Novel Bimetallic Model System for Cytochrome P450: Effect of Membrane Environment on the Catalytic Oxidation

✍ Scribed by Dipl.-Chem. Albertus P. H. J. Schenning; Dominicus H. W. Hubert; Dr. Jan H. van Esch; Dr. Martinus C. Feiters; Prof. Dr. Roeland J. M. Nolte

• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 367 KB
• Volume: 33
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/anie.199424681

✦ Synopsis

l a 16 Scheme 4. a) [BuLi. T H E 90 min, -78'C; BzCl, pyridine, 12h, 20-C; 5% Na/Hg. 5h. -20 C. 3 5 % : h) Bu,NE THF, 1 h, 0'C. 85%; c) tiBuLi. CICO,Et, THF, 1 h, ~ 30 C. 8 5 % ; d ) morpholine. THF. 2h, reflux; 60% CH,CO,H, 2h. 5 0 °C 75%; e) TBDPSCI. imidazole. DMF. ?d, -60 C, 9 6 % ; f) Ac,O, pyridine, 4-dimethylaminopyridinc. 30 min. 0 'C, 9 8 % ; g) HC(OMe),. CH,CI,, MeOH. 4d, 20°C. 99%. h) Ti(OiPr),. 2-(trimethylsilyl)ethanol, 3d, 100"C, 90%; i) CsF, DMF, 1 d. 20 'C. 9 8 % . j ) thexyldimethylsilyl chloride (TDMSCI), CH,CI,, triethylamine, 20 min. 20 C: (CH,),C=CBr(NMe,). CH,CI,, triethylamine, 1 h, 20'C. 91 %; k) triethylamine. acetone. H,O. 15 min. RT; Cs,CO,, DMF, 1 d. 20"C, 50%; I) tetrahutylaiimionium fluoride. THF. 411, 0'C. 1 M HCI, T H E 1 d, 20 'C, 9 5 % , m) 2 cquiv of potassiuni-2.6-di-tert-butylphenoxide, DMF. 1 d. 20°C; MeI. DMF. rnoleculiir sieves (4A). 30min, 0'C; HCI. THF, 12h, 20 C. 70%. mate after de~ilylation."~] Subsequent addition of water across the triple bond via an enamine intermediate followed by cleavage of the protecting groups resulted in the tetrahydropyran ring structure of 15. Experiments by G. Hofle et al. on the ringopened soraphen demonstrated that the lactonization is best effected by a substitution reaction of the cesium salt of the carboxylic acid."41 Therefore, benzyl alcohol 15 and the bromo enamine reported by Ghosez et al.['51 were allowed to react under mild conditions and yielded bromide 16 with complete inversion. The macrocyclization of the cesium carboxylate of 16 (20 "C. 60% yield) produced the soraphen ring structure also with inversion at the benzyl group. Since the methyl group in soraphen A,, (1 a), that is in a-position to the lactone occupies the thermodynamically favored configuration,'161 it was introduced in the last step of the synthesis. By using two equivalents of potassium 2,6-ditert-butylphenoxide, the hemiketal ring of norsoraphen 1 b was opened and deprotonated to give the potassium enolate. To avoid overmethylation, the enolate ion was quenched with an excess of methyl iodide within 30 min at 0 "C. Subsequent cyclization to the hemiketal in acidic medium gave soraphen A,, (1 a) in 70% yield.