Imino esters aminal ester synthesis

Alkylations by oxonium salts have added several new weapons to the synthetic chemist s armamentarium. For example, the O-alkylated products from amides [R1C(OR)=NR2R3]+ (R == CH3 or C2H5) may be hydrolyzed under mild conditions to amines and esters,14-34 reduced to the amines RjCH-jNRaRa by sodium borohydride,13 converted to amide acetals RiC(OR)2NR2R3 by alkoxides,4-16 and (for R3 = H) deproton-ated to the imino esters R1C(OR)=NR2.16-18 Amide acetals and imino esters are themselves in turn useful synthetic intermediates. Indeed, oxonium salts transform the rather intractable amide group into a highly reactive and versatile functionality, a fact elegantly exploited in recent work on the synthesis of corrins.34... 

An enantioselective synthesis of amino acids has been examined using chiral nonracemic a-imino esters (36) derived from (S)-l-phenylethylamine and (-)-l-cyclohexylethylamine (equation 9, Table 9). Allyl-magnesium, -copper and -titanium reagents react at both the imine and ester carbon atoms of (36), a result of the molecule s ambient electrophilicity. The addition of allyl-, methallyl- and prenyl-9-BBN and -ZnBr to a-imino ester (36), however, generates amines (38) and (39). While the absolute stereochemistry of (38) and (39 R = Ph) has been determined (entries 1-4, Table 9), that of the cyclohexyl-ethylamine-derived products has not (entries 5-8, Table 9). 

On the other hand, the Gong group reported the enantioselective [l,5]-hydride transfer/cyclization reaction between ortho tertiary amine substituted aromatic keto esters 33 and aromatic amines 34 catalyzed by chiral bisphosphoric acid (1 ,1 )-C8, developed in their own group (Scheme 4.16). In this reaction, the in situ formed a-imino esters 36 act as the hydride acceptors, allowing the efficient synthesis of cyclic aminals 35 in high stereoselectivity (up to 14 1 dr, 90% ee). 

A report from the Jorgensen laboratories detailed the enantioselective synthesis of P-phosphonic acid a-amino acid derivatives through a Cu(II)-catalyzed addition of P-keto phosphonates to an N-tosyl-a-imino ester [41]. Once again Cu(OTf)2/t-Bu-BOX (13) was found to provide the highest enantioselectivity in addition of P-keto phosphonate (141) to N-tosyl-a-imino ester (142) (Scheme 17.28). The identity of the amine base used for P-keto phosphonate deprotonation also proved critical to reaction efficiency and selectivity. Triethylamine provided the best combination of reactivity and selectivity, but it should be noted that the diastereomeric ratio was doubled when 2,6-lutidine was used as the base in the reaction. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

Although there is no reaction directly related to the Breckpot )0-actam synthesis, other methods of preparing )0-lactams include the cycloaddition of imino compound with ketene, the reaction between diazomethane and isocyanate and the use of bromomalonic ester and primary amine. ... 

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