Stereocontrolled Synthesis of Vicinal Diamines by Organocatalytic Asymmetric Mannich Reaction of N-Protected Aminoacetaldehydes: Formal Synthesis of (−)-Agelastatin A

Abstract

The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-)-agelastatin A.

(S)-Proline

“…249 β-Lactam Mannich bases (124) have been synthesized from a carbapenem core (123) A key step in the total synthesis of (−)-agelastatin A (128) involved a syn-Mannich reaction between 125 and 126, which produced vicinal diamines (127) in yields ranging from 63 to 83% and 94% ee (eq 62). 251 Computational studies using density functional theory confirmed the proposed transition state for the stereoselective step between cyclohexanone, formaldehyde, and p-methoxyaniline. An intramolecular heteroatom Michael addition of 132 for the synthesis of enantioenriched pyrrolidine, indoline, and piperidine rings (133) has been reported, but poor ee was observed (eq 64).…”

Direct Catalytic Asymmetric Mannich‐Type Reaction of α‐N3 Amide

“…Although less stereoselective in some cases, N ‐Boc imines have been successfully incorporated into the Mannich‐type reaction of glycine Schiff bases to provide syn ‐α,β‐diamino acid derivatives with labile N‐protecting groups 7. On the other hand, anti ‐α,β‐diamino counterparts are only accessed with N ‐Ts imines through a Mannich‐type reaction,3b–e, 8 and the development of a stereoselective protocol to produce anti ‐α,β‐diamino acid derivatives with tractable N‐protecting groups is anticipated 9–11. Herein we report a direct anti ‐selective catalytic asymmetric Mannich‐type reaction of N ‐thiophosphinoyl imines and α‐azido 7‐azaindoline amide promoted by soft Lewis acid/hard Brønsted base cooperative catalysis.…”

Acetaldehyde: A Small Organic Molecule with Big Impact on Organocatalytic Reactions

“…Maruoka's group described that syn ‐ and anti ‐selective Mannich reaction between N‐protected aminoacetaldehyde and N ‐Boc‐imines for the synthesis of vicinal diamines. The use of 1 gave syn ‐vicinal diamines whereas axially chiral amino sulfonamide catalyst 19 produced anti ‐vicinal diamines (Scheme ) …”

“…On the other hand, in the axially chiral amino sulfonamide‐catalyzed reaction, the nucleophilic carbon of the enamine could be positioned to a closed carbon of the Si ‐face of the N ‐Boc‐imine where ( E )‐ s ‐ cis ‐enamine ( TS4 ) interacts with activated imine by the remote acidic proton of sulfonamide moiety. Thus, the s ‐ cis conformation of ( E )‐enamine is preferred over the s ‐ trans conformation of TS3 …”