Protective groups illustrative examples

As shown in Scheme 2.12.2, the more dramatic example of cyclopropanations involving fullerenes is illustrated. The reaction proceeded with both benzyl and pivalyl protecting groups illustrating the versatility of this reaction under a variety of electronic conditions. The yields in both cases were approximately 55%. A particularly important aspect of this chemistry centers around the desired ability to functionalize the fullerenes and, especially,... 

Three selective methods to remove protective groups are receiving much attention assisted, electrolytic, and photolytic removal. Four examples illustrate assisted removal of a protective group. A stable allyl group can be converted to a labile vinyl ether group (eq. 4) a /3-haloethoxy (eq. 5) or a /3-silylethoxy (eq. 6) derivative is cleaved by attack at the /3-substituent and a stable o-nitro-phenyl derivative can be reduced to the o-amino compound, which undergoes cleavage by nucleophilic displacement (eq. 7) ° ... 

M (marginal) indicates that the stability of the protected functionality is marginal, and depends on the exact parameters of the reaction. The protective group may be stable, may be cleaved slowly, or may be unstable to the conditions. Relative rates are always important, as illustrated in the following example (in which a monothioacetal is cleaved in the presence of a dithiane), and may have to be determined experimentally. 

The use of biocatalysts for the selective introduction and cleavage of esters is vast and has been extensively reviewed." Therefore only a few examples of the types of transformations that are encountered in this area of protective group chemistry will be illustrated to show some of the basic transformations that have appeared in the literature. The selective... 

In this section, we consider several syntheses of six illustrative compounds. We examine the retrosynthetic plans and discuss crucial bond-forming steps and the means of stereochemical control. In this discussion, we have the benefit of hindsight in being able to look at successfully completed syntheses. This retrospective analysis can serve to illustrate the issues that arise in planning a synthesis and provide examples of solutions that have been developed. The individual syntheses also provide many examples of the synthetic transformations presented in the previous chapters and of the use of protective groups in the synthesis of complex molecules. The syntheses shown... 

Some illustrative examples from the field of polyquinanes are the synthesis of some derivatives of bicyclo[3.3.0]octane 6 (Scheme 6.7) [12] [15] -which have been used in the total syntheses of coriolin, hirsutic acid and quadrone- and the synthesis of triquinacene 7 and some of its derivatives. The retrosynthetic analysis of perhydrotriquinacene-l,4,7-trione (7a) is shown in Scheme 6.7bis. In the actual synthesis the hydroxy groups must be protected either as trialkylsilyl ethers or more conveniently as benzyl ethers [16] [17]. 

To exploit the reactions of the C-lithio derivatives of iV-unsubstituted pyrroles and indoles, protecting groups such as t-butoxycarbonyl, f-butylcarbamoyl, benzenesulfonyl, dimethylamino and dimethylaminomethyl have been used (81JOC157). This is illustrated by the scheme for preparing C-acylated pyrroles (396) (81JOC3760). Another useful process involves the /V-lithiation, carbonation, and C-2 lithiation of indoles, which leads for example to 2-haloindoles in excellent yields (92JOC2495). 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

Alkyl carbamates are generally more stable towards nucleophiles than amides, and are therefore of limited utility as protective groups. Amines lacking other base-sensitive functionalities can, however, be protected as alkyl carbamates. An illustrative example of the use of ethyl carbamate as a protective group is sketched in Figure 10.11 [188]. 

Phthalimide protection is stable towards acids and bases, but can be cleaved with strong nucleophiles, such as hydrazines or sulfides, or by reduction with sodium boro-hydride [230]. More sensitive towards nucleophilic attack than unsubstituted phthalimide is tetrachlorophthalimide [33]. This group has been successfully used as N(a) protection of amino acids in the solid-phase synthesis of peptides (deprotection N2H4/DMF (15 85), 40 °C, 1 h coupling DIC/HOAt/amino acid (1 1 1), 3 equiv. of each, DMF, 25 °C, 4 h [294]). Typical conditions for the removal of phthaloyl protection on cross-linked polystyrene include treatment of the resin with hydrazine hydrate [295,296], with methyl hydrazine [297], or with primary aliphatic amines [298] in DMF, EtOH, or solvent mixtures for several hours at room temperature or above [296,299,300]. Illustrative examples are sketched in Figure 10.15. It has been claimed that the hydrazinolysis of polystyrene-bound phthalimides proceeds more readily in DCM or DCE than in DMF [301]. 

An illustrative example of the introduction of the benzyloxycarbonyl group, and its removal by hydrogenolysis is given in the synthesis of L-prolylglycine (Expt 5.188). An alternative reagent for the removal of this protecting group is iodotrimethylsilane in acetonitrile at room temperature.229... 

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