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. 2023 Dec 22;9(51):eadk1704.
doi: 10.1126/sciadv.adk1704. Epub 2023 Dec 20.

Ir/Zn-cocatalyzed chemo- and atroposelective [2+2+2] cycloaddition for construction of C─N axially chiral indoles and pyrroles

Jian Yang  1 , Zhong-Yang Xie  1 , Yu-Jie Ye  1 , Sheng-Bing Ye  1 , Yi-Bo Wang  1 , Wen-Tao Wang  1 , Peng-Cheng Qian  1   2 , Ren-Jie Song  3 , Qing Sun  3 , Long-Wu Ye  4 , Long Li  1   2   4
Affiliations

Ir/Zn-cocatalyzed chemo- and atroposelective [2+2+2] cycloaddition for construction of C─N axially chiral indoles and pyrroles

Jian Yang et al. Sci Adv. .

Abstract

Here, an Ir/Zn-cocatalyzed atroposelective [2+2+2] cycloaddition of 1,6-diynes and ynamines was developed, forging various functionalized C─N axially chiral indoles and pyrroles in generally good to excellent yields (up to 99%), excellent chemoselectivities, and high enantioselectivities (up to 98% enantiomeric excess) with wide substrate scope. This cocatalyzed strategy not only provided an alternative promising and reliable way for asymmetric alkyne [2+2+2] cyclotrimerization in an easy handle but also settled the issues of previous [Rh(COD)2]BF4-catalyzed system on the construction of C─N axial chirality such as complex operations, limited substrate scope, and low efficiency. In addition, control experiments and theoretical calculations disclosed that Zn(OTf)2 markedly reduced the barrier of migration insertion to significantly increase reaction efficiency, which was distinctly different from previous work on the Lewis acid for improving reaction yield through accelerating oxidative addition and reductive elimination.

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Figures

Fig. 1.
Fig. 1.. Catalytic asymmetric [2+2+2] cycloaddition of alkynes for the synthesis of chirality and C─N axially chiral indole–based skeletons.
(A) Synthesis of chirality via catalytic asymmetric [2+2+2] cycloaddition of alkynes. (B) Synthesis of C─N axially chirality via this strategy. (C) C─N axially chiral indole–based skeletons in natural products and chiral ligands. (D) Construction of C─N axially chiral indole–based skeletons from ynamines. (E) This work: Ir/Zn-cocatalyzed chemo- and atroposelective [2+2+2] cycloaddition.
Fig. 2.
Fig. 2.. Substrate scope of enantioselective [2+2+2] cycloaddition of 1,6-diynes and ynamines.
Standard conditions: 1,6-diynes (0.15 mmol), ynamines (0.3 mmol), [Ir(COD)Cl]2 (2 mol %), L7 (5 mol %), Zn(OTf)2 (20 mol %), and toluene (3 ml) in vials. a, X = OPh. b, [Ir(COD)Cl]2 (5 mol %), L7 (12.5 mol %). c, [Ir(COD)Cl]2 (6 mol %), L7 (15 mol %). rt, room temperature.
Fig. 3.
Fig. 3.. Substrate scope of enantioselective synthesis of CN axially chiral pyrroles.
─ Standard conditions: 1,6-diynes (0.15 mmol), ynamines (0.3 mmol), [Ir(COD)Cl]2 (2 mol %), L7 (5 mol %), Zn(OTf)2 (20 mol %), and toluene (3 ml) in vials. a, [Ir(COD)Cl]2 (5 mol %), L7 (12.5 mol %). rt, room temperature.
Fig. 4.
Fig. 4.. Chemo- and enantioselective synthesis of CN axially chiral indoles.
─ Standard conditions: 1,6-diynes (0.15 mmol), ynamines (0.3 mmol), [Ir(COD)Cl]2 (2 mol %), L7 (5 mol %), Zn(OTf)2 (20 mol %), toluene (3 mL) in vials. rt, room temperature.
Fig. 5.
Fig. 5.. The study configurational stability of representative product.
To investigate the reaction mechanism of this atroposelective [2+2+2] cycloaddition of ynamines and 1,6-diynes catalyzed by Ir (–67) and Zn, the control experiments were carried out, as described in Fig. 7. First, both ynamines 84 and 85 without an ester group were introduced to react with 1,6-diyne 3 under standard conditions, but no target chiral indoles were observed (Fig. 7A). This result possibly ruled out that Zn(OTf)2 could significantly improve the yield via only the activation of ynamine without the coordination of the ester group, which was strong supported by the experiments on the chemoselective [2+2+2] cycloaddition (Fig. 4, 64 and 65). Subsequently, ynamine 88 linked with an ester group at the 2-position of indole was used to perform this reaction, and the desired product 89 was not discovered (Fig. 7B). These results strongly indicated that the carboxylic ester at the 2-position of indole ring as a chelation group plays an important role in this reaction, which was consistent with Tanaka’s research works (8, 20). To simplify the density functional theory (DFT) calculations, the pyrrolyl-ynamine 90 and 1,6-diyne 91 were prepared to undergo catalytic [2+2+2] cycloaddition, giving the expected results that the yield of the reaction in the presence of Zn(OTf)2 was much higher than that in the absence of Zn(OTf)2 (Fig. 7C). In addition, DFT calculations based on related work were performed using the substrates 90 and 91 as a model to elucidate the mechanistic details (see the Supplementary Materials).
Fig. 6.
Fig. 6.. Gram-scale reaction and product elaborations.
(A) Preparative-scale reaction of 5 and synthetic applications. (B) Synthesis and applications of 75. (C) Synthesis and applications of 80. DMSO, dimethyl sulfoxide. rt, room temperature. Cambridge Crystallographic Data Centre (CCDC), molecular sieve (MS), N-Bromosuccinimide (NBS), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 4-Dimethylaminopyridine (DMAP), 4-Nitrobenzoic acid (PNBA), Dichloromethane (DCM), Tetrahydrofuran (THF).
Fig. 7.
Fig. 7.. Mechanistic investigations.
(A to C) Control experiments. (D and E) DFT calculations. rt, room temperature.
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