Amino acid fluorenylmethyl ester

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 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). 

The protected O-glycosyl amino acid ester or O-glycosyl peptide ester (1 mmol) is stirred in morpholine (10 mL) or morpholine-dichloromethane (1 1) for 30 min. After addition of dichloromethane (100 mL), the solution is washed with diluted aqueous acid (citric acid or HC1 pH 4, 50 mL) and with water (4 x 50 mL), dried with NajSO, and concentrated in vacuo. The crude product is dissolved in 2-5 mL of ethyl acetate. During chromatography on silica gel (50 g) with petrolum ether ethyl-acetate (2 1), W-(9-fluorenylmethyl)morpho-line is eluted. Subsequently, the deblocked amino acid or peptide ester is eluted with methanol. 0-(2,3,4-Tri-0-benzoyl-(3-D- xylopyranosyl)-L-serine benzyl ester 14 yield, 0.63 g (98%) mp 55°C [a]D —41.4 (c 0.5, CH3OH). IV-(L-Asparaginyl-L-leucyl-)-0-(2,3,4,-0-benzoyl-(3-D-xylopyranosyl)-L-serine benzyl ester 17 yield, 0.85 g (98%) amorphous [a]D —42.3° (c 0.5 CH3OH). 

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 traditional method for generation of protected peptide fragments in concert with the Boc-benzyl strategy is saponification or transesterification to cleave the PAM anchor. However, such methods are used less often today because of certain incompatibilities, as well as the development of more efficient techniques [95]. Allyl, o-nitrobenzyl, phenacyl (also cleaved by photolysis) [109,110], and fluorenylmethyl (cleaved by secondary amines) [111-113] handles all offer orthogonal mechanisms of release. The Kaiser oxime-resin is also popular for the production of protected segments it is cleaved via aminolysis with an amino acid ester or transesterification with hydroxypiperidine (reduction of this ester provides the free carboxyl) [97,114]. 

Moving ahead with this analysis, the retrosynthetic sword next cut the D-ring diketopiperazine ring of 6 (see Scheme 1) at the indicated amide linkage to reveal 7 as a protected amino acid precursor. Although the selection of a methyl ester and a 9-fluorenylmethyl carbamate (Fmoc) group to protect these new functionalities... 

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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