Exploring O-stannyl ketyl and acyl radical cyclizations for the synthesis of γ-lactone-fused benzopyrans and benzofurans

Abstract

The synthesis of a series of γ-lactone-fused benzopyrans and benzofurans, analogues of the pyranonaphthoquinone antibiotics, is reported. Preparation of the heterocycles was achieved by either O-stannyl ketyl or acyl radical cyclization of benzaldehyde precursors followed by oxidation to give the pyrano- and furanobenzoquinone systems. The observed diastereoselectivity during O-stannyl ketyl radical cyclization is influenced by aromatic substitution ortho to the aldehyde, whilst acyl radical cyclization followed by stereoselective reduction of the resulting pyranones provides a complimentary approach to forming the required γ-lactone-fused benzopyran systems.

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Introduction

The redox chemistry of quinones is often linked to their biological relevance, from the central involvement of coenzyme Q₁₀ (ubiquinone) in the electron transport chain of eukaryotic organisms, through to the defence mechanism of the bombardier beetle. Not surprisingly, the presence of a quinonoid system in compounds such as 1–4 (Fig. 1) is crucial to their bioactivity, with doxorubicin 1 and mitomycin C 2 both being in clinical use for the treatment of a variety of cancers. The pyranoquinones kalafungin 3 and frenolicin B 4 are members of a large family of natural products that consistently show a broad range of antibiotic activities, many possessing cytotoxic properties.¹ A mechanism of action involving bioreductive alkylation was proposed by Moore and Czerniak for pyranoquinones such as 3 and 4,² and is supported by more recent theoretical,³ chemical⁴ and biochemical studies.⁵

Fig. 1 Bioreductive alkylating agents.

The tricyclic quinone 5 (Scheme 1) contains the essential structural features required for the bioactivity of pyranonaphthoquinones 3 and 4, based on their proposed bioreductive alkylation mode of action, and can thus be considered the pharmacophore for these natural products. The process involves an initial two-electron reduction of quinone 5 to hydroquinone 6, this being followed by opening of the γ-lactone to form the reactive ortho-quinone methide 7, which upon reaction with a nucleophile leads to the alkylated product 8. Some of the biological effects of doxorubicin 1 have been attributed to a related one-electron bioreductive process that generates reactive oxygen species,⁶ whilst mitomycin C 2 acts as a sequence specific cross-linker of DNA via alkylation at C-1 and C-10.⁷ In the later case, reduction of the quinone in 2 initiates a cascade involving loss of methanol, opening of the aziridine ring and loss of carbamate to form the alkylating species.

Scheme 1 Mechanism of bioreductive alkylation for γ-lactone-fused pyranoquinones.

Surprisingly, the proposed pharmacophore 5 of the pyranoquinones has not itself been prepared previously, although a number of analogues having substituents on the benzoquinone ring^8,9 or at C-5 on the pyran ring^10–15 are known. Apart from the alkoxycarbonylative annulation methodology¹⁶ and Lewis acid-catalyzed aryldioxolanylacetate rearrangement,¹² preparation of the fused benzopyran-γ-lactone structural motif contained in 6, which may then serve as a precursor to quinone 5, usually involves formation of each of the heterocyclic rings in separate steps. Examples include using sequential Wittig-oxa-Michael reactions followed by lactonization,⁸ Sharpless dihydroxylation to form the γ-lactone followed by oxa-Pictet-Spengler reaction¹⁰ and 2-alkoxyfuran addition to 2-acetylbenzoquinone with subsequent acid-catalyzed rearrangement.^13,15

As part of an ongoing program exploring the use of O-stannyl ketyl radical cyclizations for the synthesis of a range of structure classes, including prostanoids and dioxaspirononanes,¹⁷ we have also applied this approach to the synthesis of tricyclic systems related to 6 en route to frenolicin B 4.¹⁸ This method enabled both the pyran and cis-fused γ-lactone rings to be formed in a single step, with excellent diastereoselectivity, from a benzaldehyde precursor. The ability to rapidly access heterocycles such as 6 using this method gave us the incentive to explore the scope of this approach further for the synthesis of analogous systems that may potentially act as bioreductive alkylating agents. Additionally, it was anticipated that during the course of these studies factors affecting the diastereoselectivity during O-stannyl ketyl radical cyclization of benzaldehyde substrates would be assessed to establish more efficient and predictable outcomes in these multi-bond forming processes.

