Bioinspired intramolecular spirocyclopropanation of quinones as an interrupted photoredox process

Abstract

Intramolecular photoreactions of quinones can be interrupted by proton transfer using small molecules, such as trimethylamine N-oxide. This interruption de-excites the reactive spirocyclopropyl intermediates, the structures of which were for the first time confirmed by isolating them in their neutral form. The mild conditions of this process allow the conversion of a broad spectrum of quinones possessing linear and branched substituents to spirocyclopropanes in a catalytic, diastereoselective, and atom-conserving manner. Density functional theory (DFT) calculations were performed to investigate the possible reaction pathways and the origin of stereoselectivity. The established spirocyclopropanation route might be used to perform unconventional transformations of the side chains of quinones and to provide clues for the co-occurrence of certain natural quinones, hydroquinones, and spirocyclopropanes.

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Introduction

Quinones are a large class of natural compounds known for their redox and photoredox properties.¹ This knowledge has served to create numerous synthetic quinones with diverse applications based on the underlying redox transformations.² The ability of quinones to undergo intramolecular photoreduction through their side chains into hydroquinones is a powerful transformation of this kind, which enabled several biomimetic total syntheses of structurally diverse natural compounds.^3,4 However, the mechanistic understanding of this process still lacks experimental and computational evidence. In the 1960s, photoreactions of quinones containing enough flexible side chains were suggested to proceed through spirocyclic intermediates, but attempts to detect or isolate such intermediates have not been fruitful yet (Scheme 1).⁵ At the same time, the co-occurrence of quinones and hydroquinones possessing three-carbon ring substituents (e.g. royleanones, allylroyleanones, and coleons) together with spirocoleons in plants^6–8 raised the question of a biogenetic relationship between these natural product classes. Presumably, the spirocyclopropane moiety in spirocoleons is formed by heterolytic⁹ or homolytic¹⁰ pathways and could act as an intermediate responsible for the side chain variations in the natural quinones and hydroquinones. Although neither pathway has received an experimental validation so far, the above observations suggest that a yet unexplored way to convert an alkyl group of a (hydro)quinone into a spirocyclopropyl unit exists in nature. In this respect, quinones represent a starting point for the most atom-economical approach towards spirocyclic compounds and derivatives thereof.¹¹

Scheme 1 Natural diterpenoids from Coleus species and their suggested synthetic and biosynthetic pathways.

We hypothesized that the previous attempts to establish such a transformation in solution using the energy of light^5,10 failed due to a problematic de-excitation of the photochemically generated intermediates leading to their decomposition. Conversely, if the light energy is able to excite quinones under considerably more complex biological conditions,¹² interruptions in the quinone photoredox reactivity by enzymes or small molecules are highly likely. Although only a few examples of interrupted photoredox processes have been reported in the literature,¹³ they exhibit vast potential for neutralizing reactive species or rerouting the established photoreactivity towards new products. Herein, we show that by interrupting the photoreactivity of quinones with natural and unnatural small molecules in catalytic amounts, the reaction outcome can be directed toward the spirocyclopropanation pathway avoiding aromatization. This transformation comprises a unique one-step atom-conserving approach for constructing spirocyclopropanes from quinones in a diastereoselective manner and under mild conditions, thus expanding the toolbox of current spirocyclopropanation strategies, which are mainly based on utilizing ylide or carbene precursors.^14,15

Results and discussion

We started our investigation by elucidating the photochemistry of thymoquinone (1a) as one of the simplest quinones found in nature. Since 1877, thymoquinone has been known to undergo [2 + 2] photodimerization in the solid state,¹⁶ whereas unselective intramolecular photoredox reactions were later observed in solution.¹⁷ In order to suppress such processes in the favor of securing the desired spirocyclopropane intermediate 2a, we irradiated 1a with blue light in chloroform as a non-nucleophilic solvent in the presence of various additives that could presumably convert 2a from an excited state to its ground state (Table 1). To our surprise, several small molecules of different classes (onium salts, N-oxides, and amines) enabled the stereoselective formation of 2a in good yields, among which trimethylamine N-oxide (TMAO) gave the highest yield of 2a (84%). However, the low chemical stability of 2a did not allow us to isolate it in a higher than 51% yield. Allylhydroquinone 3a was the major reaction by-product, which predominated in the absence of additives (49% yield) and was also detected in decomposed samples of 2a. Interestingly, 3a was recently isolated together with thymoquinone from Nigella sativa.⁷

Table 1 Selected screening experiments for the spirocyclopropanation of thymoquinone^a

