Research Article Cite This: ACS Catal. 2018, 8, 10180−10189
pubs.acs.org/acscatalysis
Synthesis of Chiral Trispirocyclic Oxindoles via Organic-Base/Au(I)Catalyzed Sequential Reactions Wengang Guo,† Lu Li,‡ Qian Ding,† Xiangfeng Lin,† Xianghui Liu,† Kai Wang,† Yan Liu,*,† Hongjun Fan,*,‡ and Can Li*,† †
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State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, People’s Republic of China ‡ State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, People’s Republic of China S Supporting Information *
ABSTRACT: Chiral spirooxindole is the core structure of a large number of natural and unnatural products with biological activities. However, the construction of trispirocyclic oxindoles remains challenging because of the difficulty in the assembly, the complex skeleton, and control of the stereoselectivities of the multiple quaternary stereocenters. Herein, we present the organic base/ Au(I)-catalyzed sequential asymmetric 1,2-addition/cascade hydroamination/HDA/deisobutene reactions for the elaboration of various trispirocyclic N,O-ketal tethered oxindoles and bisoxindoles in excellent optical purities (91−99% ee). Key to the success of this methodology is Au(I)-catalyzed hetero-Diels−Alder reactions utilizing N-Boc-iminooxindoles as the heterodienes. KEYWORDS: asymmetric catalysis, sequential reaction, gold catalysis, trispirocyclic framework, hetero-Diels−Alder Reaction
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INTRODUCTION Chiral spirocyclic oxindoles are privileged structural motifs found in many biologically active natural products and pharmaceuticals.1 The diverse structures and promising biological activities make them attractive synthetic targets. Consequently, exploiting straightforward and atom-economical route to access such skeletons has gained considerable attention in the past few years.2−5 Most of them focus on the synthesis of chiral monospirocyclic compounds, while catalytic enantioselective construction of multispirocyclic frameworks poses a nontrivial challenge. To this end, initially, Barbas III and, later, others have reported seminal studies on organocatalytic cascade reactions for the synthesis of optically active bispirocyclic bisoxindoles (Figure 1A).6−12 Despite these elegant studies, the construction of chiral trispirocyclic structural motif still remains unexploited to date, probably because of difficulty in the generation of three noncontiguous spirocyclic quaternary stereocenters. Therefore, the development of alternative methodologies for the asymmetric assembly of such structures is highly desirable. On the other hand, hetero-Diels−Alder (HDA) reaction is one of the most important synthetic tools for efficient construction of complex heterocycles with stereocontrol.13−15 Over the past decades, substantial progress has been made in this area, and a diversity of hetero dienophiles have been used in the reaction. Nonetheless, the scope of heterodienes was still quite limited, and typically confined to α,β-unsaturated © XXXX American Chemical Society
ketones/aldehydes/imines, o-benzoquinones, o-benzoqinone imides/diimines, N-aryl imines, aza-olefins, and N-Bocaldimine (Figure 1B).16 Therefore, further explorations of new heterodienes would help to expand the application of HDA reactions in the synthesis of complex heterocyclic compounds. Cationic gold(I) salts are well-known to serve as powerful catalysts for the hydroamination of alkynes under mild conditions. The in situ generated electron-rich enamines are valuable intermediates to initiate the following C−C or C−X (X = O, N) bond formation reactions. Therefore, gold(I) complexes have been used in the cascade reactions17−23 for the construction of multicyclic ketals or aminals.24−27 N-Bociminooxindoles are competent electrophiles in organic synthesis.28−37 However, the Boc-moiety, usually as the N-atom of imine protective group, is seldom participated in cyclization reaction.38−40 In this work, we unexpectedly found that N-Bociminooxindoles could serve as a new kind of heterodienes in Au(I)-catalyzed cascade reactions. Based on this finding, we developed a sequential process,41−45 which couples a highly efficient organocatalytic asymmetric 1,2-addition and an Au(I)catalyzed cascade hydroamination/HDA/deisobutene, to deliver a diversity of complex trispirocyclic frameworks (up Received: June 4, 2018 Revised: September 13, 2018 Published: September 19, 2018 10180
DOI: 10.1021/acscatal.8b02157 ACS Catal. 2018, 8, 10180−10189
Research Article
ACS Catalysis
Figure 1. (A) Previous work: Organocatalytic cascade strategy for the synthesis of chiral bispirocyclic bisoxindoles. (B) The reported heterodienes in the hetero-diels−Alder Reaction. (C) This work: Synthesis of chiral trispirocyclic frameworks via organic base/Au(I) sequential asymmetric 1,2addition/cascade reactions.
to 99% ee) from readily available substrates (Figure 1C).46−55 DFT calculations suggest the key hetero-Diels−Alder reaction in the cascade process proceeds via a concerted pathway (see below).
We then conducted the reaction under cryogenic and diluted conditions. When the reaction temperature was kept at −5 °C, a relatively clean reaction was observed, and 3a was isolated in 60% yield (Table 1, entry 3, dr >10:1). Encouraged by this result, we continued to optimize the reaction conditions to further improve the yield of 3a. What is more notable is that an attempt to prepare 3a by a one-pot procedure failed, due to the well-known incompatibility of Au(I) salt and the tertiary amine moiety of the bifunctional organocatalyst;53 using an acidic additive to protonate the amine group of the organocatalyst always furnished a lower yield (
