A general approach to chiral building blocks via direct amino acid-catalyzed cascade three-component reductive alkylations: formal total synthesis of HIV-1 protease inhibitors, antibiotic agglomerins, brefeldin A, and (R)-gamma-hexanolide.
Multicatalysis cascade (MCC) process for the synthesis of highly substituted chiral building blocks (2-alkyl-CH-acids, 2-alkylcyclohexane-1,3-diones, 2-alkylcyclopentane-1,3-diones, and H-P ketone analogues) is presented based on the cascade three-component reductive alkylation's (TCRA) platform. Herein, we developed the high-yielding alkylation of a variety of CH-acids with (R)-glyceraldehyde acetonide/(S)-Garner aldehyde and Hantzsch ester through amino acid-catalyzed TCRA reaction without racemization at the alpha-position to carbonyl. Direct sequential combination of the L-proline-catalyzed TCRA reaction with other reactions like cascade alkylation/ketenization/esterification (A/K/E), alkylation/ketenization/esterification/alkylation (A/K/E/A), Brønsted acid-catalyzed cascade hydrolysis/lactonization/esterification (H/L/E), hydrolysis/esterification (H/E), hydrolysis/oxy-Michael/dehydration (H/OM/DH), and Robinson annulation (RA) of CH-acids, chiral aldehydes, Hantzsch ester, diazomethane, methyl vinyl ketone, various active olefins, and acetylenes furnished the highly functionalized chiral building blocks in good to high yields with excellent diastereoselectivities. In this context, many of the pharmaceutically applicable chiral building blocks were prepared via MCC reactions.
Ramachary
Dhevalapally B
DB
School of Chemistry, University of Hyderabad, Central University (PO), Hyderabad 500 046, India. ramsc@uohyd.ernet.in
Vijayendar Reddy
Y
Y
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000478:Alkylation; D000596:Amino Acids / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020126:Brefeldin A / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D015195:Drug Design; D004951:Esterification; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D017320:HIV Protease Inhibitors; D007659:Ketones; D007783:Lactones; C063061:agglomerin A; D020126:Brefeldin A; C430364:4-hexanolide; D015107:4-Butyrolactone