Abstract
Chiral allene and N-heteroaryl motifs are present in an ever-growing list of biologically active natural products and synthetic drugs. Although significant progress has been made in asymmetric syntheses of chiral allenes, general and practical protocols for enantioselective syntheses of chiral N-heteroaryl-substituted allenes from readily available starting materials still remain rare. Here we report a highly enantioselective synthesis of quinolinyl-substituted chiral allenes through a copper-catalyzed asymmetric allenylation of quinoline N-oxides with readily available 1,3-enynes. A variety of 1,3-enynes react with quinoline N-oxides, affording the corresponding quinolinyl-substituted allenes in high yields (up to 95%) and high enantioselectivities (up to 99% ee). This transformation tolerates a variety of functional groups, such as chloro, bromo, trifluoromethyl ether, tertiary amine, siloxy, carboxylic ester, imide, pyridine, and thiophene moieties. DFT calculations suggest a pathway involving an intramolecular nucleophilic addition of an allenyl copper intermediate with a coordinated quinoline N-oxide through a five-membered, rather than seven-membered, transition state.
Highlights
Chiral allene moieties are present in a variety of natural products, molecular materials, and a few marketed drugs due to their unique structural features, chemical reactivity, and biological properties[1,2]
Recent years have witnessed a tremendous development on metal-catalyzed enantioselective synthesis of chiral allenes[11,12,13,14,15,16], such as nucleophilic addition to 1,3-enynes[17,18,19], enantioselective functionalization of racemic allenes[20,21,22], β-hydride elimination from enol triflates[23], rearrangement of propargylic compounds[24,25,26,27], coupling of terminal alkynes with diazo compounds[28,29,30,31], and enantioselective addition of terminal alkynes to aldehydes[32]
Inspired by the suitability of quinoline N-oxides as electrophiles for alkylcopper nucleophiles, we envisioned that quinoline N-oxides could serve as proper electrophiles to react with allenyl copper species to form chiral allene products through a five-membered, rather than seven-membered, transition state (Fig. 1c)
Summary
Chiral allene moieties are present in a variety of natural products, molecular materials, and a few marketed drugs due to their unique structural features, chemical reactivity, and biological properties[1,2]. Several asymmetric organocatalytic protocols have been reported, such as nucleophilic addition to activated enynes[33,34], isomerization of alkynes[35,36], phase-transfer-catalyzed allenoMannich reaction[37,38], alkynylogous Mukaiyama aldol reactions[39], and chiral ion-pair catalysis involving a formal propargylic carbocation from racemic propargylic alcohols[40] Notwithstanding these significant advances, asymmetric synthesis of chiral allenes, N-heteroaryl-substituted chiral allenes[36], from readily available starting materials is important and still remains a highly challenging task. In 2016, Buchwald and Liu reported an asymmetric addition to ketones using nucleophiles derived from migratory insertion of 1,3-enynes to a chiral Cu-H intermediate[56] Both reactions provide propargylic products selectively (Fig. 1a)[55,56], density functional theory (DFT)-calculation studies suggest a facile isomerization of initially generated propargylic copper species to allenyl copper intermediates during conversions of 1,3-enynes. We report our studies toward the development of an enantioselective synthesis of quinolinyl-containing chiral allenes
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