ABSTRACT
The solid-phase synthesis of a library based on an unusual biphenyl-containing trypsin-like serine protease inhibitor is described. Key to this effort was the synthesis of a highly functionalized aryl boronic acid reagent which required the development of a novel and efficient method to convert a triflate to a pinacolboronate in large scale.
Subject(s)
Biphenyl Compounds/pharmacology , Protease Inhibitors/chemistry , Serine Endopeptidases/drug effects , Aspartic Acid/pharmacology , HIV Protease Inhibitors/pharmacology , Mast Cells , Molecular Sequence Data , Peptide Library , Protease Inhibitors/pharmacology , Protein Conformation/drug effects , Serine/pharmacology , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Addition of (benzotriazol-1-yl)diethoxymethane 11 to various acyclic and cyclic enol ethers and enamides produces the corresponding adducts, which were reacted with either NaAlH(4) or Grignard reagents to afford acyclic acetal-ethers (18a-f), cyclic alpha-(substituted)-beta-acetals (19a-c), amino-acetals (24a,b), and 1,3-amino-ethers (25), all known but previously difficult-to-access classes of compounds.
ABSTRACT
Reaction of N,N-bis[(benzotriazol-1-yl)methyl]aniline (2) with 1-vinylpyrrolidin-2-one gives a mixture of diastereomeric 1,7-bis(2-oxopyrrolidin-1-yl)julolidines 3. After reduction of 3 with LAH, the predominant trans diastereomer of 1,7-di(pyrrolidin-1-yl)julolidine (4) is separated. Reaction of 2 with ethyl vinyl ether yields predominantly trans-1,7-di(benzotriazol-1-yl)julolidine (11). Stepwise synthesis from tetrahydroquinoline 15 gives access to julolidines with two different substituents on C-1 and C-7. Reaction of 1-[(benzotriazol-1-yl)methyl]-1,2,3,4-tetrahydroquinoline (25) with enolizable aldehydes gives a mixture of tetrahydroquinolines 26-29 which are converted into single julolidine products upon treatment with sodium hydride, LAH, or phenylmagnesium bromide. Reactions of 1,2,3,4-tetrahydroquinolines with benzotriazole and 2 molar equiv of enolizable aldehydes gives 1,2,3-trisubstituted julolidines 38-41, which with lithium aluminum hydride, sodium hydride, or a Grignard reagent produce single diastereomers of products 42, 43, and 45, respectively.
