Delineating Origins of Stereocontrol in Asymmetric Pd-Catalyzed α-Hydroxylation of 1,3-Ketoesters

Abstract

Abstract. Systematic studies of reaction conditions and subsequent optimization led to the identification of important parameters for stereoselectivity in the asymmetric α-hydroxylation reaction of 1,3-ketoesters. Enantioselectivities of up to 98% can be achieved for cyclic substrates and 88% for acyclic ketoesters. Subsequently, the combination of cyclic/acyclic ketoester, catalyst and oxidant was found to have a profound effect on reaction rates. The stereochemistry of the reaction contradicts that observed for other similar electrophilic substitution reactions.This was rationalized by transition state modeling, which revealed a number of cooperative weak interactions between oxidant, ligand and counterion, together with C-H/π interactions that cumulatively account for the unusual stereoselectivity.2

Azidation of β-Keto Esters and Silyl Enol Ethers with a Benziodoxole Reagent

“…1-Chloro-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (9) Following a reported procedure 1 methyl 2-iodobenzoate (8) (12 mL, 76 mmol) was dissolved under N2 atmosphere in dry diethyl ether (400 mL) and then the solution was cooled down at 0 °C with an ice bath. Methylmagnesium bromide (56.0 mL, 168 mmol, 2.20 equiv) was added dropwise and the reaction was stirred for 30 min at 0 °C.…”

“…Following a reported procedure, 9 starting from methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1.0 g, 5.0 mmol, 1.0 equiv), adamantan-1-yl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (1f) 36.2 (3C), 30.9 (3C), 30.4. IR νmax 2913 (s), 2854 (w), 1712 (s), 1640 (w), 1599 (w), 1571 (w), 1519 (w), 1495 (w), 1460 (w), 1383 (w), 1351 (w), 1330 (w), 1291 (w), 1259 (m), 1210 (m), 1189 (w), 1159 (w), 1130 (w), 1095 (w), 1056 (m), 1017 (w), 990 (w), 968 (w), 937 (w), 910 (w), 862 (w), 861 (w), 816 (w).…”

“…In fact, Zhdankin and coworkers have described the synthesis of azido benziodoxol(on)e compounds, which were surprisingly stable. 9 The reactivity of these reagents was studied for the radical-based azidation of aliphatic C-H bonds. 9,10 During completion of our work, Gade and co-workers reported the first catalytic asymmetric method for the azidation of -keto esters and oxindoles using a chiral iron catalyst together with an azidobenziodoxole reagent.…”

“…9 The reactivity of these reagents was studied for the radical-based azidation of aliphatic C-H bonds. 9,10 During completion of our work, Gade and co-workers reported the first catalytic asymmetric method for the azidation of -keto esters and oxindoles using a chiral iron catalyst together with an azidobenziodoxole reagent. 11 This major breakthrough motivate us to report our own preliminary results in the area, including the very efficient azidation of cyclic -keto esters with azidobenziodoxole 2 in the absence of any catalyst and the zinc-catalyzed azidation of less reactive linear keto esters and silyl enol ethers using the same reagent (Scheme 1).…”

Palladium-Catalyzed Enantioselective Csp3–Csp3Cross-Coupling for the Synthesis of (Poly)fluorinated Chiral Building Blocks

“…13 The procedure for preparation of 4f was adapted from the work of Shibata and coworkers. 9 To a stirred solution of methyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate 10 (224 mg, 1.1 mmol, 1.0 equiv) in CH 3 CN (11 mL) was added DBU (328 mL, 2.2 mmol, 2.0 equiv) at room temperature. After stirring at room temperature for 15 min, the mixture was cooled down to 0 °C and a solution of the trifluoromethylating reagent (561 mg, 1.65 mmol, 1.5 equiv.)…”