Cu-catalyzed allylic alkylation

Gillingham DG, Hoveyda AH (2007) Chiral N-Heterocyclic Carbenes in Natural Product Synthesis Application of Ru-Catalyzed Asymmetric Ring-Opening/Cross-Metathesis and Cu-Catalyzed Allylic Alkylation to Total Synthesis of Baconipyrone C. Angew Chem Int Ed 46 3860... 

Scheme 16.7 Cu-catalyzed allylic alkylation using an in situ generated ADC ligand.

The allylic phosphate (37) and various allylic phosphates bearing steri-cally demanding electron-withdrawing aryl groups have been successfully used in a highly site- and enantioselective Cu-catalyzed allylic alkylation reaction with an easily accessible vinylaluminum reagent to give chiral 8 2 products (Scheme 10). ... 

Hoveyda and coworkers have also demonstrated that the sulfonated A-heterocyclic carbenes L5 and L6 can be efficiently used in the Cu-catalyzed allylic alkylation with vinylaluminum reagents (generated in situ by non-catalyzed and Ni-catalyzed... 

In a recent work, Fananas-Mastral and Feringa also described the use of alkyllithium reagents as an alternative to other metals for non-enantioselec-tive [(NHC)Cu]-catalyzed allylic alkylation. halides are... 

Gillingham DG, Hoveyda AH. Chiral N-heterocyclic car-benes in natural product synthesis application of Ru-catalyzed asymmetric ring-opening/cross-metathesis and Cu-catalyzed allylic alkylation to total synthesis of baconipyrone C. Angew. Chem. Int. Ed. 2007 46(21) 3860-3864. 

A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-l-substituted aryl-4-(l-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142,... 

In sharp contrast to a fully developed asymmetric palladium-catalyzed allylic substitution as described in the previous sections of this chapter, similar reactions using transition metal complexes other than palladium have not yet been fully investigated and their application to organic synthesis is quite limited at the present. In this section, examples of Cu-, Ni-, Pt-, Rh-, Ir-, Ru-, Mo-, and W-catalyzed allylic alkylation are summarized including recent developments in this field. 

We have developed asymmetric syntheses of isocarbacyclin [3] (Scheme 1.3.2) and cicaprost [4] (Scheme 1.3.3) featuring a Cu-mediated allylic alkylation of an allyl sulfoximine [5-7] and a Ni-catalyzed cross-coupling reaction of a vinyl sulf-oximine [8-10], respectively, transformations that were both developed in our laboratories. The facile synthesis of an allyl sulfoximine by the addition-elimination-isomerization route aroused interest in the synthesis of sulfonimidoyl-sub-stituted aiiyititanium complexes of types 1 and 2 (Fig. 1.3.2) and their application as chiral heteroatom-substituted allyl transfer reagents [11]. 

Among asymmetric bond-forming reactions, the metal-catalyzed asymmetric ally lie alkylation (AAA) is versatile and has found numerous applications [49], While palladium involves a net retention via a double inversion mechanism with soft nucleophiles and a net inversion path with hard nucleophiles, many other metals also catalyze allylic alkylation (e.g., Rh, Ru, Ir, Mo, W, and Cu), which may involve different stereochemical courses [49]. 

Sulfinate anions have been used as nucleophiles in palladium-catalyzed allylic alkylation [143]. More recently, both Cu- and Pd-catalyzed couplings of sulfinate anions with aryl halides have also been reported as a means to generate unsymmetrical diaryl sulfones, which are common motifs in bioactive molecules [38, 93, 144—148]. Similarly, Cu-catalyzed coupling of arylboronic acids with sulfinate anions has been reported [95,149,150]. Notably, Kantam and co-workers found that the use of ionic liquids permits Cu(OAc)2-catalyzed sulfone synthesis at ambient temperature and with convenient product separation and catalyst recyclability (17) [150]. 

Although the Ir-catalyzed aUyhc substitution was developed only recently, several applications in the areas of medicinal and natural products chemistry have aheady been reported. In many syntheses the allylic substitution has been combined with a RCM reaction [71]. Examples not directed at natural products targets have aheady been described in Sections 9.4 and 9.5. It has also been mentioned that this strategy had previously been used in conjunction with aUyhc substitutions catalyzed by other transition metals (Figure 9.5). This was pioneered by P. A. Evans and colleagues, who used Rh-catalyzed allylic amination (compound A in Figure 9.5) [72] and etherification (compound B) [73], while Trost and coworkers demonstrated the power of this concept for Pd-catalyzed aUyhc alkylations (compound C) [74] and Alexakis et al. for Cu-catalyzed (compound D) aUyhc alkylations [75]. 

