Selectivity, olefin cross-metathesis

In 2011, Hoveyda et al. reported the total syntheses of two natural products, C18 (plasm)-16 0 (PC) (162) and KRN7000 (163), an anti-oxidant plasmalogen phospholipid and a potent immunostimulant, respectively, through catalytic Z-selective olefin cross metathesis (CM) [97]. In this study (Fig. 41), the corresponding disubstituted aUcenes were efficiently formed in good yields and excellent Z-selectivity (up to >96%) by the treatment of a molybdenum aUcylidene complex. 

Olefin cross metathesis starts to compete with traditional C=C bondforming reactions such as the Wittig reaction and its modifications, as illustrated by the increasing use of electron-deficient conjugated alkenes for the ( )-selective construction of enals and enoates. 

McNaughton, B. R. Bucholtz, K. M. Camaano-Moure, A. Miller, B. L. Self-selection in olefin cross metathesis The effect of remote functionality. Org. Lett. 2005, 7, 733-736. 

As described above in Eq. 43, simple allylboronates can be transformed into more elaborated ones using olefin cross-metathesis. " Treatment of pinacol allylboronate 31 with a variety of olefin partners in the presence of Grubbs second-generation catalyst 142 smoothly leads to formation of 3-substituted allylboronates 143 as cross-metathesis products (Eq. 104). Unfortunately, these new allylic boronates are formed as mixtures of geometrical isomers with modest E/Z selectivity. They are not isolated but rather are treated directly with benzaldehyde to give the corresponding homoallylic alcohol products in good yields (Table A). 

It was recognized early that efficient olefin cross metathesis could provide new methods for the synthesis of complex molecules. However, neither (la) nor (2a) were very effective at intermolecular cross metathesis owing to poor reaction selectivity (cross vs. intramolecular metathesis) and low E. Z ratios see (E) (Z) Isomers) The advent of more active and functional group tolerant olefin metathesis catalysts recently made cross metathesis a viable route for constructing a large variety of fimctionalized acyclic alkenes. 

Scheme 21.8 shows the complex network of equilibria that are possible when two different olefins are combined in a metathesis system. The relative rates and magnitudes of the individual steps are not well enough established to fully rationalize the trends in selectivities of cross-metathesis reactions. However, a few features of the [2+2] cycloadditions should be kept in mind when considering the equilibria involved in a cross metathesis. First, some of the [2+2] processes lead to metallacycles containing substituents located in positions 1,3 to each other, and these metallacycles do not lead to productive metatheses processes. Second, the [2+2] reactions are slow in some cases... 

Chatteqee AK, Choi T-L, Sanders DP, Grubbs BJT. A General Model for Selectivity in Olefin Cross Metathesis. J Am Chem Soc. 2003 125(37) 11360—11370. 

Lin YA, Chalker JM, Davis BG. Olefin Cross-Metathesis on Proteins Investigation of Allylic Chalcogen Effects and Guiding Principles in Metathesis Partner Selection. J Am Chem Soc. 2010 132(47) 16805-16811. 

In contrast to the preparative methods described above, a functionalized allyl-boronate can be created from a simpler allylboronate by olefin cross-metathesis [81, 82]. Here, treatment of pinacol allylboronate (2) with various olefin partners, exemplified with styrene in Equation (33), in the presence of ruthenium catalyst 58 smoothly furnishes a more elaborate 3-substituted allylboronate, the cross product 38 [81]. These reactions are noteworthy for their exceptional functional group tolerance allylboronates bearing primary halides can be directly synthesized using this method. Unfortunately, the E/Z selectivity in the formation of the 3-substituted allylboronates is variable. This metathesis approach to allylboronates was employed as the beginning of a tandem cross-metathesis/carbonyl allylation process [82] (discussed in more detail in Section 6.4.1.3). 

Another study of CH2 and CD2 exchange between 1-hexene and [l,l-D2]-l-pentene showed that this reaction was approximatively 10 times faster than productive metathesis in WCl —BuLi or WCl —. AlEtCl2 systems [35]. The structural selectivity of metathesis reactions can be summed up as follows Degenerate exchange of =CH2 groups between terminal olefin > cross metathesis between terminal and internal alkenes > metathesis of internal olefins > non-degenerate metathesis of terminal alkenes. 

In summary, alkene cross metathesis has been successfully applied to numerous total syntheses of complex natural products. In most cases, this reaction can provide high yield, and good regio-, chemo-, and F-stereoselectivities. More importantly, the outcome of selective alkene cross metathesis can be predicted based on the propensity of different olefin for dimerization, making it a reliable transformation for design and implementation of complex natural product synthesis. 

