Synthesis A Ring
Ring A synthesis (scheme 4) started with reduction of the C9 ketone group in 28 to diol 29 with alane in toluene followed by diol protection in 30 as a dimethyl carbonate. This allowed selective oxidation of the C1 alcohol with DDQ after deprotection to ketone 31. This compound was alkylated to 32 at the C1 ketone group with the Grignard homoallyl magnesium bromide (C4 fragment completing the carbon framework) and deprotected at C11 (TBAF) to diol 33. By reaction with cyclohexylmethylsilyldichloride both alcohol groups participated in a cyclic silyl ether (34) which was again cleaved by reaction with methyl lithium exposing the C11 alcohol in 35. The A ring closure required two ketone groups for a pinacol coupling which were realized by oxidation of the C11 alcohol (TPAP, NMO) to ketone 36 and Wacker oxidation of the allyl group to diketone 37. After formation of the pinacol product 38 the benzyl groups (sodium, ammonia) and the trialkylsilyl groups (TBAF) were removed to form pentaol 39.
| Scheme 4 |
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The pentaol 39 was protected twice: two bottom hydroxyl groups as a carbonate ester (bis(trichloromethyl)carbonate, pyridine) and the C10 hydroxyl group as the acetate forming 40. The acetonide group was removed (HCl, THF), the C7 hydroxyl group protected as a TES silyl ether and the C11 OH group oxidized (TPAP, NMO) to ketone 41. The ring A diol group was next removed in a combined elimination reaction and Barton deoxygenation with 1,1'-thiocarbonyldiimidazole forming alkene 42. Finally the C15 hydroxyl group was introduced by oxidation at the allyl position with in two steps PPC and sodium acetate (to the enone) and with K-selectride to alcohol 43 which was protected as a TES ether in 44.
| Scheme 5 |
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Read more about this topic: Mukaiyama Taxol Total Synthesis
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