Organocatalyzed enantioselective one-pot three-component access to indoloquinolizidines by a Michael addition–Pictet–Spengler sequence

Abstract

The enantioselective three-component Michael addition-Pictet-Spengler sequence of beta-ketoesters 1, alpha,beta-unsaturated aldehydes 2 and tryptamines 4 represents a facile and rapid one-pot access to highly substituted indoloquinolizidines in moderate to excellent yields and good to excellent enantioselectivities.

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

“…Recently an enantioselective one-pot Michael addition and Pictet-Spengler sequence was developed. [131] This method is based on the synthesis of a hemiaminal from a,bunsaturated aldehydes and b-ketoesters, which is followed by treatment with tryptamine in the presence of acid. The initial organocatalytic conjugate addition of b-ketoesters to cinnamic aldehyde in the presence of a chiral pyrrolidine and benzoic acid in toluene was followed by addition of tryptamine and a stoichometric amount of benzoic acid.…”

General and Efficient Organocatalytic Synthesis of Indoloquinolizidines, Pyridoquinazolines and Quinazolinones through a One‐Pot Domino Michael Addition‐Cyclization‐ Pictet–Spengler or 1,2‐Amine Addition Reaction

“…The crude reaction mixture was directly loaded for the column chromatography on silica gel to get the product 6a; yield: 42 mg (0.14 mmol, 68%). 4,6,7,12,12 b,13,3':3,4] 3826,3188,2963,2925,2867,1578,1524,1441,1359,1302,1251,1184,1109,1036,952,819,742 = 14.4,11.8,4.7,2.4 Hz,1 H),1 H),3.17 (ddd,J = 13.5,12.0,3.8 Hz,1 H),4.16 (dd,J = 13.6,3.4 37, 22.21, 22.29, 23.11, 27.38, 34.34, 35.87, 45.05, 50.12, 63.76, 107.99, 111.05, 111.42, 117.75, 119.17, 14] Adv. Synth.…”

“…[4] Recently, FranzØn and coworkers reported an organocatalytic reaction cascade for the synthesis of quinolizidine derivatives. [5] The demand for the development of new and efficient methodologies for the synthesis of this class of compounds [6] led us to investigate an easy and useful asymmetric one-pot reaction sequence involving simple and readily available starting materials. Asymmetric cascade reactions have gained a lot of interest in recent years because of the notable advantages associated with them, including no need for time-consuming protection/deprotections steps or purification of the intermediates.…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…This cascade is initiated by a conjugate addition/condensation process. The resulting hemiacetal was treated with tryptamine ( 210 ) to yield the corresponding indoloquinolizidines by a Pictet–Spengler cyclization (Scheme ) 236…”