Entry	Additive^a	Yield of 2a^b, %	Yield of 3a^b, %
a Reactions were performed on the 0.05 mmol scale using 10 mol% of additive unless noted otherwise (see the ESI‡ for the complete list of experiments).b  ^1H NMR yield.c Isolated yield on the 0.5 mmol scale is given in parenthesis.d 5 mol%.e 15 mol%.f No irradiation.
1	—	0	49
2	Berberine	64	8
3	Canadine	44	27
4	Caffeine	0	46
5	L-Phenylalanine	0	41
6	TBAB	48	5
7	Me3SOI	64	19
8	PPTS	48	33
9	Et3N	82	12
10	[bmim]Cl	54	5
11	NMO	72	18
12	TMAO	84 (51)^c	14
13	TMAO^d	76	19
14	TMAO^e	84	14
15	TMAO^f	0	0

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Next, we studied the scope of quinones that can undergo the spirocyclopropanation reaction with TMAO as an additive (Scheme 2). First, we established that spirocyclopropane 2a can be similarly prepared from thymoquinone's linear isomer (2-methyl-5-propyl-p-benzoquinone 1a′), albeit with slightly lower diastereoselectivity and yield (44%, 12 : 1 dr). The stability of spirocyclopropanes such as 2a is affected by the substitution character of the C=C bond. Thus, less substituted compound 2b derived from 2-isopropyl-p-benzoquinone (1b) was not stable to isolation and could only be observed in solution (44% spectral yield). In contrast, spirocyclopropanes with sterically hindered C=C bonds 2c and 2d were isolated in yields close to the spectral ones (42% and 47%, respectively). Products possessing annulated C=C bonds 2e and 2f exhibited divergent behavior: benzoannulated 2e was isolated in 71% yield and with 7 : 1 dr, whereas pyridoannulated 2f was only stable in solution (80% spectral yield).

Scheme 2 The scope of quinones participating in the spirocyclopropanation reaction (the newly formed bonds are highlighted in blue). ^a Typical reaction setup: quinone 1 (0.5 mmol) and TMAO (0.05 mmol) were irradiated in CHCl₃ (5 mL) at 20–25 °C for 1–24 h; isolated yields and diastereomeric ratios of the products are given. ^b Determined by ¹H NMR analysis of the reaction mixture. ^c After subsequent separation of isomers. ^d Isolated yield on the 5 mmol scale. ^e Isolated as the O-acetate derivative.

Then, we turned our attention to the substitution of the cyclopropane ring in 2. The results show that products decorated with various carbon- and heteroatom-substituted cyclopropane rings can be assembled from the corresponding quinones. For instance, acetoxy-substituted spirocyclopropane 2g was prepared in 36% yield and with >20 : 1 dr. Only minor by-products were observed, and the yield of 2g was largely affected by isolation. Stable benzoannulated products 2h–2j bearing alkyl and phthalimide groups were synthesized in 81–89% yields, although in lower diastereomeric ratios (3 : 1–6 : 1). Nonetheless, the diastereomeric purity of these compounds can be successfully increased by a subsequent chromatographic separation or crystallization. Aryl-substituted spirocyclopropane 2k was formed in 75% yield and with 13 : 1 dr, but underwent the Cloke–Wilson rearrangement¹⁸ into 4k upon work-up (30% yield). In contrast, benzoannulated analogs 2l–2n exhibited good stability and were obtained in 54–76% yields after separating the stereoisomers. The relative stereochemistry of compounds 2a–2n was determined on the basis of single-crystal X-ray diffraction analysis of 2j and 2l in conjunction with their characteristic peaks in ¹H NMR spectra (see ESI Table S3‡). Interestingly, despite the fact that the anti-relationship between the carbonyl group connected to the cyclopropane ring and the adjacent exocyclic substituent was typical of most compounds (≥6 : 1 dr), phthalimides 2i and 2j preferred the syn-relationship (≥3 : 1 dr).

Ethylquinones can be used to prepare compounds 2 with an unsubstituted spirocyclopropyl moiety. Thus, the expectedly labile parent compound 2o can be generated from 2-ethyl-p-benzoquinone in 64% spectral yield (attempts to isolate it in pure form led to a complex product mixture). The stability of this scaffold is considerably improved by simply introducing a methyl or an ethyl group to the C=C bond: bench-stable compounds 2p and 2q were synthesized in 77% and 73% isolated yields, respectively. On the other hand, the reaction leading to the doubly methylated compound 2r was sluggish and the product was obtained in only 41% yield. The synthesis of benzoannulated spirocyclopropane 2s gave similar results on 0.5 and 5 mmol scales (72–73% isolated yield), whereas naphthoannulated product 2t was obtained in a lower yield (40%) due to an incomplete conversion of the starting quinone even after extending the reaction time to 24 h.

