Singlet oxygen addition to cyclo-1,3-hexadienes from natural sources and from organocatalytic enal dimerization

The photoxygenation reactions of the natural monoterpene aldehyde safranal ( 1 ) and its reduction product safranol ( 4 ) were studied and the endoperoxide 5 from safranol was isolated and characterized by single crystal X-ray analysis. A dyade synthesis using DCC coupling of safranol with artesunic acid delivered the reactive substrate 7 for 1,3-diene photooxygenation. Singlet oxygen reaction of the substrate 7 enabled the synthesis of the trioxane-endoperoxide dyade 8 . The diastereoisomeric 1,3-cyclohexadienes 10 were obtained from the proline-catalyzed Diels-Alder dimerization of the Michael aldehyde 9 . From the singlet oxygen addition with the diastereoisomeric substrates 10 , only the kinetically preferred cis-endoperoxide 11 was formed.


Introduction
The singlet oxygen cycloaddition to conjugated cyclodienes is a highly controlled and reliable route to 1,4-oxyfunctionalized products. 1The primary reaction event is the formation of bicyclic 1,2-dioxenes (i.e.endoperoxides) by a concerted but asynchronous 4+2 cycloaddition step.Ene reactions can sometimes compete with this cycloaddition route and for heterocyclic substrates such as thiophenes, pyrrols, oxazoles, and especially furans, the endoperoxide formation is exclusive. 2There are also numerous naturally occurring 1,2-dioxenes, that are most probably not formed biosynthetically by singlet oxygen reactions, that exhibit interesting and diverse pharmacological properties. 3A well-known natural peroxide that can also be generated by singlet oxygen addition is ascaridole. 4This compound was used as an anthelmintic drug and was among the first targets for the Schenck investigations on photooxygenations using sunlight irradiation of dye solutions which were very early examples of sustainable photocatalysis in synthesis. 5ur interest in this field of photochemistry arose from the search for new and effective antimalarial peroxides, an intensively investigated area in medicinal chemistry. 6The natural sesquiterpene artemisinin (qinhaosu), used for centuries in Chinese folk medicine as a plant extract, has initiated and stimulated this field of research. 7The enormous potency of the natural product that involves also anti-cancer drug activity just recently emerged. 8,9At the same time, however, reports appeared that describe the appearance of plasmodium species resistant against artemisinin and artemisinin-derivatives. 10,11 Three approaches are currently under investigation to deal with this fatal trend: a) artemisinin combination therapy (ACT, with other non-peroxidic antimalarial drugs), 12 b) new peroxidic substances following the structural prototype, 13,14 c) dyade concepts 15 involving structure combinations of two artemisinin monomers, 16 artemisinin and quinolines, 17 or artemisinin derivatives with synthetic 1,2,4-trioxane structures. 18,19In this context, ascaridole was also described as one potential dyade partner molecule. 20To explore new structural motifs, we envisaged other natural occuring terpenoids with pre-endoperoxide structures.One attractive example is the trimethylated cyclohexadiene safranal 1. Safranal constitutes the major spice component of crocus flowers together with crocin, crocetin and picocrocetin, and is crucial for the aroma of saffron. 21We envisaged the singlet oxygen reaction with the aldehyde 1 as a route to an electrophilic building block for dyade coupling.

