Amino acid fluorides

The synthesis of 3-aryltetrahydroisoquinolines was accomplished by electrophilic aromatic substitution of polysubstituted phenols and phenyl ethers with Lewis acid-generated tosyliminium ions of 2-tosyl-3-methoxytetrahydroisoquinoline derivatives <00SL801>. In addition isoquinoline was reported to react with N-tosylated (R)- or (S)-amino acid fluorides to afford optically active dihydroimidazoisoquinolinones. The reaction proceeds via acylation followed by attack of the tosylamino group at Cl of the intermediate 2-tosylaminoacylisoquinolinium salt <00TL5479>. 

Owing to steric hindrance, the acylation reaction must be carried out using a large excess (4-10 Eq.) of the activated acid and for an extended period. In some cases, repeat acylation is recommended. Acylation has also been successfully carried out using Fmoc-amino acid fluorides (e.g., Fmoc-Phe-F4, 4Eq. in the presence of DIEA, 1.1 Eq. 18h >98% acylation efficiency). While acylation with unhindered activated carboxylic acids are achieved in >98%, acylation with hindered carboxylic acids generally resulted in ca. 80% efficiencies. 

D Granitza, M Beyermann, H Wenschuh, H Haber, LA Carpino, GA Truran, M Bienert. Efficient acylation of hydroxy functions by means of Fmoc amino acid fluorides. J Chem Soc Chem Commun 2223, 1995. 

FIGURE 7.19 Reagents for preparing A-protected amino-acid fluorides,55-5661 Boc2-amino-acid fluorides (CyNF),58-59 and a nonbasic acid scavenger (BSA).62 CyNF = cyanuric fluoride DAST = diethylaminosulfur trifluoride TFFH = tetramethylfluoroformamidinium hexafluo-rophosphate BSA = b (trimethylsilyl)acetimide. 

LA Carpino, D Sadat-Aalaee, HG Chao, RH DeSelms. ((9-Fluorenylmethyl)oxy)car-bonyl (FMOC) amino acid fluorides. Convenient new peptide coupling reagents applicable to the FMOC/ferf-butyl strategy for solution and solid-phase syntheses. J Am Chem Soc 112, 9651, 1990. 

J-N Bertho, A Loffet, C Pinel, F Reuther, G Sennyey. Amino acid fluorides their preparation and use in peptide synthesis. Tetrahedron Lett 32, 1303, 1991. 

LA Carpino, EME Mansour, D Sadat-Aalaee. lerl-WutoxycarbonyI and benzyloxy-carbonyl amino acid fluorides. New, stable rapid-acting acylating agents for peptide synthesis. J Org Chem 56, 2611, 1991. 

J Savrda, M Wakselman. A-Alkoxycarbonylamino acid /V-carboxyanhydridcs and ALV-dialkoxycarbonyl amino acid fluorides from /V,/V-diprotcctcd amino acids. J Chem Soc Chem Commun 812, 1992. 

LA Carpino, EME Mansour, A El-Faham. Bis(BOC) amino acid fluorides as reactive peptide coupling reagents. J Org Chem 58, 4162, 1993. 

C Kaduk, H Wenschuh, M Beyermann, K Fomer, LA Carpino, M Bienert. Synthesis of Fmoc-amino acid fluorides via DAST, an alternative fluorinating agent. Lett Pept Sci 2, 285, 1995. 

H Wenschuh, D Ionescu, M Beyermann, M Bienert, LA Carpino. Peptide bond formation via Fmoc amino acid fluorides in the presence of silylating agents, in R Ramage, R Epton, eds. Peptides 1966. Proceedings of the 24th European Peptide Symposium, Mayflower, Kingswoodford, 1998, pp 907-908. 

Di-/m-butyl-4-methy I pyridine (3) is hindered, allows coupling of Fmoc-amino-acid fluorides with weak nucleophiles (see Section 7.12) and is best for minimizing the enantiomerizaton of Fmoc-Cys(tBu)-F (see Section 8.1) during its reaction with the hydroxyl group of a linker-resin. 

Diisopropylethylamine (8) is a very hindered strong base that is appropriate for use in couplings of acyl azides and is the base of choice for initiating o/inium salt-mediated reactions and neutralizing the acid liberated during the aminolysis of Fmoc-amino acid fluorides, whether prepared beforehand... 

H-Thz-OH (1.33 g, 10 mmol) was dissolved in dry DMF (100 mL) in the presence of DIPEA (3.23 mL, 19 mmol). A soln of Fmoc-protected amino acid fluoride (9 mmol) in dry DMF (100 mL) was added dropwise, and the mixture stirred for 2 h at rt. The soln was then concentrated, the residue taken up in EtOAc, washed with aq 5% citric acid and brine, and dried (Na2S04). The solvent was removed and the residue purified by flash chromatography (silica gel, EtOAc/AcOH/petroleum ether) yields 60-95%. 

Standard solid-phase peptide synthesis requires the first (C-terminal) amino acid to be esterified with a polymeric alcohol. Partial racemization can occur during the esterification of N-protected amino acids with Wang resin or hydroxymethyl polystyrene [200,201]. /V-Fmoc amino acids are particularly problematic because the bases required to catalyze the acylation of alcohols can also lead to deprotection. A comparative study of various esterification methods for the attachment of Fmoc amino acids to Wang resin [202] showed that the highest loadings with minimal racemization can be achieved under Mitsunobu conditions or by activation with 2,6-dichloroben-zoyl chloride (Experimental Procedure 13.5). iV-Fmoc amino acid fluorides in the presence of DMAP also proved suitable for the racemization-free esterification of Wang resin (Entry 1, Table 13.13). The most extensive racemization was observed when DMF or THF was used as solvent, whereas little or no racemization occurred in toluene or DCM [203]. 

This reaction has found considerable interest in peptide chemistry, since activation via an acid fluoride is mild enough to prevent raccmization of carbamate-protected amino acids." 104 On the other hand, amino acid fluorides are reactive enough for the coupling of even sterically hindered amino acids.105-109... 

Peptide Coupling via Amino Acid Fluorides General Procedure 100... 

The amino acid fluoride (1.1 mmol) in CH2C12 (10 mL) was added over a period of 60s to a stirred solution of an amino acid ethyl ester hydrochloride (1 mmol) in H20 (10 mL)containingNaHC03 (170 mg). The mixture was stirred at rt for 20 min. After the CH2C12 solution was washed with 5% aq HC1 (2 x), 10% aq NaHCO, and H20, the dried (MgS04) solution was evaporated in vacuo and purified by chromatography or recrystalli/.ation. 

Due to the suppression of racemization and the ability to couple sterically hindered substrates, this methodology has been utilized in solid-phase peptide synthesis. In particular, 9-fluorenyl-methoxycarbonyl-protected amino acid fluorides have been used with this protocol.110 1,3... 

Wenschuh H, Beyennann M, Haber H, Seydel JK, Krause E, Bienert M, Carpino LA, El-Fahan A, Albericio F, Stepwise automated solid phase synthesis of naturally occurring peptaibols using FMOC amino acid fluorides, J. Org. Chem., 60 405-410, 1995. 

In a different context, chiral reagents have been implemented in this chemistry. For instance, Liebscher and Itho developed the use of chiral acylating agents such as amino acid-fluorides 158 and -chlorides 156, respectively, (Scheme 21). The outcome of the reaction of isoquinoline (6), TMS-CN (14) and A -protected a-amino acid fluorides is dictated by the nature of the protecting group whereas Cbz- and... 

FMOC-protected amino acid fluorides afford the expected Reissert adducts 160 with a good stereoselectivities, the a-sulfonylamino acid fluorides undergo cycliza-tion to adduct 161 [47, 140, 141], Itho s protocol is amenable to using silyl enol ethers 157 as nucleophiles [142], Gibson has used bulky asymmetric acid chlorides as substrates in a Reissert reaction with TMS-CN the corresponding Reissert compound was then treated with aldehydes and sodium hydride to obtain the enantiopure adducts 4 (Scheme 3) [143],... 

Lippert JW. Amide bond formation by using amino acid fluorides. Arkivoc 2005 xiv 87-95. 

A 37% aq soln of CH2O (19.3 mL, 260 mmol) was added to H-Ser-OH or H-Thr-OH (103 mmol) in aq 2.5 M Na2C03 (32 mL) at rt. The clear soln was left standing overnight at 4°C, after which the pH was 7.8. This soln was used directly for aminoacylation with Fmoc-protected amino acid fluorides or UNCAs to produce the dipeptide synthons, - or with Z-Cl and (Boc)20 to produce the related N -protected derivatives. ... 

Fmoc-Ala-Oxa(5-Me)-OH was synthesized according to the procedure described above for Fmoc-Ala-Oxa-OH, except that the acylation reaction was performed with commercially available Fmoc-Ala-NCA, instead of the less accessible amino acid fluoride yield 50% mp 103-108 °C. 

Fmoc amino acid chlorides are used in the presence of DIPEA for the acylation of hindered secondary amines such as the tetrahydro-(3-carbolines,l l where other methods including PyBroP, PyBroP/HOAt, HATU, and amino acid fluorides only led to poor results. In the case of difficult acylations, e.g. of pipecolic acid and other secondary anoino acids under solid-phase conditions, Fmoc amino acid chlorides can be successfully applied, by shaking a solution of the acid chloride in dichloromethane with the peptide resin for 5 min, while adding a tertiary amine, e.g. DIPEA, and adjusting the supernatant to pH An alter-... 

The acid fluorides are generally available via reaction of the acid with cyanuric fluoride in the presence of pyridine according to the general technique of Olah.t An alternative method for the synthesis of Fmoc amino acid fluorides involves the use of DAST (N,N-diethylaminosulfur trifluoride), which is advantageous relative to cyanuric fluoride owing to the formation of only water-soluble compounds as byproducts, thus, facilitating the isolation of the acid fluorides.Examples can be found in Table 3. 

While there is evidence from IR investigations for the formation of traces of oxazol-5(4//)-one by treatment of Fmoc-protected amino acid fluorides, e.g. Fmoc-Val-F, with DIPEA, this reaction is not rapid enough to compete with the acylation process. In contrast to Fmoc amino acid chlorides, the related fluorides can be used in homogeneous systems with tertiary amines as efficient agents in peptide synthesis. 

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