High Asymmetric Induction in Anionic Amino-Cope Rearrangements Controlled by β-Aminoalcohol Auxiliaries

Abstract

Novel 3-amino-1,5-dienes were prepared with high diastereoselectivity by unprecedented 1,2-addition of allyl Grignard to α,β-unsaturated imines containing β-aminoalcohol auxiliaries.Asymmetric anionic amino-Cope rearrangement of the diastereoisomerically pure 3-amino-1,5-diene substrates proceeded to yield the target 3-substituted aldehyde in good yield and with high levels of asymmetric induction (up to 94% e.e.).There is growing interest in asymmetric variants of sigmatropic rearrangements. 1 We have recently initiated a programme aimed at developing the amino-Cope rearrangement as a novel synthetic cascade. Scheme 1 summarizes our ultimate goal, the one-pot synthesis of acyclic products containing (up to) three contiguous asymmetric centres via sigmatropic rearrangement (Step 1) and subsequent enamine derivatization (Step 2). Scheme 1Our group is the first to have demonstrated key steps of this protocol, including a successful tandem amino-Cope rearrangement/enamine derivatization reaction. 2 More recently we have established that an anionic variant of the amino-Cope rearrangement is possible, and that asymmetric induction can be achieved at a chiral centre created during the rearrangement of a diastereoisomerically pure substrate. 3 We believe that the asymmetric amino-Cope rearrangement has significant advantages over the analogous oxy-Cope rearrangement in terms of asymmetric induction. The reported axial/equatorial preference for an oxy-anion substituent in the proposed chair-like transition state of the oxy-Cope rearrangement can be low, leading to a product with a correspondingly low enantioselectivity. 4 For example, the asymmetric oxy-Cope and amino-Cope rearrangements can yield the same aldehyde product, but whereas the amino-Cope rearrangement has yielded the product with 75% e.e., 3 the oxy-Cope is known to lead to only 30% e.e. 4Our initial study into the asymmetric amino-Cope rearrangement suffered from drawbacks including low diastereoselectivity (1.3 : 1) in the preparation of the required 3-amino-1,5-diene substrates, and a maximum e.e. of only 75% in the amino-Cope rearrangement. 3 The diastereoselectivity obtained during preparation of the 3-amino-1,5-diene substrates is of key importance to our work, since each diastereoisomer is known to lead to opposite enantiomers of the rearrangement product, 3 hence separation of the substrate diastereoisomers is an additional problem if one aims to achieve high enantioselectivity in the sigmatropic rearrangement. The results outlined in this current paper describe the synthesis of the required 3-amino-1,5-diene substrates with much improved levels of diastereoselectivity using β-aminoalcohol chiral auxiliaries, and a significant increase in product e.e. during the amino-Cope rearrangement of these novel substrates.Following our preliminary work, we reasoned that an increase in the steric bulk of the amine component would result in a corresponding increase in product enantioselectivity during the amino-Cope rearrangement. This postulate was based on our...

The First Lateral Functionalization of Calix[4]arenes by a Homologous Anionic Ortho-Fries Rearrangement

“…Mechanism. The homologous anionic ortho-Fries rearrangement is believed to be an orbital symmetry-driven process. , Based on our results using calix[4]arene bis- O -carbamates in addition to the migrations described for other systems by Dankwardt and Chenard, we postulate that the homologous anionic ortho-Fries rearrangement proceeds via an intermediate five-membered ring (Scheme ) . In Scheme , the formation of only one five-membered ring has been outlined either at the equatorial ( 21 ) or at the axial lateral position ( 22 ) in the cone bis- O -carbamates 4a , b .…”

Applications of the amino-Cope rearrangement: synthesis of tetrahydropyran, δ-lactone and piperidine targets

“…6 The preparation of the 3-amino-1,5-diene substrate required for the asymmetric amino-Cope rearrangement has been detailed elsewhere. 5 Substrate 1 was readily isolated in diastereoisomerically pure form by recrystallization, and the relative stereochemistry has now been confirmed by single crystal X-ray analysis (Fig. 1).…”

“…3 Although the precise mechanism of the amino-Cope rearrangement remains a matter for debate, 4 we have demonstrated that the asymmetric amino-Cope rearrangement can have significant advantages over the analogous oxy-Cope rearrangement in terms of asymmetric induction. 5 For example the axial/equatorial preference of an oxy-anion substituent in the proposed chair-like transition state of the oxy-Cope rearrangement can be low, leading to a rearrangement product with a correspondingly low e.e. 6 The preparation of the 3-amino-1,5-diene substrate required for the asymmetric amino-Cope rearrangement has been detailed elsewhere.…”

Efficient 1,3-Asymmetric Inductions during Nucleophilic Additions to Imine and Iminium Ion Derivatives

“…1 Pioneering works of Takahashi et al 2 reported the diastereoselective addition of chiral imines and 1,3-oxazolidines with MeMgBr and MeLi. This study prompted many groups to synthesize by this way chiral amines, 3 optically pure b-amino alcohols 4 and various natural and non-natural products. 5 This interesting process is not restricted to such simple organometallic reagents.…”