Carbometallation enantioselective

An early example of the use of a subcatalytic amoimt of sparteine for the activation of an organolithium nucleophile was reported by Lautens et al. in the carbometallation of a meso-unsaturated oxabicycle 25, with ring opening leading to the substituted cycloheptene derivative 26 (Scheme 4) [4]. Both yield and enantiomeric excess remained virtually unchanged when the ratio n-BuLi sparteine was lowered to 1 0.15. However, when a 3 mol% amount of the ligand 1 was used, a 20% decrease in enantioselectivity was observed. 

Widenhoefer has also disclosed an interesting extension consisting of hydrosilylative cyclization of a diene catalyzed by palladium. High enantioselectivity (up to 95% ee) was achieved by using palladium catalysts with Ci-symmetric pyridine-oxazoline ligands351,364 and recent mechanistic studies have confirmed the involvement of an intramolecular carbometallation step.365... 

In the Zr-catalyzed cyclic carbometallation discussed above, a tandem process consisting of (i) transmetallation and (ii) P-H abstraction provides the missing link in the catalytic cycle. In a series of recent examples reported by Takahashi [206—208] and Hoveyda [209—214], the missing link has been provided by a process consisting of (i) [5-elimination or deheterometallation (Pattern 10), (ii) transmetallation, and (iii) P-H abstraction (Scheme 1.62). Some of these reactions have been developed into enantioselective C—C bond-forming processes, as discussed below. 

Despite its inherent difficulties, carbometallation has, in fact, played important roles in catalytic asymmetric carbon-carbonal bond formation. Isotactic and syndiotactic alkene polymerization involving both heterogeneous and homogeneous Ti and Zr catalysts must involve a series of face-selective carbometallation processes, although the main stereochemical concern in poly(alkene) formation is diastereoselectivity rather than enantioselectivity. This fascinating topic, however, is outside the scope of this chapter, and the readers are referred to Chapter 11 and other previous reviews [6]. 

One of the earliest enantioselective carbon-carbon bond-forming processes catalyzed by chiral transition-metal complexes is asymmetric cyclopropanation discussed in Chapter 5, which can proceed via face-selective carbometallation of carbene-metal complexes. Some other more recently developed enantioselective carbon-carbon bond forming reactions, such as Pd-catalyzed enantioselective alkene-CO copolymerization (Chapter 7) and Pd-catalyzed enantioselective alkene cyclization (Chapter 8.7), are thought to involve face-selective carbometallation of acy 1-Pd and carbon-Pd bonds, respectively (Scheme 4.4). Similarly, the asymmetric Pauson-Khand reaction catalyzed by chiral Co complexes most likely involves face-selective cyclic carbometallation of chiral alkyne-Co complexes (Chapter 8,7). 

In this chapter, attention is primarily focused on simple single-stage catalytic enantioselective carbometallation reactions leading to the formation of acyclic products in most cases regardless of their actual mechanisms. However, some closely related cyclic processes are also discussed. At present, the scope of such processes appears to be largely limited to those involving a few early transition metals, especially Zr. 

Chiral ligands are generally expensive. It is therefore highly desirable to use chiral ligands as catalyst components rather than those of stoichiometric regents. In the desired Zr-catalyzed enantioselective carboalumination of alkenes, for example, chiral ligands should be part of the Zr catalysts. Furthermore, it appears desirable to devise Zr-centened carbometallation processes rather than Al-centered ones. This factor can be potentially serious as both Zr- and Al-centered... 

ZIRCONIUM-CATALYZED ENANTIOSELECTIVE CYCLIC CARBOMETALLATION OF ALLYLIC ETHERS, ALCOHOLS, AMINES, AND SULFIDES... 

Despite many such promising results, development of Zr-catalyzed enantioselective reactions based on these Zr-promoted or Zr-catalyzed cyclic carbometallation processes has not been straightforward. Thus, there has been no report of Zr-catalyzed cyclic carbometallation of simple, unactivated alkenes exhibiting enantioselectivity >33% [9,29]. 

Catalytic enantioselective single-stage carbometallation of alkenes had until recently been an elusive synthetic goal, even though its principle and potential feasibility were recognized. It is... 

It was observed that when chiral ligands are used, the sterochemistry of the olefin is crucial for the enantioselectivity of the carbolithiation. Thus, asymmetric carbolithiation of 39E with w-BuLi in the presence of (—)-sparteine gives the carbometallated product (,Y)-46 and compounds 47-49 in ca 80%ee (Scheme 19)55. 

Negishi, E.-I. Some Newer Aspects of Organozirconium Chemistry of Relevance to Organic Synthesis. Zr-Catalyzed Enantioselective Carbometalation, Pure Appl. Chem. 2001, 73, 239-242. 

If an efficient method was available to render such a process asymmetric, it would acquire utility in the creation of asymmetric vicinal carbon atoms. However, until now, such enantioselective carbometallation reactions have been scarce because of the difficulty of enantiofacial differentiation of an unactivated alkene. Here we describe the more important results in this field. 

The addition of alkyllithiums to allylic alcohols, originally described by Felkin and Crandall [83], has recently acquired new interest due to the enantioselective approach of the carbometallation reaction of cinnamyl derivatives. Indeed, asymmetric carbolithiation of ( )-cinnamyI alcohol in hexane or cumene, in the presence of the readily available chiral diamine (—)sparteine, leads to the carbometallated product in 82% ee. Primary as well as secondary alkyllithiums lead to identical enantioselection [128] (Scheme 7-108). 

The zirconium-catalyzed carbometalation reaction has been developed from the initial observation by Dzhemilev in 1983 that Cp2ZrCl2 (1) catalyzes the addition of ethyl-magnesium halide to unactivated alkenes [104-106]. A plausible mechanism for this carbometalation involves zirconocene and zirconacyclopentane species (Scheme 6.5) [107-109]. Diastereo- and enantioselective carbomagnesation is accomplished by use of chiral fl .sa-zirconocene derivative [110]. 

In the Zr-catalyzed enantioselective alkylation reactions discussed above, we discussed transformations that involve the addition of alkylmagnesium halides and alkylaluminum reagents to olefins. With the exception of studies carried out by Negishi and coworkers, all other processes involve the reaction of a C-C n system that is adjacent to a C-0 bond. Also with the exception of the Negishi study [Eqs. (6) and (7)], where direct olefin carbometallation occurs, all enantioselective alkylations involve the intermediacy of a metallacyclopentane (cf. Scheme 3). In this segment of our discussion, we will examine the Ni-catalyzed addition of hard nucleophiles (e.g., alkylmagnesium halides) to olefins that bear a neighboring C-0 unit. These reactions transpire by neither of the above two mechanistic manifolds (metallacyclopentane intermediacy or direct carbometallation). Rather, these processes take place via a Ni-Ti-allyl complex. 

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