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.

Enantioselective C2‐Alkylation of Indoles through a Redox‐Relay Heck Reaction of 2‐Indole Triflates

“…This molecule can be further manipulated to produce S1P 1 agonist precursor 31 as established by Merck. 9 Optical rotation comparison of 30 to the literature allowed us to confirm the absolute stereochemistry of our product to be ( S ). This stereochemical outcome is consistent with our previously reported model for enantioselective induction in relay-Heck reactions.…”

“…9 Initially, Merck developed a route involving the de novo construction of the indole framework providing efficient access to the indole core. However, it relies on the use of traditional chiral auxiliary chemistry to set the absolute stereochemistry.…”

“…This stereochemical outcome is consistent with our previously reported model for enantioselective induction in relay-Heck reactions. 9 All other compounds were assigned by analogy to 30 , considering that switching the alkene geometry results in the opposite enantiomer of product being formed.…”

Efficient microwave synthesis of novel aromatic esters catalyzed by zirconia and its modified forms: a kinetic study

“…Esters are a group of organic compounds which are widely used in the synthesis of food additives, drugs, cosmetics, preservative solvents, perfumes, pharmaceuticals, plasticizers, lubricants, solvents, detergents, soaps, reaction intermediates, etc., [22][23][24][25][26][27][28][29] . Different approaches have been employed in both laboratory and commercial scale to prepare esters.…”

(7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists

“…This disparity was also observed in vitro, where rat S1P 1 EC 50 values in the β-arrestin platform were 2.5 (12a) and 11 nM (19a), respectively. In our experience, β-arrestin data has been historically a more reliable predictor of in vivo potency than 22 and was utilized for preparation of multigram quantities of enantiopure 24 and 25 (Scheme 2). The corresponding S-isomers (not depicted) were also evaluated but were significantly less potent.…”