Singlet oxygen synthesis

E. Friedrich, W. Lutz, H. Eichenauer, and D. Enders, Mild cleavage of /V,/V-di mcthyIhydra/nncs to carbonyl compounds with singlet oxygen, Synthesis, (1977) 893-914. 

The photooxidation of cyclopentadiene by singlet oxygen is one step of an industrial process to make 2-cyclopentene-l, 4-diol [40]. Hence the driver is a commercial one, namely to develop a continuous synthesis of this molecule. 

Vassilikogiannakis and coworkers described a simple sequential process for the biomimetic synthesis of litseaverticillol B (4-159) which includes a cycloaddition of 4-158 and singlet oxygen to give 4-160, followed by ring opening to afford the hydro-genperoxide 4-161 (Scheme 4.34) [55]. Reduction of 4-161 led to the hemiacetal 4-162, which underwent an aldol reaction to afford 4-159. 

The oxidation of 2,5-disubstuted furans by singlet oxygen was exploited for the synthesis of [5,5,5] and [6,5,6] bis-spiroketals <06OL1945>. An unusual regioselective photooxidation of 3-bromofuran to 2- and 3-bromo- hydroxybutenolides, as depicted below, was reported. The mechanism for the observed base-dependent regioselective deprotonation of the endoperoxide intermediate was not determined <06OL4831>. 

On a first, very broad, approximation singlet oxygen behaves somehow like ethylene. Three types of reactions of 102 are usually observed and have been utilized in organic synthesis 606 608) a) the Diels-Alder like cycloaddition to dienes (6.1) b) the ene reaction with olefins (6.2) and c) cycloaddition to activated double bonds (6.3). 

Singlet oxygen adds to cyclic 1,3-dienes to afford 1,4-endoperoxides 609). This type of reaction has first been applied successfully to the synthesis of ascaridole from a-terpinene 610) (6.4) and of the vesicatory compound cantharidine 6U) (6.5) some 25 years ago. 

Enamines which cannot undergo ene-like reactions add efficiently to singlet oxygen. The intermediate dioxetane can be cleaved under mild conditions to afford a ketone (and an amide). Such a sequence has been applied in a synthesis of testosterone (6.18) 624). 

Stille coupling (12, 56).1 The key step in a synthesis of (E)-neomanoalide (4) involves palladium-catalyzed coupling of an allyl halide with an a-stannylfuran. Thus 1 and 2 couple in the presence of Pd(dba)2 and P(C6H5), to form 3 as a 1 1 mixture of (E)- and (Z)-isomers in 66% yield. Conversion of 3 to 4 involves reduction (DIBAH) and selective singlet oxygen oxidation of a 2-silylfuran to a butenolide. 

A few examples to render tetrapyrrolic compounds less phototoxic can be found in the hterature. In one approach, carotenoid structures were employed for the synthesis of some carotenoporphyrin derivatives [92-94]. Figure 8 shows two stuctures by way of example. Due to similar photophysical properties of the two structural components, the excited triplet state of the porphyrin is quenched by the carotenoid moiety, thus inhibiting the formation of singlet oxygen, while its fluorescence capabilities are still preserved. Biodistribution studies revealed enhanced uptake into tumour tissue [39,93,95]. However, microscopy studies have shown that such compounds are associated with connective tissues in the tumors rather than with cancerous cells indicating low specificities for mahgnant transformation [96]. 

The synthesis of the non-natural ( )-7,14-epz-l(15),8-dolastadien-7,14-ol (rac-7yl4-epi-l09) was published by Paquette in 1986 and is highlighted by a photochemical rearrangement of the 6,6,6-tricyclic a,yS-epoxy ketone 148 into the 5,7,6-tricyclic dolastane skeleton (149) (Scheme 23) [84]. The succeeding hydroxylation of carbon atom by photo oxygenation with singlet oxygen as well as a DIBAH reduction of a keto function proceeded with an undesired substrate-induced diastereoselectivity to provide the racemic 7,14-epimer of the natural dolastane 109. 

Figure 4.14 Sensitisers used for singlet oxygen production in photochemical synthesis.

A sequence of transformations involving diastereoselective singlet oxygen photooxygenation of TBS-protected 3,5-cycloheptadienol 525 to predominantly 5yw-endoperoxide syn-526 and some anti-526, followed by reduction into the all-ci5 triol 527 as described in Scheme 146, was used by Johnson for synthesis of enantiopure methyl 2,4-dideoxyhexa-pyranosides D-528 and L-5284°5.406... 

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