Atropisomeric amides naphthamides

Crotonates bearing an atropisomeric 1-naphthamide moiety can be reacted in a Sml2-mediated reductive coupling with a variety of aldehydes to yield enantiomerically enriched 7-butyrolactones. The crotonate derived from 2-hydroxy-8-methoxy-Tnaphthamide reacted with pentanal to afford the highest ee of >99% in a combined yield of 90% with a cisltrans-mt o of 90 10. The chiral crotonate can also be linked to a Rink amide resin with the C-8 oxygen, and in the solid-phase reaction the same level of axial-to-central chirality transfer was obtained (Equation 103) <2006JOC2445>. 

In 2004, Walsh s group developed L-proline-catalysed aldol reactions of atropisomeric amides sueh as benzamides and naphthamides. " The DKR process simultaneously established the stereoehemistry of the atropisomeric amide chiral axis and a stereogenic centre, providing high enantioselectivities, as shown in Scheme 2.101. 

Attempts to induce asymmetry in the cyclisation of 57 using the chiral lithium amides, which had worked well with simple benzamides, were frustrated by the inherent chirality, at low temperature, of the naphthamide itself. This feature is common to all 2-substituted tertiary aromatic amides, which may become atropisomeric at low temperature due to slow rotation about the Ar-CO bond.48 We therefore sought to... 

Ortho-substituted aromatic amides show atropisomerism as a result of the perpendicular orientation of the aryl and amide moieties. The non-biaryl atropisomers readily undergo racemization through rotation about the aryl-amide bond, indicating the possibility of DKR. For example, (S)-proline mediated addition of acetone to 2-formyl naphthamide gave a 2 1-5.5 1 diastereoisomer mixture with the optical purity of the major anti-isomer ranging from 86% to 91% ee (Scheme 5.24) [72]. 

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