Synthesis of Quaternary Carbon Stereogenic Centers through Enantioselective Cu-Catalyzed Allylic Substitutions with Vinylaluminum Reagents

Abstract

Catalytic enantioselective allylic substitution (EAS) reactions, which involve the use of alkyl- or aryl-substituted vinylaluminum reagents and afford 1,4-dienes containing a quaternary carbon stereogenic center at their C-3 site, are disclosed. The C–C bond forming transformations are promoted by 0.5–2.5 mol % of sulfonate bearing chiral bidentate N-heterocyclic carbene (NHC) complexes, furnishing the desired products efficiently (66–97% yield of isolated products) and in high site- (>98% SN2′) and enantioselectivity [up to 99:1 enantiomer ratio (er)]. To the best of our knowledge, the present report puts forward the first cases of allylic substitution reactions that result in the generation of all-carbon quaternary stereogenic centers through the addition of a vinyl unit. The aryl- and vinyl-substituted vinylaluminum reagents, which cannot be prepared in high efficiency through direct reaction with diisobutylaluminum hydride, are accessed through a recently introduced Ni-catalyzed reaction of the corresponding terminal alkynes with the same inexpensive metal-hydride agent. Sequential Ni-catalyzed hydrometallations and Cu-catalyzed C–C bond forming reactions allow for efficient and selective synthesis of a range of enantiomerically enriched EAS products, which cannot cannot be accessed by previously disclosed strategies (due to inefficient vinylmetal synthesis or low reactivity and/or selectivity with Si-substituted derivatives). The utility of the protocols developed is demonstrated through a concise enantioselective synthesis of natural product bakuchiol.

Site- and Enantioselective Formation of Allene-Bearing Tertiary or Quaternary Carbon Stereogenic Centers through NHC–Cu-Catalyzed Allylic Substitution

“…16 Such issues did not concern the previously reported reactions with vinylmetals. 7 In this connection, during recent studies regarding allyl additions to imines, 17 we established that the corresponding NHC–Cu-allyls collapse readily to the derived π-allyl complex, resulting in a non-selective mode of reaction at the two termini. Whether the same would apply to allenyl additions was unclear and remained to be determined.…”

“…One issue relates to the significance of Lewis acidic metal salts. For example, our studies indicate that in Cu-catalyzed allylic substitutions of trisubstituted allylic phosphates 7c the equatorial Lewis basic sulfonate oxygen can be involved in a metal chelate with the phosphate unit ( I , Scheme 2); 5 reactivity might be accordingly enhanced, allowing reactions to be performed at lower temperatures (e.g., −50 °C), leading to improvement in enantioselectivity. Although in I and II , the bound substrate is orientated such that there is proper alignment of Cu–R σ-bond with the LUMO of the allylic phosphate, Lewis acid activation in I together with unfavorable steric interactions in II result in the former delivering the major isomer.…”

Room temperature and highly enantioselective additions of alkyltitanium reagents to aldehydes catalyzed by a titanium catalyst of (R)‐h8‐binol

“…[1][2][3][4] Over the past two decades, a variety of chiral ligands have been developed to deliver desired alcohols in high enantioselectivities. [5][6][7][8][9][10][11][12][13][14][15][16] Recent studies have shown that organoaluminum compounds are effective reagents, [17][18][19][20][21][22][23][24][25][26][27][28][29] and addition reactions can even be completed in 10 min. 24 Grignard [30][31][32][33] and lithium 34 reagents have also been established recently as efficient nucleophiles for addition reactions despite their high reactivity.…”

Formation of Vinyl-, Vinylhalide- or Acyl-Substituted Quaternary Carbon Stereogenic Centers through NHC−Cu-Catalyzed Enantioselective Conjugate Additions of Si-Containing Vinylaluminums to β-Substituted Cyclic Enones

“…We were aware that the attendant steric congestion, as well as stabilization of electron density at the Si-bearing carbon might result in diminution of vinylaluminum nucleophilicity to decelerate the vinyl addition process, allowing alternative pathways to become competitive. In the context of Cu-catalyzed allylic substitutions, we had observed that Si-substituted vinylaluminums, although effective in reactions that furnish tertiary C–C bonds, give rise to inefficient and non-selective processes when quaternary carbon stereogenic centers are to be generated 10. Such concerns were validated in the present studies by the observation that with the NHC–Cu derived from dimeric Ag complex 1 (easily accessed from the imidazolinium salt and Ag 2 O)11 and CuCl 2 •2H 2 O, ECA with β-methylcyclopentenone and vinylsilane 6 delivers 20% of the desired 7a (10:90 er)12 along with 15% of allylic alcohol 9 (entry 1, Table 1).…”