| alpha-Arylglycines are amino acid constituents of medically important therapeutics such as natural product macrolides, man made antibiotics, and other synthetic drug substances. The N-p-tolylsulfinyl group is a chiral auxiliary that enables the diastereoselective synthesis of alpha-arylaminonitriles when used in the Strecker reaction. The product alpha-arylaminonitriles can then by hydrolyzed to access alpha-arylglycines.; Initially, two methods for preparing p-tolylsulfinimines from aldehydes were compared. One method consisted of a one step synthesis using Andersen's reagent and arylaldehydes and gave good yields, 44--85%. A second two-step approach involved the preparation of a primary p-tolylsulfonamide, and a second step in which the sulfonamide was condensed with arylaldehydes yielding p-tolylsulfinimines 63--92% yields.; The sulfinyl mediated Strecker reaction was investigated by evaluating the roles of temperature, aberrant moisture, ligands used in reagent preparation, aryl ring substitution, and substitution of the p-tolylsulfinyl group had on the diastereoselective outcome of the reaction. When p-tolylsulfinimines were not sufficiently dried prior to using in the Strecker reaction, diastereoselectivities were eroded to 42--70% versus 70--84% for dessicated sulfinimines. When the reaction was run at room temperature the diastereoslectivity of the Strecker reaction was a modest 50%. Lowering the temperature at which the reagents were initially combined raised the observed diastereoselectivities to 70% or better. Replacement of the p-tolylsulfinyl group with a 2-methoxynapthylsulfinyl group, or the t-butylsulfinyl group yielded comparable diastereoselectivities for the Strecker reaction of 86% and 78%, respectively. Substitution of isopropanol in the Strecker reaction with bi-dentate ligands, such as ethylene glycol, accelerated the reaction with complete conversion to products within one hour but diastereoselectivities were poor (20--60%). Swapping isopropanol with water, on the other hand, yielded nearly equivalent stereoselectivities of 60--70%. The effect of aryl ring substitution was compared for several phenyl-p-tolylsulfinimines in the Strecker reaction. Little divergence in the diastereoselectivities was observed (61--79%). By treatment with hot, aqueous acid, several alpha-aminonitriles were converted to enantiomerically pure alpha-arylglycines in 58--80% yields. Finally, the utility of the Strecker reaction was demonstrated by preparing (R)-(-)-3,5-dichloro-4-methoxyphenyl glycine, a protected alpha-arylglycine found in several macrolide antibiotics, in 63% yield and >95% enantiomeric excess. |
