Bases asymmetric Heck reactions

The Heck reaction has proven to be an extremely useful method for the formation of C-C bond at a vinyl carbon centre. There are numerous reported examples of enantioselctive Pd catalyzed C-C bond forming reactions.10"13 Surprisingly, reports of Heck transformations using amino acid based phosphine, phosphinite ligands are rare. Recently Gilbertson reported a proline derived phosphine-oxozoline ligand in a catalytic asymmetric Heck reaction.5 In this paper we present some novel amino acids derived ligands as part of a catalytic system for use in asymmetric Heck reactions. 

The intermolecular asymmetric Heck reaction, a palladium-catalysed carbon-carbon bond forming process, is an efficient method for the preparation of optically active cyclic compounds.[1] Very recently, a new catalytic system has been developed based on palladium complexes having l-[4-(5)-tert-butyl-2-oxazolin-2-yl]-2-(5)-(diphenylphosphino)ferrocene (1) as the chiral ligand121 (Figure 5.2), which we have shown to be efficient catalysts for the enantioselective intermolecular Heck reaction of 2,3-dihydrofuran (2).[3] In contrast to complexes derived... 

With this step accomplished as desired, probes of the key step of the sequence, the tandem asymmetric Heck reaction, could now commence in earnest. Based on several years of intensive research in developing appropriate systems to accomplish asymmetric Heck reactions with the ability to form all-carbon quaternary carbon centers, the Overman group expected that the exposure of 10 to a 1 2 mixture of Pd(OAc)2 and (/ )-BINAP would lead to the desired... 

Selectivity between a- and p-vinylation of enol ethers has been investigated again diphosphines and nitrogen-based ligands promote a-products. Cyclic enol ethers also remain popular substrates for asymmetric Heck reactions (40-96% ee). Use of hindered bases and BINAP facilitates these reactions. Similar strategies may be employed using 2-pyrrolines (up to 83% ee) or intramolecular arylations.446 Two examples of stereodirected Heck reactions and a kinetic resolution have also appeared... 

In 2006, Stephenson s group reported the involvement of a DKR process during an intramolecular asymmetric Heck reaction carried out in the presence of a BINAP-based Pd catalyst. It was shown that chiral helical conformations of the starting 2-iodoanilide interconverted through internal bond rotations, leading to the proposal of a DKR mechanism to account for the switch of the enantioselectivity (Scheme 2.61). 

Gilbertson SR, Fu Z. Chiral P. N-ligands based on ketopinic acid in the asymmetric Heck reaction. Org. Lett. 2001 3(2) 161-164. 

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

In Figure 13.19 we have shown a route to L-699,392 published by Merck involving three steps based on homogeneous catalysts, viz. two Heck reactions and one asymmetric hydrogen transfer reaction, making first an alcohol and subsequently a sulphide [21], Stoichiometric reductions for the ketone function have been reported as well [22] and the Heck reaction on the left-hand side can be replaced by a classic condensation reaction. L-699,392 is used in the treatment of asthma and related diseases. 

Mata Y, Pamies O, Dieguez M (2007) Screening of a modular sugar-based phosphite-oxazoline ligand library in asymmetric Pd-catalyzed heck reactions. Chem-Eur J 13 3296-3304... 

One of the emerging applications of 4,5-dihydroimidazole-based compounds is as chiral auxiliaries in metal complexes used for asymmetric synthesis for example, 457 in ruthenium-catalyzed DielsAlder reactions <2001 J(P 1)1500, 2006JOM(691)3445> 458 in diethylzinc addition to aldehydes <2003SL102> 459 in asymmetric intramolecular Heck reactions <20030L595> and 460 in ruthenium-catalyzed epoxidation <2005OL3393> and iridium-catalyzed hydrogenation of imines <2004TA3365>. 

Despite an earlier failure to achieve cyclic carbopalladation-carbonylative termination in competition with the cyclic Heck reaction [67] (Eq. 3 in Scheme 35), a series of investigations by Aggarwal [117-119] has provided useful solutions to this problem. In cases where the substrates contain a heteroatom group, such as O or NTs, the cyclic Heck reaction can be suppressed [117] (Eq. 1 in Scheme 37). This reaction has been applied to an asymmetric synthesis of avenaciolide [119] (Eq. 2 in Scheme 37). A more general solution to avoiding the cyclic Heck reaction is not to use a base, e.g., Et3N, and promote rehydropalladation to reserve /(-elimination through the... 

Intramolecular Heck reactions for building up complex oxacyclic skeletons are a common theme in the synthesis of natural products. These reactions are exceptionally valuable for the installation of quaternary carbon stereocenters. In the morphine total syntheses by Overman <1994PAC1423> and Trost et al., intramolecular Heck reactions to form dihydrobenzofurans served as strategic key steps (Equation 138) <2005JA14785>. Asymmetric variants of intramolecular Heck reactions based on BINAP ligands to yield dihydrobenzofurans have also been investigated <1998T4579>. 

Thus, traMi-3-alkyl-6-(phthalimido)cyclopentenes were prepared in excellent to modest yields from the corresponding tran -chloroalkene by the palladium coupling reaction [84d]. Inexpensive and efficient Pd-TMG systems, Pd(OAc)2-TMG or PdC -TMG, have been developed for the Heck reaction of an olefin with an aryl halide, in which TMG (1) acts as a ligand [84e]. In the reaction of iodobenzene with butyl acrylate the turnover numbers were up to 1000000. TMG (1) was used as a base for the palladium catalysed asymmetric Wagner-Meerwein shift of nonchiral vinylcyclopropane and cyclobutane derivatives leading to asymmetric synthesis of cyclobutanones, cyclopentenones, y-butyrolactones and 5-valerolactones [85] (Scheme 4.34). Replacement of TMG (1) with an inorganic bases such as lithium or cesium carbonate resulted in little effect. 

Ozawa et al. reported the Pd(OAc)2-BlNAP catalysed asymmetric intermolecular Heck reaction of aryl triflate and 2,3-dihydrofiiran in the presence of a base [34]. In this reaction, the enantiomeric excess was significantly affected by the base, and Proton Sponge (1) gave the best results among the various bases, such as triethylamine, diisopropylethylamine, pyridine derivatives and inorganic bases (Table 8.9). 

Water-soluble macromolecular metal complexes based on terminally functionalized ethylene oxides and ethylene oxide-propylene oxide block copolymers have been used as catalysts for hydroformylation, hydrogenation, Wacker oxidation of imsaturated compounds, hydroxylation of aromatic compounds, oxidation of saturated and alkylaromatic hydrocarbons, metathesis, Heck reaction, and some asymmetric reactions. 

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