Chiral hydroperoxides

Bei der Reduktion chiraler Hydroperoxide mit Lithiumalanat11 und Natriumboranat12 zum Alkohol bleibt die Konfiguration erhalten (nur die Peroxid-Bindung wird angegrif-fen). 

In this review, we focus mainly on the preparative utility of organic peroxides, and only few mechanistic investigations are discussed. This review covers synthetic methodologies for the preparation of alkyl hydroperoxides and dialkyl peroxides (Section II) and the synthetic use of these peroxides in organic chemistry (Section III). In Section II, general methods for the synthesis of organic hydroperoxides and dialkyl peroxides are discussed, as well as the preparation of enantiomerically pure chiral hydroperoxides. The latter have attracted considerable interest for asymmetric oxidation reactions during the last years. 

In the case of diastereomeric mixtures of chiral hydroperoxides, standard chromatography on achiral phase can be employed to separate the diastereomers. As one example for the preparation of optically pure hydroperoxides via this method, the ex-chiral pool synthesis of the pinane hydroperoxides 11 is presented by Hamann and coworkers . From (15 )-cw-pinane [(15 )-cw-10], two optically active pinane-2-hydroperoxides cA-lla and trans-llb were obtained by autoxidation according to Scheme 17. Autoxidation of (IR)-c -pinane [(17 )-cw-10] led to the formation of the two enantiomers ent-lla and ent-llh. The ratio of cis to trans products was 4/1. The diastereomers could be separated by flash chromatography to give optically pure compounds. 

Hoft reported about the kinetic resolution of THPO (16b) by acylation catalyzed by different lipases (equation 12) °. Using lipases from Pseudomonas fluorescens, only low ee values were obtained even at high conversions of the hydroperoxide (best result after 96 hours with lipase PS conversion of 83% and ee of 37%). Better results were achieved by the same authors using pancreatin as a catalyst. With this lipase an ee of 96% could be obtained but only at high conversions (85%), so that the enantiomerically enriched (5 )-16b was isolated in poor yields (<20%). Unfortunately, this procedure was limited to secondary hydroperoxides. With tertiary 1-methyl-1-phenylpropyl hydroperoxide (17a) or 1-cyclohexyl-1-phenylethyl hydroperoxide (17b) no reaction was observed. The kinetic resolution of racemic hydroperoxides can also be achieved by chloroperoxidase (CPO) or Coprinus peroxidase (CiP) catalyzed enantioselective sulfoxidation of prochiral sulfides 22 with a racemic mixmre of chiral hydroperoxides. In 1992, Wong and coworkers and later Hoft and coworkers in 1995 ° investigated the CPO-catalyzed sulfoxidation with several chiral racemic hydroperoxides while the CiP-catalyzed kinetic resolution of phenylethyl hydroperoxide 16a was reported by Adam and coworkers (equation 13). The results are summarized in Table 4. 

With substrates 16b and 17a, Hoft and coworkers observed only low ee values of up to 4% for the hydroperoxides. On the other hand, phenyl ethyl hydroperoxide (16a) could be isolated in high enantiomeric excess of >99% from the CPO-catalyzed reaction. The observed enantioselectivities of the sulfoxides varied, depending on the conversion of the sulfide and the hydroperoxide used, being highest with 16a (92% ee). Unfortunately, the CPO-catalyzed resolution of chiral hydroperoxides is difficult on a preparative scale because of the high dilution necessary (0.5ttmolmL ). In the CiP-catalyzed kinetic resolution of 16a better results were obtained compared to the CPO-catalyzed reaction (see Table 5). 

The application of CPO, HRP and CiP is limited to sterically unencumbered substrates and all these peroxidases produce the same absolute configuration of the chiral hydroperoxide. To overcome this limitation, the semisynthetic enzyme selenosubtilisin, a mimic for glutathione peroxidase, with the peptide framework of the serine protease subtilisin was developed by Bell and Hilvert. This semisynthetic peroxidase catalyzes the reduction of hydrogen peroxide and hydroperoxides in the presence of 5-mercapto-2-nitrobenzoic acid. It was utilized by Adam and coworkers and Schreier and coworkers for the kinetic resolution of racemic hydroperoxides (equation 17) . The results obtained were very promising. 

SCHEME 41. Epoxidation of quinones using chiral hydroperoxides 63, 93 and 94... 

Next to the base-catalyzed asymmetric epoxidations of electron-deficient olefins with chiral hydroperoxides described above, a few examples of uncatalyzed epoxidations with... 

SCHEME 62. Titanium-catalyzed enantioselective epoxidation with different chiral hydroperoxides... 

SCHEME 64. Titanium-catalyzed asymmetric epoxidation of aUyhc alcohols with secondary chiral hydroperoxides in the presence of diol additives... 

Table 17) with two substituents in position C3 the oxygen transfer by the chiral hydroperoxides occurred from the same enantioface of the double bond, while epoxidation of the (ii)-phenyl-substituted substrates 142c,g,i resulted in the formation of the opposite epoxide enantiomer in excess. In 2000 Hamann and coworkers reported a new saturated protected carbohydrate hydroperoxide 69b , which showed high asymmetric induction in the vanadium-catalyzed epoxidation reaction of 3-methyl-2-buten-l-ol. The ee of 90% obtained was a milestone in the field of stereoselective oxygen transfer with optically active hydroperoxides. Unfortunately, the tertiary allylic alcohol 2-methyl-3-buten-2-ol was epoxidized with low enantioselectivity (ee 18%) with the same catalytic system . 

SCHEME 65. Vanadium-catalyzed asymmetric epoxidation of allylic alcohols with chiral hydroperoxides... 

TABLE 19. Comparison of published results for the asymmetric epoxidation of aUyhc alcohols employing chiral hydroperoxides, (yields are given ee and abs. configuration of the epoxides obtained are given in parentheses)... 

SCHEME 101. Uncatalyzed asymmetric sulfoxidation with chiral hydroperoxides as oxidants... 

R = 5a-cholestan-3j6-yl, chiral hydroperoxide was used as an inseparable 1 1 mixture of diastereomers. - (L)-DIPT as chiral ligand. 

The use of a chiral hydroperoxide as oxidant in the asymmetric Baeyer-ViUiger reaction was also described by Aoki and Seebach, who tested the asymmetric indnction of their TADOOH hydroperoxide in this kind of reaction . Besides epoxidation and snlfoxidation, for which they found high enantioselectivities with TADOOH (60), this oxidant is also able to induce high asymmetry in Baeyer-ViUiger oxidations of racemic cyclobntanone derivatives in the presence of DBU as a base and LiCl as additive (Scheme 174). The yields and ee values (in parentheses) of ketones and lactones are given in Scheme 174 as... 

TABLE 32. Results of the aluminum-catalyzed asymmetric Baeyer-VilUger oxidation using chiral BINOL ligand and achiral and chiral hydroperoxides... 

Chiral endoperoxides, synthesis, 260, 261 Chiral hydroperoxides aUyhc alcohol asymmetric epoxidation, 401-6, 407-9... 

NMR spectroscopy, 694-5 vibrational spectra, 692 X-ray diffraction, 695-6 synthesis, 309-51 tertiary, 690-1 theoretical aspects, 67-84 thymine ozonolysis, 616 see also Chiral hydroperoxides DNA... 

Chiral hydroperoxide Ti(OiPr)4 Toluene 80 trans 50 Ph 2006EJ0713... 

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