Wacker enantioselective

Asymmetric variants of these reactions are highly interesting since they provide access to chiral heterocycles. A recent comprehensive study by Stahl and coworkers reports the synthesis of various enantiopure [Pd( 4-C1)C1(NHC)]2 complexes and their application in asymmetric aza-Wacker cyclisations. The reactions generally proceed with low yields or enantioselectivity [43]. The best enantio-selectivity (63%) was achieved using complex 28 (Table 10.8). 

W-Heterocyclic Carbene Complexes in Oxidation Reactions Table 10.8 Enantioselective aza-Wacker cycUsations [43]... 

In 1997, Uozumi and Hayashi found high enantioselective Wacker-type cycUza-tion of o-allylphenols or o-homoaUylphenols by using Pd(II) catalysts coordinated with chiral bis(oxazoline) ligands based on the 1,1 -binaphthyl backbone (Eq. 6.36)... 

Several Pd-catalyzed domino processes start with a Tsuji-Trost reaction, a pal-ladation of alkynes or allenes [5], a carbonylation [6], an amination [7] or a Pd(II)-cat-alyzed Wacker-type reaction [8]. A novel illustrious example of this procedure is the efficient enantioselective synthesis of vitamin E [9]. 

The most important reaction based on Pdn-catalysis is the Wacker oxidation [171], which is used industrially for the synthesis of acetaldehyde, starting from ethane. This process can be combined with a Heck reaction and has been used by Tietze and coworkers [172] for an efficient enantioselective synthesis of vitamin E (6/1-... 

When 1,3-dienes containing a tethered alcohol are subjected to Wacker-type reactions, the initial intramolecular oxypalladation event creates a 7r-allylpalladium species, which can then undergo an additional bond-forming process to effect an overall 1,4-difunctionalization of the diene with either cis- or // -stereochemistry (Scheme 18).399 An array of substrate types has been shown to participate in this reaction to generate both five- and six-membered fused or ro-oxacycles.435-437 Employing chiral benzoquinone ligands, progress toward the development of an asymmetric variant of this reaction has also been recorded, albeit with only modest levels of enantioselectivity (up to 55% ee).438... 

Wacker cyclization has proved to be one of the most versatile methods for functionalization of olefins.58,59 However, asymmetric oxidative reaction with palladium(II) species has received only scant attention. Using chiral ligand 1,1 -binaphthyl-2,2 -bis(oxazoline)-coordinated Pd(II) as the catalyst, high enantioselectivity (up to 97% ee) has been attained in the Wacker-type cyclization of o-alkylphenols (66a-f) (Scheme 8-24). 

Figure 15.6. Enantioselective Wacker-type ring-closure of an allylphenol...

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

Palladium(II)-promoted oxidative cyclization of alkenes bearing tethered nucleophiles represents an intramolecular variant of the Wacker reaction. These reactions, which typically generate five- and six-membered heterocycles, have been the subject of considerable interest in organic chemistry [89-96]. Contemporary interest centers on the development of enantioselective examples [95,97] and reactions that employ dioxygen as the sole oxidant for the Pd catalyst [92-96]. 

The key features of a new total synthesis of vitamin E from 2,3,5-trimethylhydroquinone are an enantioselective Wacker cyclisation which generates the chroman ring system with the... 

Application of a Pd-catalysed domino Wacker - carbonylation reaction to 2-(3-methylbut-3-enyl)phenols and the related allyl aryl ether provides an enantioselective route to chromans and 2,3-dihydrobenzodioxins respectively (Scheme 14) <07H(74)473>. 

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. ... 

According to these lines, Tietze and coworkers have recently shown that the chiral chroman moiety in vitamin E (1) can be prepared in a much more efficient way with the concurrent introduction of part of the side chain using a novel enantioselective domino Wacker-Heck Process. ... 

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. 

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. 

The Wacker-Tsuji oxidation has been applied in the synthesis of alkaloids as well. In an enantioselective total synthesis of (+)-monomorine 1, alkene 95 was oxidized to ketone 96, which was converted to (+)-monomorine I 97).6S> In addition, the synthesis of ABE tricyclic analogs of methyllycaconitine used a Wacker oxidation-aldol strategy to append the B ring to the AE fragment.7"... 

Cyclisation reactions involving a Wacker-type oxidative cyclisation have been reported to take place with very high enantioselectivity in some cases. ... 

One distinguishes palladium(0)- and palladium(ll)-catalysed reactions. The most common palladium(O) transformations are the Mizoroki-Heck and the cross-coupling transformations such as the Suzuki-Miyaura, the Stille and the Sonogashira reactions, which allow the arylation or alkenylation of C=C double bonds, boronic acid derivates, stan-nanes and alkynes respectively [2]. Another important palladium(O) transformation is the nucleophilic substitution of usually allylic acetates or carbonates known as the Tsuji-Trost reaction [3]. The most versatile palladium(ll)-catalysed transformation is the Wacker oxidation, which is industrially used for the synthesis of acetaldehyde from ethylene [4]. It should be noted that many of these palladium-catalysed transformations can also be performed in an enantioselective way [5]. 

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... 

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

Scheme 11.49 Synthesis of natural products initiated by an enantioselective Wacker oxidation [72].

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... 

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). 

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). 

Scheme 16.1 Historic context of enantioselective Wacker-type oxygenation.

Finally, Sasai showed that enols generated from 1,3-dicarbonyl precursors such as 12 could also participate in Wacker-type oxygenation reactions to 13. Again, a 6-endo cyclization was observed to occur. For R being 2-methyl-pent-2-enyl, significantly higher yield and enantioselectivity were obtained than for a simple aliphatic n-butyl substituent [24]. As for the aforementioned example of 10, it may be that the additional alkene plays a supportive ligand role in these transformations. 

However, Stahl et al. [41] could show that, with the structurally weU-defined pyridinyl oxazoline ligand 34, enantioselective aerobic amidation of alkenes can be achieved for a series of pyrrolidine-forming reactions to 36 from aminoalkenes 35 with up to 98% ee (Scheme 16.8). This regular high enantioselectivity is noteworthy and shows that general enantioselective aza-Wacker chemistry should be a feasible process. 

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