Enantioselective Syntheses of Tetrahydroquinolines Based on Iridium‐Catalyzed Allylic Substitutions: Total Syntheses of (+)‐Angustureine and (–)‐Cuspareine

Abstract

A protecting-group-free two-step approach for the preparation of tetrahydroquinolines has been developed. The procedure involves a highly regio-and enantioselective intermolecular iridium-catalyzed allylic amination followed by one-

Asymmetric synthesis of 2-alkyl-substituted tetrahydroquinolines by an enantioselective aza-Michael reaction

“…The following compounds were prepared by following literature procedures: 2-(benzyloxy)ethanol (8a), 12 2-(2,2-dimethyl-1,1-diphenylpropoxy)ethanol (8b), 13 benzyl (10a) and methyl (10b) 2-(diethoxyphosphoryl)acetylcarbamates. 10 …”

“…7 In comparison, other attempts to access these compounds by catalytic methodologies had been less efficient; these include Pd-catalysed asymmetric intramolecular alkyne hydroamination, 8 nucleophilic addition of arylboronic acids to quinolines catalysed by chiral thioureas, 9 and more recently, Ir-catalysed allylic substitution by an amine. 10 In all cases, reaction scope was rather limited, prolonged reaction times were required, and product yields and/or selectivity were modest, even at high catalyst loadings (≥10 mol%). Herein, we will describe the synthesis of these alkaloids from an optically pure tetrahydroquinoline intermediate (5), derived from an aza-Michael adduct prepared by the enantioselective addition of aniline to 7 (Scheme 1).…”

Synthesis of 1,2,3,4-Tetrahydroquinolines including Angustureine and Congeneric Alkaloids. A Review

“…81 Helmchen and co-workers expanded the scope of this methodology and applied their efforts to the synthesis of (C)-angustureine and (¡)-cuspareine. 82 The iridium-catalyzed regio-and enantioselective allylic amination of allylic carbonate 93 with o-haloaniline 94 followed by hydroboration, in situ intramolecular Suzuki-Miyaura coupling 83 and methylation provided (C)-angustureine in 42% overall yield (Scheme 28). A small amount (ca.…”

“…A subsequent ring-closing metathesis (RCM) reaction of substrate 104 led to a series of the tetrahydroquinoline derivatives 105 (Scheme 30). The excellent enantioselectivities of compounds 101 and 104 were derived from the chiral catalyst L* introduced by Helmchen et al82 (seeScheme 28).The synthesis of angustureine showed the utility of this methodology (Scheme 31). Protection of 104 and a RCM reaction with 2 mol% Zhan-1B and subsequent manipulations provided (¡)-angustureine in 64% overall yield.…”

The Hancock Alkaloids Angustureine, Cuspareine, Galipinine, and Galipeine: A Review of their Isolation, Synthesis, and Spectroscopic Data

“…Subsequent applications of this approach employed iridium catalysis with chiral ligands to impart enantioselectivity to an intermolecular process. Satyanarayana, Helmchen, et al [57] A variation on this procedure was subsequently developed by You et al [58] and applied in a synthesis of (R)-(-)-angustur- tion of a range of amino alkynes which resulted in formation of the corresponding 1,2,3,4-tetrahydroquinoline derivatives, which they employed as a key step in the synthesis of (±)-angustureine 1 and (±)-galipinine 3. The requisite amino alkyne precursors 207 and 209 were prepared in nine steps from oiodoaniline.…”