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. 2020 Aug 27;11:4293. doi: 10.1038/s41467-020-18136-x

Copper(I)-catalyzed diastereo- and enantio-selective construction of optically pure exocyclic allenes

Cheng-Yu He 1,2,3,#, Yun-Xuan Tan 2,#, Xin Wang 2, Rui Ding 1, Yi-Fan Wang 2, Feng Wang 1, Dingding Gao 1,✉, Ping Tian 1,2,4,✉, Guo-Qiang Lin 1,2,✉
PMCID: PMC7453021  PMID: 32855405

Abstract

Among about 150 identified allenic natural products, the exocyclic allenes constitute a major subclass. Substantial efforts are devoted to the construction of axially chiral allenes, however, the strategies to prepare chiral exocyclic allenes are still rare. Herein, we show an efficient strategy for the asymmetric synthesis of chiral exocyclic allenes with the simultaneous control of axial and central chirality through copper(I)-catalyzed asymmetric intramolecular reductive coupling of 1,3-enynes to cyclohexadienones. This tandem reaction exhibits good functional group compatibility and the corresponding optically pure exocyclic allenes bearing cis-hydrobenzofuran, cis-hydroindole, and cis-hydroindene frameworks, are obtained with high yields (up to 99% yield), excellent diastereoselectivities (generally >20:1 dr) and enantioselectivities (mostly >99% ee). Furthermore, a gram-scale experiment and several synthetic transformations of the chiral exocyclic allenes are also presented.

Subject terms: Asymmetric catalysis, Homogeneous catalysis, Synthetic chemistry methodology

Substantial efforts have been devoted to the construction of axially chiral allenes, however, the strategies to prepare chiral exocyclic allenes are still rare. This work describes a copper-catalyzed asymmetric synthesis of exocyclic allenes by simultaneous control of axial and central chirality.

Introduction

Chiral allene moieties exist in about 150 natural products and a variety of functional synthetic compounds1–3. Due to the unique structural features and versatile reactivity of allenes, significant applications have been found not only in medicinal chemistry and material science, but also as important intermediates in synthetic transformations, and chiral ligands or catalysts in asymmetric catalysis4–8. Among these identified allenic natural products, the exocyclic allenes constitute a major subclass, such as Neoxanthin9, Grasshopper ketone10, Citroside A11, and fungal metabolite A82775C12 which bearing a cyclohexylidene ring (Fig. 1). Additionally, the chiral exocyclic allene structural motifs are also present in pharmaceuticals, for example, allenic carbacyclin13 which is an anti-thrombotic agent (Fig. 1). Over the past decades, substantial efforts have been devoted to the construction of axially chiral allenes, however, the strategies to prepare chiral exocyclic allenes are still rare14–31. Traditional methods to access chiral exocyclic allenes are mainly focused on the nucleophilic substitution of enantioenriched propargylic derivatives through central-to-axial chirality transfer32,33. Recently, transition metal catalysis exhibited high efficiency in preparation of chiral exocyclic allenes from achiral or racemic precursors (Fig. 2)34–37. For instance, in 2004, Hayashi and coworkers reported a rhodium(I)-catalyzed chemo- and enantio-selective 1,6-conjugate addition of aryltitanates to 3-alkynyl-2-en-1-ones to produce tetrasubstituted axially chiral exocyclic allenes with good enantioselectivities (Fig. 2a)34. Later, an efficient synthesis of axially chiral exocyclic allenes was achieved by Wang and coworkers through copper(I)/chiral bisoxazoline-catalyzed asymmetric cross-coupling between tetralone-derived diazo compounds and terminal alkynes (Fig. 2b)35. In 2018, Trost and coworkers developed a palladium(II)-catalyzed asymmetric [3+2] cycloaddition reaction between racemic allenyl trimethylenemethanes and electron-deficient olefins through a dynamic kinetic asymmetric transformation process, in which the trisubstituted chiral exocyclic allenic products bearing axial and central chirality could be furnished, however, their diastereoselectivities were relatively insufficient (Fig. 2c)36. Despite these successful advances, the synthetic methods to prepare the chiral exocyclic allenes are still rare and it is highly desired to develop more practical methods to construct more diverse chiral exocyclic allenes.

Fig. 1. Bioactive allenes.

Fig. 1

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Representative examples of chiral exocyclic allenes in natural products and pharmaceuticals.

Fig. 2. Strategies for synthesis of chiral exocyclic allenes.

Fig. 2

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a–c Previous works on synthesis of chiral exocyclic allenes. d This work: Cu(I)-catalyzed intramolecular reductive coupling of 1,3-enynes to enones.

