Development of a Strategy for Linear-Selective Cu-Catalyzed Reductive Coupling of Ketones and Allenes for the Synthesis of Chiral γ-Hydroxyaldehyde Equivalents

Abstract

We report the development of a stereoselective method for the allylation of ketones utilizing N-substituted allyl equivalents generated from a chiral allenamide. By choice of the appropriate ligand for the Cu-catalyst, high linear selectivity can be obtained with good diastereocontrol. This methodology allows access to chiral γ-hydroxyaldehyde equivalents that were applied in the synthesis of chiral γ-lactones and 2,5-disubstitued tetrahydrofurans.

Access to Chiral Diamine Derivatives through Stereoselective Cu-Catalyzed Reductive Coupling of Imines and Allenamides

“… 20 In contrast, amino-substituted allyl reagents 12 have been used in reactions employing carbonyl electrophiles to provide 1,2-aminoalcohols ( 16 ). 21 − 23 Recently, the Krische 22 group and our own lab 23 have developed reductive coupling 24 , 25 procedures for the catalytic generation of amino-substituted allyl reagents 12 and have studied their reactions with carbonyl electrophiles ( Scheme 2 C). These techniques represent orthogonal methodologies whereby the Krische 22a system employs a chiral Ir-catalyst and processes aldehyde electrophiles using an achiral allenamide ( 15 ), while our work utilizes a Cu-catalyst and a chiral allenamide ( 15a ) for reactions using ketone electrophiles.…”

“…These techniques represent orthogonal methodologies whereby the Krische 22a system employs a chiral Ir-catalyst and processes aldehyde electrophiles using an achiral allenamide ( 15 ), while our work utilizes a Cu-catalyst and a chiral allenamide ( 15a ) for reactions using ketone electrophiles. 23 Based on our success in the stereoselective Cu-catalyzed reductive coupling of ketones and chiral allenamides to afford branched chiral 1,2-aminoalcohols 16 ( 23a ) or the corresponding linear products, 23b and the lack of literature data for imine allylation reaction utilizing amino-substituted allylic nucleophiles, we began to investigate the reaction of allenamide 15a with imine electrophiles 9 for the stereoselective synthesis of chiral 1,2-diamine synthons 17 ( Scheme 2 D). The results of these studies leading to the identification of a practical and highly stereoselective synthesis of diamine synthons 17 using Cu-catalyzed reductive coupling are disclosed herein.…”

Access to a Catalytically Generated Umpolung Reagent through the Use of Cu-Catalyzed Reductive Coupling of Ketones and Allenes for the Synthesis of Chiral Vicinal Aminoalcohol Synthons

“…Additionally, we recently developed a Cu-catalyzed reductive coupling of ketones and allenamide 11 for the diastereoselective synthesis of linear product l - 12 that represents a masked γ-hydroxyaldehyde equivalent (Figure 1C). 9 By tuning of the ligand in this reaction, high linear selectivity could be obtained when using phosphoramidite (PhO) 2 PNMe 2 ( 14 ) for this process. This methodology is currently proposed to proceed through the catalytically generated α,γ-aminoanion 13 .…”

“…9 Initial hydrocupration of 11 is proposed to occur trans to the large oxazolidinone group to give rise initially to the Z geometry of (σ-allyl)Cu complex l-Z- 15 . 9,16 The preferred linear selectivity is believed to occur by a preference for complexes π- 15 and/or b-σ- 15 due to the A 1,3 -strain present in l-Z - 15 and the directing effect of the oxazolidinone carbonyl 9,17 that distorts π- 15 so that Cu is biased toward the α-site. 18 The A 1,3 -strain present in l-Z- 15 appears to be the main interaction that leads to linear product formation using phosphine ligands because both electron-rich (Table 1, entry 4) and electron-deficient (Table 1, entry 1) phosphines provide linear selectivity.…”

“…9 Finally, because the A 1,3 -strain appears to play a critical role in regioselectivity, full isomerization of 15 to l-E- 15 likely is not occurring, which suggests that the alkene moiety of b-σ- 15 is still bound to Cu. 9,18…”