Chatteijee AK, Choi TL, Sanders DP, Grubbs RH. A general model for selectivity in olefin cross metathesis. J. Am. Chem. Soc. 2003 125 11360-11370. 

Olefin metathesis of vinylboronates [102] and allylboronates [103, 104] has been investigated over the past few years because organoboranes are versatile intermediates for organic synthesis. Cross metathesis of vinylboronate 108 and 2-butene 109, for example, yields the boronate 110, which can be converted to the corresponding vinyl bromide 111 with high Z selectivity. Vinyl iodides can be obtained analogously. It should be noted that vinyl bromides and vinyl... 

Bent ansa-metallocenes of early transition metals (especially Ti, Zr, Hf) have attracted considerable interest due to their catalytic activity in the polymerization of a-olefins. Ruthenium-catalyzed olefin metathesis has been used to connect two Cp substituents coordinated to the same metal [120c, 121a] by RCM or to connect two bent metallocenes by cross metathesis [121b]. A remarkable influence of the catalyst on E/Z selectivity was described for the latter case while first-generation catalyst 9 yields a 1 1 mixture of E- and Z-dimer 127, -127 is the only product formed with 56d (Eq. 19). 

Only recently a selective crossed metathesis between terminal alkenes and terminal alkynes has been described using the same catalyst.6 Allyltrimethylsilane proved to be a suitable alkene component for this reaction. Therefore, the concept of immobilizing terminal olefins onto polymer-supported allylsilane was extended to the binding of terminal alkynes. A series of structurally diverse terminal alkynes was reacted with 1 in the presence of catalytic amounts of Ru.7 The resulting polymer-bound dienes 3 are subject to protodesilylation (1.5% TFA) via a conjugate mechanism resulting in the formation of products of type 6 (Table 13.3). Mixtures of E- and Z-isomers (E/Z = 8 1 -1 1) are formed. The identity of the dominating E-isomer was established by NOE analysis. 

As illustrated above, various possible alkylidene intermediates and numerous primary and secondary pathways are involved in olefin CM. To simplify selective reaction design, an empirical product selectivity model was recently developed by Grubbs and co-workers, in which some degree of orthogonality amongst olefin cross-partners was established by categorizing the relative capacity of olefins to homodimerize in the presence of a given metathesis catalyst. ... 

Cross-metathesis, however, is usually a nonselective reaction. Transformation of two terminal alkenes in the presence of a metathesis catalyst, for instance, can give six possible products (three pairs of cis/trans isomers) since self-metathesis of each alkene and cross-metathesis occur in parallel. It has been observed, however, that terminal olefins when cross-metathesized with styrene yield trans-P-alkylstyrenes with high selectivity.5 A useful synthetic application of cross-metathesis is the cleavage of internal alkenes with ethylene called ethenolysis to yield terminal olefins ... 

The chiral Mo-alkylidene complex derived from AROM of a cyclic olefin may also participate in an intermolecular cross metathesis reaction. As depicted in Scheme 16, treatment of meso-72a with a solution of 5 mol % 4a and 2 equivalents of styrene leads to the formation of optically pure 73 in 57% isolated yield and >98% trans olefin selectivity [26]. The Mo-catalyzed AROM/CM reaction can be carried out in the presence of vinylsilanes the derived optically pure 74 (Scheme 16) may subsequently be subjected to Pd-catalyzed cross-coupling reactions, allowing access to a wider range of optically pure cyclopentanes. 

The utility of Ru-catalyzed cross-metathesis in multicomponent coupling strategies has also been demonstrated. For instance, one-pot cross-metathesis/allylboration sequences have been reported by Miyaura [170] and by Goldberg and Grubbs [171]. Pinacol allyl boronate 174 was reacted with a series of functionalized olefins, which include symmetrically 1,2-disubstituted olefins as well as hindered olefins and styrenes, in the presence of catalyst 175 to produce intermediate allyl boro-nates (e.g. 176). The latter may then be reacted in situ with aldehydes to produce functionalized homoallylic alcohols with high levels of anti-selectivity (Scheme 8.80). 

WC16 Na[Re04] [C4C im][BF4] [C4C1im]Cl-AlCl3 Cross-metathesis of linear olefins, e.g. conversion of 1-hexene to 4-octene and 5-decene rather low conversions (<15-30%) addition of 10-30% SnBu4 significantly increases the yield and the selectivity for 4-octene (> 95%). [25]... 

Taylor reported kinetically controlled cross metathesis of homoallylic alcohols and allyl trimethyl silane with (4a) gave products with high E-olefin selectivity and good yields via a five-membered chelate intermediate (equation 20). ... 

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