TY - JOUR
T1 - Novel β-amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles
AU - Gavendova, Mariana
AU - Lennon, Claire M.
AU - Coffey, Lee
AU - Manesiotis, Panagiotis
AU - Kinsella, Michael
N1 - Funding Information:
The authors would like to thank Waterford Institute of Technology WIT PhD Scholarship program for the financial support of this research (Scholarship No.: WIT/2015/09).
Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2019/7/31
Y1 - 2019/7/31
N2 - In this work, a series of novel organocatalysts derived from unique unnatural β-amino acid scaffold were synthesized and further developed to enhance the desired catalytic properties. Their evaluation was carried out in the asymmetric crossed-aldol condensation of isatin and enolizable ketone donors. Following a systematic study of the reaction parameters including variations of additive, solvent, temperature, catalyst loading and substrate scope, (1R,2R)-2-amino-N-((R)-1-phenylethyl)cyclohexane carboxamide 9 proved particularly successful, affording the corresponding 3-hydroxy-3-alkyl-2-oxindole in excellent yield (>99%) and distereoselectivity (>99% dr) with good enantioselective control (up to 52% ee) in the presence of p-nitrophenol and EtOH in <24 h. An added benefit of this catalyst was its catalytic activity and selectivity at room temperature eliminating the requirement of reduced reaction temperatures. This scaffold, comprising of β-amino amide, has not yet been applied in organocatalysis, thus, this is the first reported in this growing area. In mechanistic studies, direct infusion ESI-MS proved a valuable tool forproposal of the catalytic cycle, confirming the formation of 2 key reaction intermediates.
AB - In this work, a series of novel organocatalysts derived from unique unnatural β-amino acid scaffold were synthesized and further developed to enhance the desired catalytic properties. Their evaluation was carried out in the asymmetric crossed-aldol condensation of isatin and enolizable ketone donors. Following a systematic study of the reaction parameters including variations of additive, solvent, temperature, catalyst loading and substrate scope, (1R,2R)-2-amino-N-((R)-1-phenylethyl)cyclohexane carboxamide 9 proved particularly successful, affording the corresponding 3-hydroxy-3-alkyl-2-oxindole in excellent yield (>99%) and distereoselectivity (>99% dr) with good enantioselective control (up to 52% ee) in the presence of p-nitrophenol and EtOH in <24 h. An added benefit of this catalyst was its catalytic activity and selectivity at room temperature eliminating the requirement of reduced reaction temperatures. This scaffold, comprising of β-amino amide, has not yet been applied in organocatalysis, thus, this is the first reported in this growing area. In mechanistic studies, direct infusion ESI-MS proved a valuable tool forproposal of the catalytic cycle, confirming the formation of 2 key reaction intermediates.
KW - aldol
KW - covalent organocatalysis
KW - oxindole
KW - primary amine
KW - β-amino amide
UR - http://www.scopus.com/inward/record.url?scp=85069970136&partnerID=8YFLogxK
U2 - 10.1002/slct.201901360
DO - 10.1002/slct.201901360
M3 - Article
AN - SCOPUS:85069970136
SN - 2365-6549
VL - 4
SP - 8246
EP - 8254
JO - ChemistrySelect
JF - ChemistrySelect
IS - 28
ER -