Towards the Development of Synthetic Routes Using Theoretical Calculations: An Application of In Silico Screening to 2,6-Dimethylchroman-4-one

Abstract

This study describes an attempt to develop a synthetic route using theoretical calculations, i.e., in silico synthesis route development. The KOSP program created four potential synthetic routes for generating 2,6-dimethylchroman-4-one. In silico screening of these four synthetic routes was then performed. In silico screening involves theoretical analysis of synthetic routes prior to actual experimental work. A synthetic route using the Mitsunobu reaction had already been reported by Hoddgets et al. Theoretical investigations were also conducted on two SNAr reactions as well as a Michael reaction before they were examined experimentally. In silico screening using DFT calculations indicated that only the Michael reaction was likely to produce the target. Experimental work confirmed that the target was obtained in a yield of 76.4% using the Michael reaction. The other two routes, except for the Mitsunobu reaction, failed to generate the target. Our results demonstrate that theoretical calculations can be used to narrow down the number of experiments that need to be conducted when developing novel synthetic routes.

SAVI, in silico generation of billions of easily synthesizable compounds through expert-system type rules

“…Computational tools have been developed over the past four decades to help the synthetic chemists (and/or their CADD colleagues) find a viable synthetic route for a novel molecule. They can be broadly categorized into two classes: synthesizability estimation [5][6][7][8][9][10][11][12][13] ; and synthetic route prediction (variously called computer assisted synthesis design (CASD), computer-assisted organic synthesis (CAOS), computer-assisted synthesis planning (CASP), or computer-assisted reaction design (CARD)) [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . These tools had their heyday during the 1980s and 1990s but subsequently fell out of favor as an approach used in practice, and the entire field went essentially dormant for a good decade until the field experienced a revival of sorts in the 2010s.…”

Synthetically Accessible Virtual Inventory (SAVI)

“…Computational tools have been developed over the past four decades to alleviate these issues and help the synthetic chemist (and/or their CADD colleague) find a viable synthetic route for a novel molecule. They can be broadly categorized into two classes: synthesizability estimation [6][7][8][9][10][11][12][13][14] ; and synthetic route prediction (variously called computer assisted synthesis design (CASD), computer-assisted organic synthesis (CAOS), computer-assisted synthesis planning (CASP), computer-assisted reaction design (CARD), and yet other terms) [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . While the former is often based on statistical, QSAR-like approaches and used (only) in the context of in silico screening, the latter typically apply some kind of retrosynthetic reasoning and were meant to support the bench chemist.…”

Synthetically Accessible Virtual Inventory (SAVI)

“…Computational tools have been developed over the past four decades to alleviate these issues and help the synthetic chemist (and/or their CADD colleague) find a viable synthetic route for a novel molecule. They can be broadly categorized into two classes: synthesizability estimation [6][7][8][9][10][11][12][13][14] ; and synthetic route prediction (variously called computer assisted synthesis design (CASD), computer-assisted organic synthesis (CAOS), computer-assisted synthesis planning (CASP), computer-assisted reaction design (CARD), and yet other terms) [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] . While the former is often based on statistical, QSAR-like approaches and used (only) in the context of in silico screening, the latter typically apply some kind of retrosynthetic reasoning and were meant to support the bench chemist.…”