Inspired by recent progress in the copper(I)-catalyzed asymmetric transformations of 1,3-enynes to functional chiral allenes and our continuous interest in catalytic asymmetric desymmetrization of cyclohexadienone derivatives38–48, we envisioned that the key axially chiral allenylcopper intermediate T1, generated from the chemo-, regio-, and enantio-selective insertion of 1,3-enyne to chiral copper hydride species, would be rapidly trapped by the intramolecular enones to yield the desired chiral exocyclic allenes 2 with hopefully high enantioselectivity and diastereoselectivity (Fig. 2d). Of course, the simultaneous control of axial and central chirality of the optically pure exocyclic allenes 2 remains challenging36,49,50. Herein, we present a highly chemo-, diastereo-, and enantio-selective synthesis of chiral exocyclic allenes via copper(I)-catalyzed asymmetric intramolecular reductive coupling of 1,3-enynes to cyclohexadienones (Fig. 2d).

Results

Optimization of reaction conditions

We commenced to optimize the reaction conditions for this copper(I)-catalyzed asymmetric intramolecular reductive coupling of 1,3-enynes to cyclohexadienones by using methyl-substituted substrate 1a as model checking (Table 1). At first, the reaction was carried out with CuCl/(R,R)-Ph-BPE catalytic system in the presence of t-BuONa and dimethoxy(methyl)silane (DMMS) at room temperature, the desired exocyclic allene 2a could be obtained in 39% yield, and with moderate diastereoselectivity and excellent enantioselectivity (Table 1, entry 1). The different solvents were next screened. The diastereoselectivity of 2a had no obvious change, but the yield and enantioselectivity could be dramatically improved, when 1,2-dichloroethane (DCE) was used as solvent (Table 1, entries 2–5). To some extent, increasing the loading of DMMS could enhance the yield (Table 1, entries 6, 7). However, when 2.5 equiv DMMS was adapted, overreduction of the product 2a occurred and dramatically eroded the yield (Table 1, entry 7). Besides, the reaction temperature had a significant influence on the diastereoselectivity of 2a and high diastereoselectivity was obtained under −30 °C (Table 1, entries 7–9). Subsequently, when poly(methylhydrosiloxane) (PMHS) was applied instead of DMMS, superior yield and diastereoselectivity were observed (Table 1, entry 10). Further investigating the amount of PMHS led to a higher yield (Table 1, entries 11, 12). Ultimately, we could obtain the chiral exocyclic allene 2a with 75% yield, >20:1 dr, and >99% ee when the reaction was performed using 2.2 equiv PMHS in DCE at −30 °C (Table 1, entry 11).

Table 1.

Optimization of reaction conditionsa.

graphic file with name 41467_2020_18136_Figa_HTML.gif
Entry DMMS (equiv) Solvent T (oC) Conv. (%)b Yield (%)b drb ee (%)c
1 1.2 THF rt 51 39 6:1 98
2 1.2 CyH rt 50 27 7:1 96
3 1.2 Toluene rt 63 33 7:1 98
4 1.2 Dioxane rt 78 45 7:1 99
5 1.2 DCE rt 50 49 7:1 >99
6 1.8 DCE rt 85 63 7:1 >99
7 2.5 DCE rt 100 23 7:1 >99
8 2.5 DCE 0 100 27 7:1 >99
9 2.5 DCE -30 100 35 >20:1 >99
10d 2.5 DCE -30 100 55 >20:1 >99
11d 2.2 DCE -30 100 75 >20:1 >99
12d 2.0 DCE -30 91 66 >20:1 >99
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THF tetrahydrofuran, CyH cyclohexane.

aReactions were performed using 1a (0.1 mmol, 1.0 equiv), CuCl (10 mol%), t-BuONa (15 mol%), (R,R-Ph-BPE) (12 mol%), DMMS, t-BuOH (1.2 equiv), solvent (1.0 mL) under Ar atmosphere, unless otherwise noted.

bDetermined by 1H NMR analysis with CH2Br2 as an internal standard.

cDetermined by HPLC analysis on a chiral stationary phase.

dPMHS was used instead of DMMS.

