Stereoselectivity in a nitroso-ene cyclization: Formal synthesis of rac-manzacidins A and C

Nitroso-ene (NE) reactions have been adapted in the construction of nitrogen-containing motifs in many biologically interesting compounds. The transient and highly reactive “nitroso” species remains a challenge for designing stereocontrolled syntheses. Although chiral auxiliary-based method has been developed to achieve high diastereoselectivity, the use of the inherent chirality of the nitroso compound for stereochemical control remains underdeveloped. We chose the formation of a γ-lactam via a NE cyclization as a basis to study the applicable principles for future asymmetric syntheses. The selected examples presented herein reveal that the intramolecular hydrogen bond would provide conformational restraint to facilitate excellent facial selectivity in the NE reaction via a chair-like transition state. The sterically bulky amino group also provides excellent stereochemical control possibly through steric repulsion. The following transformations led to a key intermediate (Ohfune's lactone) in the preparation of manzacidins A and C and thus constitutes a formal synthesis.