Acyl oxazolinones

Recently, Kunz reported that dialkylaluminum chlorides add in a 1,4-mode to N-(a,f3-unsaturated acyl)oxazolidones (9 Scheme 3),12 while high enantioselectivity is obtained with the chiral N-(a, 3-un-saturated acyl)oxazolinone (11). Typically, higher dialkylaluminum halides (R = ethyl, isobutyl) do not... 

Verwendet man zur Acylierung Carbonsaureanhydridc/Py ridi n, so besteht die Gefahr, daB das 4-Acyl-oxazolinon zum a-Acylamino-keton gespalten wird (Dakin-West-Reaktion) 96>. So liefern die 4-Acyl-oxazoli-none beim Erwarmen mit Eisessig/Pyridin (96> vgl. auch 171)) oder was-serfreier Oxalsaure in guten Ausbeuten a-Acylamino-ketone. 

The oxazolinone substituents R then direct the approach of the aldehyde. Because of the differing steric encumbrance provided by 1 and 3, the products have the opposite configuration at the new stereogenic sites. The acyl oxazolidinones are easily solvolyzed... 

Cyclization of an allyl A-acyl-1 -phenylglycinate (398) with triphenylphosphine, hexa-chloroethane and triethylamine affords a 2-allyl-3-oxazolin-4-one (400) (81AG(E)395, 77AG(E)394). Reductive cleavage of the oxazolinone with chromium(II) acetate and aqueous hypophosphorous acid furnishes a j3,y-unsaturated ketone (Scheme 88). 

Wird die Carboxylgruppe einer N-Acyl-a-aminosaure aktiviert, so kann durch intramolekulare Acylierung der Amidfunktion ein A2-Oxazolinon-(5) entstehen ... 

Geht man von optisch aktiven N-Acyl-aminosauren aus, so werden ohne besondere VorsichtsmaBregeln meist racemische A2-Oxazolinone erhalten. Optisch aktive A2-Oxazolinone und N-Acyl-peptid-oxazolinone konnen nach der Dicyclohexylcarbodiimid-Methode 74,81,149,156) 0(jer durch Behandeln von N-Acyl-aminosauren und -peptiden mit Acetanhydrid/ Dioxan unter genau definierten Bedingungen 74,76) dargestellt werden. 

Sind zwei a-Substituenten vorhanden, so liegt die N-Trifluoracetyl-aminosaure in uberschussigem Trifluoressigsaureanhydrid vollstandig als A2-Oxazolinon vor. Ktirzlich wurde von Siemion 154> auch der Ein-fluB der Amid-Konformation auf die Cyclisierungstendenz von N-Acyl-aminosauren diskutiert. 

Verbindungen dieses Typs sind auch durch Cyclisierung geeigneter N-Acyl-aminosauren zuganglich. So liefem N-Isonicotinoyl-C-phenylgly-cin 177> und das Azlacton des N-Benzoyl-C-pyridyl-(4)-glycins 173) mit Acetanhydrid die (N-Acetyl-1.4-dihydro-pyridinyliden)-oxazolinone 19 und 20. 

Die Reaktionen der A2-Oxazolinone-(5) mit Nucleophilen HY werden von dem cyclischen Anhydridsystem —CO—0—C(R)=N— bestimmt. In den meisten Fallen greift das Nucleophil die CO-Gruppe an, wobei unter Ringoffnung N-Acyl-aminosaure-Derivate (21) entstehen. Seltener wird ein Angriff auf die C=N-Doppelbindung beobachtet, wobei sich das... 

Besonders reaktionsfahig sind 4.4-disubstituierte 2-Trifluormethyl-A2-oxazolinone-(5). Sie wurden von Kenner und seiner Schule los.ios.iis) zur Synthese von Peptiden sterisch stark gehinderter Aminosauren be-nutzt und reagieren selbst mit Inaminen oder Dicyclohexylcarbodiimid, wobei in einer Art Einschubreaktion N-Acyl-2.3-dihydropyrrolone-(3) (29) 175> oder Imidazolidin-Derivate (30) 85> entstehen ... 

Besonders gut untersucht wurden in letzter Zeit 4-alkylsubstituierte 4-Acyl-A2-oxazolinone-(5) (85), die durch Acylierung der A2-Oxazolinone mit aliphatischen Carbonsaurehalogeniden/Pyridin (171) oder durch Um-lagerung der 5-Acyloxy-oxazole 84 mit Pyridin i69,i7i) allgemein zugang-lich sind. Dabei konnen 4-[N-Acyl-1.4-dihydro-pyridyl]-A2-oxazoli-none-(5) (98) als Zwischenstufen nachgewiesen und in einigen Fallen isoliert werden 17 3>. 

