α-氨基酰胺类化合物的立体选择性合成新方法

Novel Method for Stereoselective Synthesis of α-Aminoamide Compounds

以(R)-1-苯乙胺为起始原料,合成了手性氨甲酰基硅烷4。通过4与无手性的亚胺5a、5b和5c以及有手性的亚胺7a、7b和7c反应,得到了立体选择性加成产物α-氨基酰胺衍生物6b、6c、8a、8b和8c,其中6c、8a和8c是高立体选择性产物。手性氨甲酰基硅烷与亚胺的反应具有立体选择性,其立体选择性大小与在亚胺双键氮原子和碳原子上所连的取代基有关,因此通过选择不同的取代基可有效地不对称合成α-氨基酰胺衍生物。

As representatives of the smallest subunit of peptides and proteins, α-aminoamides are important synthetic targets. To construct such species by establishing the carbon-carbon bond in a-position of the carbonyl group is often accomplished by the Ugi reaction, in which it affords an α-（N-acyl-N-alkylamino）amide containing a new stereogenic center at the α-carbon atom. However, there are several limitations of this approach, so an approach which can directly afford a high diastereoselective α-aminoamides is explored. It was found thatα-aminoamides can be obtained through adding carbamoylsilanes to the C = N bond of imine under promotion of equal molar amounts of BF3 · Et20. For efficient applying this reaction to synthesis of stereoselective products, enantio-enriched substrates are necessary. After exploring the potential of both single and double stereo-differentiation in these addition reactions by incorporating chiral N-auxiliaries into the imine and/or carbamoylsilane components, a chiral carbamoylsilane 4 has been synthesized using （R）-1-phenylethylamine as starting material. The reactions of chiral carbamoylsilane 4 with imines 5a, 5b, 5c and chiral imines 7a, 7b, 7c can afford stereoselective addition products 6b, 6c, 8a, 8b and 8c. Among them, 6c, 8a and 8c are highly stereoselective products. A comparison of the results obtained from 5b, 5c, 7a, 7b and 7c indicated that stereoselectivity of the reaction of chiral carbamoylsilane with imines is directly related to substituted group on C = N double bond of imines. This is a possible route to obtain enantio-pure α-aminoamides.