9-Amino-9-tert.-butyloxycarbonyl

A CONVENIENT PREPARATION OF AN ORTHOGONALLY PROTECTED C ,C -DISUBSTITUTED AMINO ACID ANALOG OF LYSINE l-tert-BUTYLOXYCARBONYL-4-((9-FLUORENYLMETHYLOXYCARBONYL)AMINO)-PIPERIDINE-4-... 

It has been found that the tris(tert-butyloxycarbonyl) protected hydantoin of 4-piperidone 2, selectively hydrolyses in alkali to yield the N-tert-butyloxycarbonylated piperidine amino acid 3. The hydrolysis, which is performed in a biphasic mixture of THF and 2.0M KOH at room temperature, cleanly partitions the deprotonated 4-amino-N -(tert-butyloxycarbonyl)piperidine-4-carboxylic acid into the aqueous phase of the reaction with minimal contamination of the hydrolysis product, di-tert-butyl iminodicarboxylate, which partitions into the THF layer. Upon neutralization of the aqueous phase with aqueous hydrochloric acid, the zwitterion of the amino acid is isolated. The Bolin procedure to introduce the 9-fluorenylmethyloxycarbonyl protecting group efficiently produces 4.8 This synthesis is a significant improvement over the previously described method9 where the final protection step was complicated by contamination of the hydrolysis side-product, di-tert-butyl iminodicarboxylate, which is very difficult to separate from 4, even by chromatographic means. 

The noteworthy advantages of the allyl ester are (a) it is readily introduced into amino acids (b) after isomerization (to 1-propenyl) by a palladium(O) catalyst it may be removed under weakly acidic or basic and neural conditions (32), even if sulfur-containing amino acids are present (34) (c) it shows orthogonal stability to the tert-butyloxycarbonyl and 9-fluorenylmethoxy-carbonyl groups (10) and (d) it is not affected by the hydrogen fluoride-pyridine complex (35). 

GE Reid, RJ Simpson. Automated solid-phase peptide synthesis use of 2-(17f-ben-zotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate for coupling of tert-butyloxycarbonyl amino acids. Anal Biochem 200, 301, 1992. 

Tesalova, E., Bosdkovi, Z., and Pacakova, V., Comparison of enantioselective separation of A -tert-butyloxycarbonyl amino acids and their non-blocked analogues on teicoplanin-based chiral stationary phase, J. Chromatogr. A, 838, 121, 1999. 

Tesafova, E., Bosdkovd, Z., and Zuskova, L, Enantioseparation of selected iV-tert-butyloxycarbonyl amino acids in high-performance liquid chromatography and capillary electrophoresis with a teicoplanin chiral selector. J. Chromatogr. A, 879, 147, 2000. 

Amino group protection may be achieved by converting the amine into its Al-tert-butyloxycarbonyl (tBOC or just BOC) derivative, by reaction with di-tert-butyl dicarbonate. This reagent should be considered as a variant of a carboxylic acid... 

Racemic cw-l-amino-2-phenylcyclohexanecarboxylic acid 693 can be prepared by Diels-Alder reaction of (Z)-4-benzyhdene-2-phenyl-5(47/)-oxazolone 621 and butadiene in an analogous manner. Coupling A-tert-butyloxycarbonyl-L-proline with 693 yielded diastereomeric dipeptides that were separated chromatographi-cally. The behavior of the individual dipeptides was studied as a means to effect p-tum modulation by such cyclohexane analogues of phenylalanine. ... 

Recently, the cyclopropanation of (Z)-4-benzyIidene-2-phenyl-5(4//)-oxazolone 621 with phenyldiazomethane was reported to give the spirocyclopropane, rac- 21 in very high yield. Subsequent ring opening and hydrolysis of rac- 21 generated frani-l-amino-2,3-diphenyl-l-cyclopropanecarboxylic acid, rac-828 (cadiPhe) (Scheme 7.256). This new, constrained phenylalanine analogue induces a y-tum in the sohd state when incorporated into model dipeptides. The enantiomers of the Al-Boc (Boc = tert-butyloxycarbonyl) methyl ester of 828 have been resolved by HPLC. 

Durch Erhitzen von 4(5)-Azidocarbonyl-imidazol in tert.-Butanol wird in 41 % Ausbeute 4(5)-tert.-Butyloxycarbonylamino-imidazol erhalten998. Analog fiihrt die Umsetzung von 4(5)-Hydrazinocarbonyl-l-methyl-imidazol mit Natriumnitrit/Salzsaure nach anschlieBender Ther-molyse des so erhaltenen Carbonsaure-azids in tert.-Butanol zu 5-tert.-Butyloxycarbonyl-amino-I-methyl-imidazol (88%)999 ... 

In ahnlicher Weise erhalt man z. B. unter Verwendung von Carbamidsaure-tert.-butylester/ N-Chlor-succinimid/Triethylamin aus 3-Phenylseleno-cyclohexen 3-(tert.-Butyloxycarbonyl-amino )-cyclohexen (85%) ... 

Pentene 3-(tert.-Butyloxycarbonyl-amino-acetoxy)- , l-difluoro-2-(mcthoxy-methoxy)-4-methyl-E10b2, 220 (OH -> O-CO-R)... 

The amino-oxy group can be incorporated into peptides or small molecules in the form of protected TV-tert-butyloxycarbonyl amino-oxy acetic acid (Boc-Aoa-OH, Nova Biochem). For peptides, the Aoa functional group can be coupled to the N-terminus. If the free N-terminus of the peptide is required for biological function, the Boc-Aoa-OH can be coupled to the side chain of some diamino acid (e g., diaminopropionic acid [Dpr], lysine [Lys], or ornithine [Om]) at the... 

Due to the widespread use of structurally diverse amino acid derivatives in practically all areas of the physical and life sciences, the synthesis and applications of these compounds are of fundamental importance. Heterocyclic f)-substituted-a-alanincs are non-proteinogenic amino acids that are widely found in nature [138-147]. Naturally occurring (l-amino acids are also compounds with interesting pharmacological aspects. N,N-Bis(tert-butyloxycarbonyl)-dehydroalanine methyl ester (186) was reacted at room... 

The temporary amino protecting group most commonly employed in the liquid phase method is A-tert-butyloxycarbonyl (Boc). This group can be removed from... 

Dimethyl-4-nitro- -methylester E16d, 208 (Michael-Addition) Essigsaure (tert.-Butyloxycarbonyl-amino)- E4, 160 (NH - N-CO-R)... 

Propan 2-(tert.-Butyloxycarbonyl-amino)-l, 3-dichlor-2-hydroxy-tetrafluor- E14a/2, 63 (Keton/ RO-CO-NH2)... 

Azetidin (35,45)-/ranx-3-tert.-Butyloxycarbonyl-amino-4-methyl-2-oxo- E16b, 567 (N-Benzyl-Spaltung)... 

Benzol 6-(tert.-Butyloxycarbonyl-lithio-amino)-2-fluor-l-lithio-EI9d, 405 (H - Li)... 

Pyrrol 3-(tert.-Butyloxycarbonyl-amino)-2-trifluoracetyl- E6a, 745 [l-CAr3 - 1-H/2-H -> 2-CO-CF3]... 

Hexansaure 2-Amino-6-(tert.-butyloxycarbonyl-amino)- -methylester XV/1, 211, 221, 477... 

Transport peptides can be synthesized using either t-Boc or Fmoc solid phase peptide synthesis strategies with a synthesizer or manually. We routinely synthesize CPPs in a stepwise manner on solid support using an Applied Biosystems Model 431A peptide synthesizer. tert-Butyloxycarbonyl amino acids are coupled as 1-hydroxybenzotriazole (HOBt) esters to a p-methylbenzylhydryl-amine (MBHA) resin (65). C-terminally amidated CPPs are less prone to degradation and show higher internalization efficiency than carboxylic acid derivatives. 

Tripeptides utilized in this study were synthesized employing synthetic steps identical to those in the cyclic peptide syntheses. Variations of the N-terminal amino acid and in the alkyl group at the nitrogen of the 2-position dehydrophenylalanine were accomplished through substitution of the appropriate tert-butyloxycarbonyl amino acid and alkyl iodide at the appropriate synthetic step, respectively. The details and physical constants of these synthetic tripeptide analogs will be reported elsewhere (Edwards J. V. and Cutler H. G., unpublished results). 

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