Fluorenylmethyl Esters

Protection of phosphates as 2-(trimethylsiIyl)ethyl esters was first developed by the Masamune group as part of their efforts to synthesise Calyculin A with its highly hindered phosphate monoester. A dially phosphate was evaluated in a model compound, but it was rejected because of incomplete deprotection under Pd(0)-catalysis. The corresponding bis-[2-(trimethylsilyI)cthyl] ester 37 1. on the 

Tetrabutylammonium fluoride is very effective for the cleavage of 2-(trimethyl-silyl)ethyl phosphate monoesters. A salient example comes from a synthesis of a partial structure of Agrocin 84 with its very sensitive glucofuranosyl phos- 

TBAF buffered with acetic acid. The buffering was necessary to prevent acyl migration. 

4 2-(Methylsulfonyl)ethyl Esters and Related Base-Labile Groups 

The 2-(methylsuIfonyl)ethyl group - together with its rm-butyl-, phenyl- and benzyl-substituted relatives, comprise a small group of phosphate protecting groups that cleave with mild bases such as triethylamine. The van Boom 

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Fluorenylmethyl esters of A -protected amino acids were prepared using the DCC/ DMAP method (50-89% yield) or by imidazole-catalyzed transesterification of... 

The other stereoselective synthesis/281 shown in Scheme 8, foresees conversion of Boc-L-Asp-OtBu 20 into the related (3-aldehyde 22 via the Weinreb amide 21 and its reduction with diisobutylaluminum hydride (DIBAL-H). Wittig condensation of 22 with the ylide derived from (3-carboxypropyl)triphenylphosphonium bromide using lithium hexamethyldisilaza-nide at —78 to 0°C, produces the unsaturated compound 23 which is catalytically hydrogenated to the protected L-a-aminosuberic acid derivative 24. Conversion of the co-carboxy group into the 9-fluorenylmethyl ester, followed by TFA treatment and reprotection of the M -amino group affords Boc-L-Asu(OFm)-OH (25). 

Scheme 8 Enantioselective Synthesis of IWert-Butyloxycarbonyl-L-a-aminosuberic Add (o-9-Fluorenylmethyl Ester[281...

Route A utilizes Boc/Bzl chemistry for the synthesis of the main peptide with Fmoc/OFm at the side-chain functions where additional chemistry is performed. For synthesis of extended cyclic peptides, the /V "-Fmoc group is removed and the extension is synthesized with Fmoc/ Bzl chemistry, whereas for reverse-extended cyclic peptides, the to-Fm ester is hydrolyzed and the peptide spacer is built up in the N-to-C direction with fluorenylmethyl esters with all the risk of epimerization or more correctly, it is incorporated by fragment condensation. 

Table 7 w-Fluorenylmethyl Esters of Aspartic and Glutamic Acid Derivatives... 

The PS-benzyloxycarbonyl resin (Fig. 16.2) shows at 1774 cm-1 the typical carbonyl absorption which disappears by loading the resin with amino acid fluorenylmethyl esters. This can be detected by a new carbonyl absorption at 1726 cm-1 and the characteristic C—C absorption band of the fluorene at 740 cm - which disappears by treating the resin with piperidine. The successful reaction to the Pfp-ester can be detected by the additional carbonyl absorption band at 1794 cm -1. The following reduction step to the amino alcohol is proofed by the disappearance of this band. The oxidation to the aldehyde and the formation of the imine is shown by the characteristic absorptions of new functional groups. [v(C—H, aldehyde = 2720 cm-1), imine (v(C=N) = 1670 cm-1].The successful Pictet-Spengler cyclization is proofed by the disappearance of the imine band. 

Fluorenylmethyl esters. The title reagent converts (V-protected amino acids to 9-fluorenylmethyl esters at 0° in the presence of (-Pr2NEt (1 equiv) and DMAP (10 mol%). 

The 9-fluorenylmethyl group, in the guise of the 9-fluorenylmethoxycarbonyl or Fmoc group, is the keystone in modern solid-phase peptide synthesis and we will examine its enormous influence in section 8.3.5. The great virtues of the 9-fluorenylmethyl group have also been adapted to the protection of carboxylic acids as 9-fluorenylmethyl esters (see section 6.5.3). Bodanszky and Bednarek realised the opportunity for extending the principle of 9-fluorenylmethyl activation, the aromaticity of the fluorenyl anion, to the protection of cysteine in peptide synthesis. 9-Fluorenylmethyl thioethers are stable towards iodine and acidic conditions, including HF, but they easily eliminate on treatment with piperidine or DBU. 

Fluorenylmethyl esters have been used for C-terminus protection in combination with P OC A-terminus protection for solution-phase coupling of protected amino acids and peptide fragments. This permits simultaneous deprotection of both termini with EtaNH/DMF (eq 7). ... 

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