Enantioselective Mizoroki-Heck Reactions

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This chapter will introduce novices to the enantioselective intramolecular Mizoroki-Heck reaction by presenting the information necessary to design and execute reactions. To tempt the expert, a summary of recent provocative results, the current status of the field and research opportunities will be highlighted. After a brief introduction, the 

The Mizoroki-Heck Reaction Edited by Martin Oestreich 2009 John Wiley Sons, Ltd. ISBN 978-0-470-03394-4 

To rationalize the enantioselective intramolecular Mizoroki-Heck reaction, other mechanistic pathways have been invoked, including the cationic pathway and nenlial pentacoor-dinate intermediates. The different pathways explain the influences that substrate, Ugands and additives have upon selectivity. As with many catalytic asymmetric systems, optimization of enantioselectivity is achieved through a combination of experimentation and the application of mechanistic knowledge. 

For alkenyl and aryl halides, a neutral mechanistic manifold has been invoked in which one arm of the phosphine ligand must dissociate (13- 17) to create a vacant site on palladium for alkene coordination (17- 18) [6,11]. The lower enantioselectivities observed for Mizoroki-Heck reactions occurring via the neutral pathway have been attributed to this ligand dissociation. To achieve higher enantioselectivities, the reaction of alkenyl and aryl halides may be directed into the cationic manifold by the addition of the silver or thallium 

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In 1990, Cabri el al. [40a] reported that the precursor Pd(OAc>2 associated with a biden-tate P P ligand as dppp (1,3-bis-diphenylphosphinopropane) appeared to be more efficient than PPhs in Mizoroki-Heck reactions performed from aryl Inflates and enol ethers (electron-rich alkenes) moreover, the regioselectivity in favour of the a-arylated alkenes was improved to 100%. Since that time, dppp associated with Pd(OAc)2 has been used extensively to catalyse Mizoroki-Heck reactions and to investigate the factors that control the regioselectivity [Ig, 40]. The chiral bidentate (7 )-Binap (2,2 -bis(diphenylphosphino)-1,1-binaphthyl) associated with Pd(OAc)2 has also been used by Shibasaki and coworkers [2b,d,41a] and Overman andPoon [41b] in intramolecular enantioselective Mizoroki-Heck reactions (also, see Link [2f] for an authorative review on the Overman-Shibasaki chemistry), as well as by Hayashi and coworkers [2a, 41c,d] to control the regioselectivity and enantioselectivity of intermolecular Mizoroki-Heck reactions performed from cyclic alkenes (see Schemes 1.3 and 1.2 (Z = O) respectively). 

ShibasaM and coworkers [117] described the first enantioselective combination of this type in their synthesis of the natural product halenaquinone (225) possessing antibiotic, cardiotonic and protein tyrosine kinase inhibitory activities. The key step is an intermolecular Suzuki reaction of 222 and 223 followed by an enantioselective Mizoroki-Heck reaction in the presence of (5 )-BINAP to construct the third ring and the stereogenic quaternary centre present in 224. The reaction proceeded with a good cc-value of 85% but with a yield of only 20% (Scheme 8.56). 

Scheme 12.4 Enantioselective Mizoroki-Heck reaction of o-iodoanilide.

Scheme 12.6 Enantioselective Mizoroki-Heck reaction with a monodentate phospho-ramidite ligand.

Intramolecular Enantioselective Mizoroki Heck Reactions 44 / Table 12.1 Intramolecular Mizoroki-Heck reaction of enantioenriched o-iodoanilides... 

The stereochemical outcome with (R)-75 and (S)-76 having opposite absolute configuration is intriguing. Hayashi et al. assumed that a kinetic resolution is operating within the enantioselective Mizoroki-Heck reaction (Scheme 7.16). 

Recently, Erase et al reported a desymmetrizing enantioselective Mizoroki-Heck reaction producing tetracycle 138, again with three adjacent stereogenic centers (136—>138 Scheme 7.32) [83]. Interestingly, a Mizoroki-Heck reaction of 136 using conventional chiral ligands such as (R)-BINAP ((R)-74) or (S)-i-Pr-PHOX resulted in very low enantioselection and/or conversion. Conversely, (S,R)-... 

