TY - JOUR
T1 - Pyrone Diels-Alder Routes to Indolines and Hydroindolines
T2 - Syntheses of Gracilamine, Mesembrine, and Δ7-Mesembrenone
AU - Gan, Pei
AU - Smith, Myles W.
AU - Braffman, Nathaniel R.
AU - Snyder, Scott A.
N1 - Publisher Copyright:
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2016/3/7
Y1 - 2016/3/7
N2 - Although the Diels-Alder reaction has long been utilized for the preparation of numerous heterocycles, opportunities to extend its power remain. Herein, we detail a simple, modular, and robust approach that combines various amines regioselectively with 4,6-dichloropyrone to create substrates which, under appropriate conditions, can directly deliver varied indolines and hydroindolines through [4+2] cycloadditions with substitution patterns difficult to access otherwise. As an initial demonstration of the power of the strategy, several different natural products have been obtained either formally or by direct total synthesis, with efforts toward one of these - the complex amaryllidaceae alkaloid gracilamine - affording the shortest route to date in terms of linear step count. Pyrone-technics: A simple, robust, and readily modifiable strategy involving [4+2]/retro-[4+2]/hydrolysis cascade sequences generates a range of indolines and hydroindolines from 4,6-dichloropyrone and appropriate amines. A 10 step synthesis was achieved of a ketone previously accessed in 15 steps, thereby accomplishing the shortest formal total synthesis of the alkaloid gracilamine. Teoc=2-(trimethylsilyl)ethoxycarbonyl.
AB - Although the Diels-Alder reaction has long been utilized for the preparation of numerous heterocycles, opportunities to extend its power remain. Herein, we detail a simple, modular, and robust approach that combines various amines regioselectively with 4,6-dichloropyrone to create substrates which, under appropriate conditions, can directly deliver varied indolines and hydroindolines through [4+2] cycloadditions with substitution patterns difficult to access otherwise. As an initial demonstration of the power of the strategy, several different natural products have been obtained either formally or by direct total synthesis, with efforts toward one of these - the complex amaryllidaceae alkaloid gracilamine - affording the shortest route to date in terms of linear step count. Pyrone-technics: A simple, robust, and readily modifiable strategy involving [4+2]/retro-[4+2]/hydrolysis cascade sequences generates a range of indolines and hydroindolines from 4,6-dichloropyrone and appropriate amines. A 10 step synthesis was achieved of a ketone previously accessed in 15 steps, thereby accomplishing the shortest formal total synthesis of the alkaloid gracilamine. Teoc=2-(trimethylsilyl)ethoxycarbonyl.
KW - Diels-Alder reaction
KW - alkaloids
KW - cascade reaction
KW - natural products
KW - total synthesis
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U2 - 10.1002/anie.201510520
DO - 10.1002/anie.201510520
M3 - Article
C2 - 26865400
AN - SCOPUS:84969351872
SN - 1433-7851
VL - 55
SP - 3625
EP - 3630
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 11
ER -