Couplings enantioselective

Miller and co-workers have reported the use of thiazolylalanine-derived catalyst 65 to render the aldehyde-imine cross-coupling enantioselective [56]. The authors comment on the time sensitivity of this transformation and found that racemization occurs when the reaction goes to complete conversion. Electron-deficient aldehydes are the most efficient couphng partners for various tosylamides leading to the corresponding products 66, 68, and 69 (Scheme 8). 

An example of practical application of the asymmetric cross-coupling, enantioselective synthesis of a-curcumene (19), is shown in Scheme 8F.6 [21]. The compound was synthesized with 66% ee through Ni/(S)-(/ )-PPFA (lOa)-catalyzed cross-coupling of 1 -(p-tolyl)ethylmag-nesium chloride (17) and vinyl bromide (4b). 

Spatial and/or coordinative bias can be introduced into a reaction substrate by coupling it to an auxiliary or controller group, which may be achiral or chiral. The use of chiral controller groups is often used to generate enantioselectively the initial stereocenters in a multistep synthetic sequence leading to a stereochemically complex molecule. Some examples of the application of controller groups to achieve stereoselectivity are shown retrosynthetically in Chart 19. 

Numerous applications of the Ni(n)/Cr(ii)-mediated coupling reaction in total synthesis have already been reported.11 Some of the more noteworthy examples derive from Kishi s laboratories and played a role in the syntheses of such complex molecules as (+)-ophiobolin C16 and halichondrin B17 (see Scheme 5). Another elegant application can be found in the enantioselective total syntheses of (+)-brefeldin C and 4-ep/-brefeldin C by Schreiber and Meyers (see Scheme 5).18... 

An unprecedented nickel-catalyzed reductive coupling between an epoxide and an alkyne to give synthetically useful homoallylic alcohols has been developed by Jamison [55a], and was recently used in a short enantioselective synthesis of am-... 

In Ghosh s enantioselective total synthesis of the cytotoxic marine macrolide (+)-amphidinolide T1 (318) [143], the C1-C10 fragment 317 was constructed by CM of subunits 315 and 316 (Scheme 62). The reaction mediated by catalyst C (5 mol%) afforded in the first cycle an inconsequential 1 1 mixture of (E/Z)-isomeric CM products 317 in 60% yield, along with the homodimers of 315 and 316. The self-coupling products were separated by chromatography and exposed to a second metathesis reaction to provide olefins 317 in additional 36% yield [144]. 

Optically active polymers are potentially very useful in areas such as asymmetric catalysis, nonlinear optics, polarized photo and electroluminescence, and enantioselective separation and sensing.26 Transition metal coupling polymerization has also been applied to the synthesis of these polymers.27 For example, from the Ni(II)-catalyzed polymerization, a regioregular head-to-tail polymer 32 was obtained (Scheme 9.17).28 This polymer is optically active because of the optically active chiral side chains. 

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-... 

Bischirogenic unsymmetric (S,S)-BisP 6b (cf. (S,S)-BisP -borane 81b) were synthesized from the coupling reaction between synthon 79 and the lithiated (S)-alkylmethylphosphine-boranes 87 in reasonable to quantitative yields with enantioselectivity over 97% (Scheme 15) [94]. These phosphines constitute the unsymmetric version of BisP in that they bear different groups on both phosphorus atoms, breaking the C2-symmetry character of BisP [32,94]. 

The couphng of N-substituted benzaldimines, mediated by the zinc-copper couple in the presence of (+)-camphorsulfonic acid (CSA) in DMF, was investigated. The best results were obtained for the imine 22, and the optimal balance of yield, diastereoselectivity and enantioselectivity for the diamine 23 was obtained using 3equiv of (+)-CSA [17] (Schemes). How-... 

Scheme 5 Enantioselective zinc-promoted reductive coupling of benzaldimines in the presence of (+)-camphorsulfonic acid...

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Netherton M, Fu GC (2005)Pa]ladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14 85-108 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of EpothUones and Polyether Natmal Products. 1 73-104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11 81-92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11 155-171... 

These transition-metal catalysts contain electronically coupled hydridic and acidic hydrogen atoms that are transferred to a polar unsaturated species under mild conditions. The first such catalyst was Shvo s diruthenium hydride complex reported in the mid 1980s [41 14], Noyori and Ikatiya developed chiral ruthenium catalysts showing excellent enantioselectivity in the hydrogenation of ketones [45,46]. 

The ability of enzymes to achieve the selective esterification of one enantiomer of an alcohol over the other has been exploited by coupling this process with the in situ metal-catalysed racemisation of the unreactive enantiomer. Marr and co-workers have used the rhodium and iridium NHC complexes 44 and 45 to racemise the unreacted enantiomer of substrate 7 [17]. In combination with a lipase enzyme (Novozyme 435), excellent enantioselectivities were obtained in the acetylation of alcohol 7 to give the ester product 43 (Scheme 11.11). A related dynamic kinetic resolution has been reported by Corberdn and Peris [18]. hi their chemistry, the aldehyde 46 is readily racemised and the iridium NHC catalyst 35 catalyses the reversible reduction of aldehyde 46 to give an alcohol which is acylated by an enzyme to give the ester 47 in reasonable enantiomeric excess. 

Kragl and Dreisbach (1996) have carried out the enantioselective addition of diethyl zinc to benzaldehyde in a continuous asymmetric membrane reactor using a homogeneous soluble catalyst, described in their paper. Here a,a-diphenyl-L-proline was used as a chiral ligand, coupled to a copolymer made from 2-hydroxy ethyl methacrylate and octadecyl methacrylate, which had a sufficiently high molecular weight to allow separation by ultra-filtration (U/F). The solvent-stable polyaramide U/F Hoechst Nadir UF PA20 retained more than 99.8% of the catalyst. The ee was 80 %, compared to 98 % for a noncoupled catalyst. 

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