Highly Enantioselective Michael Addition of Cyclic 1,3‐Dicarbonyl Compounds to β,γ‐Unsaturated α‐Keto Esters

Abstract

A highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to b,g-unsaturated a-keto esters catalyzed by amino acid-derived thiourea-tertiary-amine catalysts is presented. Using 5 mol% of a novel tyrosine-derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.Keywords: 1,3-dicarbonyl compounds; Michael addition; organocatalysts; thioureas; b,g-unsaturated a-keto esters Increased focus has recently been placed on the application of organocatalysis in reactions allowing the rapid construction of functionalized molecules from simple and readily available starting materials.[1] In this field, the asymmetric Michael addition of 1,3-cyclic dicarbonyl compounds to a,b-unsaturated carbonyl systems, which could provide many chiral compounds with biological and pharmaceutical activities such as neo-flavonoids and coumarins, has attracted much attention.[2] As a class of activated a,b-unsaturated carbonyl systems, b,g-unsaturated a-keto esters sometimes are preferred electrophiles in this kind of reaction due to their high reactivity and the easy convertibility of the resultant products to other useful structures.[3] In 2003, Jørgensen et al. reported the enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to b,g-unsaturated a-keto esters catalyzed by chiral bisoxazoline-copper(II) complexes with moderate to high enantioselectivities.[4] However, it was not until very recently that an similar organocatalyzed reaction between cyclic diketones and b,g-unsaturated a-keto esters using Cinchona alkaloid-derived pyrimidines was reported by Calter et al. [5] In contrast, several organocatalysts have been developed for the Michael addition of cyclic diketones to a,b-unsaturated ketones, in which the "imine catalysis" usually controls the enantioselectivity. [6] On the other hand, following the pioneering works of Jacobsen and Takemoto, [7] remarkable advances have been made in the development and application of bifunctional chiral thiourea catalysts in catalytic asymmetric reactions. [8] Recently, the use of inexpensive and readily available amino acids as the chiral scaffold to develop novel thiourea catalysts has attracted considerable interest and proved to be effective in several asymmetric reactions.[9] Our group has been interested in the development of organocatalytic reactions utilizing b,g-unsaturated a-keto esters as a reaction partner to synthesize useful compounds. [10] We report herein the development of several amino acid-derived thiourea-tertiary amine catalysts and their applications to the asymmetric Michael addition of cyclic 1,3-dicarbonyl compounds to b,g-unsaturated a-keto esters.Using the reaction between (E)-methyl 2-oxo-4-phenylbut-3-enoate (3a) and 4-hydroxycoumarin (4a) as the model reaction, a series of thiourea-tertiary amine catalysts (Figure 1) was evaluated and the results are summarized in Table 1. Similar to Takemotos ca...

Advanced Routes in Synthesis and Reactions of Lawsone Molecules (2‐Hydroxynaphthalene‐1,4‐dione)

“…irradiation . Michael‐hemiketalization reaction of 1 with α‐keto ester in the presence of indane thiourea 10 mol% produced compound 221 . Heating of 1 with 3‐methyl‐7‐((tetrahydro‐2H‐pyran‐2‐yl)oxy)hepta‐2,6‐dienal in the presence of 3‐aminopropionic acid in benzene generated 2‐methyl‐2‐(4‐methyl‐5‐((tetrahydro‐2H‐pyran‐2‐yl)oxy)pent‐3‐en‐1‐yl)‐2H‐benzo[g]chromen‐5,10‐dione ( 222 ) .…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…described a procedure for the synthesis of chiral dihydropyranes using cyclic diketones as nucleophiles and β,γ‐unsaturated‐α‐keto esters (Scheme ). In these cases an intramolecular cyclization takes place after the CC bond formation 60…”

“…In these cases an intramolecular cyclization takes place after the CÀC bond formation. [60] Various attempts have been undertaken to extend the substrate scope of the nucleophile in Michael additions during the last years. Jørgensen et al successfully deployed b-ketosulfones in combination with a cinchona derived cata-lyst 31.…”

The Vinylogous Michael Addition of 3‐Alkylidene‐2‐oxindoles to β,γ‐Unsaturated α‐Keto Esters by Bifunctional Cinchona Alkaloids

“…In last two decades, chiral phosphoric acids and thioureas have been recognized as chiral hydrogen‐bond donors for the activation of electrophiles for various transformations. Mainly, thioureas/squaramide have been probed for Michael reaction with β,γ‐unsaturated α‐keto esters . In addition, many chiral natural organic molecules that are known hydrogen‐bond acceptors, such as cinchona alkaloid, are also effective in activation of 3‐alkylidene oxindole for asymmetric conjugate addition .…”