N-Tosyl-a-imino ester

Two examples of such applications are outlined in Scheme 3. In the first one imidazolidinone la 10 mol% catalyzed the conjugated addition of a plethora of variously substituted N,N-disubstituted anilines to ,/fun saturated aldehydes to afford highly enantiomerically enriched /3-aryl aldehydes 5 (ee 89-97 %) in good yields (>73 %) [3]. On the other hand, the use of cationic BINAP-Cu complexes 6 (1-5 mol%) was found to be effective in the stereocontrolled 1,2-addition of indoles to the N-tosyl-a-imino ester 7 in TFIF at -78 °C [4]. 

The chiral Cu(OTf)2/BOX complexes 8 and 9 are also catalysts of asymmetric Mannich-type additions of unmodified malonates and /3-ketoesters to activated N-tosyl-a-imino esters [22]. 

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. 

Two general approaches to aza-Diels-Alder reactions have been reported. One incorporates the requisite nitrogen atom into the 2rt component (imine), while the other incorporates the requisite nitrc en in the 4rt component (azadiene). Chiral copper Lewis acids have been used with success in both approaches. Jorgensen and coworkers reported enantioselective imino Diels-Alder reactions catalyzed by CuC104 MeCN in the presence of phosphino-oxazoline (287) or BINAP (290) (Scheme 17.64) [93]. Phosphino-oxazoline (287) proved to be the ligand of choice in the aza-Diels-Alder reaction of N-tosyl a-imino ester (142) with Danishefsky s diene (286), while BINAP (290) gave the highest selectivity when dimethyl-substituted Danishefsky s diene (289) was used. 

Finally, a catalytic enantioselective approach for the formation of allyl a-amino acid derivatives by reaction of N-tosyl-a-imino esters with alkylstannanes catalyzed by chiral Cu complex was developed [162]. 

Table 15.2 Enantioselective Mannich reaction of ethyl 2-methylacetoacetate with N-tosyl-a-imino methyl ester catalyzed by Pr-trisox/Cu(CI04)2 or Pr-B0X/Cu(CI04)2 [24a].

Azetidine-2-carboxylic acid (2) is commercially available. It is readily prepared as the racemate by refluxing 2,4-dibromobutyric acid ester with benzhydrylamine in acetonitrile. If benzyl 2,4-dibromobutyrate is treated with benzhydrylamine, the resulting benzyl TV-benz-hydryl-D,L-azetidine-2-carboxylate is hydrogenolytically processed to D,L-azetidine-2-car-boxylic acid in a one-step reaction. 101,107 Resolution of the racemate can be performed by the method of Vogler 108 via fractional crystallization of the Z-D,L-Aze-OH-H-Tyr-N2H3 salt thereby the salt of the D-imino acid precipitates first from methanol. 96 A stereoselective synthesis of A-tosyl-L-azetidine-2-carboxylic acid can be achieved by a two-step reaction from N-tosyl-L-homoserine lactone. 94 ... 

Kresze and coworkers have found about a three order of magnitude rate increase in imino ene reactions when an N-tosyl group is replaced with an N-perfluoroalkanesulfonyl moiety [87]. Thus, with the glyoxylate ester-derived imine and the one from chloral 255 as the enophiles, reactions with acyclic olefins are very rapid and occur at room temperature [Eq. (60)]. In these ene reactions one stereoisomeric homoallylic amine 256 was typically generated, although the stereochemistry was not elucidated. However, in one reported case a 1 1 mixture of diastereomers was obtained. Mechanistic studies based upon kinetic isotope effects seem to indicate that this reaction may in fact be a two-step process rather than a concerted one [87b]. 

Lectka developed a series of enantioselective addition reactions of various nucleophiles to N-tosyl imino ester 110 mediated by Cu-complex 216 (Equation 17) [31, 152, 153]. In Mannich additions of enol silanes such as 215, high optical purity and yield were obtained with catalyst loadings as low as 2mol%. The reaction is notable for its convenience of execution and... 

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