Functional Group Protection

Biocatalysts usually require mild reaction conditions for an optimal activity (physiologic temperature and pH) and, in general, they show high activity, chemo- and enantioselectivity. Furthermore, when using enzymes, many functional group protections and/or activations can be avoided, allowing shorter synthetic transformations. The use of enzymes is therefore very attractive from an environmental and economic point of view. 

Enzymes are the catalyst per excellence for reactions in water, which is their natural habitat. Moreover, the use of enzymes often circumvents the need for functional group protection and deprotection steps. For example, enzymatic hydrolysis of penicillin G to 6-APA (Fig. 2.30) proceeds in one step at ambient temperature while chemical deacylation requires three steps, a temperature of - 40 C and various stoichiometric reagents, leading to a high E factor. 

The next series of four preparations describe the synthesis and/or use of recently introduced reagents for functional group protection. The first in this series describes the preparation of 2-TRIMETHYLSILYLETHANE-SULFONYL CHLORIDE (SEC-C1), an effective reagent for protection of primary and secondary amines as the corresponding sulfonamide. The SES-protected amines are stable intermediates which can be readily purified treatment with CsF in DMF or TBAF in acetonitrile liberates the parent amine. The preparation of (l/S,2,S)-METHYL-30,40-(l, 2 -DIMETHOX YCYCLOHEXANE -l, 2 - DIYL) - a -d -M ANNOPYRANO-... 

Therefore, the chiral cyanohydrins are valuable and versatile synthons as their single hydroxyl asymmetric centre is accompanied by at least one other chemical functionality. Thus with careful functional group protection, differential and selective chemical transformations can be performed. Such synthetic techniques lead to production of interesting bioactive compounds and natural products. These products include intermediates of j3-blockers 15 1117], j3-hydroxy-a-amino acids 16 [118],chiral crown ethers 17 [lll],coriolic acid 18 [120], sphingosines 19 [121], and bronchodilators such as salbutamol 20 [122] (Fig. 3). 

To illustrate the purpose and practice of functional group protection, let us suppose that the synthesis of c/.v-2-octene, which we outlined in Section 13-7, has to be adapted for the synthesis of 5-octyn-l-ol. We could write the following ... 

The formation of a dipeptide, for example, thus involves the condensation of the carboxyl group of one amino acid with the amino group of another. To achieve this apparently simple synthetic objective efficiently however, a number of reaction steps, requiring the use of appropriate functional group protection procedures (see p. 13), must be carried out. An illustrative synthesis is that of l-prolylglycine described in Expt 5.188, where the sequence is formulated in full. Note that proline is actually a secondary rather than a primary a-amino acid,... 

Functional group protection. The NH— group in proline is protected by acylation in the usual Schotten-Baumann manner with benzyl chloroformate to yield the benzyloxycarbonyl derivative (42). Correspondingly the —C02H group in glycine is protected by esterification in ethanol to form the ethyl ester, obtained as the hydrochloride (43) under Fischer-Speier conditions. 

Guibe and co-workers took advantage of this high reactivity to use N,N -dimethylbarbituric acid 231 (Scheme 47) as an efficient nucleophilic reagent in the deprotection of functional groups protected with allyl radicals. The recovery of benzylamine from its diallyl derivative 232 is one example (93JOC6109). 

Protecting group in the liquid phase Functional group protected Linkers or linker families... 

Among the factors affecting the course of the RCM reaction, those depending on substituent configuration and/or functional group protection are among the most difficult to anticipate. Several cases illustrate the important influence on the course of the reaction of apparently insignificant structural modifications to the precursor backbone. 

Shilov-type chemistry has been extended to complex organic synthesis by Sames, who finds that amino acids such as valine can be functionalized at their terminal H3 groups by conversion to -CH2OH (equation 4). The preferred catalyst is the usual Pt(II) but the oxidant is not Pt(TV) but the much more convenient Cu(II). An aqueous medium is used and functional group protection is not needed, but 130° is required for catalytic turnover. 

Polyacrylates and polymethacrylates can be end-capped by a functional group at one chain-end according to two strategies, by which either the initiator bears the envisioned functional group (protected or not), or living polymer chains are reacted with a duly substituted electrophile. 

This method can be applied to the synthesis of tripeptides and even larger polypeptides. After the protected dipeptide is prepared in Step [3], only one of the protecting groups is removed, and this dipeptide is coupled to a third amino acid with one of its functional groups protected, as illustrated in the following equations. 

Methods in Organic Synthesis—33,000 reactions, Protecting Groups—functional group protection with region/stereoselectiv-ity... 

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