Synthesis side chains

Fig. 6.1.1 Scheme for the stepwise soiid-phase peptide synthesis side-chain protecting group ... 

The final chapter by Dr Coles concerns a topic at the very forefront of active development. In the few years since their initial synthesis, side-chain liquid crystal polymers have excited interest firstly because of their response to electric and magnetic fields and thence to potential applications in areas such as information storage, which is discussed here. What has been opened up, however, is a powerful means of tailoring properties to applications by synthesis of suitable molecules. This has long been an aim of materials science and this field will surely be the source of future developments. 

The early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

In each step of the usual C-to-N peptide synthesis the N-protecting group of the newly coupled amino acid must be selectively removed under conditions that leave all side-chain pro-teaing groups of the peptide intact. The most common protecting groups of side-chains (p. 229) are all stable towards 50% trifluoroacetic acid in dichloromethane, and this reagent is most commonly used for N -deprotection. Only /ert-butyl esters and carbamates ( = Boc) are solvolyzed in this mixture. 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

Chapters 9, 10 and 11 describe methods for substitution directly on the ring with successive attention to Nl, C2 and C3. Chapters 12 and 13 are devoted to substituent modification as C3. Chapter 12 is a general discussion of these methods, while Chapter 13 covers the important special cases of the synthesis of 2-aminoethyl (tryptaminc) and 2-aminopropanoic acid (tryptophan) side-chains. Chapter 14 deals with methods for effecting carbo cyclic substitution. Chapter 15 describes synthetically important oxidation and reduction reactions which are characteristic of indoles. Chapter 16 illustrates methods for elaboration of indoles via cycloaddition reactions. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

A variation on the tryptamine synthesis is to use diethyl (3-chloropropyl)-malonate as the substrate for a one-pot Japp-Klingemann/Fischer procedure. The chloropropyl group alkylates the ct-nitrogen, forming the tryptamine side-chain. The precise stage at which the alkylation occurs is unclear[4]. 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

Oxidation of carbon side-chains has resulted in the synthesis of dithiazolyl ketone (82) and thiazolyl phenyl ketone (83). The hydrocarbon chain can also be dehydrogenated in acetic acid in the presence of... 

You will recognize the side chain oxidation of p xylene to terephthahc acid as a reaction type discussed previously (Section 11 13) Examples of other reactions encoun tered earlier that can be applied to the synthesis of carboxylic acids are collected m Table 19 4... 

The most widely used method for the laboratory synthesis of a ammo acids is a modification of the malonic ester synthesis (Section 21 7) The key reagent is diethyl acetamidomalonate a derivative of malonic ester that already has the critical nitrogen substituent m place at the a carbon atom The side chain is introduced by alkylating diethyl acetamidomalonate m the same way as diethyl malonate itself is alkylated... 

Several of the ammo acids listed m Table 27 1 bear side chain functional groups which must also be protected during peptide synthesis In most cases protecting groups are available that can be removed by hydrogenolysis... 

The standard synthesis method features side-chain chlorination of a methylpyridine (picoline), followed by exchange-fluoriaation with hydrogen fluoride or antimony fluorides (432,433). The fluoriaation of pyridinecarboxyHc acids by sulfur tetrafluoride (434) or molybdenum hexafluoride (435) is of limited value for high volume production operations due to high cost of fluorinating agent. 

Chloroacetoacetic esters are important industrial intermediates used especially for the synthesis of the aniinothia2olylacetic acid side chain of modem cephalosporins (see Antibiotics, P-LACTAMS-cephalosporins). For a review of the chemistry of 4-chloroacetoacetates see Reference 112. 

Use of D-amino acids in the synthesis of a hairpin loop portion from the CD4 receptor provides a stable CD4 receptor mimic, which blocks experimental allergic encephalomyelitis (144). This synthetic constmct is not simply the mirror image or enantiomer of the CD4 hairpin loop, but rather an aH-D-constmct in the reverse sequence, thus providing stereochemicaHy similar side-chain projections of the now inverted backbone (Fig. 11). This peptide mimetic, unlike its aH-L amino acid counterpart, is resistant to en2yme degradation. As one would expect, the aH-D amino acid CD4 hairpin loop, synthesi2ed in the natural direction, the enantiomer of the natural constmct, is inactive. 

The synthesis of copolymers of olefins with carbon monoxide (eq. 3) or ketones (eq. 4) leads to backbone or side-chain carbonyl functionaUty,... 

Cyclization of Aliphatic Precursors. This strategy consists of assembling the key functional groups in an aUphatic format, cyclizing to a cyclopentane intermediate, and completing the synthesis by further elaboration of the side chains. One appHcation of this strategy is as follows ... 

Pyridine ring syntheses (48) can be classified into essentially two categories ring synthesis from nonheterocyclic compounds, and synthesis from other ring systems. The synthesis of pyridine derivatives by transformations on the pyridine ring atoms and side-chain atoms have been considered in the previous section. 

Hydroxypyrroles. Pyrroles with nitrogen-substituted side chains containing hydroxyl groups are best prepared by the Paal-Knorr cyclization. Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by iasertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole [27472-36-2] (24). The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 

The steric bulk of the three iodine atoms in the 2,4,6-triiodoben2ene system and the amide nature of the 1,3,5-substituents yield rotational isomers of the 5-A/-acyl-substituted 2,4,6-triiodoisophthalamides. Rotational motion in the bonds connecting the side chains and the aromatic ring is restricted. These compounds also exhibit stereoisomerism when chiral carbon atoms are present on side chains. (R,5)-3-Amino-l,2-propanediol is incorporated in the synthesis of iohexol (11) and ioversol (12) and an (3)-2-hydroxypropanoyl group is used in the synthesis of iopamidol (10). Consequendy, the resulting products contain a mixture of stereoisomers, ie, meso-isomers, or an optical isomer. 

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