Letter pubs.acs.org/OrgLett
Rhodium-Catalyzed Asymmetric Conjugate Alkynylation of β,γ‑Unsaturated α‑Ketoesters Yanle Zhi,† Jianhang Huang,† Na Liu,† Tao Lu,*,†,‡ and Xiaowei Dou*,† †
Department of Organic Chemistry and ‡State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China S Supporting Information *
ABSTRACT: The first example of catalytic asymmetric conjugate alkynylation of β,γ-unsaturated α-ketoesters is reported. By using Rh(I)/(R)-DM-binap complex as the catalyst and diphenyl[(triisopropylsilyl)ethynyl]methanol as the alkynylating reagent, the alkynylation reaction proceeded smoothly to afford α-ketoesters bearing a propargylic chiral center at γ position in good yields with high enantioselectivities.
T
cobalt,10 and others11 as the catalyst have been explored. Among all these catalytic systems, rhodium catalysis has attracted much more attention in recent years since it showed high reactivity and excellent chemo- and stereoselectivity, especially for those substrates with an electron-withdrawing group activated olefin;12 thus, we envisioned that a suitable rhodium catalytic system might work for the aforementioned transformation. As a breakthrough in rhodium-catalyzed asymmetric alkynylation reaction, asymmetric conjugate addition of terminal alkyne to acyclic α,β-unsaturated ketones was first realized by Hayashi and co-workers,12b and the key of the reaction was rational selection of sterically bulky chiral bisphosphine ligand (DTBM-segphos) and terminal alkyne ((triisopropylsilyl)acetylene) to suppress alkyne dimerization. A similar strategy was also applied to rhodium-catalyzed asymmetric alkynylation of α,β-unsaturated aldehydes,12f nitroalkenes,12i and 5-benzylidene Meldrum’s acids.12g Later on, a broader scope of enones was achieved with alkynylsilanols as the alkynylating reagent.12h Recently, an easily accessible propargylic alcohol was utilized by Hayashi group as the alkynylating reagent in asymmetric alkynylation of cyclic α,βunsaturated carbonyl compounds, and the combination of the propargylic alcohol with a chiral Rh/diene catalyst was found to be crucial for high reactivity and enantioselectivity.12k In this Letter, we report our finding that, while the reported methods were not effective for asymmetric conjugate alkynylation of challenging substrates like β,γ-unsaturated α-ketoesters, a reaction system consisting of propargylic alcohol and Rh/ bisphosphine catalyst worked efficiently to enable the desired transformation. We started the investigation with rhodium-catalyzed asymmetric alkynylation of γ-unsaturated α-ketoester 1a, and the results obtained under various conditions are summarized in Table 1. In the first set of the experiments, the previously
he asymmetric conjugate addition reaction is one of the most efficient methods for generating new stereogenic carbon centers,1 while β,γ-unsaturated α-keto carbonyl compounds represent an important class of substrates in such transformations.2 Asymmetric conjugate 1,4-addition to those substrates produces α-keto carbonyl compounds bearing a γ chiral center, which are versatile synthons and can be readily converted to valuable building blocks for the synthesis of a number of natural products, bioactive compounds, and pharmaceuticals.2,3 As a direct strategy for the formation of new carbon−carbon bonds and creating γ chiral centers, asymmetric 1,4-addition of sp2- and sp3-carbon nucleophiles to β,γ-unsaturated α-keto carbonyls (e.g., β,γ-unsaturated αketoesters) has been extensively studied and a number of efficient reaction systems have been established.2−4 In contrast, asymmetric conjugate addition of sp-carbon nucleophile to β,γunsaturated α-keto carbonyls remains a formidable challenge. To the best of our knowledge, no asymmetric alkynylation reaction of those substrates has yet been reported.5 Herein, we report the first catalytic asymmetric conjugate alkynylation of β,γ-unsaturated α-ketoesters (Scheme 1). In the past decades, considerable efforts have been devoted to the development of catalytic asymmetric alkynylation reaction,6 and various systems using copper,7 iridium,8 nickel,9 Scheme 1. Asymmetric Conjugate 1,4-Addition of Carbon Nucleophiles to β,γ-Unsaturated α-Ketoesters
Received: March 27, 2017 Published: April 27, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b00909 Org. Lett. 2017, 19, 2378−2381
Letter
Organic Letters
elimination14 and effectively avoid dimerization due to the steric bulkiness, was chosen as the substitute for the terminal alkyne (Scheme 2). With propargylic alcohol 2b as the
Table 1. Rhodium-Catalyzed Asymmetric Conjugate Alkynylation of β,γ-Unsaturated α-Ketoester 1aa
Scheme 2. Alkynylating Reagent 2a versus 2b
entry
2 (equiv)
Rh catalystb
yield (%)c
ee (%)d
1 2 3 4 5 6 7 8 9
2a (2.0) 2b (1.2) 2b (1.2) 2b (1.2) 2b (1.2) 2b (1.2) 2b (1.2) 2c (1.2) 2d (1.2)
Rh/(R)-DTBM-segphos [RhCl(rac-Fc-bod)2]e Rh/(R)-segphos Rh/(R)-binap Rh/(R)-H8-binap Rh/(R)-T-binap Rh/(R)-DM-binap Rh/(R)-DM-binap Rh/(R)-DM-binap
12
