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The Rh/binap-catalyzed 1,4-addition of alkenyl zirconocenes to cycloalkenones can occur with high enantioselectivity. In this work, this reaction was optimized using the addition of hex-1-enyl zirconocene to cyclopentenone (46) as a model reaction. Temperatures of 30 to 40 °C turned out to be optimal, and the addition product 71 was formed in nearly quantitative yield with 90% ee. This method was further developed to enable trapping of the Zr-enolate as a silyl enolether. A detailled investigation of all synthetically relevant intermediates and byproducts by 1H NMR spectroscopy revealed an equilibrium of Zr-enolate 73 with its bisenolate 85. These enolates were transformed into the Li-enolate 74 by addition of MeLi and then into the silyl enolether 45, that could be isolated in 91% yield. A byproduct, characterized as Cp2Zr(SiMe3)2, was formed in stochiometric amounts and removed by an oxidative process.
This method was applied to the addition of an acetal-bearing zirconocene to cyclopentenone (46) and cyclohexenone (7), the products were isolated after transformation into their silyl enolethers in good yields of 75-81% and very good 95-96% ee.
The asymmetric addition of alkenyl zirconocenes was the starting point for the asymmetric formal synthesis of (R)-Sarkomycin (42), based on a racemic pathway that was developed in the own diploma thesis. 42 could be formed from the stable precursor 113 in presence of the ion resin K2611 under microwave irradiation in 86% yield. Due to its high sensitivity towards di- and oligomerisation, workup had to be performed at –40 °C, this allowed the preparation and characterization of virtually pure 42. The derived methyl ester 109 was then prepared by treatment with Me3OBF4 and isolated as a stable compound in 58% yield, starting from 113.
In the research group of Prof. VON ZEZSCHWITZ, cycloalkenone derived N-tosyl imines were prepared for the first time. Unfortunately, the harsh reaction conditions prevent sensitive enones from being successfully converted. Therefore, new strategies were investigated to gain access to sensitive α,β-unsaturated cyclic activated imines.
The oxidations of allylamide 234 as well as N-sulfinyl imine 209 gained synthetic access towards the cyclopentenone derived N-tosyl imine 184. As an alternative synthetic pathway towards N-sulfonyl imines, N-tert-butylsulfonyl imines 196-198 of five- to seven-membered rings were synthesized via the Hudson reaction in 20-49% yields. Also, N-phosphinoyl imines 193 and 170 of cyclohexenone (7) and 4,4-dimethylcyclohexenone (191) were prepared in 39 and 63% yield from 7 and 191, respectively.
Based on the initial results of HIRNER, the asymmetric addition of AlMe3 to N-tosyl imines was further investigated and the method was enhanced by the 1,2-addition of aryl nucleophiles, which yields enantiopure 1-arylcyclohexenyl amides. As a model substrate, N-tosyl imine 180 was converted with PhAlMe2, yielding the 1,2-adduct in 48% yield with excellent >99% ee. 1,4-Addition to 180 was inhibited by sterical effects, but occurred in the analogue addition of PhAlMe2 to the unsubstituted imine 52. The regioselectivity was improved in the presence of Xyl-binap (264) as chiral ligand, and amide 262 was isolated in 33% yield with excellent >99% ee. In addition, 3-phenylcyclohexanone, obtained after hydrolysis from 1,4-addition, was isolated in 31% yield with 90% ee. This is an evidence that both, 1,2- and 1,4-addition, proceed via the chiral [Rh]-complex.
The strong influence of alkyl-substituents at C-5 on the regioselectivity was shown by the addition of AlMe3 to imine (R)-182: in dependance of the stereoconfiguration of the binap ligand, the stereo- and regioselectivity were inverted, which is an indication, that the complex of [Rh] and the imine can be formed in two manners with different geometry, both leading to an asymmetric addition reaction. This assumption was further validated by an asymmetric addition of PhAlMe2 to (R)-182, where the regioselectivity was shifted towards the 1,2- addition, compared to the analogous addition to imine 52. This indicates, that the coordination of the imine leading to a 1,2-addition is favored in this case.
The Cu-catalyzed asymmetric addition of ZnEt2 to imine 52 is the first example of this reaction type, using cyclic imines. Addition and subsequent diastereoselective reduction yielded pure amide trans-285 in up to 91% yield with very good ee. Depending on the reaction conditions, cis-285 could also be accessed in good 64% yield with 96% ee from imine 52 using tBuNH2·BH3 for reduction.
The reactivity of N-sulfonyl-imines surpasses those of the corresponding enones in both, reactivity and selectivity. Using 0.01 mol% of the chiral complex, trans-285 was formed in 89% yield with 87% ee, which corresponds to a TON of 8900. Beside ZnEt2, ZnMe2 and AlMe3 were also used for asymmetric additions, yielding the products with 96-98% ee as diastereomerically pure compounds after reduction. The high reactivity allowed the asymmetric addition of ZnEt2 to the β,β-disubstituted imine 179, resulting in the formation of a quaternary stereocenter, which is known to be impossible with ZnEt2 in the case of the corresponding enones. Also, the cis-selective addition to imine (R)-182 was the first example, to show the possibility of overriding the substrate control in an asymmetric Cu-catalyzed 1,4- addition to a 5-alkyl-substituted cyclohexenone-derived compound.
Monitoring of the 1,4-addition with a ReactIR® device, revealed a non-linear dependence of the reaction-rate on the catalyst loading. This indicates an equilibrium state prior the 1,4- addition, which is supposed to be the rate-determining step in this reaction. The behaviour of imine 187, which is fixed in the (E)-configuration, indicates this as the reactive configuration in the 1,4-addition. This assumption is in line with the results reported by ELLMAN et al., who also suppose this in case of additions to acyclic N-sulfinyl imines. Moreover, the addition of ZnEt2 to (R)-182 revealed a non-linear dependance of the catalyst loading on the diastereoselectivity. This indicates an unusual three-membered complex, that not only consists of substrate and catalyst, but also of the formed zinc-enamide as a chiral and reactivity- enhancing ligand.