Results and discussion

To assess the viability of this approach we firstly prepared the cyclization precursor benzaldehyde 12 in two steps from benzene dimethanol 9¹⁹ (Scheme 2). When benzaldehyde 12 was treated with tributyltin hydride (0.05 M) and AIBN in benzene at reflux a mixture of cis-14 and trans-16 products were formed along with benzyl alcohol 10 resulting from reduction of the intermediate O-stannyl ketyl radical. Lowering the concentration of tributyltin hydride to 0.02 M gave improved conversion to cyclized products 14 and 16 (Table 1). Under these conditions the required γ-lactone-containing product and the trans-product are formed in equal amounts (14 : 16 1 : 1). When the para-dimethoxy substituted benzaldehyde 13 was reacted under similar conditions, however, the diastereoselectivity of the cyclization changed in favour of the trans-product 17 (15 : 17 1 : 3.4).¹⁸ The conversion of trans-product 17 to lactone 15 can be effected by exposure to potassium carbonate.¹⁸

Scheme 2 Reagents and conditions: (a) ethyl propiolate, NMM, CH₂Cl₂, 1.5 h (10 45%; 11 47%); (b) TEMPO, PhI(OAc)₂, CH₂Cl₂, 3 h (98%); (c) Bu₃SnH, AIBN, benzene, reflux, 5 h (15 13%, 17 46%).

Table 1 O-Stannyl ketyl radical cyclization products from benzaldehydes 12, 13, 22, 28 and 29

Entry	Substrate	Products^a^,^b
a Conditions: Bu3SnH (0.02 M, 1.5 equiv.), AIBN (0.1–0.3 equiv.), benzene, reflux, 5 h. b Ratio and yield of cyclized products obtained by integration of ^1H NMR spectrum of the mixture after filtration through 10% KF/silica. In each case, 15–25% of the products resulting from reduction were also observed. c [Bu3SnH] = 0.05 M. d Isolated yield.
1	12
2	13
3	22
4	28
5	29

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To further understand the factors influencing the stereoselectivity of these O-stannyl ketyl radical cyclizations the isomeric dimethoxybenzaldehydes 22, 28 and 29 were prepared as outlined in Scheme 3. Thus, reduction of phthalide 18 gave the symmetrical diol 19²⁰ that upon alkylation formed benzyl alcohol 20, along with dialkylated product 21. Oxidation of alcohol 20 then gave benzaldehyde 22 in 41% yield over the three steps. A similar sequence of reactions beginning from phthalide 23 initially gave diol 24²¹ that upon alkylation formed isomeric benzyl alcohols 25 and 26. Separation of the isomers was best achieved after their subsequent oxidation to the corresponding benzaldehydes 28 and 29. With these substrates in hand, the influence of substitution pattern on the O-stannyl ketyl radical cyclization could be assessed.

Scheme 3 Reagents and conditions: (a) LiAlH₄, THF, 0 °C, 2.5 h (19 80%; 24 93%); (b) ethyl propiolate, NMM, CH₂Cl₂, 1.5 h (20 56%, 21 24%; 25 + 26 60%, 27 21%); (c) TEMPO, PhI(OAc)₂, CH₂Cl₂, 2–3 h (22 91%; 28 + 29 90%).

The ortho-dimethoxybenzaldehydes 22 and 28, in which the methoxy substituents are remote to the aldehyde group, both gave a near 1 : 1 mixture of cis- and trans-products (Table 1, entries 3 and 4) that are comparable to the unsubstituted system 12. The ortho-dimethoxy isomer 29 in which the aldehyde group has a neighbouring methoxy group gave a preference for trans-product 35 (entry 5), with the cis-/trans-product ratio very similar to that formed from the para-dimethoxy substituted system 13. With dimethoxybenzaldehydes 13, 22, 28 and 29 having similar electronic features, the change in stereoselectivity may be a result of the steric influence of the methoxy groups. Thus, when a methoxy group is ortho to the aldehyde (Table 1, entries 2 and 5) then trans-products are favoured. Conversely, less hindered aldehyde groups (entries 1, 3 and 4) tend to give similar amounts of cis- and trans-products. The preference for trans-product formation from benzaldehydes 13 and 29 may also result from electrostatic repulsion between the oxygen of the intermediate O-stannyl ketyl group and adjacent methoxy substituent being minimized in the transition state leading to trans-products 17 and 35. Samarium diiodide has been used to effect reductive cyclization of benzaldehydes,²² however, under these conditions a strong preference for trans-product formation is observed and as such has not been attempted in the present study.