Next, we studied the synthetic possibilities toward the products having geminal and vicinal substituents in the cyclopropane ring. Thus, 2,6-di-t-butyl-p-benzoquinone (1u) yielded isolable gem-dimethyl cyclopropane 2u (25%) together with an uninterrupted reaction product 3u (69%). Less stable gem-diphenyl cyclopropane 2v was observed in 52% spectral yield and similarly to 2k, it slowly underwent the Cloke–Wilson rearrangement into 4v on standing. At the same time, vicinally substituted spirocyclopropanes 1w and 1x were formed in 75% and 58% yields as diastereomeric mixtures and exhibited good stability to isolation and storage.

Several quinones were found to be unsuitable for the spirocyclopropanation reaction. For example, despite the fact that 2a could be prepared from both linear and branched quinones, only the linear quinone 1k gave product 2k, while the isomeric branched quinone 1y gave a complex product mixture. Disubstituted naphthoquinones, such as 1z, 1aa and 1ab, did not react under the standard reaction conditions. Electron-rich 2,5-bis(dimethylamino)-p-benzoquinone (1ac) reacted slowly forming the previously reported benzoxazoline,^5b although the plausible spiroaziridine intermediate was not detected. 2-Methoxy-p-benzoquinone (1ad) was less reactive and only minor decomposition products were observed. Lastly, the trimethylsilyl group in 1ae also did not participate in the reaction, likely due to the distancing of the methyl groups caused by the large silicon atom.

After examining the scope of the spirocyclopropanation reaction, we aimed to shed light on its mechanistic details. The data presented so far indicate that spirocyclopropanes 2 do not readily undergo ring opening upon prolonged irradiation neither under the reaction conditions nor after isolation, therefore ground-state molecules 2 are not the reactive intermediates in the photoredox chemistry of quinones. Similarly, by-product 3a did not react under the standard reaction conditions, thus excluding the possibility of it forming 2a by the abnormal Claisen rearrangement.¹⁹ Hence, the formation of spirocyclopropanes 2 is a result of an interruption of the photoreactivity of quinones by small molecules. Conceivably, such interruption may commence with electron donor–acceptor (EDA) complexation or electron transfer between an electron-poor quinone and an electron-rich additive. However, the UV-Vis spectrum of the solution containing thymoquinone and TMAO did not show a bathochromic shift that could be attributed to an EDA complex (see ESI Fig. S1‡). Electron transfer between photoexcited quinones having β-H-atoms in the side chain and amines, such as triethylamine, was earlier ruled out.²⁰ In any case, an interaction between a quinone and an additive is not crucial for the formation of the cyclopropane ring: among spirocyclopropanes 2, compounds 2f and 2o–2t were also formed when the reactions were conducted without any additives, albeit in lower yields (Fig. 1). These findings indicate that (a) the key action of an additive likely happens after the photoinduced formation of the cyclopropane ring, (b) in the absence of additives, reactive spirocyclopropyl intermediates generally undergo ring opening into allylhydroquinones 3 or give complex product mixtures instead of providing spirocyclopropanes 2, and (c) in specific cases, spirocyclopropanes 2 may be formed autocatalytically (e.g. 2f) or when the cyclopropyl-allyl rearrangement is impossible (compounds 2o–2t).

Fig. 1 ¹H NMR yields of 2 in the reactions conducted with and without TMAO.

The mechanism for the photoinduced formation of the reactive spirocyclopropyl intermediates from quinones was proposed in 1968^5b and has remained substantially unchanged to date. As illustrated in Scheme 3 for 1a, the reaction begins with n–π* photoexcitation of the quinone into delocalized biradical I, and the intramolecular 1,5-HAT process leads to biradical II. This intermediate was suggested to undergo neophyl-type ring closure^5,21 into biradical III (pathway A). The subsequent conversion of biradical III into zwitterion IV is currently regarded as an electron transfer event.³

Scheme 3 Plausible spirocyclopropanation pathways.

