Complementary Asymmetric Routes to (R)‑2-(7-Hydroxy-2,3-dihydro‑1H‑pyrrolo[1,2‑a]indol-1-yl)acetate

• Published in: Organic letters Vol. 14; no. 24; pp. 6306 - 6309
• Main Authors: Schrader, Thomas O, Johnson, Benjamin R, Lopez, Luis, Kasem, Michelle, Gharbaoui, Tawfik, Sengupta, Dipanjan, Buzard, Daniel, Basmadjian, Christine, Jones, Robert M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.12.2012; Amer Chemical Soc
• Subjects: Acetates - chemical synthesis; Acetates - chemistry; Acetates - pharmacology; Catalysis; Chemistry; Chemistry, Organic; Fingolimod Hydrochloride; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Molecular Structure; Physical Sciences; Propylene Glycols - chemical synthesis; Propylene Glycols - chemistry; Propylene Glycols - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Receptors, Lysosphingolipid - agonists; Science & Technology; Sphingosine - analogs & derivatives; Sphingosine - chemical synthesis; Sphingosine - chemistry; Sphingosine - pharmacology; Stereoisomerism; RECEPTOR MODULATORS; HYDROGENATION; AGONISTS; FTY720; CONSTRUCTION
• ISSN: 1523-7060; 1523-7052
• DOI: 10.1021/ol303070k

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 S1P1 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.