Fmoc, 9-fluorenylmethoxycarbonyl preparation

Amino groups are normally protected as their tm-butoxycarbonyl (Boc), carbobenzoxy-carbonyl (Z), or 9-fluorenylmethoxycarbonyl (Fmoc) derivative prepared as described in section 25.5. The Boc group may be removed by treatment with hy(kogen bromide. Other acidic reagents such as trifluoroacetic acid may also be used. 

Krausz el al. have synthesised two series of amino acid porphyrinylsugar derivatives (Fig. 5). One of them involves the coupling of adequate glycoporphyrin derivatives, prepared by pyrrole/aldehyde condensation methodology, with 9-fluorenylmethoxycarbonyl-L-alanine (Fmoc-L-alanine) to give the tri-, di-, and mono-alanine glycoporphyrin derivatives 54—57 after the deprotection step the other series (58) involves a glucosylamino acid moiety instead of the alanine in their preparation.21,44... 

For a,a-dialkylamino acids enantiomerization is not a problem. The preparation of 4,4-dimethyl-2-[(9-fluorenylmethyl)oxy]-5(4F/)-oxazolone, an intermediate used in the synthesis of ( )-mirabazole C has been described. Recently, two new 2-aIkoxy-5(4F/)-oxazolones derived from Toac (2,2,6,6-tetramethyl-4-amino-l-oxy-piperidine-4-carboxylic acid) that incorporate Z or 9-fluorenylmethoxycarbonyl (Fmoc) protection at C-2 have been described. The Toac analogues were synthesized as part of a study of the crystal structure and ab initio calculations for these interesting systems. 

In the synthesis of analogues of calicheamicin 71 and esperamicin Ajb, Moutel and Prandi employed the glycosyla-tion of a nitrone with a trichloroacetimidate as a key step - /3-N-O glycosidic bond formation. Preparation of the nitrone begins with the alkylation of the known alcohol 69 <1992CC1494> with 1,4-dibromobutane in the presence of sodium hydride. Subsequent aminoalkylation, amine protection with 9-fluorenylmethoxycarbonyl (Fmoc), and reduction with NaBHsCN were followed by nitrone 70 formation with 4-methoxybenzaldehyde (Scheme 8) <2001J(P1)305>. 

For the 9-fluorenylmethoxycarbonyl (Fmoc) protection of amino acids, Chinchilla et al.36,37 prepared a similar ROMP-polymer that supports an activated. V-hydroxysuccinimide Fmoc-carbonate (Table VII, entry 31). Various Fmoc-amino acids are prepared in pure form after removal of the polymer reagent by filtration and aqueous phase separation. 

In this chapter we will summarize chemical methods for the stereoselective attachment of carbohydrates to amino acids, with particular emphasis on the preparation of building blocks for use in solid-phase glycopeptide synthesis based on the 9-fluorenylmethoxycarbonyl (Fmoc) protective group strategy. 

The method has been widely used and extended to the preparation of A-9-fluorenylmethoxycarbonyl (Fmoc)-o -amino aldehydes in good yields [83,92-94]. Fmoc- and Boc-/3-amino aldehydes, which are key intermediates in the synthesis of carba [16,17] and carbaza peptides [33] (see later), are also prepared in good yield from the corresponding hydroxamates [95]. In this case, the Weinreb amide can be obtained in high yield by direct Wolff rearrangement of a diazomethylketone with A,0-dimethylhydroxylamine. 

In the first step, Fmoc (9-fluorenylmethoxycarbonyl)-protected dithiocarbazate resin 43 was prepared by a three-component reaction of Merrifield resin 1 and carbon disulfide with Fmoc-protected hydrazine in the presence of sodium hydride in DMF at room temperature. Deprotection of the Fmoc group of resin 43 with 5% piperidine produced the corresponding free dithiocarbazate resin 42." In this step, the use of 5% piperidine was essential because a higher concentration caused loss of the desired substrate from resin 43. In addition, we have developed a more convenient synthetic route to the resin 42, compared to the previous report using hydrazine monohydrate and carbon disulfide with potassium hydroxide in ethanol solvent. Under these reaction conditions, we obtained the polymer-bound dithiocarbazate 42 without the Fmoc protection step of the hydrazine. 

Table 1 gives some typical examples of the N-9-Fluorenylmethoxycarbonyl (Fmoc) amino acids and their pentafluorophenyl (PFP) esters which have been prepared by these methods. The physical data are in agreement with either preparative method, and with early preparations of these compounds. - ... 

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