Helicoselective assembly of 2-pyranone-helicenoids via NHC-catalyzed [3 + 3] annulation

Abstract

Helical frameworks play a vital role in supramolecular chemistry and materials sciences. Nevertheless, the scarcity of robust stereoselective methodologies continues to impede their practical development. We herein report an NHC-catalyzed helicoselective [3 + 3] annulation approach for the assembly of chiral 2-pyranone fused helicenoids. This protocol enables the conversion of achiral starting materials into chiral 2-pyranone-helicenoids with good to high yields and high to excellent enantioselectivities.

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As a unique chiral structure, helical frameworks have recently attracted a great deal of attention due to their crucial role in biological processes and have been identified in various natural products (Fig. 1a).^1–3 In addition, the optical and electronic properties of helical frameworks, coupled with remarkable structural diversity, make their unique topologies promising for various applications in organic materials, asymmetric catalysis, and medicinal chemistry.^4–22 However, the development of efficient and versatile synthetic helical frameworks has always been a challenge in the synthetic community, especially in the field of organocatalysis. It was not until 2014 that the List group reported the first organocatalytic CPA-catalyzed Fischer indole reaction to generate helically chiral molecules.²³ By far, the reported organocatalytic examples for obtaining helical chiral scaffolds are still limited, and they are mainly manipulated by chiral phosphoric acid (CPA), bifunctional amide/thiourea, and peptide-mimic phosphonium salt (PPS) catalysis.^24–34

Fig. 1 The state of the art in NHC catalysis and the applications of alkynyl acyl azolium intermediates.

Despite these significant advancements, the exploration of new strategies for the efficient and low-cost synthesis and functionalization of helical frameworks, especially helicenes, remains essential. Our group has long focused on the field of NHC organocatalysis. Therefore, we speculate whether NHC-bound intermediates can be utilized to prepare such helicene structures (Fig. 1b). Undoubtedly, the construction of chiral helicenes may face multiple challenges, including stereoselective control in helically chiral induction, low reactivity of NHC-bound intermediates with extended π systems, limited functional group tolerance, and competitive dimerization/cyclization side reactions.

NHC catalysts can activate carbonyl compounds to produce a variety of reactive intermediates that exhibit different reaction sites and tunable reactivity profiles.^35–37 Among them, the alkynyl acyl azolium intermediates, firstly pioneered by our group,³⁸ have emerged as versatile intermediates for constructing numerous structures. Building upon the intermediate, Du,³⁹ Chi^40,41 and our group³⁸ have already reported seminal works, respectively. For example, our group successfully achieved the enantioselective NHC-catalyzed atroposelective annulation of cyclic 1,3-diones with ynals in the presence of an oxidant, thereby affording axially chiral α-pyrone-aryls with high enantioselectivities. Based on the inspiration provided by the unique intermediate, various chiral molecules containing C–N and C–C axial stereogenic elements with remarkable efficiency have been disclosed. However, to the best of our knowledge, their application in the assembly of helically chiral molecules has not yet been documented in the literature. Herein, we propose a new NHC-catalyzed [3 + 3] helicoselective annulation for the enantioselective construction of 2-pyranone fused helicenoids (Fig. 1c). While we were preparing our manuscript, a related study by the Du group was published.⁴² Polyaromatic ketones were chosen as the key prochiral substrates that can achieve stereodivergent folding upon electrophilic trapping, where helically chiral induction is determined by the chiral NHC catalyst. Concurrently, this methodology demonstrates exceptional atom economy and efficient induction of helical chirality, and facilitates late-stage diversification.

