A NÁLISIS DEL MODELO

Catalytic generation and rearrangement of oxonium ylides offers a potentially versatile approach to the synthesis of carbocycles. The first example where carbocycles were constructed using this strategy comes from Johnson’s original studies on the generation of oxonium ylides.⁴⁵ The rhodium-mediated reaction of the diazoketone 143 delivered mainly the cyclobutane 144 resulting from the [1,2]-rearrangement with ring contraction, but a small amount of the [2,3]-rearrangement product 145 was also isolated (Scheme 43). Although the carbocycles constructed were cyclobutanone and cyclohexenone, the reaction had potential for the synthesis of other ring sizes, provided that appropriate substrates were used.

N2

O OMe O OMe

OMe O

Rh₂(OAc)₄ C6H6, r.t.

45% (3:1) 10%

+

143 144 145

Scheme 43. First example of carbocycle construction by oxonium ylide generation and rearrangement.

Subsequently, West described the synthesis of O-bridged medium-sized rings via transient fused bicyclic oxonium ylides, generated by the reaction of Rh2(OAc)4 with cyclic ethers bearing a tethered diazoketone.¹⁰⁵ The tetrahydrofuran 146 underwent an efficient [1,2]-shift to give the ether-bridged cycloheptanones 147 and 148 with very good diastereoselectivity and predominant retention of configuration. This strategy was then extended to the formation of the cyclooctanones 150 and 151 using the tetrahydropyran 149 (Scheme 44).

O

Scheme 44. Synthesis of O-bridged medium sized rings via [1,2]-shift.

West and co-workers also described the efficient synthesis of fused oxabicyclo[3.2.1]octanones and oxabicyclo[4.2.1]nonanones using sulfur-directed Stevens rearrangement of oxonium ylides (Scheme 45).¹⁰⁶ The mixed cyclic acetals with pendant diazoketone side chains underwent rearrangement to afford ether-bridged cycloheptane and cyclooctane ring systems. Thus, treatment of diazoketones 152 and 155 with Cu(hfacac)2

provided the oxabicycles 153 and 156 respectively through a [1,2]-shift of the five-membered oxonium ylide intermediates. In some cases, minor amounts of products resulting from the [1,2]-shift of a sulfonium ylide were isolated. Importantly, the thioaryl group present in the product was used to direct the rearrangement as well as to trigger the cleavage of the bridging ether. After protection of the ketones, the electron transfer reductive desulfurisation produced the ring-opened products 154 and 157 in excellent yields.

Scheme 45. Synthesis of fused medium rings via [1,2]-shift.

In the meantime, Clark and co-workers reported a novel method for the preparation of medium-ring cycloalkenones by tandem intramolecular generation and [2,3]-rearrangement of an oxonium ylide (Scheme 46).¹⁰⁷ Treatment of diazoketones 158 with rhodium(II) acetate resulted in the formation of a rhodium carbenoid species which was immediately trapped by the tethered allylic ether to generate a highly reactive ylide 159.

Subsequent ylide rearrangement delivered the cyclic ketones 160 and 161. The major reaction pathway was ring-expanding [2,3]-rearrangement to give the medium ring ketone 160, whereas the cyclic ketone 161 was formed as a minor product by a ring-contracting [1,2]-rearrangement.

O N2

OMe R

OMe R O

O

OMe

R

+ O

OMe CH₂Cl₂, r.t.

158 159 160 161

a n = 1 R = H b n = 1 R = CH=CH₂ c n = 2 R = CH=CH₂ Rh₂(OAc)₄

39%

63%

26%

11%

9%

n n

n

n

Scheme 46. Synthesis of simple medium-ring ketones from acyclic precursors by [2,3]-rearrangement of catalytically generated oxonium ylides.

The synthesis of fused polycyclic compounds by employing conformationally constrained diazoketones as carbenoid precursors has been reported recently (Scheme 47).¹⁰⁸ The cyclisation reactions of substrates 162gave some interesting and unpredicted results. In the case of diazoketone 162 (n = 0), treatment of the substrate with Rh2(OAc)4

resulted in the formation of the fused bicyclic diene 163 in 70% yield. The homologous diazoketone 162 (n = 1) also underwent catalytic ylide formation and rearrangement.

