Efficient Synthesis of Chiral Trisubstituted 1,2‐Allenyl Ketones by Catalytic Asymmetric Conjugate Addition of Malonic Esters to Enynes

Abstract

An N,N′‐dioxide/scandium(III) complex catalyzed, highly efficient conjugate addition of malonic esters to enynes is described. A range of trisubstituted 1,2‐allenyl ketones were obtained in high yields (up to 99 %) with good d.r. (up to 95/5) and excellent ee values (97 %–99 %). Moreover, the products could be easily transformed into chiral furan and 5‐hydroxypyrazoline derivatives, both of which are important skeletons of many biologically active compounds and pharmacologicals.

Recent developments in enantioselective lanthanide-catalyzed transformations

“…Ever since, various other ligands have been investigated in scandium-catalyzed Michael additions of b-ketoesters, malonates, hydroxylamines, or thiols to a,bunsaturated carbonyl compounds, among which N,N 0 -dioxides [14], pybox derivatives [15], and BNP ligands [16]. As a recent example, Liu and Feng developed asymmetric scandiumcatalyzed Michael additions of malonates 2a-d to enynes 18a-s to give the corresponding chiral functionalized trisubstituted allenes 19a-v, as shown in Scheme 6 [17]. The reaction was performed in the presence of a combination of Sc(OTf) 3 and chiral N, N 0 -dioxide 20 that allowed products 19a-v to be formed in impressive enantioselectivities of 97-99% ee along with good to almost quantitative yields of 61-98% and moderate to high diastereoselectivities of 56-90% de.…”

“…Indeed, incorporation of hydrogen-bonded guanidinium cations in the secondary Scheme 6. Scandium-catalyzed Michael addition of malonates to enynes [17]. coordination sphere of the complex led to unique properties, notably, improved stability toward moisture in solution and in the solid state.…”

Efficient Synthesis of Chiral Trisubstituted 1,2‐Allenyl Ketones by Catalytic Asymmetric Conjugate Addition of Malonic Esters to Enynes

“…Thea bsolute configuration of 3cd was determined by X-ray crystallography to be (R,S a ). [16] To show the synthetic potential of this strategy,agram scale synthesis of 3abwas carried out (Scheme 2a). Under the optimized condition, 3mmol of 1a reacted smoothly with 4equivalents of 2b to provide 1.27 g 3ab (91 %y ield) with 91:9 d.r.…”

“…Based on the determination of the absolute configuration of product 3cd, [16] control experiments,a nd our previous study, [26] ap ossible catalytic cycle with at ransition-state model was proposed (Figure 1). First, the N-oxides and amide oxygen atoms of l-PiEt 2 Me coordinate to Sc 3+ in atetradentate manner to form two six-membered chelate rings.T hen, enynes 1 attach to Sc 3+ at the favorable equatorial position to give intermediate T1.A dditionally,t he enolates are generated from malonates 2 assisted by nBu 3 N. The Re face of enynes 1 are strongly shielded by the nearby benzyl ring.…”

Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies

“…Despite of the high demands of chiral allenes, the asymmetric catalytic synthesis of these axially chiral compounds remains a challenge in organic synthesis [4][5][6] . In the last two decades, a number of elegant asymmetric catalytic strategies have been developed for chiral allene synthesis, such as nucleophilic additions of 1,3-enynes [7][8][9][10][11][12][13][14][15][16][17][18][19] , dynamic kinetic asymmetric transformations (DyKAT) of racemic allenes [20][21][22] , rearrangement of alkynes [23][24][25] , coupling of alkynes with diazo compounds [26][27][28] and others [29][30][31] . Among these strategies, the direct asymmetric additions of prochiral 1,3-enynes represent as one of the most attractive strategies for synthesis of multiple-substituted chiral allenes, owing to the easy accessibility of these substrates.…”