Chemoselective protection Subject

The Mitsunobu alkylation conditions of 48 also exhibit high chemoselectivity when subjected to reaction with diol 4731 In this example, judicious choice of phosphine and diazo compound dictate which alcohol is activated. Using h-Bu3P in combination with TMAD (TV,N,V, /V -tetramethylazodicarboxamide) gives primarily reaction with the primary alcohol yielding 49. Whereas, Me3P and ADDP (l,l -(azodicarbonyl)-dipiperidide) allow for reaction at the secondary alcohol with another equivalent of 48 giving a fully protected di-amine 50. 

The high chemoselectivity of NCL relies upon the distinct reactivity of an N-terminal cysteine. The requirement for cysteine at the ligation, however, restricts the applicability of NCL. It is possible to subject the ligation product to desulfurization, resulting in the net formation of a more commonly found X-Ala bond [29]. The presence of cysteines other than that needed for ligation is not tolerated, however, since desulfurization would occur at both protected and unprotected cysteine thiols. 

A simple example is the oxidation of an alkene to a carboxylic acid 93 in Evans synthesis of cytovaricin. The alkene had been put in by allylation and the optically active unsaturated alcohol 90 was first protected 91 and then subjected to hydroboration and oxidation. Protection before the second alcohol appeared prevented impossible chemoselectivity problems.14... 

The next phase of the synthesis involved the transposition of aldol adduct 61 to the protected "aldol" adduct 60. (3-Hydroxyketone 61 was subjected to conditions (NaBH4, AcOH) which effected a direct reduction of the carbonyl moiety of 61 and thereby introduced the axial C(9) hydroxyl functionality of 67 with complete stereocontrol through an intramolecular delivery of hydride within an alkoxide intermediate at C(7). After diprotection of both hydroxyl groups of 67, chemoselective deprotection of hydroxyl at C(7) and Swern oxidation, ketone 60 was isolated. The enolate derivative of 60 could be stereoselectively p-methoxybenzylated, and the resulting ketone was reduced to the wrong equatorial alcohol 68. The C(7) stereogenic center was inverted by treatment of the nosylate derivative of 68 with rubidium acetate to afford the desired acetate 69 accompanied by the syn elimination product (15%). 

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