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Synlett 2023; 34(02): 163-167
DOI: 10.1055/s-0042-1751388
letter

A de novo Stereocontrolled Synthetic Approach to a Functionalized Indolizidine Core

Melinda Nonn
a   MTA TTK Lendület Artificial Transporter Research Group, Institute of Materials and Environmental Chemistry, Research Center for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok krt. 2, 1117 Budapest, Hungary
,
Jorge Escorihuela 
b   Department of Organic Chemistry, Universitat de València, Avda. Vicente Andrés Estellés s/n, Burjassot 46100, Valencia, Spain
,
Loránd Kiss∗
c   Institute of Organic Chemistry, Stereochemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary
› Author AffiliationsThe authors gratefully acknowledge financial support from Nemzeti Kutatási Fejlesztési és Innovációs Hivatal (NKFIH/OTKA FK 134586 and K 142266).
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Abstract

A convenient domino synthetic approach for the construction of the indolizidine core in diastereoselective manner has been developed from inexpensive starting compounds, providing triple functionalization. The novel synthetic route started from β-lactam derived from 1,5-cyclooctadiene including a ring-opening metathesis/cross-metathesis sequence as key steps with methyl acrylate followed by intramolecular ring closure across an aza-Michael addition. The process gave functionalized indolizidine framework with stereocontrol in high yields. DFT calculations supported the experimentally observed stereoselective reaction.

Key words

azaheterocycles - indolizidine - metathesis - ring closure - stereocontrol


Publication History

Received: 30 September 2022

Accepted after revision: 26 October 2022

Article published online:
23 November 2022

© 2022. Thieme. All rights reserved

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  • References and Notes

  • 9 General Procedure for the Ring-Opening MetathesisTo a solution of β-lactam (±)-2 (1 mmol) in anhydrous CH2Cl2 (35 mL), under an ethylene atmosphere, catalyst (2 mol%) dissolved in CH2Cl2 (10 mL) was added in five portions during 30 min, and the mixture was stirred at 20 °C for 2.5 h (monitored by TLC). After completion of the reaction, the mixture was concentrated under reduced pressure and purified by means of column chromatography on silica gel (n-hexane/EtOAc).General Procedure for the Cross MetathesisTo a solution of β-lactam (±)-7 (1 mmol) in anhydrous solvent (25 mL), methyl acrylate (10 equiv) and the catalyst (5 mol%) dissolved in CH2Cl2 (10 mL) were added in five portions during 30 min, and the mixture was stirred for 3.5 h at reflux temperature. After completion of the reaction (monitored by TLC), the mixture was concentrated under reduced pressure and the residue was purified by means of column chromatography on silica gel (n-hexane/EtOAc).General Procedure for the Cyclization ReactionTo a solution of β-lactam (4 mmol) in EtOH (15 mL) the solution of HCl/EtOH (23%, 6 mL) was added at room temperature. The reaction mixture was stirred at room temperature for the time indicated and then it was concentrated in vacuo. The residue was dissolved in THF (20 mL) and, after adding DBU (2 equiv), the mixture was stirred for 24 h at room temperature. After completion of the reaction (monitored by TLC), the mixture was diluted with brine (40 mL) and extracted with CH2Cl2 (3 × 12 mL). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by means of column chromatography on silica gel (eluent: n-hexane/EtOAc).Computational DetailsAll DFT calculations were performed using Gaussian09 Rev.D01.11 The Minnesota functional M06-2X12 with the 6-311+G(d,p) basis including the solvent with a polarizable continuum model (PCM)13 was used for geometry optimization of minima and transition states. A frequency analysis was performed using the same level of theory to confirm the presence of a minima with no imaginary frequency or a transition state with a single imaginary frequency. Intrinsic reaction coordinate (IRC) calculations were performed to verify the expected connections of the first-order saddle points with the local minima found on the potential energy surface.14,15 Optimized structures were illustrated using CYLview20.3.16
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