Pyrone Diels–Alder Routes to Indolines and Hydroindolines: Syntheses of Gracilamine, Mesembrine, and Δ⁷‐Mesembrenone

Abstract

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.

Diels–Alder Reaction in the Synthesis of Fluorinated (Hetero)Aromatic Compounds

“…In addition, one example of intramolecular [4+2]‐cycloaddition reaction with a CF 3 ‐alkyne motif was described by Snyder et al, who intended to prepare diverse fluorine‐containing analogues of natural indolines and hydroxyindolines by application of this strategy . Among others, compound 298 was prepared from pyrone 297 and involved in Diels–Alder reaction with subsequent CO 2 ‐elimination giving protected indoline 299 in high yield (Scheme ).…”

Asymmetric Total Synthesis of (–)‐Gracilamine Using a Bioinspired Approach

“…Recently, one more total synthesis of (±)‐ 1 appeared from Banwell's group, who employed intramolecular [3+2] cycloaddition of an azomethine ylide derived from a C‐3 a ‐formylarylhexahydroindole and l ‐leucine ethyl ester as a key step . Two other formal syntheses of (±)‐ 1 were reported, and they involved the use of a pyrone‐based intramolecular Diels–Alder reaction as the key step to assemble the ABCD ring and a Rh I ‐catalyzed [3+2+1]‐cycloaddition reaction of 1‐yne‐vinylcyclopropanes and CO to reach the ABC core . While preparing our manuscript, another two asymmetric total syntheses were reported independently by Nagasawa and Xie.…”

Regioselective Formation of Substituted Indoles: Formal Synthesis of Lysergic Acid

“…Other strategies featuring alkyne‐tethered pyrones are also known, which use 6‐aminopyrone architectures [7] . Snyder reported the cyclization of alkyne‐tethered 4‐chloro‐6‐amidopyrones to give N ‐acyl‐6‐chloroindolines [8] . Recently, Cui disclosed a reaction forming indolines from 6‐sulfonamidopyrones bearing tethered alkynes [9] …”

“…[7] Snyder reported the cyclization of alkyne-tethered 4chloro-6-amidopyrones to give N-acyl-6-chloroindolines. [8] Recently,C ui disclosed ar eaction forming indolinesf rom 6sulfonamidopyrones bearing tethered alkynes. [9] Af lexible synthesis of indoles was sought thatc ouldn ot only deliver substitution at C4, but also create indoles with programmable substitution at other positions and avoid the use of activating or protectingg roups on nitrogen.…”

“…With these expectationsi nm ind, our attemptst or ealize the 3-aminopyronet oi ndolinet ransformation began with the syn-thesis of alkyne-tethered 3-aminopyrones such as 1.W es urveyed several methods known for the synthesis of 3-aminopyrones; [7,8,11] however,w ed id not find ac onvenient and general synthesis of thesec ompounds. Interestingly,t he parentc ompound, 3-aminopyrone, was an unknownm olecule.…”