Solid-phase, anhydride

Quantitative studies of solid-state organic reactions were performed by Glazman (267. 268). Equal amounts of acetic anhydride and 2-aminothiazole (grain diameter 0.15 mm) were mixed for 20 rain, and the mixture was heated in a glycerol bath at 0.5°C per minute. Heating curves showed that the reaction starts in the solid phase the use of an eutectic composition of organic reactants increases the yields. 

Pulici and coworkers have reported a solid-phase variation of the Robinson-Gabriel for the production of parallel libraries of ox azole-containing molecules." The preparation is based on a solid supported 2-acylamino ketone 16 that can be cleaved by means of a volatile anhydride and cyclized in solution to obtain a substituted oxazole ring (17) that does not contain traces of the linker moiety. 

Unsymmetrical as well as symmetrical anhydrides are often prepared by the treatment of an acyl halide with a carboxylic acid salt. The compound C0CI2 has been used as a catalyst. If a metallic salt is used, Na , K , or Ag are the most common cations, but more often pyridine or another tertiary amine is added to the free acid and the salt thus formed is treated with the acyl halide. Mixed formic anhydrides are prepared from sodium formate and an aryl halide, by use of a solid-phase copolymer of pyridine-l-oxide. Symmetrical anhydrides can be prepared by reaction of the acyl halide with aqueous NaOH or NaHCOa under phase-transfer conditions, or with sodium bicarbonate with ultrasound. 

Milbemectin consists of two active ingredients, M.A3 and M.A4. Milbemectin is extracted from plant materials and soils with methanol-water (7 3, v/v). After centrifugation, the extracts obtained are diluted to volume with the extraction solvent in a volumetric flask. Aliquots of the extracts are transferred on to a previously conditioned Cl8 solid-phase extraction (SPE) column. Milbemectin is eluted with methanol after washing the column with aqueous methanol. The eluate is evaporated to dryness and the residual milbemectin is converted to fluorescent anhydride derivatives after treatment with trifluoroacetic anhydride in 0.5 M triethylamine in benzene solution. The anhydride derivatives of M.A3 and M.A4 possess fluorescent sensitivity. The derivatized samples are dissolved in methanol and injected into a high-performance liquid chromatography (HPLC) system equipped with a fluorescence detector for quantitative determination. 

One of the first dedicated applications of microwaves in solid-phase chemistry was in the synthesis of small peptide molecules, as described by Wang and coworkers [22]. As a preliminary test, the authors coupled Fmoc-Ile and Fmoc-Val, respectively, with Gly-preloaded Wang resin using the corresponding symmetric anhydrides (Scheme 7.1). 

The earliest published example of microwave-assisted SPOS involved diisopropyl-carbodiimide (DlC)-mediated solid-phase peptide couplings [24], Numerous Fmoc-protected amino acids and peptide fragments were coupled with glycine-preloaded polystyrene Wang resin (PS-Wang) in DMF, using either the symmetric anhydride or preformed N-hydroxybenzotriazole active esters (HOBt) as precursors (Scheme 12.1). 

The mild conditions employed for the activation of sulfoxides, and the high reactivity of the glycosyl donor, suggested that the method might translate well to the solid phase. Moreover, the nonpolar nature of the sulfoxide, triflic anhydride, and DTBMP (solution-based reagents) should enable them to partition effectively into a non-polar, polystyrene-based resin. 

EJ Heimer, C Chang, T Lambros, J Meienhofer. Stable isolated symmetrical anhydrides of (Va-9-fluorenylmethyloxycarbonylamino acids in solid-phase peptide synthesis. hit J Pept Prot Res 18, 237, 1981. 

The reagents and methods employed for coupling in solid-phase synthesis are the same as for synthesis in solution, but a few are excluded because they are unsuitable. The mixed-anhydride method (see Section 2.6) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (see Section 2.15) are not used because there is no way to eliminate aminolysis at the wrong carbonyl of the anhydride. Acyl azides (see Section 2.13) are too laborious to make and too slow to react. The preparation of acyl chlorides (see Section 2.14) is too complicated for their routine use this may be rectified, however, by the availability of triphosgene (see Section 7.13). That leaves the following choices, bearing in mind that a two to three times molar excess of protected amino acid is always employed. 