The optimization of reaction conditions is systematically summarized in Table 1. We started by using 3,4-dihydrobenzo[c]phenanthren-2(1H)-one 1a and p-nitrophenyl ester 2a as model substrates. Preliminary studies demonstrated that N-mesityl substituted NHC pre-cat. A afforded the corresponding product 3aa in a moderate yield, albeit with only a 90 : 10 er under conditions employing Cs₂CO₃ as a base, dichloromethane (DCM) as a solvent and room temperature (entry 1). The corresponding 3aa was obtained in 90% yield with a worse enantioselectivity (84 : 16 er) when the N-1,3,5-tribromophenyl substituted NHC pre-cat. B was used (entry 2). An obvious increase in the yield was achieved by using 1,3,5-trihexylphenyl substituted NHC pre-cat. C (entry 3). The application of either NHC pre-cat. D bearing a chiral pyrrole structure or NHC pre-cat. E bearing a morpholine structure did not result in any improvement in enantioselectivity (entries 4 and 5). A slight enhancement in the er value was observed upon using NHC pre-catalyst G (entry 7). Solvent screening revealed that tetrahydrofuran (THF), toluene, and N,N-dimethylformamide (DMF) were suitable for the reaction (entries 8–10) and methyl tert-butyl ether (MTBE) afforded a better yield and enantioselectivity (entry 11, 99%, 94 : 6 er). We subsequently explored a variety of both organic and inorganic bases; however, we were unable to identify any base that demonstrated greater efficacy than Cs₂CO₃ (entries 12–14). Neither increasing nor decreasing the temperature, nor reducing the catalyst loading, could further enhance the enantioselectivity (entries 15–17). Additionally, cooling the temperature to −20 °C or decreasing the catalyst loading to 10 mol% could substantially compromise the reaction efficiency. Ultimately, by decreasing the reaction concentration to 0.05 M, we successfully achieved the optimal result of 95% yield and 95 : 5 er (entry 18).

Table 1 Optimization of the reaction conditions^a

Entry	Conditions	Yield^b [%]	er^c
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), NHC pre-cat. A–G (20 mol%), base (2.0 equiv.), solvent (1.0 mL) at room temperature for 72 h under an N2 atmosphere. b Isolated yield. c The er values were determined via chiral phase HPLC analysis. d 10 mol% of NHC pre-cat. G, 7 d. e The reaction was performed at a concentration of 0.05 M.
1	NHC A, Cs2CO3, DCM, R.T.	61	90 : 10
2	NHC B, Cs2CO3, DCM, R.T.	90	84 : 16
3	NHC C, Cs2CO3, DCM, R.T.	85	90 : 10
4	NHC D, Cs2CO3, DCM, R.T.	66	15.5 : 84.5
5	NHC E, Cs2CO3, DCM, R.T.	68	16 : 84
6	NHC F, Cs2CO3, DCM, R.T.	55	92 : 8
7	NHC G, Cs2CO3, DCM, R.T.	69	93.5 : 6.5
8	NHC G, Cs2CO3, THF, R.T.	77	93 : 7
9	NHC G, Cs2CO3, Tol, R.T.	54	92 : 8
10	NHC G, Cs2CO3, DMF, R.T.	28	82 : 18
11	NHC G, Cs2CO3, MTBE, R.T.	99	94 : 6
12	NHC G, DIPEA, MTBE, R.T.	49	91 : 9
13	NHC G, ^tBuOK, MTBE, R.T.	55	92 : 8
14	NHC G, AcOK, MTBE, R.T.	50	90 : 10
15	NHC G, Cs2CO3, MTBE, −20 °C	57	90 : 10
16	NHC G, Cs2CO3, MTBE, 50 °C	88	92.5 : 7.5
17^d	NHC G, Cs2CO3, MTBE, R.T.	59	95 : 5
18	NHC G , Cs 2 CO 3 , MTBE, R.T.	95	95 : 5

