Domino- Wacker-Heck reaction

This chapter deals with the total synthesis of vitamin E (1) comprising a Pd(II)-catalyzed domino Wacker-Heck reaction as the key step, which allows not only the formation of the chiral chroman framework with an enantioselectivity of 96 % ee but also the simultaneous introduction of part of the side chain. ... 

Key Chemistry Palladium(II)-catalyzed Domino Wacker-Heck Reaction... 

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. 

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. 

For the enantioselective total synthesis of a-tocopherol (177), which was also developed by Tietze et al. [69, 131], a domino Wacker/Heck reaction was used (Scheme 14.50). 

Scheme 5-208. A domino Wacker-Heck reaction for the synthesis of oxygen heterocycles. EWG Electron withdrawing group. ...

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. 

Tietze LF, Stecker F, Zinngrebe J, Sommer KM. Enantioselective palladium-catalyzed total synthesis of vitamin E by employing a domino Wacker-Heck reaction. Chem. Eur. J. 2006 12(34) 8770-8776. 

Tietze and coworkers developed a new total synthesis of vitamin E (1) using a novel enantioselective domino Wacker Heck process as the key step. This allows the formation of the chroman framework 22 with the required i -configuration at the stereogenic center C-2 in 97 % ee with concomitant introduction of part of the vitamin E side chain in 84 % yield. Condensation with (3i )-3,7-dimethyloctanal (21), synthesized from 7 -citronellol (20), followed by reaction with methyl lithium and hydrogenation completed the synthesis. 

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). 

Tietze et al. [72] has developed several domino processes initiated by an enantioselective Wacker oxidation, which is followed by a Heck reaction and a... 

Toyota, Ihara and coworkers [178] used a combination of a Wacker- and a Heck-type transformation to construct the cedrane skeleton. Thus, reaction of 6/1-374 using 10mol% Pd(OAc)2 under an atmosphere of 02 led to the domino product 6/1-375 in 30% yield. In addition, 58% of the mono-cyclized compound 6/1-376 was obtained (Scheme 6/1.94). 

Divinylbenzene and related compounds undergo an internal domino acetoxy-palladation (Wacker-type, 1) and subsequent carbMalladation reaction (Heck-type, 3) to form indenes (Experimental Procedure below). " ... 

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