Cope rearrangement enantioselectivity

Allin, S. M., Baird, R. D., Lins, R. J. Synthetic applications of the amino-Cope rearrangement enantioselective synthesis of some tetrahydropyrans. Tetrahedron Lett. 2002, 43, 4195-4197. 

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]. 

In contrast to the synthesis of carbocyclic rings, the Cope rearrangement has been used sparsely for generating azepinones. Recently, the enantioselectivity of the conversion of 2-aza-divinylcyclopropane 286 has been investigated. The synthesis started from the optically active cyclopropanecarboxylic acid (90% ee), which had been converted into the isocyanate 286 by initial azidation to 285 and a consecutive Curtius rearrangement. Furthermore, the conditions of the iso-... 

A domino-cyclopropanation/Cope rearrangement was used by Davies et al. for the enantioselective... 

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. 

Anionic oxy-Cope rearrangement was also employed for the enantioselective total synthesis of compounds related to marine metabolites (equation 230)305 307, as well as for the preparation of diterpenoide vinigrol (equation 231)308 and cerorubenic acid-in... 

Rhodium(II) (iV-dodecylbenzenesulfonyl)prolinate has been found to act as an effective catalyst for the enantioselective decomposition of vinyldiazoacetates to c -divinylcyclopropanes. Combination of this process with a subsequent Cope rearrangement has resulted in a highly enantioselective synthesis of a variety of cycloheptadienes containing multiple stereogenic centres (see Scheme 40). The tandem... 

The reaction of vinyldiazoacetates at allylic C-H sites does not result in the predominant formation of the products of a simple C-H insertion [25]. Instead, combined C-H insertion/Cope rearrangement products are formed with very high enantioselectivity as illustrated by the example shown in Eq. (20) [25]. This process has been applied to a very short asymmetric synthesis of (+)-sertraline (38). 

In conclusion, mention should be made of dendronised chiral salen ligands and their Co2+ and Ni2+ complexes, which were prepared for use as Jacobsen-type catalysts by diaza-Cope rearrangement [24]. However, instead of the meso compounds produced, the enantiomers will have to be synthesised directly in enantioselective manner (Fig. 4.69). 

Cycloheptadiene (340) is obtained by the Cope rearrangement of cis-divinylcyclopropane (339.) Based on this reaction, highly diastereoselective and enantioselective construction of the 1,4-cycloheptadiene 343 (98% ee) was achieved by domino asymmetric cyclopropanation to generate cA-divinylcyclopropane... 

Attempted allylic C-H insertion by vinyldiazoacetates results in an even more complicated transformation, a combined C-H activation/Cope rearrangement [27]. These reactions tend to proceed with very high enantioselectivity as illustrated in a short enantioselective synthesis of the antidepressant (+)-sertraline (33) [27a]. Recent studies have shown that this reaction is both highly diastereose-lective and enantioselective [27b],... 

Brown CJ, Bergman RG, Raymond KN (2009) Enantioselective catalysis of the aza-cope rearrangement by a chiral supramolecular assembly. J Am Chem Soc 131 17530-17531... 

Although further work in this area is desirable, it appears that in the Cope rearrangement of simple frans-divinylcyclopropanes, such as (33) and (34), enantioselectivity is poor. 

During the enantioselective total syntheses of (-)- and (+)-strychnine and the Wieland-Gumlich aldehyde, L.E. Overman and co-workers used the tandem aza-Cope rearrangement/Mannich reaction as a key step. This central aza-Cope/Mannich reorganization step proceeded in 98% yield. 

The enantioselective construction of a key tricyclic intermediate of spinosyn A utilizing a highly stereocontrolled anionic oxy-Cope rearrangement was accomplished in the laboratory of L.A. Paquette.The precursor tertiary alcohol was treated with potassium hydride in THF and the oxy-Cope rearrangement was complete within 3 hours at room temperature. Interestingly, the yield varied between 77 and 91% depending on the source of KH. 

For a related enantioselective cyclopropana-tion/Cope rearrangement sequence, see Davies, H.M.L. Huby, N.J.S. Tetrahedron Lett. 1992, 33, 6935. 

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