Functional side chains

In the preparation of the thiazides containing more highly functionalized side chains (183-185), an acetal of the aldehyde is usually used rather than the free carbonyl compound. Thus, trichlomethiazide (183) is prepared by reaction of 160 with the dimethyl acetal from dichloroacetaldehyde. In a similar vein, alkylation of the acetalthiol, 190, with allyl bromide affords 191. This yields altizide (184) on condensation with 160. Alkylation of 190 with 2,2,2-trifluoroethyl iodide gives 192. This leads to epithiazide (185) on condensation with 160. 

Seebach, D., Sifferlen, T., Mathieu, P. A., Hane, A. M., Krell, C. M., Bierbaum, D. J., and Abele, S. (2000). CD spectra in methanol of /3-oligopeptides consisting of /3-amino acids with functionalized side chains, with alternating configuration, and with geminal backbone substituents. Fingerprints of new secondary structures Helv. Chim. Acta 83, 2849-2864. 

A series of fluorene copolymers with amino-functionalized side chains 373 and 374 has been prepared by the same group (Chart 2.92). Upon quaternization, they gave copolymers 375 and 376, which were soluble in polar solvents (methanol, DMF, DMSO) [439]. Devices from the... 

First, the above-mentioned sensors have major drawbacks, as the detection and recognition event is a function of the nature and characteristics of the side chains, and the side chain functionalization of the CP requires advanced synthesis and extensive purification of numerous monomeric and polymeric derivatives. Second, this generation of sensors primarily employed optical absorption as the source for detection, resulting in lower sensitivity when compared with other sensing systems for biological processes. However, the use of fluorescence detection within these sensing systems could justify continued development. More recent examples include a fluorescent polythiophene derivative with carbohydrate functionalized side chains for the detection of different bacteria [15] and novel synthesis schemes for ligand-functionalization of polythiophenes [16]. 

These results can be rationalized as follows. Cyclic imide formation is maximal with a Gly residue because of its minimal steric interference. In contrast, steric bulk (i.e., size and branching) of the C-flanking residue is the major factor decreasing the reactivity of Asn to form a succinimide. Residues with a functionalized side chain, namely serine, threonine, and histidine, behaved as exceptions to this rule (see above). 

A first and apparently straightforward strategy to improve pharmacokinetic behavior of bioactive peptides is to derivatize the N-terminus, the C-terminus, and/or one or more functionalized side chains. Different biological consequences are conceivable depending on the stability and intrinsic activity of the derivative. 

Pitt CG, Gu Z-H, Ingram P, Hendren RW (1987) The synthesis of biodegradable polymers with functional side chains. J Polym Sci A Polym Chem 25 955-966... 

APPLICATIONS OF NONCOVALENTLY FUNCTIONALIZED SIDE CHAIN COPOLYMERS... 

Having discussed self-assembly strategies toward noncovalently functionalized side chain supramolecular polymers as well as studies toward the orthogonahty of using multiple noncovalent interactions in the same system, this section presents some of the potential applications of these systems as reported in the literature. The apphcations based on these systems can be broadly classified into two areas 1) self-assembled functional materials and 2) functionalized reversible network formation. 

Pitavastatin (3) was launched in 2003 and is currently marketed in Japan under the trade name Livalo . Like rosuvastatin and fluvastatin, pitavastatin is a completely synthetic HMG-CoA reductase inhibitor that was developed by Kowa, Nissan Chemical, and Sankyo (Sorbera et al., 1998). Multiple syntheses of pitavastatin have been reported and an exhaustive review of these efforts is beyond the scope of this text (Hiyama et al., 1995a, b Minami and Hiyama, 1992 Miyachi et al., 1993 Takahashi et al., 1993, 1995 Takano et al., 1993). Instead, we will focus our discussion on two related and innovative synthetic approaches that differ strategically from the routes we have previously examined for rosuvastatin and fluvastatin. These routes to pitavastatin employed palladium-mediated coupling reactions to install the 3,5-dihydroxyheptanoic acid side-chain. This key retrosynthetic disconnection is highlighted in Scheme 12.6, in which a suitable functionalized side-chain (52 or 53) is attached to the heterocyclic core of pitavastatin (51) through palladium-mediated coupling. 

Burnett et al., 1994) allowed efficient preparation of gram quantities of advanced intermediates (Scheme 13.1). Functionalized side-chain intermediates such as 4 and 5 were envisioned and proved synthetically useful for the late introduction of the 3 -hydroxyl and pendent aryl moieties. 

The amino acids used for the covalent coupling are types with functional side chains e.g. Cys, Lys, Tyr and Asp, comprising thiol, amino, phenohc and caiboxylic groups. The reactivity of these residues will be determined by the chosen coupling chemistry and its conditions, where Lys and the N-terminal amino group are the most frequently used amino acids for covalent attachment. 

The fact that benzene derivatives are much more generally accessible than pyrroles has relegated pyrrole annelation to a relatively minor role in indole synthesis. Nevertheless the concept provides a viable synthetic approach and the existing methods serve as useful prototypes. One strategy is to build up an appropriately functionalized side-chain and complete indole formation by electrophilic substitution-aromatization. Reactions (135)-(137) illustrate this type of approach (79TL3477, 79JA257, 73JPR295). 

L-Aze with functionalized side chains have been synthesized as rigidified congeners of glutamic acid[109 and a stereoselective synthesis of related 3-alkyl derivatives has been reported. 110 ... 

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