N-Acylation during the addition of carboxylic acids to N-tert-butylacylketenimines and the use of the reagent N-tert-butyl-5-methylisoxazolium perchlorate for peptide synthesis

Abstract

Diacylamide precursors of amide impurities have been detected in spectral tests of the addition of carboxylic acids to N-tert-butylacylketenimines. Variations in the product distribution with an inefficient acylketenimine in media of differing acidity suggest that diacylamide formation involves a second intermediate adduct that does not convert rapidly to the desired enol ester. A high free acid concentration results in interception of the intermediate to give acid anhydrides. Partial deuterium incorporation a t the vinylic position of the enol esters indicates that intramolecular 0,O-acyl migration is relatively slow for the adducts of N-tert-butyiacylketenimines, and possible substituent influences are discussed. The preparation of p-acyloxy-N-tertbutylcrotonamide enol ester acylating agents from iV-tertbutyl-Gmethylisoxazolium perchlorate succeeds with unprotected hydroxyl groups and the carboxamide function of glutamine. However, amide dehydration was observed in the case of asparagine and competing azlactone formation was detected with benzoylleucine. Crystalline esters were not obtained with Z-Ala-OH, Z-Tyr-OH, and Z-Met-OH. Test couplings have established compatibility of the enol esters with unprotected hydroxyl groups in the amine component but results are not markedly improved relative to iV-ethyl-5-phenylisoxazolium 3'-sulfonate. A new side reaction, condensation of the amine component with the coupling by-product, is shown to be a likely source of impurities in the use of the esters of hindered carboxylic acids. The original zwitterionic isoxazolium salt reagent is much less susceptible to the side reaction.(8) Other workers# have reported that the enol ester of 3,5-diamino-6-chloropyrazine-2-carboxylic aaid similarly gives the Naert-butylamide on treatment with triethylamine, hut a compound assigned the diacylamide structure was obtained with methoxide in polar media. If the latter structure is correct, it remains unclear why fragmentation took place only in the former medium and what special factors account for imide stability in the latter experiment. (9) I<. L. Shepard, W. Halczenko, and A. J. Cragoe, Jr., Tetrahedron Ldt., 4757 (lQ69).ADDITION O F ACIDS TO N-led-BUTYLACYLKETENIMINES J. Ory. Chem., Vol. 38, No. 25, 1073 4289 R1 CMe, + R3C02--la, R1 "Me; % = H b, R1= Ph; & P H c,R1 =Me,C;&-H e, Rl = H &=Me f, Rl 3 Ph; &=Me d, R1= H % H NHCMe, NCMe, %-ON 2 RIYoH I Rz +OCOR3 I NCMe3 J 3 5 6J.

Stable Cyclic Carbenes and Related Species beyond Diaminocarbenes

“…Clearly, compared to H, the NH 2 substituents stabilize the P + moiety of N-YHC 2 , thereby preventing some back donation of the carbanion lone pair of electrons to the P center. Experimentally, carbenes N-YHC 1,2 are not interesting targets since, considering the resonance structure N-YHC', it is quite likely that such carbenes would be unstable towards ring opening, as found for isoxazole [125] and isothiazole carbenes. [126] To prevent such a process, the positive part (Y) of the ylide has to be exocyclic, as in N-YHC 3 , since the formation of an endocyclic triple bond is highly unlikely.…”

Catalyst‐Free Regio‐ and Stereospecific Synthesis of β‐Sulfonamido Dithiocarbamates: Efficient Ring‐Opening Reactions of N‐Tosyl Aziridines by Dialkyldithiocarbamates

“…The reported stability of carbenes 2 S was even more unexpected since, four decades ago, Woodward13a and Woodman13b reported the formation of ketoketenimines 4 O in the deprotonation of 3‐unsubstituted isoxazolium salts 1 O , the oxygen analogues of heterocycles 1 S . Indeed, considering the ylidic structure of the putative carbene 2 O (and of course 2 S ), one can readily imagine a very simple ring‐opening process (Scheme ).…”

Stabile cyclische Carbene und verwandte Spezies jenseits der Diaminocarbene

“…Die NH 2 -Substituenten in N-YHC 2 stabilisieren die P + -Einheit und unterdrücken zu einem gewissen Ausmaß die Rückbindung des einsamen Elektronenpaars am Carbanion zum Phosphorzentrum. Aus präparativer Sicht sind Carbene N-YHC 1,2 wenig vielversprechend, da es angesichts der Resonanzstruktur N-YHC' sehr wahrscheinlich ist, dass sie bezüglich Ringöffnung instabil sind (wie von Isoxazol- [125] und Isothiazolcarbenen [126] bekannt). Um einen solchen Prozess zu verhindern, müsste der kationische Teil Y des Ylids exocyclisch sein -wie in N-YHC 3 -, da die Bildung einer endocyclischen Dreifachbindung sehr unwahrscheinlich ist.…”