During the first decade when solid-phase synthesis was executed using Fmoc/tBu chemistry, the first Fmoc-amino acid was anchored to the support by reaction of the symmetrical anhydride with the hydroxymethylphenyl group of the linker or support. Because this is an esterification reaction that does not occur readily, 4-dimethylaminopyridine was employed as catalyst. The basic catalyst caused up to 6% enantiomerization of the activated residue (see Section 4.19). Diminution of the amount of catalyst to one-tenth of an equivalent (Figure 5.21, A) reduced the isomerization substantially but did not suppress it completely. As a consequence, the products synthesized during that decade were usually contaminated with a small amount of the epimer. In addition, the basic catalyst was responsible for a second side reaction namely, the premature removal of Fmoc protector, which led to loading of some dimer of the first residue. Nothing could be done about the situation,... 

The major side reaction associated with the use of mixed anhydrides is aminolysis at the carbonyl of the carbonate moiety (Figure 7.4, path B). The product is a urethane that resembles the desired protected peptide in properties, except that the amino-terminal substituent is not cleaved by the usual deprotecting reagents. Hence, its removal from the target product is not straightforward. The problem is serious when the residues activated are hindered (Val, lie, MeXaa), where the amounts can be as high as 10%. Other residues generate much less, but the reaction cannot be avoided completely, with the possible exception of activated proline (see Section 7.22). This is one reason why mixed anhydrides are not employed for solid-phase synthesis. 

RB Merrifield, AR Mitchell, JE Clarke. Detection and prevention of urethane acylation during solid-phase peptide synthesis by anhydride methods. J Org Chem 39, 660, 1974. 

GC = gas chromatography EC = electrochemical (detector ECD = electron capture (detector HCD = Hall conductivity detector HFBA = heptafluorobutyric anhydride HPLC = high performance liquid chromatography NCI-MS = mass spectrometry in the negative chemical ionization mode NPD = nitrogen-phosphorus detector ppb = parts per billion UV = ultraviolet absorption SPE = solid phase extraction wt wt = weight weight... 

There are solid phase enthalpy of formation data for four aromatic acyl peroxides dibenzoyl peroxide and the bis-o- and bis-p-toluyl derivatives and dicinnamoyl peroxide. The last three were reported in the same publication . The first disconcerting observation is that the p-methyl substituted benzoyl peroxide is less stable than the ortho isomer by nearly 50 kJmol. We cannot reconcile the large difference between the enthalpies of formation of these two isomers, especially since the corresponding anhydrides have comparable enthalpies of formation, —521.0 + 7.9 (p ) and —533.5 + 7.9 (o )kJmol . However, they too exhibit an unexpected stability order and were measured by the same... 

The enthalpies of reaction 16 for solid and gaseous dibenzoyl peroxide are —45.8 and —47.3 kJmoU, respectively. These values are much smaller than those calculated for the liquid dialkyl peroxides ca —56 kJmoU ), the acyl peresters ca —70 kJmoU ) or the non-aromatic diacyl peroxides (—89 or —59 kJmol ). However, we have no reason not to accept the result. It would be futile to use this result for further calculations concerning the solid phase enthalpies of formation of bis(o-toluyl) peroxide, bis(p-toluyl) peroxide and dicinnamoyl peroxide because all the peroxide and the anhydride product enthalpy of formation data are from the same suspect source . 

The rationale behind the synthesis of phosphohomoserine-containing peptides [Hse(P)] is that this phosphorylated residue is inert to base-mediated (3-elimination and thereby may provide an interesting surrogate for the study of Ser(P)-based processes. In initial work, Boc-Hse[PO(OPh)2]-OH[21l was prepared by a simple four-step procedure but was found to be unsuitable for use in Boc-based solution synthesis due to extensive amine-mediated intramolecular dephosphorylation of the Hse[PO(OPh)2] residue during mixed anhydride coupling of its N-terminus. This side reaction was subsequently minimized through the use of Fmoc-Hse[PO(OPh)2]-OH in a Fmoc-based solid-phase approach in which the use of a large... 

---