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A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.

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Experimental SectionMelting points were determined on a Mel-Temp apparatus and are uncorrected.NMR spectra were measured on Varían A-60A and JOEL FX-90Q NMR spectrometers. Optical rotations were measured on a Perkin-Elmer 241 polarimeter. Solvents were purified by standard methods. Diastereomeric oxaziridines 1-4 were prepared as previously described10 and were greater than 95 % ee. Sulfides were prepared by standard methods.Oxidative Kinetic Resolution Procedure. In a 5-mL, single-necked round-bottom flask equipped with magnetic stirring bar and drying tube was placed 0.8 mmol of the appropriate sulfoxide, 6a or 6b, in 1 mL of the designated solvent. The chiral oxaziridine, 0.4 mmol, was added as a solid portionwise with stirring to the reaction mixture. After 24 h of stirring at 25 °C, the solvent was removed under vacuum. The residue was taken up in a minimum of CHC13 and the sulfoxide isolated by preparative TLC (silica gel) using chloroform. Methyl p-tolyl sulfoxide (6a) required a second purification by TLC, developing with pentane-chloroform (1:1). Two-Step Kinetic Resolution Procedure. In a 10-mL, round-bottom flask equipped with a magnetic stirring bar and drying tube was placed 38 mg (0.27 mmol) of methyl p-tolyl sulfide (5a) in 1 mL of chloroform. The reaction mixture was cooled to -50 °C in a dry ice/methanol bath, and 132 mg (0.27 mmol) of oxaziridine (+)-(RJl)-4 in 1 mL of chloroform was added dropwise. After 1 h of stirring at room temperature, an additional 66 mg (0.135 mmol) of oxaziridine (+)-(Rfi)-4 was added. The reaction mixture was allowed to stir for 24 h, and methyl p-tolyl sulfoxide (6a) was isolated as described above. The optical purity of the sulfoxide, 11.4 mg (54%), was determined to be 27.9 % ee by using a chiral shift reagent.General Procedure for Determining Optical Purities of Sulfoxides. Optical yields were ascertained by comparing the optical rotations of sulfoxides 6a,b obtained via kinetic resolution using chiral 2-sulfonyloxaziridines 1, 3, and 4 with those reported in the literature.10 The optical yields determined in this manner were verified by comparing a series of 60-and 90-MHz 1 2H NMR spectra (CDC13) at increasing concentration of the chiral shift reagent tris [3 [(heptafluoropropyl)hydroxymethylene)]-d-camphorato]europium(III) derivative [Eu(hfc)3]. When the shift difference of the appropriate absorption was at least 9 Hz, the peak areas were determined by integration. Agreement between the two methods was approximately ±1.0 % ee.All asymmetric oxidations were carried out at least twice and the results averaged (Table I).Acknowledgment. Financial support from the National Science Foundation through Grant No. CHE-8114769 and Merck Sharp and Dohme are gratefully acknowledged. We thank a referee for constructive criticism.Registry No.