Synthesis and Structural Characterization of Trivalent Amino Acid Derived Chiral Phosphorus Compounds

Abstract

Reaction of the N-toluenesulfonyl derivatives of (S)-alanine, phenylalanine, and valine (4-6) with PhPCl(2) gave in high yield the 4-methyl, benzyl, and isopropyl derivatives (7-9) of 2-phenyl-1-p-toluenesulfonyl-1,3,2-oxazaphospholidin-5-one. The ratios of the (2S,4S)/(2R,4S) diastereomers (cis/trans isomers) were 1:1, 2:1, and 10:1 for the methyl, benzyl, and isopropyl derivatives 7a,b, 8a,b, and 9a,b, respectively. For 7a,b, both isomers could be crystallized, but for the others only the major isomers were isolable. The X-ray crystal structure of 9a shows that the isopropyl and phenyl groups are mutually cis and that the tolyl moiety is oriented s-trans to both the isopropyl and phenyl groups. Reaction of 6 with Cl(2)PCH(2)CH(2)PCl(2) (10) gave a 56:38:7 mixture of the cis/cis, cis/trans, and trans/trans diphosphorus heterocycles 11a-c. The major isomer could be crystallized and isolated free of the other diastereomers. Reaction of 6 with EtPCl(2) gave a 6:1 mixture of cis/trans isomers of the ethyl-substituted heterocycles 12a,b as an inseparable oil but allowed confirmation of the structure of 11a. Slow epimerization at phosphorus may occur by inversion but more likely by ring opening/closure, since 7b, 9a, and 11a give rise upon standing in solution to mixtures containing starting material and 7a, 9b, and 11b, respectively, along with the free amino acid derivatives 4 and 6. The NMR spectra, and in particular the coupling constants between the alpha-hydrogen atom of the amino acid moiety and phosphorus, were used to establish the identities of the cis and trans isomers. Reaction of 9a with (THF)W(CO)(5) gave the phosphorus-ligated adduct (9a)W(CO)(5) (13), and the IR spectrum of this complex shows that 9a is a strongly electron-withdrawing ligand. The geometry of the sulfonamide moiety is discussed in detail, as are the (1)H NMR coupling constants. The data are consistent with the presence of little steric interaction between the cis isopropyl and phosphorus substituent in 9a, 11a, and 12a and orientation of the tolyl moiety s-cis to the isopropyl group in 9b, 12b, and 13.

Stereoselective Synthesis of P-Chiral Phosphorus Compounds from N-tert-Butoxycarbonyl Amino Acids

“…The stereoselectivity was presumed to arise by minimization of steric interactions between the phenyl groups. Like ephedrine, amino acids and their N -substituted derivatives have the same β-nitrogen−oxygen functionality, and have similarly been used to give 1,3,2-oxazaphospholidinones. − Until our report of the use of N -toluenesulfonylvaline, however, none of the amino acid examples had been shown to lead to diastereomerically pure heterocycles. In contrast to the ephedrine example, the N -sulfonamide amino acid derivative gave the cis-substituted heterocycle 2 .…”

“…In contrast to the ephedrine example, the N -sulfonamide amino acid derivative gave the cis-substituted heterocycle 2 . Here, the stereoselectivity was shown to arise for steric reasons, since the use of N -toluenesulfonylalanine, having a methyl instead of an isopropyl group on the β-carbon, gave a 1:1 cis:trans ratio of 3a : 3b . , We proposed that the selectivity was driven by repulsive steric interactions of the toluenesulfonyl moiety with the neighboring isopropyl and phenyl groups. We have now extended this method to the use of N - tert- butoxycarbonyl (Boc) derivatives of amino acids, a study that was initiated to investigate the utility of other electron-withdrawing moieties on nitrogen.…”

A Non-Karplus Effect: Evidence from Phosphorus Heterocycles and DFT Calculations of the Dependence of Vicinal Phosphorus–Hydrogen NMR Coupling Constants on Lone-Pair Conformation

“…35 Unlike typical N -alkyl 1,3,2-oxazaphospholidines which adopt an envelope conformation, 36,45,46 the N -Boc derivative is planar, resulting from the presence of two sp 2 centers in the ring, namely, the ring carbonyl carbon and the amide nitrogen. Due to this planarity, the PNCH and PNCC(isopropyl) dihedral angles (−118.7° and 119.9°, respectively) are nearly equal albeit opposite; for the purposes of this paper, since the sign of the dihedral angle is relevant, all values are reported for the S P configuration – i.e.…”

“…The X-ray crystal structure of the N -toluenesulfonylvaline-derived heterocycle 6a has been described in detail; 36 it exhibits an envelope conformation and non-identical PNCH and PNCC(isopropyl) dihedral angles of 139.0° and −98.4°. Optimization of this structure as described above but without the PCM calculation again gave a similar structure, with for instance very similar dihedral angles of 135.0° and −102.8°.…”

“…34–36 While there is a long history of related syntheses of amino acid-derived heterocycles, 37–43 until our work there were no reports of diastereoselectivity, and so one focus of our analysis was the proof of relative stereochemistry of the ring substituents. This was done using a combination of X-ray and NMR methods.…”