Tandem cyclopropanation

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

Scheme 5.1 Tandem cyclopropanation/ring closing metathesis of dienyne using Gmbbs catalyst...

A method for highly efficient asymmetric cyclopropanation with control of both relative and absolute stereochemistry uses vinyldiazomethanes and inexpensive a-hydroxy esters as chiral auxiliaries263. This method was also applied for stereoselective preparation of dihydroazulenes. A further improvement of this approach involves an enantioselective construction of seven-membered carbocycles (540) by incorporating an initial asymmetric cyclopropanation step into the tandem cyclopropanation-Cope rearrangement process using rhodium(II)-(5 )-N-[p-(tert-butyl)phenylsulfonyl]prolinate [RhjtS — TBSP)4] 539 as a chiral catalyst (equation 212)264. 

The reaction of vinylcarbenoids with allylic C-H bonds leads to a remarkable transformation, a combined C-H insertion/Cope rearrangement, which is reminiscent of the tandem cyclopropanation/Cope rearrangement of vinylcarbenoids. An interesting application of this chemistry is the asymmetric synthesis of the antidepressant (-i-)-ser-traline 191 (Scheme 14.26) [134]. The Rh2(S-DOSP)4-catalyzed reaction of the vinyldia-zoacetate 189 with 1,3-cyclohexadiene generates the 1,4-cyclohexadiene 190 in 99% enantiomeric excess. The further conversion of 190 to (-t)-sertraline 191 is then achieved using conventional synthetic transformations. 

Rhodium(ll)-catalyzed decomposition of vinyldiazoacetates 84 in the presence of 7V-phenoxycarbonyl-l,2-dihydro-pyridine 85 gives 6-azabicyclo[3.2.2]nonanes 86 (Equation 3). The overall reaction is a [3+4] cycloaddition which occurs by a tandem cyclopropanation/Cope rearrangement <1998TL2707, 2001JOC7898>. 

With strained bicycloalkenes such as norbornene derivatives a ruthenium-catalyzed tandem cyclopropanation occurred together with common [2+2+2] cy-clotrimerization, showing a biscarbenoid hybride structure for the ruthenacyclopentadiene intermediate [92] (Eq. 72). 

A catalytic tandem cyclopropanation-ring-closing metathesis of dienyne 80 led to derivative 81 in good yield (Scheme 30 <2004JA9524>). For internal alkynes, carbene-mediated ring-closing enyne metathesis was observed. Less favorable alkyne binding leads to preferential reactions of the metal carbene with the 1-alkene moiety. 

The rhodium(ii)-catalyzed intramolecular reaction between linked vinyldiazomethanes and pyrroles leads to a novel synthesis of fused tropanes <1996JOC2305>. The reaction occurs by a stepwise [3- -4]-annulation mechanism between a rhodium-stabilized vinylcarbenoid intermediate and the pyrrole rather than by the typical tandem cyclopropanation/Cope rearrangement sequence. The outcome of the reaction is very sensitive to the vinylcarbenoid structure. In particular, the presence of a siloxy substituent on the vinylcarbenoid strongly favors the formation of fused tropanes 1063 or 1064 (Scheme 206) <1996JOC2305>. 

The strained bicydic structure of norbornene is essential for the tandem cyclopropanation. Less strained cyclopentene furnished the corresponding tandem cyclopropanation product only in 25% yield [38]. Similarly, 2,5-dihydrofuran gave 48 in low yield (18%), but in this case, a normal [2 -1- 2 -1- 2] cycloadduct 47 became a major product (23%) (Scheme 4.15). Employing Cp RuCl(cod) 17 in place of the indenyl... 

Davies, H. M. L. Tandem cyclopropanation/Cope rearrangement a general method for the construction of seven-membered rings. Tetrahedron 1993, 49, 5203-5223. 

A tandem cyclopropanation/Cope rearrangement sequence precluded the isolation of the bi-cyclic c -l,2-divinylcyclopropane9, when ( , )-hexa-2,4-dienyl 2-diazo-4-phenylbut-3-enoate and related dienylic esters were catalytically decomposed. When the double bond next to the tether had the Z configuration, however, the diastereomeric tra 5-l,2-divinylcyclopropane was formed and isolated it underwent the Cope rearrangement leading to the same product 10 only at 140 C. ... 

The tandem cyclopropanation/Cope rearrangement sequence between metal-stabilized vinylcarbenoids and dienes is more widely applicable, since this method allows cyclopropanes with a wide range of substitution patterns to be synthesized, and the carbenoids are readily prepared by heating a vinyldiazomethane in the presence of a metal salt829,... 

The tandem cyclopropanation/Cope rearrangement sequence is also applicable to the synthesis of cycloheptatriene derivatives by using dienes with a potential leaving group, e.g., 23f and 23g824. 

Instead of dienes, aromatic substrates can also participate in tandem cyclopropanation/Cope rearrangement sequences893 894. Rhodium(II) trifluoroacetate catalyzed decomposition of 17 affords the unstable bicyclo[3.2.2] compound 149 in 29% yield893. The reactions of anisol and 1-methoxynaphthalene with 17 show that in the case of electron-rich aromatics side reactions (alkylation reactions) can compete with cyclopropanation reactions due to dipolar intermediates and products 150 and 151, respectively, are formed893. 

This method of diastereoselective cyclopropanation can also be used with reasonable success for the enantioselective entry to tropanes by a tandem cyclopropanation Cope rearrangement of the 2-diazobut-3-enoate with the (i )-pan-tolactone auxiliary group in the presence of N-( err-butoxycarbonyl)pyrrole (8.185). The product 8.186 was obtained by Davies and Huby (1992) with 69% ee. It can be transferred in three steps into 8-azabicyclo[3.2.1]octane-2-carboxylates (8.187), which are the parent compounds for the corresponding 3-aryl derivatives. The latter are valuable probes for studying the neurochemistry of cocain abuse (Carroll et al., 1992 Lewin et al., 1992 Abraham et al., 1992). 

Independently, Austin and co-workers also adopted the isomunchnone generation and trapping protocol to the solid-phase synthesis of furans. Model studies revealed that rhodium perfluorobutyroamidate (Rh2(pfm)4) afforded none of the by-product 495, which forms via a tandem cyclopropanation-Cope rearrangement. Moreover, this catalyst is more soluble in organic solvents than is rhodium trilluoroacetate (Scheme 4.21). The cycloadducts 494 and 497 readily fragment to the corresponding furans (e.g., 498) on heating in benzene, which was found to be superior as a solvent to methanol or chloroform. 

To avoid the formation of alkylated products, the reaction was repeated with iV-acylated pyrroles, such that the pyrrole ring would be less electron-rich and less prone to rearomatize. Rhodium(II) acetate catalyzed decomposition of the vinyldiazomethane 4 in the presence of A-carbomethoxy pyrrole results in the formation of the [3+4] annulation product (entry 1, Table 12), and this reaction is applicable to a range of vinylcarbenoid derivatives. The tropanes are formed as the endo isomers, which is the expected stereochemistry for the tandem cyclopropanation/Cope rearrangement sequence. 

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