The enantioselective spiro ring construction is an important issue because many natural compounds have chiral spiro centers [103,104]. Pd catalyses of Spiro cyclizations have been reported by asymmetric intramolecular Mizoroki-Heck reactions [105,106]. In spite of a similar potential, transition metal-catalyzed ene-type carbocyclization has never been applied to asymmetric spiro cyclizations [107-110]. 

There are two major realizations of the polar pathway in intermolecular Mizoroki-Heck reactions (1) enantioselective arylation of cyclic alkenes (Chapter 11) and (2) regioselective internal arylation of terminal alkenes (Chapter 3). 

In most of the palladium-catalysed domino processes known so far, the Mizoroki-Heck reaction - the palladium(0)-catalysed reaction of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - has been apphed as the starting transformation accordingly to our classification (Table 8.1). It has been combined with another Mizoroki-Heck reaction [6] or a cross-coupling reaction [7], such as Suzuki, Stille or Sonogashira reactions. In other examples, a Tsuji-Trost reaction [8], a carbonylation, a pericyclic or an aldol reaction has been employed as the second step. On the other hand, cross-couphng reactions have also been used as the first step followed by, for example, a Mizoroki-Heck reaction or Tsuji-Trost reactions, palladation of alkynes or allenes [9], carbonylations [10], aminations [11] or palladium(II)-catalysedWacker-type reactions [12] were employed as the first step. A novel illustrative example of the latter procedure is the efficient enantioselective synthesis of vitamin E [13]. 

Scheme 8.21 Influence of the substitution pattern on the enantioselectivity in intramolecular double Mizoroki-Heck reaction.

Fortunately, by fine tuning of the reactivity of the different functionalities, not only the combination of a Mizoroki-Heck with a Suzuki reaction but also a Suzuki with a Mizoroki-Heck reaction is possible, even in an enantioselective manner. 

In their enantioselective total synthesis of the alkaloid cephalotaxine (246), Tietze and Schirok [127] used a combination of a Tsuji-Trost and a Mizoroki-Heck reaction (Scheme 8.62). It was necessary to adjust the reactivity of the two palladium-catalysed transformations to allow a controlled process. Reaction of 243a using Pd(PPh3)4 as catalyst led to 244, which furnished 245 in a second palladium-catalysed reaction. In this process, the nucleophilic substitution of the allylic acetate is faster than the oxidative addition of the arylbromide moiety in 243a however, if one uses the iodide 243b, then the yield drops dramatically due to an increased rate of the oxidative addition. 

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... 

At first glance, therefore, the Mizoroki-Heck reaction is not a good candidate for enantioselective catalysis, since the sp centre (labelled in Scheme 11.2) formed in the migratory 5yn-insertion step is converted back to an sp centre in the achiral product in the -hydride elimination step. However, closer inspection of these steps suggested that... 

Shibasaki and coworkers [18] carried out the intermolecular asymmetric Mizoroki-Heck reaction with dihydrodioxepines 20 using the palladium-(50-BlNAP catalytic system (Scheme 11.11). The product 21 was obtained in yields up of to 86% and with up to 75% ee. When the aryl group on the triflate 13 was changed, the enantioselectivity was not found to vary appreciably. 

To date, the large majority of asymmetric Mizoroki-Heck reactions reported have utilized palladium complexes of BINAP (5). However, since their first application to the asymmetric Mizoroki-Heck reaction, P,N ligands have proven successful and have thus received a greater amount of attention recently [30], The phosphinooxazoline PJSl ligands 41-45 developed independently by the groups of Pfaltz [31], Williams [32] and Hehnchen [33] have shown dramatic improvement in enantioselectivity in a number of asymmetric transformations, including the intermolecular asymmetric Mizoroki-Heck reaction [34]. 

Dai et al. [55] reported the only example of P,0 ligands applied to the asymmetric Mizoroki-Heck reaction. The atropisomeric amide-derived ligands 88 were applied to the reaction of phenyl triflate (2) and 2,3-dihydrofuran (1). Conversions were low (<30%) in all cases, although moderate enantioselectivity was observed (52% ee, ligand 88a). 

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