With the goal of more efficiently accessing the required γ-lactone-containing product 15 from benzaldehyde 13, we considered an approach that involved a diastereoselective reduction of ketone 37 (Scheme 4). To prepare the required ketone we envisaged the direct formation of 37 from benzaldehyde 13 using an acyl radical cyclization under conditions of polarity reversal catalysis.^23,24 Firstly using the unsubstituted benzaldehyde 12, treatment with tert-dodecanethiol and 1,1′-azobis(cyclohexanecarbonitrile) (ACCN) resulted in only 30% conversion to ketone 36 after 18 hours in toluene at reflux. Similar treatment of the dimethoxybenzaldehyde 13 gave 50% conversion after 22 hours, with ketone 37 being isolated in 23% yield (44% based on recovered 13). Longer reaction times with further addition of initiator and/or catalyst failed to complete the conversion of benzaldehyde 13 to ketone 37 without further decomposition taking place. We considered that competitive abstraction of hydrogen at the activated benzylic ether positions in 12 and 13 by the thiyl radical may be inhibiting efficient intramolecular hydroacylation to form the expected ketones 36 and 37. In accord with this, the analogous carbocyclic ketone products are obtained efficiently using this method^24a and we have observed that increasing steric hindrance by the introduction of further substitution at the benzylic ether position in 13 gives improved conversion to the corresponding ketone using the thiyl radical catalysed process.^24b

Scheme 4 Reagents and conditions: (a) tert-dodecanethiol (0.3 equiv.), ACCN (0.3 equiv.), PhMe, reflux, 22 h (37 23% [48% recovered 13]).

We then turned to the isomeric benzaldehyde 40 (Scheme 5), prepared from salicylaldehyde 38,²⁵ to further investigate the acyl radical cyclization process. When 40 was heated in the presence of thiol and initiator the ketone product 42²⁵ was isolated in 68% yield. Similarly, the dimethoxy-substituted system 41 underwent acyl radical cyclization efficiently to form ketone 43 in 64% yield. Complete consumption of benzaldehyde 41 was evident after 20 h, supporting the proposition that the presence of readily abstractable hydrogen at the benzylic ether position in previous substrates 12 and 13 significantly hinders the efficiency of these thiyl radical-catalysed reactions. As anticipated, ketones 42 and 43 could be stereoselectively reduced under Luche conditions (CeCl₃–NaBH₄–MeOH) to form the corresponding lactones 44 and 45 in 69% and 84% yields, respectively. The presence of trans-alcohol products under these conditions was not evident.

Scheme 5 Reagents and conditions: (a) methyl-4-bromobut-2-enoate, K₂CO₃, DMF, 16–20 h (40 61%; 41 80%); (b) tert-dodecanethiol (3.0 equiv.), ACCN (1.5 equiv.), PhCl, 100 °C, 20 h (42 68% [26% recovered 40]; 43 64%); (c) (i) CeCl₃·7H₂O, NaBH₄, CH₂Cl₂, MeOH, −78 °C, 45 min; (ii) pTsOH·H₂O, CHCl₃, 2 h (44 69%; 45 84%).

Direct formation of the γ-lactone-fused benzopyrans 44 and 45 should also be possible using the previously described O-stannyl ketyl radical cyclization conditions. Thus, upon treatment of benzaldehyde 40 with tributyltin hydride an inseparable 1.4 : 1 mixture of lactone 44 and alcohol 46 (Scheme 6) was obtained in a combined 92% yield, in accord with previous reports.²⁶ Incorporation of methoxy substituents onto the aromatic ring in benzaldehyde 41 led to only a slight change in the diastereoselectivity with 45 and 47 being isolated in 39% and 40% yields, respectively. In contrast to the β-alkoxy acrylate systems described earlier (Table 1), the isomeric crotonate systems 40 and 41 showed no evidence of undergoing competitive reduction and shorter reaction times were required suggesting that the barrier to radical cyclization may be less significant for 40 and 41.

Scheme 6 Reagents and conditions: (a) Bu₃SnH, AIBN, benzene, reflux, 2 h (44 + 46 92%; 45 39%, 47 40%).

We then sought to further explore both the O-stannyl ketyl and acyl radical cyclization approach for the formation of benzofuran systems having an appended γ-lactone ring (Scheme 7). Such systems, when converted to benzoquinones, should potentially be able to act as bioreductive alkylating agents in a manner similar to that proposed for the benzopyran systems (Scheme 1). The 6,5,5-ring systems in 50/51 resemble the ring system contained in mitomycin C 2 and may be considered as a ‘hybrid’ of the mitomycin C 2 and pyranonaphthoquinone 3 pharmacophores.

