Epimerization tertiary amines

Based on nucleophilic addition, racemic allenyl sulfones were partially resolved by reaction with a deficiency of optically active primary or secondary amines [243]. The reversible nucleophilic addition of tertiary amines or phosphanes to acceptor-substituted allenes can lead to the inversion of the configuration of chiral allenes. For example, an optically active diester 177 with achiral groups R can undergo a racemization (Scheme 7.29). A 4 5 mixture of (M)- and (P)-177 with R = (-)-l-menthyl, obtained through synthesis of the allene from dimenthyl 1,3-acetonedicar-boxylate (cf. Scheme 7.18) [159], furnishes (M)-177 in high diastereomeric purity in 90% yield after repeated crystallization from pentane in the presence of catalytic amounts of triethylamine [158], Another example of a highly elegant epimerization of an optically active allene based on reversible nucleophilic addition was published by Marshall and Liao, who were successful in the transformation 179 — 180 [35], Recently, Lu et al. published a very informative review on the reactions of electron-deficient allenes under phosphane catalysis [244]. 

FIGURE 4.14 Reactions of activated A-alkoxycarbonylamino acids in the presence of tertiary amine. Acyl halides and mixed and symmetrical anhydrides generate 2-alkoxy-5(4/7)-oxazolone in the presence of tertiary amine. Aminolysis of 2-alkoxy-5(47f)-oxazolone in the presence of E N led to partially epimerized products. OAct = activating group. 

Use an onium salt-based reagent such as PyBOP, T/HBTU (see Sections 2.18-2.21), PyAOP (see Section 7.19), or other with me corresponding additive and diisopropylethylamine or trimethylpyridine as tertiary amine without an excess. The additive may, however, promote epimerization. 

Since carbohthiations usually proceed as syn additions, 458 is expected to be formed first. Due to the configurationally labile benzylic centre it epimerizes to the trani-substitu-ted chelate complex epi-45S. The substitution of epi-458 is assumed to occur with inversion at the benzylic centre. Sterically more demanding reagents (t-BuLi) or the well-stabilized benzyllithium do not add. The reaction works with the same efficiency when other complexing cinnamyl derivatives, such as ethers and primary, secondary, or tertiary amines, are used as substrates . A substoichiometric amount (5 mol%) of (—)-sparteine (11) serves equally well. The appropriate (Z)-cinnamyl derivatives give rise to ewf-459, since the opposite enantiotopic face of the double bond is attacked . 

Indeed, there were those who described the azide coupling method as racemization-free. [15l However, this viewpoint proved to be overly optimistic. In 1970, Sieber reported that during a synthesis of calcitonin M by the azide method, significant epimerization occurred during two of the segment condensation steps in one of these reactions 40% of the epimerized product was observed. 16 There is a crucial detail in the experimental procedure here. The workers used tert-butyl nitrite to convert a peptide hydrazide into a peptide azide, but did not isolate the azide as was typical for research at that time. Instead, they neutralized the active intermediate in situ with DIPEA and added the amino segment for acylation. This demonstrates another important theme in the control of epimerization, the presence of a tertiary amine in the reaction mixture, even if only as a neutralization equivalent, can result in the formation of epimerized products. Indeed, most observations of racemization during... 

There are numerous studies of control of racemization for specific subsets of amino acids. For example, Benoiton has carried out extensive studies on racemization of Al-methyl amino acids. In particular, McDermott and Benoiton1261 demonstrated that the presence of tertiary amine salts in coupling reactions had a profound effect on activated TV-methyl amino acids in contrast to the nonmethylated form. In one example, when Z-Ala-MeLeu-OH was coupled to the tosylate salt of Gly-OBzl with ethyl 2-ethoxy-l,2-dihydroquinoline-l-carboxylate (EEDQ) in the presence of TEA, 15% of the l-d dipeptide was formed with a yield of 68%, compared to 0.5% for Z-Ala-Leu-OH with a yield of 78%. When the free base of Gly-OBzl was utilized in a DCC/HOSu coupling in the absence of tertiary amine, no l-d products were detected. The authors attributed this increased susceptibility to epimerization to an ox-azolonium intermediate, which can epimerize by proton abstraction or merely by tauto-merization (Scheme 11). 

This hypothetical intermediate is supported by the observation that AT-acyl protected N-methyl amino acids have a higher propensity for epimerization than the corresponding N-carbamoyl protected analogues. Once again the theme of tertiary amine leading to epimerization is demonstrated. 

This polarimetric method was made even more general by utilizing chiral HPLC techniques. The L-UNCAwas dissolved in the solvent at a concentration of 0.33 M at 20 °C. The tertiary amine (1.5 equiv) was added at time zero. The solution was allowed to stand for an experimentally determined delay time, during which the only process that can occur was epimerization, since there is no nucleophile present. The delay time was determined after carrying out several experiments with different delay times and chosen so as to fall within or just after the first half-life for racemization. At the end of the delay period, benzylamine was added. Benzylamine is a very powerful nucleophile that reacts virtually instantly (regardless of the type of activation) with the resulting mixture of l- and d-UNCAs to form the benzyl amides and quench the epimerization process. Thus, a snapshot of the ratio of l/d activated intermediates at the instant of benzylamine addition was obtained by measurement of the l/d ratio of the benzyl amide products. 

