Acylation methyl isocyanoacetate

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

Metkoxycarbonyloxazoles. Condensation of carboxylic acids with methyl isocyanoacetate in the presence of K2C03 and DPPA (1 equiv.) leads to 5-substituted 4-methoxycarbonyloxazoles. Racemization is only slight when this C-acylation is applied to Boc-amino acids.1... 

Ozaki and co-workers prepared an extensive series of 5-aryl(heteroaryl)-4-oxazolecarboxylic acid methyl esters 368 (20 compounds) from acylation of methyl isocyanoacetate, followed by in situ cyclization (Scheme 1.100). These compounds were elaborated further and evaluated as blood platelet aggregation inhibitors. 

Hydroxy-a-amino-acids are available by reduction and hydrolysis of the corresponding jS-keto-esters, obtained from methyl isocyanoacetate and acyl halides via oxazole-4-carboxylate intermediates. ° A synthesis of L-y-amino-/3-hydroxybutyric acid has been reported in which the key step is a dehydration of L-a-hydroxysuccinamic acid to the corresponding y-cyano-acid, presumably via a y-iminobutyrolactone. ° This could prove to be a general route to (3- and y-cyano-carboxylic acids. 

DPPA has been used for the direct C-acylation of methyl isocyanoacetate with carboxylic acids to give 4-methoxycarbonyloxazoles. t-Daunosamine, the glycone component of anticancer anthracycline antibiotics, has been synthesized from L-lactic acid in 9 steps with a 24% overall yield, where a key step in the sequence is the direct C-acylation of methyl isocyanoacetate with the lithium salt of the lactate ester using diphenyl phosphorazidate (eq 7). 

Treatment of N-benzoyl-L-alanine with oxalyl chloride, followed by methanolic triethylamine, yields methyl 4-methyl-2-phenyloxazole-5-carboxylate 32 <95CC2335>. a-Keto imidoyl chlorides, obtained from acyl chlorides and ethyl isocyanoacetate, cyclise to 5-ethoxyoxazoles by the action of triethylamine (e.g.. Scheme 8) <96SC1149>. The azetidinone 33 is converted into the oxazole 34 when heated with sodium azide and titanium chloride in acetonitrile <95JHC1409>. Another unusual reaction is the cyclisation of compound 35 to the oxazole 36 on sequential treatment with trifluoroacetic anhydride and methanol <95JFC(75)221>. 

Several other methods for the synthesis of N-acyl A -amino acid derivatives have been described. These include the condensation of aldehydes or ketones with isocyanoacetates followed by transformation of the resultant iV-formyl derivatives, 7V-chlorination of A -acyl amino acid esters followed by elimination of HCl using DBU, reaction of a-oxo carboxylic acids with amides or methyl carbamates and enzymatic dehydrogenation of A -acyl amino acid amides ". With the exception of the last, these methods have not been reported so far in isotope chemistry. 

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