Intramolecular chiral relay at stereogenic nitrogen. Synthesis and application of a new chiral auxiliary derived from (1R,2S)-norephedrine and acetone.
(1R,2S)-Norephedrine has been employed in the synthesis of a novel 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one via reductive alkylation with acetone, N-nitrosation, reduction, and cyclization. The oxadiazinone was treated with either propionyl chloride or 3-thiophenylpropionyl chloride to afford the corresponding N(3)-acylated oxadiazinones 9a and 9b, respectively. X-ray crystallographic analysis of the N(3)-thiophenylpropionyl oxadiazinone 9b revealed that the C(2)-urethane carbonyl and the N(3)-carbonyl are arranged in an anti-periplanar conformation. The oxadiazinones were subsequently applied in the titanium-mediated asymmetric aldol addition reaction by treatment with titanium tetrachloride, triethylamine, and a variety of aldehydes at 0 degrees C. The aldol adducts 10a-i and 11a,b were found to have diastereoselectivities ranging from 8:1 to >99:1 favoring the formation of the non-Evans syn configuration. The absolute stereochemistry of the adduct 10a was determined by acid hydrolysis. This process afforded the N(4)-isopropyloxadiazinone 8 and (2S,3S)-3-hydroxy-2-methyl-3-phenylpropanoic acid 14 in >/=95% enantiomeric excess.
Hitchcock
Shawn R
SR
Department of Chemistry, Illinois State University, Normal, Illinois 61790-4160, USA. hitchcock@xenon.che.ilstu.edu
Casper
David M
DM
Vaughn
Jeremy F
JF
Finefield
Jennifer M
JM
Ferrence
Gregory M
GM
Esken
Joel M
JM
D000096:Acetone / Q000737:chemistry*; D000215:Acylation; D000447:Aldehydes / Q000737:chemistry; D000478:Alkylation; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D010084:Oxidation-Reduction; D010665:Phenylpropanolamine / Q000737:chemistry*; D013237:Stereoisomerism
D000447:Aldehydes; D010069:Oxadiazoles; D000096:Acetone; D010665:Phenylpropanolamine; D009584:Nitrogen