1,4-Oxazines via intramolecular ring closure of .beta.-hydroxydiazoacetamides: phenylalanine to tetrahydroindeno[1,2-b]-1,4-oxazin-3(2H)-ones

Abstract

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.

Synthesis of optically active N‐protected α‐aminoketones and α‐amino alcohols

“…Although arylation of amino acids has been reported [12], the yield was very low and the admired ketone was hard to separate from the reaction mixture. Moreover, Friedel-Crafts reaction of the acid chloride was very sluggish and the product was not isolable because of contamination of impurities [13]. However, the Grignard reaction of the Weinreb amides 2 and 6 has overcome these problems associated with the aforementioned two methods.…”

Amino Acids as a Chiral Pool: Synthesis of (S)‐and (R)‐2‐N‐Carbomethoxy‐5‐aminoindane from (S)‐ and (R)‐Phenylalanines

“…Unsubstituted phenylalanine undergoes intramolecular Friedel -Craft aminoacylation to afford 2-amino-1-indanone. [5,6] Thus, carbomethoxylation of (S)-phenylalanine under Schotten -Baumann Scheme 1.…”

“…One of the major hurdles was to avoid the racemization of the 2-carbomethoxyamino-1-indanone (3). [5,6] Reverse quenching of the reaction mixture at low temperature (25 to 18C) into 3 N HCl over 45 min controlled racemization. The pH of the mixture had to be adjusted to 6.9 by adding aqueous sodium bicarbonate.…”

“…Although chiral cis-1-amino-2-indanol has been studied extensively, [1,4] the isomeric 2-amino-1-indanol and its aromatic-substituted derivatives have been studied to a limited extent. [5,6] We envisioned that an appropriately protected chiral 2-amino-1-indanol derivative, prepared from a chiral amino acid, might lend itself to regioselective nitration, which upon further manipulation would provide the target compound. Unfortunately, literature points to a severe racemization problem of the amino ketone intermediate in this synthesis.…”

“…Unfortunately, literature points to a severe racemization problem of the amino ketone intermediate in this synthesis. [5,6] Despite this, we decided to pursue this approach because the absolute configuration at the C-2 center of the target compound is known, cheaper and easily accessible starting materials are available, and racemization might be controlled through optimized reaction conditions. In this article, we describe a synthesis of enantiomerically pure [(R)-8] and [(S)-8] from optically pure phenylalanines.…”