Remove Labile Groups First

An alternative mechanistic scheme in which TMCS first reacts with alcohols to form hydrogen chloride which then activates the phosphoroamidite in situ seems to be unlikely. It is known that TMCS reacts very slowly with alcohols unless a catalyst is present [36]. Formation of HCl would effect the removal of an acid labile group like DMTr attached to a base or tert-hutyl... 

The exchange of the labile chlorine atoms (which act as initial sites for dehydrochlorination, for less easily removable thiolate groups) is an extremely important stabilizing function, which has also preventive character. This exchange reaction has first been proposed and established by Frye et al. (Scheme 3.3.2). 

Section lO.S.B.i suggested thai labile groups should be disconnected first. Removing the reactive conjugated systems and 3-amino alcohol unit in the first disconnection of (-)-histrionicotoxin illustrated this... 

Where the phenolic product is labile towards acid the trimethylsilyl ether may be used. Riemann circumvented [39] the final difficult dealkylation step [40] in the synthesis of hydroxystilbenes (42) by use of the trimethylsilyl protecting group—first to prepare the ylid (40) and secondly in the condensation step (e.g., 41). Removal of the trimethylsUyl ether grouping was then achieved by refluxing in aqueous methanol. 

Two approaches for solid-phase chemical ligation have been described. Canne et al. have developed an elegant system that utilizes an oxime forming ligation to attach the first peptide to the resin, a selectively cleavable ester link to remove the peptide from the resin as a C-terminal carboxylic acid, and the Acm group to protect the N-terminal cysteine residue)311 A complementary approach has been developed by Brik et al. that utilizes native chemical ligation to attach the first peptide to the solid support, a safety-catch acid labile linker to remove the final polypeptide from the support as a C-terminal amide and either Acm or Msc group for N-terminal cysteine protection)32 ... 

The reactions described so far all yield medium-ring tertiary amines. Reinecke s group have recently extended their methods to synthesize the more useful secondary amines.288 Three syntheses were developed. The first [Eq. (31)] involves reductive cleavage of the benzyl indolizidinium salt 229 with lithium aluminum hydride, followed by replacement of the benzyl group with the labile trichloroethoxycarbonyl group. The latter may be removed under mild conditions with zinc-methanol, which does not cause migration of the double bond. 

The first general protecting group for cysteine was the 5-benzyl group developed by du Vigneaud and co-workers in 193512 and used by them for the synthesis of oxytocin in 1953J3 Since the conditions for its removal are rather harsh in the context of peptide synthesis, it has been eclipsed by various substituted 5-benzyl derivatives that are more labile towards acidolysis. 

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