Synthesis of the Spermidine Alkaloids (−)‐(2R,3R)‐ and (−)‐(2R,3S)‐3‐Hydroxycelacinnine: Macrocyclization with Oxirane‐Ring Opening and Inversion via Cyclic Sulfamidates

The two epimers (−)‐ 1a and (−)‐ 1b of the macrocyclic lactam alkaloid 3‐hydroxycelacinnine with the (2 R ,3 R ) and (2 R ,3 S ) absolute configurations, respectively, were synthesized by an alternative route involving macrocyclization with the regio‐ and stereoselective oxirane‐ring opening by the terminal amino group ( Schemes 2 and 6 ). Properly N ‐protected chiral trans ‐oxirane precursors provided (2 R ,3 R )‐macrocycles after a one‐pot deprotection‐macrocyclization step under moderate dilution (0.005–0.01 M ). The best yields (65–85%) were achieved with trifluoroacetyl protection. Macrocyclization of the corresponding cis ‐oxiranes was unsuccessful for steric reasons. Inversion at OHC(3) via nucleophilic displacement of the cyclic sulfamidate derivative with NaNO 2 led to (2 R ,3 S )‐macrocycles. The synthesized (−)‐(2 R ,3 S )‐3‐hydroxycelacinnine ((−)‐ 1b ) was identical to the natural alkaloid.