Organocatalytic Michael Addition of Aldehydes to Protected 2‐Amino‐1‐Nitroethenes: The Practical Syntheses of Oseltamivir (Tamiflu) and Substituted 3‐Aminopyrrolidines

One‐Pot Synthesis of (−)‐Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction

“…The absolute configuration of the major stereoisomer 15 of the Michael reaction of 2 with 14 catalyzed by (S)-diphenylprolinol silyl ether was (2S, 3R), which was determined after conversion to 1 (see below). This is consistent with the observations of the groups of Ma, [7] Sebesta, [8a] and Lu. [9] The absolute configuration of the minor isomer 16, however, was not known.…”

“…Ma et al obtained the products 15/16 in approximately 80 % yield with good diastereoselectivity (15/16 = 5:1) by using PhCO 2 H as an additive and CHCl 3 as the solvent. [7] Sebesta et al used CHCl 3 /H 2 O as the solvent system and chloroacetic acid as an additive to obtain good yield (88 %) and diastereoselectivity (15/16 = 81:19). [8a] Recently, the addition of rac-mandelic acid and 2,4-dinitrophenol was also found to be effective.…”

“…Recently, the groups of Ma, [7] Sebesta, [8a] and Lu [9] have independently reported the synthesis of 1 in a short number of steps by similar routes to ours. [3] The key change from our original route is that they all employed (Z)-N-2-nitro-A C H T U N G T R E N N U N G ethenylacetamide (14) as a starting material instead of a (E)-tert-butyl-3-nitropropenoate (3).…”

Organocatalytic Michael Reaction of Nitroenamine Derivatives with Aldehydes: Short and Efficient Asymmetric Synthesis of (−)‐Oseltamivir

“…[14] To the best of our knowledge, there are just two re-Nitroenamine derivatives were used as a new class of Michael acceptors in the organocatalytic Michael reaction of aldehydes. ports, which were published practically at the same time, on the use of nitroenamines in the Michael reaction, [15] albeit these compounds are also valuable starting materials for the synthesis of many interesting building blocks. Moreover, a highly efficient, enantioselective, and simple synthesis of (À)-oseltamivir was accomplished in only five steps: two separate one-pot operations and one purification step.…”

Catalyst‐Controlled, Enantioselective, and Diastereodivergent Conjugate Addition of Aldehydes to Electron‐Deficient Olefins

“…[2] This is in contrast to how enzymes achieve complementary diastereocontrol in biocatalytic reactions,w hich can be attained through single amino acid mutations in the active site. [4] To reverse the stereochemical preference of this reaction to favor the anti adduct, substrate control has previously been exploited, by using either specific Z olefins as acceptors (TS2), [5] or siloxyacetaldehydes as nucleophiles,w hich form Z enamines in the presence of ap rimary amine catalyst (TS3). Specifically,w ep resent our findings in the context of conjugate addition of aldehydes to electron-deficient olefins.…”