The parameters that control epimerization in a peptide-bond-forming reaction can be assessed in terms of their thermodynamic and kinetic components. Thermodynamic effects are those that stabilize the deprotonated activated intermediate or the protonated tertiary amine. Kinetic effects are expressed based on the degree of steric hindrance between the tertiary amine and activated intermediate. Table 4 summarizes these contributions and shows examples of high, moderate, and low propensities for contribution to the intrinsic rate of racemization among the various parameters. 

Tertiary amine oxides can be converted into TV-hydroxy secondary amines provided that one of the TV-substituents can be selectively eliminated. This procedure has been applied to the synthesis of secondary A-hydroxy-a-amino acids 34 from the corresponding secondary a-amino acids using the /V-cyanoethyl group for transient protection of the secondary amine (Scheme 10) J40l More recently, direct oxidation with 2,2-dimethyldioxirane of a primary amine has been described for H-L-Val-OMe (82% yield) and H-L-Phe-OMe (54% yield))13 The reaction proceeds smoothly without epimerization, but no experimental details have been reported. 

Active esters are chirally stable under the usual conditions of coupling in peptide synthesis, but with the single exception of piperidino esters they may undergo isomerization if left in the presence of tertiary amines. In addition to their role as shelf-stable reagents, active esters are postulated as intermediates in carbodiimide-mediated reactions where a substituted hydroxylanoine is added in order to suppress the side reaction of epimerization in the... 

Numerous bases can be used, particularly DIPEA or NMM. In the case of fragment coupling, other tertiary amines, such as collidine, are recommended to decrease the degree of epimerization.t Addition of DMAP improves the halophosphonium-mediated activation of a,a-dialkylamino acids. 

In the presence of a tertiary amine, in particular pyridine (Sec. 31.6), an equilibrium is established between an aldonic acid and its epimer. This reaction is the basis of the best method for converting an aldose into its epimer, since the only configuration affected is that at C-2. The aldose is oxidized by bromine water to the aldonic acid, which is then treated with pyridine. From the equilibrium mixture thus formed, the epimeric aldonic acid is separated, and reduced (in the form of its lactone) to the epimeric aldose. See, for example, Fig. 34.4. 

We must mention that intensive research is on-going in the design of metal-free catalysts for the REX ROP of lactide. By comparison with metal-based catalysts like Sn(Oct)2, the advantages of these metal-free catalysts are that they are less harmful for biomedical applications and readily removed during, e.g., extrusion processes. Among the simplest ones, some selected enzymes, tertiary amines, urea- and iodine-based compounds, phosphines and carbenes have proven efficient metal-free catalysts. However, most of these investigations have shown that these metal-free catalysts are less active and may yield intensive side-reactions, such as epimerization, when applied during bulk REX ROP of LA. ... 

The direct action of alkali or pyridine on the sugars is of particular value for the preparation of the ketoses, but the action of pyridine on the aldonic acids is solely an epimerization. The action of hot tertiary amines (particularly aqueous pyridine and quinoline), as well as of alkali, on the aldonic acids and their methylated derivatives results in the establishment of an equilibrium between the two epimeric acids 219). 

Closely related to this reaction is the base-catalyzed epimerization of aldonic acids and their lactones (see Lundt and Madsen, this voL). This reaction is, of course, even older than the LdB-AvE process, and was first used by Emil Fischer [29]. Potassium hydroxide and tertiary amines (pyridine, quinoline) have been used as bases. The reaction is much slower than the epimerization of sugars and requires prolonged heating, but the aldonic acids are much more stable to the action of bases than the sugars, and no side reactions occur. The reaction proceeds even if the hydroxyl group at C-2 is methylated [30]. The kinetics and the mechanism of the interconversion of the aldopentonic acids in potassium hydroxyde solution have been studied this reaction also occurs via the enediol and the removal of H-2 is the rate-determining step [31]. It is of industrial importance, as indicated by numerous patents [32]. 

Methylation of a phenolic -OH group in (S)-3 -hydroxy-JV-methyl-coclaurine by SAM gives (S)-reticuline through the usual Sn2 pathway, and epimerization of the chirality center forms (i )-reticuline. The epimerization is a two-step process, the first an oxidation of the tertiary amine to an intermediate iminium ion and the second a hydride reduction of the iminium ion. The mechanism of the oxidation step is not yet known, but the reduction of the iminium ion requires NADPH as cofactor (Figure 25.11). 

With a source of 2(S)-mercapto-Y-butyrolactone (19) in hand we next turned our attention to coupling this molecule with the key steroid intermediate 15 as shown in Figure 9. If this route was to be successful, we needed to find a mild method to form the thioester bond without racemization of 2(S)-mercapto-Y-butyrolactone, or epimerization of the GR250495X product. It soon b ame apparent that standard coupling conditions involving tertiary amine bases could not be utilized in this reaction since thiol and reaction product are rapidly racemized and epimerized, respectively, by even the most hindered of these bases. 

The bicyclic amine 11-methyl-l l-azabicyclo[5.3.1]hendecanc (71) provided a model system in which the hydrogens on the equivalent a-tertiary-carbon atoms cannot be trans to the nitrogen-mercury bond in the mercur-ated complex and in which epimerization at these a carbons is impossible (77). This bicyclic system is large enough to accommodate a... 

In the patent literature, processes are described for the epimerization of the benzyhc chiral center at the 4-posihon using an alkoxide base [28] and for reagent-based dehydrogenation, then rehydrogenation, of the amine [29]. We envisaged racemization of the chiral amine center using the SCRAM catalyst and the tertiary carbon center using an alkoxide base (Scheme 13.10). 

---