title: Complementary asymmetric routes to (R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate.
abstract: Two distinct and scalable enantioselective approaches to the tricyclic indole (R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate, an important synthon for a preclinical S1P(1) receptor agonist, are reported. Route 1 employs a modified version of Smith's modular 2-substituted indole synthesis as the key transformation. Route 2 involves a highly enantioselective CuH-catalyzed 1,4-hydrosilylation as the stereodefining step. Both routes can be performed without chromatography to provide multigram quantities of the tricycle in ≥98% ee.
authors.affiliation: Department of Medicinal Chemistry, Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, California 92121, United States. tschrader@arenapharm.com
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Schrader
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Johnson
authors.forename: Luis
authors.initials: L
authors.lastname: Lopez
authors.forename: Michelle
authors.initials: M
authors.lastname: Kasem
authors.forename: Tawfik
authors.initials: T
authors.lastname: Gharbaoui
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Sengupta
authors.forename: Daniel
authors.initials: D
authors.lastname: Buzard
authors.forename: Christine
authors.initials: C
authors.lastname: Basmadjian
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D000068876:Fingolimod Hydrochloride; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011409:Propylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D013110:Sphingosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: C578912:(R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo(1,2-a)indol-1-yl)acetate; D000085:Acetates; D007211:Indoles; D011409:Propylene Glycols; D011758:Pyrroles; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine