Benzotriazoles solid-phase synthesis

In a solid-phase synthesis of a,a-difluoro-/ -amino acids (equation 38), supported iV-(a-aminoalkyl)benzotriazole 59 is reacted with lc and zinc to give adducts 60 in d.e. values which depended on the steric bulkiness of the R1 group, ranging from 0 (R1 = H)... 

A review on the 1,2,3-triazole formation via 1,3-dipolar cycloaddition of acetylenes with azides under mild conditions has been published <03H(60)1225>. The synthesis of a benzotriazole azo dye phosphoramidite and the subsequent use in solid phase synthesis of oligonucleotides has been reported <03TL1339>. The chemical reactivity of [l,2,3]triazolo[l,5-a]- and [l,5-c]-pyrimidinium salts has been published <03T4297>. A review on the use of benzotriazole as an ideal synthetic auxiliary has been disclosed <03CEJ4586>. 

In the absence of base, active esters of both N-alkoxycarbonyl amino acids and N -protected peptides undergo anninolysis with preservation of chiral integrity. There is ample evidence to substantiate this statementP d and no evidence to the contrary. But there is a wealth of accumulated evidence that active esters undergo isomerization when left in the presence of tertiary annine.t In this regard, 4-nitrophenyl esters are much more sensitive than trichlorophenyl esters and piperidino esters are exceptions in that they are unaffected by tertiary anoine.W The isomerization recently observed in the TBTU-mediated couplings of Fmoc-Cys(R )-OH in the presence of 1,2,3-benzotriazol-l-ol in continuous flow solid-phase synthesis is a further example of this phenomenon. The result can be attributed to the effect of tertiary amine on the benzotriazolyl ester that is formed by capture of the acyluronium intermediate before it has time to be aminolyzed. 

For the parallel synthesis of ureas based on amino acids, a solid-phase synthesis as well as a solution-phase synthesis were used (Scheme 5) [11]. Solution-phase synthesis gave the desired compounds 21 in yields ranging from 80-100% and purities in the range 71-97%. The work-up involved extraction of the benzotriazole formed in the coupling steps. An aqueous borax buffer (pH 9.2) was used and the separation of the CH2CI2 layer from the aqueous phase was performed in cartridges equipped with a PTFE frit. 

Meutermans and Alewood [48] reported the solid-phase synthesis of tetrahydroisoquinolines 13 and dihydroisoquinolines 13a using the Bischler-Napieralski reaction (Fig. 5). The polystyrene resin-bound deprotected L-3,4-dimethoxyphenylalanine was acylated with acetic acid derivatives using N- [(IH-benzotriazol-1 -yl)(dimethylamino)methylene] -iV-methylmethana-minium hexafluorophosphate A-oxide (HBTU) as a coupling reagent. The product obtained was then treated with phosphorus oxychloride under optimized conditions to afford a Bischler-Napieralski cyclization. Hutchins and Chapman [49] reported the synthesis of tetrahydroisoquinolines 13b and 4,5,6,7-tetrahydro-3H-imidazol[4,5-c]pyridines 14 via cyclocondensation of the appropriate dipeptidomimetic with various aldehydes (Fig. 6). 

Synthesis of 4(6)-amino-l,3,5-triazine-2-ones and 2-thiones starting from benzotriazole derivatives has been reported <01JOC6797>. The first template photochemical synthesis of a 1,3,5-triazine derivative as a receptor capable of differentiating between thymine and uracil has been described <01CC1446>. A new solid phase synthesis of trisubslituted 6-amino(substituted)-2,4-dioxo-3,4-dihydro-l,3,5-triazines from a resin-bound amine component has been reported <01JCO278>. The synthesis of thirteen lris(azol-l-yl)-13,5-triazines, as a new class of multidentatc ligands, has been described <01H(55)905>. Tris(pyrazolyl-13,5-triazincs) 14 have been prepared by cyclotrimerization of aromatic nitriles, in piperidine and in solvent-free conditions <01T4397>. 

A further application of the benzotriazole linker is the synthesis of fi-diketones 382. Polymer-supported benzotriazoles 371 were transformed into the corresponding azolides which were cleaved with various ketone hhio eno-lates to build diketones 382 [261]. Other cleavage reactions with nucleophiles should be possible as benzotriazole auxiliaries are often used as advantageous N, C-, S- and 0-acylating reagents [262]. A well-known application is the solid phase synthesis of unsymmetric ureas (R = NR2) with secondary amines as cleaving nucleophiles [258]. 

Schiemann K, Showalter HDH. Development of polymer-supported benzotriazole as a novel traceless linker for solid-phase organic synthesis. J Org Chem 1999 64 4972 1975. 

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

This reagent, benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (14, PyBOP)P l (Scheme 4), was designed in order to avoid the formation of toxic HMPA during acylation. As with BOP, it is assumed that the first step is the carboxylic acid activation which involves formation of an acyloxyphosphonium salt.P This initial salt is then attacked by the benzotriazolyloxy anion to form the benzotriazolyl active ester which then reacts with the amino component. PyBOP can easily replace the BOP reagent and is especially suitable for solid-phase peptide synthesis. It is soluble in a wide range of solvents such as DMF, di-chloromethane, THF, and NMP. PyBOP is more useful in peptide synthesis on solid support than in solution. The byproduct, tris(pyrrolidino)phosphine oxide is partially water-soluble and is easily removed by washing. PyBOP is used under the same experimental conditions as BOP. Note that PyBOP is a white, crystalline and non-hygroscopic solid. It can be kept as a solid, but solutions of PyBOP cannot be stored for more than 24 hours. 

Peptide synthesis. CoupUng reactions in peptide synthesis using active esters are greatly accelerated in the solution phase or the solid phase by addition of 1 -hydroxy benzotriazole. 

Figure 2.2 Modern solid phase peptide synthesis. Process begins with a-N terminal Fmoc deprotection of resin bound C-terminal amino acid residue with piperidine (mechanism illustrated). Peptide link formation follows (typical solvent Al-methylpyrrolidone [NMP]) by carboxyl group activation with dicyclohexylcarbodiimide (DCC) (mechanism illustrated) in presence of hydroxybenzotriazole (HOBt). HOBt probably replaces DCC as an activated leaving group helping to reduce a-racemization during peptide link formation. Other effective coupling agents used in place of DCC/HOBt are HBTU 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate Py-BOP benzotriazole-l-yl-oxy-tns-pyrrolidino-phosphonium hexafluorophosphate. The Process of a-N deprotection, and peptide link formation, continues for as many times as required (n-times), prior to global deprotection and resin removal.

Although azidotris(dimethylamino)phosphonium hexafluo-rophosphate has not been used in solid-phase peptide synthesis, other commercial phosphonium salt derivatives such as Benzotriazol-l-yloxytris(dimethylamino)phosphonium Hexa fluorophosphate (BOP)," benzotriazoI-l-yloxytris(pyrroli-dino)phosphonium hexafluorophosphate (PyBOP), or bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) are commonly used in that strategy. 

In the absence of the carboxylic component, HBTU reacts with amino groups leading to the formation of a Schiff base (eq 2). Thus in syntheses conducted in solution, the excess of both HBTU and amino component should be avoided. In both solution and solid-phase strategies the sequence of reagent addition is critical. HBTU should be delivered to the carboxylic component for preactivation, prior to the addition of the amine. The Schiff base formation can also occur during slow reactions, such as the preparation of cyclic peptides, where both amino and carboxylic components are in equimolar amounts and an excess of the uronium salt can block the amino group. For the synthesis of cyclic peptides the phosphonium derivatives Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate (BOP) and benzotriazol-l-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), can be more useful. 

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