Substrate scope of 1,3-enyne-tethered cyclohexadienones

With the optimal reaction conditions identified, we started to evaluate the scope for this diastereo- and enantio-selective Cu-catalyzed intramolecular reductive coupling reaction (Fig. 3). At first, we examined the diversity of O-linked substrates 1. With the R2 substituents in the cyclohexadienone as simple alkyl, cyclohexyl, even sterically hindered adamantyl, vinyl, benzyl, and phenyl groups, the reactions proceeded smoothly with good to high yields (68–99%) and excellent diastereo- and enantio-selectivities (up to >20:1 dr and >99% ee, Fig. 3, 2a–2i). Notably, the steric hindrance had an obvious effect on the efficiency of this reaction (Fig. 3, 2a vs 2f). Furthermore, phenyl bromide, nitrophenyl, phenyl nitrile, and even pyridine groups which potentially coordinate with copper, were totally compatible in this process, providing the corresponding products with good to high diastereoselectivities and excellent enantioselectivities (Fig. 3, 2j–2m). The absolute configuration of chiral exocyclic allene 2k was unambiguously established by X-ray crystallography analysis. It’s worthy to mention that various functional groups, such as alkyl ketone, ester, silyl ether, alkyl halogens (Cl, Br, and I), amine, and imide, were also tolerant with equally excellent diastereo- and enantio-selectivities (Fig. 3, 2n–2u). When the readily available O-linked 1,3-enynes 1v and 1w, derived from estrone and δ-vitamin E, were applied to this transformation, the cyclization products could be successfully offered with moderate to good yields and excellent catalyst-controlled diastereoselectivities.

Fig. 3. Reaction scope of 1,3-enyne-tethered cyclohexadienones.

Fig. 3

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aConditions A: Reactions were performed using 1,3-enyne 1 (0.2 mmol), PMHS (2.2 equiv), CuCl (5 mol%), (R,R)-Ph-BPE (6 mol%), t-BuONa (7.5 mol%), and t-BuOH (1.2 equiv) in DCE (2 mL) under Ar atmosphere, -30 °C. bYield of isolated product. cDetermined by 1H NMR analysis of unpurified mixtures. dDetermined by HPLC analysis using a chiral stationary phase. eDMMS (1.8 equiv), rt. fPMHS (5.0 equiv), -15 °C. gConditions B: Reactions were performed using 1,3-enyne 4 (0.2 mmol), PMHS (2.2 equiv), CuCl (5 mol%), (R,R)-Ph-BPE (6 mol%), and t-BuONa (7.5 mol%) in DCE (2 mL) under Ar atmosphere, −30 °C, then work-up with NH4F (0.5 M in MeOH). hDMMS (1.5 equiv) was used instead of PMHS.

More importantly, when internal enynes 1x and 1y were subjected to this reaction, optically pure exocyclic allenes were uneventfully obtained, albeit in slightly low yields (Fig. 3, 2x and 2y). To our delight, for the free amine-linked (N-linked) substrates 4a–4c, the corresponding cis-hydroindole products could be also generated with good yields and exceptional diastereo- and enantio-selectivities (>20:1 dr and 96->99% ee, Fig. 3, 5a–5c). It’s interesting that none of the desired products were observed for the N-Boc- and N-Ts-linked substrates. Then, we concentrated on the more challenging C-linked substrates 4d–4f. Surprisingly, the reactions occurred ideally to give the cis-hydroindene products with perfect diastereo- and enantio-selectivities (>20:1 dr and >99% ee, Fig. 3, 5d–5f). The extensive functional group compatibility displayed in Fig. 3 proved that this mild reaction system was an extremely efficient access to construct chiral exocyclic allenes, containing cis-hydrobenzofuran, cis-hydroindole, and cis-hydroindene frameworks with good yields, as well as excellent diastereo- and enantio-selectivities. Finally, other types of 1,3-enyne substrates were investigated. For longer tethered cyclohexadienone 4g, the in-situ generated chiral allenylcopper intermediate underwent direct protonation to form the optically pure 1,3-disubstituted allene 5g rather than conjugate addition to produce six-membered ring product, which demonstrated that the formation of six-membered product was less favorable than five-membered one in this case, probably due to the ring strain48. In the previous report on Cu-catalyzed asymmetric semi-reduction of ketone-tethered 1,3-enyne, only direct protonation product and no further cyclized product was detected42. In our cases of 1,3-diketone-tethered 1,3-enynes 4h and 4i, similar results, ie, only the optically pure 1,3-disubstituted allene products 5h and 5i, were observed, which revealed that it remains challenging for the addition of allenylcopper intermediate to ketone.

Gram-scale experiment and synthetic transformations

To demonstrate the synthetic applicability of this method, a gram-scale experiment of 1e was carried out and the chiral exocyclic allene 2e was isolated with constant yield, diastereoselectivity and enantioselectivity (Fig. 4a). Then, several transformations of 2e were conducted to show the unique utilities of allene unit. In the presence of palladium catalyst, the allene structure could be easily converted to conjugate 1,3-diene (Fig. 4b)51. Next, upon treatment of 2e with p-toluenesulfonic acid, ring-opening and aromatization of the cis-hydrobenzofuran section occurred and a subsequent gold-catalyzed intramolecular nucleophilic addition of hydroxyl to allene led to the formation of chiral dihydrofuran product 7e (Fig. 4c)52,53. The axial-to-central chirality transfer of allene 2e was also realized through a rhodium-catalyzed hydroarylation reaction of allene 2e with N-methoxybenzamide 8 (Fig. 4d)54. Moreover, a practical transformation of N-linked product 5b was also performed. The exposed amine in 5b could easily react with isothiocyanate 10 to generate a tricyclic product 11b (Fig. 4e)43.