However, in this case the best yield (71%) of diene 163 (mixture of diastereoisomers) was obtained when Cu(tfacac)2 was employed as the catalyst; substantial amounts of [1,2]-rearrangement product 164 were obtained from the Rh2(OAc)4-catalysed reaction of this substrate.

O

Scheme 47. Catalytic carbenoid generation, ylide formation and rearrangement using the trans-diazo ketone 162.

The metal-catalysed reactions of substrates 165, in which the diazoketone and ether-containing chains on the cyclohexane ring have a cis relationship, were also investigated (Scheme 48).¹⁰⁸ In these cases, the yields of diene 166 were lower than those of the trans-fused bicyclic products 163, and substantial amounts of the corresponding [1,2]-rearrangement products 167 were isolated.

O

Scheme 48. Catalytic carbenoid generation, ylide formation and rearrangement using the cis-diazo ketone 165.

The combined yields of ylide-derived products were high, but substantial amounts of [1,2]-rearrangement products were obtained in addition to the required [2,3]-rearrangement products. The divinyl substrates 162 and 165 were selected in order to avoid having an additional stereogenic centre at the ether-bearing carbon and to permit participation of the vinyl group in the rearrangement reaction, irrespective of the conformation of the intermediate cyclic oxonium ylide.

The reactions of the diastereomeric mono-vinyl systems 168 and 170 were then explored in order to discover whether substrates bearing a single vinyl group would

undergo the required rearrangement reaction (Scheme 49).¹⁰⁸ The trans-substituted cyclohexyl systems 168 and 170 differ only in the relative configuration at the vinyl-bearing stereogenic centre, but substrates of these types are potentially problematic because the stereochemistry of the additional stereogenic centre in the substrate must be defined and may have an unfavourable conformational influence. Interestingly, both substrates underwent the required ylide formation and rearrangement reaction, but the choice of the catalyst was crucial. In the case of the diazoketone 168, copper(II) hexafluoroacetylacetonate was the catalyst of choice and the [2,3]-rearrangement product 169 was obtained in 51% yield. In contrast, the rhodium- and copper-catalysed reactions of the substrate 170 both afforded the ketone 171 in excellent yield.

O

Scheme 49. Catalytic carbenoid generation, ylide formation and rearrangement using the mono-vinyl diazo ketones 168 and 170.

Clearly, the presence of two vinyl groups is not essential for the success of the rearrangement reaction. However, the relative configurations of the stereogenic centres in the substrate have an important influence on the yield and stereochemical outcome of the reaction. In a final preliminary study, the cyclisation of the diazoketone 172 was investigated in order to discover whether it would be possible to access fused bicyclic systems from a substrate in which the alkene is embedded in a carbocyclic framework (Scheme 50). The rhodium-mediated reaction of the diazoketone 172 was successful and afforded the bicyclic ketone 173, albeit in modest yield.¹⁰⁹

N₂

Scheme 50. Catalytic carbenoid generation, ylide formation and rearrangement using the diazoketone 172.

Oxonium ylide generation and [2,3]-rearrangement strategy was envisaged as novel way of accessing linearly fused polycarbocyclic systems. Two carbocycles, one attached to the diazocarbonyl functionality and the other containing an alkene, tethered by a hydrocarbon chain should react to give a middle ring and afford a linearly fused tricyclic system, once exposed to this reaction sequence (Scheme 51). This transformation would simply require the alkene to be contained in a ring as in the diazoketone 174; the derived ylide intermediate would then undergo [2,3]-rearrangement to give the fused tricyclic system 175. The catalytic oxonium ylide formation and rearrangement reaction would therefore be applicable to the synthesis of fused polycyclic compounds. A natural product that would possibly be amenable to synthesis using this methodology is the anti-cancer natural product Taxol.

O N₂

OR n

O MLn

n

175 OR

174

Scheme 51. Hypothetical strategy for the construction of fused medium-sized carbocycles by catalytic carbenoid generation, oxonium ylide formation and [2,3]-rearrangement.