The formation of zwitterionic intermediates in the process was confirmed using time-resolved UV-Vis spectroscopy by Görner,²⁰ although the structure of these species and their ability to produce spirocyclopropanes 2 remained unclear. Nevertheless, the evidence collected so far points at zwitterionic species such as IV or its resonance form V as the main candidates to be intercepted by ionic additives, such as TMAO. In this respect, the most straightforward and sufficiently general interception pathway is the collapse of V into 2a by proton transfer. Indeed, if the proton shuttle is not available, the driving force of aromatization leads to ring-opening product 3a. An unconsidered alternative reaction pathway towards 2a and 3a could involve intramolecular recombination of biradical II into cyclobutanol VI, ring contraction of which would directly provide zwitterion V (pathway B).

In order to procure the missing mechanistic evidence, we first attempted to trap the reactive intermediates with stable radicals. The photoreactivity of 1a was expectedly shut down in the presence of galvinoxyl, whereas TEMPO surprisingly interrupted the reaction in the same way as TMAO: 2a was formed as the major product in 80% yield (Scheme 4a). The latter observation could be explained by the participation of the in situ generated oxammonium chloride of TEMPO.²² In the pursuit of cyclobutanol intermediates (such as VI, Scheme 3), we spotted the signs of a minor product possibly having a cyclobutane ring in the reaction mixture of quinone 1g, although in an amount not sufficient for characterization (see ESI Fig. S2‡). Luckily, when analogous naphthoquinone 1af was used as the starting material, the desired cyclobutanol 5 was observed as the major product regardless of the presence of TMAO (Scheme 4b). However, the attempted isolation of 5 only gave 26% of dihydrofuran 4af, which could be formed by the ring expansion directly or through the initial ring contraction into spirocyclopropane 2af (detected after the reaction). This exceptional behavior of quinone 1af forming 5 appears to be the result of the stabilization of 5 induced by the benzene ring and the acetate group. Interestingly, a similar transformation producing 4-membered oxetanol was noticed previously during the photolysis of 12-O-methyl royleanone.¹⁰ Lastly, to track the protons transferred in the spirocyclopropanation reaction, the conversion of deuterium-labelled thymoquinone d-1a into d-2a was monitored by ¹H NMR (the use of CDCl₃ as a solvent did not result in any deuterium incorporation in previous experiments). The results depicted in Scheme 4c show that the deuterium atoms from the labelled isopropyl group were mainly transferred to the methylene group in the 6-membered ring of d-2a (30% D, 60% of the theoretical amount). Additionally, the cyclopropane ring of d-2a was partially deuterated in the methine position (20% D), possibly caused by a reversible [1,2-H] shift in the isopropyl group during the process.²³ However, this event appears unproductive, otherwise the 1-phenethyl group in 1y would participate in the reaction similarly to the 2-phenethyl group in 1k giving rise to 2k. Overall, the preservation of the deuterium label in d-2a is consistent with the proposed mechanism and indicates that TMAO only transfers the protons originating from the quinone itself.

Scheme 4 Mechanistic experiments.

To understand the energy requirements of the reaction pathways outlined in Scheme 3, we performed density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations on 1a. First, we investigated the photoactivation of 1a and performed a relaxed geometry optimization scan along the 1,5-HAT coordinate. We observed that thermal 1,5-HAT is inaccessible due to a high activation energy exceeding ∼40 kcal mol⁻¹ (see ESI Fig. S7‡). However, biradical II can be accessed through an excited-state process from 1a. Following the initial population of S₁ or S₂ excited states with the n–π* or π–π* character, the intersystem crossing to the lower-lying T₁ state can drive the conversion of 1a to II. Subsequently, we assessed the energetics of biradical II reactivity, both with and without TMAO (Fig. 2). At the DFT level, biradical II is described with one unpaired electron at the methylene group and another electron delocalized over the semi-quinone moiety with the highest spin density at C₄, C₆, C₈ and O₁₂ atoms (cf. Fig. 2). The addition of TMAO resulted in H-bonding interaction but not proton transfer to TMAO, with a free energy gain of ∼7.7 kcal mol⁻¹, minimally affecting the electronic structure of biradical II. The electronic distribution suggests potential reactivity toward closing the spirocyclopropane ring (pathway A in Scheme 3) or radical recombination, yielding two possible cyclobutanes (see ESI Fig. S8 and S9‡). Pathway A, involving spirocyclopropane ring closure into biradical III was found to have substantially lower activation free energy than radical recombination pathways regardless of the presence of TMAO. Considering stereochemistry, the activation free energy was lower for the anti-isomer by ∼1.8 kcal mol⁻¹ (both with and without TMAO), leading to preferential anti-orientation of the spirocyclopropyl intermediate III. According to the Eyring equation (see ESI section 3.2.2‡), the difference in activation free energies favors anti-orientation of the spirocyclopropyl intermediate III in the ratio of ∼20 : 1 at 25 °C, in agreement with the experiment. Biradical III was found to be energetically higher than zwitterionic species IV/V, suggesting a barrier-less relaxation to IV/V via intramolecular electron transfer. The calculated electron density of the zwitterion IV/V suggests an electronic distribution that is an average between the resonance forms IV and V. Intermediate IV/V is stabilized by deprotonation by TMAO, which can further shuttle protons to the enol moiety and yield product 2a. In the absence of a proton shuttle, the push–pull character of zwitterionic intermediate IV/V promotes heterolytic ring opening,²⁴ leading to aromatic product 3a.

