Total Synthesis of (−)-Nakadomarin A

Abstract

A short and highly stereoselective synthesis of (-)-nakadomarin A has been developed using combinations of catalyst-controlled bond formations, one-pot multistep procedures, and powerful route-shortening reaction cascades. Several unprecedented chemical transformations were developed, including a highly Z-selective, eight-membered-ring-forming intramolecular Julia-Kocienski reaction, a highly diastereoselective intramolecular furan/iminium ion cyclization, and a sulfonic acid-controlled Z-selective macrocyclic ring-closing metathesis. In conjunction with a diastereoselective nitro olefin Michael addition under bifunctional organocatalysis and a nitro-Mannich/lactamization cascade, these transformations allowed the construction of this architecturally complex natural product in significant quantities in 12 steps (longest linear sequence) from commercially available starting materials.

Conjugate addition nitro-Mannich reaction of carbon and heteroatom nucleophiles to nitroalkenes

“…Other simple alcohols EtOH and BnOH when refluxed with 1 gave the corresponding addition products 7 and 8 in 89% and 62% yield respectively (entries 5 and 6). Reaction with phenol was unsuccessful (entries [7][8][9][10] as was attempts at the 1,4-addition of H 2 O/hydroxide ion. The 1,4-addition of nitrogen nucleophiles was subsequently investigated.…”

“…1 The product β-nitroamines have emerged as flexible synthetic building blocks due to the complimentary oxidation states of the two nitrogen atoms. They have been used in the synthesis of many nitrogen containing functional groups including α-amino carbonyls, 2, 3 1,2-diamines, [4][5][6][7] peptidomimetics, 8 natural products [9][10][11][12][13][14][15] and many heterocyclic small molecules. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] To address the paucity of structurally diverse nitroalkanes we have developed conjugate addition nitro-Mannich protocols (Scheme 1).…”

Organocatalytic Conjugate Addition in Stereoselective Synthesis

“…69 This example of catalysis on a highly elaborated system further demonstrates the power of this methodology. A combination of the two elaborated fragments 141 and 142, catalyst 143, another bifunctional catalyst easily available from cinchona alkaloid, constructed the key fragment 144.…”

A Versatile Chiral Pyrrolidine Aldehyde Building-Block for Synthesis and Formal Synthesis of ent-Nakadomarin A

“…Dixon used lactam 18 in his seminal recent synthesis of nakadomarin A, 11 which is a member of the manzamine family of alkaloids (Scheme 5).…”