Diastereoselective Additions of Titanium Enolates from N-Glycolyl Thiazolidinethiones to Acetals

Abstract

The stereochemical outcome of the Lewis acid-mediated glycolate addition of the titanium enolates from protected N-hydroxyacetyl-4-isopropyl-1,3-thiazolidine-2-thiones to dimethyl and dibenzyl acetals depends on the hydroxyl protecting group. Particularly, the pivaloyl protected glycolate derivative provides the reluctant anti adducts in high yields and diastereomeric ratios, which can be isolated and further converted in enantiomerically pure form to β-methoxy or β-benzyloxy α-pivaloyloxy carbonyl fragments in a straightforward manner.

Direct anti Glycolate Aldol Reaction of Protected Chiral N‐Hydroxyacetyl Thiazolidinethiones with Acetals Catalyzed by a Nickel(II) Complex

“…All together, these examples show that the direct glycolate aldol reaction from chiral thiazolidinethione 7 catalyzed by a nickel(II) complex gives access to anti adducts 14 in high yields. These adducts may be considered as protected α,β‐dihydroxy carboxylic compounds, which can be easily converted into enantiomerically pure intermediates …”

“…( S )‐4‐Isopropyl‐ N ‐(2‐pivaloyloxyacetyl)‐1,3‐thiazolidine‐2‐thione (7): A mixture of glycolic acid (1.52 g, 20 mmol) and pivaloyl chloride (4.4 mL, 36 mmol) was stirred at room temperature for 60 h under N 2 . Then, the volatiles were removed and the resulting O ‐pivaloylglycolic acid was used in the next step without further purification.…”

“…( S )‐ N ‐(2‐ tert ‐Butyldimethylsilyloxyacetyl)‐4‐isopropyl‐1,3‐thiazolidine‐2‐thione (2): A solution of the deprotected N ‐acyl thioimide, TBSOTf (0.65 mL, 2.9 mmol, 1.25 equiv. ), and 2,6‐lutidine (0.35 mL, 3.0 mmol, 1.3 equiv.)…”

“…( S )‐4‐Isopropyl‐ N ‐[(2 R ,3 R )‐3‐methoxy‐3‐phenylpropanoyl‐2‐pivaloyloxy]‐1,3‐thiazolidine‐2‐thione (14e): The reaction was carried out as described in General Procedure using (Me 3 P) 2 NiCl 2 (7.0 mg, 25 µmol, 5 mol‐%), 7 (152 mg, 0.5 mmol), benzaldehyde dimethyl acetal ( e , 83 µL, 0.55 mmol), and TESOTf (249 µL, 1.10 mmol). The crude was purified by column chromatography twice (first, from hexanes/EtOAc, 93:7 to 85:15; finally, from hexanes/CH 2 Cl 2 , 70:30 to 15:85) to give 84 mg (0.20 mmol, 40 % yield) of 14e as a yellow solid.…”

“…Interestingly, Shibasaki described a related enantioselective aldol addition of α‐sulfanyl 7‐azaindolinylamide catalyzed by a copper(I) complex,, whereas Aoki has recently reported that direct aldol reactions of a protected dihydroxyacetone with aromatic aldehydes catalyzed by zinc complexes containing histidine produce syn aldol adducts with good yields and enantioselectivities . In view of the lack of methods to prepare anti glycolate adducts and taking advantage of our experience with stoichiometric reactions of titanium(IV) enolates with acetals, and direct and highly stereoselective carbon‐carbon bond forming reactions from chiral N ‐acyl‐1,3‐thiazolidene‐2‐thiones catalyzed by nickel(II) complexes,, we envisaged that Lewis acid‐mediated glycolate aldol‐like additions to dialkyl acetals might proceed in a highly efficient manner. Importantly, such an approach was supported by the high yields and diastereomeric ratios achieved in the direct addition of N ‐azidoacetyl‐4‐isopropyl‐1,3‐thiazolidine‐2‐thione to dialkyl acetals promoted by 2–5 mol‐% of (Me 3 P) 2 NiCl 2 , a commercially available and easy to handle complex (Scheme ) .…”