Hydroxy group activation ester synthesis

Despite the relatively high reactivity of the serine hydroxy group, serine esters and serine-containing peptides with free hydroxy groups have been used as amine components in solution synthesis. Syntheses with free serine hydroxy groups can be performed with azides, without the risk of 0-acylation.b l Mixed anhydrides, active esters, and carbodiimides have also been successfully used for the coupling reactions. Therefore, for this couphng reaction, any over activation has to be avoided. 

LCAT catalyzes the transfer of a preferentially unesterified fatty acid from the sn-2 position of phosphatidylcholine to the 3/i-hydroxy group of cholesterol, and thereby produces lysophosphatidylcholine and a cholesteryl ester [50]. Depending on the mutation in the LCAT gene, homozygous or compound heterozygous patients present with one of two clinical phenotypes, classical LCAT deficiency or fish-eye disease [58, 85]. Classical LCAT deficiency is caused by a broad spectrum of missense and non-sense mutations that interfere with the synthesis or secretion or affect the catalytic activity of LCAT [10]. Fish-eye disease is caused by a limited number of missense point mutations that alter the surface polarity, and thereby interfere with the binding of the enzyme to apoA-I containing lipoproteins [77]). 

Under the conditions used in peptide synthesis, unprotected aliphatic hydroxy groups can undergo two types of side reactions they can be acylated or dehydrated, the latter leading to dehydroamino acids. The hydroxy group of serine is a primary alcoholic function and therefore exhibits the highest reactivity. The secondary alcoholic functions of threonine, hydroxyproline, (3-phenylserine, hydroxynorvaline, and hydroxynorleucine, as well as of other noncoded amino acids, are less reactive and thus more suited for use in the unprotected form. The aromatic hydroxy group of tyrosine is more acidic than the ahphatic hydroxy groups nevertheless, it can be acylated to form esters. These are active esters which in turn can react with primary amines to form amide bonds. 

Initially, researchers focused on the separation of paclitaxel from cephalomannine, a paclitaxel analogue that shares the C-13 ester side-chain and, therefore, exhibits cytotoxic activity. Cephalomannine was found to elute close to paclitaxel and caused interferences for determination and purification purposes. Lately, the main taxane targets are baccatin III and 10-deacetyl-baccatin III (10-DAB III). Both compounds lack the C-13 side-chain (Fig. 1) thus, they do not show antitumour activity. Both baccatins, especially 10-DAB III, serve as synthons for the synthesis of paclitaxel or analogues. 7-Epi-paclitaxel differs from paclitaxel only in the stereochemistry of the hydroxy group in the C-7 position. 7-Epi-paclitaxel, a product of paclitaxel epimerization, shows cytotoxic activity and difficulty in separation from paclitaxel. The deacetyl derivatives of paclitaxel, 7-epi-paclitaxel, baccatin III, and cephalomannine, are also quite often the... 

---