Chirality Transfer and Oxazolidine Formation in Reaction of L and D Enantiomers of β-Hydroxy Amino Acids with Nitrogenous Carboxaldehydes and Nickel(II)

Abstract

The reaction of either the L (2S3R) or D (2R3S) enantiomers of H₂N-C*H(R)CO₂^- (R = -C*H(OH)CH₃ or -C*H(OH)CH(CH₃)₂) and the L (2S) or D (2R) enantiomers of H₂N-C*H(C(CH3)₂OH)CO₂^- with imidazole-4-carboxaldehyde and nickel(II) acetate in methanol yields a single stereoisomer of an oxazolidine. There is retention of chirality on ring positions 4 and 5 (if C_β is chiral) of the oxazolidine, C_α and C_β of the parent amino acid, and transfer of chirality to the newly generated stereogenic centers, ring positions 3, the amino acid nitrogen atom, N_AA, and 2, the aldehyde carbon atom, C_ald. Specifically, when C_α has an S configuration, both N_AA and C_ald are formed as R. Likewise, a C_α which is R results in both N_AA and C_ald being formed as S. For example, the reaction of L threonine (C_α is S and C_β is R) with 4-imidazolecarboxaldehyde in the presence of nickel(II) gives the facial Λ NiL₂, where L is (2R, 3R, 4S, 5R) 4-carboxylato-5-methyl-2-(4-imidazolyl)-1,3-oxazolidine. The same reaction with D threonine produces the enantiomeric Δ complex of (2S, 3S, 4R, 5S) 4-carboxylato-5-methyl-2-(4-imidazoyl)-1,3-oxazolidine. The high stereospecificity is thought to be based on the fused three-ring structure of the characterized nickel complexes in which the hydrogen atoms of C_α, N_AA, and C_ald must be cis to one another. Identical reactions occur with 2-pyridine carboxaldehyde and LT or DT. In contrast, the reactions of L allo threonine (2S3S) and the primary alcohols, L or D serine, give the conventional meridionally coordinated aldimine product.

Keywords: beta hydroxy amino acids; chirality transfer; homochirality; oxazolidine; threonine.

Figure 1

Sketch of serine (R = H) threonine (R = CH₃) ligation (STL) method of coupling an N terminal residue with S or T residue to another polypeptide. The proposed mechanism goes through an oxazolidine, whose numbering is depicted.

Figure 2

Chirality transfer in the reaction of chiral phenylglycinol with a salicylaldehyde, a prochiral aldehyde. On further reaction with nickel(II), the imine ligand gives the illustrated oxazolidine. Note the three-atom sequence in the product, C*_{Phenyl glycinol}-N*_{Phenylglycinol}-C*_ald, is SRS or RSR for S or R phenylglycinol, respectively. An * after the symbol of an atom indicates that it is chiral.

Figure 3

Line drawings and abbreviations of aldehydes employed in this study.

Figure 4

The L ((left) hand side) and D ((right) hand side) enantiomers of the five βOHAAs examined. One-letter symbols are used for serine (S), threonine (T), valine (V), and leucine (L). For LT and LβOHL, C_α is S and C_β is R, while for the D enantiomers, C_α is R and C_β is S. For L and D, βOHV C_α is S and R, respectively, and C_β is achiral. For LalloT, both C_α and C_β are S, and in the enantiomer, both are R.

Figure 5

The reaction of the L enantiomer of the βOHAAs with either 4Im or 5Me4Im. The products of LS with 5Me4Im and LT with 4Im are labeled Ni(LS^Ald5Me4Im)₂ and Ni(LT^Ox4Im)₂, respectively. Use of the D enantiomer of the βOHAA results in formation of the enantiomer of the pictured product.

Figure 6

Labeling of the donor atoms of the aldimine (left) and oxazolidine (right) complexes, O_CA, N_AA, and N_Im and the other ligand atoms that define the chelate rings, C_CA, C_α, C_β, O_Ox, C_Im, and C_ald. If Py rather than Im is used as the aldehyde, the N_Im and C_Im symbols are replaced with N_Py and C_Py.

Figure 7

The reaction of the anion of glycine or L alanine with 2-pyridinecarboxaldehyde gives the aldimine complex which on addition of Ni(II) and reduction of the imine gives facial coordination of the ligand.

Figure 8

Ni(LT^Ox4Im)₂ with omission of hydrogen atoms for clarity. The pseudo-three-sided box is easily seen for the bottom ligand. The five-atom carboxylate and imidazole sides are on the left and right, respectively, with the oxazolidine ring on the bottom. Note that the N_AA atoms are cis and N_Im atoms are trans. Color codes: Ni (green); O (red); N (purple); C (gray).

Figure 9

The labeling of the three fused five-membered rings and their component atoms present in all eight βOHAA complexes (L and D enantiomers). The rings are far from coplanar. The carboxylate and imidazole/pyridine rings are ~perpendicular to one another and form the left and right sides of the pseudo-three-sided box. The oxazolidine ring forms the bottom of the box and is bent down from the two sides.

Figure 10

The overlayed structures of Ni(LT^Ox4Im)₂ and Ni(LβOHL^Ox4Im)₂. Hydrogen atoms have been omitted for clarity. The overlayed atoms are nickel and each of the six donor atoms in each complex. The RMS is 0.0861. Color codes: Ni (green); O (red); N (purple); C (gray).

Figure 11

Diagram of Ni(LT^Ox4Im)₂ (left) and Ni(DT^Ox4Im)₂ (right) complexes. The two are mirror images of one another. Only one of the ligands is shown for clarity. The important C_αN_AAC_ald linkage is beneath the nickel and is SRR for LT and RSS for DT. C_β is in the foreground and is R and S for LT and DT, respectively. Color codes: Ni (green); O (red); N (purple); C (gray); H (yellow).

Figure 12

Structure of bivalvane, (C₁₀H₁₅)₂, showing one of the two fused three five-membered rings. The three atoms that link the rings together and their hydrogen atoms are shown as spheres to highlight the linkage. Note that the three hydrogen atoms of the linkage are all cis, as are the present oxazolidine complexes. Color codes: C (gray); H (yellow).