Boc-protected amino acids

Step 1 The Boc protected amino acid is anchored to the resin Nucleophilic substitution of the benzylic chloride by the carboxylate anion gives an ester... 

Q A Boc-protected amino acid is covalently linked to the polystyrene polymer by formation of an ester bond (Sn2 reaction). 

A second Boc-protected amino acid is coupled to the first by reaction with DCC. Excess reagents are removed by washing them from the insoluble polymer. 

It has been shown recently that diazoketones 13 can also be alkylated to provide y9 -amino acids in moderate to high diastereoselectivities [102]. The a-methylation of Boc-protected -amino acid methyl esters through the doubly lithiated derivative 17 was chosen by Seebach to gain access to both like and unlike amino acids 18 [103-105] (Scheme 2.2). 

Although these Boc derivatives underwent methylation with poor selectivity (compared to 3-amino-N-benzoyl butanoates [106] and Z-protected methyl 4-phen-yl-3-aminobutanoate [107]), epimers were succesfully separated by preparative HPLC or by flash chromatography. However, saponification of the methyl ester caused partial epimerization of the a-stereocenter and a two-step (epimerization free) procedure involving titanate-mediated transesterification to the corresponding benzyl esters and hydrogenation was used instead to recover the required Boc-y9 -amino acids in enantiomerically pure form [104, 105]. N-Boc-protected amino acids 19 and 20 for incorporation into water-soluble /9-peptides were pre-... 

It should be also noted that, in a very recent publication, Liu and coworkers were successful in applying microwave radiation within their domino approach towards the synthesis of pyrrolo[2,l-fc]quinazoline alkaloids such as deoxyvasicinone, 8-hy-droxydeoxyvasicinone, mackinazolinone and isaindigotone, which exhibit a promising broad spectrum of biological activities. In the case of isaindigotone, the authors were able to extend their strategy to a three-component procedure, which comprises the domino conversion of anthranilic acids and Boc-protected amino acids into the tricyclic core skeleton [43]. 

The reaction of A-Boc protected amino acids alanine (184) and valine (185) with phenyldichlorophosphine in the presence of NEt3 was reported to lead to the clean formation of essentially one compound in each case, the P-chiral, tricoordi-nated, 1,3,2-oxazaphospholidinones 186 and 187 respectively (Scheme 52) [83],... 

The process was also applicable to microwave-assisted reactions. Thus, 140a, 140b, and 140 (R1 = z-Pr, R4 = indol-3-ylmethyl) were prepared in a two-step, one-pot synthesis in yields of 55%, 39%, 20%, and with 70%, 73%, 50% ee, respectively. In the first step anthranilic acid was reacted with the appropriate A-BOC-protected amino acid (glycine, L-alanine, and L-valine, respectively) in the presence of P(OPh)3 and dry pyridine under irradiation at 150 °C for 140a or conventional heating at 55 °C for 140b and 140 (R1 = z-Pr, R4 = indol-3-ylmethyl). In the second step the resulting... 

In the initial step, the first BOC-protected amino acid is bound to the polymer, e.g. polystyrene in which a proportion of the phenyl rings have chloromethyl substitution. Attachment to these residues is through the carboxyl via an ester linkage. This involves a simple nucleophilic substitution reaction, with the carboxylate as nucleophile and chloride as leaving group (see Section 6.3.2). After each stage, the insoluble polymer-product combination is washed free of impurities. 

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

One of the pioneer works in the synthesis of DKPs through MCRs was reported by Hulme and coworkers in a three-step solution phase protocol based on UDC [33, 34]. They have obtained a series of different DKPs by reacting Armstrong s convertible isocyanide with aldehydes, M-Boc-protected amino acids as bifunctional acid component containing a protected internal amino nucleophile, and amines in methanol at room temperature. After Ugi-reaction, the isonitrile-derived amide is activated with acid (UAC) and allows cyclization to the DKP with the... 

The A V-di-Boc protection can be removed with HC1 (5.2 M soln in THF) at rt to give 9. The mono JV -Boc protected amino acid derivative is then obtained with Boc20 under standard procedures. 

The peptide was synthesized on Boc-Trp(For)-PAM-PSty-resin (0.67 mmol-g 1, 0.5 mmol scale). The peptide was assembled by consecutive addition of the Boc-protected amino acids Boc-Dap(Fmoc)-OH,... 

To expedite peptide syntheses of up to 124 amino acid units, beads of solid polystyrene— with chloromethyl groups, —CH CI, para to about every hundredth phenyl group—are used in an automated process. The sequence of steps is (1) attach C-terminal Boc-protected amino acid by... 

A Boc-protected amino acid is first attached to the resin and then the Boc is removed to liberate a free amino group. This is reacted with another Boc-protected amino acid. To synthesize, e.g., Ala.Gly, the Gly is first attached to the resin. 

Scheme 32 Aminodiacetic Acid Modified Boc-Protected Amino Acids and PeptidesI70-711...

To a soln of /V-Boc-protected-amino acid (Boc-Ala-OH, Boc-D-Val-OH, or Boc-Aib-OH, 1 mmol), an a-hydroxy add benzyl ester (H-L-Lac-OBzl, or H-i.-Hyv-OBzl, 1 mmol) and 4-(dialkylamino)pyridine (DMAP or Ppyr, 1 mmol) in CH.Ch (15 mL), a soln of DCC (1.1 mmol) in CH.Ch (5 mL) was added. The mixture was stirred at 25 °C and followed by TLC (silica gel, CHC13 or hexane/EtOAc 4 1). The iV V -dicyclohexylurea was filtered off and the filtrate concentrated to dryness. The residue was dissolved in EtOAc, cooled and the /V,/V -dicyclohexylurea was removed by filtration. The filtrate was washed with 1M aq KHS04, H20, 5% aq NaHC03, dried (MgS04), and concentrated to dryness in vacuo. The resulting oil was washed with petroleum ether and dried in vacuo to afford the analytically pure dep-sipeptide in 90-98% yield. The purity of the products was confirmed by TLC quantitative analysis IR and NMR spectra. 

Scheme 16 Attachment of a Boc-Protected Amino Acid to the Thiol Linker 811...

The synthesis of a dipeptide dihydrothiazole by way of an imidate is shown in Scheme 13.[521 The Boc-protected amino acid 37 (in this case Val) was converted into the primary amide 38 by the mixed anhydride coupling with ammonia. The amide was then directly converted into the imidate 39 using triethyloxonium hexafluorophosphate which was subsequently condensed with H-Cys-OEt to provide the dihydrothiazole 40. 

In an alternative route,2 Boc-protected amino acids are reduced to the protected amino alcohol with borane-THF (45-95% yield) and pyridinium dichromate is used for oxidation to the aldehyde (75-90% yield). The optical rotations of the aldehydes obtained by these two procedures differ considerably, presumably owing to racemization encountered in the PDC oxidation. 

In contrast, the rotation per chiral end group of first- to fifth-generation POPAM dendrimers with sterically demanding Boc-protected amino acids as end groups (Fig. 4.75) decreased significantly with increasing generation number and approached the value zero [30]. 

Fig. 4.75 POPAM dendrimer with chiral Boc-protected amino acids in the molecular periphery (according to Meijer et ai.)...

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