Asymmetric synthesis of alpha-amino acids based on carbon radical additionto glyoxylic oxime ether

The first asymmetric synthesis of cr-amino acids based on diastereoselectiv e carbon radical addition to glyoxylic imine derivatives is reported. The a ddition of an isopropyl radical, generated from i-PrI, Bu3SnH, and Et3B in CH2Cl2 at 25 degrees C, to achiral glyoxylic oxime ether 1 proceeded regios electively at the imino carbon atom of the oxime ether group to give an exc ellent yield of the C-isopropylated product 2. The competitive reaction usi ng glyoxylic oxime ether 1 and aldoxime ether 4 showed that the reactivity of the glyoxylic oxime ether toward nucleophilic carbon radicals was enhanc ed by the presence of a neighboring electron-withdrawing substituent. Thus, the alkyl radical addition to glyoxylic oxime ether 1 proceeded smoothly e ven at -78 degrees C, in contrast to the unactivated aldoxime ether 4. A hi gh degree of stereocontrol in the carbon radical addition to the glyoxylic oxime ether was achieved by using Oppolzer's camphorsultam as a chiral auxi liary. The stannyl radical-mediated reaction of the camphorsultam derivativ e 6 with an isopropyl radical at -78 degrees C afforded a 96:4 diastereomer ic mixture, 7a, of the C-isopropylated product. The reductive removal of th e benzyloxy group of the major diastereomer (R)-7a, by treatment with Mo(CO )(6) and the subsequent removal of the sultam auxiliary by standard hydroly sis, afforded the enantiomerically pure D-valine (R)-12 without any loss of stereochemical purity. To evaluate the new methodology, a variety of alkyl radicals were employed in the addition reaction which gave the alkylated p roducts 7 with excellent diastereoselectivity, allowing access to a wide ra nge of enantiomerically pure natural and unnatural a-amino acids. Even in t he absence of Bu3SnH, treatment of 6 with alkyl iodide and Et3B at 20 degre es C gave the C-alkylated products 7 with moderate diastereoselectivities. The use of Et2Zn as a radical initiator, instead of Et3B, was also effectiv e for the radical reaction. The enantioselective isopropyl radical addition to 1 using (R)-(+)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) and MgBr2 gave excellent chemical yield of the valine derivative 2 in 52% ee.