Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates

molecules Article Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates Marcel Bauch, Werner Fudickar and Torsten Linker * Department of Chemistry, University of Potsdam, Karl-Liebknecht-Street 24-25, 14476 Golm, Germany; [email protected] (M.B.); [email protected] (W.F.) * Correspondence: [email protected]; Tel.: +49-331-977-5212 Abstract: Stereoselective reactions of singlet oxygen are of current interest. Since enantioselective photooxygenations have not been realized efficiently, auxiliary control is an attractive alternative. However, the obtained peroxides are often too labile for isolation or further transformations into enantiomerically pure products. Herein, we describe the oxidation of naphthalenes by singlet oxygen, where the face selectivity is controlled by carbohydrates for the first time. The synthesis of the precursors is easily achieved starting from naphthoquinone and a protected glucose derivative in only two steps. Photooxygenations proceed smoothly at low temperature, and we detected the corresponding endoperoxides as sole products by NMR. They are labile and can thermally react back to the parent naphthalenes and singlet oxygen. However, we could isolate and characterize two enantiomerically pure peroxides, which are sufficiently stable at room temperature. An interesting influence of substituents on the stereoselectivities of the photooxygenations has been found, ranging from 51:49 to up to 91:9 dr (diastereomeric ratio). We explain this by a hindered rotation of the carbohydrate substituents, substantiated by a combination of NOESY measurements and theoretical calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide, which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form. Citation: Bauch, M.; Fudickar, W.; Linker, T. Stereoselective [4+2] Keywords: singlet oxygen; photooxygenation; naphthalenes; carbohydrates; stereoselectivity; auxil- Cycloaddition of Singlet Oxygen to iary control; [4+2] cycloaddition Naphthalenes Controlled by Carbohydrates. Molecules 2021, 26, 804. https://doi.org/10.3390/ molecules26040804 1. Introduction 1 Academic Editor: Axel G. Griesbeck Singlet oxygen ( O2) is an excited state of molecular oxygen and has been used for Received: 13 January 2021 various oxidations, in biology, or medical applications [1]. Although the lifetime of this Accepted: 2 February 2021 reactive species is short [2], depending on the solvent [3] or the biological environment [4], Published: 4 February 2021 it can react with high regio- [5] and stereoselectivity [6]. It was the pioneering work of Adam, who discovered that OH groups can control the diastereoselectivity in ene reac- 1 Publisher’s Note: MDPI stays neutral tions [7,8] or [4+2] cycloadditions of O2 to naphthalenes [9,10]. Later on, the influence with regard to jurisdictional claims in of other functional groups on photooxygenations has been investigated [6,11], and our published maps and institutional affil- group described the influence of acids and esters on ene reactions [12,13]. However, the iations. 1 enantioselective transfer of O2 is still challenging, because of its short lifetime. Although the α-hydroxylation of aldehydes and ketones was realized by organocatalysis with moderate to good ee (enantiomeric excess)[14–16], ene reactions or cycloadditions proceed less successfully. Thus, asymmetrically modified zeolites [17], chiral salts [18], or chiral sensi- Copyright: © 2021 by the authors. tizers [19] afforded only low stereoselectivities. Best results with up to 90% ee have been Licensee MDPI, Basel, Switzerland. obtained in photooxygenations of 2-pyridones in the presence of chiral bicyclic lactams, This article is an open access article which, however, had to be used in excess [20]. distributed under the terms and Another possibility to control the face-selectivity of singlet oxygen attack are chiral aux- conditions of the Creative Commons iliaries. First attempts with oxazolines gave no selectivity [21], but menthol derivatives [22] Attribution (CC BY) license (https:// or tartrates [23] showed moderate to good induction. Best results have been obtained with creativecommons.org/licenses/by/ oxazolidines [24], sultams [25], and especially enecarbamates [26], all developed in the 4.0/). Molecules 2021, 26, 804. https://doi.org/10.3390/molecules26040804 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x 2 of 18 Molecules 2021, 26, 804 2 of 17 with oxazolidines [24], sultams [25], and especially enecarbamates [26], all developed in the group of Adam [27]. However, to the best of our knowledge, carbohydrates have not group of Adam [27]. However, to the best of our knowledge, carbohydrates have not served served as chiral auxiliaries for