Although not discussed in this chapter, the Tsuji-Trost reaction159 is undoubtedly the most extensively investigated Pd-catalyzed allylation with allyl electrophiles. There have also been some uncatalyzed and Cu-catalyzed reactions of allyl electrophiles with alkyl metals and metal cyanides. On the other hand, the Pd- or Ni-catalyzed reactions of allyl electrophiles with organometals containing allyl-, benzyl-, propargyl- and other alkylmetals do not appear to have been extensively investigated. 

Where possible, it may be most economical to effect a chiral transformation on a pre-formed, pro-chiral ring. Ben Feringa of the University of Groningen prepared (Chem Commun. 2005, 1711) the enone 2 from 4-methoxypyridine 1. Cu -catalyzed conjugate addition of dialkyl zincs to 2 proceeded in up 96% . Pd-mediated allylation of the intermediate zinc enolate led to 3, with the two alkyl subsituents exclusively trans to each other. 

Scheme 30 Application of 33 in the Cu-catalyzed enantioselective allylic alkylation...

Pyridine and related aromatic (quinoline, quinazoline) P,N derivatives (11, 12) have been created for Rh-catalyzed hydroboration-oxidation [44] or -amination [45]. Other pyridine-related auxiliaries have been synthesized for Pd-assisted allylic alkylation [46] in test conditions furnishing the substitution product in up to 93 % ee. The QUIPHOS ligand 13 has been tested in Pd-assisted allylic amination (up to 94 % ee) [47], allylic alkylation of -ketoesters (up to 95 % ee) [48], and Cu-catalyzed Diels-Alder reaction between an acryloyl derivative and cyclopentadiene [49]. 

The same catalyst system works well in hetero-allylic asymmetric alkylations (h-AAA Scheme 1-16). Substrates such as enol esters 163 provide entry to nonracemic esters of allylic alcohols. Remarkably, competing 1,2-addition and/or acyl transfer were not issues yields are good (80-99%). In these cases, catalyst loading can go as low as 0.8%, and ee s are mostly >95%. Additional chemoselectivity has been noted in the case of cinnamyl ester 163, where the desired Sn2 AAA takes place without competing Cu-catalyzed 1,4-addition to the enoate. This sets the stage for a subsequent metathesis (GH-2 = Grubbs-Hoveyda second-generation catalyst) en route to butenolide 164. 

As discussed above, the efficiency of the Hpase-catalyzed acetylation heavily depends on the E factor. Thus, the purification of 2-aUcyl-l-alkanols lacking any proximal r-bonds or heterofunctional groups by Hpase-catalyzed acetylation is generally more difficult than that of their proximally functionalized derivatives, their commonly reported E factors being < 10 [316]. In more demanding (feebly chiral) cases, especially when two aUcyl groups are very similar, it is difficult to purify to > 98% ee even from enantiomerically enriched mixtures by lipasecross-coupHng sequential process as outlined in Scheme 3.100 was considered for the synthesis of various feebly chiral 2-alkyl-l-alkanols [318]. The first step involves a one-pof conversion of inexpensive allyl alcohol to various... 

Scheme 15.6 Enantioselective synthesis of bi-spirolactones via Cu-catalyzed alkylation with allylic alcohols and subsequent acid-catalyzed cyclization [35].

Homillos V, Perez M, Fananas-Mastral M, Feringa BL (2013) Cu-catalyzed asymmetric allylic alkylation of phosphonates and phosphine oxides with Grignard reagents. Chem Eur J 19 5432-5441... 

Eananas-Mastral M, ter Florst B, Minnaard AJ, Feringa BE (2011) Stereoselective synthesis of syn and anti 1,2-hydroxyalkyl moieties by Cu-catalyzed asymmetric allylic alkylation. Chem Commun 47 5843-5845... 

Since acetals are more reactive than the corresponding carbonyl compounds under Lewis acid-catalyzed conditions, alkyl transfer reaction of acetals provides alkylated ethers in high yield. Recently, combined use of AlBrs/MesAl (10 1) and CuBr was reported as an excellent catalytic system for allylation reactions of dimethyl acetals with allyltrimethylsilane (Scheme 6.34) [40]. Catalytically active species are believed to be a mixed Al-Cu species. MesAl acts as a desiccant scavenging harmful HBr from the reaction mixture. 

Stable precursors, such as boranes and silanes, were also shown to display good reactivity in NHC-Cu-catalyzed conjugated additions. The groups of Ohmiya and Sawamura reported the copper-catalyzed 1,4-addition of alkyl-boranes to enones, respectively in a racemic and enantioselective version. Organosilanes, te. RSiFj or RSi(OR )3, can also be used with NHC-Cu catalysts in conjugate addition to enones and allylic epoxides. ... 

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