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With the optimized conditions in hand (Table 1, entry 18), the generality of this reaction was explored. As shown in Scheme 1, the steric and electronic effects on the aromatic ring of alkynyl esters 2 were evaluated by the variation of substituent patterns. The reactions of 2b–2i and 1a proceeded smoothly to give the corresponding products 3ab–3ai in moderate to high yields with high er values. para- or meta-Substituted alkynyl esters maintained excellent enantiocontrol across diverse electronic perturbations, although the reaction efficiency diminished when a strong electron-donating methoxy group occupied the para-position. When a fluorine atom appeared at the ortho-position, the corresponding product 3af could still be efficiently obtained but with slightly decreased enantioselectivity. Substrates containing 1-naphthyl or 2-naphthyl could also be converted into the corresponding products with moderate yield and high enantioselectivity (3aj and 3ak). Heterocycles were also compatible with this catalytic system, although 3-(quinol-6-yl)propiolate suffered from severely depressed yield (3am), and 3-(thien-2-yl)propiolate maintained the yield but with attenuated enantiocontrol (3al). Crucially, the methodology accommodated aliphatic systems such as methyl-, ethyl- and n-pentyl propiolates (3an–3ap) and achieved moderate yields and er values as well. The absolute configuration of product 3ag was determined by single crystal X-ray analysis (CCDC 2466074), and other structures were assigned by analogy. This protocol could be further extended to other polycyclic ketones to access products 3ba and 3ca, albeit with slightly reduced yields and enantioselectivities for the corresponding product 3da which bears a thiophene.

Scheme 1 Substrate scope. Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), NHC pre-cat. F (20 mol%), Cs₂CO₃ (2.0 equiv.), MTBE (2.0 mL) at room temperature for 72 h under an N₂ atmosphere. ^a64% of 1a was recovered. ^bent-NHC pre-cat. F was used instead of G.

The robustness and practical applicability of this asymmetric protocol were evaluated. A scale-up (1 mmol) synthesis of helicenoid 3aa under standard conditions confirmed that high enantioselectivity is maintained, demonstrating the method's readiness for practical use (Scheme 2a). Furthermore, the obtained helicenoid products were successfully elaborated into structural analogues through further transformations, confirming their role as versatile synthetic intermediates for developing functional chiral molecules (Scheme 2b). The thermal stability experiment of compound 3aa indicates that the racemization rate (100 °C, t_1/2 = 15.35 h) of this type of helicenoid at room temperature is very low. For the detailed experimental data, see the SI.

Scheme 2 Scale-up synthesis and transformation.

As depicted in Scheme 3a, a plausible mechanism is proposed. Upon nucleophilic addition of cat. G to phenylpropiolate, alkynyl acyl azolium Int-I is generated. Subsequently, enolated 1a reacts with Int-I to form allenolate Int-II through Michael addition. After the transfer of protons from polyaromatic ketone to allene, Int-III is achieved. Finally, the NHC catalyst is released from Int-III and product 3aa is obtained simultaneously. We identified the initial Michael addition of enolated 1a to alkynyl acyl azolium Int-I as the stereodetermining step. Our proposed model for the favored transition state is depicted in Scheme 3b. The catalyst's S-configuration effectively shields the specific side of Int-I. Consequently, the enolate nucleophile approaches preferentially from the less hindered side to form the P-configured product.

Scheme 3 Postulated mechanism.

Conclusions

In summary, the NHC-catalyzed helicoselective [3 + 3] annulation of polyaromatic ketones with alkynyl esters has been reported for the assembly of chiral 2-pyranone-helicenoids. This protocol features good functional group tolerance and allows the rapid preparation of helically chiral molecules from simple and readily available starting materials under mild conditions. Further investigations concerning helically chiral compounds with more topologically intricate characteristics are currently underway in our laboratories.

Author contributions

J. H. Z. conducted the main experiments. S. J. J., Z. P. L., Y. H. L. and Y. N. L. prepared several starting materials, including substrates. J. W. conceptualized and directed the project, and drafted the manuscript with the assistance from the co-authors. All authors contributed to discussions.

Conflicts of interest

There are no conflicts to declare.

Data availability

All data supporting the findings of this study are available within the article and its supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5qo01328c.

CCDC 2466074 contains the supplementary crystallographic data for this paper.⁴³

Acknowledgements

We thank the National Natural Science Foundation of China (21871160, 21672121, 22071130, 22571179), the Bayer Investigator fellowship, and the fellowship of Tsinghua-Peking Centre for Life Sciences (CLS).

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Footnote

† These authors contributed equally.

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