Epimerization 3 -hydroxyl

By contrast, if attempts are made to insert Ni(II) into 4.26 while this latter is exposed to air in a nucleophilic solvent such as methanol or water, a different reaction occurs. For instance, when the homoporphyrin derivative 4.26 was treated with Ni(OAc)2 in water in the presence of O2, a mixture of two compounds was produced. On the basis of H NMR spectra and an X-ray structural analysis (on 4.29b), these compounds were determined to be the epimeric hydroxyl-substituted compounds 4.29a and 4.29b (Scheme 4.1.12). Running the reaction in methanol under otherwise identical conditions gave rise to the analogous methoxy-substituted compounds 4.30a and 4.30b. 

The latter results from an unusual intramolecular Cannizzaro-tjrpe reaction involving a transannular hydride transfer from C-20 to C-7. Oxidation of LXXVI followed by reduction gave the epimeric hydroxyl lactam LXXVII with the hydroxyl (p ax 1682 cm i) in the original configuration of ajaconine. The hydroxyl in LXXVI is thus trans to the i r-bridge and in LXXVII is cis thereto. Further evidence on this point is provided by the behavior of the methiodide (LXXVIII) of the azo-methine alcohol (LXVII). The product liberated from this salt by hot, methanolic alkali is a hydroxyl-free base (LXXIX, 10) and hence... 

A classic diagnostic use of such stereochemical requirements, due to Ruzicka, is the ring contraction induced in natural products containing the 4,4-dimethyl-5a-3 -ol system (94). The epimeric, axial 3a-alcohols (95) dehydrate without ring contraction. Barton suggested that it is necessary for the four reacting centers (hydroxyl, C-3, C-4, C-5) to be coplanar for ring contraction to occur, and this is only the case with the 3)5-alcohol. 

Treatment of an epimeric mixture of l-hydroxy-8-methylene-4-phenyl-perhydropyrido[2,l-c][l,4]oxazines with 4% aqueous solution of OSO4 in aqueous THE in the presence of NaI04 at room temperature gave an epimeric mixture of l-hydroxyl-8-oxo derivatives (OOJOC4435, 01EJOC2385). 

The facile and selective oxidation of both primary and secondary hydroxy groups with certain nucleotides led Pfitzner and Moffatt (48) to explore the scope of the carbodiimide-methyl sulfoxide reagent with steroid and alkaloid alcohols. Relatively minor differences were apparent in the rate of oxidation of epimeric pairs of 3- and 17- hydroxy steroids whereas the equatorial lLx-hydroxyl group in several steroids was readily oxidized under conditions where the axial epimer was unreactive [cf. chromic oxide oxidation (51)]. 

The aldehyde function at C-85 in 25 is unmasked by oxidative hydrolysis of the thioacetal group (I2, NaHCOs) (98 % yield), and the resulting aldehyde 26 is coupled to Z-iodoolefin 10 by a NiCh/CrCH-mediated process to afford a ca. 3 2 mixture of diaste-reoisomeric allylic alcohols 27, epimeric at C-85 (90 % yield). The low stereoselectivity of this coupling reaction is, of course, inconsequential, since the next operation involves oxidation [pyridinium dichromate (PDC)] to the corresponding enone and. olefination with methylene triphenylphosphorane to furnish the desired diene system (70-75% overall yield from dithioacetal 9). Deprotection of the C-77 primary hydroxyl group by mild acid hydrolysis (PPTS, MeOH-ClHhCh), followed by Swem oxidation, then leads to the C77-C115 aldehyde 28 in excellent overall yield. 

The 1H NMR spectra of the epimeric cyclohexanols in DMSO reveal that the hydroxyl proton in the axial alcohol shows a resonance absorption at a higher field than in the equatorial one, indicating that the conformational effect of the hydrogen bond influences the XH NMR chemical shifts128. 

This dry ozonation procedure is a general method for hydrox-ylation of tertiary carbon atoms in saturated compounds (Table 1). The substitution reaction occurs with predominant retention of configuration. Thus cis-decalin gives the cis-l-decalol, whereas cis- and frans-l,4-dimethylcyclohexane afford cis- and trans-1,4-dimethylcyclohexanol, respectively. The amount of epimeric alcohol formed in these ozonation reactions is usually less than 1%. The tertiary alcohols may be further oxidized to diols by repeating the ozonation however, the yields in these reactions are poorer. For instance, 1-adamantanol is oxidized to 1,3-adamantane-diol in 43% yield. Secondary alcohols are converted to the corresponding ketone. This method has been employed for the hydroxylation of tertiary positions in saturated acetates and bromides. 

To obtain this compound the key step consisted in the epimerization of the C-5 in compound 6. This was acomplished by triflation of the alcohol 6 and nucleophilic substitution of the triflate by a large excess of tetrabutylammonium acetate in dichloromethane. A controlled (4 °C, 3 h) basic methanolysis of the enol benzoate led to the keto-ester 11" whose hydroxyl functions at C-4 and C-6 were simultaneously deprotected under acidic conditions to furnish 12. Finally a Zemplen deprotection of the 5-acetoxy group led to 13 obtained in five steps and 11% overall yield from 6 (figure 4). 

As for the synthesis of 5-e/j/-KDG, compound 6 seemed to be a suitable precursor of the methyl ester of 5-deoxy-KDG 20 since only the C-5 hydroxyl was unprotected. In this case the key step was not the epimerization but the removal of that hydroxyl. Our attempts of radicalar deoxygenation of 6 were unsuccessful because the intermediate radical was intramolecularly trappy by the C-2.C-3 double bound. Therefore we first reduced the double bond and then converted the resulting diastereoisomeric alcohols 14 into the corresponding triflates 15 which were submitted to the action of sodium iodide. Finally the iodides 16 Aus obtained were hydrogenolyzed in the presence of diisopropylethylamin to give 17. 

The synthesis of aldehydes and ketoamides was performed on solid phase as well as in solution (Scheme 2.2). A semicarbazone linker (6) was employed for the assembly of the aldehydes on solid phase whereas the corresponding aminoalcohol was coupled in solution to the tripeptide and oxidized to the aldehyde, which produced epimeric mixtures [137]. For the synthesis of the ketoamides, hydroxyester THP resins were used as solid support ((7), Scheme 2.2) [138]. In solution the peptide bond was formed using an aminohydroxycarboxylic acid building block [138, 147]. Oxidation of the free hydroxyl group yielded the final inhibitors ((8), Scheme 2.2). 

With AT. trichosporium 0B3b, epimerization with exo, exo, exo, exo-2,3,5,6-d4-norbornane upon hydroxylation occurs (83), which parallels results for cytochrome P-450 hydroxylation with this substrate (91). The extent of epimerization with MMO, however, was significantly lower, being 2% following hydrogen atom abstraction from the endo position compared to 18% with cytochrome P-450, and 5% after abstraction at the exo position as compared to 14% with cytochrome P-450... 

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