]-shift and [1,4]-migration reactions, oxonium ylide intermediates can react with nucleophiles or react through other pathways. A recent example is a multicomponent reaction of the diazoketone 96 with an alcohol and an aldehyde (Scheme 26).⁵⁵ This reaction is presumed to involve a tricyclooxonium ylide intermediate 97 that undergoes ring opening to bicyclic zwitterion 98. Subsequent selective nucleophilic attack of the alcohol and aldol condensation with the aldehyde gave the product 99.

96

Scheme 26. Multicomponent reaction of oxonium ylide.

1.3.3.5. Enantioselective generation and rearrangement of oxonium ylides

The development of asymmetric versions of reactions involving oxonium ylides, in particular by using asymmetric catalysts, is very challenging.^20b,56 If the catalyst remains associated with the ylide during the subsequent rearrangement process, asymmetric induction might be observed (Scheme 27). However, if the catalyst dissociates and therefore is not involved in the ylide rearrangement step, it would lead to either a ‘free’

ylide, for which asymmetric induction would be very unlikely, or to an enantioenriched

‘configurationally restricted’ ylide, where subsequent enantioselective transformations might be possible (Scheme 27).

R2C N2

ML^*n

R2C ML^*n

:X Y R2C

X ML^*_n

Y

-ML^*n

R2C X Y racemic product formation

R₂C X Y enantioselective product

formation possible achiral

diazo compound

chiral metallocarbene

catalyst associated ylide

'free' ylide -ML^*n

enantioenriched 'configurationally restricted'

ylide Scheme 27. Asymmetric ylide reactions.

Recent developments have shown that catalytic asymmetric synthesis is possible in several ylide transformations. Nozaki was the first to recognize the potential of the asymmetric reaction, and he showed that optically active tetrahydrofurans can be obtained from racemic oxetanes (Scheme 28).⁴² The reaction of (±)-2-phenyl-oxetane 49 and methyl diazoacetate 50 with the chiral copper complex 104 furnished a mixture of diastereomeric tetrahydrofurans 52a and 52b resulting from a [1,2]-shift of the benzyl group. Although the products were obtained in good yield, the level of asymmetric induction was very low.

These promising results prompted Katsuki to explore the reaction with another chiral copper complex (e.g. 105). He obtained a mixture of cis and trans tetrahydrofurans 102a and 102b, but this time with high enantiomeric purity.⁵⁷

O

Scheme 28. First examples of catalytic asymmetric [1,2]-shift of oxonium ylide.

The asymmetric version of the carbenoid-mediated ylide formation and [2,3]-sigmatropic rearrangement sequence has also been explored and was first reported by McKervey in 1992.⁵⁸ A chiral Rh(II) phosphate catalyst was employed, which resulted in enantioselectivities of up to 30% ee. Further improvement of enantiocontrol (up to 60% ee) was achieved when chiral carboxylate Rh(II) catalysts were used. Indeed, treatment of the diazoketone 106 with the chiral rhodium(II) complex 108 afforded the benzofuranone 107 in excellent yield and with reasonable enantiomeric purity (Scheme 29).

Rh₂L^*₄

Scheme 29. First examples of catalytic asymmetric [2,3]-rearrangement of oxonium ylides.

Following this initial study, an intramolecular asymmetric tandem oxonium ylide formation and [2,3]-rearrangement sequence catalysed by a chiral Cu(I) diimine complex 111 was reported by Clark and co-workers.⁵⁹ The achiral diazoketone 109 was converted in the non-racemic cyclic ether 110 with up to 57% ee.

In summary, the formation of oxonium ylides and their subsequent rearrangement reactions are becoming increasingly popular reactions for organic synthesis. High levels of chemo-, regio- and stereoselectivity can be achieved by paying attention to the design of the substrate and the choice of the catalyst to favour the desired reaction pathway. Even though oxonium ylide chemistry has already been successfully applied in complex natural product synthesis, the potential of this chemistry is yet to be fully exploited.

In document Modelo para la evaluacion por competencias en proyectos informaticos de la Universidad de las Ciencias Informaticas (página 68-73)