the stereoselective transfer of 1O2 until now. Only sugar- as chiral auxiliaries for the stereoselective transfer of 1O until now. Only sugar-furans furans have been photooxygenated, but the intermediary formed2 peroxides rearrange have been photooxygenated, but the intermediary formed peroxides rearrange thermally thermally and cannot be isolated [28–30]. and cannot be isolated [28–30]. Based on our experience in carbohydrate chemistry [31–33] and acene oxidations [34– Based on our experience in carbohydrate chemistry [31–33] and acene oxidations [34–37], 37], we became interested in a combination of both research topics and in sugar-substi- we became interested in a combination of both research topics and in sugar-substituted1 tuted naphthalenes 1 (Scheme 1). The advantage of such arenes is that they react with1 O2 bynaphthalenes a [4+2] cycloaddition1 (Scheme in1). high The yields advantage to endoperoxides of such arenes (EPOs) is that 2, they as pointed react with out withO2 by a simple[4+2] cycloaddition alkyl- [38] and in meth highoxy-substituted yields to endoperoxides [39] systems (EPOs) 1a (R1 =2 Alk,, as pointedOMe). Furthermore, out with simple 1 thealkyl- EPOs [38 2a] and reconvert methoxy-substituted quantitatively to [ 39the] systemsparent naphthalene1a (R = Alk, 1a under OMe). thermal Furthermore, condi- the tionsEPOs and2a reconvertunder release quantitatively of singlet oxygen to the parent[40–42]. naphthalene We investigated1a under the influence thermal of conditions sub- stituentsand under R2 releaseon the kinetics of singlet ofoxygen such reactions [40–42]. [43] We and investigated could establish the influence an intramolecular of substituents 2 transferR on the of kinetics1O2 [44]. ofHowever, such reactions carbohydrate-substituted [43] and could establish naphthalenes an intramolecular 1b–f were hitherto transfer of 1 unknown,O2 [44]. However, but will generate carbohydrate-substituted new stereogenic centers naphthalenes during the1b– foxidationwere hitherto (Scheme unknown, 1). Herein,but will we generate describe new the stereogenicsynthesis of such centers compounds, during the their oxidation photooxygenation, (Scheme1). isolation Herein, we ofdescribe peroxides, the release synthesis of singlet of such oxygen, compounds, and a transformation their photooxygenation, into an enantiomerically isolation of peroxides, pure epoxide.release of singlet oxygen, and a transformation into an enantiomerically pure epoxide. Scheme 1. 1. ReversibleReversible reaction reaction of ofnaphthalenes naphthalenes 1 with1 with singlet singlet oxygen oxygen to endoperoxides to endoperoxides 2. 2. 2. Results Results and and Discussion Discussion TheThe synthesis synthesis of of carbohydrate-substituted carbohydrate-substituted naphthalenes naphthalenes 1b1b–f– startedf started from from 1,4-naph- 1,4-naphtho- thoquinonequinone (3b (3b), an), an inexpensive inexpensive andand easily available available precursor. precursor. Addition Addition of alkyl of alkyl radicals, radicals, generated by by decarboxylation decarboxylation of ofacids acids 4, 4afforded, afforded substituted substituted naphthoquinones naphthoquinones 3c–f 3cin– f in moderate to to good good yields, yields, in in analogy analogy to toliterat literatureure (Scheme (Scheme 2) 2[45].)[ 45 In]. situ In situreduction reduction with with sodiumsodium dithionite dithionite [46] [46 gave] gave the the co correspondingrresponding 1,4-dihy 1,4-dihydroxynaphthalenesdroxynaphthalenes 5, which5, which were were directly used used for for the the next next step step without without puri purification,fication, because because of their of their oxidation oxidation lability. lability. Finally, Schmidt’s Schmidt’s trichloroacetimidate trichloroacetimidate 6 [47,48]6 [47,48 gave] gave best best results results for forglycosylations, glycosylations, and and thethe hitherto hitherto unknown unknown glucose-substituted glucose-substituted naphthalenes naphthalenes 1b–1bf were–f were isolated isolated in good in good yields yields as single single ββ-anomers-anomers in in analytically analytically pure pure form. form. We started the photooxygenations with unsubstituted naphthalene 1b (R = H). Thus, substrate 1b (123 mg, 0.15 mmol) and sensitizer tetraphenylporphyrin (TPP, 1.0 mg) were dissolved in CD2Cl2 (3.0 mL) on an NMR scale. Oxygen was slowly bubbled through the solution, which was irradiated externally with a sodium lamp (400 W) at room temperature. The progress of the reaction was followed by TLC and NMR (300 MHz, measurements for every 60 min), however, even after 6 h, no conversion was observed (Table1, entry 1). This can be explained by a steric hindrance of the carbohydrate substituents,

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