Fig. 4. Synthetic applications.

Fig. 4

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a Gram-scale experiment. b Palladium-catalyzed isomerization of allene. c one-pot synthesis of chiral dihydrofuran. d chirality transfer of allene by rhodium-catalyzed C–H activation. e cyclization of N-linked product 5b.

Discussion

In conclusion, we have developed a copper(I)-catalyzed intramolecular reductive coupling of 1,3-enynes to cyclohexadienones to construct trisubstituted chiral exocyclic allenes. The reactions took place efficiently and were compatible with diverse functional groups. The chiral exocyclic allenic products, containing cis-hydrobenzofuran, cis-hydroindole, and cis-hydroindene frameworks, were obtained with good yields, excellent diastereo- and enantio-selectivities. Additionally, a gram-scale reaction and several synthetic transformations of the chiral exocyclic allenes were also presented.

Methods

General procedure for the preparation of product 2a

A dried Schlenk flask was charged with CuCl (1.0 mg, 0.01 mmol, 5 mol%), (R,R)-Ph-BPE (6.1 mg, 0.012 mmol, 6 mol%), t-BuONa (1.5 mg, 0.015 mmol, 7.5 mol%), backfilled with argon. Then under −30 °C, anhydrous DCE (1.0 mL) was added and the solution was stirred for 10 min under −30 °C. After that, PMHS (26.4 ul, 0.44 mmol, 2.2 equiv) was added dropwise and the solution was stirred for another 10 min under −30 °C. Finally, a solution of substrate 1a (0.20 mmol, 1 equiv) and anhydrous t-BuOH (22 μL, 0.24 mmol, 1.2 equiv) in DCE (1.0 mL) was added. The resulting reaction mixture was stirred at −30 °C for 12 h. The reaction mixture was filtered through a short column of silica gel. The diastereomeric ratio of the crude reaction mixture was determined by 1H NMR spectroscopy. The residue was purified by flash silica gel (300–400 mesh) chromatography (hexanes/acetone = 5/1) to afford the desired products 2a in 70% yield as colorless oil.

Supplementary information

Supplementary Information (13.8MB, pdf)
Peer Review File (725.5KB, pdf)

Acknowledgements

Financial support was generously provided by the National Natural Science Foundation of China (Nos. 21871184, 81903423, and 21871284), the Shanghai Municipal Education Commission (2019-01-07-00-10-E00072), the Science and Technology Commission of Shanghai Municipality (18401933500), the Shanghai Sailing Program (19YF1449300), the Program of Shanghai Academic/Technology Research Leader (20XD1403600), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB 20020100), and the Key Research Program of Frontier Science (QYZDY-SSW-SLH026).

Author contributions

G.-Q.L., P.T., and D.G. directed the research. C.-Y.H. and Y.-X.T performed the synthetic experiments and analyzed the experimental data. Y.-X.T. and P.T. prepared the paper. X.W., R.D., Y.-F.W., and F.W. contributed to the preparation of substrates.

Data availability

Detailed experimental procedures and characterization of compounds can be found in the Supplementary Information. The X-ray crystallographic structure reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 1975229 (2k). These data can be obtained free of charge from The CCDC via www.ccdc.cam.ac.uk/data_request/cif. All data are available from the authors upon request.

Competing interests

The authors declare no competing interests.

Footnotes

Peer review information Nature Communications thanks Jian Liao, J. Enrique Oltra and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Cheng-Yu He, Yun-Xuan Tan.

Contributor Information

Dingding Gao, Email: gaodingding@shutcm.edu.cn.

Ping Tian, Email: tianping@shutcm.edu.cn.

Guo-Qiang Lin, Email: lingq@sioc.ac.cn.

Supplementary information

Supplementary information is available for this paper at 10.1038/s41467-020-18136-x.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information (13.8MB, pdf)
Peer Review File (725.5KB, pdf)

Data Availability Statement

Detailed experimental procedures and characterization of compounds can be found in the Supplementary Information. The X-ray crystallographic structure reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC 1975229 (2k). These data can be obtained free of charge from The CCDC via www.ccdc.cam.ac.uk/data_request/cif. All data are available from the authors upon request.

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