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Chemoselective Flow Hydrogenation Approaches to Diversify the Cytotoxic Tetrahydroepoxyisoindole Carboxamide Scaffold
Author(s) -
Spare Lawson K.,
Harman David G.,
AldrichWright Janice R.,
Nguyen Thanh V.,
Gordon Christopher P.
Publication year - 2018
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201701471
Subject(s) - chemistry , flow chemistry , catalysis , intramolecular force , olefin fiber , cycloaddition , furan , stereoselectivity , medicinal chemistry , combinatorial chemistry , organic chemistry
An Intramolecular Diels‐Alder cycloaddition reaction between a furan diene and an alkynic dienophile was performed within a flow hydrogenator fitted with an inert titanium column at 150 °C, no H 2 , under 100 bar pressure. A single column pass ( t R =1.6 min) afforded ≈55% conversion to the tetrahydroepoxyisoindole carboxamide scaffold with a product turnover of ≈0.035 g/h, a 95% improvement over batch procedures. The cycloaddition protocol is performed in water and ethanol, and does not require catalysts or other additives. Quantitative hydrogenation of the resulting dual π‐bonds within the oxabicyclo system was effected with either a 10% Pd/Al 2 O 3 or 10% Pd/CaCO 3 catalyst at 20 °C, 20 bar, with full H 2 whereas utilisation of a Raney Ni catalyst under these conditions resulted in a quantitative mono‐olefin reduction of the C4‐C5 double‐bond. With regard to di‐olefin reduction, a degree of stereoselectivity was observed with the aforementioned palladium‐based catalysts yielding exclusive formation of ( R ) configuration at C7 while utilisation of a 5% Pt/C (sulfided) catalyst at temperatures below 60 °C promoted the formation of the ( S )‐isomer at C7. Hence this work further highlights that flow‐hydrogenation provides unprecedented convenience for establishing robust protocols to effect chemoselective transformations.