A case of remote asymmetric induction in the peptide-catalyzed desymmetrization of a bis(phenol).
We report a catalytic approach to the synthesis of a key intermediate on the synthetic route to a pharmaceutical drug candidate in single enantiomer form. In particular, we illustrate the discovery process employed to arrive at a powerful, peptide-based asymmetric acylation catalyst. The substrate this catalyst modifies represents a remarkable case of desymmetrization, wherein the enantiotopic groups are separated by nearly a full nanometer, and the distance between the reactive site and the pro-stereogenic element is nearly 6 A. Differentiation of enantiotopic sites within molecules that are removed from the prochiral centers by long distances presents special challenges to the field of asymmetric catalysis. As the distance between enantiotopic sites increases within a substrate, so too may the requirements for size and complexity of the catalyst. The approach presented herein contrasts enzymatic catalysts and small-molecule catalysts for this challenge. Ultimately, we report here a synthetic, miniaturized enzyme mimic that catalyzes a desymmetrization reaction over a substantial distance. In addition, studies relevant to mechanism are presented, including (a) the delineation of structure-selectivity relationships through the use of substrate analogs, (b) NMR experiments documenting catalyst-substrate interactions, and (c) the use of isotopically labeled substrates to illustrate unequivocally an asymmetric catalyst-substrate binding event.
Lewis
Chad A
CA
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Gustafson
Jeffrey L
JL
Chiu
Anna
A
Balsells
Jaume
J
Pollard
David
D
Murry
Jerry
J
Reamer
Robert A
RA
Hansen
Karl B
KB
Miller
Scott J
SJ
D000085:Acetates / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D030562:Databases, Protein; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009089:Mucor / Q000201:enzymology; D010455:Peptides / Q000737:chemistry*; D019800:Phenol / Q000737:chemistry*; D013237:Stereoisomerism; D013696:Temperature
D000085:Acetates; D010455:Peptides; D019800:Phenol