Fig. 2 Computed energy profile for the formation of 2a and 3a from II. All computational details are provided in section 3 of the ESI.‡

Finally, to demonstrate how the side chains of quinones can be modified through spirocyclopropanes 2 as the reaction intermediates, we developed a series of sequential transformations. First, when 2a was generated from thymoquinone, the addition of methanol to the reaction mixture caused slow solvolysis that was accelerated thermally (60 °C) and provided hydroquinone 6 in 79% yield (Scheme 5). This hydroquinone was previously isolated from Nigella sativa and exhibited platelet aggregation activity.⁸ Second, the isopropyl group of thymoquinone was converted into the allyl group in 48% yield (compound 1ag) by treating the in situ formed 1a with phenyliodine(III) diacetate (PIDA) at room temperature. Benzoannulated spirocyclopropane 1s showed similar reactivity to 1a. Thus, a product of a formal C–H acetoxylation 1af was obtained from 2-ethylnaphthoquinone via 2s in a three-step semi-one-pot sequence in 40% overall yield. Lastly, the dihydrofuran ring of 4s was constructed from the ethyl group of 2-ethylnaphthoquinone in 69% yield over two steps. Overall, the above transformations represent simple and efficient synthetic routes to compounds that are relatively difficult to prepare by other methods, thus opening numerous opportunities for using spirocyclopropanes 2 as acceptor-activated cyclopropanes.^18,24 Furthermore, this reactivity may help to explain the co-occurrence and the biosynthetic origin of natural quinones and hydroquinones bearing alkyl, oxyalkyl and allyl groups.^6–8 In particular, the fact that thymoquinone was earlier isolated together with hydroquinones 3a and 6 suggests that spirothymoquinone 2a could also be a natural compound, which remained elusive to isolate due to its chemical sensitivity. Similarly, the interrupted photoredox reactivity of quinones may play a role in the formation of other spirocyclopropanes in nature.^6,25

Scheme 5 Transformations of quinones via spirocyclopropanes 2.

Conclusions

In summary, the photoredox reactivity of quinones was successfully steered away from the aromatization route toward the spirocyclopropanation pathway by introducing a catalytic amount of TMAO to the reactions. The thus formed spirocyclopropanes were earlier suggested as the reaction intermediates, yet we showed that they are isolable compounds, the stability of which is strongly affected by the substitution character of the cyclopropane ring and of the enedione fragment. Still, the mild reaction conditions allow one to selectively convert a broad variety of benzo- and naphthoquinones having linear or branched side chains into the corresponding spirocyclopropanes that can be directly used in synthesis. Based on the experimental and computational data, TMAO enables the spirocyclopropanation pathway by incorporating a proton transfer step into the non-catalytic photoredox process. We believe that interruptions in the photoredox chemistry of quinones by such a universal mechanism may also occur in nature, and certain natural spirocyclopropanes could be biosynthesized accordingly and anticipated through synthesis.

Author contributions

A. A. F. – synthetic investigation, D. B. – computational investigation, I. C. – single-crystal X-ray diffraction analysis, and M. K. – supervision and funding acquisition. The manuscript was composed with input and approval from all authors.

Data availability

The data supporting this article can be found in the ESI.‡ Crystallographic data for compounds 2j, 2l and 2m have been deposited at the CCDC repository (https://www.ccdc.cam.ac.uk) under accession numbers 2352748, 2352747, and 2352749, respectively.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Czech Science Foundation (Lead Agency Grant No. 21-39639L). The authors would like to thank Prof. Jiří Mosinger for helpful discussions.

References

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Footnotes

† Dedicated to Professor Igor V. Trushkov on the occasion of his 60th birthday.

‡ Electronic supplementary information (ESI) available. CCDC 2352748, 2352747 and 2352749. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01291g

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