Formamido esters

Formamido esters and amides can be generated in two steps starting from (natural) a-amino acids (7). Owing to the wide availability of optically pure formamides, the s)mthesis of optically pure a-substituted a-acidic isocyano amides (2) and esters (1) has been envisioned using the dehydration route. 

The synthesis of glycidic esters in a two-phase solid-liquid system has been reported yields of between 32 and 92 % are obtained for eleven examples. 2,3-Dibromoalkyl esters react with excess sodium azide on heating to give 2-azido-2-alkenoic esters in 71 to 87 % yield over five examples. The chiral formamido-ester (71) reacts with oxomethylenebis-(3 f+-imidazolium) bis(methanesulphon-ate) (72), a non-basic dehydrating agent, to give the a-isocyano-ester (73) in 80 % yield with only 1 % racemization, as shown by the re-hydration of the product (73) (Scheme 38). ... 

One effective method for synthesis of tryptophan derivatives involves alkylation of formamido- or acetamido- malonate diesters by gramine[l,2]. Conversion to tryptophans is completed by hydrolysis and decarboxylation. These reactions were discussed in Chapter 12. An enolate of an a-nitro ester is an alternative nucleophile. The products can be converted to tryptophans by rcduction[3,4],... 

Benzaldehyde dimethyl acetal 121 reacts, for example, with the silylated allylic alcohol 645, in the presence of SnCl2-MeCOCl, via an intermediate analogous to 641, to the 3-methylenetetrahydrofuran 646 and methoxytrimethylsilane 13 a [182], whereas benzaldehyde dimethyl acetal 121 reacts with the silylated homoallylalco-hol 640 in the presence of TMSOTf 20 to afford exclusively the ds 4-vinyltetrahy-drofuran 647 and 13 a [183]. A related cyclization of an a-acetoxy urethane 648 containing an allyltrimethylsilane moiety gives the 3-vinylpyrrohdine 649 in 88% yield and trimethylsilyl acetate 142 [184, 185]. Likewise, methyl 2-formylamido-2-trimethylsilyloxypropionate reacts with allyltrimethylsilane 82 or other allyltri-methylsilanes to give methyl 2-formamido-2-aUyl-propionate and some d -unsatu-rated amino acid esters and HMDSO 7 [186] (Scheme 5.56). 

Jiang and Zhu (2001) became interested in synthesizing additional polyanhydrides with fluorescence after their discovery of the fluorescent properties of PCPS. They synthesized the series of poly(anhydride-co-amide)s poly p-[carboxyphenoxy(ethyl/propyl/butyl)formamido]benzoic anhydride (PCEFB, PCPFB, and PCBFB) (Jiang et al., 2001c). Only the ethyl polymer emitted strong fluorescence, which was consistent with their previous study of the poly(anhydride-co-ester)s of similar chemistry... 

Formamidine formation gives a different result if carried out in the presence of alkylating agents in that case a formimidic ester is formed as intermediate, which reacts with the excess of formamide to give first the formamidine and then tris(formamido)methane [A A A -methylidynetris(formamide)] 861 which is an intermediate of manifold reactivity ... 

More hindered silylanuno boionic esters such as 33 failed to undergo useful amounts of CHCl insertion with (dichloromethyl)lithium. The 0-silylated and AT-benzylated formamido compounds 34 and 35 likewise am>eaied to undergo no more than 30% chain extension with (dichloromethyl)lithiom (Scheme 9). The major difference between 31 and 33 is presumably steric, and these results are in accord with the hypothesis that the major interference to these chain extensions is steric hindrance resulting from complexation of zinc chloride with nucleophilic oxygen or nitrogen. 

The rate of the bifunctionally catalyzed solvolysis of CCXX-A was found to be 1000 times faster than that of the unassisted 16jS-axial acetate ester CCXXI (see Table II). Conversion of the ester CCXXI into the l,3-diaxial-20-hydroxy-16-acetate CCXXIII resulted in a 40-fold increase in rate of solvolysis. Participation of the alkaloid nitrogen in the facilitation of solvolysis of CCXX-A was supported by the 25-fold increase in the rate of solvolysis relative to the formamido ketone CCXXIII. Intramolecular base catalysis of the solvolysis of CCXX-A and CCXXII was confirmed by the experimentally determined buffer ratio-rate profile and by the results obtained upon variation of buffer concentration at different buffer ratios (119). 

Deoxy-5 -isocyanonucleosides of type (88, B=T, U X=OH, N3) have been prepared by dehydration of the 5 -formamido-compounds. 06 Although detailed discussion is beyond the scope of this report, the preparation of compounds of type (89) in which S -amino-S -deoxyadenosine is linked via a spacer to a derivative of Kemp s triacid is noteworthy. Rebek s fascinating work on self-replicating systems has shown that these compounds catalyse their own formation from the adenosine derivative and an active ester of the left-hand side.iO O ... 

The formamides are sufficiently, stable to find wide use, particularly in peptide synthesis. An important general method for preparing a-amino acids starts from a malonic ester and involves nitrosation, reductive formylation, and alkylation of the formamido-malonic ester (4) [27-29]. The corresponding acetamido [28, 20-32] and benzamido [33, 34] derivatives have also been used. In conventional peptide synthesis the formyl group has been used to protect oc-amino acids while coupling them to oc-amino esters [35]. Mild, selective hydrolysis... 

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