Pathway development and pilot library realization in diversity-oriented synthesis: exploring Ferrier and Pauson-Khand reactions on a glycal template.
Through a correlation of the ability of small molecules to bind biological macromolecules and their ability to modulate cellular and organismal processes, chemistry can inform biology and vice versa. Diversity-oriented organic synthesis (DOS), which aims to provide structurally complex and diverse small molecules efficiently, can play a key role in such chemical genetic studies. Here we illustrate the trial-and-error experimentation that can refine an initial pathway-planning exercise and result eventually in an effective diversity pathway. By exploring Ferrier and Pauson-Khand reactions on a glycal template, we have developed efficient and stereoselective syntheses of tricyclic compounds. In this pathway, diversity results from the substituents and their spatial relationships about the tricyclic rings. A pilot split-pool library synthesis of 2500 tricyclic compounds highlights the use of planning considerations in DOS and a "one-bead, one-stock solution" technology platform. Additionally, it illustrates a promising synthetic pathway for future chemical genetic studies.
Kubota
Hideki
H
Howard Hughes Medical Institute at Harvard University, Institute of Chemistry and Cell Biology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA.
Lim
Jongwon
J
Depew
Kristopher M
KM
Schreiber
Stuart L
SL
D002241:Carbohydrates / Q000138:chemical synthesis* / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism; D013698:Templates, Genetic
D002241:Carbohydrates; D006575:Heterocyclic Compounds, 3-Ring