Enantioselective Synthesis of α-Quaternary Mannich Adducts by Palladium-Catalyzed Allylic Alkylation: Total Synthesis of (+)-Sibirinine

Abstract

A catalytic enantioselective method for the synthesis of α-quaternary Mannich-type products is reported. The two-step sequence of (1) Mannich reaction followed by (2) decarboxylative enantioselective allylic alkylation serves as a novel strategy to in effect access asymmetric Mannich-type products of “thermodynamic” enolates of substrates possessing additional enolizable positions and acidic protons. Palladium-catalyzed decarboxylative allylic alkylation enables the enantioselective synthesis of five-, six-, and seven-membered ketone, lactam, and other heterocyclic systems. The mild reaction conditions are notable given the acidic free N–H groups and high functional group tolerance in each of the substrates. The utility of this method is highlighted in the first total synthesis of (+)-sibirinine.

Catalytic Asymmetric Mannich Reaction with N‐Carbamoyl Imine Surrogates of Formaldehyde and Glyoxylate

“…Gram‐scale reactions for both formaldehyde imine and α‐imino esters were conducted in the presence of 10 mol % of chiral primary amine catalyst B /HOTf (Scheme ). In both cases, the reaction worked well with comparable yield and enantioselectivity and the chiral primary amine catalyst could be quantitatively recycled through simple aqueous workup, thus confirming the practicability of the current method in the synthesis α‐amino esters and β‐ amino carbonyls …”

“…Multiple steps are generally required to reach the useful N ‐carbamoyl amino products in these cases. Very recently, Stoltz reported an aminomethylation with N‐carbamoyl imines using sulfonylmethyl carbamates precursors, but the stereoselectivity was generated in the late decarboxylative alkylation stage, not in the Mannich step.…”

Enantioselective Total Synthesis of (–)-Myrifabral A and B

“…1 The first Myrioneuron alkaloids from Myrioneuron nutans were reported in 2002, with altogether 10 structures reported to date. 2 Since 2013, many new alkaloids have been isolated from Myrioneuron faberi, 3 Myrioneuron tonkinesis, 4 and Myrioneuron effusum. 5 In addition to their interesting structural features, a number of of these alkaloids possess a range of biological activities such as antimalarial properties, KB cell cytotoxicity, antimicrobial, and hepatitis C virus (HCV) replication inhibition.…”

“…5 In addition to their interesting structural features, a number of of these alkaloids possess a range of biological activities such as antimalarial properties, KB cell cytotoxicity, antimicrobial, and hepatitis C virus (HCV) replication inhibition. [1][2][3][4][5] Despite possessing promising biological properties and synthetically attractive motifs, relatively few of these alkaloids have been prepared by total synthesis efforts. 2d,e,6 Figure 1.…”

Scope and limitations of optical pure hydantoins as chiral auxiliaries in asymmetric Mannich reactions

“…Concerning the strategies employed to achieve the desired stereochemical control during the Mannich reaction, the use of chiral auxiliaries linked covalently either to the imine [6][7][8] or the enolate reagent [9][10][11] is one of the most powerful strategies employed so far.…”