Bis-phosphoramides

Ligands 35 and 36 were prepared from precursor 10 and from unprotected cyclen, respectively, using standard methods. Ligands 38 and 39, which have the uncommon 1,7-substitution pattern, were prepared with 4,10-protection of the cyclen residue achieved using bis(phosphoramide) 37 (57). The Zn(II) complexes of 35, 36, 38, and 39 as well as 32 selectively bind to the adenine/thymine-rich regions of double-stranded DNA via the thymine base using the fifth coordination site of the Zn(II) ion. 

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. A SiCl4-mediated reaction in the presence of a chiral bis-phosphoramide gives an a-hydroxy amide with good enantioselectivity. The following mechanism has been postu-... 

Scheme 12.34) [87]. In this procedure bis-phosphoramides with a methylene tether prove more advantageous for achieving high enantioselectivity than the mono-phosphoramides, strongly supporting a two-phosphoramide pathway [88]. 

Denmark has described several chiral bis-phosphoramides as Lewis base activators of weak Lewis acid SiCL and demonstrated their ability to mediate an enantioselective Passerini-type reaction. Catalytic bis-phosphoramide 36 and stoichiometric SiCU, in the presence of a proton scavenger (Htinig s base), promoted the formation of a-hydroxyamides with remarkably good enantioselectivity and yield. A variety of aromatic and unsaturated aldehydes and aryl, alkyl, and functionalized alkyl isocyanides proved to be useful and effective starting materials. High yields of Passerini products were attributed to the production of imidoyl chloride 37, which reduced the prevalence of the nitrilium intermediate and prevented the addition of a second equivalent of isonitrile. 

This system could be successfully extended to the catalytic enantioselective crossed-aldol reaction of aldehydes [3], The geometrically defined ( )- and (Z)-trichlorosilyl enol ethers of aldehydes underwent efficient, highly diastereoselec-tive addition to different aldehydes under the influence of chiral bis-phosphoramide 2, which possess a tether of five methylene units, to give the corresponding anti-and syn-P-hydroxy aldehydes as a form of dimethyl acetal, respectively, with good yet variable enantioselectivity (Scheme 7.2). 

In addition, this class of chiral phosphoramides could catalyze the enantioselective ring opening of epoxides with silicon tetrachloride (SiCfl) [4]. For instance, the reaction of ds-stilbene oxide with SiCl, proceeded smoothly in the presence of 1 to afford the desired chlorohydrin in an enantiomericaUy enriched form (Scheme 7.3). The reactive ion pair shown in the scheme was proposed to be generated through the activation of SiCl, by the coordination of one phosphoramide 1, serving to activate the epoxide it was confirmed that bis-phosphoramide 2 was far less selective in this reaction. 

Scheme 7.4 Catalytic activation of SiCl4 with chiral bis-phosphoramide 2.

This concept has been further applied to the development of various stereoselective bond-forming reactions using chiral bis-phosphoramides as catalysts. The most well-explored system is the aldol addition of silyl ketene acetals to aldehydes [6). In general, combination of a catalytic amount of 2 and a stoichiometric quantity of SiCl, was very effective for the reactions of methyl acetate-derived silyl ketene acetal with various aldehydes (Scheme 7.5). 

An analogous propargylation can be attained with allenyl tributylstannane however, this reaction is catalyzed by SiCk that is activated by a bis-phosphoramide catalyst. Note that, in this case, the role of the Lewis basic phosphoramide is to increase the Lewis acidity of SiCLj rather than to increase the nucleophiUcity of the stannane [66bj. For a discussion of these effects, see Section 15.4. ... 

Benzaldehyde (1, R = Ph) (100pi, 2.0mmol, 1.0 equiv) was added in one portion to a solution of bis-phosphoramide (R,R)-81 (84mg, 0.1 mmol, 0.05 equiv) at-78°C under nitrogen in a flame-dried, round-bottom flask with a magnetic stirrer, followed by SiCLj (252 pi, 2.2 mmol, 1.1 equiv) and the mixture was stirred at -78 °C... 

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