Regiospecific and Enantiospecific Ring Opening of Methyl (+)-(1'R, 2R)- and (-)-(1'R, 2S)-1-(2-phenylethanol) Aziridine-2carboxylates

The acid-catalyzed ring-opening of methyl (+)-(1'R, 2R) and (-)-(1'R, 2S)-1-(2-phenylethanol) aziridine-2-carboxylates (1) and (2) lead quantitatively to the corresponding 2(S)-(-)-chloro-3-[2'-hydroxy-1'(R)-phenyl-ethylamino] propionic acid methyl ester (3) and 2(R)-(-)-chloro-3-[2'-hydroxy-1'(R)-phenyl-ethylamino] propionic acid methyl ester (4) hydrochlorides.


Introduction
The ring-opening reactions of aziridines by hydrogen halides, water and other nucleophiles are among the oldest known reactions of aziridines and have been studied extensively [1][2][3].The ringopening of aziridines provides a route for the synthesis of haloamines.
The strain associated with the three member ring of aziridine accounts for its reactivity towards ring opening, while additional regio-and stereochemical control on the ring opening reaction can be gained by the presence of specific substituents.We are concerned with the stereochemical control of such ringopening reactions, which becomes very important in regard to making these reactions synthetically useful.
The mechanism and regioselectivity of the acid catalyzed ring-opening of the nonactivated aziridine-2-carboxylates may exhibit important differences, depending on the conditions used, as it was demonstrated by E. Kyburz  To the present, the mentioned reaction shows more often poor regioselectivity and it is less common to find reports where the ring-opening of aziridines occurs with high regio-and stereospecificity.[5][6][7][8].1) and (2) were obtained in good yield after reaction of racemic methyl 2, 3-dibromopropionate [9] with (R)-(-)-2phenylglycinol [10].Flash chromatography readily afforded each diasteromer in pure form [11].
The 1 H and 13 C NMR spectral data for each crude reaction showed only one product.These results were consistent with the single spots observed by TLC.Finally, the solvent was removed in vacuo affording the corresponding (3HCl) and (4HCl) in quantitative yields respectively.
Two sets of 1 H NMR spectra were performed for compound (3HCl); a dramatic improvement in resolution was achieved after addition of a small amount of DMSO-d 6 .In addition, this allowed the precise measurement of coupling constants.Important differences in chemical shifts were found in the 1 H NMR spectra for (3HCl) and (4HCl) hydrochlorides after addition of DMSO-d 6 .These results confirm that each diasteromer was obtained in pure form and has a particular 1 H NMR spectrum that can be clearly identified (Scheme 2. See Experimental).
Next, a single crystal of (4HCl) was obtained and X-ray diffraction analysis performed.The absolute configuration for C-4(R) and C-2(R) was established from the known configuration of (R)-(-)-2phenylglycinol. Based on X-ray diffraction analysis of (4HCl) and the NMR of (3HCl) and (4HCl), we concluded that the stereochemical configuration of (3HCl) was C-4(R) and C-2 (S) (Figure 1).
Finally, based on these results, we concluded that the ring-opening was enantiospecific [12].This can be explained by an SN 2 mechanism in which chloride ion attacks C-2 with total inversion [13].An SN 1 mechanism is not possible because C-2 is α to a carbonyl group which is not capable of stabilizing a positive charge.
The regiospecific ring-opening by the chloride ion could be explained by the increasing of the electrophylicity in C-2, via intramolecular hydrogen bonding between the carboxyl methyl ester and the hydroxyl group.
The participation of the hydroxyl group in the regiospecific ring-opening was confirmed by the ringopening of methyl (-)-(1'S, 2R) (phenylethyl)aziridine-2-carboxylate, carried out in the conditions previous described, affording the corresponding (3HCl) and (4HCl) in quantitative yields respectively.
To the best of our knowledge, this is the first report of the regio-and enantiospecific ring-opening of nonactivated enantiopure aziridine-2-carboxylates derivatives of (R)-(-)-2-phenylglycinol.

General
Melting points were determined in open capillaries and are uncorrected.IR spectra were recorded in KBr disks on a Nicolet Magna-750 spectrophotometer.NMR spectra were measured on Varian Unity 300 and 500 MHz.Spectrometers, using TMS as internal standard.Optical rotations were measured on a Perkin-Elmer Polarimeter M241.The X-ray structure was determined on a Siemens P4/PC diffractometer.Elemental analysis was carried out on a Perkin-Elmer 2400 CHN analyzer.