Results and Discussion
The photooxygenation of the aldehyde 1 in CDCl 3 delivered after long reaction a mixture of the ene product 2 and the desired endoperoxide 3 (Scheme 1) together with unreacted starting material.Column chromatography allowed the isolation of 2 22 but unfortunately led to decomposition of the endoperoxide 3. Therefore, we reversed the dyade concept and allocated the nucleophilic part to the endoperoxide component, i.e. conversion of the aldehyde safranal to the corresponding alcohol.Near quantitative reduction of safranal (1) was achieved with LiAlH 4 , and the subsequent photooxygenation of the alcohol 4 in CDCl 3 resulted in the endoperoxide 5 in a chemoselective singlet oxygen 4+2 cycloaddition (Scheme 2).No ene products were detected in the crude NMR of the reaction mixture indicating that the hydroxymethyl group strongly activates the diene system towards 4+2 cycloaddition.The endoperoxide 5 was crystallized in racemic form from acetone and analyzed by crystal structure analysis (Figure 1). 24 accomplish the dyade synthesis from endoperoxide 5 and an artemisinin skeleton, the Steglich esterification of 5 with artesunate (6) was investigated; a well-known process with numerous alcohols. 25In contrast to the literature reports coupling was not successful and led to Broensted-acid catalyzed decomposition of the alcohol component.Consequently, safranol was used as the alcohol component and esterified with artesunate using DCC/DMAP to give the ester 7 in 19% isolated yield.Photooxygenation under standard conditions led to the desired artesunate-endoperoxide couple in 21% yield (Scheme 3).In the NMR spectra of the dyade 8 (Figure 2), the characteristic signals for the artemisinine skeleton -acetal H-11 and epimeric center H-12 -clearly show that 8 exists in an epimerically pure form with the ester substituent at C-12 in anti-position to the methyl group at C-13.The safranol endoperoxide part that is linked by the succinate chain appears as one set of signals in the 1 H as well as 13 C NMR (significant for carbon: the methylene group C-20 and the stereogenic carbon center C-21).No single signal doubling was observed neither in the 13 C nor in the 1 H-NMR spectra indicating that only one diastereoisomer of the dyade 8 was formed in the final photooxygenation process (7 8).
During this study, we discovered an alternative approach to 1,3-cyclohexadiene-1carbaldehydes as substrates for dyade coupling.We performed these experiments in the context of organocatalytic photooxygenation reactions following the α-hydroxylation route developed by Cordova et al. from aliphatic ketones and aldehydes, respectively, with singlet oxygen and amino acids as chiral organocatalysts. 26,27When these conditions were applied to α,ß-unsaturated aldehydes, complex mixtures of peroxides were observed that could not be separated.We expected the formation of dieneamines, as described in the work by Jørgensen et al. 28,29 Obviously, we were not able to trap these dienes with singlet oxygen.Thus, the reaction conditions were modified and the photooxygenation was designed as a delayed step.When the Michael aldehyde 9 was treated with proline in the absence of any (additional) dienophile, the 1,3-cyclohexadiene carbaldehyde 10 was isolated as a mixture of trans/cis-isomers (3:2, enantioselectivity was not determined) in good yields.The rationale for this reaction is shown in Scheme 4 following the sequence that was described for intramolecular cycloaddition by Christmann and coworkers. 30During the subsequent reaction with singlet oxygen, one new set of signals appeared in the NMR spectra with concurrent disappearance of the signals of the cisisomer.After completion of the reaction, a complete conversion of cis-10 was observed with less than 5% of the trans-endoperoxide 11 observable.The endoperoxide 11 with cis configuration, that could not be isolated from the reaction mixture, appeared in the 13 C NMR with a new indicative set of signals at 73.2 (C-4), 98.6 (C-1), 127.1 (C-5), and 135.1 ppm (C-6).We are currently investigating this new synthetic approach to 1,3-cyclohexadienes 31 together with the unusual high stereoselective singlet oxygen cycloaddition.

Experimental Section
General.Meso-tetraphenylporphyrin (TPP) was purchased from Porphyrin Systems, Bremen.The solvents for solution photooxygenation were puriss.and used as purchased.NMR spectra were recorded on Bruker DPX 300 and DPX 600 spectrometers, chemical shifts are given in δ (ppm) versus 0.0 (TMS for 1 H) and 77.0 (CDCl 3 for 13 C), multiplicities were determined by DEPT; IR spectra were obtained from a Perkin-Elmer 1600 series FTIR spectrometer; melting points were determined with a Büchi melting point apparatus (type Nr. 535) and are uncorrected; CHN-combustion analyses were measured using an Elementar Vario EL instrument.

Figure 1 .
Figure 1.Structure of the endoperoxide 5 in the crystal.23