Enantio- and Diastereoselective Two-Pot Synthesis of Isoquinuclidines from Glutaraldehyde and N-Aryl Imines with DFT Calculations

Abstract

A pot-economic method for the enantio-and diastereoselective synthesis of a [2.2.2] azabicyclic isoquinuclidine system is developed. This protocol involves the proline-catalyzed direct Mannich reaction-cyclization/IBX-mediated site-selective oxidation/NaBH 4 -reduction sequence between glutaraldehyde and imines to generate in situ chiral 1,2-DHPs, followed by the diastereoselective Diels−Alder reaction with N-aryl maleimides furnishing isoquinuclidines in overall five steps. A variety of isoquinuclidines having five-contiguous chiral centers, including an all-carbon quaternary, were prepared with high yields (up to 78%) and excellent stereoselectivity (>50:1 dr, and up to >99:1 er). DFT calculations support the observed high stereoselective reaction outcome.

Asymmetric Synthesis of Bridged N-Heterocycles with Tertiary Carbon Center through Barbas Dienamine-Catalysis: Scope and Applications

“…In particular, dienamine-catalysis, an extended conjugated HOMO-raising concept, initially developed by Barbas and co-workers, has been demonstrated for [4 + 2] cycloadditions or other cascade/tandem conversions . To offer easy access to nitrogen heterocycles, our group is continuing to explore amine-catalyzed asymmetric transformations . With this background, the reaction between 2-phenyl-3 H -indol-3-one 2a and 2-cyclohexene-1-one 3 was investigated to obtain the optimized conditions (Table ).…”

Direct Amine-Catalyzed Enantioselective Synthesis of Pentacyclic Dibenzo[b,f][1,4]oxazepine/Thiazepine-Fused Isoquinuclidines along with DFT Calculations

“…Recently, the concept of amine catalysis via a dienamine intermediate has been extensively studied for the Diels–Alder reaction and several other cascade/tandem transformations . As part of our continued interest in accessing chiral nitrogen heterocycles, a highly stereoselective Diels–Alder reaction between 1,2-DHPs, a dienamine generated from aqueous glutaraldehyde and acyclic imines, and N -aryl maleimides was developed to synthesize [2.2.2] isoquinuclidines . Having experience in this direction, we selected 2-cyclohexene-1-one 2 and dibenzoxazepine 3a as model substrates for reaction optimization (Table ).…”

“…18 As part of our continued interest in accessing chiral nitrogen heterocycles, 19 a highly stereoselective Diels−Alder reaction between 1,2-DHPs, a dienamine generated from aqueous glutaraldehyde and acyclic imines, and N-aryl maleimides was developed to synthesize [2.2.2] isoquinuclidines. 20 Having experience in this direction, we selected 2-cyclohexene-1-one 2 and dibenzoxazepine 3a as model substrates for reaction optimization (Table 1). Our initial reaction using L-proline 1a (20 mol %) in dimethyl sulfoxide (DMSO) as the choice of solvent, furnished the corresponding oxazepane-fused isoquinuclidine 4a in 58% yield with good enantioselectivity (90:10 enantiomeric ratio (er) (entry 1, Table 1).…”

Design of primary amine-functionalized polymer containing chiral isosorbide in the main chain for the asymmetric synthesis of isoquinuclidine derivatives

“…26 Later, a two-potenantio-and diastereoselecive synthesis of isoquinuclidines via the reaction between glutaraldehyde and imines to generate in situ chiral 1,2-DHPs, followed by the Diels-Alder reaction with N-aryl maleimides was developed. 27 Recently Kumar et al developed a protocol for the asymmetric synthesis of dibenzoxazepine/thiazepine-fused [2.2.2] isoquinuclidines. 28 The main objective of the present work is the synthesis of isosorbide containing primary amine-functionalized chiral polymer (Chiral-ISO-PECH-Amine) and its application as a homogeneous organocatalyst for the asymmetric synthesis of the most demanding isoquinuclidine derivatives via aza-Diels-Alder reaction.…”