Scheme 7 Reagents and conditions: (a) Bu₃SnH, AIBN, benzene, reflux, 2–3 h (50 + 52 86%; 51 71%, 54 25%); (b) Ac₂O, pyridine, DMAP, CH₂Cl₂, 1.5 h; (c) tert-dodecanethiol (3.0 equiv.), ACCN (1.5 equiv.), PhCl, 100 °C, 18 h (56 47%, 57 11%).

Consistent with previous reports benzaldehyde 48²⁷ (Scheme 7) underwent O-stannyl ketyl radical cyclization efficiently to form an inseparable mixture of benzopyrans 50 and 52 in a combined 86% yield (50 : 52 34 : 66).²⁸ Acetylation of this mixture assisted separation of acetate 53 from lactone 50 to allow characterization of the products. The corresponding dimethoxy benzaldehyde 49 also cyclized efficiently to form cis-lactone 51 (71% yield) and trans-alcohol 54 (25% yield). In contrast to formation of the corresponding benzopyran systems (Table 1, entries 1 and 2) in which the incorporation of para-methoxy substituents led to the trans-product being favoured, introduction of methoxy substituents onto benzaldehyde 49 results in the cis-lactone 51 being formed in preference to the trans-alcohol 54 (51 : 54 2.8 : 1).

Benzaldehydes 48 and 49 also underwent acyl radical cyclization, with the unsubstituted system 48 only progressing to approximately 30% conversion to ketone 55 after 18 h at 100 °C in chlorobenzene. The dimethoxy benzaldehyde 49, however, was completely consumed after the same reaction time to give ketone 56 and enol 57 in 47% and 11% yields, respectively. Interconversion of ketone 56 and enol 57 was not observed upon standing the purified materials in deuterated chloroform for two days.

Having prepared a series of benzopyran and benzofuran heterocycles, their conversion to the corresponding benzoquinones was effected as shown in Scheme 8. Thus, oxidation of benzopyran 15 using cerium(IV) ammonium nitrate (CAN) gave benzoquinone 5 in 93% yield. Attempted oxidation of the isomeric benzopyran 45 using CAN gave mixtures of products resulting from oxidative dimerization, however, using phenyliodine bis(trifluoroacetate) (PIFA) to effect oxidation of 45 led to the isolation of benzoquinone 58 in 76% yield. Further elaboration of benzoquinone 58 was undertaken by employing a regioselective Diels–Alder reaction to give the ‘iso’-pyranonaphthoquinone system 59. Finally, the benzofuran system 51 was also oxidized using PIFA to give furanobenzoquinone 60, a novel hybrid of the mitomycin C and pyranonaphthoquinone pharmacophores.

Scheme 8 Reagents and conditions: (a) CAN, MeCN, H₂O, 30 min (93%); (b) PIFA, MeCN, H₂O, 1–2 h (58 76%; 60 63%); (c) 1,3-dimethoxy-1-trimethylsiloxybuta-1,3-diene, CH₂Cl₂, 1.5 h, then SiO₂, air, 1 h (55%).

Conclusions

The diastereoselectivity of O-stannyl ketyl radical cyclization of benzaldehydes with tethered acrylates has been investigated. The 6-exo cyclization of β-alkoxy acrylates having methoxy groups ortho to the aldehyde (13 and 29) tend to favour trans products, whereas an unsubstituted ortho position (12, 22 and 28) leads to formation of a near equal mixture of cis (lactone) and trans products. A similar trend, though less pronounced, is observed for the isomeric crotonate systems 40 and 41. During formation of benzofurans the opposite outcome is observed, with the addition of methoxy groups onto the aryl system favouring the formation of the cis-lactone product 51. Furthermore, a complimentary approach that uses an acyl radical cyclization of the same benzaldehyde substrates followed by diastereoselective reduction of the resulting pyranones has provided a more efficient method for the preparation of the required cis-lactone products. These approaches have made available a series of benzopyran- and benzofuran-fused γ-lactones that have been converted to benzoquinones 5, 58 and 60 and naphthoquinone 59, which are expected to have potential as bioreductive alkylating agents.

Acknowledgements

Financial support from the Australian Research Council through the Centres of Excellence Scheme is gratefully acknowledged. Professor Carl Schiesser, The University of Melbourne, is acknowledged for useful discussions.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Full experimental details and copies of ¹H and ¹³C NMR spectra of new compounds. See DOI: 10.1039/c3ob42090f

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