N-Acyl-1.4-dihydro-pyridyl]-oxazolinone (98) und 4-Acyl-A2-oxazolinone (85) konnten NMR-spektroskopisch auch als Zwischenstufen der klassischen Dakin-West-Reaktion 50> nachgewiesen werden 170>. 

Substituted oxazolinones (see Scheme 4.23, p. 78) were synthesized directly by heating amino acids with TFA anhydride at 150°C for 10 min or by the action of dicyclo-hexylcarbodiimide on N-acylated amino acids [266]. Oxazolinones of eleven amino acids were chromatographed on 0.325% EGA on Chromosorb G at 40—140°C. 2-H-, 2-methyl-and 2-phenyloxazolinones of Leu were analysed on OV-17 together with 2-trifluoro-methyloxazolinone, which has the shortest retention time and is very volatile. 

Acylaminocarboxylic acids 288 are converted into 5(4//)-oxazolinones 289 by acid anhydrides (Scheme 140). In an extension of this reaction, A-acyl derivatives of glycine 290 react with aldehydes with concomitant cyclization to give azlactones 291 (Scheme 141) this is the basis of the Erlenmeyer synthesis of amino acids. Treatment of amino acid derivatives 292 with PBr3 affords the thiazolidine-2,5-dione 293 (Scheme 142) <1971CB3146>. 

The basis for exploring heterocycles as inhibitors of HLE came from the discovery that some heterocycles, for example, sultones (12-1, Table 2.12) [174], oxazolinones (12-2) [175], or lactones (12-3) and (12-4) [176], were alternate substrates for serine proteinases. The proteinases reacted with these compounds to (a) cleave the heterocyclic ring, (b) form an intermediate acyl-enzyme and (c) then hydrolyze the acyl-enzyme by the normal catalytic mechanism to release active enzyme and the ring-opened heterocycle. 

In another investigation, 5-acyloxyoxazoles (257) were found to rearrange to 2- and 4-acyl-5-oxazolinones (259 and 260).417 The reaction in the presence of 4-dimethyIaminopyridine proceeds 20,000 times faster... 

I -Acylation. A/-Acylation and related reactions ate brought about in straightforward ways with acyl chloride or acid anhydride, although the proximity of the carboxyl group may produce other reactions, eg, oxazolinone formation, under some conditions. 

A Dakin-West reaction on plant scale is demonstrated by elaboration of a modified procedure avoiding uncontrolled release of carbon dioxide. It seems to be generally accepted that the mechanism involves dehydrative formation of an azlactone (oxazolinone), which is then C-acylated (in equilibria with G-acylation), undergoes ring-opening hydrolysis, and then decarboxylates to form the acylamino ketone. Pyrimidine ring formation is achieved in a simple one-pot reaction, which is followed by a simple isomerization. Laboratory experiments had made clear that the mechanism... 

Another precursor for DALA is succinoyl chloride monomethyl ester that can undergo chain extension in the presence of hippuric acid and a base catalyst such as Y-picoline (Figure 5) (22). The initial reaction involves acylation of the dianion of hippuric acid. The resulting oxazolinone 9 can be hydrolyzed in aqueous hydrochloric acid to yield DALA. In a similar manner, succinic anhydride can serve as acylating agent when it is treated with the dianion of ethyl hippurate (23). 

Merrifield s original idea was based on the general scheme of stepwise condensation of N-protected amino acids to the first one, which is linked with its carboxyl function by an ester bond to the insoluble polymer support. This way of solid phase peptide synthesis resulted from the well-known risk of racemization during activation of peptidic carboxyl components, which is minimized in activated amino acid derivatives, N-acylated by urethane-type protecting groups [40] (Fig. 7). Depending on the chosen method, the C-terminal activation of N-protected peptides tends to racemize a certain amount of the material because of the possible formation of an oxazolinone intermediate [41] (Fig. 8). 

The oxazolinone 107, a new recoverable chiral auxiliary that gives a high level of asymmetric induction in model aldol reactions and Diels-Alder cycloadditions (in which the reactant is connected to the auxiliary by -acylation), has been synthesized from L-gulonic acid. The key step in its synthesis was the thermal intramolecular nitiene insertion shown in Scheme 21. The formation of oxazolinethiones on hydrolysis of isothiocyanato-sugar derivatives is covered in detail in Chapter 9, section 3.3. Base-catalysed reaction of StS-O-isopropylidene-D-xylofuranosylamine with P-isothiocyanato-alkanals led to tricyclic derivatives such as 108, considered as cyclonucleoside analogues. ... 

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