Heck couplings enantioselective

The synthesis of lycorane (13) by Mori and Shiba-saki121 is breathtaking for its use of three consecutive Pd catalyzed C-C bond forming reactions. Thus, Pd-catalyzed asymmetric allylic substitution of a benzoate in meso 7 in the presence of the chiral bisphos-phine 8 leads to the regioselective formation of 10 in 40 % ee It is easy to overlook this low level of enantioselectivity when we are faced with the subsequent elegant Pd-catalyzed reactions Pd-catalyzed intramolecular animation is followed by a Pd-catalyzed Heck coupling to afford 12, which is then readily converted to the target molecule... 

Heterogenization of homogeneous metal complex catalysts represents one way to improve the total turnover number for expensive or toxic catalysts. Two case studies in catalyst immobilization are presented here. Immobilization of Pd(II) SCS and PCP pincer complexes for use in Heck coupling reactions does not lead to stable, recyclable catalysts, as all catalysis is shown to be associated with leached palladium species. In contrast, when immobilizing Co(II) salen complexes for kinetic resolutions of epoxides, immobilization can lead to enhanced catalytic properties, including improved reaction rates while still obtaining excellent enantioselectivity and catalyst recyclability. 

The same approach was applied in the enantioselective total synthesis of a complex natural product, quadrigemine C. The key step of the reaction sequence, establishing the chirality in the molecule is shown in 3.15.20 Besides the regular Heck coupling product a minor product was also identified in the process arising from the / -elimination of a methoxide moiety instead of the hydride. 

A common application of aryl halides is Pd-mediated coupling to form C-C bonds. Graham Meek of Chirotech Technology Ltd., Cambridge, UK has found (Tetrahedron Lett. 2004,45, 9277) that the enamide 6 participates efficiently in Heck coupling. The product 7 is an excellent substrate for enantioselective hydrogenation, to give 8. 

Hudlicky et al. described an elegant strategy based on two intramolecular Heck coupling reactions for the enantioselective synthesis of codeine from 2-phenylbro-moethane (Scheme 10.36).64... 

The phosphine-thiazole ligand 149 has been shown to promote asymmetric intermolecular Heck coupling of 2,3-dihydrofuran with aryl triflates <07ASC2595>. Microwave irradiation of a mixture of 2,3-dihydrofuran (6 equiv.), aryl triflates (1 equiv.) and DIPEA (3 equiv.) in THF in the presence of Pd2(dba)3 (3 mol%) and the ligand 149 (6 mol%) at 120 °C provides 2-aryl-2,5-dihydrofurans 150 in high enantioselectivity. Other phosphine-thiazole ligands have also been evaluated, and ligand 149 proves to be the best in terms of enantioselectivity. 

Intramolecular Heck coupling of good enantioselectivity is also known [34]. Products exhibiting quaternary benzylic centers of asymmetry give particularly good enantiomeric enrichment (eq. (9)). 

As mentioned above, the enantioselective desymmetrization of prochiral, as well as meso compounds, by using a Mizoroki-Heck coupling represents another pos-sibiUty to effect asymmetric transformations [81-84]. Therefore, the plane of symmetry in these precursors must be broken by differentiation of enantiotopic alkene-containing groups with a chiral palladium complex. 

Reductive Mizoroki-Heck couplings of azanorbornenes would allow for short syntheses of the alkaloid epibatidine [102-104] and analogues thereof [104, 105]. Kaufmann et al. elaborated a straightforward one-step enantioselective access to N-protected epibatidine 165 (Scheme 7.38) [102,103]. Hydroarylation of 7-azanor-bornene 163 with functionalized aryl iodide 164 produced 165 in moderate yield with good enantiomeric excess [103]. Zhou et al. later tested a ligand similar to 158 (Figure 7.3) in the same reaction, and with a number of other heteronorbom-enes (49-85% ee) ]104]. 

