BOXAX ligand

It is assumed that in the first step of the domino Wacker-Heck Reaction the chiral catalyst generated from Pd(II) and an enantiomeri-cally pure BOXAX-ligand 5 coordinates enantiofacially to the aliphatic double bond in 6. The resulting intermediate 7 further reacts by oxypalladation to give 8 with enantioselective formation of the chroman. A p-hydride elimination is not possible because of the absence of H-atoms in the P-position. Thus, the palladium species then forms intermediate 11 in a subsequent Heck reaction with methyl acrylate (10) or methyl vinyl ketone (9) providing the final product 12 and Pd(0) after a P-hydride elimination. 

The Wacker oxidation [146], amongst other nucleophilic additions to alkenes, is the most important reaction based on a palladium(II) catalysis. It is also used industrially for the synthesis of acetaldehyde from ethene and water. This oxidative process has been combined with a Mizoroki-Heck reaction by Tietze and coworkers [13] for an enantioselective total synthesis of vitamin E (293) [147] using BOXAX ligand 291 [148]. In this way the chromane ring and parts of the side chain of vitamin E (293) can be introduced in one... 

In 2008, Tietze et al. [466] reported on the stereoselective synthesis of 4-dehydroxydiversonol (413) utilizing pathways involving both Pd-catalyzed domino-Wacker-Heck and domino-Wacker-carbonylation reactions. The Wacker-Heck substrate 410 was treated with methyl acrylate in the presence of Pd ditriflate and the (S,S)-Bn-BOXAX ligand 411 along with p-benzoquinone (as a catalyst reoxidant), giving the chromane 412 with 80% ee in 55% yield (Scheme 8.82). 

This domino Wacker-Heck reaction is the key step of this total synthesis. In the presence of catalytic amounts of Pd(OTFA)2, the chiral ligand (S,S)-Bn-BOXAX (5) and j -benzoquinone (13) as reoxidant, phenol 19 first undergoes an intramolecular enantioselective Wacker oxidation and then reacts with methyl vinyl ketone (9) in a Heck reaction to afford chroman 22 with part of the vitamin E side chain in 84 % yield with 97 % ee. 

One of the exciting developments of the Wacker-type oxidation is the asymmetric synthesis of the reaction. For instance, using a new chiral bis(oxazoline) ligand L = 3,3 -Disubstituted 2,2 -bis(oxazolyl)-l,r-binaphthyls (boxax), a catalytic asymmetric Wacker -type cyclization converted allyl-phenol 55 to dihydrofuran 74 with 67% ee.ss... 

Binaphthyl-bisoxazoline ligands (the so-called boxax) [165,166] have also been immobilized on various polymer supports [167]. A palladium complex of polymeric boxax 116 catalyzed the Wacker-type cyclization [168, 169] of al-lylphenol 117 with up to 96% ee (Scheme 38) [170]. 

Pd(0Ac)2, but the benzofuran 67 was obtained by exo cyclizadon with PdCb [34], Catalytic asymmetric cyclization of 2-(2,3-dimethyl-2-butenyl)phenol (68) using the binaphthyl-based chiral ligand 70, called (5,5)-ip-boxax afforded the furan 69 with high ee (97%) [35],... 

An alternate synthesis of enantiopure (—)-diversonol was recently reported by Tietze et al. using an enantioselective transition-metal-catalyzed domino process (Scheme 14.48). Key step in the synthesis is the formation of a chromane with concomitant introduction of the quaternary stereocenter at C-4a with 96% ee using a domino Wacker/carbonylation/methoxylation reaction in the presence of (S,S)-Bn-BOXAX (310) as ligand [73]. In this reaction phenol 308, containing an alkene moiety, was treated with catalytic amounts of Pd(tfa)2 and 310 in MeOH in the presence of CO and p-benzoquinone the latter is necessary to reoxidize Pd to Pd". One can assume that the first step is an enantiofacial coordination of the Pd" species, which is attacked by the phenolic hydroxyl group to give intermediate... 

Allylpalladium complexes with BOX-type ligands and glucopyrano-oxazoline-palladium catalysts were used as catalysts for enantioselective allylic substitution (277). A chiral bisoxazoline ligand (BOXBZ) developed by Pfaltz has been used for asymmetric carbo- and heteroannulation reactions (278). An axial binaphthyl-based ligand possessing oxazolyl substituents (BOXAX) was developed by Hayashi and co-workers and successfully applied for the asymmetric Wacker-type cyclization (279). 

Recent studies revealed that (2S)-tocopherols have no antioxidant effect in biological systems because they are not accepted as substrates by the a-tocopherol transfer protein (TTP), which is responsible for the transport of vitamin E into the tissue. As a result, the enantioselective synthesis of the a-tocopherol became attractive, and several groups have reported on its asymmetric synthesis. In addition, Tietze and co-workers reported on an enantioselective palladium-catalyzed total synthesis of vitamin E by employing a domino Wacker-Heck reaction (Scheme 21.15). ° In their study, reaction of 64 with methyl acrylate in CH2CI2 with catalytic amounts of Pd(TFA)2 (TEA = trifluoroacetate), the chiral ligand (5,5)-Bn-BOXAX 65, and p-benzoquinone afforded the desired chroman 66 with 96% ee in 84% yield. The enantioselective cascade reaction described therein provided the efficient construction of the chroman firamework of vitamin E 67 with concomitant introduction of part of the side chain in high yields and high enantioselectivities. 

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