Enantioselective 1,4-additions of ClMeAl(CHCHR) (R = alkyl, alkenyl, Ph) to cyclohexenones

Abstract

Chloromethylvinyl alanes (E)-ClMeAl(CHQ Q QCHR) prepared directly from terminal alkynes undergo 1,4-addition to cyclohexenone and 3-methylcyclohexenone in moderate to good yield (30-70%) and good to excellent stereoselectivity (80-98% ee) using readily available copper(I) sources and chiral ligands.Asymmetric conjugate addition (ACA) has become a mainstay of contemporary chiral synthesis in the last 10 years. 1 Sublime levels of enantioselectivity are realised in 1,4-additions of simple alkyl groups to various Michael acceptors, but the situation for C(sp 2 ) vinyl-based nucleophiles is not so clear cut. Rhodium-diphosphine catalysts are normally preferred for additions of C(sp 2 ) nucleophiles, especially aryls, to mono substituted enones 2 but these fail to elicit any reaction for b,b-substituted enones -where copper(I)/phosphorus-ligand catalysts are required. 1,3 The choice of C(sp 2 ) nucleophile also has issues: vinyl boronic acids, and their derivatives, are rather more susceptible to hydrolytic deboronation compared to their aryl cousins -causing lower yields or the need for excess reagents. Alkenylalanes, used with Cu I catalysts, are often prepared from RCCH and DIBAL-H (either through heating, 4 or Ni-catalysis 5 ) have issues: (i) deprotonation by-products are common under thermal DIBAL-H procedures except for alkyl substituted cases; (ii) b-aryl Bu i 2 AlCHQCHAr, prepared by Ni-catalysis, are normally contaminated with B5% of the a-aryl isomer; finally (iii) the bulky Bu i substituents can cause problems in the subsequent ACA catalysis leading to low yields and slow reactions. Alternative hydroalumination-ACA approaches are desirable, particularly if they use simple reagents catalysts and conditions to deliver high ee values for 1,4-additions to both mono and b,b-disubstituted enones.

Formation of Quaternary Stereocentres by Copper-Catalysed Enantioselective Conjugate Addition Reaction

“…Recently, Woodward et al have described the synthesis of alkenylaluminium reagents from their corresponding alkynes and HAlCl2·2THF, using Cp*2ZrCl2 as catalyst. The initially obtained aluminium species can be activated with MeLi (1 equiv) * to generate the alane (E)-ClAlMeCH=CHR 1 which, under copper(I)-phosphoramidite catalysis with a cyclic enone, provides the corresponding 1,4-addition product with high enantioselectivity (Scheme 11) [46]. This process shows good generality for 1,4additions to a wide variety of -substituted cyclohexenones.…”

“…Scheme 11. Copper-phosphoramidite catalysed ECA of alkenyl aluminium reagents (prepared via zirconium catalysed hydroalumination) to -substituted cyclohexenones by Woodward [46].…”

Asymmetric Conjugate Additions and Allylic Alkylations Using Nucleophiles Generated by Hydro‐ or Carbometallation

“…Eur.J.2015, 21,5668 -5678 www.chemeurj.org used in the total synthesis of an isomer of riccardiphenol B (Scheme 9). [48] Hoveyda et al recently reported an impressive sequence of hydro-and carboalumination reactions converging on af inal copper-catalysed ACA. [47] Recently,W oodward and Alexakis et al obtained alkenylaluminiums [48] using HAlCl 2 ·2 THF and catalytic Cp* 2 ZrCl 2 .A ctivation of the initially obtained aluminium species with MeLi, followed by addition of copper(I) and ac hiral phosphoramidite ligand,r esulted in highly enantioselective 1,4-addition reactions (Scheme 11).…”

ChemInform Abstract: Asymmetric Conjugate Additions and Allylic Alkylations Using Nucleophiles Generated by Hydro‐ or Carbometalation

“…[45,46] These silicon-substituted alkenyl aluminiums, as well as other vinylaluminium reagents, have also been used in AAAs to form all-carbon quaternary centres (Scheme 10). [47] Recently,W oodward and Alexakis et al obtained alkenylaluminiums [48] using HAlCl 2 ·2 THF and catalytic Cp* 2 ZrCl 2 .A ctivation of the initially obtained aluminium species with MeLi, followed by addition of copper(I) and ac hiral phosphoramidite ligand,r esulted in highly enantioselective 1,4-addition reactions (Scheme 11). [48] Hoveyda et al recently reported an impressive sequence of hydro-and carboalumination reactions converging on af inal copper-catalysed ACA.…”

“…[47] Recently,W oodward and Alexakis et al obtained alkenylaluminiums [48] using HAlCl 2 ·2 THF and catalytic Cp* 2 ZrCl 2 .A ctivation of the initially obtained aluminium species with MeLi, followed by addition of copper(I) and ac hiral phosphoramidite ligand,r esulted in highly enantioselective 1,4-addition reactions (Scheme 11). [48] Hoveyda et al recently reported an impressive sequence of hydro-and carboalumination reactions converging on af inal copper-catalysed ACA. [49] Here, the addition of alkenyl nucleophiles to linear 4-substituted enones gives all-carbon quaternary stereogenic centres with consistently high enantioselectivities (Scheme 12).…”