Very recently, the same researchers also discovered the potential of variation at the CS-vinyl moiety of the Cinchona alkaloid and performed Mizoroki-Heck coupling reactions between the Cinchona alkaloid-derived dimer and di-iodide, affording the chiral polymer PTC 14d (henzylation, 95% enantiomeric excess). The insolubility of the polymer makes it possible to recover the catalyst from the reaction mixture and recycle it several times without a decrease in the chemical yield or enantioselectivity (Scheme 16.9). ... 

An interesting combination is that of a Heck coupling with an enantioselective dihydroxylation reaction. To achieve this, a bifunctional catalyst consisting of active palladium and osmium species anchored on silica gel through a mercaptopropyl spacer, and a cinchona alkaloid, respectively, was prepared and applied using N-methylmorpholine N-oxide as a cooxidant This one-pot process of alkene formation and subsequent dihydroxylation afforded diols of type 282 in excellent yields and with high enantiomeric excesses (Scheme 8.59) [385]. 

Larhed et al. investigated enantioselective Heck reactions with 2,3-dihydrofuran as alkene [86]. In the coupling with phenyl triflate, conditions previously reported by Pfaltz [87] were attempted under microwave irradiation. Interestingly, the catalytic system Pd2(dba)3/(4S)-4-t-butyl-2-[2-(diphenylphosphanyl)phenyl]-4,5-dihydro-l,3-oxazole, identified by the Swiss team, was found suitable for high-temperature microwave-assisted enantioselective Heck reactions (Scheme 76). Using a proton sponge as a base and benzene as a solvent gave the best conversions (Scheme 76). At tempera-... 

Phosphine ligands based on the ferrocene backbone are very efficient in many palladium-catalyzed reactions, e.g., cross-coupling reactions,248 Heck reaction,249 amination reaction,250 and enantioselective synthesis.251 A particularly interesting example of an unusual coordination mode of the l,l -bis(diphenylphosphino)ferrocene (dppf) ligand has been reported. Dicationic palladium(II) complexes, such as [(dppf)Pd(PPh3)]2+[BF4 ]2, were shown to contain a palladium-iron bond.252,253 Palladium-iron bonds occur also in monocationic methyl and acylpalladium(II) complexes.254 A palladium-iron interaction is favored by bulky alkyl substituents on phosphorus and a lower electron density at palladium. 

As mentioned previously, the partially reduced forms of five membered heteroaromatic systems might act as olefins in insertion reactions. This behaviour is characteristic particularly of dihydrofuranes. The olefin insertion and the following / hydride elimination should in principle lead to a trisubstituted olefin, which is rarely observed, however. Typical products of this reaction are 2-aryl-2,3-dihydrofuranes. A characteristic example of such a reaction is presented in 6.54. The coupling of 4-iodoanisole and dihydrofurane led to the formation of the chiral 2-anisyl-2,3-dihydrofurane in excellent yield.83 The shift of the double bond, which leads to the creation of a new centre of chirality in the molecule, opens up the way for enantioselective transformations. Both intermolecular and intramolecular variants of the asymmetric Heck reaction have been studied extensively.84... 

In a related study, the Shibasaki group examined cyclizadon of naphthyl triflate 10.1 (Scheme 8G.10) [23], Cyclization of 10.1 under standard cationic conditions gave Heck product 10.2 in 78% yield and 87% ee. Evidently, the reaction is fairly tolerant of the nature of the aryl group, because both 10.1 and 9.3 behaved similarly. An interesting variation of this reaction was also demonstrated in which Suzuki coupling and asymmetric Heck cyclization were performed in a one-pot operation. Thus, treatment of ditriflate 10.3 with borane 10.4 under standard Heck conditions provided 10.2 in similar enantioselectivity to the stepwise procedure, albeit in quite low yield. Heck product 10.2 was converted in several steps to the natural products, halenaqui-none (10.5) and halenaquinol (10.6). 

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