Asymmetric Cope rearrangement

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]. 

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. 

Keywords Aza-Claisen rearrangement 3-Aza-Cope rearrangement Chirality transfer Asymmetric induction Charge acceleration... 

In particular the synthetic approach to dihydrofurans (first equation in Figure 4.23) represents a useful alternative to other syntheses of these valuable intermediates, and has been used for the preparation of substituted pyrroles [1417], aflatoxin derivatives [1418], and other natural products [1419]. The reaction of vinylcarbene complexes with dienes can lead to the formation of cycloheptadienes by a formal [3 + 4] cycloaddition [1367] (Entries 9-12, Table 4.25). High asymmetric induction (up to 98% ee [1420]) can be attained using enantiomerically pure rhodium(II) carboxylates as catalysts. This observation suggests the reaction to proceed via divinylcyclopropanes, which undergo (concerted) Cope rearrangement to yield cycloheptadienes. 

It has been established that the course of the sequential pericyclic reaction of cyclopentadienones with acyclic conjugated alkadienes depends on the reaction temperature, thermal treatment at low temperatures affording 3a,4,7,7a-tetrahydroinden-l-one derivatives by way of a Cope rearrangement (see Scheme 38). Roman et al have developed an efficient stereoselective synthesis of enantiomerically pure i-nitrotricyclo[5.2.2.0 ]undeca-3,8-dienes via a tandem consecutive asymmetric Diels-Alder-Cope rearrangement (see Scheme 39). Adducts... 

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. 

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). 

The use of a cationic aza-Cope rearrangement in concert with a Mannich cyclization has also been applied to the total synthesis of enantiomerically pure (—)-crinine (359) (205). In the event, nucleophilic opening of cyclopentenoxide with the aluminum amide that was formed on reaction of (/ )-a-methylbenzyl-amine and trimethylaluminum gave the amino alcohol 485 together with its (15,25) diastereomer. Although there was essentially no asymmetric induction in this process, the diastereomeric amino alcohols were readily separated by chromatography, and the overall procedure therefore constitutes an efficient means for the preparation of enantiomerically pure 2-amino alcohols from epoxides. When the hydrochloride salt derived from 485 was treated with paraformaldehyde and potassium cyanide, the amino nitrile 486 was formed. Subsequent Swem oxida-... 

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... 

An interesting example of the transfer of center chirality to helicity is the work by Ogawa et al., based on an asymmetric aromatic oxy-Cope rearrangement to provide nonracemic [5]helicenes (Fig. 15.8) [75]. The starting material with center chirality, bicyclo[2,2,2]ketone (-)-21 (>98% ee), was obtained by enzymatic resolution. In the annelation step, the phenanthrene derivative was subjected to aromatic oxy-Cope rearrangement, to afford a pentacyclic product in 47 % yield. The corresponding [5]helicene 22 was obtained in 7 % overall yield (> 98 % ee) after six steps. 

The method of using TiCl4 as a catalyst has been extended to the asymmetric 3-aza-Cope rearrangement, and asymmetric induction as high as 90% for the substrate (iQ-A a-methylbenzy -A-allylamine was achieved107. 

A general, asymmetric polyol synthesis has been developed by Schneider et al. [18] which takes advantage of the benefits of the silyloxy-Cope rearrangement of the chiral aldol product... 

Ethyl lactate was used for diastereocontrol and asymmetric transmission in a sequential 2,3-Wittig-oxy-Cope rearrangement, affording product in 91% ee (eq 9). - 4 Excellent asymmetric induction has also been noted in the Lewis acid-mediated ene reaction of (5)-ethyl lactate-derived intermediates (eq 10). ... 

---