N-Methyl b-amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3-oxazolidin-5-ones to synthesise N-methyl a-amino acids. Starting from a-amino acids, two approaches were used to prepare the corresponding N-methyl b-amino acids. First, a-amino acids were converted to Nmethyl a-amino acids by the so-called 1,3-oxazolidin-5-one strategy, and these were then homologated by the Arndt-Eistert procedure to afford N-protected N-methyl b-amino acids derived from the 20 common a-amino acids. These compounds were prepared in yields of 23 -57% (relative to N-methyl a-amino acid). In a second approach, twelve N-protected a-amino acids could be directly homologated by the Arndt-Eistert procedure, and the resulting b-amino acids were converted to the 1,3-oxazinan-6-ones in 30 -45% yield. Finally, reductive cleavage afforded the desired N-methyl b-amino acids in 41 -63% yield.
One sterically congested b-amino acid, 3-methyl-3-aminobutanoic acid, did give a high yield (95%) of the 1,3-oxazinan-6-one (65), and subsequent reductive cleavage gave the corresponding AIBN-derived N-methyl b-amino acid 61 in 71% yield (Scheme 2).
Thus, our protocols allow the ready preparation of all N-methyl b-amino acids derived from the 20 proteinogenic a-amino acids.
Experimental Part
General. AcOEt and hexane used for chromatography were distilled prior to use. All solvents were purified by distillation. For anh. solvents, procedures from Perrin and Armarego [42] were followed. Anh. CH 2 Cl 2 was distilled and stored over Linde-type 4-molecular sieves. All other reagents and solvents were purified or dried as described in the literature [42]. The following compounds were prepared previously: 68 [43], 69 [44], 70 [45], and 150 [37]. All melting points (m.p.) are uncorrected and were recorded on a microscope hot-stage apparatus. Infrared (IR) spectra were recorded on an FT-IR spectrometer, using a diffuse reflectance accessory with KBr background; in cm À1 . NMR Chemical shifts d and coupling constants J are reported in ppm (rel. to Me 4 A C H T U N G T R E N N U N G Si) and in Hz, resp. Electrospray mass spectra (ESI-MS) were obtained on a triple quadrupole mass spectrometer using H 2 O/MeOH/AcOH 0 : 99 : 1:0 or 50 : 50 : 1 as the mobile phase. Low-and high-resolution mass spectra (l.s.i.m.s.) were recorded at the University of Tasmania by Dr. Noel Davies and co-workers.
General Procedure for the Preparation of the Diazoketones 14 -24 and 67 of N-(Benzyloxycarbonyl)-Protected L-Amino Acids. The Cbz-protected L-a-amino acid (1 mmol) was dissolved in anh. THF (25 ml) and cooled to À 158. To this soln., ethyl chloroformate (1.05 mmol) and N-methylmorpholine (NMM, 1.05 mmol) were added successively, and the mixture was stirred for 15 min. Then, an anh. soln. of CH 2 N 2 (5 mmol; CAUTION!) [24] in CH 2 Cl 2 was added slowly, and the yellow soln. was allowed to warm to r.t. Stirring was continued until there was no acid remaining (TLC control). Excess CH 2 N 2 was destroyed by addition of AcOH. The mixture was concentrated under reduced pressure, and the residue was taken up in AcOEt. The org. phase was washed successively with sat. aq. NaHCO 3 soln., 10% aq. citric acid, and brine. The org. layer was dried (MgSO 4 ), filtered, and evaporated to dryness in vacuo. The product was of sufficient purity to be directly used in the next reaction. An anal. sample was purified by flash chromatography (FC) for characterization. The anal. data of 14 [46], 16 [47], 17 [48], 18 [49], 19 [50], 20 [51], 21 [52], and 22 [51] were identical to those previously described. Phenylmethyl [(1S)-3-Diazo-1-ethyl-2-oxopropyl]carbamate (15). Yield: 65%. Clear yellow oil. [a] 19