Tert-Leucinol

Ph N-N r-V XBenzoin condensation [6.9] Several synthetic steps from e.g. L-tert.-leucinol... 

From a practical viewpoint the recently discovered vanadium-based and iron-based asymmetric sulfoxidation with hydrogen peroxide is worth mentioning [305, 306]. For vanadium, in principle as little as 0.01 mol% of catalyst can be employed (Fig. 4.111). With tridentate Schiff-bases as ligands, formed from readily available salicylaldehydes and (S)-tert-leucinol, ees of 59-70% were obtained for thioanisole [305], 85% ee for 2-phenyl-l,3-dithiane [305] and 82-91% ee for tert-butyl disulfide [307]. For iron, similar results were obtained using 4 mol% of an iron catalyst, synthesized in situ from Fe(acac)3 and the same type of Schiff base ligands as in Fig. 4.111 (see Ref. [306] for details). 

Bromo-5-(trifluoromethyl)benzonitrile (14) (1.00 g, 4.0 mmol) and (S)-tert-leucinol (15) (469 mg, 4.0 mmol) were dissolved in anhydrous chlorobenzene (4 mL) in a flame dried Schlenk flask (25 mL). The reaction mixture was heated to 60 °C prior to the dropwise addition of ZnCl2 (0.80 mL, 8.0 mmol, 1 M in Et20). The reaction was heated to reflux (140 °C) and stirred for 48 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resulting orange oil was purifled by silica gel column chromatography (CH2Cl2/MeOH, 99 1) to yield the product as a pale yellow solid (829 mg, 59 %). 

The functionalization of cyclopropanes such as 1 via amide-directed metalation followed by quenching with an electrophile (e.g., iodine) is well known in the literature (Scheme la) [17, 18]. However, it was not until 2005 that the first example of a transition-metal-catalyzed direct functionalization process of a cyclopropane C-H bond was disclosed [19]. The use of a chelating oxazoUne-based auxiliary (derived from (S )-tert-leucinol) enabled iodination of primary C(sp )-H... 

Subsequently, Vedejs and coworkers [20] uncovered a new class of chiral 4-(dimethylamino)pyridines. These compounds, named AcOLeDMAP (8) and BnOLeDMAP (9), were designed to favor a specific C3-side chain conformer (Figure 40.2) they can be easily obtained from (S)-tert-leucinol. 

Typical procedure. N-tert-Butyloxycarbonyl-L-leucinal 1872 [1365] N-tert-Butyloxy-carbonyl-L-leucinol (217 g), prepared by the reduction of Boc-Leu-OMe with sodium borohydride/sodium chloride, was dissolved in dichloromethane (1.5 L) and then DM SO (250 mL) was added. To the homogeneous solution, anhydrous pyridine (900 mL), trifluoroacetic acid (40 mL), and EDC (576 g) were added, and the mixture was stirred at room temperature for 24 h. Work-up gave a 98% yield of crude N-fert-butyloxycarbonyl-L-leucinal 1872 as a syrup, which could be used directly for aldol condensation in the preparation of statine. 

The same catalytic system disclosed by Bolm was further extended by Ellman to the asymmetric oxidation of t-Bu-disulfide with H2O2. The corresponding tert-butyl tert-butane thiosulfinate was obtained with 91% ee and with 92% on scales as large as 1 mol with as low as 0.25% mol of V catalyst, with a Schiff base ligand and stoichiometric amovmt of H2O2 (Scheme 23.21)." " Extensive ligand modification was necessary for the substrate of interest. In particular, it turned out that 3,5-di-tert-butyl salicylaldehyde was the best aromatic fragment, while variation on the properties of the amino alcohol confirmed the superior enantioselectivity possible with t-leucinol. 

---