Crystal structure of methyl (S)-2-{(R)-4-[(tert-butoxycarbonyl)amino]-3-oxo-1,2-thiazolidin-2-yl}-3-methylbutanoate: a chemical model for oxidized protein tyrosine phosphatase 1B (PTP1B)

The title compound crystallized with two independent molecules (A and B) in the asymmetric unit. In the crystal, separate chains of A and B molecules, propagating along the b-axis direction, are formed via N—H⋯O, C—H⋯S and C—H⋯O hydrogen bonds


Chemical context
X-ray crystallographic analyses of the enzyme PTP1B have revealed an unprecedented post-translational modification that may be important in redox regulation of protein function Salmeen et al., 2003;van Montfort et al., 2003;Tanner et al., 2011;Sivaramakrishnan et al., 2010). Specifically, oxidation converts the catalytic cysteine in this enzyme to an isothiazolidin-3-one heterocycle that is commonly referred to as a sulfenyl amide residue. As part of early efforts in the area of cephalosporin synthesis, a dipeptide containing a protein sulfenyl amide residue was synthesized (Morin et al., 1973). However, to the best of our knowledge, there are no examples of low molecular weight sulfenyl amides that have been characterized crystallographically, although structures of related 1,2-benzisothiazol-3(2H)-ones have been reported (Kim et al., 1996;Ranganathan et al., 2002;Wang et al., 2011). Herein we describe the synthesis and crystal structure of the title compound, a low molecular weight mimic of oxidized PTP1B.

Structural commentary
The molecular structures of the two independent molecules (A and B) of the title compound are shown in Fig. 1. The two ISSN 2056-9890 molecules differ only in the orientation of the isopropyl group (Fig. 1). The bond lengths and angles are very similar to those seen in the crystal structures of the oxidized enzyme PTP1B (see: pdb codes 1oem, 1oes, 3sme). In both molecules, the isothiozolidin-3-one ring adopts an envelope conformation with the methylene C atom (C1A in molecule A and C1B in molecule B) as the flap, similar to the conformation of oxidized PTP1B (pdb code: 1oem). In previously reported chemical models (1,2-benzisothiazole compounds) of PTP1B, the five-membered ring is planar (Kim et al., 1996;Ranganathan et al., 2002;Wang et al., 2011;Sivaramakrishnan et al., 2005). The S-N bond lengths in the title compound [S1A-N1A = 1.740 (2) Å and S1B-N1B = 1.733 (2) Å ], are similar to the same bond distance of ca 1.71 Å in oxidized PTP1B (pdb code: 1oem).

Supramolecular features
In the crystal, N-HÁ Á ÁO hydrogen-bonding interactions give infinite, separate columns of A and B molecules along the b-axis (Table 1 and Fig. 2). Within the columns there are C-HÁ Á ÁS and C-HÁ Á ÁO hydrogen bonds present (

Figure 2
A view along the b axis of the crystal packing of the title compound. Hydrogen bonds are shown as dashed lines (see Table 1 for details; A molecules are blue and B molecules are red).

Synthesis and crystallization
The title compound was prepared by a modification of a previously published procedure (Shiau et al., 2006). Pyridine (20 eq) was added to a solution of l-valine ester of N,N-di-tertbutyloxycarbonyl-l-cystine (1.0 g, 1.5 mmol) in 50 mL of anhydrous CH 2 Cl 2 . The solution was cooled in a liquid nitrogen bath, under an N 2 atmosphere, and stirred for 15 min. Bromine (135 mL, 2.6 mmol) in dry CH 2 Cl 2 was added dropwise over a period of 30 min. The solution was allowed to warm to 273 K over 1 h, and then CH 2 Cl 2 was evaporated in vacuo using a rotatory evaporator to afford the crude material.
Flash chromatography (50% EtOAc/hexanes) of the crude material gave the title compound as a white solid (360 mg, 72% yield). Crystals suitable for X-ray diffraction analysis were obtained by slow evaporation of a solution of title compound in DMF.